“8. …Sufficiency of disclosure must be satisfied at the effective date of the patent, ie on the basis of the information in the patent application together with the common general knowledge then available to the skilled person. Acknowledging sufficiency of disclosure on the basis of relevant technical information produced only after this date would lead to granting a patent for a technical teaching which was achieved, and, thus, for an invention which was made, at a date later than the effective date of the patent. The general principle that the extent of monopoly conferred by a patent should correspond to, and be justified by, the technical contribution to the art, has to be kept in mind… 9. Where a therapeutic application is claimed … 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…. As a consequence, under Article 83 EPC, unless this is already known to the skilled person at the priority date, the application must disclose the suitability of the product to be manufactured for the claimed therapeutic application. It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application … 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… 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. 10. The appellant argued that experimental tests were in fact irrelevant because no prediction could be made on their basis that the observed effect would equally be seen in vivo. The board will agree that an in vitro effect may not necessarily be reflected in vivo, but this does not lessen the usefulness of in vitro tests in general in relation to sufficiency of disclosure. Indeed, the in vitro tests cannot be performed unless the “protagonists” of the test are available. This means that the skilled person is made aware of the structure of the active ingredient proposed for the pharmaceutical composition as well as, in technical terms, of a definite link between the ingredient and the mechanism allegedly involved in the disease state. The presence of a cause/effect relationship is, thus, made plausible. For how incomplete the data might be, they nonetheless go one step further towards disclosing the invention without leaving an undue burden to the reader. In this context, it should be noted that it is on the very same kind of tests (but published some three to four years later) that the appellant based its arguments in favour of sufficiency of disclosure. In any case, the appellant’s argument could not justify the recognition of sufficiency of disclosure in relation to a claim to a therapeutic application of a composition when in the specification there exists no evidence at all of its potential effectiveness.”
“36. The Court of Appeal’s statement of the effect of the plausibility test has already been quoted (para 20 above). They considered that the threshold was not only low, but that the test could be satisfied by a “prediction ... based on the slimmest of evidence” or one based on material which was “manifestly incomplete”
“It is true that, as Lord Sumption noted at [23], the concept of plausibility originated as a response to over-broad claims, in particular claims to whole classes of compounds, as in Agrevo. Idenix is an example of its application in that context by the courts of this country. It is also true that, as Lord Sumption noted at [19]-[20], that the concept was also found to be of utility in addressing one of the problems with second medical use claims. Nevertheless the concept was applied by the Board of Appeal to a claim to single compound in BMS/Dasatinib, which was one of the cases relied upon by Lord Sumption (and one of the cases reviewed by the Enlarged Board in G 2/21). As the Claimants point out, the present case is strikingly similar to BMS/Dasatinib. Moreover, BMS/Dasatinib does not stand on its own, because the claim in Johns Hopkins, which was another of the cases relied upon by Lord Sumption and reviewed by the Enlarged Board, was effectively a claim to a specific molecule. The concept has also been applied by this Court in Generics v Yeda to a claim to what was in substance a single product, albeit a product comprising a mixture of polypeptides. Furthermore, the underlying principles are applicable as much to claims to single chemical compounds as to claims to classes of compounds and second medical use claims. The fundamental principle is that the scope of the patent monopoly must be justified by the patentee’s technical contribution to the art. This remains so whether the scope of the claim is broad or narrow. Thus when considering inventive step it is necessary to consider what technical problem the claimed invention solves. If it is not plausible that the invention solves any technical problem then the patentee has made no technical contribution and the invention does not involve an inventive step. Equally, when considering insufficiency it is necessary to consider whether the specification sufficiently discloses the claimed invention. If it is not plausible that the invention solves any technical problem then the patentee has made no technical contribution and the specification does not disclose any invention. It follows that, in order for a claim to a single chemical compound to be patentable, the application must make it plausible, when read in the light of the skilled person’s common general knowledge, that the compound has the utility asserted for it. Moreover, it makes no difference whether the claim incorporates the use of the compound as a technical feature or whether the claim is simply to the compound per se and the assertion of utility is only to be found in the specification. This is because, as explained above, there is no invention in merely identifying a new chemical compound; invention can only lie in identifying its utility.”
“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.”
“52. It may be a matter of taste only but I prefer to refer to this fourth principle as reasonable prediction rather than simply plausibility, however whatever it is called, it is the same principle. 53. To apply the reasonable prediction principle one has to take three steps. First one must identify what it is which falls within the scope of the claimed class. Second one must determine what it means to say that the invention works. In other words what is it for? Once you know those two things, the third step can be taken: to answer the question whether it is possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim.”
“In some cases the second step is the aspect which is a bit more involved. So in Idenix v Gilead, claim 1 was to a Markush class of molecules (see Kitchin LJ para [61]). The claim language did not include any reference to what they were for and so one could not answer the question at the second step by looking at the words of the claim. This is also not unusual. If the compounds are new, then a claim to those compounds will be novel without including a claim feature which refers to what they are actually for. However that does not prevent the reasonable prediction principle being applied. In fact the answer in Idenix was clear from the patent specification. That showed that the point of the invention was to treat infections caused by viruses in the Flaviviridae family. So one can assess the validity of the claim on the basis that it is a claim to compounds with anti-Flaviviridae activity, which is what Kitchin LJ said at paragraphs [113] and [124]. So, in the language coined above, anti-Flaviviridae activity was a step two functional feature. The issue in Idenix arose in the context of inventive step but the same approach applies to reasonable prediction/plausibility. Note that this does not mean that claims to compounds per se are actually limited to using the compounds for treating Flaviviridae infections, but for the purposes of assessing questions like inventive step and reasonable prediction/plausibility, one needs to know what the compounds are supposed to be useful for. In fact in Idenix the outcome of the third step was against the patentee. The court held that it was not plausible that substantially all the claimed molecules would be effective against Flaviviridae infections, and hence it was Agrevo obvious and also insufficient for lack of plausibility for the same reason (see paragraphs [129] and [140]).”
“66. In my view BMS is right overall on this point, and in cases where the objection is of lack of plausibility in an Agrevo-type situation, a patentee is not necessarily limited to the most demanding teaching of utility in the specification and is entitled to try to rely on a less ambitious degree of utility, or a utility of a different but related kind. … 68. So I conclude that what it means for the invention to “work” is to be determined from the specification where the claim is not explicit (I do not think this in itself was in dispute), but that the patentee is not restricted to the most ambitious assertion made. In some cases the patentee may be able to rely on a more limited contribution, but this must be fact-dependent and will still have to find a basis in the specification.”
“93. The relevant standard for the reliance on a purported technical effect when assessing whether or not the claimed subject-matter involves an inventive step concerns the question of what the skilled person, with the common general knowledge in mind, would understand at the filing date from the application as originally filed as the technical teaching of the claimed invention. The technical effect relied upon, even at a later stage, needs to be encompassed by that technical teaching and to embody the same invention, because such an effect does not change the nature of the claimed invention. 94. Hence, a patent applicant or proprietor may rely upon a technical effect for inventive step if the skilled person, having the common general knowledge in mind, and based on the application as originally filed, would consider said effect as being encompassed by the technical teaching and embodied by the same originally disclosed invention.”
“In the present case, the current Board does not need to give a definitive answer as to whether it can endorse all the conclusions of decision T 116/18 regarding the two requirements set out in point 2 of the order of decision G 2/21. The Board considers that the purpose of these requirements is to prevent patents from being granted for inventions that are not complete at the filing date. Such speculative applications arise where either the existence of the claimed technical effect or its generalisation is speculative. This may occur because relevant data have not yet been generated or, if available to the patent applicant, have not been disclosed in the patent application.”
“The reasoned findings of the boards of appeal in the decisions referred to above make clear that the scope of reliance on post published evidence is much narrower under sufficiency of disclosure (Article 83 EPC) compared to the situation under inventive step (Article 56 EPC). In order to meet the requirement that the disclosure of the invention be sufficiently clear and complete for it to be carried out by the person skilled in the art, the proof of a claimed therapeutic effect has to be provided in the application as filed, in particular if, in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved. A lack in this respect cannot be remedied by post-published evidence.”
“The presumption prevails, therefore, that the selected [compound]of claim 1 will exhibit the same pharmacological activity as that compound represents an arbitrary selection out of a known class of active compounds. In the absence of evidence to the contrary, the Board concludes that faced with the problem indicated above, namely to provide merely further compounds having a dopamine D 2 receptor agonist activity, a skilled person would not require any inventive skill in picking out at random from structural variants outlined in document (1) the [relevant substitutions] thereby arriving without inventive ingenuity at the compound of claim 1, which is the solution proposed by the present application.”
“40. So I think the better approach is to see what the EPO Boards do when a patented product or class of products falls within a greater class. They deploy the objection of obviousness where the patentee has in truth made no real technical advance. … 44. What then does the EPO do? The answer is essentially this: that it regards what can fairly be regarded as a mere arbitrary selection from a class as obvious. If there is no more than an arbitrary selection then there is simply no technical contribution provided by the patentee.”
“50. … The EPO jurisprudence is founded firmly around a fundamental question: has the patentee made a novel non-obvious technical advance and provided sufficient justification for it to be credible? That is the basis of all the reasoning – see e.g. [2.4.2] of AgrEvo. A “selection”(by which I mean the later claimed compound or sub-class) which makes a real technical advance in the art is patentable. 51. More specifically Mr Carr contended that a sub-class or individual member of a prior art published class was taken to be obvious if it was a random selection from the earlier class. I have no difficulty with that. Such a “selection” provides no technical contribution. Mankind can learn nothing new from it. Nor indeed does Lilly dispute that proposition. It said in its skeleton argument: “Lilly does not dispute that in relation to obviousness a selection from the prior art cannot be merely arbitrary.” 52. Of course one has to consider here what is meant by an “arbitrary selection.”
“None of that indicates a mere “arbitrary selection” telling the reader in effect no more than he would get from reading 235.”
“Once it is accepted that the whole field is unpredictable, then the woolly teaching of 235, if not totally useless, is no guide to any particular compound. You cannot say a particular compound out of a vast class is obvious if you have no real idea as how any individualised member of that class might behave.”
“109. …This seems to me to establish that the correct question to ask is whether the selection of olanzapine, out of the class of 86,000 compounds in 235, was “arbitrary”, or whether the teaching of the patent established that the selected compound achieved “a particular technical result”, and, in answering that question, one must bear in mind that it arises in the context of the broader proposition that “the extent of a patent monopoly should correspond to and be justified by the technical contribution to the art”. 110. Whether one looks at the broader proposition or the narrower question, it appears to me that the answer is, unsurprisingly, the same. There can be no doubt but that the teaching of the patent in relation to a single compound, as described by Jacob L.J. in paras. 7 to 10, is unusual in its extent, as he points out in paras. 11 to 13, and it was at least open to the judge to conclude that it represented a significant technical contribution to the art over and above the “teaching” (which is a generous description of what appears to be no more than mere speculation about a wide collection of different possible applications of an enormous number of compounds) of the 235 patent. 111. As to the narrower question, I do not consider that it can be said that the selection of olanzapine was arbitrary. There is no doubt that the patent credibly reveals that that single selected compound has technical applications or features which represent a contribution to the art, wholly absent from 235’s generalised and unsupported claims for 86,000 compounds which include the selected compound, although it is not referred to specifically. The patent’s disclosure is not merely enormously more specific, in terms of both identifying the right compound and its technical application, than 235, but, unlike 235, but it also reports experimental evidence to support the claim. It is true that there is only limited evidence to show that no other compound claimed by the 235 patent has the same therapeutic benefits as olanzapine, but I do not consider that that can invalidate the patent. …”
“A selection from the prior art which is purely arbitrary and cannot be justified by some useful technical property is likely to be held to be obvious because it does not make a real technical advance.”
“The law is clear enough that a ground of invalidity exists which can be called different things including: lack of technical contribution, Agrevoobviousness, and failure to solve the technical problem. Depending on the facts one of these descriptions may be more apt in a given case than another but they are all getting at the same thing. [He then cited T 409/91 Exxon / Fuel Oils and AgrEvo.] The general principle there identified is that the extent of the patent monopoly, as defined by the claims should correspond to the technical contribution to the art. This theme – that the patent monopoly should be justified by the actual technical contribution to the art – has often been referred to with approval in the UK, most recently in the two recent Supreme Court decisions [i.e. Warner-Lambert and Actavis v ICOS[2019] UKSC 15 ].”
“One way in which this principle has been applied in the context of inventive step is to deny validity to a selection from the prior art “which is purely arbitrary and cannot be justified by some useful technical property”
“there are five questions to answer: Is it disclosed in the patent? Is it plausible? Is it true? Is it a technical advance? Does it support claims of the breadth they are?”
“…it can be said that the Respondent’s technical contribution in this case was to make available, for the first time, a product which had previously been unavailable, namely the isolated (+)-enantiomer of citalopram. On that basis, it would appear to follow that the respondent was entitled to claim the enantiomer.”
“Finally, there is no requirement for an invention to have to be “better” than the prior art (and not a sensible way this could be evaluated). A new and non-obvious alternative solution to solve a problem remains patentable. This is made clear in a number of cases at the EPO, see for example the Case Law of the Boards of Appeal and decision T 588/93 where it makes clear that it is not necessary to show substantial or gradual improvement over the prior art, an invention can instead be an alternative solution to a known problem (see also T 179/108 [sic, T 1791/08] at §12.5 and the Case Law book at §4.5).”
“On the other hand, in T 1179/16 the board noted that if the only contribution of the invention was to propose something different from the prior art (i.e. the provision of an alternative), then it was usually appropriate to consider that the skilled reader would take into account any alternative known in the underlying technical field (unless the closest prior art teaches away from it). The board stated that in such cases it might not be required to justify the selection of a particular solution, because it was assumed that an invention based on incorporating known features for the sole purpose of establishing novelty must be rendered obvious by a corresponding step of selecting any alternative known in the art.”
“The invention consists merely in selecting particular chemical compounds or compositions (including alloys) from a broad field. Example: The prior art includes the disclosure of a chemical compound characterised by a specified structure including a substituent group designated "R". This substituent "R" is defined so as to embrace entire ranges of broadly-defined radical groups such as all alkyl or aryl radicals either unsubstituted or substituted by halogen and/or hydroxy, although for practical reasons only a very small number of specific examples are given. The invention consists in the selection of a particular radical or particular group of radicals from among those referred to as the substituent "R" (the selected radical or group of radicals not being specifically disclosed in the prior art document since the question would then be one of lack of novelty rather than obviousness). The resulting compounds: (a) are neither described as having nor shown to possess any advantageous properties not possessed by the prior art examples; or (b) are described as possessing advantageous properties compared with the compounds specifically referred to in the prior art, but these properties are ones which the skilled person would expect such compounds to possess, so that they are likely to be led to make this selection.”
“The present invention relates to C-aryl glucosides which are inhibitors of sodium dependent glucose transporters found in the intestine and kidney (SGLT2) and to a method for treating diabetes, especially type II diabetes…”
“Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.”
“Hyperglycemia is a hallmark of type II diabetes (NIDDM); consistent control of plasma glucose levels in diabetes can offset the development of diabetic complications and beta cell failure seen in advanced disease. Plasma glucose is normally filtered in the kidney in the glomerulus and actively reabsorbed in the proximal tubule. SGLT2 appears to be the major transporter responsible for the reuptake of glucose at this site.”
“The SGLT specific inhibitor phlorizin or closely related analogs inhibit this reuptake process in diabetic rodents and dogs resulting in normalization of plasma glucose levels by promoting glucose excretion without hypoglycemic side effects.”
“Long term (6 month) treatment of Zucker diabetic rats with an SGLT2 inhibitor has been reported to improve insulin response to glycemia, improve insulin sensitivity, and delay the onset of nephropathy and neuropathy in these animals, with no detectable pathology in the kidney and no electrolyte imbalance in plasma.”
“Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity, and delaying the development of diabetic complications.”
“Ninety percent of glucose reuptake in the kidney occurs in the epithelial cells of the early S1 segment of the renal cortical proximal tubule, and SGLT2 is likely to be the major transporter responsible for this reuptake.”
“Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced glucose excretion in diabetic patients.”
“Administration of phlorizin, a specific inhibitor of SGLT activity, provided proof of concept in vivo by promoting glucose excretion, lowering fasting and fed plasma glucose, and promoting glucose utilization without hypoglycemic side effects in several diabetic rodent models and in one canine diabetes model. No adverse effects on plasma ion balance, renal function or renal morphology have been observed as a consequence of phlorizin treatment for as long as two weeks. In addition, no hypoglycemic or other adverse effects have been observed when phlorizin is administered to normal animals, despite the presence of glycosuria.”
“Administration of an inhibitor of renal SGLTs for a 6-month period (Tanabe Seiyaku) was reported to improve fasting and fed plasma glucose, improve insulin secretion and utilization in obese NIDDM rat models, and offset the development of nephropathy and neuropathy in the absence of hypoglycemic or renal side effects.”
“Concurrent inhibition of facilitative glucose transporters (GLUTs) is undesirable since such inhibitors would be predicted to exacerbate peripheral insulin resistance as well as promote hypoglycemia in the CNS. Inhibition of SGLT1 could also have serious adverse consequences as is illustrated by the hereditary syndrome glucose/galactose malabsorption (GGM), in which mutations in the SGLT1 cotransporter result in impaired glucose uptake in the intestine, and life-threatening diarrhea and dehydration.”
“The familial glycosuria syndromes are conditions in which intestinal glucose transport, and renal transport of other ions and amino acids, are normal. Familial glycosuria patients appear to develop normally, have normal plasma glucose levels, and appear to suffer no major health deficits as a consequence of their disorder, despite sometimes quite high (110-114 g/daily) levels of glucose excreted. The major symptoms evident in these patients include polyphagia, polyuria and polydipsia, and the kidneys appear to be normal in structure and function. Thus, from the evidence available thus far, defects in renal reuptake of glucose appear to have minimal long term negative consequences in otherwise normal individuals.”
“The compounds of formula I possess activity as inhibitors of the sodium dependent glucose transporters found in the intestine and kidney of mammals and are useful in the treatment of diabetes and…complications of diabetes…”
“The compound of formula I possesses activity as inhibitors [sic] of the sodium dependent glucose transporters found in the intestine and kidney of mammals and is useful in the treatment of diabetes and…complications of diabetes…”
“The mRNA sequence for human SGLT2 (GenBank #M95549) was cloned by reverse-transcription and amplification from human kidney mRNA, using standard molecular biology techniques. The cDNA sequence was stably transfected into CHO cells, and clones were assayed for SGLT2 activity essentially as described in Ryan et al. (1994). Evaluation of inhibition of SGLT2 activity in a clonally selected cell line was performed essentially as described in Ryan et al., with the following modifications. Cells were grown in 96-well plates for 2-4 days to 75,000 or 30,000 cells per well in F-12 nutrient mixture (Ham’s F-12), 10% fetal bovine serum, 300 ug/ml Geneticin and penicillin-streptomycin. At confluence, cells were washed twice with 10 mM Hepes/Tris, pH 7.4, 137 mM N-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl 2, 1.2 mM MgSO 4. Cells then were incubated with 10 M [14C]AMG, and 10 M inhibitor (final DMSO =0.5%) in 10 mM Hepes/Tris, pH 7.4, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl 2, 1.2 mM MgSO 4 at 37oC for 1.5 hr. Uptake assays were quenched with ice cold 1X PBS containing 0.5 mM phlorizin, and cells were then lysed with 0.1% NaOH. After addition of MicroScint scintillation fluid, the cells were allowed to shake for 1 hour, and then [14C]AMG was quantitated on a TopCount scintillation counter. Controls were performed with and without NaCl. For determination of EC 50 values, 10 inhibitor concentrations were used over 2 log intervals in the appropriate response range, and triplicate plates were averaged across plates.”
“(i) To start by asking what problem does the invention aim to solve? (ii) That leads one to consider what the established field which existed was, in which the problem in fact can be located. (iii) It is the notional person in that established field which is the relevant team making up the person skilled in the art.”
“I intend to apply that approach. I take particular note of: i) The requirements not to be unfair to the patentee by allowing an artificially narrow definition, or unfair to the public (and the defendant) by going so broad as to “dilute” the CGK. Thus, as Counsel for Alcon accepted, there is an element of value judgment in the assessment. ii) The fact that I must consider the real situation at the priority date, and in particular what teams existed. iii) The need to look for an “established field”, which might be a research field or a field of manufacture. iv) The starting point is the identification of the problem that the invention aims to solve.”
“Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.”
“Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity, and delaying the development of diabetic complications.”
“(i) dapagliflozin and/or that dapagliflozin possesses activity as an SGLT2 inhibitor and is useful in the treatment and/or delayed progression of diabetes…; (ii) dapagliflozin is a selective SGLT2 inhibitor in vitro and/or it reduces plasma glucose and/or blood glucose in vivo; (iii) dapagliflozin is a more selective SGLT2 inhibitor in vitro than the compound in Example 12 of WO 128 and/or it reduces plasma glucose and/or blood glucose in vivo more effectively than the compound in Example 12 of WO 128; (iv) dapagliflozin has a comparable in vivo efficacy to the compound in Example 10 of WO 128 but the compound in Example 10 of WO 128 cannot be used as a therapeutic agent due to stability issues.”
“Phlorizin itself is unattractive as an oral drug since it is a nonspecific SGLT1/SGLT2 inhibitor…. Inhibition of SGLT1 could also have serious adverse consequences as is illustrated by the hereditary syndrome glucose/galactose malabsorption (GGM), in which mutations in the SGLT1 cotransporter result in impaired glucose uptake in the intestine, and life-threatening diarrhea and dehydration. The biochemical differences between SGLT2 and SGLT1, as well as the degree of sequence divergence between them, allow for identification of selective SGLT2 inhibitors.”
“SGLT2 inhibitor activity of the compounds of the invention may be determined by use of an assay system as set out below.”
“A novel series of 4'-dehydroxyphlorizin derivatives was synthesised and the effects of these compounds on urinary glucose excretion were evaluated in rats. There was a strict structural requirement for activity. Introduction of a small substituent or a flat ring at the 3- and/or the 4-position on the A ring was permissible, but any change at the bridge part between the A and B rings or in the sugar moiety resulted in complete lack of activity. The 6'-OH group on the B ring was also necessary, and even small structural modifications of the 6'-OH group reduced the activity considerably. Among the compounds synthesised, the 5-benzofuryl derivative 25 [T-1095a] was the most potent and was selected as a new lead for further structure-activity relationship investigations.”
“AZ need not establish that dapagliflozin is a more effective treatment than any specific compound encompassed within the teaching of WO 128 (either as a matter of plausibility or of fact). That is particularly so because WO 128 does not plausibly establish that each alternative compound encompassed within its disclosure accesses the technical contributions on which AZ relies (namely that each of them is (i) an SGLT2 inhibitor, and/or (ii) useful in the treatment of diabetes). AZ therefore does not need to rely on a technical contribution that dapagliflozin is more effective than any particular compound identified in WO 128.”
“While the Medicinal Chemist would not be able to identify which of the compounds encompassed by WO 128 were tested in the assay, they would not doubt that the assay had in fact been used in relation to some of them. While no biological data are provided, it would be a reasonable assumption that at least the Examples – for each of which characterisation data are provided, indicating that they were synthesised – would have been tested for activity using this assay.”
“I do not believe that the Medicinal Chemist would have any reason to doubt the assertion in WO 128 that the class of compounds of Structure IB do inhibit SGLT2, albeit they may not expect all of the very large number of compounds captured by Structure IB to have this effect.”