“36. 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. 37. 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.”
“This submission also is contrary to the legal basis of this particular head of insufficiency. We know that pregabalin works for the treatment of … neuropathic pain, because like any other medicament on the market, it underwent demanding clinical trials after the priority date, the results of which were made public. On that basis it received marketing authorisation for … neuropathic pain. This is always the case for a commercially valuable medicament, and no other kind will be worth litigating about. The question is not whether it 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.”
“… 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.”
“70. The Enlarged Board takes note of the classification done by the referring board in respect of the case law of the boards of appeal concerning the relevance of post-published evidence to prove an asserted technical effect for acknowledgement of inventive step ... 71. However, when analysing the case law in more detail and irrespective of the conceptual terminologies for what questions 2 and 3 refer to as two distinct plausibility approaches, the Enlarged Board understands from the case law of the boards of appeal as common ground that the core issue rests with the question of what the skilled person, with the common general knowledge in mind, understands at the filing date from the application as originally filed as the technical teaching of the claimed invention. 72. Applying this understanding to the aforementioned decisions, not in reviewing them but in an attempt to test the Enlarged Board’s understanding, the Enlarged Board is satisfied that the outcome in each particular case would not have been different from the actual finding of the respective board of appeal. Irrespective of the use of the terminological notion of plausibility, the cited decisions appear to show that the particular board of appeal focussed on the question whether or not the technical effect relied upon by the patent applicant or proprietor was derivable for the person skilled in the art from the technical teaching of the application documents.”
“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.”
“86. Like the EPC, none of the legal systems of the EPC Contracting States provide for an explicit patentability requirement for what the referring decision discusses and addresses with what is referred to in questions 2 and 3 under the term ‘plausibility’. 87. Notwithstanding the fact that the aforementioned decisions were taken on the decisive facts of the case in hand and the particular submissions made by the parties to those proceedings, the Enlarged Board recognises a certain degree of common ground that the courts of the EPC Contracting States, when confronted with the examination of an asserted technical effect in the assessment of inventive step and with the question whether a patent proprietor may rely on post-published evidence to confirm that technical effect, ponder on the technical teaching of the claimed subject-matter that the person skilled in the art, with the common general knowledge in mind, understands from the patent application.”
“92. The term ‘plausibility’ that is found in the case law of the boards of appeal and relied upon by the referring board in questions 2 and 3 of the referral and the reasons for it, does not amount to a distinctive legal concept or a specific patent law requirement under the EPC, in particular under Article 56 and 83 EPC. It rather describes a generic catchword seized in the jurisprudence of the boards of appeal, by some national courts and by users of the European patent system. 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. 95. The Enlarged Board is aware of the abstractness of some of the aforementioned criteria. However, apart from the fact that the Enlarged Board, in its function assigned to it under Article 112(1) EPC, is not called to decide on a specific case, it is the pertinent circumstances of each case which provide the basis on which a board of appeal or other deciding body is required to judge, and the actual outcome may well to some extent be influenced by the technical field of the claimed invention. Irrespective of the actual circumstances of a particular case, the guiding principles set out above should allow the competent board of appeal or other deciding body to take a decision on whether or not post-published evidence may or may not be relied upon in support of an asserted technical effect when assessing whether or not the claimed subject-matter involves an inventive step.”
“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 derive the said effect as being encompassed by the technical teaching and embodied by the same originally disclosed invention.”
“… 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 …”
“Overall, I do not perceive any material difference between the case law of the EPO and the UK case law (which is to be expected, given that the intention of the Court of Appeal in Dr Reddy’s was to adopt the EPO approach). The requirement is for the claimed invention to in fact constitute a technical advance and for the patent to disclose enough to make that technical advance plausible. If the patent claims a compound selected from a previously disclosed genus of compounds which are said to have a particular property, then that requirement is not satisfied if the compound does not in fact have some different or improved property compared to those previously individually disclosed (a new effect or an increase in an effect), or the patent does not make such improved property plausible.”
“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, as well as hyperglycaemia, hyperinsulinemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis and related diseases, employing such C-aryl glucosides or in combination with one, two or more other type antidiabetic agent and/or one, two or more other type therapeutic agents such as hypolipidemic agents”
“The term ‘other type of therapeutic agents’ as employed herein refers to one or more anti diabetic agents (other than SGLT2 inhibitors of formula I) …”
“SGLT2 inhibitor activity of the compounds of the invention may be determined by use of an assay system as set out below.”
“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 CaCl2, 1.2 mM MgSO4. Cells then were incubated with 10 μM [14C]AMG, and 10 μM inhibitor (final DMSO =0.5%) in 10 mM Hepes/Tris, pH 7.4, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM MgSO4 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.”
“2. The compound as defined in Claim 1 having the structure [formula I i.e. dapagliflozin]. 14. Use, in the manufacture of a medicament for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycaemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels, of a compound as defined in claim 1. 15. The use as defined in claim 14 where the SGLT2 inhibitor compound has the structure [formula I i.e. dapagliflozin].”
“Other disclosures and publications which disclose SGLT2 inhibitors include the following: K. Tsujihara et al, Chem. Pharm Bull.44, 1177-1180 (1996) M. Hongu et al, Chem. Pharm Bull. 46, 22-23 (1998) M. Hongu et al, Chem. Pharm Bull. 46, 1545-1555 (1998) A. Oku et al, Diabetes, 48, 1794-1800 (1999)”
“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.”
“… what it means to ‘work’ for the purpose of the second Fibrogen step in respect of claim 15 is treating etc. diabetes, in the sense of having sufficient efficacy to treat diabetes, and in respect of claim 2 is either (a) the same as in the case of claim 15 or (b) reducing blood or plasma glucose in vivo with sufficient efficacy to allow it to be used as an experimental tool.”
“239. Further, I accept the Claimants’ submission, supported by their cross-examination of Prof. Bailey, that the skilled person reading the Patent would understand that the assay could have been performed by the patentee on other compounds, either in the validation of the assay, in which case phlorizin might have been used as the inhibitor, or in assessing the SGLT2 inhibitory activity of other compounds. The fact that paragraph [0115] tells the reader that the assay has been performed on an inhibitor does not tell the reader that it has been performed on dapagliflozin. 240. The reader might guess that had been done, but that is not the same as a disclosure that it has been. While Prof. Bailey and Prof. Potter said that the reader would understand that the assay had been performed on dapagliflozin, that was based on their assumption that a pharmaceutical company would not apply for a patent (let alone be granted one) if it did not have data to support the assertion that dapagliflozin was an SGLT2 inhibitor. That is a bootstraps argument, and in my judgment the assumption is not a permissible one to make …. Further, both Dr Edwards and Prof. Potter said that the fact that 20g dapagliflozin had been made did not make any difference to the assessment of whether it had been assayed. 241. Overall, I reject AZ’s characterisation of the Patent's description of dapagliflozin as an SGLT2 inhibitor as a verbal statement of an experimental result. On the contrary, it is an assertion unsupported by any experimental results. 242. As Warner-Lambert makes clear, a priori reasoning can provide an alternative basis for plausibility of an effect. However, the Patent contains no reasoning, based on structural similarities or otherwise, to support the suggestion that dapagliflozin is an SGLT2 inhibitor.”
“245. It was quite clear from the evidence of Dr Edwards and Prof. Potter that, given the CGK that small structural differences can make large differences to activity, the number and nature of the differences between dapagliflozin and phlorizin were such that no prediction could be made, based on the activity of phlorizin, about the activity of dapagliflozin as an SGLT2 inhibitor. The most that could be said was that the removal of the O-glucoside bond might reduce the risk of hydrolysis of dapagliflozin compared to phlorizin, and that the glucose moiety in dapagliflozin might interact with SGLT2. However, I accept Dr Edwards’ evidence that the presence of the glucose moiety, together with the two phenyl rings, does not provide the skilled team with the ability to make a reasonable prediction that dapagliflozin would be an SGLT2 inhibitor. 246. Indeed, AZ accepted that the similarities (such as they are) with phlorizin would not on their own be sufficient to make plausible the assertion that dapagliflozin was an SGLT2 inhibitor. It relied on them only to ‘reinforce the confidence’ that the skilled team would be given by ‘the positive assay result’. However, in my judgment there is no ‘positive assay result’ disclosed in the Patent for the reasons explained above.”
“253. AZ repeatedly asserted that the teaching of the Patent was that ‘positive results’ had been obtained in the assay of dapagliflozin. However, even if one were to accept (which I do not) that the teaching of the Patent was that dapagliflozin had been assayed, that begs the question as to what the ‘positive results’ were. Even if the skilled person were to understand the Patent as disclosing that dapagliflozin had been assayed and determined to be an SGLT2 inhibitor, it does not disclose the EC 50 that had been obtained (or even how it compared with that of phlorizin). 254. Nor, on the evidence, did the description of the assay mean that any positive result must have been a EC50 in a range which would confer utility. Dr Edwards said, and Prof. Bailey accepted, that the potency could have been in the millimolar range. AZ submitted that the assay could have been one with a 10 μM EC 50 cut-off, and that a compound which passed such an assay would have been a ‘hit’. I do not think there was anything in the evidence to suggest that the skilled team would have understood the assay to have such a cut-off, but in any event, on the evidence a ‘hit’ in itself is not a compound with practical utility …. 255. AZ submitted that the statements in the Patent that dapagliflozin was an SGLT2 inhibitor useful for the treatment of diabetes must be read as teaching that the EC 50 for dapagliflozin was such that it would be useful to treat diabetes. I agree with the Claimants’ characterisation of this as another bootstraps argument. On the contrary, the Patent makes bare assertions that dapagliflozin is an SGLT2 inhibitor and useful to treat diabetes.”
“257. Overall, the evidence was that not every compound which produced a measurable EC 50 in an in vitro SGLT2 inhibition assay would have been regarded as plausibly having a useful effect on … the diabetes disease state. Indeed, while my conclusion does not depend on this, the skilled team which had the Tanabe Seiyaku papers cited in WO 128 would, as Prof. Potter accepted, note that Tsujihara et al. presents results showing that some compounds which had SGLT2 activity in vitro were indistinguishable from the control in vivo and so were categorised as inactive. 258. The skilled team which had the Tanabe Seiyaku papers cited in WO 128 would also note that Oku et al. provides the IC 50s for phlorizin (160 nM against both SGLT1 and SGLT2) and for [a compound designated] T-1095a (20 nM against SGLT1 and 5 nM against SGLT2). It also presents the results of a study of T-1095a in diabetic rats, though it does not appear to be the study referred to in paragraphs [0004] and [0007] of the Patent (the source of that study was not clear from the materials in the case). There is nothing in the Tanabe Seiyaku papers to displace the skilled team’s CGK about potency requirements for an SGLT2 inhibitor which could be useful to treat diabetes. They provide the IC 50 for phlorizin as a benchmark for someone seeking an experimental tool to lower blood/plasma glucose. However, as I have said, the Patent provides no information on the EC 50/IC 50 of dapagliflozin. 259. The absence of information about the EC 50 of dapagliflozin is significant. The skilled team cannot reasonably predict any useful effect on … the diabetes disease state from merely being told that dapagliflozin is an SGLT2 inhibitor. 260. For the reasons I have given above, in my judgment the Patent does not disclose enough to make it plausible that dapagliflozin … will treat etc. diabetes.”
“277. There was no suggestion that any particular compounds covered by formula IB would be regarded as likely exceptions to the prediction - in particular there was no suggestion that the skilled medicinal chemist would regard a compound with R 1 = Cl and/or R 4 = OEt as being a likely exception. On the contrary, Prof. Potter’s evidence was that the skilled medicinal chemist would have no expectation that a compound with an alternative alkoxy group would have better, the same or worse activity data than one with a methoxy group (as in Example 12). 278. Therefore, on the hypothesis on which I am considering matters, WO 128 contains what the skilled team would regard as a plausible prediction, based on assay data for the compounds of the Examples, that compounds of formula IB (including dapagliflozin with its close relationship to Example 12) will be SGLT2 inhibitors and that they will … be useful to treat etc. diabetes. 279. All that the Patent does (on that hypothesis) is to verify that WO 128’s prediction of SGLT2 inhibitory activity and utility is correct in the case of dapagliflozin. It does not show that dapagliflozin has properties that are in any way different from those predicted by WO 128. On that hypothesis, while the Patent may make it more plausible that dapagliflozin … be useful to treat etc. diabetes, it does not make that plausible for the first time. So I reject AZ’s argument which I have recorded in paragraph 270 above.”
“would the skilled person, having the common general knowledge on the filing date in mind, and based on the application as filed, have legitimate reason to doubt that the purported technical effect can be achieved with the claimed subject-matter?”
“Contrary to what [the generics] argue, this interpretation of G 2/21 by the Court of Appeal does not lead to a free pass for speculative patents. After all, the fact that protection is granted based in a purely speculative patent for an invention that is only made afterward is prevented because it is required that the technical effect is already included by the technical teaching of the application and embodies the same invention that is disclosed therein. Moreover, it is established that EP 415 does not concern a speculative patent. BMS undisputedly argued that the inventors had already determined the favourable affinity and selectivity of apixaban experimentally prior to the submission of the application.”
“If the criterion that the claimed technical effect is considered by the skilled person to be embodied in the invention as originally disclosed is understood as the Boards of Appeal did in decision T 116/18 and T 1989/19 [a decision not cited to this Court that the Swiss Court stated had followed T 116/18], namely that this criterion is fulfilled if the skilled person has no reason to doubt that the invention achieves the technical effect, speculative applications are not prevented. In the case of a technical effect claimed in the original application without any basis, there are no reasons for its occurrence, but often also no reasons against its occurrence – especially since, in practically significant cases, it has subsequently been found that the invention achieves the claimed effect.”
“The second criterion is fulfilled if the technical effect is obvious to a person skilled in the art, taking into account the general knowledge at the time of filing, based on the application as filed. Experimental data or an express statement on the technical effect are not necessary for this purpose. However, since the purpose of derivability is to prevent abusive speculative applications, the hurdle must not be set too high, otherwise inventions that are worthy of protection will not be protected.”
“The decisive factor for whether a technical effect can be built upon in the assessment of inventive is whether at the time of application, based on the BMS application in combination with the general subject knowledge, it appeared credible – i.e. plausible – to the expert team that this effect would be achieved.”
“If the patent claims a compound selected from a previously disclosed genus of compounds which are said to have a particular property, then that requirement is not satisfied if the compound does not in fact have some different or improved property compared to those previously individually disclosed (a new effect or an increase in an effect), or the patent does not make such improved property plausible.”