CA-2025-001040 - [2025] EWCA Civ 903

The judge’s judgment

Plausibility

The judge approached the issue of plausibility by asking himself the three questions proposed by Birss LJ in Akebia Therapeutics Inc v FibroGen Inc [2021] EWCA Civ 1279, [2022] RPC 7 at [53] for addressing claims to classes of products:

“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.”

It was common ground that the answer to the first question is that claim 2 is limited to the single compound dapagliflozin, while claim 15 is limited to the use of that compound in the manufacture of a medicament for treating or delaying the progression or onset of diabetes (“treating diabetes” for short).

It was also common ground that the answer to the second question in the case of claim 15 is that “working” means treating diabetes. That is the relevant technical effect. As for claim 2, AstraZeneca did not advance any case that the identification of dapagliflozin per se was a technical contribution (i.e. without identifying any useful properties of dapagliflozin). The judge concluded at [232] that:

“… 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.”

On the appeal AstraZeneca confined its case to finding (a), which made it unnecessary for the Claimants to pursue a respondents’ notice challenging finding (b).

The judge considered the third question at [233]-[262]. He began by noting that Prof Thorens and Prof Bailey were in agreement that the mechanism proposed in the Patent, i.e. that SGLT2 inhibition would lead to a reduction of blood/plasma glucose in vivo and hence an effect on the diabetes disease state was a plausible one, given the support provided by the phlorizin and Tanabe Seiyaku studies referred to in [0004] and [0007]. The question was whether the Patent disclosed enough to make it plausible that dapagliflozin has activity as an SGLT2 inhibitor which is sufficient to have a useful effect on the diabetes disease state.

The issue between the parties was whether the statements in the Patent referring to dapagliflozin as an SGLT2 inhibitor were a bare assertion, as the Claimants contended, or verbal statements of an experimental result, albeit without numerical data, as AstraZeneca contended. The crux of this dispute was the correct interpretation of [114] and [115].

So far as [114] was concerned, the judge interpreted this as a statement that the assay described in [115] could be performed to determine SGLT2 activity.

As for [115], it was common ground that, given that this was expressed in the past tense, it was to be taken as a description of an assay that had been carried out. The judge noted, however, that what was used in the assay was “inhibitor”. There was nothing to tell the reader what the inhibitor was. The judge went on:

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.

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.

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.

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.”

The judge explained that AstraZeneca relied on structural similarities between dapagliflozin and phlorizin as giving the skilled team “additional reassurance” that dapagliflozin would be an SGLT2 inhibitor. Having identified five differences between the structures of dapagliflozin and phlorizin, the judge went on:

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.

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.”

Next, the judge explained that there was a debate between the parties as to whether the skilled team when presented with the Patent would obtain and study any of the documents referred to in it, and if so which. The judge directed himself that this was “a context- and fact-dependent question, and thus it depends firstly upon the wording of the specification and secondly on the evidence” (Akebia Therapeutics Inc v FibroGen Inc [2020] EWHC 866 (Pat), [2020] RPC 15 at [218]).

The judge went on:

Prof. Potter’s view was that the skilled medicinal chemist reading the Patent would see the reference to WO 128 at paragraph [0011] and look it up. I accept that - in my judgment a skilled medicinal chemist presented with a statement that dapagliflozin is an SGLT2 inhibitor but no experimental data to support it, and a statement in paragraph [0011] that compounds of a Markush formula which covers dapagliflozin have been reported in WO 128 to be SGLT2 inhibitors, would want to obtain WO 128 to see whether it contained SAR information that could be used to assess the claim of SGLT2 inhibition for dapagliflozin. Of course, if the skilled medicinal chemist were to obtain WO 128, they would find that it too contains no experimental data, and therefore no SAR information which might make it plausible that dapagliflozin was an SGLT2 inhibitor, let alone indicate what its EC₅₀ might be.

Prof. Thorens and Prof. Potter said that the skilled team presented with the statements in paragraphs [0004] and [0007] of the Patent about the Tanabe Seiyaku 6 month rat study (or their equivalents in WO 128) would want to find out more about that work. However, no attempt was made to recreate the kind of search that would have been done at the priority date to locate that work. The skilled team which had WO 128 would, however, see that it contained a number of references to prior work on compounds which are said to be SGLT2 inhibitors. Those references include the papers by Tsujihara et al., Hongu et al. and Oku et al. …; in my judgment the skilled team would regard those as potential sources for the Tanabe Seiyaku work referred to in paragraphs [0004] and [0007]. Further, Prof. Potter said that the skilled medicinal chemist would want to look at materials cited in WO 128, including those papers, and would be interested in any SAR information they contained. Therefore, in my judgment the skilled team which had WO 128 (which for the reasons explained in the previous paragraph, the skilled team reading the Patent would have done) would also look at the four Tanabe Seiyaku papers which it cites.

Even a brief consideration of those papers would reveal that the SAR work conducted by Tanabe Seiyaku indicated strict structural requirements for activity of phlorizin analogues. The position can be summarised by setting out the abstract of the first Hongu et al. paper (which follows on from the Tsujihara et al. paper which had shown a benefit of removing the 4'-hydroxy group from the first phenyl ring, referred to as the B ring by Tanabe Seiyaku):

‘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.’

This emphasises the importance, in phlorizin analogues, of retaining the structure of the linker between the two phenyl rings, and the hydroxy group on the first phenyl ring that has the ability to hydrogen bond to the carbonyl in the linker. Both those features are absent in dapagliflozin, and so the skilled team considering the Tanabe Seiyaku papers would find nothing to suggest that dapagliflozin would be an SGLT2 inhibitor. Indeed, in my judgment the message that they convey, namely that structural features of phlorizin analogues (which are absent from dapagliflozin) are important for activity, would give the skilled team reason to doubt whether dapagliflozin would be an SGLT2 inhibitor.

As neither WO 128, nor the Tanabe Seiyaku papers which it cites, contain any information to support the suggestion that dapagliflozin is an SGLT2 inhibitor, it is not necessary to consider whether it would be permissible to rely on information in these cross-referenced documents to establish or support a case of plausibility applying the approach in Warner-Lambert.”

Finally, the judge considered the question of potency:

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 EC₅₀ that had been obtained (or even how it compared with that of phlorizin).

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 EC₅₀ 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 ….

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 EC₅₀ 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.”

Having quoted two passages from the cross-examination of Prof Bailey in [256], the judge went on:

Overall, the evidence was that not every compound which produced a measurable EC₅₀ 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.

The skilled team which had the Tanabe Seiyaku papers cited in WO 128 would also note that Oku et al. provides the IC₅₀s 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 IC₅₀ 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 EC₅₀/IC₅₀ of dapagliflozin.

The absence of information about the EC₅₀ 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.

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.”

Arbitrary selection

The judge explained at [266]-[268] that AstraZeneca’s case at trial was that it was not necessary for dapagliflozin to have greater efficacy than (or be in any other way superior to) any of the other compounds encompassed by the disclosure of WO 128, including the compounds of the Examples. AstraZeneca did not advance any case that dapagliflozin was, so far as utility for the treatment of diabetes was concerned, any different in its properties to any of the other compounds of WO 128 (and in particular to the compound of Example 12).

In those circumstances the judge held as follows:

…. in my judgment that means that the Patent does not make a technical contribution over WO 128. There is nothing in the Patent nor in the evidence at trial to indicate that dapagliflozin is anything other than an arbitrary selection from the genus of compounds disclosed by WO 128.

The argument advanced by AZ was that the Patent made it plausible that dapagliflozin was an SGLT2 inhibitor which … was useful to treat etc. diabetes, whereas that was not made plausible by WO 128. That, AZ submitted, taught the skilled person something new and so was a technical contribution.

In my judgment there is some sleight of hand going on here. A technical contribution needs to be both present in fact and made plausible by the specification ….. I do not see how making something plausible can in itself be a technical contribution. Indeed AZ did not plead a technical contribution consisting of making something plausible - it pleaded (correctly, in my judgment) actual properties of dapagliflozin as being technical contributions.

Even if this argument were a permissible one, in my judgment it does not work in this case. The parties were agreed that, in order for the arbitrary selection case to add anything to the plausibility case, it is necessary to assume that the Patent does make it plausible that dapagliflozin is an SGLT2 inhibitor which … is useful to treat etc. diabetes. That requires me to approach matters on the basis that the Patent would be understood as disclosing that dapagliflozin had been assayed and had generated an EC₅₀ which meant that it would plausibly … be useful to treat etc. diabetes.

If that is so, then in my judgment WO 128 must also be understood as disclosing that compounds which it discloses had been assayed and had generated EC₅₀s which meant that they would plausibly … be useful to treat etc. diabetes. Prof. Potter (whose view was that the skilled medicinal chemist reading the Patent would assume that dapagliflozin had been tested) said this:

‘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.’

Therefore, on this approach the skilled team would understand that the compound of Example 12 of WO 128 (amongst others) had been tested and produced an EC₅₀ which meant that it would plausibly … be useful to treat etc. diabetes.”

The judge went on to refer to Prof Potter’s evidence that the skilled medicinal chemist would regard the statement in WO 128 that the compounds of Formula IB are SGLT2 inhibitors and useful in the treatment etc. of diabetes as being a prediction based on assay results of the compounds of the Examples, and continued:

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 R¹ = Cl and/or R⁴ = 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).

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.

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.”