Plausibility - Generics (UK) Ltd and others v AstraZeneca AB

 

Jane Lambert

Court of Appeal (Lords Justices Peter Jackson, Arnold and Stuart Smith) Generics (UK) Ltd and others v AstraZeneca AB  [2025] EWCA Civ 903 (16 July 2025)

This was an appeal by AstraZeneca AB from the judgment of Dr Michael Tappin KC sitting as a deputy judge of the High Court in  Generics (UK) Ltd v AstraZeneca AB [2025] EWHC 1012 (Pat) (28 April 2025).  In that case, Generics (UK) Limited and several other generic pharmaceutical manufacturers had claimed a declaration that the following supplementary protection certificates were invalid and an order for their revocation:

• SPC/GB13/021 for dapagliflozin and pharmaceutically acceptable salts thereof; and
• SPC/GB14/050 for a combination of dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof. 

Those SPCs derived from European patent (UK) 1 506 211 B1.  The claimants contended that the patent was invalid and sought a declaration to that effect.  Dr Tappin tried the action between 10 and 14 and 19 and 20 March 2025.   At para [280] of his judgment, he concluded that the patent was invalid for obviousness and insufficiency and that, accordingly, the SPCs were also invalid.  The deputy judge gave AstraZeneca permission to appeal, which Lords Justices Peter Jackson, Arnold and Stuart Smith heard on 25 and 26 June 2025.  Their lordships handed down their judgment in Generics (UK) Ltd and others v Astrazeneca AB [2025] EWCA Civ 903 on 16 July 2025. Lord Justice Arnold delivered the lead judgment with which the other Lords Justices agreed.   He dismissed the appeal.

Dapagliflozin

Dapagliflozin is used to treat type 2 diabetes, heart failure and chronic kidney disease.   According to Wikipedia, it is on the World Health Organization's List of Essential Medicines and was the 115th most commonly prescribed medication in the United States, with more than 5 million prescriptions.   The patent expired on 15 May 2023, and the SPCs were due to expire on 13 May 2028 and 14  May 2028, respectively.  Because of the product's commercial success, both Dr Tappin and Lord Justice Arnold expressed regret at the invalidity of the Patent and SPCs.

The Patent

Paragraph 0001 of the specification of EP 1 506 211 B1 stated that the patented invention related to C-aryl glucosides (inhibitors of sodium-dependent glucose transporters (SGLT2) found in the intestine and kidney) and to a method for treating diabetes (especially type II) and other diseases. SGLT2 inhibitors are understood to reduce blood glucose levels by preventing glucose reabsorption into the blood, thereby facilitating excretion into the urine.

The specification acknowledged that WO 01/27128 A1 (an application by Bristol Myers Squibb under the Patent Cooperation Treaty published on 19 April 2001) disclosed compounds which were "reported to be inhibitors of the SGLT2 transporter and consequently represent a mode for treatment of diabetes and complications thereof”. One of those compounds was the following, including pharmaceutically acceptable salts thereof, all stereoisomers thereof, and all prodrug esters thereof:

The specification taught that the compound possessed activity as an inhibitor of the sodium-dependent glucose transporters found in the intestines and kidneys of mammals and that it would be useful for treating diabetes. The specification stated that the compound could be used for treating diabetes.  

The claims in dispute were 1, 2, 14 and 15.   Claim 1 claimed the above structure or "a compound having the structure or a pharmaceutically acceptable salt, a stereoisomer thereof, or a prodrug ester thereof".  Claim 2 was to "the compound as defined in claim 1, having the structure". Claim 14 was to "Use, in the manufacture of a medicament for treating or delaying the progression or onset of diabetes, of a compound as defined in claim 1". Claim 15 was to "The use as defined in claim 14 where the SGLT2 inhibitor compound has the structure".

The Claimants' Contentions

The Claimants contended that the patent was invalid for obviousness and/or insufficiency for the following reasons:

(a)  The patent did not make it plausible that the compound was an SGLT2 inhibitor, a selective SGLT2 inhibitor or even useful for the treatment of diabetes; and

(b) The patent did not make a technical contribution over WO 01/27128 A1 but merely made an arbitrary selection of that compound from the class of compounds disclosed in that application without disclosing any advantage for the compound compared to that class.

Plausibility

To understand the claimants' contentions, it is necessary to understand the concept of plausibility.  Lord Justice Arnold explained the principle in para [9] of his judgment in Generics (UK) Ltd and others v AstraZeneca AB [2025] EWCA Civ 903 (16 July 2025):

"Article 52 (1) of the European Patent Convention (“EPC”) provides that European patents 'shall be granted for any inventions' provided that (among other things) they 'involve an inventive step'. Article 56 provides that an invention 'shall be considered as involving an inventive step if, having regard to the state of the art, it is not obvious to a person skilled in the art'. Article 83 requires that an application for a European patent 'shall disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art'.  Article 100 provides that the grant of a European patent may be opposed on grounds that include lack of patentability under Article 56 and failure to comply with Article 83. Article 138 (1) provides that a European patent may be revoked with effect for a Contracting State by the courts of that State on grounds that again include lack of patentability under Article 56 and failure to comply with Article 83. Sections 1 (1) (a), 3, 14 (3) and 72 (1) of the Patents Act 1977 give effect in the United Kingdom to Articles 52 (1), 56, 83 and 138 (1) EPC. None of those provisions mentions the criterion of plausibility. It has been developed through the case law initially of the Boards of Appeal of the European Patent Office and latterly of the courts of the Contracting States including the UK."

Essentially, the grant of a monopoly of a new invention is conditional upon the invention's technical contribution to the art and its disclosure to persons skilled in the art.

WO 01/27128 A1

This PCT application discloses a wide class of compounds defined by an extremely broad Markush formula, Formula I, that are said to be SGLT2 inhibitors. It also describes a narrower but still very broad class defined by Formula IA and a still narrower but broad) class defined by Formula IB. A Markush structure is a representation of alternatively usable members. A typical example might be: "A compound of the formula where R1 is selected from the group consisting of A, B, and C; and R2 is selected from D, E, and F". This formula covers several compounds, each with a different combination of R1 and R2.  Dr Tappin compared the patent to the application and found that the patent appeared to have been transposed from the application.

Use for Treating Diabetes

Dr Tappin's starting point was the following passage from Lord Justice Birss's judgment in FibroGen Inc v Akebia Therapeutics Inc [2021] EWCA Civ 1279 (24 Aug 2021):

"[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."

It was common ground that claim 2 of the patent was limited to the single compound dapagliflozin, while claim 15 was limited to the use of that compound in the manufacture of a medicament for treating or delaying the progression or onset of diabetes. The answer to the second question in the case of claim 15 was that “working” meant treating diabetes.  As for the third question, the issue was whether the statements referring to the compound as an SGLT2 inhibitor were a bare assertion or verbal statements of an experimental result, albeit without numerical data.  That turned on the meaning of para [0115] of the specification. After considering the evidence, the deputy judge concluded at [247] of his judgment:

"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."

Technical Contribution

Dr Tappin assessed the patent's contribution to the art and said at [268]:

"…. 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."

"WO 128" was an abbreviation for the WO 01/27128 A1 PCT application used by both Lord Justice Arnold and Dr Tappin.

The Appeal

AstraZeneca appealed on no less than 8 grounds:  

• Ground 1 was that the deputy judge wrongly assessed the disclosure of the patent between paras [238] and [241] of his judgment in finding that it did not comprise a verbal statement of an experimental result.  
• Ground 2 was that the deputy judge wrongly assessed the disclosure of the patent at [253]-[260] when he found that the patent did not disclose enough to make it plausible that dapagliflozin would treat diabetes.
• Ground 3 was that, had the deputy judge correctly interpreted the patent, he should have concluded that the claimed inventions were plausible even applying the standard laid down in Warner-Lambert.
• Ground 4 was that the Warner-Lambert test set too high a standard for plausibility, and must be revisited in the light of G 2/21.  
• Ground 5 was that, in the light of G 2/21, the court should have treated claim 2 as a claim to a product per se, differently from claim 15, as a claim comprising a functional technical feature.
• Ground 6 was that the deputy judge erred (i) in taking the Tanabe Seiyaku papers into account and (ii) finding that they would have given the skilled team reason to doubt whether dapagliflozin would be an SGLT2 inhibitor.
• Ground 7 was that the deputy judge had been wrong in his approach to the issue of arbitrary selection.  
• Ground 8 was that the deputy judge had failed properly to assess the contribution of WO 01/27128 A1 when considering whether the Patent made a technical contribution.
  

Lord Justice Arnold expedited the appeal because of the commercial importance of dapagliflozin and because the claimants and other generic manufacturers had been prevented from launching competing products by injunctions and undertakings.

Ground 1

AstraZeneca relied on the principle stated by Mr Justice Chitty in Lister v Norton Brothers & Co (1886) 3 RPC 199 at 203 and quoted by Mr Justice Arnold (as he then was) at para [192] of his judgment in Generics (UK) Ltd v Yeda Research and Development Co Ltd [2012] EWHC 1848 (Pat) [192]) that a skilled addressee reads a patent with a “mind willing to understand, not a mind desirous of misunderstanding”. It argued that the patent was all about dapagliflozin, that it contained repeated references to “the SGLT2 inhibitor of formula I” and that the purpose of the assay described in [0115] was to measure “SGLT2 activity of the compounds of the invention” as stated in [0114].  AstraZeneca contended that the skilled team would have understood the “inhibitor” referred to in [0115] to be dapagliflozin. 

Lord Justice Arnold rejected that argument at [85]:

"What would immediately strike the skilled team about [0115] is that it does not identify the “inhibitor”. It is purely a description of a method. If one is looking for linguistic clues, it is noticeable that it does not even refer to “the inhibitor”, which might be taken to be a reference to a specific, even if unidentified, inhibitor. It simply uses the word “inhibitor” as a generic term for the substance being tested. If [0115] was intended to record a test that had been performed on dapagliflozin, then it would surely have said so. Nothing would have been easier, and there is no good reason why that statement should not have been made had that been the case."

He added in the next paragraph that the skilled reader would have noted that para [0115] of the specification did not contain even a verbal statement of a result. It did not say, for example, “the inhibitor was found to have SGLT2 activity”, let alone significant, suitable or some other such term for SGLT2 activity. Again, nothing would have been easier, and there was no good reason why that statement should not have been made had that been the case.

Ground 2

Lord Justice Arnold said that that argument could get off the ground only if AstraZeneca had succeeded on Ground 1, but even on that basis, he would not have accepted it because the specification did not contain any of the information that would have supported a contention that dapagliflozin could be used to treat diabetes.

Ground 3

This ground required AstraZeneca to succeed on Grounds 1 and 2 and therefore did not arise.

Ground 4

Lord Justice Arnold observed that Warner-Lambert was binding on the Court of Appeal and the Enlarged Board of Appeal in G 2/21 considered that their decision was consistent with the Supreme Court's judgment.

Ground 5

His lordship was not persuaded that G 2/21 justified departing from Sandoz v BMS.  He proceeded to review decisions of the European Patent Office's Boards of Appeal and the courts of contracting states.   He concluded at para [127] that parties to the European Patent Convention are some way from unanimity as to what test G 2/21 lays down and how to apply it. Accordingly, neither the jurisprudence of the Boards of Appeal nor the case law of courts of other contracting states justified a departure from Sandoz v BMS any more than G 2/21 did.  

Lord Justice Arnold added at [129] that the claimants had contended that even if AstraZeneca had prevailed on the law and established that the correct standard to be applied to the assessment of inventive step was a "no legitimate reason to doubt" standard,"  the patent failed even to satisfy that standard. The claimants relied on four papers cited in WO2001027128A1 called "the Tanabe Seiyaku papers" which  “would give the skilled team reason to doubt whether dapagliflozin would be an SGLT2 inhibitor”. They also relied on Dr Tappin's finding at para [259] of his judgment that the absence of information about the EC50 of dapagliflozin meant that a skilled addressee could not reasonably predict any useful effect on diabetes.  

Taking the second point first, Lord Justice Arnold said that there was nothing in the judge’s findings to suggest that the absence of information about the EC50 of dapagliflozin would in itself give skilled addressees a reason to doubt the efficacy of dapagliflozin to treat diabetes if they would not otherwise doubt the efficacy of dapagliflozin.

As for the first, AstraZeneca argued that there was an inconsistency in the deputy judge's findings on whether a skilled addressee would read the Tanabe Seiyaku papers.  Lord Justice Arnold thought that a skilled reader would read the PCT application and the documents referred to in it but it would not change his conclusion.

Ground 6

The problem with this contention is that it challenged the deputy judge's findings of fact after hearing expert evidence.  AstraZeneca tried to argue that those findings were not open to the judge on the ground that none of the experts had referred to the PCT application or papers referred to in it. Lord Justice Arnold rejected that argument.  Dr Tappin had been supplied with those documents.  AstraZeneca had not shown why he should not have read them.  Nor had they explained why he should not have arrived at his findings of fact.

Ground 7

AstraZeneca objected to the last sentence of para [59] of the deputy judge's judgment on the grounds that it was wrong in law:

“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.”

AstraZeneca contended that Dr Tappin ought to have held that, where the prior art merely asserted that the genus had a given advantage or property without rendering it plausible, then a subsequent patent would have made a technical contribution by making the same assertion in respect of a selected compound and rendering it plausible.

Lord Justice Arnold disagreed. In his view, mere plausibility was not enough. All the previous case law had made clear that a selection from a prior-disclosed genus is only inventive if the selection makes a technical contribution in that the selected compound has some useful property, which means that the selection is a technical advance.

Ground 8

At first instance, AstraZeneca had argued that the patent had taught the skilled addressee something new, namely that it was plausible that dapagliflozin was an SGLT2 inhibitor which would be useful for treating diabetes, whereas the PCT application had only indicated that such property and use was possible. If that premise were accepted, such teaching would be a technical contribution.  Dr Tappin had rejected that argument at [279] of his judgment:

"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 will reduce blood/plasma glucose in vivo and/or be useful to treat etc. diabetes, it does not make that plausible for the first time."

Lord Justice Arnold agreed with that reasoning.  He added that the PCT application disclosed up to 50 compounds to which AstraZeneca's reasoning could have applied.    He observed at [143] that on AstraZeneca’s argument, none of those applications would have been objectionable on the ground of arbitrary selection. He concluded:

"What this submission highlights is the complete absence from the Patent of any basis for distinguishing between dapagliflozin and other compounds falling within Formula IB of WO 128, such as the compound of Example 12."

Comment

With the benefit of hindsight, European patent (UK) 1 506 211 B1 was vulnerable to challenge.  Given the size of the market for dapagliflozin, I should be interested to know why the generic pharmaceutical manufacturers did not try to clear the way sooner.   Anyone wishing to discuss this article may call me on 020 7404 5252 during office hours or send me a message through my contact form at any time.