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

Background of the invention

The specification sets out the background to the invention at [0002]-[0009]. The judge found that much of this was common general knowledge. Work on phlorizin “or closely related analogs” is referred to in [0004] and [0007], including a 6 month study of “an SGLT2 inhibitor” in diabetic rats by Tanabe Seiyaku.

At [0010] the specification acknowledges that two items of prior art “disclose C-aryl glucoside SGLT2 inhibitors for treating diabetes”. The first is WO 128, which it says in [0011] discloses compounds which “are reported to be inhibitors of the SGLT2 transporter and consequently represent a mode for treatment of diabetes and complications thereof”.

Description of the invention

This section begins:

“[0013] In accordance with the present invention, a C-aryl glucoside compound is provided which has the structure [labelled I]

[i.e. dapagliflozin] including pharmaceutically acceptable salts thereof, all stereoisomers thereof, and all prodrug esters thereof.

[0014] The compound of formula I possesses activity as inhibitors of the sodium dependent glucose transporters found in the intestine and kidney of mammals and is useful in the treatment of diabetes and the micro and macrovascular complications of diabetes such as retinopathy, nephropathy, and wound healing.”

The specification goes on in [0019] to state:

“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) …”

Detailed description of the invention

This section begins by describing how dapagliflozin can be made. It then sets out a list of definitions. It then gives a long description of how dapagliflozin, pharmaceutically acceptable salts, stereoisomers and prodrug esters may be used. The only parts of this that either side suggests are relevant are references in [0051], [0052], [0053], [0074] and [0102] to “the SGLT2 inhibitor of formula I”.

The specification then states at [0114]:

“SGLT2 inhibitor activity of the compounds of the invention may be determined by use of an assay system as set out below.”

Assay for SGLT2 activity. Under this sub-heading the specification states at [0115]:

“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 37^oC 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 EC₅₀ values, 10 inhibitor concentrations were used over 2 log intervals in the appropriate response range, and triplicate plates were averaged across plates.”

I have italicised the word “inhibitor” which appears twice in this paragraph and is central to some of the arguments. Although it is not a point relied on by the Claimants, it may be noted that the last sentence does not identify the “10 inhibitor concentrations”. The reference for the paper by Ryan et al. is given in [0116].

Example. From [117]-[128] the specification describes in detail the preparation and characterisation of dapagliflozin. It does not set out any results from the assay for SGLT2 activity described in [0115] for dapagliflozin.

Claims

The only claims relied upon by AstraZeneca for its appeal are claims 2 and 15. Claim 15 is dependent on claim 14. AstraZeneca applied unconditionally to amend claim 14 as shown below:

The compound as defined in Claim 1 having the structure [formula I i.e. dapagliflozin].

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.

The use as defined in claim 14 where the SGLT2 inhibitor compound has the structure [formula I i.e. dapagliflozin].”

In making the application to amend claim 14, AstraZeneca made no admission that the specification did not support the claim to efficacy in respect of the deleted diseases, but nor did it advance any case that it did.