In February 2023, the Korean Supreme Court issued two significant decisions in long-running disputes over the two patents covering AstraZeneca’s blockbuster Forxiga (dapagliflozin), the first SGLT-2 inhibitor anti-diabetic. The first patent (KR 085) claims a ‘genus’ of compounds (i.e., a group of compounds covering dapagliflozin in a Markush structure) and expires on April 7 2023, and the second (KR 752) claims a ‘species’ (i.e., dapagliflozin itself), expiring on January 8 2024.
Because the ‘species’ patent expires later than the ‘genus’ patent, both patent barriers must be removed one way or another in order for generic companies to sell any drugs. For this purpose, one local pharmaceutical company called Dong-A ST developed an ester prodrug of dapagliflozin, (i.e., dapagliflozin formate), and then sought court confirmation that its prodrug lies outside the scope of the ‘genus’ patent (KR 085). Other generic companies took a different strategy and filed invalidation trials against the ‘species’ patent (KR 752).
AstraZeneca prevailed in the prodrug design-around case. Under the doctrine of equivalents (DOE), the Korean Supreme Court ruled in favour of AstraZeneca, confirming that Dong-A ST’s prodrug generic of dapagliflozin falls within the scope of the ‘genus’ patent (KR 085) (Supreme Court Decision 2022Hu10210, February 2 2023).
However, in the validity case, in which 17 generic companies had filed invalidation trials against the ‘species’ patent (KR 752), the court found KR 752 invalid based on lack of inventiveness (Supreme Court Decision 2020Hu11738, February 2 2023). As a result, it has become possible for generic companies to enter the Korean market after the ‘genus’ patent (KR 085) expires on April 7 2023.
Infringement under the DOE by prodrug ester of dapagliflozin
While the Trial and Appeal Board (IPTAB) decided in favour of Dong-A ST in the confirmation-of-scope trial, ruling that dapagliflozin formate is neither literally read on the claims nor considered as equivalent to dapagliflozin, the Patent Court and the Supreme Court took a different view and ruled in favour of AstraZeneca, stating that while the prodrug is not literally claimed in the ‘genus’ patent (KR 085), it nonetheless falls within the scope thereof under the DOE.
In affirming the ruling of the Patent Court, the Supreme Court found that it is obvious for a person of ordinary skill in the art (POSITA) to modify dapagliflozin to dapagliflozin formate in view of common general knowledge existing at the time of issuing the decision in this case, on the grounds that:
Modification from hydroxyl to ester is well known in the art of prodrug design;
The site chosen for esterification is easily conceivable due to low steric hindrance; and
Formic acid, as the structurally simplest carboxylic acid and which is known to be safe in the body, can be easily selected for developing prodrugs.
In the decision, the court also confirmed that the deletion of the ‘prodrug ester’ was made solely to resolve the examiner’s formality rejection that the term is functional, and the applicant had no intention of excluding all possible prodrug esters from the scope of the claims, and thus dapagliflozin formate had not been intentionally excluded.
Inventiveness of species dapagliflozin when prior art teaches genus
While the ‘species’ patent (KR 752) enabled longer protection of Forxiga, it was vulnerable to validity attacks because its genus concept had been disclosed in the publication of the ‘genus’ patent (KR 085). As many as 17 generic companies initiated invalidity actions in 2015 with the aim of earlier generic entry. The Supreme Court finally concluded that the ‘species’ patent (KR 752) lacked inventiveness.
As for the inventiveness of genus–species inventions (so-called selection inventions), the Korean Supreme Court made an important decision in 2021, holding that species concept inventions should be examined under the same general inventiveness standard as all other inventions, and thus the ‘technical difficulty’ of an invention as well as the ‘remarkableness of effect’ should be considered (Supreme Court Decision 2019Hu10609 on April 8 2021). Before this decision, Korea had applied a very strict standard to selection inventions, and in practice required a remarkable technical effect from all species concepts disclosed in the originally filed specification.
In this case, under the previous strict standard, the IPTAB had found the ‘species’ patent (KR 752) invalid. On appeal, the Patent Court and the Supreme Court applied a more relaxed standard according to Decision 2019Hu10609, however, reaching the same conclusion. The court found that the prior art reference discloses a genus Markush structure covering dapagliflozin, and that among the most preferred sub-group of compounds disclosed, the compound of Example 12 is one of 15 compounds for which a preparation method and physicochemical properties are specifically disclosed therein, which is sufficient basis for the POSITA to note the compound of Example 12 for further development.
The court also found that the only difference between the compound of Example 12 and dapagliflozin lies in the terminal substituent (methoxy versus ethoxy). In view of the prior art reference suggesting lower alkoxy as the terminal substituent regardless of the number of carbons, the court found that the POSITA would recognise methoxy and ethoxy groups as interchangeable functional groups, and preferentially try to substitute the methoxy of the compound of Example 12 with an ethoxy substituent.
In addition to the above technical difficulty, the court also reviewed whether the claimed invention had a remarkable effect, but only concluded that the improvement so argued was minor compared with those disclosed in the prior art reference.
Remarks
Applying the DOE, the 2022Hu10210 case concerning the claim scope is a very encouraging decision for developers of new chemical entity drugs. It signals that simply making an ordinary prodrug is not sufficient for designing around an original drug.
In the case of Forxiga, the patent term of the ‘genus’ patent (KR 085) had already expired on December 2 2020; however, its term has been extended to April 7 2023 by patent term extension. Although Dong-A ST lost the case in the 2022Hu10210 decision, there is a surprising twist in the story.
Dong-A ST had filed another trial seeking to confirm that its prodrug ester does not belong to the scope of the ‘extended’ ‘species’ patent (KR 085), and it prevailed at the trial court level (IPTAB). Dong-A ST was ultimately able to launch its prodrug product based on this decision. However, while appealing before the Patent Court, AstraZeneca filed a motion for preliminary injunction seeking to stop Dong-A ST’s infringement until the Patent Court’s ruling is issued. The preliminary injunction has been granted.
Another decision, 2020Hu11738, was meaningful in that it provides a further example of cases judging the inventiveness of selection inventions in Korea. While the 2019Hu10609 decision made in 2021 lowered the standard for approving inventiveness, it looks as if proving the effect of species inventions convincingly is still the most important point in Korea.
