October 2026 Yes, a pro-drug can be a new product for the purposes of an SPC!
Questions relating to what is intended by the terms “product” and “active ingredient” in an SPC have been raised in two actions at the UK Patents Court.
Aristo Pharma GmbH and Stada Arzneimittal AG filed actions against Takeda Pharmaceuticals International AG and Takeda Pharmaceutics USA Inc respectively, with the cases being heard together as they concerned the same issues.
Aristo and Stada contended that Takeda’s SPC for their drug Elvanse, used in the treatment of attention deficit hyperactivity disorder, is invalid. The SPC identified the product, as lisdexamfetamine (LDX), when, according to Aristo, the active ingredient is in fact dexamfetamine (DEX). As a previous marketing authorisation (MA) had been issued for DEX, the MA for Elvanse and LDX was not the first authorisation relating to this active ingredient, resulting in an invalid SPC.
LDX is a pro-drug consisting of lysine covalently attached to DEX. Once ingested, LDX is hydrolysed and releases DEX, which produces the therapeutic effect – this being in the treatment of ADHD.
Takeda argued that LDX is a distinct active ingredient and product.
It was acknowledged during the trial that LDX provided an improved treatment for ADHD when compared to DEX, due to a slower release of DEX resulting from the hydrolysation required to release DEX from LDX. As a result, dosing once a day only is required, increasing convenience to patient and thus dosing compliance. This is particularly the case with children who make up a significant proportion of ADHD patients. This is a genuine and significant improvement in treatment for the patients, resulting in a genuine and significantly improved outcome for these patients.
The Judge reviewed the case law on this matter and noted that where the product comprises a combination of the active ingredient together with an adjuvant having no therapeutic effect, this did not qualify as a new product. However, a substance that is covalently bound to a known active ingredient could qualify for separate SPC protection only if it has a pharmacological, immunological or metabolic action of its own.
Specifically, the Judge considered the Halozyme case, currently pending at the CJEU. While the decision is still pending, the Advocate General has given his opinion on the question of whether one of a combination of two substances had such an action on its own. The AG concluded that:-
“the qualification of a substance as an “active ingredient” within the meaning of that provision is to be determined by reference to the classification of substances set out in the marketing authorisation relied on in support of the application for a supplementary protection certificate. Consequently, a substance which is expressly designated as an “excipient” in that marketing authorisation cannot be regarded as an “active ingredient” for the purposes of that regulation.”
From this, the Judge considered in order to determine whether an active ingredient is considered to be a new product, it is necessary to refer to the MA only, and whether a separate MA was necessary or issued in relation to the new active ingredient. If it was, the active ingredient is a new active ingredient and a new product.
In order to try to persuade the Judge that the true product is DEX and not LDX, Aristo and Stada referred to the MA for LDX, which refers to doses of LDX as folllows:-
“30 mg Capsules: Each capsule contains 30 mg lisdexamfetamine dimesylate, equivalent to 8.9 mg of dexamfetamine.
50 mg Capsules: Each capsule contains 50 mg lisdexamfetamine dimesylate, equivalent to 14.8 mg of dexamfetamine.
70 mg Capsules: Each capsule contains 70 mg lisdexamfetamine dimesylate, equivalent to 20.8 mg of dexamfetamine.’
This is in accordance with the European Commission’s Guidelines, which requires that:-
“If an active substance is an ester or pro-drug, the quantitative composition should be stated in terms of the quantity of the ester or pro-drug. When the active moiety is an active substance of an already approved medicinal product, the quantitative composition should also be stated in terms of the quantity of this active moiety (e.g. 75 mg of fosphenytoin is equivalent to 50 mg of phenytoin).”
Aristo and Stada thus argued that this confirms that DEX is the true active substance.
However, the Judge disagreed, concluding that LDX was the active substance, while DEX was the active moiety. It is whether the substance or substances taken by the patient have their own and independent pharmacological, immunological or metabolic action that matters. In this case, there are genuine benefits assocaited with LDX over DEX.
Aristo and Stada also argued that the MA notes that LDX is an inactive prodrug, with DEX being responsible for the drug’s activity. Thus, Aristo and Stada were able to conclude that LDX cannot be the active ingredient.
Again, the Judge disagreed, noting that in the context of the SPC regime, the term active ingredient encompasses pro-drugs.
Finally, the Judge reviewed the Decision of the German Federal Patent Court relating to the same issue. This Decision is that the SPC is invalid, although an appeal is currently pending.
The German Court considered that whether the product of an SPC is new is not determined by the issuance of a MA. The UK Judge disagreed, following the AG conclusion that this is the correct test. In addition, the German Court referred to the statements in the MA indicating the equivalence of LDX to DEX is terms of drug quantity, set out above, and again concluded that LDX and DEX are identical active substances. Again, as set out above, the UK Judge disagreed.
Thus, the Judge concluded that the SPC was valid, concluding that a pro-drug could be considered as a new active ingredient for the purposes of an SPC even if it is metabolised on ingestion to form a previously known active substance. Importantly, the Judge concluded that the regulatory classification and MA material consider LDX as a new active ingredient, and this is the relevant test for a new product of an SPC. Finally, the clinically significant pharmacokinetic different, including a change from multiple daily doses to once-daily dosing, can establish a pharmacological and/or metabolic action distinct from that of the earlier product, confirming the presence of a new product and new active ingredient.
