Pro = Active? CJEU asked to decide

In a new referral to the EU’s Court of Justice (C-794/25), the CJEU has been asked to rule on the question whether an approved pro-drug of a previously approved active pharmaceutical ingredient is eligible for SPC protection in the EU independently of the originally approved active.  The CJEU’s answer will hopefully provide clarity to the industry and resolve litigation in this field.

Background – Dexamphetamine (DEX) and its pro-drug lisdexamfetamine (LDX)

A pro-drug of an active pharmaceutical ingredient is a compound which typically has no pharmaceutical activity of its own, but is converted to the corresponding active ingredient in the body.  Examples of classes of pro-drugs include esters and amides, the ester or amide bond typically being cleaved in the body by the action of one or more enzymes.

Dexamphetamine (DEX) is the more active enantiomer of the well-known drug amphetamine.   It was first marketed in the 1930s to treat depression, and is still sold as a generic drug in many countries.  However, its adverse effects and potential for abuse are also well-known.

Lisdexamfetamine (LDX) is a pro-drug of DEX comprising a residue of the naturally amino acid L-lysine bonded via an amide functional group to a DEX molecule.  It was developed to create a longer-lasting and less easily abused version of DEX.  The compound is metabolised in the body by enzymes in the red blood cells, the amide group bring cleaved to release the active agent DEX.  LDX is marketed by Takeda as Elvanse®.

Marketing authorisations and SPCs for LDX

Despite the parent drug DEX having long been on the market, LDX was granted marketing authorisations (MAs) as a New Active Substance (NAS) in EU countries in the early 2010s under the EU’s Medicinal Products Directive (MPD, Directive 2001/83/EC).  In this regard, Article 10.2.b of the MPD currently states as follows:

“the different salts, esters, ethers, isomers, mixture of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance unless they differ significantly in properties with regard to safety and/or efficacy. In such cases additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant.”

The legislation is silent on the specific question of whether pro-drugs of an existing active substance can or cannot be designated as an NAS – they must simply meet the test of differing significantly in properties with regard to safety and/or efficacy.  In this regard, Takeda provided scientific evidence to the regulatory authorities in order to support their position that LDX did meet this test in differing significantly from DEX, and they accepted this in granting LDX an MA as an NAS.  The fact that the active moiety in the bloodstream is the same following administration of both LDX and DEX was not considered relevant.

Takeda applied for, and were granted, SPCs for LDX in multiple EU countries based on the LDX MA and a basic patent (EP 1644019) claiming LDX.  The basic patent expired in 2024, and the SPCs extended the protection for LDX until 2028.

The Law – SPC Regulations and prior CJEU decisions

Article 1(b) of the EU medicinal products SPC Regulation (469/2009) defines a “product” for SPC purposes as “the active ingredient or combination of active ingredients of a medicinal product”.  However, the legislation does not specifically define what is meant by “active ingredient”, and in particular does not distinguish between compounds which are active in their own right and derivatives such as pro-drugs which only become active when metabolised in the body.

As with most EU legislation, the recitals of the Regulations can be used to interpret the purpose and meaning of the law.  In this regard, recital 14 of the EU plant protection products SPC Regulation (1610/96) states that the issue of an SPC for an active substance does not prejudice the issue of other SPCs for derivatives (salts and esters) of the substance, provided that the derivatives are the subject of patents specifically covering them.  Recital 17 of this Regulation specifically indicates that this recital can also be used to interpret the corresponding Articles in the medicinal products SPC Regulation.

Prior CJEU decisions (Santen, C-673/18 and Abraxis, C-443/17) had forbade SPCs for new uses (Santen) or reformulations (Abraxis) of a previously approved active ingredient,  Similarly, in prior decisions (MIT, C-431/04 and Forsgren, C-631/13), attempts to obtain SPC protection for excipients added to (MIT) or carrier proteins covalently bonded to (Forsgren) a previously approved active, were rejected by the Court.  However, the CJEU has not been previously asked to consider the specific question of whether a prodrug or other derivative of a previously approved active is eligible for SPC protection in its own right.

The LDX SPC litigation and the national court decisions

Following expiry of the basic patent for LDX, various generics companies sought to invalidate the LDX SPCs to clear the way for generic market entry.  Invalidation actions were pursued against the SPCs in Germany, Denmark, and Sweden, as well as in Switzerland which, although not an EU country, allows for SPCs under its national law.

The generics argued that, as LDX converts to DEX in the body, the true “active ingredient” in both cases was DEX.  Based on this, they argued that, as DEX had long been on the market before LDX was approved, the MA for LDX was not the “first” MA for DEX, and therefore the LDX SPC did not comply with either Article 3(d) or 2 of the SPC Regulation.  In doing so, they referred to the earlier CJEU case law to argue that the concept of “product” (or “active ingredient”) should be interpreted narrowly.

Takeda counter-argued that LDX and DEX are completely different actives, as confirmed by the grant of both a separate patent and NAS regulatory status to LDX, and therefore the prior marketing of DEX was irrelevant to the question of whether the LDX SPC was valid.

The Swedish and Swiss courts both favoured Takeda’s arguments in upholding the SPCs. They decided the active ingredient in the approved product was LDX, as this was the subject of the MA – considering the term “active ingredient” in the SPC Regulation should be interpreted in the same way as “active substance” in the MPD.  The earlier CJEU case law was considered irrelevant in this regard.

However, the German courts took the opposite view and invalidated the SPC.  The Court decided that LDX and DEX were the same active substance, noting that as LDX itself does not have any pharmaceutical activity, the true active in both products can only be DEX.  The Court followed the earlier CJEU case law in considering that the change from DEX to LDX did not create a new active, in spite of the grant of NAS status to LDX by the regulatory authorities.

Question 1 referred by the Danish Court

The Danish court noted that, when considering the Abraxis case, the CJEU’s Advocate General pointed out that the CJEU had not ruled on the question of whether a derivative of an active ingredient can be considered an independent active ingredient, and in particular whether the term “active ingredient” in the SPC Regulation and “active substance” in the MPD are the same. It therefore referred the matter to the CJEU, the first question being as follows (which we have simplified for ease of understanding):

1.Must a derivative, [such as LDX], of an active ingredient, [such as DEX], … be considered to be an independent active ingredient, which thus comes within the concept of ‘product’ within the meaning of Article 1(b) of [the SPC Regulation], if:

(a) the derivative itself is protected by a patent or

(b) the derivative in connection with the grant of [an MA] is considered to be an NAS within the meaning of Article 10(2)(b) of [the MPD]?

If the fact that a derivative [such as LDX] enjoys independent patent protection or is classified as an NAS does not mean that it must be considered to be an independent active ingredient, what conditions must a derivative of an active ingredient satisfy in order to be considered to be an independent active ingredient coming within the concept of ‘product’ within the meaning of Article 1(b) of the SPC Regulation?

Question 2 referred by the Danish court

The German SPC was invalidated following an independent examination by the Court of whether LDX was a separate active ingredient.  The generics argued that a similar assessment should be carried out by the Danish court.  Takeda opposed this, arguing that EU law does not empower the courts to review the scientific assessment that forms the basis for the regulatory authorities to grant an MA.

Specifically, the parties differed on the applicability of the Polpharma case (T-611/18) to the issue of SPCs.  Takeda argued it created a general principle that the Courts have no power to make a new assessment of matters already decided by the competent EU authorities.  The generics disagreed, considering Polpharma did not consider the validity of SPCs and therefore was not relevant.

In view of this, the Danish court referred a second question to the CJEU, as follows:

2. Are there any limitations on judicial review by a court of a Member State in a case such as the present case concerning the alleged invalidity of [an SPC], similar to those referred to in the Polpharma case [on the review by the EU courts of MAs for medicines]?

Next steps and practice points

The CJEU is likely to reach its decision on this matter some time in 2027.  As with previous decisions, it could have an impact not only on currently pending SPCs for derivatives (such as pro-drugs) of previously approved actives, but also those previously granted.  The eventual decision may also have bearing on the extent to which the industry chooses to invest in developing pro-drugs and similar derivatives of previously approved drugs.

The CJEU has also recently been asked to clarify whether a veterinary MA for an active ingredient can be considered the “first” MA for SPC purposes when there has been a prior MA for the same product as a human medicine.  However, as in that case the actives are identical, its outcome is unlikely to affect the present case.

We would advise that applicants request the prosecution of currently pending SPCs be stayed until the CJEU has reached its decision – some Patent Offices may do so automatically.  Please contact the HGF SPC team if you require any further advice.

This article was prepared by Partner and Patent Attorney Garreth Duncan