UK – What is an active ingredient (again)?

Background

SPCs are granted for “products”. Products are defined as active ingredients or combinations of active ingredients (Art. 1(b) SPC Regulation). But what constitutes an active ingredient? The CJEU and English Courts have a long history of ruling on this question and have consistently adopted a narrow approach to Art. 1(b) such that polymers facilitating sustained release (MIT, C-431/04), adjuvants (GSK, C-210/13), and carrier proteins which have a pharmacological effect when covalently bonded to other active ingredients (Forsgren, C-631/13) have not been considered active ingredients.

Furthermore, reformulation of a previously approved drug as albumin-coated nanoparticles has been held not to lead to a distinct active ingredient from the previously approved drug (Abraxis, C-443/17; [2017] EWHC 14 (Pat)).

Notwithstanding this extensive body of case law, there are currently three pending referrals relating to this question:

-          Halozyme (C-456/24) concerns an application for an SPC for trastuzumab in combination with recombinant human hyaluronidase (RHH).  The SmPC names trastuzumab as the only active ingredient and RHH is referred to as an excipient.  Halozyme rely on evidence outside of the regulatory documents to suggest that RHH has its own therapeutic effect and is therefore an “active ingredient”.

-          Stada (C-794/25) concerns an SPC application for lisdexamfetamine (LDX), a pro-drug in which lysine is covalently bonded to dexamfetamine (DEX).  DEX was first approved as a medicine many years ago.  LDX was considered to be a New Active Substance (NAS) by the EMA.  Furthermore, in accordance with the Commission’s Guidelines on SmPCs insofar as pro-drugs are concerned, LDX is referred to as the active substance in the SmPC, notwithstanding that it is pharmacologically inactive.

-          Boehringer Ingelheim Vetmedica (C-15/26) concerns an application for an SPC for ciclesonide based on an MA for its use as an asthma treatment in horses, for which it was granted NAS status.  Ciclesonide had been earlier approved to treat asthma in humans1.

A key question underpinning each of these referrals is whether terms such as active ingredient/substance should be construed consistently across regulatory and SPC law or whether the terms are context-dependent.  In particular, (i) if a substance is referred to as an excipient in an SmPC, does that preclude a finding that it is an active ingredient for SPC purposes?; and (ii) if an active ingredient is granted NAS status, does that render it distinct from earlier approved active ingredients for SPC purposes?

Halozyme is the most advanced case.  In April this year, AG Emiliou opined that the classification of substances set out in the MA should be determinative; it is therefore not open to an applicant to argue that a substance which is classified as an excipient is an “active ingredient”.  The application of the so-called Forsgren test, i.e. that a substance must have a pharmacological, immunological or metabolic effect of its own in order to be an “active ingredient” should be confined to situations where there is ambiguity in the MA.

In the UK, the trastuzumab/ RHH SPC application was initially rejected by the UKIPO; although it was permissible to rely on evidence other than the regulatory documents to support a contention that a substance was an active ingredient, there must be some indication in the MA that the substance has an effect of its own on the therapeutic indications covered by the MA (which was not the case for RHH)2.  On appeal, Meade J upheld the UKIPO’s findings of fact but, in part due to the pending CJEU referral, did not consider it appropriate to consider the legal question, i.e. what materials can an applicant rely upon to determine whether something is an active ingredient?  Meade J’s decision was not appealed.

Recent Decision from the Patents Court re LDX

Most recently, HHJ Hacon handed down a decision upholding the validity of the LDX SPC.  The Judge considered the AG’s approach in Halozyme to be “compelling” and found that the reasonable reader of the LDX SmPC would consider LDX to be the active ingredient.  He further agreed that the Forsgren test should be confined to the exceptional circumstances of that case.

Having agreed in principle with the AG on the primacy of regulatory documents and determinations, HHJ Hacon held that the characterisation of pro-drugs as active substances in the Commission Guidelines meant that “what is generally regarded as an inactive compound, such as a pro-drug, can also be an 'active ingredient' within the meaning of the SPC Regulation”.  Furthermore, in relation to LDX’s NAS status, he opined “I have no doubt that the criteria for assessing whether a substance is a new active substance under the Medicines Products Directive and whether it qualifies as an active ingredient under the SPC Regulation are identical.”  This approach is at odds with the approach taken by the Federal Patent Court of Germany in parallel proceedings3, where the LDX SPC was held invalid, a decision which is under appeal.  It will be interesting to see if/how the pending referrals bring clarity to the issue.

Are pro-drugs special?

In light of HHJ Hacon’s decision, an interesting question arises as to whether pro-drugs hold a special position in the UK SPC regime as distinct from other methods of “modification” of a drug.

Fosaprepitant and paliperidone palmitate, prodrugs of aprepitant and paliperidone respectively have been considered by the UKIPO to be distinct active ingredients from the active moiety for Article 1(b) purposes4.  In Abraxis, the applicant sought to rely on these examples to support its argument as to why nab-paclitaxel was a distinct active ingredient to paclitaxel.  Although Arnold J held that paclitaxel is the sole active ingredient and albumin is a carrier, he did not expressly comment on the applicant’s attempt to rely on the pro-drug examples nor on the UKIPO’s attempt to distinguish them.

HHJ Hacon nevertheless felt able to deduce that “although he did not expressly say so, the judge appears to have accepted that pro-drugs were different from nab-paclitaxel because pro-drugs are new molecules…”  In the event that the LDX decision is appealed, it will be interesting to see if/how Arnold LJ addresses this “reading between the lines” of his Abraxis decision and whether pro-drugs do in fact hold such a special position within the SPC regime.

Conclusion

Although UK Court proceedings will no longer be stayed pending the outcome of CJEU referrals post-Brexit, it seems clear from the decisions of Meade J in Halozyme and HHJ Hacon in LDX that the Courts are somewhat reluctant to render decisions which might ultimately contradict CJEU jurisprudence.

It is not yet clear whether the LDX decision will be appealed but if it is, we might expect a decision from the Court of Appeal in early 2027. Furthermore, we are likely to see a decision from the CJEU in the Halozyme case in late 2026 or early 2027 and in the LDX case in late 2027 or early 2028.  Should the CJEU decision be handed down before any UK appeal, it will be interesting to see how the decision is treated.

It remains to be seen whether these cases will finally bring clarity to the question of “what is an active ingredient?” and, specifically insofar as the LDX referral is concerned, the status of pro-drugs in the SPC regime.  As in many other instances, the tension between achieving the aims of the SPC regime to encourage true innovation on the one hand, and the desire for a transparent and easy to apply system on the other, remains central to the challenge. 

• 1In the UK, the corresponding SPC application was rejected by the UKIPO (O/0600/25) and it does not appear that an appeal has been filed.
• 2BL O/0257/24
• 33 Ni 22/22 (EP)
• 4See SPC/GB08/021 and SPC/GB11/044.  The paliperidone palmitate SPC was the subject of a nullity action in the UK but the case did not proceed to trial (Case No: HP-2020-000021)