09 February 2024

Mathys & Squire presents SPC combination therapeutics case in front of Court of Appeal

Partner Martin MacLean & Associate Lionel Newton of Mathys & Squire LLP, instructing Richard Davis KC of Hogarth Chambers, sought clarification from the Court of Appeal on whether supplementary protection certificates (SPCs) can be granted for a “combination product” (i.e. a product requiring two or more “active ingredients”).

The trial concluded on 24 January 2024 and the awaited decision will be seminal on this point of law, potentially adding £billions back on to the value of Big Pharma marketing this class of medicinal product in the UK. Moreover, the persuasive effect of UK jurisprudence should not be underestimated, as this decision will inevitably impact the outcome of parallel scenarios across Europe where proceedings have been stayed (notably in Germany and Ireland).

The technical subject-matter relates to the use of safinamide as an “add-on therapy” to patients with Parkinson’s disease (PD) and who are already receiving conventional levodopa treatment, which has been the “gold standard” treatment for PD patients for the last 50+ years. However, as the disease state progresses, the response to levodopa doses becomes shorter and patients experience symptom recurrence at the end of the dose effect. These “OFF” periods typically become refractory to treatment and are often associated with dyskinesias. The addition of safinamide increases the timeframe during which a patient’s symptoms can be controlled (the so called “ON” time) and without increasing troublesome dyskinesia.

Newron S.p.A. was granted a European patent for this “add-on” combination therapy in 2009 but had to wait a further 6 years (until regulatory approval was granted in 2015) before being able to commercialise the therapy in Europe. The SPC Regulations were introduced to address this specific problem, namely to provide patent owners with a means for legal redress to recover loss of effective patent term when this has been due to regulatory delay. Newron therefore sought SPC protection to recover as much of this lost time patent term as possible.

By way of general background, the travaux préparatoires of the SPC Regulation confirm that the legislators intended that a wide range of medicinal inventions should be acknowledged as meritorious of SPC protection. However, with stakes so high in this niche area of patent law, all Courts must be alert to attempts to obtain undeserved patent term extension (aka “evergreening”). The various sub-sections of Article 3 of the Regulation cooperate with one another and collectively protect against this type of abuse and, as a result, it has become established primarily by way of CJEU case law that SPC protection should be denied when the “product” (for the purpose of article 3) can only be distinguished on the basis it constitutes a new formulation, a new patient category (e.g. human vs. veterinary), or a new clinical indication.

At the heart of the present case is Article 3(b) of the SPC Regulation and how one should interpret a Marketing Authorisation (MA) in order to determine what “product” has been authorised; the meaning of ‘product’ being explicitly defined in Article 1(b) of the SPC Regulation?

Article 3(b)

“A certificate shall be granted if … a valid authorisation to place the product on the market as a medicinal product has been granted in accordance with Directive 2001/83/EC or Directive 2001/82/EC, as appropriate.”

Article 1(b)

“The following definition(s) shall apply … ’product’ means the active ingredient or combination of active ingredients of a medicinal product.”

In other words, should one adopt a strict or literal approach (e.g. as a lawyer might favour), or should one read an MA through the eyes of its intended addressee (e.g. a clinician, or a Regulatory operative)?

Turning now to the European Medicines Agency (EMA) and its regulatory process. Before a manufacturer is permitted to place a product on the market in Europe, the manufacturer must first convince the EMA that its proprietary product is both safe and efficacious for a specified clinical use. If successful, the EMA will then grant the manufacturer a MA, which allows the manufacturer to place its proprietary product on the market for the particular clinical use that has been approved by the EMA. The relationship between the EMA and a MA holder doesn’t end here as grant of an MA is conditional on the MA holder maintaining quality control standards and addressing any notified “adverse event” to the satisfaction of the EMA. In this way, the EMA is able to ringfence the responsibility it places on a MA holder to those steps that are under its control, namely all aspects of manufacture and marketing, though not extending to third party use of the proprietary product that goes beyond what the EMA has approved as being safe and efficacious (as specified in the MA).

In the case of a “combination product” (consisting of two different active ingredients, A+B), EMA practice therefore gives rise to two different outcomes depending on whether the MA holder’s proprietary product contains A+B (i.e. both actives formulated in the form of a single delivery vehicle), or whether the proprietary product contains only one or A or B and to which the “other” active (i.e. B or A, respectively) is added either prior to administration or in use. To distinguish one form from the other, the EMA relies on the following terminology:

  • a “fixed-dose” combination product:
    = A+B formulated as a single delivery vehicle;
  • a “fixed” combination product:
    = A or B, which is then combined with B or A (respectively) prior to administration or in use.

Whilst this quirk of the EMA process is no doubt be well understood by regulatory affairs personnel and clinicians alike (i.e. the intended addressees of a MA), the same is not necessarily true of IP professionals. One should also be mindful that the EMA’s primary role is to safeguard the public by carefully controlling which pharmaceutical products are permitted onto the marketplace. Thus, the EMA has no nexus to patent law or SPC practice, and how the UKIPO might choose to interpret one of its MAs will be a long way down any list of priorities (should the EMA even be aware of this issue in the first place).

So, returning to the MA in question, when approving a combination product (consisting of active ingredients A & B), the EMA will always issue the corresponding MA in a form that identifies the MA holder’s proprietary product:

  • for a “fixed-dose” combination product, the MA identifies the proprietary product as:
    “A +B” [the MA itself then restricts all use of this product to the specified clinical use as approved by the EMA and as specified in the MA] 
  • for a “fixed” combination product, the MA identifies the proprietary product as:
    “A” [the MA itself then restricts all us of this product unless in combination with B and for the specified clinical use as approved by the EMA and as specified in the MA]

Indeed, this mere presentation of “form” (over substance) is what forms the crux of this appeal.

Partner Martin MacLean and Richard Davis KC argued that the term “product” as authorised by the MA must be the “combination product” as the underlying basic patent provided patent protection only for the combination product as required by article 3(a), and because the “product” must be the same for all aspects of article 3. It was further noted that the regulatory term “add-on therapy” (specified in the Summary of Product Characteristics) only made technical and practical sense in the context of a “combination product”. Finally, it was argued, as a matter of fact, Newron had sought regulatory approval from the EMA for the “combination product” and not for any single active ingredient, that no other conclusion made practical sense, that this was consistent with the EMA’s assessment of the phase 3 clinical trials data package, and that by granting Newron its MA the EMA was therefore confirming the “combination product” was both safe and efficacious. Indeed, no similar conclusion could be drawn from the clinical data package for any single active ingredient.

The intended take-home message here was that, in the case of combination products, one must be mindful that the proprietary product identified on page 1 of a MA might only be part of the product that the EMA has assessed for safety and efficacy compliance and thus only part of the product that the EMA has approved. However, from an SPC examination practice perspective, this scenario will always be easy for an Examiner to spot, for example, by reference to Form SP1 (section 6) where applicant will have identified the “product” in terms of two of more active ingredients and/ or by reference to the Summary of Product Characteristics of the MA where more than one active ingredient will be identified, and Regulatory terms like “add-on therapy” should act as a flashing beacon.

The key arguments from the respondent, the UK Intellectual Property Office (UKIPO), were that, since the MA is a legal document, a strict legal approach should be followed, and the “product” must therefore be “A” (safinamide alone) as per page 1 of the MA. It is true that “safinamide” is the only active ingredient explicitly identified on page 1 of the MA, and that one has to read on to the “Summary of Product Characteristics” before one sees any mention of a second “active ingredient”, but as noted above this shouldn’t cause any impediment.  The UKIPO also presented a policy-type defence asserting that the MA must be read in a way that allows an Examiner to conclude a swift and simple answer, arguing that any form of detailed review of a MA was inconsistent with what the legislators had intended and in any case was inappropriate due to insufficient resource/ regulatory expertise at the UKIPO.

Partner Martin MacLean and Richard Davis KC argued that, both from a practical and factual point of view, the UKIPO conclusion must be incorrect if for no other reason than because “X” (safinamide) alone had no recognised clinical efficiency (and certainly no regulatory approval). This only left levodopa, and it would be nonsense to consider this as “product” authorised Newron’s MA. Thus, it was argued, the product authorised by the EMA could only be the “combination product”.

It was further noted that, had the combination product in question been a “fixed-dose” combination product, the UKIPO would likely have granted SPC protection for this product at an early stage in the examination process. Thus, to deny Newron SPC protection for their “fixed” combination product would amount to an arbitrary discrimination based purely on form over substance (i.e. the form in which the same active ingredients are presented), and for which no legal basis exists.

We await the Court of Appeal’s decision in earnest.