The challenges of patenting cell therapies

The use of living cells as therapeutic agents is a revolutionary step forward, often said to be the next major development in human medicine. Cell therapies present unique therapeutic opportunities and differ significantly from conventional small molecule therapies, and also more complex biologics, in many respects: in development, production, mechanism of action, regulation, and in some cases even the ability to be copied.

While the science develops and the regulatory framework adapts to these developments, the European patent and supplementary protection certificate (SPC) framework does not change each time a new technology is established. Therefore, careful thought must be given to the strategies employed to protect cell therapies effectively, using a combination of patents, SPCs and regulatory exclusivities, to ensure that the very significant investment made in the development of these therapies is adequately compensated.

In 2009 the European Medicines Agency (EMA) approved its first cell therapy: TiGenix’s Chondrocelect, comprising autologous cartilage cells expanded ex vivo, to treat knee cartilage defects. Since then, several further cell therapies have been approved: Genzyme’s MACI and Dendreon’s Provenge, in 2013; Chiesi’s Holoclar in 2015; and GSK’s Strimvelis and MolMed’s Zalmoxis in 2016. The first stem cell therapy, Holoclar, was approved in February 2015, comprising corneal epithelial cells containing stem cells for the repair of corneal injury. The first allogeneic (donor) cell therapy, Zalmoxis, comprising genetically modified donor T cells, was approved earlier this year as an adjunct to haematopoietic stem cell (HSC) transplantation of patients with high-risk haematological malignancies.

There are hundreds of cell therapies in development, many already in the clinic, testing a range of stem cells and somatic (differentiated) cells for regenerative and non-regenerative therapies, including mesenchymal, cardiac and neural stem cells, induced pluripotent stem cell (iPSC)-derived cells, hepatocytes, T cells and chimeric antigen receptor (CAR) T cells. Therefore, it vital that IP practitioners in this area have a strategy in place to maximise the exclusivity of these products.

“SPCs have been granted in a number of countries for authorised cell therapies, but variations in the practices of national patent offices are visible.”

Product characterisation

A challenge for cell therapies is characterising the product. This cuts across the regulatory, patent and SPC considerations. Unlike a small molecule that can be defined exactly by its chemical structure, or even a biologic that can be largely defined by its sequence and glycosylation pattern, a cell is a complex living entity that responds to external signals.

From the regulatory perspective, the EMA requires validation of numerous characteristics of the cells, their source, and production process to ensure a consistent and reproducible final product. The patent portfolio surrounding a product should ideally support claims that closely define the product that is ultimately authorised. This may not be the same as the definition in the earliest patent filings. A close agreement between the authorised product definition and patent claims should also simplify obtaining an SPC for the authorised product.

Patentability

The majority of cells are patentable subject matter in Europe. Claims to human cells per se, medical uses of cells, formulations and production methods can all be obtained.

The European biotechnology directive (98/44/EC) sets out that “an element isolated from the human body or otherwise produced is not excludedfrom patentability”.

This is law in each country of the EU and has been incorporated into the European Patent Convention, even though the European Patent Office (EPO) is not strictly bound by the biotechnology directive.

The patentability of cells is therefore assessed in the same way as any other invention. For a patent to be granted, the cells must be novel, inventive and industrially applicable.

European patent law does not contain any specific references to the patenting of human embryonic stem cells, but some provisions have an indirect effect on the patentability of these cells. In particular, the biotechnology directive prohibits patenting “uses of human embryos for industrial or commercial purposes”. A detailed review of the law surrounding this provision is outside the scope of this overview, but a very simple summary is that the exclusion from patentability is narrow, and isolated human cells (including stem cells) can be patented, except for human pluripotent cell cases having a filing date before June 2003.

Drafting, prosecution and defence at the EPO

A challenge for patent applicants (and, in opposition proceedings, patentees) in this area is proving that a claimed cell or cell population is novel, not merely a new characterisation of a previously known cell or population. A common approach is to characterise the claimed cells by positive and negative cell-surface markers. However, the prior art may not test the same combination of markers, so objections can remain regarding whether the cell or population is actually new. What exactly is meant by “positive” and “negative” markers may also be relevant, and should be defined carefully in the specification.

To overcome such objections, the patentee may need to conduct experiments to confirm the novelty of the claimed cells. Planning and including these experiments in the patent specification can simplify prosecution and provide a stronger patent.

Innovation capture

The emerging nature of cell therapies requires much innovation, which can of course be protected by patents. In addition to patents on cells themselves and their medical uses, thought should be given to protecting the technologies around the scale-up of production, methods of manufacturing and verifying, formulating the cells to maximise shelf-life, and delivery devices.

Regulatory process and data protection

Cell therapies are typically classified by the EMA as “advanced therapy medicinal products” (ATMPs). The approval of these products in the EU is centralised through the EMA and cannot be assessed by individual countries’ regulatory bodies. The EMA’s Committee for Advanced Therapies assesses cell therapies and prepares a draft opinion on their quality, safety and efficacy for consideration by the Committee for Medicinal Products for Human Use, which in turn adopts an opinion recommending (or not) authorisation by the European Commission.

Once the product is approved, the well-known ‘8+2+1’ years of protection apply, where a biosimilar applicant is not able to make use of the reference product’s data (to file an abridged application for authorisation) for the first eight years after authorisation, and can make an abridged application but will not be granted authorisation for the next two years. An additional year of exclusivity is provided if a new indication is authorised by the innovator within the first eight years and brings significant clinical benefit over existing therapies.

The first cell therapy under this framework was approved in 2009 (and has recently been discontinued), so there is little real world guidance on how this scheme will work in practice for cell therapies.

However, for some cell therapies, it is conceivable that it may not be possible to demonstrate that a proposed biosimilar product has biological equivalence to the reference product, which is required to make use of the reference product’s regulatory dossier. Therefore, follow-on products may be forced to submit their own complete dossier. This could mean that a competitor comes to the market earlier, because it does not have the ten-year wait, but must invest much more to achieve marketing authorisation and is in effect providing a new product, not a biosimilar.

In this scenario, the value of patents broad enough to cover follow-on (not necessarily identical) products is perhaps enhanced. Even if a competitor develops its own product and submits its own regulatory dossier, patent claims can prevent that competitor from reaching the market, or generate a royalty for the patentee. The patent portfolio should be designed to have such—relatively broad—claims.

Thought should also be given to the nature of the product and the barriers to entry for any competitor, for example how in practical terms would a biosimilar allogeneic product provide cells that are biologically equivalent to the reference product? Or for an autologous cell product, how would the follow-on producer gain market penetration?

For products granted an orphan (rare disease) designation, there is a ten-year period of market exclusivity, in which no marketing authorisation application shall be accepted for the same therapeutic indication in respect of a similar medicinal product. This differs significantly from the ‘8+2+1’ scheme, because it prevents any similar products from reaching the market, and is a powerful tool for the innovator. This protection is extended by a further two years upon completion of an agreed paediatric investigation plan (PIP). Zalmoxis, Strimvelis and Holoclar all hold orphan designations.

SPCs

Cell therapies are approved under Directive 2001/83/EC relating to medicinal products for human use. A therapy that is protected by a patent will therefore be eligible for an SPC, which extends the term of protection for the product by up to five years (plus an additional six months upon completion of paediatric studies, not available for orphan designations).

Development of cell therapies is often lengthy, so SPCs on cell therapies can be expected to be maximum term. These will be extremely valuable, in particular when a biosimilar of the cell therapy is possible but perhaps also in other situations, depending on the scope of the SPC. The SPC strategy should be considered during prosecution of the patent portfolio, to ensure that patents are in place with suitable claims upon which to base the SPC.

Is the product protected by the patent?

A key issue for SPCs on cell therapies is likely to be the requirement in article 3(a) of the SPC Regulation (No. 469/2009) for the product to be “protected by a basic patent in force”. The interpretation of article 3(a) has been a rich source of litigation and referrals to the Court of Justice of the European Union (CJEU) on small molecules and antibodies, but there has not yet been a referral on cell therapy products.

Significantly, the requirement for the patent to “protect” the authorised product is not an infringement test, but requires that the wording of the claims identifies or specifies the product. For functionally-defined claims, they must relate—implicitly but necessarily and specifically—to the active ingredient.

SPCs have been granted in a number of countries for authorised cell therapies, but variations in the practices of national patent offices are visible and cell therapy SPCs have been refused based on failure to meet the requirement of article 3(a). To minimise the possibility of article 3(a) posing a problem to obtaining SPCs, at least one claim in the designated basic patent should ideally be immediately recognisable as the cell or population of cells that are defined in the authorised summary of product characteristics. Therefore, claims that narrowly define the product, even “picture claims”, may be desirable.

Scope of the SPC

Article 4 of the SPC regulation sets out that an SPC shall extend only to the authorised product, within the limits of the protection conferred by the basic patent. The CJEU has held (in a small molecule case) that SPCs are capable of covering the product in any form enjoying protection of the basic patent. What this means with respect to biologics and cell therapies is not clear, in particular how much variation (if any) from the actual authorised product is protected.

Some guidance on the scope of a biologic SPC in Europe has been provided by the highest court of the European Free Trade Agreement (EFTA) in a 2015 case (Pharmaq v Intervet International) relating to fish vaccines. The court held that the scope of an SPC extends to a strain covered by the basic patent but which is not referred to in the marketing authorisation, if the specific strain constitutes “the same active ingredient” as the authorised product. What is meant by “the same” is open to interpretation and will likely lead to further referrals to the CJEU. The EFTA court also commented on the potential invalidity of SPCs granted with product definitions that are broader than the marketing authorisation.

Careful thought should therefore be given to the choice of basic patent and its scope, in addition to the definition of the product in SPCs for cell therapies.

A combination of patents, SPCs and regulatory exclusivities should be considered carefully, to maximise the exclusivity available for cell therapies. Regulatory and patent/SPC teams should work together to create a holistic strategy, giving particular thought to the opportunities and challenges presented by the unique nature of these products.

Glyn Truscott is a partner at  Elkington + Fife. He can be contacted at:  glyn.truscott@elkfife.com