Falling between the cracks: The challenges of patent strategy for stem cell therapies (T 1259/22)

Cell therapy is a highly innovative therapeutic strategy that uses living cells to combat disease. Cell therapy strategies include stem cells for tissue regeneration and repair, immune cells engineered to combat cancer and genetically edited cells for the treatment of genetic disorders. Drug products composed of populations of living cells are vastly more complex than a small molecule or even antibody therapeutic, and the field faces substantial challenges, not least of which is developing processes for manufacturing cell therapy products at scale. IP strategy for cell therapy also has unique challenges. The patent at issue in T 1259/22, although relatively old (expiring August 2024 with SPCs), nonetheless highlights some of the key challenges for cell therapy IP strategy. 

Stem cell replacement therapy for cancer patients

The patent in T 1259/22 (EP2371361) related to a cell therapy treatment for cancer patients using plerixafor. Treatment of cancers such as lymphoma and myeloma may require high doses of chemotherapy. A side effect of high doses of chemotherapy is the destruction of the patient's healthy stem cells along with the cancer.  Plerixafor (Mozobil) is used in a method of cell therapy for cancer patients in which the patient's stem cells are harvested prior to chemotherapy. The harvested cells are then transplanted back into the patient after the patient has received chemotherapy. Plerixafor is specifically used to stimulate mobilisation of the healthy stem cells from the bone marrow to the blood so that they can be easily harvested. The stem cells may also be harvested from a genetically matched healthy donor.

Cell therapy: A unique IP challenge

The unusual nature of the clinical product in cell therapy is a challenge for IP strategy. Specifically, it can be uniquely difficult to define the "product" in cell therapy. New small molecule drugs may be protected by a product claim for the chemical structure. New monoclonal antibody therapeutics may be protected by a product claim for the amino acid sequence. Further medical uses of these products may be protected by second medical use patents. In cell therapy, however, the "product" is a heterogenous population of living cells. Defining such a product in a patent claim can be difficult. 

Cells - and a cat!

In some cases, cells for use in therapy are modified to express novel proteins, e.g. chimeric antigen receptors (CARs) in CAR-T cell therapy. In these cases, the novel protein itself can be protected with a product claim, similar to a claim for an antibody. However, there are many examples of cell therapies in the clinic that use non-modified cells, including the stem cells used in the method described in the patent at issue in T 1259/22. In this case, the method involved merely harvesting stem cells from a donor and then using these cells for transplantation. How then was the cell therapy product to be defined?   

Absent clear product IP, companies developing non-modified cell therapies often seek protection for cell therapy manufacturing processes. However, patenting manufacturing processes has its own challenges. In contrast to product claims, process claims may be easier to design around and/or be more difficult to enforce. The case in T 1259/22 also illustrates another potential issue with a process-claim IP strategy for cell therapies in cases where the process involves harvesting cells from a donor. In Europe, processes involving the human or animal body may be considered surgical or medical methods. As the case in T 1259/22 exemplifies, absent a defined product in the form of a "substance or composition" having a medical use in these steps, the claimed subject matter will be considered excluded from patentability (Article 53(c) EPC). 

Legal Background: Second medical use claims 

In Europe, methods for treatment practised on the human or animal body are explicitly excluded from patentability (Article 53(c) EPC). This exclusion is intended to ensure medical professionals can treat patients without worrying about patent infringement (G 1/07). Nonetheless, to reward innovation into new therapeutics, it is possible to patent "substances or compositions for use" in a method of treatment (Article 54(4) and (5) EPC). In contrast to non-medical use claims, a second medical use claim is construed as including the functional effect of the claimed use in the form of a purpose-limited product claim. The new medical use of a known substance or composition is therefore considered novel (G 2/88, Article 54(4) and (5)). 

A key question for determining whether the use of a known product falls under the provisions of Article 54(4) and (5) EPC is whether the claimed use is "a method of treatment, surgery or diagnosis practised on the human or animal body" (see also T 0815/22, IPKat). If the use is not a therapeutic use, the use of the known product will not be considered novel. The decision in T 1259/22 considered an additional criteria for a process-limited use claim, namely that the claimed substance or composition is actually linked to the claimed therapeutic use. 

The patent (EP2371361) in T 1259/22 claimed plerixafor for use in a multi-step method of stem cell therapy comprising the separate steps of harvesting and transplanting stem cells. Plerixafor had previously been disclosed as a potential treatment of HIV. The question for the Board of Appeal was whether the claim should be considered a second medical use claim for plerixafor. Citing G02/08, the Board of Appeal confirmed that a second medical use claim may define a therapeutic use by way of a multi-step method. However, the Board of Appeal also found that, in order for such a claim to qualify as a purpose-limited product claim "the claimed substance or composition must have a treatment-related link to a medical step of the multi-step method". For the Board of Appeal, to be patentable, it is necessary for a second medical use claim to include at least one step in which the claimed substance or composition has a medical effect (r. 3.21). 

Finding a treatment-related link between the claimed composition and a claimed medical step

Claim 1 on appeal specified a method comprising: i) administering plerixafor to a subject to mobilise stem cells in said subject, ii) harvesting said stem cells, and iii) using the harvested stem cells in cell transplantation. The Board of Appeal considered each step of the claim in turn to see if there was a treatment related link between the composition and a claimed medical step. This first required assessing whether each step was in fact a medical (or surgical) step. 

Step i) comprised administering plerixafor to a subject to mobilise the subject's stem cells. The purpose of this step was to mobilise stem cells to move to the blood so that the stem cells could be harvested and used in cell transplantation. The Board of Appeal found that this first step was not a medical or surgical step. The Board of Appeal specifically rejected the patentee's argument that the use of plerixafor to mobilise the donor's stem cells might have beneficial side effects on the donor (r. 3.32).  

Step ii) comprised harvesting stem cells from the donor. The Board of Appeal agreed that this step should be considered a surgical step. However, plerixafor was not defined as having any explicit role in this step. For the Board of Appeal, the harvesting step therefore could not be considered related to a treatment effect of plerixafor (r. 3.35). The patentee argued that the mobilisation effect of plerixafor reduced surgical complication associated with the stem cell harvesting from the donor. However, the Board of Appeal rejected this argument, finding that any reduction in side effects was independent of the actual surgical step, which could take place without it. 

The final step of the method comprised using the harvested cells in cell transplantation. Whilst this step was clearly a method of treatment, plerixafor was not directly involved in the step. The Board of Appeal again concluded that this step could thus not be considered a medical use of plerixafor. Therefore, whilst plerixafor was considered "essential" for the overall method (3.39), specially for ensuring that sufficient stem cells could be harvested, the Board of Appeal found no treatment-link between plerixafor or a claimed medical or surgical step. 

The Board of Appeal concluded that whilst the multi-step method of claim 1 comprised two medical/surgical steps, the claimed compound (plerixafor) did not have any activity in relation to surgery or therapy in either of these two steps. Claim 1 was therefore found not to be a purpose-limited product claim under Article 54 (5) EPC. Given that plerixafor was known, a claim construed as plerixafor "suitable for" a use was found to lack novelty. The patent was revoked. 

Final thoughts

The patentee in T 1259/22 (Genzyme) was therefore stuck between a rock and a hard place as far as the patentability of its invention was concerned. The cell therapy product itself was difficult to define, and a process claim for the manufacturing process would have been rejected for relating to a surgical and/or medical use. However, the Board of Appeal refused to see a direct medical effect of the drug utilized in the method. A problem for the patentee was that their invention was essentially presented as a manufacturing process. The original claim, for example, did not include the step of actually using the harvested cells in transplantation. This approach interacted badly with the fact that the manufacturing step involved a surgical step practised on the human body. 

The decision in T 1259/22 is also another decision that highlights the disparity between the current direction of patent law with respect to therapeutic inventions and the supposed raison d'etre of second medical use claims, namely that of rewarding innovation into new use of known therapeutics. In the present case, in order to market plerixafor for the claimed used, it was necessary for the patentee to demonstrate the safety and efficacy of plerixafor for use in the method of stem cell therapy in the full complement of clinical trials. In this context, the Board of Appeal's insistence that the drug had no direct medical effect feels overly pedantic to say the least. 

Image credit: Midjourney

Further reading

• Substance or device - a distinction without a difference? (Dec 2018)
• Board of Appeal proposes a substantially broader definition of "substance or composition" in second medical use claiming (T 1252/20) (Feb 2024) 
• The nutritional benefits of baby formula is not a therapeutic use (T 0815/22) (Jul 2024)
• Fishy evidence: Do we have the right sufficiency standard for therapeutic use? (T 1057/22) (Aug 2024)