Cell therapies and their methods of manufacture are often technically complex inventions, typically having prolonged and iterative development processes. Securing patent protection for such inventions often presents intricate and subject specific patentability issues, providing unique challenges in the pursuit of robust protection.
Here, we take a closer look at a selection of decisions from 2025 that highlight the recent patentability and procedural issues seen in the field of cell-based therapeutics.
Added Subject Matter – Article 123(2) EPC
T 0250/24 concerned a patent directed towards a lentiviral vector for use in a CAR-T cell therapy. The claimed vector required several nucleic acid components, including a region encoding chimeric antigen receptor comprising: (a) an scFv that binds B cell maturation antigen (BCMA); (b) a CD8alpha hinge region; (c) a CD8alpha transmembrane domain; (d) a CD137 co-stimulatory signaling domain; and (e) a CD3zeta primary signaling domain." Despite the opponents’ providing arguments to the contrary, the Opposition Division held that granted claim 1 as granted did not add subject matter beyond the content of the application as filed.
However, the Board of Appeal disagreed and held that claim 1 required multiple selections from lists, thereby creating an impermissible intermediate generalization. Specifically, the Board of Appeal held that the following features recited in claim 1 required selection from lists: “(a) an scFv that binds B cell maturation antigen (BCMA)”; "(b) a CD8alpha hinge region"; and "(d) a CD137 co-stimulatory signaling domain".
Regarding feature “(a)…”, the board held that BCMA must be selected as the scFv target from the list of antigens provided in claim 2 of the earlier application as filed. The Board also contended that the examples cannot provide a specific pointer to BCMA as a target antigen, because they disclose three different alternative target antigens, namely CD19 (Examples 1, 5), kLC (Examples 1, 3, 4, 6, 7), and BCMA (Example 8).
Regarding feature “(b)…”, the board held that although claim 14 of the earlier application as filed requires the presence of the hinge region of CD8alpha, because claim 14 was dependent on claim 13, and thus claims 1 to 12, this specific embodiment supposedly required selection from a range of options resulting from the various dependencies of claim 13.
Regarding feature “(d)…”, the board held that although claim 12 of the earlier application as filed requires the presence of a CD137 co-stimulatory signaling domain, the claimed domain supposedly requires selection from the three alternatives disclosed in claims 10 to 12 (or claim 9) of the earlier application as filed.
Further to the above, the Board of Appeal held Example 8 (in combination with Example 1) failed to provide a pointer to the claimed combination because claim 1 omitted further the features present in the exemplified lentiviral construct. The Board considered that if Example 8 were considered as basis for the features of claim 1, this would represent an intermediate generalisation falling between the lentivirus vector disclosed in Example 8 (in combination with Example 1) and the lentiviral vectors described elsewhere in the description or the claims of the earlier application as filed.
Consequently, the Board of Appeal held that the subject matter of claim 1 extends beyond the content of the earlier application as filed and, by the same reasoning, the application as filed.
T 0868/23 concerned a patent directed towards a process for manufacturing T cell therapies. Claim 1 of the Main Request recited an in vitro method for manufacturing a T cell therapeutic comprising: a) providing a population of human peripheral blood mononuclear cells (PBMCs) that comprise T cells and antigen presenting cells (APCs); b) culturing the population of PBMCs for 16 hours to 32 hours prior to transduction in a cell culture medium comprising, inter alia, interleukin-2 (IL-2); c) transducing the population of PBMCs with a lentiviral vector encoding a CAR; and d) culturing the population of PBMCs in a cell growth medium to expand the transduced T cells; thereby manufacturing T cell therapeutics.
The primary issue dealt with by the Board of Appeal was whether the subject matter defined by claim 1 extended beyond the content of the application as filed. Specifically, it was to be decided whether a step comprising the combination of culturing the PBMCs for “16 hours to 32 hours” in a cell culture medium comprising, among other things, “IL-2” was directly and unambiguously disclosed in the application as filed.
The feature "16 hours to 32 hours" activation time in step b) of claim 1 was disclosed in claim 31 of the application as filed. However, alternative ranges were mentioned in claims 28, 30, 32 and 33 of the application as filed. The Board of Appeal therefore concluded that there was no indication or pointer towards “16 hours to 32 hours” being preferred, and therefore recital of this feature supposedly constituted a selection from a list of equally preferred alternatives.
Regarding the use of IL-2 in the cell culture medium, the Board of Appeal decided that there was also no specific disclosure of such use provided in the detailed description of the application as filed. The detailed description taught that “the cellular compositions may further be cultured in the presence of one or more additional growth factors or cytokines, e.g., IL-2, IL7, and/or IL-15, or any suitable combination thereof”. Accordingly, IL-2 is one component of a list of at least three alternatives. The Board concluded that there was no pointer to the specific use of IL-2 over and above these other cytokines. The specific use of IL-2 in culture media was disclosed elsewhere in the description, but only in the context of a T cell growth medium (TCGM), which was not specified in the claims. Examples 1 and 2 of the application as filed use media comprising IL-2 but in the context of a TCGM that contains a specific set of activating factors at defined concentrations. These features were similarly not defined in the claims.
The Board thus concluded that at least the features "16 hours to 32 hours" and "interleukin-2 (IL-2)" in claim 1 of the main request had been selected from different lists of equally preferred alternative in the absence of a pointer.
T 0250/24 and T 0868/23 are further examples of the hardline approach the EPO takes regarding application of the gold standard with respect to complex technical inventions, such as cell therapy inventions. Indeed, these decisions provide a yet further reminder of the importance of including explicit basis for preferred combinations of features when drafting patent applications and, where possible, avoiding reciting features in lists of equally preferred alternatives. It is thus of particular importance that embodiments of interest should be explicitly and unambiguously defined in their entirety during the drafting process. Thought should also be given as to how the originally envisaged invention may change over the course of development, and clear basis for such embodiments included in the application as filed. An undue reliance on so-called “pointers” to preferred combinations of features should also be avoided wherever possible.
Inventive Step – Article 56 EPC
T 0936/22 related to the parent of the patent considered in T 0250/04 (see above). The parent was similarly directed to a lentiviral vector comprising a myeloproliferative sarcoma virus enhancer, negative control region deleted, and an MND promoter operably linked to a nucleic acid encoding a CAR comprising: (a) an scFv; (b) a CD8α hinge region; (c) a CD8α transmembrane domain; (d) a CD137 co-stimulatory signaling domain; and (e) a CD3ζ primary signaling domain.
Comprehensive added matter objections were not put forward under opposition or appeal; the Board of Appeal therefore focused primarily on the question of inventive step. In this respect, the subject matter of claim 1 of EP3134432 was seemingly distinguished from the closest prior art by virtue of the use of an MND promoter, whereas the vector of the prior art comprised an EF-1alpha promoter. The patentee argued that this difference provided for persistent expression of the CAR, particularly in the absence of a WPRE element which was used in the lentiviral vector disclosed in the closest prior art document. However, the board noted that the patent did not compare the claimed lentiviral construct with the lentiviral vector disclosed in the closest prior art document, and therefore from the data in the patent it could be concluded that the claimed constructs are improved in terms of persistent levels of expression of the CAR in amounts suitable to achieve a therapeutic effect or in terms of therapeutic efficacy.
In submissions provided almost two years following their reply to the statement of grounds of appeal, the patentee filed new evidence in the form of a direct comparative example which was said to show that MND-transduced CAR-T cells had a higher transduction efficiency and provided for extended anti-cancer activity in vivo. The patentee argued that the claimed invention thus represented a credible improvement over the prior art and that the objective technical problem ought to be framed accordingly. However, as this submission was provided after their reply to the grounds of appeal, and therefore represented an amendment to their appeal case, it was at the Board’s discretion whether to permit this evidence into proceedings under Article 13 RPBA. No reasons were provided by the patentee for why this evidence was submitted at this late stage of proceedings and no details were provided on how the additional experiments were performed. Accordingly, in the Boards view, admittance of the experimental data would have raised further issues that would have been detrimental to procedural economy. It was therefore decided not to admit the experimental evidence and the associated arguments into the proceedings.
In the absence of this further comparative data, the board concluded that the data in the patent failed to support the patentee’s position that the claimed lentiviral vector represents an improvement over disclosure of the closest prior art. The objective technical problem was thus defined by the Board as the provision of an alternative CAR expression vector. The Board noted that starting from the EF-1alpha promoter based vector construct of the closest prior art and faced with the objective technical problem of providing an alternative CAR expression vector, the skilled person would have consulted the literature for suitable alternative promoters and would also have been aware of those promoters already known to be effective for CAR expression in T cells and shown to be effective in vivo, such as the MND promoter. The patentee argued that the skilled person could have selected the MND promoter from the prior art but would not have contemplated to do so because there was no pointer provided in the prior art to specifically make that selection; however, because the objective technical problem was formulated as the provision of an alternative CAR expression vector, the Board were of the opinion the skilled person would have modified the lentiviral vector as used in the closest prior art in any manner within the framework of routine experimentation and arbitrary choice. The Board stated that “for applying routine measures and making arbitrary choices, the skilled person does not need any specific pointer in the closest prior art”.
Given the known utility of the MND promoter in similar contexts and the structural similarity between the CARs of the closest prior art and the claimed invention, it was held the skilled person would have considered the use of the MND promoter as an obvious and reasonable alternative to the EF-1alpha promoter. The Main Request was therefore held to lack an inventive step.
Interestingly, the patentee requested that the case be remitted to the opposition division "for discussion regarding maintenance of the patent in amended form" should the main request not be granted. The Board agreed that remittance was justified since the decision of the opposition division did not discuss maintenance of the patent in amended form. An auxiliary request had been filed during the opposition proceedings. However, in the appeal proceedings, the patentee did not pursue maintenance of the patent in amended form on the basis of that auxiliary request, nor did the patentee file any other auxiliary requests for consideration by the board; the only request presented for consideration and decision in appeal proceedings was the patent as granted. Accordingly, the board decided that there was no basis for remitting the case to the opposition division as requested by the proprietor.
T 0936/22 serves as a reminder of procedural issues that can arise as a result of the EPO’s heavily front-loaded appeal process, in which a party is required to set out their case, including all facts, evidence and arguments, from the outset. Article 13(2) RPBA dictates that a late filed amendment to a party's appeal case (such as the late filing of experimental evidence) must, as a rule, not be taken into account unless there are exceptional circumstances justified with cogent reasons. In the context of cell therapy inventions, experimental data is frequently relied upon to support the presence of an inventive step. Thus, during appeal proceedings relating to such inventions, any newly generated or newly discovered experimental data must be filed at the earliest opportunity and, if late filed, accompanied by persuasive arguments underscoring why it is late filed and why it is of prima facie relevance. For patentees, pertinent experimental data should ideally be provided in the application as filed or, where this is not possible, placed on file as soon as practicable thereafter, ideally during prosecution or first-instance proceedings where admittance of post-filed evidence is more lenient. Indeed, when dealing with biotechnological inventions more broadly, regular monitoring of newly generated data and relevant post-filled publications can ensure early knowledge of relevant facts and evidence, helping negate potential procedural headaches down the line.
T 1004/22 concerned a patent directed towards cell populations expressing markers characteristic of the pancreatic endoderm lineage, and, in particular, co-expressing PDX1 and NKX6.1, and methods for generating such cell populations. Inventive step was once again the primary substantive matter considered by the Board.
In this case, the Main Request and Auxiliary requests filed in response to the Opponent’s appeal comprised a method claim directed or generating a cell population of pancreatic endoderm lineage comprising three steps: (a) culturing a population of pluripotent stem cells; (b) differentiating the cell population of step a. into a "population of cells expressing markers characteristic of the definitive endoderm lineage" (see paragraph [0036] of the patent); and (c) differentiating the cell population into a "population of cells expressing markers characteristic of the pancreatic endoderm lineage" (see paragraph [0037] of the patent) in a medium supplemented with noggin and a particular protein kinase C (PKC) activator, such as Indolactam V (ILV).
The difference between the claimed invention and the closest prior art appeared to reside in the additional use of a PKC activator (e.g. ILV) in the noggin-containing medium used for differentiating the definitive endoderm lineage. This difference was said to result in the technical effect of improved NKX6.1 co-expression in PDX1**(+) cells, thereby generating a population of cells suitable as a source of beta-cells. The Board of Appeal thus formulated the objective technical problem as the provision of an improved method for generating a cell population of pancreatic endoderm lineage co-expressing higher levels of PDX1 and NKX6.1.
In determining obviousness, the Board of Appeal noted that a further cited document relating to differentiation of human embryonic stem cells (hESCs) into insulin secreting beta cells disclosed the screening of several compounds to identify those that increased PDX1**(+) pancreatic cells. The document disclosed that ILV resulted in up to 26.9% of PDX1**(+) cells and that of this population, 83.5% of the cells co-expressed NKX6.1.
Although the closest prior art failed to provide a pointer towards the specific use of a PKC activator in the medium, the Board concluded that a pointer was provided prompting the skilled person to look for additional factors that increase expression of pancreatic endoderm markers, particularly NKX6.1 co-expression in PDX1**(+) cells.
The Board were therefore of the opinion that, in view of the teachings of the cited prior art, the skilled person has clearly envisaged the claimed subject matter, and only routine methods are necessary to achieve the solution of the invention. Accordingly, a “try and see” situation supposedly existed, in which the concept of a "reasonable expectation of success" does not apply. It was thus held that the skilled person would have no reasons to adopt a conservative approach and would thus combine the teachings of the relevant documents to arrive at the claimed subject matter without the use of inventive skill.
The case of T 1004/22 shows that even in cases where the solution is deemed the provision of an “improvement” over the prior art, technical pointers existing in the prior art to a particular combination of features can, in some circumstances, lower the bar by which an invention is deemed obvious. Indeed, in the context of biotechnological and pharmaceutical inventions, this case shows that clear teachings in the prior art towards an invention obtainable by routine methods act shift the emphasis from whether a skilled person can foresee the invention solving a purported technical problem, to whether a skilled person would merely seek to try the invention.