Originally posted on IPKat
Indeed, the problem of how to define cells goes far beyond the field of IP, and is in fact something which immunologists have been grappling with since the field began. Within immunology, T cells have represented a particularly complex group of cells to characterise, with scientists constantly grappling with the challenge of defining an ever-increasing number of T cell subtypes. The publication of a new consensus statement in Nature Reviews Immunology is the latest attempt of the field to standardise T cell definitions (Masopust et al.). The authors propose a new modular nomenclature for T cell subsets, to aid transparency and clarity of communication in the field. With T cells also representing the most clinically significant cell therapy products, what is the impact of these new definitions for IP?
T cell heterogeneity and cell therapy
The history of T cell biology is a story of constant expansion and increasing complexity. In the 1960s, lymphocytes were simply split into B and T cells. Today, T cells are known to represent a highly diverse family, primarily divided into CD4+ helper T cells, which differentiate into specialised subsets like Th1, Th2, Th17, and T-follicular helper (TfH) cells to coordinate immune responses, and CD8+ cytotoxic T cells that specialise in the direct destruction of virally infected or malignant cells. This system also includes regulatory T cells (Tregs) that prevent overactive immunity and autoimmunity, as well as “unconventional” T cells, such as γδT cells and Natural Killer T (NKT) cells, at the intersection of innate and adaptive immunity.
The different types of T cells are identified and classified using flow cytometry. This involves labelling cells with fluorescent antibodies that bind to specific cell markers and then measuring the intensity of the fluorescent signal from each cell in the population to identify subsets of cells expressing the same markers.
For cell therapy, different T cell subsets represent distinct therapeutic opportunities. Conventional CD8+ cytotoxic T cells are used for conventional CAR-T cell therapies for cancer, whilst CAR-Tregs are being developed for the treatment of autoimmune diseases and organ transplant rejection (Quell Therapeutics/AstraZeneca, Sonoma Bio, GentiBio) and the naturally tissue-resident γδT cells are being investigated for the treatment of solid tumours (GammaDelta Therapeutics/Takeda, Adicet Bio, In8bio).
An extra layer of complexity: T cell differentiation
T cells are classified not only according to their functional lineage but also by the differentiation state. T cells begin as naïve T cells (TN) which have not yet encountered their specific antigen and express markers such as CD45RA and CCR7. Upon activation, naïve T cells undergo a process of progressive differentiation into increasingly specialised subsets, moving from stem cell memory T cells (TSCM), which possess high self-renewal capacity, to central memory T cells (TCM) that home to secondary lymphoid organs, and then to effector memory T cells (TEM) that patrol peripheral tissues, and then to the most terminally differentiated stage, activated T cells (TEFF). Under conditions of persistent antigen exposure such as chronic infection or cancer, T cells can also diverge into a distinct exhaustion (TEX) lineage rather than forming functional memory.
Differentiation state also matters for cell therapy. Cell therapies enriched with younger, less differentiated T cells (TSCM and TCM) correlate with better expansion and longer persistence in the patient. These cells act as a reservoir, continuously generating new effector cells to fight the tumour over months or years. By contrast, if the starting material or the final product is dominated by exhausted T cells (TTEX), the therapy is likely to fail. These cells may kill some tumour cells initially but will quickly die off. Differentiation state also impacts the likelihood of toxicity. Highly differentiated TEFF cells release huge amounts of cytokines rapidly, increasing the risk of severe Cytokine Release Syndrome (CRS) compared to the slower, more controlled expansion of TSCM cells.
A crisis in T cell characterisation
The authors of the new nomenclature identify a crisis of descriptive inadequacy in T cell characterisation and definitions. The proposal notes that T cell naming has historically relied on a limited vocabulary of “all-encompassing and tidy subsets” that forced researchers into an ad hoc expansion of nomenclature. According to the authors, labels like TEM or TCM have become amorphous and often carry unintended implications, with the old system providing conceptual and verbal simplicity at the cost of biological accuracy.
The problem of correctly classifying T cells has recently become more acute with the rise of sophisticated technologies such as single-cell RNA-seq. More and more overlap between different T cell categories has been discovered. Exhausted T cells and TfH cells, for example, share many of the same markers. Despite having opposite functions, Th17 and Tregs can be difficult to distinguish. The historical use of mouse models in the field of immunology has made things even worse, given the significant evolutionary divergence between mouse and human T cell populations.
The inherent fuzziness of cell definitions also represents a challenge for IP, where we prefer to use words with clear and precise definitions. Defining a cell type incorrectly in a claim carries the risk that the eventual clinical product may fall outside the specified markers. Additionally, a field of rapidly shifting scientific understanding and evolving terminology means that a definition used in an early-stage patent filing might quickly become obsolete or incorrect and/or lead to insufficiency issues. For example, a broad definition of a cell therapy product may be challenged for lack of sufficiency if it is later determined that its functional effects require a subset of cells not defined in the original patent, or because the cell population was incorrectly defined. Additionally, insufficiency or lack of clarity may arise from claiming a specific subtype of cell but with data that does not actually establish the cell as being of that subtype.
New system of T cell definitions
The proposed new modular nomenclature aims to take account of the combinatorial complexity in T cell subsets, with a focus on five parameters: lineage, function, migration, and differentiation state, with an optional descriptor for antigen status. The new nomenclature provides detailed standards and definitions for various CD4 and CD8 lineages. The new syntax is further designed to allow for refined specificity in T cell classification. If a claim of tissue residence is desired, “R” is appended as a subscript to “D” (DR). Differentiation states are denoted by “N” (Naïve), “A” (Activated), “M” (Memory), “X” (Exhausted), and “G” (Anergic), with further subsets also defined.
The authors anticipate that this shift in naming should directly influence the design and interpretation of experiments, moving cellular immunology away from assigning cells into a few rigid boxes and towards embracing high-dimensional single-cell data. Finally, the authors note that whilst some of the new terms “are more difficult to verbalize than conventional nomenclature, […] this seems to be a reasonable price for increasing the precision of our language“. A sentiment we are sure will resonate with patent attorneys.
The challenges and opportunities for IP
A new, more precise way of defining T cells is a welcome step forward from an IP point of view. After all, patents also rely on “transparency” and “clear communication”, the two goals cited by the authors of the new nomenclature. However, the process of change in definitions creates problems of its own if existing patents and applications are acknowledged to be using outdated “amorphous” definitions. The consensus statement could arguably give rise to insufficiency or clarity objections against existing T cell definitions based on “idealized subsets” that don’t really exist or are unclear.
We are also left with the question of whether the definitions provided in the paper are now the “official” definitions of these terms in the art, and whether information in the description of a patent may override these definitions (G 1/24). The authors of the consensus statement are additionally expecting a proliferation of new definitions that can now be fit into the new framework and that the system will be applied to cell types other than T cells. Patent attorneys operating in any field of cell therapy should take note.
One strategy for ameliorating the risks is to align IP and regulatory definitions of the product (Evolve Insights). In a field of fluid biological definitions, the characteristics of a product that are likely to provide the most protection and remain meaningful and relevant are likely to be those that are used to define the product for the International Nonproprietary Name (INN) in the Release Criteria and/or on the eventual product label. Additionally, including sufficient functional definitions can help secure against the risk of defining a product too narrowly using criteria that become redundant later on. Indeed, for cell therapy products, INNs also are generally based on functional characteristics as well as cell markers.
Analysis
The remarkable complexity of the immune system means that our definitions of its components will always be challenging. This recent effort to standardise the lexicon of T cell biology also highlights just how much definitions in the field rely on scientific consensus. Within cell therapy, and biotech more generally, words may rapidly change their meaning and IP strategy and patent drafting needs to take account of this and mitigate the risks as far as possible. Success in the cell therapy space requires a strategy that facilitates a flexible approach to defining the product, with drafts that include sufficient alternative wording and backup positions to define the product both structurally and functionally.
Author: Rose Hughes
Rose is a biotech and pharmaceutical patent specialist with over a decade of experience in intellectual property. Rose is a patent attorney at Evolve, where she leverages our unique fractional in-house model to provide clients with deep patent law expertise combined with the strategic commercial oversight typically associated with senior in-house counsel.
With a PhD in Immunology from UCL, Rose applies her technical background to complex innovations in biologics, cell and gene therapies, and the rapidly emerging field of AI-assisted drug development. Previously, Rose held the role of Director. Patents at AstraZeneca, where she was responsible for global IP portfolios and IP strategy at every stage of the pharmaceutical pipeline, from platform development and on-market commercialization to SPCs and patent term extensions.
A recognized thought leader in the field, Rose has been a regular contributor to IPKat since 2018, offering practical insights into European patent law developments. She is also a frequent speaker on the epi podcast, a guest lecturer for the Brunel University IP law Postgrad Certificate, and a contributing author to published books A User’s Guide to Intellectual Property in Life Sciences (2021) and Developments and Directions in Intellectual Property Law (2023).
