The Bioindustry Association (BIA) recently published its latest report on the cell and gene therapy sector in the UK (found here). The report demonstrates that the UK is a thriving ecosystem for the development of the advanced therapies, and we have taken this opportunity to review the key technologies in this space, and discuss considerations for an effective IP strategy.
Cell and gene therapies involve using cells, or genetic material, to elicit changes in patients’ tissue, cells or DNA. These therapies may offer longer-lasting effects than traditional medicines, and have the potential to address complex diseases for which there are currently no effective treatments or cures. In recent years, there has been a steady increase in both the number of patent applications filed and patents granted, to UK based entities, related to cell and gene therapy, as shown below.
The UK is a key player in the research and development of novel cell and gene therapies, as highlighted in the BIA report. For example, in the UK:
- 47 cell and gene therapy developers have headquarters
- 23 cell and gene therapies have been approved
- 84 advanced therapies are currently in clinical development
Research interest and clinical development in this area is therefore growing. A number of treatments based on cell and gene therapy are now available to patients, with the NHS starting to deliver these potentially life-saving therapies to patients with blood cancer and some rare genetic diseases. This number is certainly set to increase, with therapies under development for conditions such as Alzheimer’s disease, Crohn’s disease and multiple sclerosis, amongst others. To tackle such a variety of disorders, multiple approaches are required, and four key technology areas that address these needs are discussed below.
CAR-T cell therapy
Chimeric antigen receptor (CAR) T cell therapy is a growing immunotherapy approach in the treatment of blood cancers. CARs are engineered synthetic receptors that function to redirect T-lymphocytes to recognise and eliminate cells expressing a specific target antigen. CAR binding to target antigens expressed on a cell’s surface results in potent T-cell activation and subsequent anti-tumour response. The ability to engineer the receptors to a specific antigen from the patient’s own tumour cells provides a patient with individualised and specialist treatment.
In the UK, there are currently three CAR-T cell therapies approved for use in the treatment of lymphoma and leukemia – Kymriah®, Yescarta® and Tecartus®. All three are targeted to cells expressing CD19, a B-lymphocyte antigen that is a biomarker for B-cell malignancies. As such there is scope for a plethora of novel targets, and interest in CAR-T cell therapy is likely to increase significantly in the future.
Compared to haematological malignancies, CAR-T cell therapy is currently limited for use in the treatment of solid tumours by the ability of CAR-T cells to traffic to and infiltrate said tumours. Alternative administration routes to infusion may result in direct delivery of CAR-T cells to disease sites. Another current limitation is the phenomenon known as antigen escape, in which CAR-T cells display partial or complete loss of target antigen expression, which has been observed in leukaemia patients receiving CD19 targeted CAR-T cell therapy. Dual targeting with a second antigen may decrease antigen escape and thus reduce the rate of disease relapse. Further, the immunosuppressive microenvironment of many cancers results in the production of tumour facilitating cytokines, chemokines, and growth factors. This results in poor T cell expansion and short-term T cell persistence. Development of CARs that are resistant to immunosuppressive factors in the hostile tumour microenvironment is crucial for overcoming this barrier to effective therapy. A need for solutions to these limitations will lead to increased research interest and clinical development for future CAR-T cell therapies.
CAR-T technology is relatively mature and there are a number of big players with strong IP portfolios in this area including Novartis, who developed Kymriah®, and Gilead/Kite Pharma who market Yescarta®. As such, the patent landscape is already crowded and rapidly expanding. Companies working in this space will therefore need to ensure that they have a clear strategy to get their therapeutic to the market whilst negotiating this crowded field. This may be achieved by negotiating licensing or cross-licensing deals, or by developing an attractive portfolio that sees them acquired by a larger pharmaceutical company.
Hematopoietic stem cell (HSC) gene therapy
Hematopoietic stem cells (HSCs) are multipotent primitive cells that can develop into all types of blood cells. Hereditary and somatic mutations in HSCs give rise to a number of disorders, including anaemia, leukaemia, lymphoma, myelodysplastic syndrome and sickle-cell disease, among others. The correction of disease-causing mutations in HSCs provides an opportunity to cure these diseases, rather than just treat symptoms.
The current typical gene therapy of haematopoietic stem cells involves isolating of HSCs from a patient, ex vivo genetic engineering to correct the mutation/faulty disease-causing gene and transplantation of the genetically modified HSCs back into the patient. Gene therapy using HSCs is a promising treatment option because of their unique differentiation and expansion capabilities, which ensure the correct transfer and expression of genes added to a small number of cells result in gene correction of much greater numbers of cells by self-renewal. Data from clinicaltrails.gov reports 428 current studies into HSC gene therapy from a range of indications. These include metabolic diseases, bleeding disorders, primary immunodeficiency diseases and infectious diseases, such as HIV/AIDS. As such the potential for this therapy is far-reaching.
The ex vivo genetic engineering method is typically achieved by retroviral transduction or CRISPR-based platforms. Lentiviral vectors allow for insertion of transgenes into the genetic material of the patient’s HSCs, whilst the CRISPR-Cas9 system creates a double strand break at a specific target DNA sequence and repairs a faulty gene through the non-homologous end joining pathway. Interest in CRISPR technology has boomed in the last 12 years. The first patent application related to CRISPR-Cas9 was filed in 2012 by UC Berkeley and University of Vienna. Since then, just over 45,000 patent applications have been filed worldwide. The technological progress afforded by advances in CRISPR-based gene editing is now having real-world applications. In 2023, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became first regulator to approve a therapy that utilises CRISPR/Cas9 technology. The treatment, Casgevy, aims to cure sickle-cell disease and beta-thalassemia. This is likely to be the first of many such treatments, although the volume of patent applications in this space highlights that competition is high.
Given the competition in this space, it is imperative to be aware of what third parties and any competitors are doing. As demonstrated in the graph above then number of granted patents in this space is increasing year on year as such the likelihood of litigation also increases. Therefore, a freedom to operate (FTO) assessment is an essential exercise in this space to ensure the any product or manufacturing processes do not infringe on any existing patents.
Regenerative cell therapy
Regenerative medicine is another important branch of cell therapy. It enables human tissues – such as muscle, skin or cartilage – to be repaired or replaced. Regenerative medicine promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. This therapy represents a move away from traditional medical treatment towards helping the body heal itself. Applications include organ transplantation which uses stem cells instead of donor organs, which are limited in supply.
Central to regenerative cell therapy are the aforementioned stem cells – cells which have the ability to differentiate into specialised cells and continuously divide to generate exact copies of themselves. The main types of stem cells include embryonic stem cells, induced pluripotent stem cells and adult stem cells. It is important to bear in mind the different patentability requirements regarding stem cells in different jurisdictions, as explored in one of our previous articles by Oliver Herd here.
Stem cell-based therapies which do not require a patient’s own stem cells to be extracted are also currently in development. These “off the shelf” cell therapies involve using genetically uniform, appropriately programmed cells, expanded from a single starting stem cell, which can be applied to multiple patients. These approaches may ultimately be used to treat a variety of diseases, including bone degeneration, organ failure, neuro-degenerative diseases such as Alzheimer’s, and chronic obstructive pulmonary disease (COPD). Given its potential in therapeutic applications, it is likely the patent landscape will see an increase in applications related to this area.
It is also important to note that inventions relating to stem cells derived from the destruction of human embryos are not patentable at the EPO. In the US, an invention derived from a natural product must be ‘markedly different’ from their natural counterpart. However, it is possible to protect methods, processes or devices used in the culture, maintenance, modification or storage of stem cells. To maximise patent protection, applications must be drafted with these considerations in mind.
AAV gene therapy
The advent of advances in gene therapy has driven the need for safe and effective gene therapy vehicles. Adeno-associated virus (AAV) vectors are currently the leading technology for gene delivery, and can be engineered for a very specific clinical indication. AAVs consist of a viral capsid composed of three viral proteins. The protein capsid contains a single-stranded DNA genome that is delivered to the host cell nucleus, and can be readily adapted for therapeutic purposes.
AAVs are attractive delivery vehicles as they are non-pathogenic, meaning they are safe and well-tolerated in humans. Indeed, the first AAV gene therapy product Glybera, was approved by the European Medicines Agency to treat lipoprotein lipase deficiency in 2012, while Luxturna was approved in the United States in 2017 to treat retinal dystrophy. There are now over 160 AAV trials registered on clinicaltrials.gov, indicating this is a rapidly growing technology.
Despite these promising advances in AAV gene therapy, some challenges remain to optimise patient safety and avoid off-target effects elsewhere in the body. For example, as AAVs occur in nature, around ~50% of the population have antibodies against these viruses. Similarly, the small genome size of the virus limits the size of the gene that can be delivered. Innovative solutions to address these challenges will increase the number of treatment options available to patients for a variety of indications. It is therefore likely that the increase in clinical trials and patent applications will continue.
Final thoughts
The cell and gene therapy sector is a fast-moving and expanding market in the UK, with many exciting innovations being developed. When considering a company’s path to market in this area, there are many factors for developing an effective IP strategy which aligns with commercial goals, such as freedom-to-operate, patentability and timing of filing patent applications. If you would like to discuss any of these please get in touch.
