In this article, first published in the November edition of Intellectual Property Magazine, Stephen Bennett and Mary Foord-Weston examine how new therapies for cancer treatment are challenging patent law. The authors discuss protecting IP in individual medicine, defining the product, process claims, dosage regimen claims and what’s next for adoptice T cell therapies
With two products being recommended for marketing authorisations in the EU at the end of June, followed by one of the fastest funding approvals in the NHS’s history, adoptive T cell (“ATC”) therapies have hit the headlines in recent months. Frequently referred to as “game changers”, these new therapies promise to radically change cancer treatment and have already demonstrated the ability to produce durable remissions in patients whose disease has proved resistant to conventional treatment. IP practitioners working in the pharmaceutical sector can increasingly expect to encounter T cell therapies in the near future, as these treatments reach the market and competing companies jostle to position themselves as industry leaders.
The growing maze of overlapping patents, the prevalence of collaboration and licensing agreements and the ongoing involvement of academic institutions means that there is likely to be litigation in Europe in the coming years, as has already been the case in the USA .
We explore what makes T cell therapies different to previous cancer drugs and how the departure from small molecule pharmaceuticals towards cell-based therapies blurs the line between patient and medicine. This is likely to place pressures on the existing IP system as it struggles to cope with the pace of change in personalised medicines.
What is adoptive T cell Therapy?
T cells play a number of vital roles in our immune system, including identifying and killing our own damaged or diseased cells. However, in cancer, mutations arise that allow tumour cells to evade detection. ATC technology combats these techniques of evasion by giving T cells engineered receptors which enable them to detect and destroy tumour cells.
The first ATC therapies that have reached the market are chimeric antigen receptor T cell (“CAR-T”) therapies, though other types of ATC (e.g. T Cell Receptor (“TCR“)) have produced promising results in vitro and in vivo and are in clinical trials. Both CAR-T and TCR treatments involve the extraction and modification of the patient’s T cells, introducing DNA coding for an engineered receptor, which is expressed on the cell’s surface. In CAR-T, this “chimeric” receptor combines a domain derived from an antibody with internal regions from the T cell signalling complex. The modified T cell population is expanded before the modified cells are infused back into the patient, where they are now equipped to seek out the cancer cells and kill them.
Both of the CAR-T therapies that have received marketing approval in the USA and EU are “autologous” therapies, meaning that the patient’s own T cells are used in the treatment. The process takes several weeks and, in the United States, costs hundreds of thousands of dollars per patient. Some companies are working on “off-the-shelf” or “allogenic” therapies that use donor CAR-T cells and would allow the treatments to be made available more quickly and cheaply.
What makes ATC therapies so different to existing cancer treatments?
Traditional chemotherapies work by killing actively dividing cells. While this has the effect of targeting cancer cells it can also attack bone marrow, hair and gut linings, leading to a plethora of unpleasant side effects. Oncology research has worked towards producing drugs with greater specificity – leading to some small molecule drugs that inhibit the activity of mutated proteins produced by specific cancer-causing “oncogenes”. Immunotherapy too has been around for decades. Antibody therapies indicated for the treatment of cancer, such as MabThera® and Herceptin®, reached blockbuster status in the early 21st century, with both remaining amongst the top ten selling pharmaceuticals globally in 2017.
In all of these technologies, mass production is possible, and there are well-understood ways to secure patent protection for compounds and biologics, their methods of production and dosage regimens. The key difference between conventional drugs and ATC therapies is that in the latter, each patient receives a treatment engineered specifically for them using their own immune cells, generating ambiguity around what the “drug” really is.
Protecting IP in Individual Medicine
It is usual for the inventor of a pharmaceutical to seek to protect their invention with patents covering products, methods and processes. These might include claims covering the structural formula of the chemical compound or a series of DNA or amino acid sequences representing a biologic drug. Medical use patents may claim the use of the compound for treatment of a specific disease or a dosage regimen. Patents are also available covering manufacturing techniques used in the production of the drug. Most pharmaceutical products will be protected by a number of patents combining some or all of these claim types.
Defining the “product”
Some academic and industry commentators have suggested that the current IP system is ill-equipped to provide predictable protection for ATCs . The fact that the treatment administered to the patient is unique in each instance makes the “product” hard to define using structural formulae or DNA sequences. If the engineered cell itself is considered to be the medicinal product then the active substance will be different every time and will be derived directly from the patient. However, this has not prevented a number of applicants from seeking to claim the modified cell, engineered to express the receptor, via product claims. Other applications have avoided claiming the manipulated cell and have focused their attention on the receptor itself, or to its component parts, by setting out the DNA and amino acid sequences encoding these. Other product claims relate to the viral vectors used to insert the DNA encoding the receptor into the modified T cell, or special equipment used in the process.
It may be that obtaining a patent claiming the manipulated cell as the medicinal product is possible but that the real test will arise at the point of enforcement. Proving infringement is likely to provide some new challenges, not least because any potentially infringing “product” will be made up of the patient’s cells. If testing is needed to check whether they fall under the claims in the patent, that will cause difficulties not encountered with mass-produced medicines.
The fact that the clinical application of these immunotherapies is still in its nascent stages means that, at least in the short term, competition for patent-holders is likely to come not from generic companies but from other innovator companies and academic institutions. Unlike with a small molecule or biologic drug, we are unlikely to see “generics” or “biosimilars” in the same way. In light of this, in possible future litigation we may see fewer injunctions and more frequently the negotiation of licences and royalty payments.
Process claims are likely to be more important in protecting these personalised medicines. Any process by which the manufacturing process can be made more efficient, make a better product or do it more cheaply is likely to provide competitive advantages. However, companies should still consider potential challenges around enforcement. Steps relating to manipulation and processing of the cells are likely to take place in a number of different countries, particularly as manufacturing processes are scaled up. In principle, under UK law, the use in the UK of a product obtained directly by a patented process could result in a finding of direct infringement, even if the process is carried out in a different jurisdiction. However, it is not clear what the position would be where a number of distinct steps are involved, potentially covered by claims in multiple patents, or where the definition of the final “product” is unclear or disputed. Demonstrating that infringing processes are being carried out in other jurisdictions is a potentially difficult and costly exercise and patent applicants will need to construct their process claims carefully.
Dosage regimen claims
Dosage regimen claims are a popular feature of many patent portfolios, protecting novel ways of administering the treatment for optimal results. However, obtaining patents for dosage regimens in cellular therapies is likely to be challenging. At present, patients receive a one-off infusion of cells in suspension and the cell density of each infusion can vary hugely in each case, depending on how the population of cells has expanded in vitro. As CAR-T therapies advance, it may be that we see new dosing methods, such as multiple, smaller infusions to reduce side effects, or dosage regimens for drugs administered in combination with the modified cells. These might prove more amenable to dosage regimen patents but claims will need to be constructed to reflect the fact that proving infringement by testing the cell density of each individual batch of cells is not practicable.
What’s next for ATC therapies?
While cellular immunotherapies are drawing public attention and are already demonstrating remarkable effects, they are still in their relative infancy. Researchers are working on a variety of mechanisms to minimise side effects, as well as striving to demonstrate results for solid cancers. Innovations in the field are likely to make these treatments available for a wider range of patients and offer valuable patenting opportunities.
At present, the side effects associated with these therapies, as well as the cost per patient, mean that they are used only as a last resort. A number of patients receiving cell therapy experience cytokine release syndrome (“CRS”), a dangerous side effect whereby the immune system floods the bloodstream with proteins called cytokines, which produce inflammation and can cause fevers & cardiac arrhythmia. Alongside treatments that reduce the effects of CRS, the development of more specific ATC therapies is likely to be a major area for innovation. Safety mechanisms will include “off-switches” and co-receptors that will limit the activity of the engineered receptor to certain tissue environments or cell types. Likewise, we can expect to see patents for combination therapies that combine the administration of chemotherapeutic drugs with T cell therapies to maximise their chances of success.
The ATC field is full of exciting opportunities and we can expect to witness remarkable progress in the coming years as these personalised therapies are applied to treat a wider range of cancers and other diseases, and are made safer and more effective. The huge interest in these drugs and their potential to become blockbuster successes like other immunotherapies before them has sparked a charge to obtain valuable IP rights in this area. But as patent applicants strive to protect their innovations in this multi-billion dollar industry, they are entering murky and uncharted waters. As the line between medicinal product and patient is increasingly blurred, the European IP system is likely to need to adapt to keep up.
 e.g. Kite Pharma, Inc. v Sloan-Kettering Institute of Cancer Research
 E.g. http://www.managingip.com/Article/3826939/Pharmaceutical-firms-reveal-IP-challenges-in-personalised-medicine.html; Knowles, L.; Luth, W. & Bubela, T 2017. Paving the road to personalized medicine: recommendations on regulatory, intellectual property and reimbursement challenges. Journal of Law and the Biosciences, 453-506