How will patent litigation need to change in an age of bespoke treatments for every patient?

The FDA approval of Kymriah was the first in the area of adoptive immunotherapy and chimeric antigen receptor (CAR)-modified T cells. This has been closely followed by approval for Yescarta. Companies such as Kite Pharma and Juno Therapeutics are reporting response rates of ~80 percent for treatment of blood cancers using CAR-T, and with around 300 clinical trials currently in progress it is clear that we are at the beginning of a new age in cancer therapy.

As these new treatments reach the clinic, we can expect to see an increase in patent litigation in this area. With treatments costing around $500,000 per patient, there is a lot at stake. Infringement scenarios must be considered at an early stage, as they are different from those that have been traditionally considered for patents for pharmaceutical products. This is because of the particularities of the therapeutic methods, which may involve different steps being performed in different countries. Patients’ own immune cells are isolated from their blood, processed, and returned to them, meaning that each patient is given their own bespoke therapeutic agent, not an ‘off-the-shelf’ product.

Significant method claims

‘Composition of matter’ patent claims directed to particular actives or formulations have traditionally been a priority for pharmaceutical companies. However, enforcement of product claims relating to CAR-T cells may be trickier because of the need to demonstrate that each individual batch of cells falls within the scope of the claim. There can, however, be significant value in method claims relating to methods for engineering the CAR-T cells, and methods for culturing and expanding the CAR-T cells, provided the claims are not overly complex.

Patents covering all or part of a method that becomes a de facto standard required by the FDA for approval could be especially valuable. It’s notable that both current approvals relate to blood cancers, using CAR-T cells that target CD19. The autologous cells are transformed using lentiviral vectors in both cases. Therefore, although the FDA floodgates may be considered opened to some extent, the FDA is likely to be cautious about significant step-changes, and look more favourably upon treatments that are based substantially on methods and techniques that have been previously approved. Patents relating to improvements and refinements of the processing steps should not be overlooked.

The most useful claims will define methods in such a way that all steps will be performed by the same party (i.e. there is a direct infringement). This is a particular concern in autologous CAR-T cell therapy, where different parts of the therapeutic process may be performed in different jurisdictions.For example, the patient may be in one country while their extracted cells are sent for processing at an approved facility in another country.

Some jurisdictions such as the USA would require one party to be shown to be controlling the actions of another, in order to consider there to have been an induced infringement. When drafting and prosecuting claims for CAR-T therapies attorneys should therefore consider the practicalities of how and where steps of the therapeutic process will be performed.

Current patent landscape

There are currently many patent applications directed to particular CAR constructs, and the use of CARs/CAR-T cells specific for particular target molecules. Different companies have their own proprietary CARs, with modifications in the transmembrane and endodomain co-stimulatory structures and signal peptides, in addition to the antigen-recognition regions. Both treatments so far approved by the FDA modify cells to recognise CD19, and many other groups are also using CD19 as a target. Areas of the clinical and patent landscapes are thus crowded, and companies should consider their freedom to operate at the early stages of CAR design and pre-clinical development.

With knowledge of potential freedom to operate issue, it is possible to take preventative action.  For example, changes could be made to the CAR construct or treatment to work around a patent right, steps taken to prevent a patent from being granted, or action taken to try to force an applicant/proprietor to amend the patent claims to reduce the risk. Many patent offices around the world enable the filing of observations against a patent application during the examination phase, providing a potential infringer a cost-effective way to take action. Any action taken should be considered on a global scale, as proceedings in one jurisdiction can have significant implications on proceedings in others.

Developments on the horizon

A current limitation to CAR-T technology is the per-patient treatment cost. Kymriah and Yescarta use autologous T cells, which are taken from the patient to be treated and modified to express CARs. Many companies are now generating ‘banks’ of immune cells, containing cells from donors with a variety of different HLA types that can be matched to a patient, which would provide for the generation of ‘off-the-shelf’ allogeneic CAR-T cells.

These first FDA approvals relate to CARs with relatively simple structures, and developments in CAR-T technology to date have focused on global changes to the CAR construct. In the coming years we are likely to see therapies using CARs having intracellular signalling domains that allow for greater control of the quality and kind of signal induced by target binding, along with systems providing control over the number and location of CAR-T cells within the patient. These improvements will be designed to enhance therapeutic benefit to the patient and reduce side effects.

There have also been exciting advances in the CAR-T cell engineering recently, facilitated by CRISPR/Cas9–targeted genome editing, in which genetic material encoding CARs has been introduced into specific locations of the T cell genome. The resulting CAR-T cells have improved CAR expression, are more potent and more resistant to inhibition compared to CAR-T cells prepared using lentiviral vectors. Research and development in these different areas is expected to yield patentable subject-matter in the future.

A promising future

The recent FDA approvals are an important landmark in cellular immunotherapy. Investment and research in this area is growing, and with the numerous technical challenges there remains huge scope for innovation. With a large and growing number of patents and applications in this space we can expect a large amount of patent litigation in the years to come as companies look to safeguard their market share. Considering freedom to operate at an early stage and a globally coordinated strategy for obtaining, enforcing and defending patent rights will be very important for parties looking to bring CAR-T therapies to market.

Partner Frances Salisbury and associate Adam Gregory are European patent attorneys in the life sciences team at Mewburn Ellis LLP