Routes to Exclusivity in Cell-Based Therapy Development

Cell-based therapies are widely considered to be a cornerstone of future healthcare, with a 2017 global market assessed at $5.22 billion. These therapies utilize living cells to treat a variety of diseases in the areas of oncology, immunology, neurology, rheumatology, and cardiology. Cell-based therapies have the potential to provide robust treatments for a growing list of indications, particularly those which currently lack any effective treatment options. While powerful, the development and commercialization of these therapies present challenges and opportunities that markedly differ from those of traditional, small-molecule drugs.

Of course, it is crucial that cell-based therapies be legally protected to the same degree as conventional small-molecule drugs. Obtaining and controlling market exclusivity for one of these therapies, whether through patents, regulation, contract manufacturing, and/or partnering, safeguards an entity’s investment, innovation, and intellectual property (IP) by discouraging the development and marketing of competing therapies that could threaten market share in the same or overlapping therapeutic spaces. For optimal success, companies should consult IP attorneys who are well versed in the cell-therapy patent landscape and are adept at generating, executing, and defending an exclusivity strategy across a biomedical company’s technology portfolio. 

Once an entity has secured sophisticated legal counsel, there are a number of basic steps through which intellectual property attorneys will guide their clients:  

• Evaluate each therapy in a company’s portfolio to determine which protection strategy or mix of strategies should be employed to cover that therapy’s research and development, indications, and geographies.

• Craft protection strategies that accurately reflect the unique characteristics of each therapy in the company’s portfolio and that align with the company’s long-term business goals.

• Review, as needed, current patents and exclusivities to determine which could be extended to provide the greatest protection and financial benefit.

• Throughout the organization, define and emphasize the overarching exclusivity strategy to more quickly identify and develop future innovations. 

Patents offer a pathway to exclusivity 

Patents are indispensable when establishing exclusivity for small-molecule drugs, and this is also the case for cell-based therapies. Patenting a biological, as opposed to a chemical, product comes with particular obstacles, however, and the past several years have seen significant restrictions in patentability rulings for biologics. Many of these biologically-based products have characteristics that may weaken or limit patentability such as their inherent complexity and patient specificity. Some cell-derived therapies have also been deemed “products of nature” in certain jurisdictions and, therefore, not patentable as human-made inventions. Consequently, several patenting approaches should be considered as more than one layer of defense may be required.

Companies developing cell-based therapies will typically need to file a variety of different patents around a single technology to obtain robust patent coverage. This can generate an effective multi-layered patent portfolio, which is time-intensive and expensive to navigate, especially for a company seeking to enter a market for the first time.

There are several ways to generate a multi-layered patent portfolio and components can be based on:

• Milestones achieved during the product development process (e.g., based on the addition of a new component or feature to the product).

o  Each successful patent filed during the process will bring an additional term of protection. It also may be possible (and highly desirable) to patent aspects of the manufacturing process in addition to the product itself. An example of this is Advanced Cell Technology (ACT)’s 2014 patent (U.S. Patent No. 8,822,218) covering the large-scale manufacturing process for dendritic cells from non-donor sources in order to produce dendritic cell vaccines. 

• New formulations or next-generation products that produce more favorable therapeutic outcomes than the previous formulation or generation. 

o  An example here is the several generations of chimeric antigen receptors (CAR) that were (and are being) developed as the technology matures.

• Different drug delivery techniques for a formulation (e.g., by varying where the therapeutic cell is prepared from ex vivoto in vivo).

• New clinical applications for an existing product;

o  An example here is Novartis’ CAR-T therapy Kymriah,which was originally FDA-approved in 2017 for non-Hodgkin lymphoma (NHL) and became approved for B-cell acute lymphoblastic leukemia (ALL) in 2018.

• Different, pre-existing, components that are combined (e.g., physically or through sequential or concurrent administration) into a new product.

o An example of this is Calidi Biotherapeutics’ 2018 US patent (U.S. Patent No. 10,105,436) covering the combination of oncolytic vaccinia virus and adipose-derived stem cells administered to combat solid or hematologic tumors.

Regulatory pathways to exclusivity 

In addition to patenting their innovations, developers of cell-based therapies can take advantage of the 12-year market exclusivity for biologics that is provided by the Biologics Price Competition and Innovation Act (BPCIA, 2009). The BPCIA offers developers a regulatory path for products that are biosimilar to, or interchangeable with, previously licensed biologics. The BPCIA also gives the reference biologic maker 12 years of market exclusivity after approval. The first four years provide data exclusivity in that no biosimilar application accepted by the FDA during that time can be based on data obtained by the maker of the reference drug.

Additional strategies to extend the period of exclusivity based on regulatory approval include:

• Pediatric exclusivity, which adds six months to existing exclusivity periods and patent terms based on clinical studies in the pediatric population. 

• Patent term extension of up to five years for one patent covering the product and which issued before the product was approved by the FDA.

• Orphan drug exclusivity, which provides seven years of exclusivity for products that treat certain rare diseases. Obtaining a series of orphan disease approvals for an expanded set of indications, for instance, can provide additional exclusivity to maximize potential revenue.

• One caveat here: the FDA has recently (July 2018) published clarifications with regards to the designation of biologics as orphan drugs in pediatric populations, so as these regulatory guidelines evolve, these routes may prove less effective in the long-term.

Exclusivity through contract manufacturing arrangements 

The manufacturing considerations for any cell-based therapy, or component thereof, that is intended to undergo clinical trials or manufacture at a commercial scale under GMP conditions represent a substantial hurdle. To scale up production of cell-based therapies involves specific challenges, including: obtaining and maintaining a sufficient and consistent source of materials; patient-specific batch processing; specialized materials handling; and contamination concerns, to name but a few. Furthermore, developing cell-based therapies requires the use of purpose-designed, accredited good manufacturing facilities, but few manufacturing facilities can meet those stringent requirements.

This has created high demand for contract manufacturing organizations (CMOs) that have the essential expertise and capacity to meet those demands. Securing capacity with those highly sought after CMOs during clinically or commercially relevant periods of time can be an effective strategy to establish and maintain market share. An alternative, albeit an expensive one, can be to build out the required manufacturing capacity in-house. Depending upon the organization, this can allow for revenue generation through monetizing any excess capacity, in some instances.

Exclusivity through strategic partnerships 

Strategic partnerships, collaborations, and licensing agreements are becoming increasingly important paths to exclusivity. Companies in the field are trying to secure as much market share as possible in a rapidly evolving market that is not yet dominated by any one developer. Partnering with other entities provides valuable opportunities to enter a new therapeutic market or to extend the commercial life of an existing cell-based therapy. These collaborations give developers the chance to partner with other parties that have aligned objectives. Each partner helps to diminish or at least share risk, as both parties “own” some of the responsibility related to product development and marketing as a result of the partnership. 

Exclusivity rights under collaborative arrangements will vary. For instance, a licensing agreement can give one party exclusive or co-exclusive research, commercialization, or marketing rights to a specific therapy in a certain geographic region or therapeutic indication, for instance. Or, a licensing or partnership arrangement can enable a company to gain exclusive access to the best safety technologies or manufacturing components. 

IP importance

Securing expert, strategic IP counsel ensures developers of cell-based therapies can properly leverage the various means of market exclusivity available to them. In doing so, companies will be able to optimally create, execute, and defend an exclusivity strategy that will safeguard their competitive advantage and propel their future development efforts.  

Charles E. Lyon, DPhil, is Partner and Co-chair of Choate’s Intellectual Property Group. Brian E. Reese, PhD, is Counsel at Choate