Genetically engineered models (GEMs) serve as a backbone of drug discovery. Yet, accessing the most relevant GEM for a particular research objective is not always a simple task. Licensing issues can create hurdles for investigators who need a model ideally suited to their study objectives. Intellectual property (IP) factors must be considered early on; otherwise, a researcher could inadvertently violate a model's licensing restrictions, delaying the study and exposing the organization to liability risks. Understanding the licensing and IP considerations associated with acquiring and distributing GEMs can facilitate access to these essential research tools.
Common Intellectual Property (IP) Risks When Using GEMs
The growing complexity of drug discovery has fueled an increase in the number of existing GEMs and their prevalence in research. In many cases, these complex, sophisticated GEMs take significant time and expense to develop. In turn, organizations that invest in generating a GEM may seek to gain a reasonable return on that investment, which is often achieved by distributing the model to academic institutions or for-profit companies.Proper due diligence of the IP landscape is always vital when acquiring or distributing a GEM, but especially in situations like the following:
- When a research entity outsources its study to a third party, such as a contract research organization (CRO), the third party is equally responsible for adhering to model licensing requirements and ensuring proper IP use.
- When a research model comprises material from multiple sources, IP clearance may be more complicated.
- When a GEM is intended for research on a drug candidate that has blockbuster potential, the specter of large revenues raises the stakes on assuring IP protection to avoid costly lawsuits down the road.
Licensing Differences Between Not-for-Profit and For-Profit Research
The use of GEMs in academic and government settings also can raise unique IP issues. Investigators in these institutions often conduct research sponsored by for-profit companies, making it likely that their work will be used in commercial applications. However, it is common for academic and government institutions to acquire a research model under an agreement that assumes not-for-profit use only. If a GEM will be used in research that eventually may benefit a for-profit company, a different form of licensing may be required.Similarly, certain GEMs used in biologics drug discovery may be more prone to IP disagreements in the absence of proper due diligence. For instance, sophisticated GEMs that can produce human antibodies are commonly employed to generate therapeutic antibodies. The complexities of developing such a model make the IP and licensing issues more challenging. Generally speaking, the closer the model gets to the actual therapeutic, the greater the risk of IP issues arising, in part due to the associated revenue potential of the resulting drug.
Several highly publicized lawsuits — some involving models used in biologics drug discovery — have brought to light the potential for model IP disputes. In one case, Regeneron Pharmaceuticals alleged that Ablexis infringed on a Regeneron-patented technology used to develop a GEM that produces part-human and part-mouse antibodies. The case was settled when the court determined that Ablexis had designed its model in a manner that did not infringe on the patent. Nevertheless, it became clear that IP issues associated with a GEM have the potential to cost an organization substantially. In fact, some research reagent IP cases have resulted in huge settlements. When Novartis and Juno Therapeutics filed suit against each other over misuse of materials shared under material transfer agreements and patent infractions involving CAR-T therapy technology, Novartis ended up settling with Juno for $12 million.
Types of Model Use Agreements
Dr. Megan MacBride, director of product marketing, authored an article on the IP and licensing issues associated with genetically engineered models in the Journal of Precision Medicine:
To avoid IP disputes and ensure smooth access to the model most relevant for a particular study, it is essential to understand the types of agreements typically used when distributing or granting use rights to a GEM. The most common types of agreements include a Material Transfer Agreement, a License Agreement, and a Label License. A Material Transfer Agreement (MTA) is most often used when the distribution or transfer of a research model occurs between non-profit institutions. Typically, an MTA will specify that the model is intended only for use in internal, non-profit research, and its use is granted only to the recipient researcher named in the agreement. It is also common for an MTA to prohibit the recipient from distributing the model without the provider's written consent. Some MTAs outline the terms under which the recipient may distribute modifications made to the model and grant back to the provider the rights to those modified materials.
A License Agreement is the more likely arrangement for granting model use rights to a commercial organization. A license agreement typically involves fees, which may be assessed upfront and/or via annual maintenance charges. It can also take significant time and resources to negotiate and review the agreement with multiple parties, which can delay a study's start and elongate the study timeline.
A Label License is a type of simple license agreement that's designed to speed and simplify the process of obtaining a GEM. Much like the licensing used with "shrink wrapped" software, a label license's terms are considered accepted upon purchase, with no signature needed and no separate licensing fees assessed.
The Role of Due Diligence
When acquiring or distributing a GEM, proper due diligence is key to avoiding running afoul of model transfer or licensing agreements and preventing IP issues. At a minimum, it's essential to know where the model was developed and whether any materials used in generating it came from third parties. Additionally, factors such as the technologies used to generate the model and whether they are governed by patents or other restrictions are important considerations.While a wide variety of genetic modifications techniques may be used to develop a GEM, CRISPR/Cas9 is an increasingly common choice. For certain types of genetic modifications, CRISPR/Cas9 can be used instead of the more time-intensive process of targeting embryonic stem (ES) cells, reducing the time and cost of generating the model. However, multiple organizations hold CRISPR/Cas9 patents, furthering complicating the IP landscape. The Broad Institute holds a patent that covers the use of CRISPR/Cas9 in eukaryotic cells. A group comprising investigators from The University of California at Berkeley and the University of Vienna hold a patent for CRISPR/Cas9 gene editing use outside of bacterial and archaeal cells. The CRISPR/Cas9 inventors have formed numerous companies for the purpose of licensing the technology to commercial organizations. Before acquiring a CRISPR/Cas9-generated model, investigators need to ensure the organization that developed and distributes the model has obtained the necessary licenses from the right entities.
In addition to CRISPR/Cas9, other genetic modification technologies may also be patented. Often patent holders will allow non-profit institutions to use materials or technologies for non-commercial use without requiring a license but will prohibit the sale, transfer, or licensing of materials covered by the patent or generated using the patented technology. That puts the onus on the organization acquiring a GEM to determine if it has the rights to use the model as intended or if it is subject to restrictions.
If a non-profit organization generates a GEM using a patented technology (CRISPR/Cas9 or otherwise) and wishes to distribute it, one approach that can prove useful is to deposit the model in a repository that possesses the requisite licenses. Once in the repository, the GEM becomes available for wider distribution, even to investigators in commercial settings.
Proper due diligence also includes gaining a thorough understanding of the intended use of the model long term, especially when third-party companies are involved in any aspect of the research. Most model use agreements prohibit transferring the material to a third party. Even if the investigator does not initially intend to use the model commercially, outsource the study to a CRO, or engage with a collaborator, if any of these activities are possible down the road then the investigator should determine if the licensing agreement will permit them.
Finally, it is essential that investigators who use GEMs in their research are fully aware of the terms and conditions of the model transfer or licensing agreement. If the investigator who will use the model is not involved in discussions about the agreement, he/she could violate the agreement simply due to a lack of awareness of the terms, including any limits on the model's use or even the existence of an expiration date. When using a GEM, investigators can benefit from a thorough review of the transfer or licensing agreement's terms and conditions and an understanding of their responsibilities under the agreement.
Simple due diligence steps such as these can greatly reduce IP risks associated with acquiring or distributing the GEMs necessary to facilitate drug discovery.
