Avoiding Freedom-to-Operate Pitfalls in Antibody Discovery
In antibody discovery, identifying a promising therapeutic candidate is only part of the challenge, and even that is no easy task. For well-established drug targets, securing freedom-to-operate (FTO) is especially critical to ensuring a clear path to commercialization. The antibody therapy market is becoming increasingly competitive, with rising saturation that is only expected to intensify.
Conventional immunization-based discovery techniques frequently result in overlapping sequences with intellectual property (IP) concerns, due to the high number of antibody sequences already patented. These limitations can restrict opportunities for development, increase legal uncertainty, and reduce commercial viability. Encountering this issue at a late stage could be catastrophic for any biotech company or research team. In fact, over the years we have been approached by many companies who had previously found great VHH candidates, only to discover at candidate selection that the sequences were already in the public domain or, worse, already covered by active patents, who were in need of a new solution.
Isogenica’s synthetic VHH libraries offer a solution by generating new, non-convergent sequences. They enable biotech and pharma companies to minimize prior art issues and advance drug development without IP barriers.
The IP Challenge in Antibody Discovery
The therapeutic antibody market has grown exponentially over the past decade, but this expansion has not been accompanied by a diversification of molecular targets. Instead of focusing on new antigens, the industry has continued to exploit a limited set of well-validated targets such as PD-1/PD-L1, CD20, HER2, and TNF-α, as shown in Figure 1. This issue is particularly prevalent in oncology, where more than 50% of new antibodies in development target the same antigens as multiple existing therapies. This trend is driven by factors such as lower regulatory uncertainty, access to prior efficacy and safety data, and the opportunity to enter established markets with optimized variants of existing therapies. However, this concentration has led to saturation within certain therapeutic classes, reducing differentiation between products and increasing competition among treatments with similar mechanisms of action.
Figure 1: Targets of approved or pending antibody therapeutics for noncancer indications in the US or EU as of November 2021. Bispecifics indicated by hash marks. Adapted from Kaplon et al., mAbs (2022).
The impact of this saturation extends beyond drug development to market dynamics. The proliferation of antibodies targeting the same antigens has fragmented the market and intensified competition, forcing manufacturers to differentiate their products through improvements in formulation, administration, or pricing. In the case of PD-1/PD-L1 inhibitors, for example, the first-to-market drug, Keytruda, captured more than 50% of the global market share, while late entrants have struggled to establish themselves. Additionally, the focus on developing new antibodies against existing targets has diverted investment away from the discovery of novel therapeutic targets.
For well-established drug targets like interleukins or checkpoint inhibitors, IP limitations pose a challenge in biologics development. The significant volume of prior art for popular targets raises the possibility of finding antibody sequences that are either non-patentable or patent-infringing. This poses three concerns to companies:
- FTO restrictions – If a sequence of an antibody is too close to existing sequences, it may infringe on existing filings and cannot be used in a commercial setting.
- Legal complexities – Overlaps with existing patents can lead to expensive IP litigation and licensing costs.
- Commercial uncertainty – Without FTO, you will be confronted with obstacles in obtaining funding, regulatory approvals and getting treatments to market.
The traditional VHH antibody discovery method of llama immunization, has a propensity to yield extremely similar sequences due to the immune system’s natural selection process. As a result, many of the antibodies produced do not represent true novelty, and companies are driven into lengthy lead engineering to differentiate their candidates. With no early strategy for dealing with FTO concerns, companies can lose time and money on candidates that may never reach commercialization.
How Synthetic VHH Libraries Open the IP Bottleneck
Isogenica’s synthetic VHH libraries provide a systematic, IP-friendly approach to antibody discovery. Using a Colibra® build method for enhanced diversity alongside fewer liabilities rather than immunization, the libraries generate fully synthetic, non-immunized sequences that give:
- Novelty from the beginning, minimizing overlap with prior art.
- Enhanced patentability for commercial feasibility.
- More direct route to IND enabling, condensing drug development timelines.
Synthetic VHH libraries are particularly beneficial for well-characterized targets with extensive prior art. They are not limited by natural immune selection, and they have greater sequence diversity compared to the traditional approaches that rely on immune responses. Furthermore, Isogenica offers the largest VHH synthetic library on the market, with sequence diversity 100 to 1,000 times greater than most other synthetic libraries.
These libraries facilitate high-throughput screening efficiently, allowing selection of high-affinity binders with optimal developability profiles, or earlier functional screening.
Lessons from AbbVie vs. Janssen – The Risks of Structural Similarity
Although not directly related to sequence, one story about a dispute between Abbvie and Janssen highlights the importance of antibody diversity in securing your IP.
AbbVie’s IL-12 neutralizing antibodies, derived from a single parent (Joe-9), were optimized through site-directed mutagenesis, generating a closely related set of variants, including J695. Despite designing over 200 antibodies, most shared 90% sequence similarity, relying on the same VH3 heavy chain and Lambda light chain combination. Janssen’s Stelara, on the other hand, was created in transgenic mice, with antibodies having a VH5 heavy chain and Kappa light chain, and just 50% sequence identity to AbbVie’s hopefuls. It was this structural distinction that ultimately enabled Janssen’s successful challenge, with the court deciding their structural diversity was sufficiently novel to be classed as a novel invention. The table below shows the differential features of each antibody.
Figure 2: Comparative Analysis of Antibody Variants: Stelara, J695, and Joe-9
Extracted from “3 cases that changed the patent disclosure landscape of proteins”, Drug Discovery & Development, Troy Groetken (2020).
Although the conventions in antibody patenting have changed since the target-based claims granted to Abbvie in the early 2000s, this example highlights a key issue in antibody discovery: excessively convergent libraries limit innovation potential and compromise IP protection. Unlike AbbVie, Janssen successfully avoided this pitfall through structural and epitope differentiation. In this case, Janssen were fortunate to have developed a sufficiently different antibody to invalidate Abbvie’s extremely broad original claim.
Another key consideration for FTO can sometimes be epitope differentiation. The Biogen v. GSK litigation demonstrated how the creation of antibodies to alternative epitopes can be the deciding factor where there is no patent infringement. GSK was able to successfully defend its anti-CD20 antibody, Arzerra®. It proved that it was attached to a distinct epitope from Biogen’s Rituxan®, which enabled commercialization despite being against the same antigen. This decision underlines the importance of epitope diversity in therapeutic antibody development
Extremely diverse synthetic libraries, such as those of Isogenica, however, deliver novel, non-convergent sequences with minimal redundancy. Furthermore, the fact that selections occur in the absence of an animal’s immune response mean that all epitopes on the target are interrogated equitably by the library, reducing immunization bias. Taken together, this supports the identification of new sequences against common targets with good fFTO for including in innovative new healthcare applications.
In addition to this epitope distinction, speed is crucial in the IP landscape, which allows companies to assess and secure FTO early. With just 6 weeks separating your target from your hit sequences, initial diversity assessments can be made rapidly, allowing agile and data-driven decision making. A faster development reduces costs and also minimizes patent overlap risks, ensuring a clearer, more secure path to commercialization.
This case highlights why antibody discovery platforms must not only deliver therapeutic performance, but also generate sequences with patentable novelty. Using synthetic libraries that avoid immune system convergence reduces IP overlap and improves long-term commercial freedom
Conclusion – Minimizing IP Risk in a Competitive Antibody Market
For developers of drugs against common targets, IP issues are an important potential stumbling block. Conventional immunization-based approaches give rise to low-patentability sequences that hinder progress and introduce legal uncertainty. Isogenica’s synthetic VHH libraries offer an easy answer by creating de novo, non-convergent sequences that enable companies to avoid IP bottlenecks – especially on familiar targets, speed up discovery, and attain FTO.
For companies navigating the complexities of antibody discovery, prioritizing IP strategy is essential. Talk to our experts today to discover how Isogenica’s synthetic VHH libraries can streamline your antibody development and interface with your IP strategy to ensure freedom-to-operate.
References:
Abbvie vs Janssen: https://www.drugdiscoverytrends.com/3-cases-that-changed-the-patent-disclosure-landscape-of-proteins/
GSK vs Biogen: Deng, X., Storz, U., & Doranz, B. J. (2018). Enhancing antibody patent protection using epitope mapping information. mAbs, 10(2), 204–209. https://doi.org/10.1080/19420862.2017.1402998
Graph libraries size: https://isogenica.com/library_size/
Abs targets saturation figure: Kaplon, H., Chenoweth, A., Crescioli, S., & Reichert, J. M. (2022). Antibodies to watch in 2022. mAbs, 14(1), 2014296. https://doi.org/10.1080/19420862.2021.2014296
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