Combination therapies: IP considerations for synergistic biologic products

By targeting complementary pathways, these combinations can deliver clinically meaningful synergy, improve efficacy, and help address drug resistance in ways that monotherapies often cannot.

As the science advances, so do the intellectual property and regulatory challenges, particularly where multiple stakeholders are involved in bringing these therapies to market.

Synergy in action: the growing clinical trend toward combination therapies

Combination therapies are now central to innovation in areas such as oncology and immunology. A common approach is to pair a targeted small-molecule inhibitor with an immunotherapy biologic to enhance tumour response through complementary mechanisms.

A recent example illustrates this trend. In September 2025, the FDA granted Breakthrough Therapy Designation to olomorasib, a KRASG12C inhibitor, in combination with pembrolizumab (Keytruda), for advanced non-small cell lung cancer (NSCLC).

This combination highlights the intersection of small-molecule innovation and biologics-driven immuno-oncology. Olomorasib is typically protected by composition-of-matter patents covering the chemical entity and related analogues. Pembrolizumab, by contrast, is usually protected by a broader estate covering sequences, formulations, methods of use, and manufacturing processes. When the two are combined, the key IP issue is often not ownership of the individual assets, which are usually held by different parties, but who can secure and enforce rights over the combination itself.

Combination therapies are often protected through method-of-use patents directed to administering olomorasib and pembrolizumab together (though not necessarily simultaneously) for defined patient groups, dosing regimens, or therapeutic outcomes. Although narrower and potentially easier to design around than composition claims, such patents can still provide meaningful exclusivity when supported by clinical data showing synergistic efficacy or reduced toxicity.

A further layer arises from biomarker-driven approaches. Because olomorasib targets KRAS G12C and pembrolizumab response is often influenced by PD-L1 status or tumour mutational burden, patentees may seek claims to specific patient populations. These personalised medicine claims can strengthen protection by linking it to clinically relevant diagnostic criteria, although they may face eligibility challenges in some jurisdictions.

Freedom-to-operate (FTO) is another key issue. Even where a company owns or licenses olomorasib, it may still need rights to combine it with pembrolizumab, which is typically controlled by another patent holder. This often leads to collaboration agreements, cross-licensing, or co-development partnerships that align commercial incentives and reduce infringement risk.

Lifecycle management is also important. As primary patents on pembrolizumab and KRAS inhibitors near expiry, combination patents, alongside data exclusivity and other regulatory protections, may extend commercial value. Enforcement, however, can be complex if competitors use different KRAS inhibitors or PD-1 antibodies to follow a similar clinical approach without infringing existing claims.

The olomorasib–pembrolizumab example shows how modern oncology innovation depends not only on scientific synergy, but also on layered IP strategies spanning composition, method-of-use, biomarker, and collaboration rights.

Patentability: evidencing a technical effect for combination therapies

Synergy is often central to establishing inventive step where the individual components of a combination therapy are already known.

At the European Patent Office, it is well established that:

• a mere combination of known agents will typically be considered obvious;
• a synergistic effect can support inventive step, but only where it is credibly demonstrated; and
• the effect must be plausible across the full scope of the claims.

In practice, this places emphasis on:

• including robust comparative data in the specification, showing that the combination delivers an improved effect over the individual monotherapies that is not merely additive
• aligning claim scope with the experimental evidence; and
• carefully considering whether to claim specific doses, ratios, or treatment regimens.

Failure to demonstrate synergy convincingly remains a common vulnerability during prosecution and opposition.

Claiming strategies for combination therapies: balancing breadth and enforceability

Protecting combination therapies requires a coordinated claiming strategy. Common approaches include:

• Purpose-limited (second medical use) claims
• Combination or co-administration claims
• Regimen or dosing claims
• Kit claims

Careful design of patent claims around projected label language can often make a significant difference to the value of a patent, particularly when the dosage regimen is not expected to involve simultaneous administration of the individual drugs.

Each approach presents trade-offs. For example:

• broad claims may be difficult to sustain without sufficient data;
• narrow claims may be easier to defend but offer limited commercial protection; and
• enforcement may be complicated by divided infringement, particularly where products are supplied separately.

These issues should be considered early when developing a filing strategy.

Multi-party development: structuring IP ownership and rights for combination therapies

Combination therapies often emerge from collaborations between different rights holders, particularly where each party contributes a distinct therapeutic component.

A notable example of this collaborative trend is the June 2025 global co-development and co-commercialisation agreement between BioNTech and Bristol Myers Squibb. Under this arrangement, the parties shared development responsibilities and profits for an oncology biologics platform, reflecting the need for coordinated access to complementary IP portfolios in complex therapies.

From an IP standpoint, these collaborations can help address freedom-to-operate constraints and support lifecycle management by enabling layered protection around combination regimens, biomarker-driven patient selection, and follow-on improvements.

From an IP perspective, key considerations include:

• Ownership of foreground IP arising from combination studies
• Rights to use each party's background IP in future combinations
• Restrictions on competing combinations
• Control over prosecution and enforcement
• Access to clinical and regulatory data

These issues can determine long-term commercial flexibility and should be addressed clearly at the outset.

SPC considerations: an additional layer of complexity

In Europe, supplementary protection certificates (SPCs) add a further layer of complexity for combination products.

Questions frequently arise as to:

• whether the relevant “product” is the individual active ingredient or the combination;
• whether the combination is “specified” in the basic patent; and
• how SPC rights should be allocated between collaborators.

Given the evolving CJEU case law in this area, early alignment of patent drafting, regulatory strategy, and contractual arrangements is critical.

IP for combination therapies: the key takeaways

For innovators developing combination therapies, several points are particularly important:

• Ensure that any alleged synergy is supported by robust and early-stage data
• Align claim scope with the demonstrated technical effect
• Structure collaboration agreements to preserve freedom to operate and future development options
• Anticipate enforcement challenges arising from multi-actor use

In conclusion, combination therapies offer a significant opportunity to improve patient outcomes, particularly where small molecules and biologics act in concert. As the olomorasib–pembrolizumab example shows, these approaches are already influencing clinical practice. At the same time, they raise increasingly complex IP and regulatory issues, especially in collaborative development settings. A joined-up approach to patent strategy, regulatory planning, and contractual structuring will be essential to realise their full value.

If you would like to find out more about this subject, the following reference points may be of interest:

• Intellectual Property (IP) for Life Sciences
• CJEU clarifies SPC eligibility for combination products
• FDA grants breakthrough therapy designation to olomorasib with pembrolizumab for NSCLC
• BioNTech and Bristol Myers Squibb announce global strategic partnership to co-develop and co-commercialize next-generation bispecific antibody candidate BNT327 broadly for multiple solid tumor types

If you are considering the IP implications of combination therapies involving synergistic small molecule-biologic products, please get in touch with Naomi Cheong or Fiona Law from our Life Sciences team. Naomi, Fiona and their colleagues are well placed to support you in converting complex scientific data into strong, strategically positioned and enforceable IP rights.