The Scale of the 2028 Keytruda Patent Cliff

Keytruda (pembrolizumab) is the world’s best-selling oncology drug, and its core composition-of-matter patent in the United States is expected to expire in 2028 — an event that places more than $25 billion in annual revenue directly in the path of biosimilar competition. No single patent expiry in the history of oncology pharmacology carries a comparable revenue figure, making the Keytruda patent cliff one of the most consequential intellectual property events of the decade.

The 2028 date refers specifically to the expiry of the core pembrolizumab molecule patent. Merck has, however, constructed a layered patent estate around Keytruda that includes method-of-use patents tied to its more than 40 approved indications, formulation patents covering its intravenous and subcutaneous delivery presentations, and dosing-regimen patents that may individually extend exclusivity on specific clinical uses beyond the core expiry date. This layered architecture — common among blockbuster biologics — means that the effective competitive landscape will be more complex than a single cliff event suggests, as documented in patent expiry analyses published by organisations such as IQVIA and reviewed in biosimilar policy frameworks from the FDA.

Understanding the full Keytruda patent family — not merely the headline 2028 date — is essential for any pharmaceutical company assessing biosimilar entry timing, licensing opportunities, or competitive positioning in PD-1/PD-L1 checkpoint inhibition. According to WIPO‘s global patent data, pembrolizumab-related patent families span dozens of jurisdictions, with expiry timelines varying significantly across the EU, Japan, China, and emerging markets.

Biosimilar Competition: Who Is Filing and Why It Matters

The biosimilar threat to Keytruda is already taking shape in patent offices and regulatory agencies worldwide. Multiple pharmaceutical manufacturers — concentrated in South Korea, India, and China — have initiated pembrolizumab biosimilar programmes, with some having already filed Investigational New Drug applications or begun Phase I comparability studies ahead of the 2028 US exclusivity window.

The regulatory pathway for pembrolizumab biosimilars in the United States follows the 351(k) biologics pathway established under the Biologics Price Competition and Innovation Act (BPCIA), overseen by the FDA. Biosimilar applicants must demonstrate no clinically meaningful differences from Keytruda in terms of safety, purity, and potency — a high analytical and clinical bar that, for a complex monoclonal antibody like pembrolizumab, typically requires two to three years of comparability work before a Biologics License Application can be submitted.

In markets where Keytruda’s patents have already expired or were never filed — including several emerging markets — biosimilar and “biobetter” versions of pembrolizumab are already in clinical or commercial use. This provides important real-world data on the pricing erosion and market share dynamics that Merck can expect in the US and EU post-2028. Historical biosimilar launches in oncology (such as those for trastuzumab and bevacizumab) suggest that innovator brands can retain 40–60% market share in the first two years post-biosimilar entry when supported by strong payer contracts and clinical inertia — but that share erodes significantly over a five-year horizon.

“Historical biosimilar launches in oncology suggest that innovator brands can retain 40–60% market share in the first two years post-biosimilar entry — but that share erodes significantly over a five-year horizon.”

Pembrolizumab Successor Pipeline and Next-Generation PD-1 Assets

Merck’s most durable long-term defence against the Keytruda patent cliff lies in developing next-generation immunotherapy assets that can succeed pembrolizumab in clinical practice before biosimilar substitution erodes the brand. The successor pipeline encompasses three broad categories: enhanced PD-1/PD-L1 molecules with improved pharmacokinetics or reduced immunogenicity, bispecific antibodies pairing PD-1 blockade with a second immune checkpoint target, and novel subcutaneous formulations that provide patient convenience advantages over biosimilar IV pembrolizumab.

Subcutaneous pembrolizumab represents a near-term differentiation lever that Merck has already pursued. A subcutaneous formulation — co-formulated with hyaluronidase — carries its own distinct patent protection covering the formulation, device, and administration method. Because biosimilar manufacturers would need to separately develop and patent a comparable subcutaneous product (or license the hyaluronidase technology), the subcutaneous presentation creates a practical barrier to substitution even after the IV molecule’s core patent expires.

Bispecific antibodies targeting PD-1 in combination with a second checkpoint — such as LAG-3, TIM-3, or TIGIT — represent the most scientifically ambitious pillar of the successor strategy. These molecules are wholly new chemical entities with independent composition-of-matter patent protection, clinical profiles that biosimilar pembrolizumab cannot replicate, and the potential to demonstrate superior efficacy in tumour types where single-agent PD-1 blockade has plateaued. The bispecific landscape in immuno-oncology is tracked extensively by patent databases and clinical registries monitored by bodies such as the NIH National Cancer Institute.

Fixed-Dose Combinations as a Patent Evergreening Mechanism

Fixed-dose combination (FDC) patents are one of the most commercially effective tools available to innovator pharmaceutical companies facing a blockbuster patent cliff. An FDC bundles pembrolizumab with a co-administered therapeutic agent — such as a VEGF inhibitor, a CTLA-4 antagonist, or a small-molecule kinase inhibitor — into a single formulation or co-packaged product protected by patents that are wholly independent of the core pembrolizumab molecule patent.

The strategic logic is straightforward: once the core pembrolizumab patent expires, a biosimilar manufacturer can produce and market standalone pembrolizumab. However, they cannot market the FDC product without either separately developing the combination formulation (and navigating its own patent estate) or waiting for the FDC patents to expire. If Merck can shift clinical practice toward FDC regimens before 2028 — through clinical trial data demonstrating superior efficacy or convenience versus sequential administration — it can effectively ring-fence a significant portion of Keytruda revenue within a patent-protected FDC wrapper.

The FDC strategy is well-documented in the pharmaceutical patent literature and has been examined by the OECD in the context of pharmaceutical patent evergreening and competition policy. Critics argue that FDC patents can delay generic and biosimilar competition without commensurate clinical benefit; proponents counter that genuine FDC innovation — demonstrated through rigorous comparative clinical trials — represents legitimate intellectual property deserving protection. For Merck, the commercial imperative is clear: each approved FDC indication filed as a new patent application represents an independent revenue stream with its own exclusivity timeline.

ADC Partnerships and the Combination Oncology Defence

Antibody-drug conjugates represent the most strategically significant external partnership category in Merck’s post-2028 oncology portfolio. An ADC combines a targeting antibody with a cytotoxic payload via a chemical linker, delivering a concentrated dose of chemotherapy directly to tumour cells — a mechanism that is clinically and mechanistically distinct from checkpoint inhibition, yet highly synergistic with it in multiple tumour types.

The rationale for combining ADCs with pembrolizumab (or a pembrolizumab successor) rests on preclinical and clinical evidence that ADC-mediated tumour cell killing can increase neoantigen presentation, thereby enhancing the anti-tumour immune response that PD-1 blockade sustains. This immunogenic cell death hypothesis has driven a wave of ADC-plus-checkpoint combination trials across breast, lung, bladder, and gastric cancers — and has made ADC partnership agreements one of the most active deal categories in oncology business development since 2022.

From a patent strategy perspective, ADC partnerships are particularly valuable because each ADC asset carries its own independent patent estate covering the antibody sequence, the linker chemistry, the cytotoxic payload, and the conjugation method. When combined with pembrolizumab in a clinical regimen, the combination can be protected by additional method-of-treatment patents covering the specific combination, dose, and schedule — patents that are wholly independent of the core pembrolizumab molecule and that biosimilar pembrolizumab manufacturers cannot circumvent simply by producing a biosimilar version of the checkpoint inhibitor. The global ADC patent landscape is monitored by agencies including the EPO, which has seen a significant increase in ADC-related patent filings since 2019.

What the Keytruda Cliff Means for Oncology Patent Strategy

The Keytruda patent cliff is not merely a Merck problem — it is a case study in how the pharmaceutical industry manages the transition from a single dominant asset to a diversified, patent-layered portfolio. The strategic playbook being deployed around pembrolizumab will influence how every major oncology innovator approaches blockbuster lifecycle management over the next decade.

For patent professionals, the Keytruda estate illustrates the increasing importance of prosecution strategy beyond the core molecule. Method-of-use patents tied to specific indications, formulation patents covering novel delivery presentations, and combination patents covering co-administered regimens collectively create a patent thicket that biosimilar manufacturers must navigate claim by claim — a process that adds time, cost, and legal uncertainty to biosimilar entry even after the headline 2028 date passes.

For R&D leaders and business development teams at both innovator and biosimilar companies, the Keytruda cliff underscores the value of real-time patent intelligence. Knowing which Keytruda-related patents are expiring, which are being challenged in inter partes review proceedings, and which new FDC or combination patents are being filed is essential for making informed decisions about biosimilar entry timing, partnership opportunities, and pipeline investment priorities. PatSnap’s innovation intelligence platform, used by more than 18,000 customers across 120+ countries, provides this level of granular patent family analysis for complex biologic estates including Keytruda.

The broader oncology patent landscape — tracked by global bodies including WIPO — is shifting toward combination therapy patents and platform technology patents as the primary vehicles for long-cycle exclusivity. The Keytruda cliff accelerates this shift: as the world’s most valuable oncology patent approaches expiry, every strategic decision Merck makes in response becomes a data point that shapes industry norms for blockbuster lifecycle management.