Evergreening Strategies and Their Impact on Modern Therapies

Pharmaceutical innovation drives new treatments, but concerns arise when companies use legal tactics to extend market exclusivity beyond the original patent term. Known as evergreening, these strategies delay generic competition, keeping drug prices high and affecting healthcare costs and accessibility.

Mechanisms Of Patent Extension

Companies employ legal and scientific methods to prolong drug exclusivity, often modifying formulations, altering compositions, or identifying new structural variants to delay generics.

Extended-Release Versions

A common tactic is developing extended-release (ER) formulations that modify drug pharmacokinetics for less frequent dosing. This allows manufacturers to file new patents, extending market control. OxyContin, an ER version of oxycodone, was patented separately from its immediate-release form, delaying generics. A 2017 JAMA Internal Medicine study found that ER formulations accounted for 60% of new opioid patents between 2000 and 2015, despite offering no novel active ingredients. While ER versions can improve adherence, their introduction often extends monopolies without meaningful innovation. The FDA has acknowledged their potential benefits but also noted their role in sustaining high drug costs.

Novel Excipients

Reformulating drugs with new excipients—inactive substances used as carriers—can lead to separate patents even if the active ingredient remains unchanged. AbbVie’s HIV drug Kaletra, for example, was reformulated with a heat-stable excipient to improve storage in warm climates, resulting in a new patent that delayed generics. A 2022 Lancet Global Health review highlighted how excipient modifications have prolonged exclusivity in low- and middle-income countries, limiting access to affordable alternatives. While some excipients enhance stability or bioavailability, regulatory bodies such as the EMA caution that many patents lack true therapeutic advancements and primarily serve to extend market control.

Polymorphic Variants

Pharmaceutical compounds can exist in multiple crystalline forms, or polymorphs, which may differ in solubility, stability, or bioavailability. Patenting a new polymorph secures additional exclusivity even if therapeutic effects remain unchanged. AstraZeneca’s Nexium (esomeprazole), a single-enantiomer form of Prilosec (omeprazole), was patented separately, maintaining market dominance after Prilosec’s patent expired. A 2019 Pharmaceutical Research review found polymorph patents delayed generic entry in over 40% of small-molecule drugs analyzed. While some polymorphs marginally improve absorption, critics argue these patents often serve as legal barriers rather than genuine treatment advancements. The WHO has called for stricter scrutiny of such applications to prevent unnecessary delays in generic competition.

Combination Therapy Patents

Companies frequently patent combination therapies—co-formulations of multiple active ingredients—claiming benefits like enhanced efficacy or improved adherence. While some combinations offer real therapeutic advances, others extend exclusivity without meaningful clinical improvements.

A notable example is Entresto, a combination of Valsartan and Sacubitril for heart failure. Though both drugs were available separately, their combination received a novel patent, delaying generic versions. A 2021 JAMA Cardiology study found nearly 70% of cardiovascular drug patents granted between 2005 and 2020 were based on pre-existing compounds rather than new molecular entities.

Oncology drugs frequently use this strategy. The combination of Lapatinib and Capecitabine for HER2-positive breast cancer was patented despite both drugs being individually approved years earlier. A 2018 Oncologist analysis found oncology combination therapy patents extended exclusivity by an average of 6.3 years beyond the original drug patents. While some combinations improve survival rates, many lack novel mechanisms of action, instead leveraging regulatory frameworks to delay generics.

Patent protections on combination therapies also influence pricing, as branded manufacturers bundle drugs into single formulations, complicating generic competition. Janumet, a diabetes medication combining Sitagliptin and Metformin, maintained exclusivity longer than either component alone due to its combination patent. A 2020 Health Affairs review found combination therapy patenting contributed to a 35% rise in total drug expenditure for metabolic disorders over the past decade.

Patent Thickets In Complex Therapeutic Areas

In specialized fields such as oncology, neurology, and biologics, companies construct dense networks of overlapping patents—known as patent thickets—to maintain market control. These clusters cover minor modifications, manufacturing processes, dosing regimens, or delivery mechanisms, creating legal and regulatory barriers that delay biosimilars and generics.

Biologics, especially monoclonal antibodies and gene therapies, are heavily affected due to their complex structures and production methods. Unlike small-molecule drugs, biologics involve large proteins requiring specialized manufacturing. Companies file numerous secondary patents related to cell lines, purification processes, or formulation tweaks to extend exclusivity. AbbVie’s Humira had over 130 associated patents in the U.S., delaying biosimilar entry until 2023. This strategy has been widely replicated, forcing competitors into prolonged litigation or settlements that postpone market entry.

Neurology drugs for conditions like Alzheimer’s and Parkinson’s are similarly protected by extensive patent layering. Given high failure rates in neuropharmacology, companies maximize the lifespan of successful drugs by patenting incremental innovations, such as alternative dosing schedules or adjunctive therapies. A 2022 Journal of Law and the Biosciences review found leading Alzheimer’s drugs, including aducanumab, were protected by patents covering both the active compound and biomarker-driven patient selection criteria, restricting competing therapies that rely on similar diagnostics.

Oncology drugs, particularly targeted therapies and immunotherapies, are deeply entrenched in patent thickets. Merck’s Keytruda (pembrolizumab), an immune checkpoint inhibitor, has over 90 patents covering combination regimens and specific cancer indications. This extensive portfolio has deterred biosimilars despite the drug generating over $20 billion in annual revenue. A 2021 I-MAK report estimated that patent thickets on leading cancer drugs extend monopolies by an average of 8.2 years beyond the original patent expiration, significantly delaying cost reductions that could benefit patients and healthcare systems.