Innovative medicinal products (also referred to as originator or reference products), whether chemical or biological, generally represent major therapeutic advances for patients. However, the high price of these products – necessary to offset the substantial investments made by innovators over many years of research and development – represents a significant burden on both public and private healthcare and social security systems, and may, in some cases, limit patient access to these treatments.
In this context, the market entry of generic or biosimilar medicines, once the intellectual property rights associated with the originator have expired and regulatory protections have lapsed, constitutes a key lever for ensuring the sustainability of healthcare systems and improving access to heatlhcare.
Regulatory differences
The concepts of generic and biosimilar medicines arise from regulatory definitions.
A generic medicinal product must contain the same active substance (so-called “qualitative identity,” i.e., strict identity), in the same quantities, and in the same pharmaceutical form as the reference (originator) product; and its bioequivalence with the reference product must be demonstrated through bioavailability studies (i.e., the same efficacy and safety profile under equivalent conditions of administration)[1].
Pharmaceutical products based on conventional chemical compounds (“small molecules”) can be reproduced identically[2].
Accordingly, obtaining a marketing authorization for a generic product relies solely on studies demonstrating bioequivalence, and no preclinical or clinical trial data are required. As a result, the investment needed to develop and obtain approval for a generic medicine is significantly lower than for the originator product, typically amounting to only a few million dollars (on average, USD 2.4 million) in straightforward cases[3].
Conversely, biological medicinal products – being complex biological macromolecules – cannot be reproduced identically due to their intrinsic variability. For example, in the case of a monoclonal antibody, even if the primary structure (amino acid sequence) is identical between the reference product and its biosimilar, structural differences may still exist. Such differences may arise from post-translational modifications, which are closely dependent on the manufacturing process.
Biosimilars are therefore highly similar, but not identical, versions of the reference product.
Although biological medicinal products are not expressly excluded from the scope of generic medicines under European legislation, the requirements of qualitative identity of the active substance and bioequivalence cannot, in practice, be met by such products (this issue has recently been addressed by the Court of Justice of the European Union for peptides products, which are small proteins that can be produced either by chemical synthesis or by biotechnological means)[4].
In this context, a specific regulatory approval pathway for biosimilars has been established in Europe. The data required to obtain marketing authorization for a biosimilar are more extensive than for a generic and may include, on a case-by-case basis, analytical, preclinical and/or clinical study results aimed at demonstrating comparability between the products, particularly with respect to pharmacokinetics and immunogenicity[5].
As a result, the investment and development timelines for biosimilars are significantly higher, increasing from a few million dollars over a period of 2 to 3 years for a generic, to approximately USD 100 to 300 million over 6 to 9 years for a biosimilar[6].
Distinct barriers to market access
Unlike generic medicines, whose market entry generally occurs rapidly and concurrently with the expiry of the originator’s protections (whether intellectual property rights or regulatory market exclusivity), biosimilars are often launched several years after such protections have lapsed. This was notably the case for the first biosimilars of trastuzumab and rituximab, which were launched in Europe 3 and 4 years, respectively, after the expiry of protection[7]. Such delays can be explained not only by the existence of secondary patents creating legal uncertainty – and, in some cases, litigation – but also by the intrinsic complexity of their development and regulatory approval, as discussed above.
Moreover, even after obtaining marketing authorization, biosimilars face greater barriers to market access than generics, particularly due to a distinct framework governing substitutability.
In France, a reference medicinal product may be substituted by its generic counterpart at the time of dispensing. This substitution is almost automatic, notably because reimbursement – where applicable – is capped at the level of the most expensive generic within the same “group”. In contrast, substitution for biosimilars falls under a specific derogatory regime that has only been in force since 2024. It is currently limited to ten groups of biological medicinal products and is subject to strict conditions, including the requirement to inform the prescribing physician[8].
Intellectual Property rights: A barrier to non-innovative medicines?
Because innovative companies typically protect their originator biological products with a large number of patents (“patent thicket”[9]), determining the date on which a biosimilar can be launched without infringing the rights conferred by these titles is particularly complex.
Ensuring legal certainty for the launch of a biosimilar (i.e., de-risking) therefore requires:
- identifying a large number of patents covering to the reference biological product, significantly more than for a reference chemical product,
- conducting a freedom-to-operate analysis with respect to these patents and, where appropriate,
- assessing the validity of these IP titles,
all as early as possible.
In Europe, the regulatory framework for marketing authorization of medicinal products – whether generics or biosimilars – is decoupled from intellectual property considerations. As such, there is no mechanism allowing originators to list the patents protecting their products, nor any requirement for regulatory authorities, such as the EMA, to take into account the status of the patents covering the reference product when granting marketing authorization. At most, some national provisions provide for a duty on the generic manufacturer to inform the marketing authorization holder of the reference product in the event of an at-risk launch.
In practice, this decoupling requires European stakeholders to anticipate infringement risks, in particular by proactively carrying out the various analyses outlined above.
In contrast to the European system, the U.S. framework brings generic and biosimilar manufacturers face to face with patent issues during the regulatory approval process.
The procedure for obtaining marketing authorization for a generic drug (ANDA, Abbreviated New Drug Application) under the Hatch-Waxman Act is based on a “patent linkage” system. The holder of a reference chemical product lists the patents covering it in the “Orange Book”. The applicant for a generic marketing authorization (ANDA) must then take a position on each of the listed patents, for example by asserting that a patent is invalid and/or not infringed. In such a case, the generic manufacturer notifies the rights holder of its invalidity and/or non-infringement arguments, who must then initiate infringement proceedings within a short timeframe. Such an action generally triggers a 30-month stay of FDA approval of the generic marketing authorization. The system also includes an incentive mechanism, whereby the first generic applicant to challenge a patent benefits from a 180-day period of market exclusivity vis-à-vis other generic manufacturers.
For biosimilars, the “patent dance” framework was introduced under the Biologics Price Competition and Innovation Act (BPCIA). Such system, which differs from and is more flexible than the ANDA framework applicable to generics, takes into account the specificities of biological products, for which identifying all relevant patents is difficult without exchanges between the originator company and the biosimilar manufacturer. Under this framework, following FDA approval of a biosimilar application (BLA), the biosimilar manufacturer may provide the originator company with the information contained in its BLA application. The originator then provides a list of patents it considers potentially infringed. This is followed by a series of exchanges regarding infringement and validity, potential licensing proposals, and good-faith negotiations over a defined period. If no agreement is reached, the originator must initiate infringement proceedings.
Although the U.S. system is not without shortcomings (notably due to its complexity and its now optional nature), it gives patents some visibility within the regulatory process and allows biosimilar developers – should they choose to engage[10] – to anticipate potential litigation.
The opportunity of acquiring IP rights for biosimilars
Unlike generic medicines, whose business model has historically relied on the absence of proprietary protection – manufacturers merely reproduce an active substance that has fallen into the public domain, with an identical formulation and the same therapeutic indications as the originator – the development of biosimilars follows a different approach, in which patent protection may be contemplated.
The impossibility of producing “identical copies” of reference biological products creates the possibility that a biosimilar may exhibit differences, which may arise from its manufacturing process, as this process cannot be identical to the one of the reference product due to the use of living systems (cells). This also provides an opportunity to introduce intentional modifications in order to offer improvements over the reference product. Such products are referred to as “biobetters”. These may possess distinct and differentiating characteristics – such as improved stability or reduced immunogenicity – which may be patentable.
Unlike generic medicines, for which the intellectual property rights covering the originator product primarily constitute barriers to market entry, in the case of biosimilars, intellectual property rights may also serve as a lever for competitive differentiation vis-à-vis other biosimilar manufacturers. IP rights can thus, on the one hand, secure the substantial investments required for their development, and on the other hand, support a form of incremental innovation that is largely absent from the generic paradigm.
Patent protection for biosimilars and biobetters may be pursued across several subject matter.
First, manufacturing processes (including cell culture conditions, expression vectors, control of post-translational modifications, purification steps, etc.) represent a particularly strong area of protection, provided that they meet the requirements of novelty and inventive step over the prior art, as these processes directly determine the characteristics of the final products.
Second, specific formulations may also be protected. Their parameters (such as pH, excipients, and concentration) may confer significant advantages, particularly in terms of stability and shelf life, or may enable new modes of administration.
Finally, medical devices (for example, single-use injectors) used for the administration of these products may also be protected, where they exhibit specific technical features improving, for instance, safety, ease of use, or treatment adherence, thereby constituting an additional axis of differentiation and competitive positioning.
Blurred Boundaries
Although generic and biosimilar medicines fall within strictly distinct regulatory categories, the boundary between them may become blurred when considering products that can fall within both the scope of chemical and biological medicinal products. This is the case, for instance, with therapeutic peptides, which may be produced either by chemical synthesis or through biotechnological processes.
This issue has recently been addressed by the Court of Justice of the European Union for a preliminary ruling[11] and will be the subject of a forthcoming article.
[1] Article 10 2.b) of directive 2001/83/CE, amended by directive 2004/27/CE.
[2] “From small molecules to biologics” https://www.santarelli.com/en/from-small-molecules-to-biologics/
[3] “Cost of generic drug development and approval”, Eastern Research Group, Inc, 31/12/2021
[4] CJUE, Judgment of April 23, 2026, C-118/24.
[5] Article 10 4. and appendix I of directive 2001/83/CE, amended by directive 2004/27/CE.
[6] Fontanillo et al., Three imperatives for R&D in biosimilars, McKinsey & Company – Life sciences practice
[7] Moorkens et al., An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry? MAbs. 2020, 12(1)
[8] Order of 4 December 2025 amending the Order of 20 February 2025 establishing the list of groups of similar biological medicinal products substitutable by community pharmacists, and the conditions for substitution and for informing the prescribing physician and the patient, as provided for in 2° of Article L. 5125-23-2 of the French Public Health Code.
[9] « Des médicaments chimiques aux médicaments biologiques » https://www.santarelli.com/des-medicaments-chimiques-aux-medicaments-biologiques/
[10] The “patent dance” is no longer mandatory following the U.S. Supreme Court’s decision in Sandoz Inc. v. Amgen Inc.
[11] CJUE, Judgment of April 23, 2026, C-118/24.
May 2026
Contributing author
