European investigators say their analysis of court cases involving innovator monoclonal antibodies suggests secondary patents have generally failed to stop biosimilar competition.
The main hurdle preventing biosimilars from coming to market is the primary patent on the originator product, not supplementary patents, according to a European study. Investigators also found that product exclusivity extensions, which are customary in Europe, delay the market entry of competitor products.
A patent protects the intellectual property of pharmaceutical manufacturers, guaranteeing them market exclusivity for a set number of years to recoup their drug development costs. Pharmaceutical corporations routinely get secondary patents for tweaks to those drugs to extend their exclusivity, but the study of biosimilar litigation in Europe found that secondary patents were not sufficient to delay the market entry of biosimilars for 9 top-selling monoclonal antibodies.
“Except for 1 patent on trastuzumab where the decision to reject the patent was overturned in appeal, biosimilar developers have won all identified opposition and national patent litigation cases. This indicates that some patents on trastuzumab were seen as a real hurdle for biosimilar entry, but that biosimilar developers can challenge these patents and win,” the authors wrote.
In the United States, patents are often considered formidable barriers to biosimilar market entry, and the multiple patent filings over individual products are known as patent thickets. Limits on patent litigation have been sought to improve access to these lower-cost medicines. In Europe, the authors of this new study suggest, some patent barriers may be more illusory than real.
Standard 20-Year Protection
The drugs in the study received the standard 20-year European patent protection, and much of that time elapsed before development and approval stages were complete and the products could be brought to market. Many of the drugs received 5-year exclusivity extensions through the award of a supplementary protection certificate (SPC); in some cases, extensions were awarded to encourage the development of pediatric medicine.
In total, the drugs studied had market exclusivity for between 10 and 17 years, which the study authors described as “rather large” but consistent with European guidance that innovators “should be able to enjoy an overall maximum of 15 years of exclusivity” after marketing authorization is received.
Innovators sought to extend that exclusivity by patenting variations on the formulation, new dosage regimens, routes of administration, and combination therapies. They also sought to protect their markets by developing next-generation products related to the patented antibody.
Detailed Case Studies
The study authors analyzed patent filings and legal challenges from biosimilar developers to determine how basic patents, patent extensions, and secondary patents affected market entry for biosimilars. They provided detailed case studies of 3 monoclonal antibodies used for to treat cancer: trastuzumab (Herceptin), bevacizumab (Avastin), and cetuximab (Erbitux).
They found that the developers of each reference product filed for multiple patents after receipt of their original product patent; however, in most cases, the secondary patents were either not upheld by the European Patent Office or successfully challenged by competitors in court.
The European Medicines Agency has approved more than 50 biosimilars since 2005, with the first monoclonal antibody biosimilars approved in 2013. The study authors noted biosimilar developers face “substantial hurdles arising from patents taken after the basic patent,” but they said those hurdles are “surmountable, given that many cases were observed to have been won by biosimilar developers and agreements were made to settle ongoing cases.” In some cases, rather than litigate, the biosimilar developers were able to “invent around” a patent.
The authors also found patents on new formulations were not an effective protection strategy; they noted that these secondary patents often are ruled invalid because they are not “inventive.” They noted that AbbVie filed a patent for a formulation of Humira with less injection pain but that this patent was later revoked.
A Desirable Strategy
Patenting of a new administration route is a desirable strategy for an innovator seeking to retain market share, they wrote. For example, an agent becomes more convenient for patients if a subcutaneous route for a previously intravenously delivered drug becomes available. The authors add that this path is also open to developers of biosimilars. Celltrion received European market authorization for a subcutaneous formulation of its infliximab biosimilar (Remsima) in 2019. Biosimilars developers may also take advantage of new techniques for production of the antibody, which may be patentable.
A new dosage regimen may be patentable if it provides “unexpected advantages” over previous regimens. Biosimilar developers may have the option to leave the patented dosage regimen out of the label of the biosimilar, but they prefer to use a dosage regimen consistent with that of the reference product, according to the authors. At the basic patent expiration of adalimumab (Humira) in 2017, there were still 2 dose regimen patents active. However, biosimilar developers eventually gained market entry in 2018 following litigation.
The authors concluded that in Europe, secondary patents have not been the major barrier for biosimilars; instead, “the key protection instruments are the basic patent and the additional protection provided by the award of an SPC with possible pediatric extension, which provide for an average effective market protection of the innovator product of 15 years.”
Additionally, in cases where biosimilars were not available until several years after patent expiration, the authors attributed some of this delay to the complexity of development and manufacturing, not the patent strategies of the developers of the originator biologics.
Moorkens E, Vulto AG, Huys I. An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry? MAbs. 2020;12(1):1743517. doi: 10.1080/19420862.2020.1743517.