Dosage regimen patent applications are typically filed a few years after the original application to compounds and their medical uses. Often a clinical trial will already be underway, investigating different dosages in patients. The claims may be tailored to the administration regimen as set out on the product label, offering important protection for a marketed product. The potential value of these patents is clear – as an example, the dosage regimen patent maintained by the EPO’s Board of Appeal for Bayer’s blockbuster drug Xarelto® extended the patent protection by almost two years beyond the term of protection provided by the patent covering the API1. However, regulatory submissions and investor communications mean that dosage regimens can be disclosed at an early stage in the development of a treatment. Further, under new transparency requirements, information inputted to the EU’s Clinical Trials Information System (CTIS) as part of the application dossier, is made publicly available – this includes dosage information in Phase II clinical trials2. Consequently, prosecution of these claims at the EPO can be challenging and even following grant they are vulnerable to revocation during opposition proceedings.
This article is in two parts. Part (I) focusses on pitfalls to be aware of and strategies for success. In this second part, we look at some recent decisions by the Boards of Appeal, highlighting the EPO’s approach to these claims.
Dosage regimen claims typically refer to treating a condition with a compound taken at a specific frequency of administration, for example, ‘once daily’, or ‘once every four weeks’. Treatment might be defined to be for a specific length of time (for example, for 5 days or 12 weeks), at a specific dose or within a specific dosage range. Sometimes details of the formulation, such as a specific buffer or stabiliser, and the administration mode are also included, reflecting the dosage regimen and formulation of an approved product.
While a novel dosage regimen is not excluded from patentability3, it can be a challenge for a dosage regimen claim to meet the EPO’s inventive step criteria. We often see clinical trial related publications and associated data cited as prior art against these claims – a complication arising from the later date of dosage regimen patent filings. The EPO’s default position is that specific dosages are ‘obvious to try’ and thus fall within routine experimentation of the person skilled in the art. Further, the existence of a published Phase II clinical trial protocol – even without results – leads to an expectation of success that can impede inventive step being acknowledged for the claims.
Another stumbling block for dosage regimen patents at the EPO is the requirement of sufficiency. To meet this requirement, the claimed efficacy must be credible at the filing date of the patent, based on the information provided in the patent application together with the common general knowledge of the person skilled in the art at the filing date.
The arguments put forward by patentees to overcome these objections can be two sides of the same coin and navigating sufficiency and inventive step can involve treading a fine line. For example, where one relies on data in the prior art for sufficiency of a claim, the EPO will often find that the claim lacks an inventive step over this same data4.
A recent Decision5 issued by the EPO Boards of Appeal illustrates these challenges. In the Appeal proceedings on EP 3199172, inventive step was considered for a claim directed to ‘glatiramer acetate for use in treating a human patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, comprising administering […] three subcutaneous injections of 40mg glatiramer acetate for every seven days with at least one day between every subcutaneous injection […]’.
The efficacy of a 20mg or 40mg dose given every day was known from the prior art. The efficacy of a 20mg dose given every other day was accepted to be part of the common general knowledge of the person skilled in the art. The Board considered the person skilled in the art would have considered a 40mg dose given every other day, which was disclosed in the prior art but without data, to be suitable for the claimed use. The difference over the prior art was considered to be the dosage regimen of three injections per week compared to an injection every other day, amounting to six rather than seven injections in a fortnight. The Board considered that in the absence of comparative data, no effect of the difference in the claimed dosage regimen could be recognised. The difference over the prior art was considered to be minor and obvious to try, as the claimed dosage regimen would be clearly desirable for both patients and healthcare providers in order to allow for weekends. Further, the Board considered that there was at least an overlap between the patient group in the prior art and the patient group defined in the claim. The skilled person would therefore have considered the dosage regimen disclosed in the prior art to also be applicable to a patient as defined in the claim, in view of the conditions to be treated being closely related. Accordingly, the claim was found not to meet the inventive step requirement.
A slightly different claim was considered by the Board for sufficiency. The claim was as set out above, but additionally required the regimen ‘to increase the tolerability of glatiramer acetate treatment in the human patient.’
The Board considered both frequency and severity of post-injection reactions to be relevant to increasing the tolerability of the treatment. The application as filed did not provide any data or mechanistic explanation of improved tolerability in regard to the severity of post-injection reactions and injection site reactions. Nor was there any evidence on file that from their common general knowledge the skilled person could assume that a dosage regimen of ‘40mg three times per week’ would result in improved tolerability compared to ‘20mg every day’ or ‘20mg every other day’. It was therefore found not credible from the teaching of the application as filed that the dosage regimen defined in the claim would increase tolerability of the treatment. Post-published data was not able to remedy this lack of sufficiency. The Board referred to the Enlarged Board of Appeal decision G2/21, where it was held that for sufficiency of disclosure of medical use claims the proof of a claimed therapeutic effect has to be provided in the application as filed, in particular if, in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved. A lack in this respect cannot be remedied by post-published evidence (see our article series on post-published data at the EPO here).
This decision follows the usual position of the EPO, where the threshold for what is considered to be an unexpected technical effect giving rise to an inventive step is high. The greater the challenges linked to a particular target, the higher the chances that an inventive step will be acknowledged - the Boards of Appeal have upheld dosage regimen claims where a disease is complex and results are unpredictable between patient populations, or even within the same patient population over time6. Another factor that can work in favour of dosage regimen claims is if the prior art is considered to ‘teach away’ from the claimed dosage regimen. This could, for example, be due to perceived safety concerns or assumed doubts as to the efficacy of a treatment, which surprisingly turn out not to be the case. See our article discussing inventive step and clinical trials here.
Claims to dosage regimens of combinations may have better chances at the EPO, as illustrated by another recent Board of Appeal decision7. Here, claim 1 as granted related to a pharmaceutical combination product comprising umeclidinium and vilanterol, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease (COPD) and/or asthma, wherein the product is administered once per day.
The claim was considered to meet the sufficiency requirement: vilanterol and umeclidinium monotherapies were disclosed in the prior art as potential agents for the treatment of respiratory diseases, such as COPD and asthma. The application itself included data in which a combination of umeclidinium bromide and vilanterol triacetate was administered to healthy volunteers, showing that the combination was well tolerated and effective in providing bronchodilation compared to placebo. The Board held that based on the information provided in the application as filed, there was a ‘strong presumption’ that the combination therapy would be effective in the treatment of asthma or COPD, and that a dosage regimen of once-daily administration would be feasible. Both aspects were considered to be credible at the filing date. Corroboration was provided by a post-published document, which showed that a combination product conforming to the invention as set out in the claim was authorised for the treatment of COPD by once-daily administration.
Turning to inventive step, the objective technical problem addressed by the claimed invention was formulated by the Board to be ‘to provide an improved pharmaceutical product for use in the treatment of COPD and/or asthma which allowed for once-daily administration and high patient compliance’. In relation to vilanterol, preclinical results in the prior art referred to onset time and duration of action, but were indicated for the group of particularly preferred compounds, rather than for any individual compounds. The Board considered that while this group presumably included vilanterol, the values did not permit the conclusion to be drawn that once-daily administration in human subjects would be possible. Efficacy and safety of the compound in actual patients (monotherapy or combination therapy including vilanterol), had not yet been confirmed. The situation was similar in relation to umeclidinium, where a separate prior art document did not disclose therapy with umeclidinium - the positive evaluation in the prior art was based only on preclinical data (in vitro and animal studies).
The Board concluded that at the filing date of the patent in suit, both vilanterol and umeclidinium were still in the early stages of their pharmaceutical development and that ‘favourable preclinical data […] does not necessarily give rise to a well-founded expectation of success, even less in the case of a combination product when neither combination partner has, as yet, progressed to the clinical stage of development’. While the information derivable from the prior art might have provided the person skilled in the art with the hope to succeed, there would have been ‘a high level of uncertainty regarding the potential for a successful dual therapy’ and this was found not to amount to a reasonable expectation of success. Accordingly, the presence of an inventive step was acknowledged.
As these cases illustrate, dosage regimen patents can be challenging to obtain, requiring detailed technical argumentation to succeed. However, their potential value is undisputed and they are certainly worth the tenacity required. For practical tips on maximising the likelihood of success of your dosage regimen patent application at the EPO, see part (I) of our article here.
If you have any questions relating to this topic, please get in touch with Andrea Coles or your usual Kilburn & Strode advisor.
1 T 1732/18
2 Limited redaction is possible, where commercially confidential information is at issue, but justification must be given.
3 G 2/08
4 T 2963/19
5 T 843/22
6 T 799/16
7 T 209/22