When your formulation IP is beyond compare (T 0722/24)
Rose Hughes
When your formulation IP is beyond compare (T 0722/24)
The recent decision in T 0722/24 is an example of effective patent strategy for a clinical stage product. Pharmaceutical innovation involves far more than identification of a therapeutic molecule. Over the course of a drug's life cycle, there is the need for considerable and lengthy further development, leading to new inventions. This innovation leads to new patentable inventions, including finding the therapeutically safe and effective dose, developing the pharmaceutical formulation, and finding precision medicine approaches. However, these types of invention are also often challenged on the grounds that they merely constitute a routine part of the drug development process (IPKat). In these cases, invention capture is primarily about documenting the myriad of challenges that needed to be overcome to reach the clinic, even if these don't make it into the regulatory submissions. The Patentee in T 0722/24 was able to convince the Board of Appeal that their formulation was "outstanding" at solving a difficult problem in formulation development.
Case background
The patent at issue EP 3725778, owned by Medivation Prostate Therapeutics and Astellas Pharma, relates to a solid pharmaceutical composition of the prostate cancer drug, enzalutamide. A total of eleven opponents challenged the patent, but the Opposition Division ultimately upheld the granted claims. Claim 1 of the main request on appeal defined a solid pharmaceutical composition comprising a solid dispersion containing amorphous enzalutamide and the concentration-enhancing polymer HPMC-AS. Enzalutamide is marketed as XTANDI for the treatment of prostate cancer, and is a multibillion dollar product.
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New formulation
The main issue on appeal was inventive step. The Board of Appeal identified the closest prior art to be the prescribing information for the commercial product XTANDI. This product was a liquid-filled soft gelatin capsule containing enzalutamide dissolved in a solvent. The claims of the main request on appeal were found to differ from the prior art in that they defined a solid pharmaceutical composition comprising a solid dispersion of amorphous enzalutamide with a specific polymer, hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
The key question for the Board of Appeal was what technical problem was solved by this change in formulation. To support their inventive step argument, the Patentee argued that the claimed invention embodied a combination of three distinct effects. First, argued the Patentee, there was an effect of convenience, whereby the claimed solid dispersion formulation allowed for more convenient dosing. Second, the new formulation was purported to provide no loss in bioavailability compared to the prior art. The patent contained data from bioavailability studies in humans showing that the claimed tablet achieved an area under the curve (AUC) comparable to the XTANDI capsules. Finally, the Patentee submitted that the composition demonstrated "outstanding" physical stability. The Patentee pointed to data in the patent showing that the amorphous form of enzalutamide was remarkably stable, even under harsh conditions.
Beyond compare
The Enlarged Board of Appeal decision in G2/21 addressed head-on an issue at the heart of the problem-solution approach to inventive step, whereby a Patentee may need data comparing their invention to the prior art, but may not have known of the existence of the prior art when the patent was filed (IPKat). This problem is particularly acute for antibody inventions, where the technical problem to be solved may be very narrow. However, it also applies to other fields involving iterative innovation within a crowded field, including software (IPKat). The decision in this case is remarkable for the Board of Appeal observation that comparative data was not needed with respect to the stability effect relied on by the Patentee. The Board of Appeal particularly found that the "outstanding" effect of the claimed formulation was so good, that a direct comparison with the prior art was deemed unnecessary and that the lack of a direct comparison could not justify disregarding this property of the formulation (r. 5.2.4).
Content with the data, the Board of Appeal went on to formulate the objective technical problem as the provision of a further pharmaceutical composition of enzalutamide freed from the practical constraints of the XTANDI capsules, exhibiting comparable bioavailability in humans, and with outstanding physical stability.
The Opponents argued that using HPMC-AS to formulate a poorly soluble drug into an amorphous solid dispersion was a well-known and obvious strategy. They pointed to a host of prior art documents that described HPMC-AS as a uniquely effective and broadly applicable polymer for this exact purpose. However, the Board of Appeal was not convinced by these arguments. The Board of Appeal instead gave significant weight to other documents, which painted a picture of a field still reliant on a "tedious trial-by-error approach" (r. 5.3.3). For the Board of Appeal, these documents underlined the persisting difficulty and unpredictability in developing stable and effective amorphous solid dispersions. Interestingly, the Board of Appeal noted that whilst many compounds had been successfully formulated in the lab, products reaching the market remained the exception.
The Board of Appeal thus found that the prior art did not provide the skilled person with a reasonable expectation of success that using HPMC-AS for enzalutamide would solve the multi-faceted objective technical problem of achieving comparable bioavailability and outstanding stability in a more convenient dosage form. The Board of Appeal concluded that the solution was therefore not obvious, and the appeals were dismissed.
Final thoughts
A challenge for invention capture in this space, is the different priorities and requirements of regulatory submissions and patents. In this case, the Patentee successfully framed the invention not as a simple, obvious development of a new formulation technology, but as an effective solution to a complex, multi-variable challenge in a difficult field. However, for a regulatory submission, there is little to no incentive in outlining all the trials and tribulations that went on behind the scenes in order to arrive at a new formulation. All that matters for the regulatory process is that the commercial and clinical embodiment of the formulation has the properties that it needs. The challenge for the Patentee is to remember all the challenges that were overcome in development, even if these don't get a mention in the regulatory documents, so that the invention story is not lost.
This case also joins the now long list of decisions to apply G2/21. As attention turns to the latest Enlarged Board of Appeal referrals and decisions (G1/23, G1/24 and the recently announced G1/25 (IPKat)), it is interesting to see how commonplace and routine the application of the EBA's reasoning from a previous referral has now become. The EBA order in G2/21 was self-confessedly "vague". However, the Boards of Appeal have generally found few issues with working out how to apply it (IPKat). As we have seen with the recent decisions applying G1/24, Boards of Appeal strive hard to fit decisions from the EBA as much as possible within the framework of the existing case law (IPKat).
Further reading
- Second medical use dosage regimen claim successfully traverses both insufficiency and "obvious-to-try" attacks (T 0799/16) (Mar 2021)
- Crystal clear? G 2/21 applied to polymorph patents (T 1994/22) (Jul 2024)
- Functional claims for pharmaceutical formulations: Validity versus enforcement (T 2130/22) (Jan 2025)