In this article, we consider patent applications to new drug formulations and combinations. Where a substance or composition is already known for a medical use, it may still be patentable for treating the same condition, provided the specific formulation or combination of active products is novel and inventive (Art. 54(5) EPC).
We set out details of how such claims are assessed by the European Patent Office (EPO) and some practical tips on how to maximise the chances of success. In particular, the complex relationship between the concepts of plausibility and inventive step are discussed, focussing on how data in the application are often important to support the patentability arguments at the EPO and how the prior art can be relied upon for plausibility if little or no data are available.
Practical considerations
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When seeking protection for new combinations or formulations in Europe, you must include data in your application or provide a credible scientific theory as to why your new combination or formulation provides an advantage over the prior art.
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When seeking protection for known combinations or formulations in a new medical use, you must include data in your application or provide a credible scientific theory as to why the known combination or formulation would be useful in the treatment of the specified clinical condition.
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Relying on what is known in the prior art rather than providing data in your application can make it difficult to meet the requirement of both sufficiency and inventive step, in particular for medical use claims.
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When preparing and filing applications before you have any data (for example on the basis of a clinical trial protocol), include data in the application at the earliest opportunity in the priority year and prior to any public disclosures to increase your chances of getting a patent in Europe.
For our more detailed analysis, read on.
Benefits of new formulations and combinations
Combining two or more active compounds to treat a condition is a key foundation of modern medicine, particularly in the treatment of complex multifactorial diseases such as cancer. The efficacy of treatments for a number of conditions, such as tuberculosis and AIDS, have been transformed by the use of combination treatments. Combined treatments and reformulations of existing treatments have also brought numerous other benefits to patients, particularly in cases where therapies can be administered as a single pill or tablet.
Combined treatments packaged in a single pill or reformulations that optimise half-life or bioavailability of the active compound can help make treatment regimens less complex and improve patient compliance. This can be crucial in the context of treating certain diseases, where strict compliance with the treatment regimen is required to provide effective treatment. In other instances, poor compliance may result in undesirable side-effects such as development of drug resistance.
Development of improved combinations and formulations clearly requires substantial research effort and often extensive clinical studies to demonstrate an improvement over existing treatment options. Accordingly, the patent system offers opportunities to gain protection for the specific improvements provided by a new combination or formulation to incentivise this important work. This additional protection can provide valuable extra patent term on developments relating to active compounds, sometimes for many years after the earliest patents on the original compound have expired.
Protection for known formulations and combinations
For new formulations and combinations of known active ingredients, the specific preparation of components within a product itself may be novel and inventive independently of the medical use and therefore may be protectable with a product claim. Alternatively, if the formulation or combination is known, they may still be protectable by a second medical use claim. Such claims allow a new medical use of a known formulation or combination to be protected with a purpose-limited product claim.
In the US and other territories, known formulations and combinations may also be protected with method of treatment patents. However, in Europe, methods of treatment are excluded from patentability.
New combinations
Where two or more known compounds have been combined, this may give rise to new patentable subject-matter. A new combination of active ingredients creates a new composition of matter, provided that the exact combination has not been disclosed previously.
It is well established precedent at the EPO that combined preparations, the individual components of which are known therapeutic agents, can be protected in a formulation. This is the case even when claimed as a kit‑of‑parts, providing all the active components have a unified function. Even if all of the active ingredients are known as therapeutics, the combination may be patentable if it provides an unexpected technical effect, beyond a mere aggregation of the known effects of the individual components (T 9/81).
Therefore, if a research programme indicates that a combination of active compounds provides an improvement in the treatment of a particular disease, it may be possible to gain relatively broad protection for the combination of the compounds generally, without limitations to the specific formulation. Even if the prior art in the field provides a generic indication that two or more compounds could be combined, it is still possible in some circumstances for a particularly effective combination to be inventive over a boilerplate suggestion to combine compounds, or classes of compounds.
If the effect of a new combination is based on elucidating a previously unknown biochemical mechanism, for example where a second compound provides a newly discovered beneficial effect in relation to a known side-effect of a first compound, then this can form the basis of a robust inventive step narrative. Conversely, if a combination comprises two known compounds which both interact with well established biochemical pathways involved in the disease then it can be more challenging to show that merely combining these two compounds as a single therapy is inventive. In the latter case, such a combination can still be patentable, for example if it is possible to demonstrate that the combination provides a synergistic effect (i.e. an effect of the two compounds that is greater than the sum of their individual effects).
New formulations
Similarly, new formulations of either individual compounds or combinations of compounds may also be patentable in Europe. Production of a new formulation, for example through use of alternative excipients, creates a new composition of matter, provided that the exact formulation has not been disclosed previously. Protection for new formulations can be very valuable, even if the scope of the claim is very narrow, provided that it covers the approved pharmaceutical product.
Trivial variations of known compositions are unlikely to be considered inventive. However, alternative formulations that provide a surprising technical advantage can be considered inventive. The surprising technical advantage of the new composition can take many forms such as improving pharmacokinetics or bioavailability, allowing the drug to be administered by a different route, improving patient compliance, reducing side effects and/or reducing dosage frequency.
A common example of this is extended-release formulations of known drugs, which have often been commercially successful long after the patent for the original drug has expired. In some cases the magnitude of the effect can be modest, but if the formulation was not taught or suggested by the prior art (even if the modification relative to known compositions is small), it may still be considered inventive.
The field of formulation chemistry has developed significantly in recent years and much is known about the effect of standard excipients in pharmaceutical formulations. Therefore, reformulations which achieve predictable effects using well known excipients are unlikely to be considered inventive. However, even if a formulation may seem “standard” in hindsight, if the development of the formulation overcame particular challenges, this may be indicative of an inventive step. In general, if a formulation uses an unusual excipient or achieves a previously unattainable property (e.g. a particular concentration of active compound) then this could provide the basis of a robust inventive step narrative.
Plausibility
A key consideration when reviewing the patentability of research findings in relation to new combinations or formulations of drugs is what data are required to demonstrate the effect of the new product. Under European assessment of inventive step, the EPO typically prefers to have at least some data demonstrating a technical effect. However, given the research timelines, particularly those relating to known pharmaceuticals, it may be necessary to file patent applications earlier in the development cycle, before significant data on the proposed new combination or formulation is generated (perhaps on the basis of clinical trial designs). In this regard, the concept of plausibility of the disclosure in a patent application becomes crucial.
It is a well-established practice in all jurisdictions that it is not possible to add additional information to a patent application after filing. However, in limited circumstances, it is possible to submit additional evidence to the EPO which does not form part of the application, but can be used to substantiate a technical effect disclosed in the original application. With regard to medical use claims, any additional data can only be considered by the EPO if the original application provides at least a plausible disclosure of the claimed therapeutic effect or the effect is derivable from the prior art. Therefore, if at least a small amount of early data can be included in the application, this may significantly help the demonstration of a technical effect.
Nevertheless, it is possible to satisfy the plausibility threshold without disclosing any experimental results in the application. With regard to new combinations of compounds it may be possible to conduct in vitro experiments to demonstrate a technical effect, particularly if there are good cellular models of the relevant disease available. Since it is often not possible to include human clinical trial data in a patent application, because clinical trial protocols are made publicly available, it can be sufficient to provide limited data from appropriate animal studies to support a change in a sutiable parameter, for example, improved bioavailability of new formulations.
If no experimental data are available, but a new formulation or combination is supported by a technical theory, in order to meet the plausibility threshold the application must at least disclose this plausible technical concept in enough detail to make the invention credible. An entirely prophetic patent application covering a desired combination or formulation, without any indication of the likely mechanism or effect, is unlikely to be successful at the EPO. The technical concept underlying a new combination or formulation may lie in a number of different aspects of the invention and may be at least partly speculative. Once this threshold of plausibility has been met, then post-published evidence may be taken into account to support the inventive concept disclosed in the application.
Practical considerations
For the purposes of sufficiency (Art. 83 EPC), the level of disclosure required for claims directed to pharmaceutical compositions or kits is not the same as that which is required for medical use claims. For pharmaceutical composition claims it is, in principle, sufficient that the application merely provides information that allows the skilled person to produce the composition, and that there are no substantiated doubts that it could indeed be used in therapy. For a pharmaceutical composition comprising two compounds which have both already been used in therapy in the prior art, no specific functional effect has to be demonstrated. The requirements of sufficiency of disclosure for medical use claims at the EPO are generally assessed in terms of whether a compound (or combination of compounds) could treat a given condition. If there is a plausible underlying mechanism in the prior art, this is generally sufficient.
However, a combination product based on two or more known compounds is unlikely to be considered inventive without data to show that the combination provides an unexpected technical effect. It is challenging to rely on structural non-obviousness arguments at the EPO without some evidence or suggestion that the claimed combination behaves in an unexpected way. The requirements of inventive step for medical use claims at the EPO are generally assessed in terms of whether a compound (or combination of compounds) treat a given condition better or more effectively than known methods of treatment.
If there are no data in the application indicating an effect on the relevant medical condition then it is likely to be necessary to rely on the prior art or common general knowledge to meet the threshold of plausibility. In this case, it becomes very challenging to simultaneously argue in favour of an inventive step since it is difficult to empirically demonstrate that the invention has solved a problem (i.e. provided a technical effect over the prior art). Arguing in favour of both sufficiency of disclosure and inventive step in this situation is like walking a difficult tightrope between ensuring the prior art renders the invention plausible but also that the application provides enough additional information to be inventive over the prior art.
In light of this, to improve the chance of successfully arguing for inventive step of a new combination or formulation, it is advisable to include as much data as possible in the new application demonstrating an advantage of a new combination or formulation. In particular, direct comparative data showing the benefit over known formulations or individual components can be very useful. The inclusion of both in vitro and in vivo data is likely to improve the chances of securing protection for the new formulation, particularly if the composition is structurally similar to prior art compositions.
If no data are available even at the end of your priority year, it may still be possible to argue for inventive step during prosecution on the basis the prior art provides no motivation for the skilled person to arrive at the claimed formulation or combination, in particular if that would require going against an established practice or prevailing opinion in the relevant field.
Finally, the interpretation of second medical use and pharmaceutical product claims during enforcement proceedings has been considered in great detail in recent years in the UK, in light of a key decision from the Supreme Court (Actavis v Eli Lilly [2017] UKSC 48), which introduced a doctrine of equivalents into UK patent enforcement. A corresponding doctrine has existed in several European jurisdictions for many years. In some cases, this may provide slightly broader protection for even very narrow claims, limiting the opportunity for potential competitors to derive simple workarounds to narrow product definitions.
Summary
In Europe, it is possible to patent:
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New combinations of active compounds, even where the prior art suggests combining those compounds;
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New formulations of known compounds where the formulation provides an unexpected technical advantage; and
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Known combinations and formulations for new medical uses
Consideration must be given to the evidence that is available to support the claimed effect or, in the absence of data, the application must at least disclose a plausible mechanism by which the combination or formulation is advantageous.
For more information please contact Duncan Bull or your usual Kilburn & Strode advisor.