In this article for Intellectual Property Magazine, Mathys & Squire partner Juliet Redhouse and technical assistant Angela Stephen examine the different strategies for lengthening patent coverage at the European Patent Office (EPO).
It can be difficult to balance the need to file patent applications early on during drug product development and the length of time it takes to obtain regulatory approval. As patent term is calculated from the date of filing, much of the 20-year patent term has already passed by the time the drug product gets to market. A successful patent strategy needs to extend well beyond the time taken for regulatory approval. This article explores the patent strategies that can assist in extending protection around the drug product.
Patentable aspects of drug development
In addition to the drug product itself, separate patent protection may be obtained for secondary aspects including therapeutic indications, the drug product formulation, methods of manufacturing the drug product and drug combinations. These categories are discussed below, along with examples of what a claim under each category might look like when presented to the EPO.
The drug product
Antibody X against target Y, comprising heavy chain CDRs1-3 of SEQ ID NOs: 1-3 and light chain CDRs1-3 of SEQ ID NOs: 4-6, respectively
For new drug products, the initial patent application will be directed to the drug product itself. Typically, the drug product will be defined by its structure. For example, a chemical compound may be defined by a Markush structure or a specific chemical formula, and an antibody may be defined by the six CDR sequences that are required for binding. At the EPO, there can be some flexibility as to what level of structural definition is required. For example, in the field of antibodies, an antibody may be defined solely by a functional property such as its target epitope, if it is shown that the prior art antibodies do not possess this functional property.
Product X for use in the treatment of breast cancer
It may be possible to obtain separate patent protection for a therapeutic indication following the initial drug product application. However, this can be difficult because treatment of the therapeutic indication with related drug products may already be known and/or data relating to the therapeutic indication may have been included in the initial drug product patent application to support inventive step. A later patent application for the therapeutic indication of the drug should ideally be filed before the drug product patent application is published, so that the latter application is not citable at the EPO as prior art for lack of inventive step.
Product X for use in the therapy of breast cancer, wherein product X is administered at a dose of 0.5-1.0 mg/day
It is well established at the EPO that more specific aspects of a known therapeutic indication may be protected. For example, the particular dosage regimen of a known drug product for a known therapeutic indication may be patentable. In practice, demonstrating an inventive step can be a significant hurdle for dosage regimens at the EPO because determination of the dosage that yields the best effect when the effect as such is already known is considered to be routine. A dosage regimen may, however, be patentable if the prior art teaches away from using the claimed regimen.
Product X for use in the treatment of breast cancer in patients carrying the ABC variant of XYZ gene
In certain circumstances the EPO considers the treatment of a particular patient subgroup with the drug product to be novel over the prior treatment of a broader patient group with the drug product, and the treatment of the specific patient subgroup may therefore be the subject of a later patent application.
Product X for use in the treatment of leukaemia
A later patent application for a new therapeutic indication may be warranted if there is data available supporting that treatment of the new indication with the drug product.
Formulations and crystalline forms
A pharmaceutical composition comprising 2.0 to 5.0 wt % product X, 5.0 to 10.0 wt % excipient Y and the remainder up to 100 wt % water
A patent to the commercial formulation of the drug product can provide another layer of protection. The technical effect of a particular formulation may be related to improved stability or may solve a problem such as low solubility. The scope of protection is likely to be narrow, with the claims limited to the particular drug product. In the case of antibodies, this is often the full sequence of the antibody. The concentrations of the drug product and the components of the formulations are also typically required, often within narrow ranges of the exemplified compositions in the patent application.
A crystalline form of product X having an x-ray powder diffraction pattern comprising peaks at 7.9°, 9.8° and 13.2° ±0.2° 2theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 Å
Patents can also be directed to particular crystalline forms of a drug product, generally defined by reference to peaks in its x-ray power diffraction pattern. In such cases, it is important that a method for obtaining the claimed crystalline form that does not require the use of seed crystal is described in the patent application. The EPO does not accept arguments that crystalline forms are inherently unpredictable and therefore non-obvious, and therefore evidence that the claimed crystalline form is associated with a surprising advantage over the prior art is also crucial. In this respect, evidence of improved filterability and drying characteristics of the amorphous form of a drug substance is not generally accepted, because the EPO considers these to be expected advantages of crystalline forms.
Method of manufacture
A method of purifying monoclonal antibody Y, comprising the steps of.
There may be patentable aspects to manufacturing the drug product, for example to overcome difficulties in large-scale production, or achieving a high level of purity. As for formulations, such improvements are often considered by the EPO to be tied to the particular drug product. The patent examiner may also require very specific details of the method in the claim, unless it can be shown that they are not required for achieving the effect. For example, if an improved purity has been shown using a particular wash buffer composition, this may be required in the claim unless this improved purity is demonstrated using a different wash buffer.
Composition comprising product X and product Z for use in the treatment of breast cancer
Patents for new combinations of two or more active ingredients can provide useful protection when patent protection for the single active ingredients has expired. To satisfy inventive step at the EPO, synergism of the combination greater than the additive effect of the single active ingredients needs to be shown.
Patent filing strategy
The main factors that influence patent filing strategy are the availability of supporting data and the timing of upcoming disclosures.
A guiding principle at the EPO is that if a technical effect is relied on for the patentability of the claimed subject matter, such as improved binding affinity of the drug product, or improved stability of the formulation, this technical effect must have been made plausible at the filing date of the patent application. If the technical effect of the claimed invention is not rendered plausible in the patent application, then it is unlikely to be taken into account and this will increase the likelihood of the invention being found to lack an inventive step, or lack enablement if the technical effect is stated in the claim. If the technical effect of the claimed subject matter is plausible at the filing date, post-filed data may be filed to support an inventive step. However, plausibility cannot be shown solely by post-filed data.
The nature and amount of data required to demonstrate plausibility will depend on the technical effect being asserted and the scope of the claim. The EPO has been clear that any kind of experimental data for showing plausibility is acceptable, and that in vivo or clinical trial data are not necessarily required. For example, for therapeutic indications, in vitro data is accepted if the observed effect directly and ambiguously reflects the therapeutic indication. In some cases, it may be possible to rely on data that is available in the prior art to demonstrate plausibility.
Comparative data will often be key for arguing an inventive step over the prior art. In particular, patent applications to the drug product formulation should include comparative data over a standard or prior art formulation, and patent applications to the manufacture of the drug product should include comparative data to a standard or prior art protocol. Data showing flexibility on various method steps or formulation components is also desirable, to support breadth for these features in the claim. Comparative data is also important for protecting crystalline forms, to show an unexpected advantage over the prior art forms of the drug product.
A patent application will need to be filed before a public disclosure so that it is novel over that disclosure. Disclosures may be in any form, including conference presentations, journal publications, clinical trial protocols and interim clinical trial results. Clearly, a good publication review system needs to be in place so that the patent attorney is aware of any upcoming disclosures by the technical teams. However, even when there are no planned public disclosures, it can be difficult to keep control of disclosures and maintain confidentiality, and this in particular can apply to clinical trials. It could therefore be appropriate in some cases to file patent applications at several stages of the clinical trial process to try to mitigate this issue.
If there are no planned disclosures, one option might be to retain the knowledge within the company as a trade secret. This could be appropriate for the optimized manufacturing process of the drug product, for example. However, again, it can be difficult to keep control over the disclosures, and the merits of filing a patent application to the manufacturing process should be considered.
Supplementary protection certificates
Supplementary protection certificates (SPCs) are a form of extended protection in Europe for patented pharmaceutical products and agrochemicals after patent expiry. They are designed to compensate for up to five years of patent term that is lost while the product is going through regulatory approval. While a detailed review of SPCs is beyond the scope of this article, as only one SPC can be granted to each patent holder for a particular authorised product, strategic considerations on which patent to nominate for SPC protection, including the strength and scope of the patent, the potential expiry date of the SPC, and the eligibility of the patent for SPC protection, should be borne in mind.
The availability of patents for different aspects of a drug product can extend the patent protection of a drug product beyond the 20-year term provided by the initial product patent. Although the scope of protection generally reduces for the later, more specific patent filings, these patents can still confer meaningful protection of the drug product and provide a barrier to third parties. The precise patent filing strategy will depend on the particular circumstances of each case, including when data will be available to include in the application to support the plausibility of any technical effect that will be important for patentability, and the content and timing of any expected public disclosures.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.