As the regulatory requirements to obtain marketing authorization of medicines become more stringent, the research required becomes ever longer and more costly; it can typically take 12-14 years and cost up to $1bn to bring a new drug from its initial discovery to the market. Patent protection is therefore critical to protect this investment: both small molecule and biologic drugs are routinely patented, and it is rare in the pharmaceutical industry for a drug to be developed and marketed without patent protection for the molecule itself.
Most major pharmaceutical companies are currently facing the expiry of patents covering blockbuster drugs: examples include Pfizer’s Lipitor (atorvastatin), whose extended patent terms of which expired in 2010 and 2011, and AstraZeneca’s Seroquel (quetiapine), whose extended patent will expire in March 2012 in most countries. As the compound patent application is typically filed at an early stage in the R&D process, the innovator is often left with a short term of exclusivity before generic entry, even when patent term extensions and regulatory data protection are taken into account. With many pharmaceutical companies currently facing a weak pipeline with few strong new drug candidates, the need exists now, more than ever, for innovator companies to manage and extend the life cycle of existing products.
One way commonly used by innovator pharmaceutical companies to extend the exclusivity of a drug product is to patent new formulations of the drug. The basic compound patent typically contains general text indicating possible formulations of the drug such as tablets, capsules, injectable formulations and transdermal patches, and lists typical excipients used in these formulations. For a formulation of a known drug to be patentable, the formulation must be both novel and exhibit an inventive step (typically by providing a technical effect or advantage) over and above these generally described formulations.
Extended release formulations of a drug are particularly common in the pharmaceutical industry. Such extended release forms can be used to reduce dosing frequency from twice or three times a day to once a day. Solving this problem can require additional invention and therefore allow the formulation to be patented in its own right. Provided the new formulation is launched and established on the market before the basic compound patent expires, it can provide valuable additional exclusivity for the innovator.
A good example of how such a strategy has been successful is AstraZeneca’s Seroquel XR, which is an extended release, once a day quetiapine formulation. This formulation was launched in 2008 and by 2011 was achieving worldwide sales of over $1bn in its own right. The patent for the XR formulation expires in 2017: although a number of generic companies are challenging the patent, if upheld it may provide AstraZeneca with exclusivity for an additional five years after expiry of the basic quetiapine patent.
Another common way to extend the exclusivity of a product is to protect new crystalline forms (polymorphs) of the drug. Patent protection for a new crystalline form of a compound can be extremely valuable, for example, if the new form possesses a desirable physical property, such as improved stability, or if it is an unavoidable component of a commercial drug product, so that competition is postponed whilst third parties try to design around the patent to avoid making this polymorph and avoid infringement. Increasingly, the use of polymorph patents has also become an important strategy for generic companies vying to keep their competitors off the market for as long as possible. The European Patent Office’s practice in respect of claims to crystalline forms has evolved with time and over recent years it has tightened its approach to the allowance of such claims.
Where an invention relates to a crystalline form of a known compound (‘compound X’), but which was only known in amorphous or oil form, it was formerly possible to obtain a broad claim to ‘crystalline compound X’ at the EPO. However, such claims are now routinely objected to by the EPO as unclear, and it is now generally necessary to characterise crystalline forms by suitable experimental parameters (such as powder X-ray diffraction, IR spectra or DSC thermograms). Therefore, the first consideration in drafting claims to a new polymorphic form is the selection of a suitable set of experimental parameters with which the crystalline form can be characterised and distinguished over the prior art. Only the minimum number of parameters essential to distinguish over the prior art should be included in the claim to ensure a broad claim scope.
It is not always possible to predict whether the selected parameters will be sufficient to distinguish over prior art uncovered after filing. It is therefore essential to include in the patent application a raft of other parameters (eg, alternative and secondary XRD peaks, XRD peak intensities, IR absorption bands, and DSC thermograms) that can be relied on to provide basis in the event that amendment is needed in view of prior art. The experimental conditions used to produce the new polymorph (eg, temperature, solvent quantities and proportions, seeding step, heating or cooling rates, water content, etc) and obtain the measurements (eg, the wavelength of the X-ray source in the case of XRD, the disc material in the case of IR, and the heating rate in the case of DSC) should also be included to ensure sufficient disclosure.
The assessment of novelty can also present a challenge in polymorph cases. Owing to the fact that characterisation of a particular crystalline form is typically reliant on its internal structure the problem of inherent disclosures can arise when assessing novelty. This is particularly the case where the prior art discloses the same compound and a similar crystallisation procedure or solvent. The EPO and many national courts may then take the view that, although the prior art is silent on the existence and characterisation of the claimed polymorph, it is nevertheless considered to be disclosed. The onus would then switch to the patent applicant to demonstrate that carrying out the prior art process does not inherently result in the same polymorph.
The most significant area in which EPO has tightened its criteria for allowance of claims to new crystalline forms is inventive step. The EPO’s current approach to assessing inventive step or polymorph claims starts from the assumption that polymorph screening experiments are a routine part of the drug development process. Thus, it is becoming standard practice for the applicant claiming a new polymorphic form to be required to demonstrate the existence of an unexpected effect or advantage by the provision of comparative data. It is good practice to provide a discussion of the potential advantages of the claimed polymorphic forms, at least in general terms, so that the description provides support for later-filed experimental data showing an advantage.
Patenting second medical uses and dosage regimes
Claims to further medical uses of known products (‘second medical use claims’) have long been acceptable before the EPO. The wording for second medical use claims currently accepted by the EPO is as follows:
“Substance X for use in the treatment of disease Y”. The EPO has also permitted second medical use claims directed to new treatments of a disease where the use of substance X to treat disease Y was already known in general terms. Examples include those relating to a novel group of subjects to be treated and those relating to a novel mode of administration.
In 2010, the Enlarged Board of Appeal, which is the EPO’s highest legal authority, decided second medical use claims are also permissible where the only novel feature relates to a dosage regime. Examples of dosage regime claims include the following: “Substance X for use in the treatment of disease Y, wherein substance X is administered every morning for a 10 day period.”
“Substance X for use in the treatment of disease Y, wherein substance X is administered at a dosage of 50 to 100 mg/day.”
However, the Enlarged Board has indicated that, in order to meet the requirement of inventive step, the dosage regime defined in the claim must also exhibit a technical effect (such as an improvement or advantage) over the prior art which discloses substance X for treating disease Y in general terms.
Granted second medical use patents prevent generics from packaging and labelling pharmaceutical products for the claimed use. As the indication must be specified on the label to satisfy regulatory requirements, use patents can therefore provide valuable additional exclusivity to pharmaceutical products. Dosage regime claims can be particularly valuable when the claimed dosage is the only one which obtains marketing authorisation, so a generic cannot market the drug without infringing the dosage regime claim.
In summary, formulation, polymorph and second medical use patents can be valuable tools to enable innovator pharmaceutical companies to extend the lifecycle of marketed drug products beyond the expiry date of the basic patent. Generics companies in turn aim to design around such patents or revoke them to clear the way to market, and the consequent disputes between the two will continue to develop the law in this area.
This article was originally published in, and is republished here with the permission of, Pharmacology Matters, published by the British Pharmacology Society.