The Growing Regulatory Battlefield of the Pharmaceutical Industry
Racemates - With the ongoing pressure within the pharmaceutical industry to develop new products and keep them protected for as long as possible from generic companies regulatory battles are brewing.
Many medicines are chiral molecules; that is they exist in different forms, or enantiomers, that are mirror images of each other, and these forms are known as "S" and "R" or (+) and (-). Chiral compounds can exist as 50/50 mixtures of the single enantiomers, when they are known as racemates.
Because the proteins that drugs target in the body are also chiral, then the effects of each single enantiomer on the target protein can differ. So, for example, one enantiomer may fit well to a particular receptor, but the other may not - like trying to put a left-handed glove onto your right hand. As a result of these differences the single enantiomers of a molecule may exhibit very different therapeutic effects as well as side effect profiles.
If a medicine in development, or even on the market, is a chiral molecule then pharmaceutical companies often try to resolve the racemic mixture into its single enantiomers, although this may not be straightforward, as individual enantiomers have the same physical and chemical properties such as melting and boiling points.There are several benefits of isolating single enantiomers. Firstly, single enantiomers are generally preferred by regulatory authorities over the racemate, so this may help with product approval. Secondly, a single enantiomer may be a better medicine than the racemate, with superior therapeutic efficacy and a better safety profile. Lastly, the development of a single enantiomer from a marketed racemate is a useful product lifecycle strategy in order to extend the exclusivity of the product. Patients and doctors may be persuaded to move from the racemate as it goes off patent to a new single enantiomer medicine protected by new patents and regulatory data exclusivity. Some examples of this approach are the development of the single enantiomer esomeprazole from the racemate omeprazole and the single enantiomer escitalopram from the racemate citalopram.
The legal and regulatory tools allowing innovators to protect a single enantiomer that has been developed from a racemate are patents and regulatory data exclusivity.
In order for a patent to be valid, the invention that it claims has to be new (in that it has not been clearly publicly disclosed before the patent was filed) and must also contain an inventive step over the existing technology.
Two recent cases in the UK have explored these requirements in relation to two single enantiomers resolved from previously marketed racemates; escitalopram and levofloxacin. In these cases, the court adopted the same approach to novelty as the European Patent Office, and said that the fact that the racemate was known, and therefore it was known that the single enantiomer existed, did not, from a legal standpoint, disclose the single enantiomer, because no one had ever been able to make it independently before.
What about the inventive step? All medicinal chemists know that there are various possible routes to resolve a single enantiomer from the racemate, such as reacting the racemate with an enantiomerically pure reagent to create two different salts, separating them and then recovering the optically pure enantiomer. Alternatively, if the synthetic route of making the racemate involves a chiral intermediate then it would be possible, starting with the right stereospecific intermediate, to create the single enantiomer through a series of reaction steps whilst preserving the stereochemistry. However, although these general tools are well known, in the cases of levofloxacin and escitalopram the court said that there were no pointers or guidance within the existing technology as to which techniques would work and which reagents to use to resolve these particular enantiomers. The solution could only be obtained by carrying out a research programme and therefore the patents were inventive and valid.
Regulatory Data Protection
If you can obtain a patent to cover a single enantiomer then you get a 20 year period of protection, but if you cannot, for example if it is easy to resolve the racemate and therefore not inventive, can you rely on regulatory data protection to keep competitors at bay? By way of background, the data that innovators submit to regulatory authorities to obtain a marketing authorisation for their product is protected, such that generic pharmaceutical companies cannot refer to it for a period of eight years from the grant of the innovator's marketing authorisation. After that, they can refer to it to support their "abridged" application for a marketing authorisation for that product, but cannot launch their generic product for a further two years (or three years if the innovator has obtained new indication for the product that is of significant clinical benefit). In this way the innovator is rewarded with 10 or 11 years exclusivity for the effort and expense that it has incurred to carry out clinical trials to show that the product is safe and effective.
In order to obtain a marketing authorisation for a single enantiomer, even where the racemate has previously been marketed, the innovator still has to submit a full data package to the regulatory authorities, in accordance with what is known as the chiral guidelines. Some innovators had thought that they would get a full period of data exclusivity for the enantiomer as they equated the requirement to submit a full data package with the designation of the product as a new active substance. However, the law changed in 2005 to the effect that single enantiomers are considered to be the same active substance as the racemate unless they differ significantly in properties with regard to safety and/or efficacy. Therefore, prima facie, a single enantiomer will not get any extra period of data protection over and above that given to the racemate. This defeats the object, from a regulatory point of view, of developing a single enantiomer from a racemate in order to extend the product's lifecycle. Further, it appears that the decision as to whether or not the single enantiomer differs significantly from the racemate will be made at the time of the generic application, not when the innovator's authorisation for the single enantiomer was originally granted. But this issue is currently a matter of dispute in the European courts.
Supplementary Protection Certificates
Returning to patents, it is possible to obtain an extension in Europe, called a Supplementary Protection Certificate (SPCs), of up to five years to the basic 20 year patent term. However, the scope of the patent protection during this extra period is limited to covering a product that falls within the patent claims, rather than simply extending the patent across its full scope. In order to obtain this extra period of protection, several requirements have to be met, one of which is that the product that falls within the claims of the patent is covered by a marketing authorisation. Further, this marketing authorisation must be the first authorisation to place the product on the market as a medicinal product. In a very recent case relating to an SPC for the single enantiomer levofloxacin, a generic company argued that the SPC was invalid because the marketing authorisation for the racemate ofloxacin was the first marketing authorisation for that product as the racemate contained the single enantiomer. The Court disagreed and the SPC was valid. The main reason it gave was that there were significant differences in the activity of the two single enantiomers and the racemate, so they were not the same product, although to the observer the differences in this case do not seem to have been that great.
Single enantiomers are important products for pharmaceutical companies. They can be protected by patents, SPCs and data exclusivity. Clearly, for innovators, the more layers of protection for the product, the better, but to achieve the maximum protection the single enantiomer has to satisfy some quite disparate requirements. So, to obtain patent protection the resolution of the single enantiomer has to overcome some technical difficulty. Then when obtained, the single enantiomer must also exhibit significant differences from the racemate in terms of safety and efficacy in order to obtain data exclusivity protection and also the protection of an SPC. As the pressure on pharmaceutical companies to find more new products to fill their pipelines intensifies, the legal and regulatory battles in this field will only intensify as well.