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.

Legal Tools

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.

Patents

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.