Polymorphism refers to the ability of a compound to exhibit more than one crystalline form. Each polymorph exhibits different physical properties such as density, solubility, melting point, and stability under storage or use conditions, among others. Solid state characterization techniques provide electromagnetic spectra with particular data for a polymorph through which it can be distinguished from others.
In the pharmaceutical field, polymorphs are important because of advantageous properties such as better solubility, compressibility, and/or bioavailability; however, they may also exhibit undesired side-effects as in the case of deformities in children by maternal intake of a crystalline form of thalidomide during pregnancy.
A drug may show to be effective only through a determined polymorph. Therefore, the selection of polymorphs is typical in healthcare-related patents because of the regulatory barriers to market entry for products in this industry and the advantages of polymorphs as pharmaceutical active ingredients.
However, protection of crystalline forms is sometimes a real challenge in Mexico.
The Mexican Industrial Property Law (MIPL) establishes the following:
"Article 19: Will not be considered inventions for the purposes of this Law:
VIII. The juxtaposition of known inventions or mixtures of known products, variations in their use, form, dimensions or materials, unless actually it is about a combination or a merger so that they cannot function separately, or that the qualities or characteristic functions thereof are modified to obtain an industrial result or use not obvious to a person skilled in the art."
It seems that article 19, section VIII obliges the applicant to a burden of proof, particularly when the compound is already disclosed in the prior art, since the crystallography is being construed as a routine experimentation. Thus, some examiners of the Mexican Institute of Industrial Property (IMPI) take a strict position in terms of the inventive step requirement, as sometimes they consider that the production of a polymorph is achieved through routine experimentation, and an inventive step is not involved, so it becomes difficult to convince Mexican examiners about the inventiveness of patent applications regarding crystals which contain characterization tests as the only experimental evidence.
Moreover, Mexican examiners have adopted common criteria in considering a crystalline form as a product without involving an inventive step if the application does not contain experimental data other than characterization techniques. So, examiners require proof which demonstrates the advantageous technical effect provided by such crystalline form over the amorphous form known, particularly when the compound in amorphous or another crystalline form is already known in the art.
However, it is important to consider that until now, there is no an infallible method for predicting that a specific compound is going to have polymorphs and the technical features of the same. From a thermodynamic point of view of polymorphism, the thermodynamic stability and the time it takes for a transformation to equilibrium should be considered. The pharmacokinetics of this transformation will finally establish the type and stability of the polymorphs.
The existence and identity of polymorphs is not predictable, and even if it were possible to predict that a compound might be susceptible to having polymorphs and what their structures might be, generally a person skilled in the art could not deduce how to produce a specific polymorph (eg, crystallization conditions) or predict its properties.
Frequently the crystallization of new polymorphs requires between hundreds and thousands of experiments that analyse the effects of various parameters such as temperature, solvents and mixtures thereof, mixing time, cooling rate, agitation rate and concentrations, as well as methods and processes for the precipitation, cooling, evaporation, and thermal cycles.
In this way, the number of crystallization conditions is so great that if it were possible to predict the most stable crystalline form, a person skilled in the art would not have defined a series of specific experiments or variables on which it could be based for its production.
The rationale above has been successfully used to overcome objections made by Mexican examiners when inventive step is questioned based on the idea that polymorphs are obtained by routine experimentation and when there are enough experiments described on the application showing how different parameters of the specific crystallization procedure were defined, for example, by trial and error.
Nevertheless, in order to face the challenge of protecting polymorphs in Mexico with the highest chances of success and to demonstrate without a doubt the inventiveness of polymorphs, it is recommended that applicants include further evidence duly supported by examples and comparative examples in addition to solid state characterization techniques.
This evidence should be specially focused on demonstrating an advantage and/or unexpected effect of said polymorph when compared with the amorphous form of the compound or already known crystalline form.
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.