For about at least three years, the Mexican patent examiners have adopted the practice of issuing official letters in order to reject the term "prodrug", arguing that the meaning thereof is neither restricted nor clearly supported by the patent application description. These rejections are based on the grounds of Article 47 of the Mexican Industrial Property Law (MIPL), wherein Section III states the following:
"The patent applications must be accompanied by:
III.- One or more patent claims, which must be clear and concise and may not exceed the content of the description.
In reference to the particular, it is important to point out that numerous applicants have demonstrated their disagreement with such rejection, saying that the meaning of the term "prodrug" should be well-known and perfectly understood by any person possessing average skill and knowledge in the discipline, especially considering that in several scientific publications the use of the prodrug concept in the design of drugs with improved pharmaceutical, physicochemical and biological properties has already been discussed in detail.
As a reference, applicants mention that Albert1 defined the term prodrug as "a substance which, after being administered and combined with some receptors, is converted in the final substance". This definition includes metabolites of administered drugs that are the original active drug species as well as biologically active compounds, which are chemically modified to alter their absorption, distribution, etc. Harper2, on the other hand, explained the "prodrug" concept by defining the term drug latentation as "the chemical modification of a biologically active compound to form a new compound, which will liberate the parent compound upon in vivo enzymatic attack".
In this sense, it is believed that the rejection of the term "prodrug" does not arise merely from the presumed lack of knowledge about its meaning, but rather from the fact that the chemical nature of the claimed prodrugs, as in Europe, is not clearly defined by the description of the patent in question nor by the examples provided, which, in some cases, do not allow a complete determination of which compounds can be considered within the scope of the invention.
It is important to emphasize that according to the provisions of Article 47 of the MIPL and Article 29 of its Rules and Regulations, the claims must be clear and concise and must not exceed the contents of the description; that is, the claims should clearly and precisely define the matter for which the applicant seeks protection. Therefore, simply mentioning the term "prodrug" in a particular claim does not appear to be sufficient to clearly define the matter to be claimed.
Concerning this particular issue, the Mexican examiners believe that within the pharmaceutical industry the term "prodrug" does not have an accurate meaning that allows an unambiguous determination of whether or not a specific compound falls within the claimed scope and is appropriate for patentability. This opinion prevails even in those cases in which the description of the patent application reveals the definition of "prodrug", by establishing, for example, that "a prodrug is a pharmaceutically acceptable ester and amide derivative, wherein the resulting product, obtained from the biotransformation of the derivative, is the active drug". However, and despite this definition, the examiners claim that the chemical nature of the compound remains undefined; an entirely questionable opinion given that, for many experts on the subject, the above assertion should be interpreted as a clear definition of the chemical nature of the prodrug, so that claiming the ester, amide, etc. of the drug itself should also be perfectly valid.
While it may be true that the position of the Authorities is rather drastic and clearly tends to restrict the scope of the claims, it is also true that should the applicant be able to demonstrate which compounds are those that can be transformed from the original drugs, undoubtedly, it would be possible to argue against it, since once the chemical structure of such prodrugs had been established, the compounds could be defined based on their structural characteristics.
On the other hand, the examiners point out that as the structure of every possible prodrug may vary in relation to its parent compound, it is also very likely that their type of activity differ in relation to the activity of said parent compound as well. Thereby such prodrugs could indeed be considered a distinct invention. In this case, the application would not only be unclear but would also lack of inventive concept, thus infringing that stipulated by both, Article 47, Section III and Article 43 of the Mexican law respectively.
Concerning this specific point, it is worthwhile to emphasize that the essentially unanimous opinion of the Industrial Property agents in Mexico is totally contradictory to that of the authorities, because if it is considered that a prodrug is directly derived from a compound, its essence prevails and the desired activity is certain to take place. Even though the aforementioned activity may be improved, neither indication nor any argument whatsoever exists to establish that for this reason the prodrug lacks of inventive concept. Contrary to what might be believed, that concept is irrevocably evidenced in view of the fact that the compound and its prodrug share a common chemical structure, and also simply because the drug is directly produced from the prodrug.
Likewise, although not recurrently, the term prodrug also tends to be rejected when the patent application neither contains any explanation about which experiments must be carried out in order to obtain the claimed prodrugs, nor explains how the given prodrugs should be tested in order to determine whether or not they are appropriate. Judging by the nature of this type of rejections, it would appear what the examiner aims is a demonstration that an expert in the field has carried out the experiment "in vivo" and that from the results thereof has determined which specific compounds can be considered within the claimed scope. Otherwise, the simple mention of the term prodrug, without any additional substantiation in the application description, would lead to an unclear set of claims and would not allow the aforementioned expert to be able to carry out the claimed invention.
There is no agreement with the authorities concerning this point either. It is assumed that by simply reading the invention description an expert in the field should be able to identify which compounds qualify as prodrugs, bearing in mind that the preparation of the given compounds is independent. Preparing a compound, once the compound is known, is different than determining whether or not it is a prodrug.
In light of the above, and taking the distinct rejections issued by the authorities with respect to the term prodrug into consideration, it is quite evident that if applicant does not have a clear idea of the exact nature of the compounds that fall under this concept, the protection of these compounds would be practically impossible. If the mentioned prodrugs have never been proved or synthesized, there would not be any manner of defining this matter and its rejection would be without doubt eminent, because it would be considered as a clear intention of increasing the scope of the invention, thus contravening the aforementioned Article 47 fraction III of the Mexican Industrial Property Law.
In conclusion, if the applicant would be able to demonstrate which compounds are appropriate to be considered as prodrugs, there would be no apparent reason for which their chemical structure could not be determined or for which the corresponding claims that include the structural characteristics thereof could not be then established, instead of simply defining the matter for which protection is sought based on the result to be obtained by it.
The above implies that if a specific prodrug is claimed and fully supported by the application description, there should not be any obstacle for the given prodrug to be claimed, especially if it is proved that the compound is indeed a prodrug. The application description is precisely what enables and provides support to the matter being claimed, in addition to strengthening the former before any rejection related to the topic in question.
1. A. Albert, "Selective Toxicity", 2nd Ed. New York, NY, 1960.
2. J. Harper, "Absorption and Distribution of Drugs". Ed. Williams.
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