Not worth its salt: Merck's patent application covering JANUVIA® does not survive Teva's opposition

Introduction

In a decision[1] rendered earlier this month, the Deputy Commissioner of Patents, Jacqueline Bracha, allowed an opposition filed by Teva Pharmaceutical Industries Ltd. ("Teva") against a patent application filed by Merck, directed to the dihydrogen phosphate salt of sitagliptin, the active ingredient in Merck's blockbuster diabetes drug JANUVIA®. Merck's application was denied on the grounds of both lack of novelty and lack of inventive step. 

Factual Background

In 2001, Merck filed a patent application directed to a Markush formula covering a class of dipeptidyl peptidase-IV ("DPP-4") inhibitors, which were said to be useful in the treatment of diabetes. The international application was published as WO 03/004498 ("WO '498"). WO '498 specifically disclosed 33 compounds. For seven of these compounds, examples were provided which described the preparation of their HCl salts. Example 7 described the preparation of the HCl salt of sitagliptin. WO '498 also included a claim (claim 15) directed to all 33 compounds and pharmaceutically acceptable salts thereof.

WO '498 further included a list of eight "particularly preferred" acids for the preparation of salts, which included phosphoric acid.

Two years later, in 2003, Merck filed another patent application, directed to the dihydrogen phosphate salt of sitagliptin ("the DHP salt"). The DHP salt is a 1:1 salt, namely—it comprises one molecule of sitagliptin and one molecule of phosphoric acid. Following the acceptance of Merck's application by the examiner in Israel, Teva opposed the application, in accordance with the pre-grant opposition system which was adopted in the Israeli Patents Law, 1967.

Teva's opposition was mainly based on the grounds of lack of novelty and lack of inventive step. Essentially, Teva argued that the DHP salt was anticipated by WO '498, since the specific disclosure of sitagliptin and the identification of phosphoric acid as a particularly preferred acid, amounted to the disclosure of a phosphate salt of sitagliptin. Teva further argued that the DHP salt was the only stable phosphate salt that would be expected to result, and actually results, from a reaction of sitagliptin and phosphoric acid.

Teva further argued that, at the very least, the DHP salt would have been obvious to a person skilled in the art in view of the teachings of WO '498 and the common general knowledge at the priority date.

Merck denied Teva's arguments. Merck's focus centred on two arguments: First, Merck argued that WO '498 disclosed a very broad class of compounds, as well as a broad list of possible salt formers. In addition, no teaching can be drawn from the identification of certain acids as being "particularly preferred", since this was merely boilerplate language. Thus, according to Merck, nothing in WO '498 disclosed, or directed a person skilled in the art to prepare, a phosphate salt of sitagliptin. Second, Merck argued that a number of phosphoric acid salts of sitagliptin were possible.

The Decision

With respect to novelty, the Deputy Commissioner held that for a publication to be regarded as disclosing a species, the species need not be expressly exemplified; rather, it suffices that the species was disclosed as part of a genus for a question of novelty to arise. The Deputy Commissioner noted that this approach differs from the "individualised description" approach adopted in the UK, according to which a Markush formula does not take away the novelty of a species not expressly disclosed.

In the present case, although WO '498 did not expressly disclose the DHP salt of sitagliptin, it nonetheless described the preparation of seven bases, including sitagliptin, and eight "particularly preferred" acids, including phosphoric acid. Thus, the group from which selection was recommended in WO '498 was limited, and consisted of only 56 members.

By claiming sitagliptin as a free base, as well as its pharmaceutically acceptable salts in WO '498, Merck expressed its position that each of these salts was useful. Furthermore, Merck identified eight "particularly preferred" acids in WO '498, and therefore cannot deny their preference over other acids. Importantly, the Deputy Commissioner rejected Merck's argument that this was merely "boilerplate language". That argument, according to the Deputy Commissioner, runs counter to the very basic principle that patents are granted subject to the disclosure of an invention to the public, and counter to the ability to rely upon the information disclosed by the inventor.

Thus, the Deputy Commissioner held that WO '498 should be regarded as disclosing the preparation of a phosphate salt of sitagliptin.

The Deputy Commissioner then turned to determine whether the specific phosphate salt claimed in Merck's patent application – namely, the DHP salt – was inherently anticipated in WO '498. For this purpose, the Deputy Commissioner needed to determine whether any phosphate salt, other than the DHP salt, could result from a reaction of sitaglitpin and phosphoric acid. This question was addressed by the experiments submitted by the parties. Since the theoretical basis of these experiments focused on a rule for evaluating the likelihood of salt formation, known in the art as the ΔpKa rule, the Deputy Commissioner began by addressing the parties' arguments in this regard.

The Deputy Commissioner agreed with Teva that the ΔpKa rule was widely accepted. Based on the ΔpKa rule and the available information at the priority date with regard to the pKa values of sitagliptin and phosphoric acid, a person skilled in the art would have expected only the DHP salt to form in a reaction between sitagliptin and phosphoric acid (the Deputy Commissioner noted, however, that such expectation, in and of itself, was relevant to the analysis of inventive step, rather than novelty).

Turning to the experiments submitted by the parties, the Deputy Commissioner held that Merck failed to establish that a phosphate salt other than the DHP salt can actually be formed when reacting sitagliptin and phosphoric acid.

Based on the above, the Deputy Commissioner held that the claimed invention was indeed anticipated by WO '498 and lacked novelty.

Notwithstanding the above, the Deputy Commissioner went on to address the parties' arguments with respect to inventive step. According to the Deputy Commissioner, it was undisputed that sitagliptin was already known at the priority date, and that it was unstable and poorly soluble. Thus, sitagliptin could not have been used as the free base. In order to overcome these difficulties, it was commonplace to prepare salts. Salt selection was a common process in the pharmaceutical industry, which included the reaction of a compound with various acids to form salts. It transpired that Merck's own expert, Prof. Atwood, was of the opinion that the ΔpKa serves as guidance to salt selection.

In the present case, the possibility of obtaining a salt and the manner for doing so were already known from WO '498, as was the list of particularly preferred acids. The ΔpKa rule also pointed to a very high likelihood of obtaining the DHP salt. No evidence was presented by Merck of there being any difficulties in obtaining the DHP salt, or any other salts that were tried. Based on the teaching of WO '498, Merck faced a very limited salt selection process. Indeed, Merck's own factual witness testified that the process was short. In view of the foregoing, the Deputy Commissioner concluded that the claimed invention also lacked inventive step.

Comment: an applicant cannot brush off its own statements in an earlier patent/application as "boilerplate language" to avoid anticipation and/or obviousness

An important aspect of the Deputy Commissioner's decision is the rejection of Merck's argument that its own statements in WO '498 were merely "boilerplate language" and would have provided no guidance whatsoever to a person skilled in the art. The decision emphasizes the rationale underlying the patent system, and makes it clear that applicants cannot brush off their own statements in previous patents/applications as being uninstructive to the public. The Deputy Commissioner's decision is of particular significance in the field of pharmaceutical patents, where brand manufacturers frequently attempt to extend the patent protection afforded by a compound patent by seeking subsequent patents covering various aspects of the same drug, e.g., salts and formulations (a practice often referred to as "evergreening"). Where subsequent "inventions" such as these have already been envisaged in the compound patent itself, the patentee will not be allowed to dismiss his own statements as being of no instructive value.

Adv. Tal Band and Adv. Noam Blei represented Teva in these proceedings.