Eli Lilly Inc v Mylan Pharmaceuticals ULC, 2015 FC 178

The Federal Court rejected an application by Eli Lilly Canada Inc. (“Eli Lilly”) to prohibit the Minister of Health from issuing a Notice of Compliance to Mylan Pharmaceuticals ULC (“Mylan”) for Mylan’s generic version of tadalafil and accepted Mylan’s Notice of Allegation that the relevant patent, Eli Lilly’s Canadian Patent No. 2,379,948 (the ‘948 Patent), is not infringed and is nevertheless invalid for obviousness. [1-3] Mylan did not infringe the ‘948 Patent because Mylan’s tadalafil compound did not have the claimed particle size distribution and the formulation did not contain the claimed concentration of hydrophilic binder. [95, 133] In doing so, the Court rejected two purposive arguments by Eli Lilly in favour of a more literal reading of the patent. [91, 104] The ‘948 was deemed obvious because its only inventive concept, the improvement of the dissolution and stability of tadalafil, [138] was achieved by selecting entirely conventional excipients in conventional proportions that were obvious or at least obvious to try, [149-150] and by reducing the particle size of tadalafil which was also obvious or at least obvious to try. [154]

The chemical structure of tadalafil and its use in erectile dysfunction were disclosed in a prior patent. [7] The problem, however, was the poor solubility of tadalafil. [8] Eli Lilly’s ‘948 Patent is directed to a pharmaceutical formulation of reduced particle size tadalafil with particular excipients, [1] with the standard goal of achieving uniform potency and desirable stability and bioavailability characteristics. [6] Reading the specification, the skilled person would understand that the salient effects of the claimed formulation results from the chosen excipients and the chosen particle size distribution of tadalafil. [12] The ‘948 Patent contains 33 claims, all of which depend from independent claim 1. [19] The claimed particle size distribution and excipients are listed in claim 1:

1. A pharmaceutical formulation comprising a compound having the structural formula

wherein said compound is provided as free drug comprising particles wherein at least 90% of the particles of the compound have a particle size less than about 40 microns; about 50% to about 85%, by weight, of a water-soluble diluent; a lubricant; about 1% to about 5%, by weight, of a hydrophilic binder selected from the group consisting of a cellulose derivative, povidone, and a mixture thereof; and a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and a mixture thereof.

Emphasis is added to the claimed particle size and claimed concentration of hydrophilic binder, elements which Mylan successfully argued it did not infringe.

There was generally no dispute over the person skilled in the art or their common general knowledge. The skilled person would be a pharmaceutical formulator with experience in a pharmaceutical research setting and, in particular, measuring particle size. [76] There was also little dispute over claim construction except with respect to the time when particle size should be measured, as discussed in the infringement section below. [77]

Mylan-Tadalafil Does Not Infringe

Mylan successfully argued that two elements of claim 1 were not infringed by its Mylan-Tadalafil compound. First, Mylan-Tadalafil tablets does not contain tadalafil particles of the same size distribution claimed in the ‘948 Patent. [106, 133] Second, Mylan-Tadalafil tablets do not contain the “about 1% to 5% hydrophilic binder” also required by independent claim 1. [95]

On particle size distribution argument, the critical issue was the time at which particle size should be measured. [120] Eli Lilly argued for a purposive interpretation that is contrary to the wording of the ‘948 Patent. The patent states that particle size is measured prior to formulation, [103] but Eli Lilly asserted that particle size should be measured after formulation since this is the point in time when affecting bioavailability, which is the aim of the invention, can occur. [102] The Court rejected Eli Lilly’s argument, siding with the wording of the patent and with the normal pharmaceutical practice that particle size is typically measured prior to formulation. [104]

Also on particle size, Eli Lilly argued that Mylan’s data on pre-formulation particle size was unreliable, particularly with regard to the risk that the data included measurements of large agglomerates of tadalafil rather than just tadalafil itself. [110] The Court ultimately decided that it was not necessary to conclude on the accuracy of this data to determine that Eli Lilly did not meet its burden of proving that Mylan-Tadalafil employs the claimed particle size distribution. [114] The matter was not thoroughly addressed by the experts, [114] and curiously Eli Lilly’s own expert did not produce the data of his own particle testing that might have proved otherwise. [120] Eli Lilly had objected that discoveries are not held in NOC proceedings. [120] Eli Lilly’s further argument that the milling process used for Mylan-tadalafil would bring the particle size within the claims of the ‘948 Patent was similarly dismissed for lack of evidence. [128]

On hydrophilic binder concentration argument, Eli Lilly’s main assertion was that a particular unnamed compound that was highly prevalent in Mylan-Tadalafil was acting as both a solubilizer and a hydrophilic binder, but was acting as a hydrophilic binder in a proportion that brought it into the purview of the ‘948 Patent. [84-85] The Court rejected this argument as resting on multiple layers of speculation, [86] and relied on the fact that the compound was listed only as a “binder” in Mylan’s regulatory submission to determine that the whole proportion of the compound should be deemed a binder and thus outside of the purview of the patent. [91] The identity of the particular compound and its precise concentration in the formulation was redacted.

The ‘948 Patent is Obvious

The inventive concept, as agreed upon by the expert witnesses, could be expressed as “the improved dissolution and stability of tadalafil achieved by reducing its particle size and formulating it with specific excipients.” [138] However, the poor solubility of tadalafil would have been readily ascertained, and it was within the common general knowledge of the skilled person that the dissolution rate of a poorly soluble drug can be increased through the use of excipients and by reducing the particle size of the drug compound itself. [142] Thus, “[t]he only difference between the inventive concept and the common general knowledge, therefore, lies in the use of particle size reduction and the exact amounts of these excipients in a formulation with tadalafil.” [142, emphasis retained]

Unfortunately for the validity of the ‘948 Patent, it uses conventional excipient categories and selects the most common excipients within those categories, and uses those excipients in amounts that are very similar to the suggested ranges in the prior art. [147] Based on these findings, and with support of Mylan’s expert who thought making minor adjustments from what is in the prior art to suit the formulation of tadalafil would be obvious, and which were even referred to as “conventional” by Eli Lilly’s own formulation scientists, [148] the Court concluded that there was nothing inventive about the formulation disclosed in the ‘948 Patent. [149] The Court also added that it would have been obvious to try the excipients in the ‘948 Patent to achieve the tadalafil tablet, since the skilled person would have had better than a fair expectation of success in using the excipients, and it was more or less self-evident that the strategy ought to work. [150-151]

Furthermore, it was obvious to try particle size reduction to improve bioavailability of tadalafil. [154, 159] Reducing particle size to improve solubility was well within the common general knowledge, [142] and the Court agreed with Mylan’s expert that the extent of effort required to achieve the invention through particle size reduction would have been no more than routine testing. [159]

Commentary

This case illustrates what can sometimes be a tension between the plain wording of the specification and a purposive interpretation of the invention by an expert. This was a theme in both of the infringement arguments. First, Eli Lilly argued that particle size should be measured at the time when an expert understood that particle size would matter – that is, after formulation. Second, Eli Lilly argued that the unnamed compound should be considered a hydrophilic binder when it matters – that is, when it is acting as a binder (as opposed to when it is acting as a solubilizer). Both of these arguments were rejected in favour of a literal reading of the patent (and in the case of the hydrophilic binder, also regulatory documents), and highlights the power and responsibility that a patent agent has to confine the science of the invention within their chosen boundaries in the patent.