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Expert Opinion as to What “One Would Expect” is Speculation, not Evidence

March 4, 2015

By Andrew McIntosh and Michael Burgess

In the latest of a trilogy of cases under the Patented Medicines (Notice of Compliance) Regulations relating to the drug tadalafil (CIALIS), Justice de Montigny dismissed Eli Lilly’s application for an order prohibiting the Minister of Health from issuing a Notice of Compliance to Mylan Pharmaceuticals for its generic tadalafil until expiry of Canadian Patent No. 2,379,948 (the 948 Patent). The Court found that Mylan’s allegations that it would not infringe the 948 Patent, and that the claimed subject matter of the 948 Patent was obvious, were justified. The case is Eli Lilly Canada Inc v Mylan Pharmaceuticals ULC 2015 FC 178.

The 948 Patent is directed to a pharmaceutical formulation of tadalafil for treating erectile dysfunction. The formulation has better solubility, stability and bioavailability than previous formulations. The improvement was said to reside in a reduced tadalafil particle size and the use of certain excipients in the formulation.

A key infringement issue was whether Mylan’s formulation contained between about 1% to about 5% by weight of a hydrophilic binder. There was no dispute that Mylan’s formulation had more than 5% of an excipient that acted as a hydrophilic binder. Lilly argued that the excess excipient over the claimed amount acted as a solubilizer, not a binder.  Lilly’s expert opined that “one would expect” solubilizers to be present in the range of about 10% to 12% for a drug like tadalafil and that it would be “normal” for a tablet "normally" to have a binder in the amount of about 2% to 5%. Thus, according to Lilly, Mylan’s excipient had two roles: both as a solubilizer and as a hydrophilic binder. Lilly’s expert opined that, to calculate the amount acting as a binder, one could simply deduct 10% to 12% from the total amount of the excipient in the tablet to account for the amount acting as a solubilizer. According to Lilly and its expert, this approach resulted in Mylan’s formulation having 1% to 5% of a hydrophilic binder as claimed.

The Court summarily rejected Lilly’s evidence about what “one would expect” as being speculative, since there was no evidence as to the extent to which the hydrophilic binder in Mylan’s formulation acted as a solubilizer. In doing so, it stated “Speculation, even by experts, is not evidence, and is clearly not sufficient to meet the burden of proof…”. The Court’s message is clear: a finding of infringement requires more than evidence about what is expected based on the state of the art – it requires evidence about the actual characteristics of the product in issue.

Obviousness was the sole allegation of invalidity at issue. The Court found that the inventive concept of the patent was that the bioavailability of tadalafil would be improved by reducing its particle size and mixing it with select excipients.

Regarding excipient selection, Lilly argued that there is an infinite combination of excipients available to a formulator tasked with formulating a new drug.  It would not be known whether any particular formulation would work, let alone provide the rapid onset found in the patented formulation.  However, the Court observed that textbooks in the area noted that the task was not so daunting, stating “It will become obvious to the formulator, on reviewing the literature, that the total number of significant excipients currently in use is probably less than 25.” One text listed the most common excipients used in tablet formulations, which were the same excipients identified in the 948 Patent.  Accordingly, Justice de Montigny found that there was nothing inventive about the excipients used, and concluded that a person skilled in the art would have had a high expectation of success in using the selected excipients of the 948 Patent in obtaining a tadalafil formulation with the desirable bioavailability, and that it more or less self-evident that such a strategy ought to work.

In relation to particle size, while the prior art did not disclose formulations that gave information about the particle size of tadalafil, it was known that smaller particles should increase the dissolution rate of the tablet and thus bring about more rapid gastrointestinal absorption. The Court concluded it was an obvious strategy to reduce particle size in order to achieve greater bioavailability, stating: “If the person skilled in the art would not be able to predict with any certainty that particle size reduction would improve the bioavailability of tadalafil, it was certainly an obvious strategy, and one for which there was certainly a fair expectation of success.”

The Court therefore found Mylan’s allegations of non-infringement and invalidity were justified, and dismissed Lilly’s prohibition application. Of note, Lilly was successful against Mylan in an earlier prohibition application regarding Canadian Patent No. 2,226,784. As a result, subject to any appeals, Mylan will not receive a Notice of Compliance for its tadalafil product until at least July 11, 2016 when the 784 Patent expires.

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Andrew McIntosh Andrew McIntosh
B.Sc. (Chem.), J.D., LL.B.
416.957.1677  email Andrew McIntosh