Monday, August 9, 2010

Unpredictable but not surprising: enantiomer patents and obviousness

There was some big news last Wednesday in a case I was involved in - a decision by the Federal Court regarding a patent for repaglinide. We (Gilbert's) argued successfully in a PM(NOC)application for Cobalt that Canadian patent no. 2,111,851 (owned by Novo Nordisk) should be invalid - although see the footnote.*  This is a big deal because the '851 is an enantiomer patent.  There were significant findings of fact and law that should be widely applicable to patents covering enantiomers.

Here's an article by Sana Halwani on the decision.

Unpredictable but Not Surprising
The Federal Court clarifies the application of the obvious-to-try test

On August 3, 2010, the Federal Court released reasons in Novo Nordisk Canada Inc. et al. v. Cobalt Pharmaceuticals Inc. et al. (2010 FC 746; “Novo Nordisk”)) finding Cobalt’s allegation of obviousness justified with respect to Canadian Patent No. 2,111,851. The patent covers repaglinide (an (S) enantiomer), its use for the treatment of Type 2 Diabetes, and processes to make it.

Novo Nordisk
is an important case both from legal development and commercial perspectives. The Federal Court has made clear that scientific knowledge evolved after 1987, the date considered by the Supreme Court of Canada (“SCC”) in Sanofi, and that by 1991 it was the state of the art to separate and test enantiomers of racemic potential drugs. This decision refines the obvious-to-try test set out by the SCC and suggests a review of all enantiomer patents applied for in or after 1991.

The decision in a nutshell

The patent involved in this proceeding (the “851 Patent”) essentially covers the enantiomer repaglinide. Repaglinide is sold under the brand name GLUCONORM™.

Enantiomers are mirror image molecules that cannot be superimposed on each other (think of right and left hands). They are normally synthesized together, as a “racemate”, and one cannot know how each of the two enantiomers comprising the racemate (denoted (S) and (R)) will act in the body until it has actually been made and tested. Activity and toxicity can be different as between the racemate, the (S) enantiomer and the (R) enantiomer.

Unlike other recent cases, the racemate comprising repaglinide was never approved or marketed as a drug product, although the racemate had been identified in a previous “genus” patent covering numerous compounds, as well as a patent covering new solid forms of the racemate.

Nonetheless, Cobalt alleged repaglinide to be obvious, and the 851 Patent to be invalid on this and other grounds. The Court agreed and found the 851 Patent obvious to try.

This is only the second decision known to the author in which the Court found allegations of invalidity of an enantiomer patent justified.

Refining the obvious-to-try test

In the Sanofi case, the SCC dealt with an enantiomer patent and in that context, set out the obvious to try analysis applied by the Court to repaglinide in this case. The obvious to try factors include asking whether it is more or less self-evident that what is being tried (i.e. the invention) ought to work.
In answering this question, the SCC stated:

As I have observed earlier, Shore J. found that the skilled person would not know, before separating this particular racemate into its isomers and then testing the separated isomers, that the properties of the dextro-rotatory isomer [(R) enantiomer] would be different from the properties of the racemate or the levo-rotatory [(S) enantiomer] isomer (para. 81). Similarly, he found that the person skilled in the art would not know before trying the different salts in combination with the dextro-rotatory isomer what the bisulfate salt’s beneficial properties would be (para. 82).

Just because there are known methods of separating a racemate into its isomers does not mean that a person skilled in the art would necessarily apply them. The fact that there are such known methods of separation will be of no account if the evidence does not prove that it was more or less self-evident to try them. It is true that at the relevant time there was evidence that a skilled person would know that the properties of a racemate and its isomers might be different. However, a possibility of finding the invention is not enough. The invention must be self-evident from the prior art and common general knowledge in order to satisfy the “obvious to try” test. That is not the evidence in this case. [emphasis added]

At its broadest, this holding would mean that – in the case of an enantiomer or other selection patent – the discovery of advantageous properties could be the foundation of a valid patent, as long as the properties were not predictable in the particular selection of compounds. Given that routinely-identified properties (such as toxicity, solubility, pharmacokinetic profile, etc.) are often unpredictable, it was unclear how this holding would be reconciled with previous jurisprudence suggesting that routine testing may not qualify as an inventive step.

Novo Nordisk addresses this seeming tension by clarifying that unpredictable but unsurprising properties are not necessarily a bar to a finding of obviousness.

The Court found that an enantiomer claim can be obvious even if the enantiomer’s advantages were unknown. In addition, the Court held that it was impossible to predict what the differences in the pharmacokinetic profiles of enantiomers would be before actually separating and testing them. Nevertheless, as of 1991, it was known that these differences could well exist, and that it was, therefore, important to test for them.

The Court held Cobalt’s allegation of obviousness justified even though the Court found that there was no clear preference for one enantiomer or the other expressed in the prior art, and that the advantages of the (S) enantiomer were not previously identified. The basis of this finding was that pharmacokinetic properties that differ between enantiomers would inevitably have been discovered as a result of testing that was a routine part of the state of the art in 1991.

The evolution of enantiomer science

In addition to refining the obvious to try test, this decision should make all patentees ask the question: “Are enantiomers patentable after 1991?”

In Sanofi, the SCC found that as of 1987 there was little motivation to pursue enantiomers. The relevant date in Novo Nordisk is in 1991. The Federal Court found it clear on the evidence that by 1991:

- the world had evolved and it was now the state of the art to separate and test enantiomers;

- techniques for separating racemates into their isomers were generally known; and

- testing enantiomers for differences in pharmacokinetic properties was a routine matter.

The evidence in this case included the fact of an enantiomer policy approved in 1989 by Dr. Karl Thomae GmbH – the patent owner – which confirmed that “A forced move towards the development of enantiomer-pure active substances results out of the necessity to minimize development time and costs, as well as in order to comply with the current state of the art. The development of racemates will thus only still be justifiable in exceptional circumstances” [emphasis added].

This decision also highlights the importance of strong evidence of how drug development was actually undertaken at the relevant time.

The Court specifically contrasted the evidence presented by Cobalt in this case to that presented in the recent Lundbeck case, where the evidence was found to be “appallingly thin”. In Novo Nordisk, Cobalt’s experts all had significant drug development experience – none was simply an academic talking head.

* * *

Moving forward it will interesting to see how other Federal Court decisions grapple with the issue of unpredictable but not surprising properties of compounds claimed in selection patents.

Sana Halwani
August 4, 2010

* Technically, as it was a PM(NOC) application, we argued that the plaintiff had not rebutted our assertion that the patent was obvious, which is not the same as the court declaring the patent invalid. The '851 patent still exists in Canada and can be asserted against anyone, including Cobalt. The valuable part of the win in purely Canadian terms is that Cobalt now has permission from Health Canada to market generic repaglinide in Canada - it has received a Notice of Compliance.

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