Pharma in brief - Canada: Federal Court prohibits the approval of a generic prodrug [CELLCEPT® (mycophenolate mofetil)]

July 2011 Author: Jason Markwell

Contacts

Case: Hoffmann-La Roche Limited v. Apotex Inc. et al.

Drug: Mycophenolate mofetil (CELLCEPT®)

Nature of case: Application pursuant to section 6 of the Patented Medicines (Notice of Compliance) Regulations

Successful party: Hoffmann-La Roche Limited

Date of decision: July 13, 2011

Summary

On July 13, 2011, the Federal Court allowed an application by Hoffman La-Roche Limited (“Roche”), pursuant to section 6 of the Patented Medicines (Notice of Compliance) Regulations, for an order prohibiting the Minister of Health from issuing a Notice of Compliance to Apotex Inc. (“Apotex”) in respect of its generic version of the drug mycophenolate mofetil (“MMF”) until after the expiry of Canadian Patent No. 1,333,285 (the “285 Patent”).

The Decision of the Federal Court

Apotex asserted in its Notice of Allegation that each claim of the ‘285 Patent was invalid for obviousness and lack of utility, inter alia. Roche denied these allegations and sought an Order preventing the Minister from approving the Apotex Product until after the expiry of the ‘285 Patent. Roche relied on a single claim of the ‘285 Patent pertaining to MMF, the morpholinoethyl ester of mycophenolic acid (“MPA”). MPA was known to be useful as an immunosuppressive drug; however, it exhibited poor bioavailability and solubility.

Construction

The Court held that “the task of construing a patent does not simply involve a search for that morsel of utility on which the patent holder hopes to rely.” Rather, “the Court must review the patent’s specification with an eye to the essence of the invention, appreciating how a skilled person would interpret the words used to describe it”. A patent holder “cannot read up the invention for obviousness and read it down for utility.” In this case, the Court held that the “the essence of the invention lies in the identification of a prodrug version of MPA. A prodrug is really a delivery system for a payload; here, MPA is the payload. The sole mission of MMF is to deliver MPA. MMF has no independent beneficial properties.”

Utility

The Court held that the promise of the 285 Patent was “the enhancement of MPA’s bioavailability through a prodrug – specifically, a mofetil ester of MPA – that has advantageous pharmacokinetic properties and improved activity over MPA, making it useful for the treatment of a variety of conditions, and as an immunosuppressive agent, in mammals, including humans”.

The Court held that the utility of the 285 Patent was demonstrated at the filing date. The Court relied specifically on animal data contained in the patent (Example 16), which demonstrated that MMF had “advantageous pharmacokinetic properties that achieve higher concentrations of MPA in the bloodstream at the same dose” and which “showed that MMF could serve as an effective prodrug for MPA.” The Court held that the demonstration of MMF’s effectiveness as a prodrug in animals constituted a demonstration of its utility in humans, as MPA was known to be useful in the treatment of human conditions. Apotex’s allegation of invalidity for lack of utility was not justified.

The Court held in obiter that the utility of the 285 Patent was also soundly predicted, as the factual basis and sound line of reasoning were disclosed in the patent. The Court held that “a skilled person would have understood that an ester derivative of MPA would have the potential of acting as an effective MPA prodrug by virtue of its conversion to MPA on absorption”. Apotex’s allegation of inutility for lack of sound prediction was not justified.

Obviousness

The Court applied the four-part test for obviousness from Sanofi-Synthelabo Canada Inc. v. Apotex Inc. (2008 SCC 61).

The Court held that the inventive concept of the 285 Patent was “improved gastric solubility in the stomach and improved delivery of MPA to the general circulation compared to when MPA itself is given orally”. A skilled person would have known that a prodrug could be used to overcome the solubility limitations of MPA, and that esters of MPA were known to have therapeutic properties; however, no ester of MPA had been shown to have better activity than MPA. While the mofetil ester prodrug of penicillin was disclosed in a prior publication, this would not have been discoverable by a skilled person conducting a reasonably diligent search.

The Court held the claimed invention was not obvious or obvious to try. Several hundred analogues and prodrugs had been screened, but few were promising. Those that were explored proved to be unstable. In due course, the mofetil ester of MPA was tried and it was shown to have better bioavailability than MPA in a monkey model. Overall, this process took more than five years. The Court held that there was “clearly … a motive to find a solution to MPA’s bioavailability constraints, but the prior art was not encouraging.” The inventors “showed persistence in continuing to explore a field of inquiry in which the prior art suggested success was doubtful.” Although hindsight may have allowed one to identify the mofetil ester of penicillin as a key marker, this was not noticed by any skilled person in the field at the time. Apotex’s allegation of invalidity for obviousness was not justified.

Link to decision:

Hoffmann-La Roche Limited v. Apotex Inc. et al. 2011 FC 875

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