Bupropion - Canada

On Aug 20, 2018, Federal Circuit of Canada found Ranbaxy’s generic product non-infringing & dismissed the application by Valeant to prohibit the Minister of Health from issuing a Notice of Compliance.

The Applicant, Valeant applied to the Court on December 22, 2016, under the prior Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [NOC Regulations] for an order prohibiting the Minister of Health [the Minister] from issuing a Notice of Compliance [NOC] to the Respondent, Ranbaxy Pharmaceuticals. This prohibition order would prevent Ranbaxy from marketing Ran-Bupropion XL Tablets (150 mg and 300 mg), an extended relief medication that Valeant says infringes Patent No. CA 2,524,300 [the 300 Patent]. The 300 Patent expires on August 8, 2023. The 300 Patent is titled "Modified-Release Tablet of Bupropion Hydrochloride". The 300 Patent discloses ' and claims a daily anti-depression medicine that improves patient compliance with extended drug release, which Valeant markets as "Wellbutrin XL''.

The only issue was whether Ranbaxy’s product infringes the 300 Patent. Ranbaxy's argument was that its product falls outside of claim 1 of the 300 Patent -namely, its tablets are not comprised of a permeation enhancer in the amount of “about 20% to about 40%" of the moisture barrier dry weight.

Claim 1 is reproduced herein below:

A modified-release tablet comprising:

(i) a core comprising an effective amount of pharmaceutically acceptable salt of bupropion, a binder, a lubricant and optionally other conventional excipients;

(ii) a first control-releasing coat surrounding said core wherein said first control-releasing coat comprises a water-insoluble water-permeable film-forming polymer, a plasticizer and a water-soluble polymer, wherein the ratio of the water-insoluble water-permeable film-forming polymer to the water-soluble polymer is from about 3:4 to about 5:3; and

(iii) a moisture barrier surrounding said first control releasing coat, wherein said moisture barrier comprises an enteric polymer and a permeation enhancer and optionally comprises a plasticizer and wherein the permeation enhancer is present in an amount of from about 20% to about 40% of the moisture barrier dry weight;

wherein the modified release tablet is bioequivalent to Wellbutrin® or Zyban®/Wellbutrin® SR tablets over a 24 hour period when administration of said modified-release tablet is as a once-a-day bupropion treatment regimen to a patient in need of such administration and wherein more than 10% of the pharmaceutically acceptable salt of bupropion is released in one hour in 0.1N HCL or less than 75% of the pharmaceutically acceptable salt of bupropion is released in 45 minutes in pH 6.8 buffer.

Silicon dioxide is the preferred permeation enhancer in the 300 Patent, in the amount of "about 20% to about 40%" of the moisture barrier dry weight. Ranbaxy argued that the word "about" in the 300 Patent means plus or minus 10%, which works out to a range of 18% to 44%. And while Ranbaxy's formulation also uses silicon dioxide as the permeation enhancer, it argued it is present in an amount below the range claimed in the 300 Patent.  But Valeant argued that two other chemicals in Ranbaxy's product-polyethylene glycol [PEG] and triethyl citrate [TEC] (used as plasticizer) should be treated as permeation enhancers and therefore are included in the weight calculation.

Court however, denied Valeant’s proposed construction & held that specification of 300 patent mentions PEG & TEC as plasticizer & to some extent as glidant, but not as permeation enhancers. Court accepted Ranbaxy’s expert (Dr. Laskar) testimony & said that PEG would not fall under the definition of permeation enhancers given in specification as PEG while allowing water to come inside would disrupt the membrane. Although there are certain literatures available which discloses PEG as permeation enhancers but purposive construction requires reference to specification & not to functional characteristics of excipients. Therefore, only Silicon dioxide present in Ranbaxy’s product act as permeation enhancers.

Next, turning to the term “about”, Court held that it should be construed as plus or minus 10%. Court relied on Dr. Laskar's opinion that a POSITA would understand that "about" means a 10% deviation of the percentage range in the 300 Patent's formulation based on certain authorities such as USP monographs which use the range 90.0-110.0% of label claim as the quality standard. Therefore, amount of permeation enhancer works out to a range of 18% to 44% as argued by Ranbaxy. And since Ranbaxy’s product contains silicon dioxide below this range, it would not infringe the 300 patent. Thus, Valeant failed to satisfy its onus to show on a balance of probabilities that Ranbaxy's allegation of non-infringement is unjustified.