Apotex Inc v. UCB Biopharma SPRL

1. Case Identification

• Case #: IPR2019-00400
• Patent #: 8,633,194
• Filed: December 13, 2018
• Petitioner(s): Apotex, Inc.
• Patent Owner(s): UCB Biopharma S.A.
• Challenged Claims: 1-11

2. Patent Overview

• Title: Pharmaceutical composition of piperazine derivatives
• Brief Description: The ’194 patent relates to a liquid pharmaceutical composition containing the antihistamine levocetirizine and a specific preservative mixture of methylparaben and propylparaben in a 9/1 weight ratio. The invention alleges that active substances like levocetirizine possess an inherent preservative effect, allowing for stable compositions with reduced amounts of traditional preservatives.

3. Grounds for Unpatentability

Ground 1: Obviousness over WO '094 and the Handbook - Claims 1-11 are obvious over WO '094 in view of the Handbook.

• Prior Art Relied Upon: WO '094 (International Publication No. WO 2004/050094) and the Handbook (Kibbe, "Handbook of Pharmaceutical Excipients," 3rd ed. 2000).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that WO '094 disclosed liquid oral formulations of levocetirizine containing both methylparaben and propylparaben as preservatives. However, WO '094 was silent on the specific ratio and concentration of these preservatives. The Handbook, a standard industry reference, was asserted to supply these missing details. It taught that methylparaben and propylparaben are widely used together for their synergistic effects and specifically disclosed their use in a 9/1 ratio (0.18% methylparaben and 0.02% propylparaben) for parenteral formulations. The Handbook also provided concentration ranges for parabens in oral solutions (0.15 to 2 mg/ml) that overlap with the claimed range of "up to 0.75 mg/ml." Petitioner contended the "substantially free of bacteria" limitation was an inherent property of levocetirizine itself, a fact allegedly admitted in the ’194 patent specification.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) formulating the levocetirizine composition of WO '094 would consult a standard reference like the Handbook for guidance on appropriate preservative ratios and concentrations. The Handbook's disclosure of a common and synergistic 9/1 paraben ratio would have motivated a POSA to use it. Furthermore, the Handbook’s mention of potential irritant properties of parabens would motivate a POSA to optimize the formulation by using a lower concentration within the disclosed acceptable ranges, leading to the amounts recited in the claims.
  • Expectation of Success: A POSA would have a high expectation of success because the combination involved using a well-known active ingredient (levocetirizine) with a widely used, synergistic, and predictable preservative system (9/1 parabens) at conventional concentrations.

Ground 2: Obviousness over EP '203, US '558, and the Handbook - Claims 1-11 are obvious over EP '203 in view of US '558 and the Handbook.

• Prior Art Relied Upon: EP '203 (European Patent Application # 0605203 A2), US '558 (Patent 5,698,558), and the Handbook.
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that EP '203 taught liquid pharmaceutical compositions (ophthalmic/nasal) containing racemic cetirizine and a preservative mixture of methylparaben and propylparaben in a 2/1 ratio. US '558 taught that levocetirizine is the active (-) isomer of cetirizine and disclosed its use in liquid formulations for treating allergic disorders. A POSA would thus be motivated to substitute the active isomer (levocetirizine) for the racemate in the EP '203 formulation. The Handbook was again relied upon to teach the claimed 9/1 paraben ratio and overlapping concentration ranges, which a POSA would use to optimize the preservative system disclosed in EP '203.
  • Motivation to Combine: A POSA would combine these references for two main reasons. First, to improve upon the EP '203 formulation by replacing the racemic cetirizine with its known, more active isomer, levocetirizine, as taught by US '558. Second, to optimize the preservative system of EP '203 by replacing its 2/1 paraben ratio with the more common and synergistic 9/1 ratio taught in the Handbook and other prior art. This substitution would be a predictable variation to achieve a known benefit.
  • Expectation of Success: A POSA would reasonably expect success in making these modifications. Substituting an active isomer for a racemate was a known strategy for improving drug efficacy and safety, and using a widely known and effective preservative system like the 9/1 paraben mixture was a routine and predictable formulation choice.

4. Arguments Regarding Discretionary Denial

• Petitioner argued that the Board should not exercise its discretion to deny institution under 35 U.S.C. § 325(d). The petition asserted that the prior art references and arguments presented were substantially different from those considered by the Examiner during the original prosecution. Petitioner noted that the Examiner never rejected the pending claims based on WO '094, EP '203, US '558, or the Handbook, and that mere citation of a reference in an Information Disclosure Statement (IDS) is insufficient to conclude that the Examiner substantively considered it.

5. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of claims 1-11 of the ’194 patent as unpatentable.