Apotex Inc v. Wyeth LLC

1. Case Identification

• Case #: IPR2015-00873
• Patent #: 7,879,828
• Filed: March 12, 2015
• Petitioner(s): Apotex Inc.
• Patent Owner(s): Wyeth LLC
• Challenged Claims: 1-23

2. Patent Overview

• Title: Pharmaceutical Compositions of Tigecycline
• Brief Description: The ’828 patent relates to stable, lyophilized pharmaceutical compositions containing the antibiotic tigecycline. The compositions include lactose as an excipient and an acid, such as hydrochloric acid, to maintain the solution pH within a specific acidic range, allegedly to reduce degradation.

3. Grounds for Unpatentability

Ground 1: Claims 1-3, 6-9, 12-13, 18, and 19 are obvious over CN ’550, Herman, and Kirsch.

• Prior Art Relied Upon: CN ’550 (Chinese Patent Publication No. 1390550A), Herman (a 1994 pharmaceutical research article), and Kirsch (a 2001 pharmaceutical development article).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that CN ’550 discloses every limitation of the challenged claims except for the use of tigecycline. Specifically, CN ’550 teaches a stabilized, lyophilized powder composition of minocycline (a known chemical analog of tigecycline) that includes lactose as a potential "freeze drying supporting agent" and hydrochloric acid as a pH adjusting agent, prepared in a solution with a preferred pH of 2.0-3.5. This pH range overlaps with the broader range claimed in the ’828 patent.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would have been motivated to substitute tigecycline for its known analog minocycline in the stable formulation of CN ’550. The motivation would be to achieve the same stability benefits (protection against degradation from light, heat, oxygen, and water) for tigecycline, a similar tetracycline antibiotic. Further, a POSITA would be motivated by Herman and Kirsch to specifically select lactose from the list of possible excipients in CN ’550. Both references teach that lactose is superior to other common excipients like mannitol for stabilizing water-sensitive drugs in lyophilized compositions because amorphous lactose acts as an "internal desiccant," while crystalline mannitol can increase water concentration near the drug, accelerating hydrolysis.
  • Expectation of Success: A POSITA would have a reasonable expectation of success in making this substitution, as it involved applying a known stabilization technique (using lactose in a controlled pH lyophilized formulation) to a known analog (tigecycline) of the drug for which the technique was developed (minocycline).

Ground 2: Claims 4, 5, 10, 11, 14-17, and 20-23 are obvious over CN ’550, Herman, and Kirsch in view of Pawelczyk and Remmers.

• Prior Art Relied Upon: CN ’550, Herman, Kirsch, Pawelczyk (a 1982 journal article on minocycline degradation), and Remmers (a 1963 journal article on tetracycline epimerization).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground built upon the base combination of CN ’550, Herman, and Kirsch to challenge dependent claims reciting narrower, specific pH ranges (e.g., between 4.0 and 6.0). Petitioner contended that Pawelczyk and Remmers provided the specific motivation to optimize the pH of the tigecycline solution to within these claimed ranges.
  • Motivation to Combine: A POSITA knew that tetracyclines like tigecycline degrade via two primary, pH-dependent pathways: oxidation at higher pHs and epimerization at lower pHs. Pawelczyk taught that for minocycline, oxidative degradation decreases as the pH is reduced below about 7.5, preferably towards 5.0. Conversely, Remmers taught that for tetracycline, epimerization is highest around pH 3.2 and is significantly reduced as the pH is increased towards 6.0. A POSITA would therefore be motivated to balance these competing degradation pathways by selecting a pH high enough to limit epimerization (per Remmers) but low enough to limit oxidation (per Pawelczyk). This optimization process would have led a POSITA directly to the overlapping pH range of approximately 4.0 to 5.0, which is encompassed by the challenged dependent claims.
  • Expectation of Success: A POSITA would have reasonably expected to find an optimal pH that minimized overall degradation by balancing the known, competing degradation mechanisms taught by Pawelczyk and Remmers for structurally similar antibiotics.

4. Key Technical Contentions (Beyond Claim Construction)

• Predictable Analog Substitution: Petitioner asserted that tigecycline and minocycline are closely related chemical analogs that were known to share the same primary degradation pathways (oxidation and epimerization). Therefore, stabilization strategies proven effective for a lyophilized minocycline formulation, as disclosed in CN ’550, would be predictably applicable and effective for a tigecycline formulation.
• Excipient Properties Drive Formulation: The petition emphasized that the choice between lactose and mannitol as a lyophilization excipient was a critical and understood design choice. The teachings of Herman and Kirsch established that amorphous lactose is superior for stabilizing water-sensitive drugs by uniformly distributing residual moisture. In contrast, mannitol tends to crystallize, which concentrates residual water in the amorphous drug domains and accelerates degradation, making lactose the obvious choice for improving stability.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that the grounds presented in this petition were not redundant to those considered in a prior proceeding (IPR2014-00115). The current grounds relied on different combinations of prior art (notably, the addition of Herman and Kirsch) and were supported by new expert testimony. Petitioner asserted that because the Board had previously declined to institute on a similar ground in the prior IPR, deeming it "redundant" without a full review, Petitioner was not estopped from raising these improved and distinct grounds in a new petition.

6. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 1-23 of Patent 7,879,828 as unpatentable under 35 U.S.C. §103.