In Apotex, Inc. v. Wyeth LLC, the Federal Circuit affirmed the decision of the USPTO Patent Trial and Appeal Board (PTAB) finding that Apotex had failed to show that claims directed to a specific formulation of tigecycline were invalid as obvious. Both the PTAB and Federal Circuit decisions show that while the burden of proof is lower in an inter partes review proceeding than a district court proceeding, it still can be difficult to invalidate a patent. Indeed, Apotex’s second attempt to invalidate this Tygacil formulation patent in an inter partes review proceeding was denied institution in September 2015, while this appeal was pending.

The Tygacil Formulation Patent At Issue

The patent at issue was Wyeth’s U.S. Patent No. 7,879,828, which is directed to a specific formulation of tigecycline, a tetracycline antibiotic and the active ingredient of Wyeth’s Tygacil® product.

1. A composition comprising tigecycline, lactose, and an acid selected from hydrochloric acid and gentisic acid, wherein the molar ratio of tigecycline to lactose is between about 1:0.2 and about 1:5 and the pH of the composition in a solution is between about 3.0 and about 7.0.

As set forth in the Federal Circuit decision, “[a]ccording to the specification [of the ‘828 patent], the acid minimizes oxidative degradation, and the carbohydrate stabilizes the tigecycline against epimer formation at acidic pH.”

The Inter Partes Review Proceeding

Apotex sought inter partes review of the ‘828 patent, which was instituted based on the following references:

• Chinese Patent Publication No. 1390550A, which discloses a minocycline-based powder injection (like tigecycline, minocycline is a tetracycline antibiotic).

• Naggar et al., “Effect of Solubilizers on the Stability of Tetracycline,” 29 PHARMAZIE 126 (1974)

• Pawelczyk et al., “Kinetics of Drug Decomposition: Part 74: Kinetics of Degradation of Minocycline in Aqueous Solution,” 34 POL. J. PHARMACOL. PHARM. 409 (1982)

The Federal Circuit decision summarizes the PTAB’s findings as to the disclosures of the cited references as follows:

• CN ‘550 discloses a formulation comprising “‘minocycline hydrochloride, … [a] lyophilized powder supporting agent, and a suitable amount of a pH adjusting agent,'” where “[t]he powder supporting agent can be lactose, and the ‘pH adjusting agent is an inorganic acid, such as hydrochloric acid.'” The reference teaches that “[t]he composition is stable against “degradation by light, heat, oxygen, and water,'” but does not discuss epimerization.

• Pawelczyk discusses “the stability of minocycline in solutions over a broad range of pHs, specifically ‘teach[ing] that oxidation is the predominant minocycline degradation process above pH 5.'”

• Naggar discusses “tetracycline epimerization, specifically teaching that ‘at a pH of 2–6, tetracycline undergoes a reversible epimerization at the C4 dimethylamino group.'”

The PTAB determined that Apotex has not established obviousness based on these references:

It first reasoned that Apotex failed to explain why a skilled artisan “would have substituted tigecycline for minocycline in the CN ’550 composition for any reason, much less in an attempt to make a lyophilized tigecycline composition that was stable against epimerization.” …. It then reasoned that Apotex failed to establish why a skilled artisan would have been motivated to combine CN ’550, Pawelczyk, and Naggar, and use lactose, as a means for stabilizing tigecycline against epimerization.

Apotex appealed, arguing that the PTAB “wrongly relied on the failure of CN ’550 to teach the epimeric stability of its composition,” and “failed to consider any motivation to combine the prior art of record beyond the problem the patentee was trying to solve.”

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Lourie and joined by Judges Wallach and Hughes.

The opinion starts with this reminder of the applicable standards of review:

We review the Board’s legal determinations de novo, … and the Board’s factual findings underlying those determinations for substantial evidence, …. Obviousness is a question of law based on underlying factual findings, … such as what a reference teaches, … and whether a skilled artisan would have had a reason to combine references….

With regard to Apotex’s first argument, the Federal Circuit agreed that “the challenged claims do not require epimeric stability,” but found no PTAB error in this regard. To the contrary, the PTAB itself “stated that the purported ‘obviousness of the claims [could] be demonstrated without a showing of epimeric stability in the prior art.'”

With regard to Apotex’s second argument, the Federal Circuit determined that the PTAB had “correctly considered several purported motivations to combine the prior art beyond epimeric stability.” For example, while Apotex argued that “the structural similarity of tigecycline and minocycline would have motivated a skilled artisan to replace minocycline with tigecycline in the CN ’550 composition,” the PTAB “fully considered that potential motivation to combine and found it wanting.” In particular, the PTAB “found that no evidence suggested that tigecycline would be as stable in the CN ’550 composition,” and that “the notion of ‘identical A and B rings’ alone was insufficient to show that,” particularly where Wyeth had proffered evidence that the compounds have different oxidation rates.

The Federal Circuit refused to disturb these findings:

[T]here is not necessarily a motivation to substitute one antibiotic for a structurally related one when the prior-art antibiotic has a favorable stability profile, and there is nothing in the record here to show that the substitution would solve any other problem.

With regard to epimeric stability, the PTAB found that a skilled artisan would not have been motivated to combine the asserted references to stabilize tigecycline against epimerization. The Federal Circuit noted four specific findings underlying this determination:

• none of the references discloses tigecycline

• Naggar and Pawelczyk do not disclose lactose, much less disclose it as a stabilizing agent against epimerization

• CN ’550 teaches lactose only as a “powder supporting agent”

• Apotex failed to show why a skilled artisan would have been motivated to use lactose in view of Naggar, when Naggar teaches a different polysaccharide, polysorbate 20, as the least effective solubilizer in a larger list of solubilizers, such as urea.

Considering the record as a whole, the Federal Circuit concluded:

[W]hile tigecycline is closely related to minocycline structurally and in terms of benefit, the Board did not err in concluding that there was insufficient basis in the record to show that it would have been obvious to a skilled artisan to substitute tigecycline in the prior art minocycline composition.

If At First You Don’t Succeed …

As noted above, while this appeal was pending, Apotex filed another IPR petition against the ‘828 patent, based on CN ‘550 reference and two other references. The PTAB denied institution, finding similar holes in Apotex’s case as it found here.