In what has been a rare outcome to date, the Federal Circuit in Apotex v. Wyeth, dkt. no. 2015-1871 (Fed. Cir. Aug. 16, 2016) affirmed in a non-precedential decision the PTAB’s final written decision in IPR2014-00115 that the challenged claims were not unpatentably obvious over three references. At trial, the PTAB found that Apotex did not sustain its burden of showing by a preponderance of the evidence that there was a reason to substitute the claim-recited antibiotic for a prior art antibiotic and that there was a reason to combine the three references. In its appeal, Apotex unsuccessfully argued that the structural similarity of the antibiotics provided a reason to substitute, and argued that the PTAB failed to consider reasons to combine other than solving the problem addressed by the Patent Owner.

The PTAB instituted IPR on the single ground that claims 1-23 of USPN 7,879,828, drawn to compositions of tigecycline, lactose and an inorganic acid at acid pH, were obvious in view of three references. Tigecycline is an antibiotic in the tetracycline family that is active where other antibiotics fail. In challenging the claims as obvious, Petitioner relied on a translated Chinese patent application publication (CN ‘550), and printed publications Pawelczyk and Naggar. CN ‘550 disclosed an injectable powder composition of minocycline, a lyophilized powder stabilizing agent, and a pH adjusting agent. Minocycline is another antibiotic in the tetracycline family bearing some structural similarity to tigecycline. The lyophilized powder stabilizing agent can be lactose. Pawelczyk discloses that minocycline undergoes oxidative degradation at alkaline pH. Naggar discloses epimerization of minocycline leads to a loss of anti-microbial activity, particularly at acidic pH, and solubilizers such as polysorbate 20, urea and thiourea stabilize against epimerization.

Relying on this art and expert testimony addressing the reason to combine the art, petitioner argued that one of ordinary skill would have substituted tigecycline for minocycline because tigecycline is an antibiotic that is effective where others are not and because tigecycline is a structural analog of minocycline, sharing a common structure in the region of the molecules responsible for activity-affecting epimerization. Petitioner further argued that one of ordinary skill would have lowered the pH of the composition to avoid oxidative degradation as taught by Pawelczyk and would have added a stabilizing agent in the form of lactose in view of Naggar’s teaching that solubilizing agents such as lactose could stabilize a tetratcycline antibiotic against epimerization-induced degradation at low pH.

In its final written decision, the PTAB found that petitioner had failed to show that there was a reason for substituting tigecycline for the minocycline of the references because petitioner had not shown that minocycline was one of the antibiotics that failed where tigecycline showed activity and because Petitioner’s expert testimony lacked support. The PTAB further found that one of skill would not select lactose as a lyophilized powder stabilizing agent that also provided stability against epimerization because CN ‘550 disclosed lyophilization-stabilizing agents that were superior to lactose.

On appeal, Petitioner argued that the PTAB erred in importing an epimer stability limitation into the claims and in refusing to consider reasons to combine other than addressing the problem solved by the Patent Owner. With respect to the epimer limitation, the court found that the PTAB had expressly stated that the claims do not recite an epimer stability limitation and that obviousness could be established without a showing of epimeric stability in the art.

The court acknowledged that the PTAB addressed epimer stability in the context of assessing a reason to combine references, but distinguished that usage from importing the subject matter into the claims. As to the asserted failure to consider all possible reasons to combine the references, the court disagreed with Petitioner, noting that the PTAB considered all possible reasons but found them wanting. In support of this conclusion, the court emphasized the lack of factual evidence supporting the conclusions drawn by Petitioner’s expert.

[T]he Board rejected Apotex’s expert testimony as ‘not supported by objective evidence or analysis,’ instead relying on Wyeth’s evidence as persuasive.

In particular, the court found that Petitioner’s expert did not explain how knowledge that tigecycline worked where other antibiotics didn’t work would lead one of skill to substitute tigecycline for minocycline, particularly where the record failed to show minocycline was one of the failed antibiotics. Further, the court recognized that the PTAB found the assertion of partial structural similarity to be insufficient to establish that tigecycline, like minocycline, would be stable in the CN ‘550 composition. The court also agreed with the PTAB that Petitioner failed to show that one of skill would have had a reason to use lactose to stabilize tigecycline against epimer-induced degradation because none of the references disclosed tigecycline, only CN ‘550 disclosed lactose and that disclosure was in the context of providing lyophilized powder stability, and there was no showing that one of skill would choose lactose as a solubilizer (i.e., epimer-stabilizing agent) when Naggar taught a different polysacchararide, and that polysaccharide was the least effective solubilizer identified in the reference. The court found no reversible error in the PTAB’s asserted failure to consider other reasons to combine the three references in view of the dispositive failure of Petitioner to establish a reason to substitute tigecycline for minocycline. Accordingly, the court affirmed the PTAB’s decision.