By Michael Greenfield --
Last Friday, the Federal Circuit issued an opinion in Hoffman La-Roche Inc. v. Apotex Inc. that is a cautionary tale of patent lifecycle and the difficulties those seeking to extend patent protection face -- namely the blooming of prior art relating to an approved product.
The defendants, generic drug manufacturers, filed an ANDA seeking approval to manufacture and sell generic versions of Boniva® before expiration of Roche's patents, and Roche sued under 35 USC § 271(e)(2).
At issue was whether it would have been obvious to select a once-monthly dosage regimen of 150 mg ibandronate to treat osteoporosis. The District Court found the claimed method of treatment obvious and the Federal Circuit affirmed.
The prior art
1. Due to low bioavailability and side-effects, patients taking bisphosphonates were required to adhere to a dosing regimen that required taking a tablet in a fasting state at least 30 minutes before eating or drinking. This led to undesirably low patient compliance. Hence, researchers thought less-frequent dosing would be desirable to increase patient compliance.
2. Weekly administration of prior art bisphosphonate Fosomax® was known, as was monthly oral administration of ibandronate and other bisphosphonates for the treatment of osteoporosis. The prior art Chen patent (U.S. Patent No. 6,468,559) taught monthly administration of bisphosphonates, including ibandronate.
3. Roche argued that the prior art taught away from the claimed method of monthly administration, but the Federal Circuit found the evidence wanting and relied heavily on a publication by Riis, which taught that "increases in BMD [bone mineral density] equivalent to those obtained with a 2.5 mg per day treatment regimen were obtained with a regimen of 20 mg of ibandronate every other day for the first 24 days of every three-month period." The Court found that Riis concluded that total dosage rather than dosage regimen was paramount.
4. Other art showed that oral ibandronate dosages 2.5 mg and 5 mg daily were equally effective at increasing BMD and lowering bone turnover and taught weekly doses of 35-50 mg (the Court noting that the total dosage of 35 mg/week was equivalent of 7 daily doses of 5 mg/day).
The Court's reasoning
The Court found that Riis taught that total dosage was the primary driver of success and the other prior art directed one of ordinary skill in the art to the figure of 150 mg. The Court reasoned that over a 30-day period the 5 mg/day regimen yielded a total dose of 150 mg (30 days x 5 mg/day = 150 mg), as claimed. In the alternative, the Court opined that given the prior art teachings of 5 mg daily and 35 mg weekly administration in light of Riis's teaching of the primacy of total dosage, there were a finite number of predictable solutions, making it obvious to try the claimed method with an expectation of success.
The Court swatted away Roche's evidence of teaching away and assertions that the District Court misinterpreted and misapplied the total dose concept.
More interesting was the Court's treatment of Roche's arguments of surprising results:
1. The 150 mg once-monthly regimen was more effective than the 2.5 mg once-daily regimen.
2. Ibandronate has nonlinear bioavailability, Roche demonstrating that increasing the oral dose by 50% (from 100 mg to 150 mg once-monthly) resulted in an increase in bioavailability of 150%.
The Court reasoning that the greater efficacy was insufficient to undercut the showing of the reasonable expectation that 150 mg once-monthly dosage would be effect. Although surprising properties of an otherwise obvious invention can result in non-obviousness if the difference is one in kind rather than degree, the Court characterized the enhanced efficacy as "somewhat greater than expected" (emphasis added), and, thus presumably viewed the improvement as a difference in kind rather than degree.
And with respect to the nonlinear bioavailability, the Court found that the evidence did not establish that unexpectedly increased bioavailability at the 150 once-monthly level resulted in improved osteoporosis treatment. The Court concluded that this nonlinearity was not relevant to the obviousness inquiry. Although the Court did not discuss a need for a connection between an unexpected result and the claimed invention vis-à-vis nonobviousness, the Court's conclusion is consistent with a need to establish that at least in the case of a method of treatment, the unexpected result must in some way affect treatment outcome.
Judge Newman had a different take. In dissent she asserted that the evidence demonstrated that despite extensive exploration, the prior art found lesser success and entirely missed the claimed protocol. Judge Newman dissected each piece of prior art and pointed out what she considered the deficiencies of each for supporting the majority's opinion.
Of particular note with respect to the prior art, Judge Newman asserted that the majority ignored the FDA's refusal to approve a 5 mg/day regimen because of toxic side-effects and concluded that "[s]urely this leads away from the obviousness of a single dose thirty times higher." Roche had argued that the FDA's findings taught away from the higher dose. But the majority rejected the argument because, they asserted, "the FDA never made any findings contrary to the 5 mg daily dose, because it was never asked to approve that dose." So, on the face of the opinion, there is an inconsistency between the majority and the dissent not in the interpretation of the facts but in what the facts themselves are. Either the FDA considered the toxicity of the 5 mg/day regimen and acted accordingly, or it did not.
Judge Newman also criticized the majority for acknowledging the unexpected results presented by Roche but, in essence, ignoring them.
Judge Newman ultimately concluded that the majority had reached its conclusion through hindsight, relying heavily on Roche's proven success, and proffered a warning to those seeking to extend patent lifecycle: "The court's holding today will simply discourage improvements in crowded fields, by holding that even if such investigation should succeed, a patent is not available."
Hoffman-La Roche Inc. v. Apotex Inc. (Fed. Cir. 2014)
Panel: Circuit Judges Newman, Lourie, and Bryson
Opinion by Circuit Judge Bryson; dissenting opinion by Circuit Judge Newman
 Interestingly, ibandronate was included among a Markush listing of 11 bisphosphonates useful in the formulations and methods of the Chen patent, and the Federal Circuit characterized Chen's teachings as "specifically" teaching monthly administration of ibandronate. Presumably the Markush group was sufficiently small for the Chen teaching of monthly administration of bisphosphonates to be a "specific" teaching as opposed to a generic teaching. Judge Newman, in dissent, impliedly criticized the majority, noting that Chen did not provide any example using ibandronate.