Hoffmann-La Roche v. Apotex: Scaling Daily Dosage Values to Teach a Monthly Dosage

Category: 103  
By: Jesus Hernandez, Blog Editor/Contributor    
TitleHoffmann-La Roche, Inc. v. Apotex Inc., No. 2013-1128, -1161, -1162, -1163, -1164 (April 11, 2014).
IssueThe issue in this case is whether it would have been obvious at the time of invention to select a once monthly oral dosing regimen of ibandronate to treat osteoporosis and to set that dose at 150 mg [based on prior art references teaching a daily dosage amount].
Hoffmann-La Roche, Inc. at *9 (text added).
Holding[T]he prior art pointed to a monthly treatment of 150 mg of ibandronate. At the very least, the 150 mg dose was obvious to try: There was a need to solve the problem of patient compliance by looking to less-frequent dosing regimens. And, based on Ravn and Daifotis, in light of Riis’s total-dose concept [in which a daily dosage over a month may be the equivalent of a single monthly dosage], there were only a “finite number of identified, predictable solutions.” [...] Id. at *13 (internal citations omitted, text added).


Procedural HistoryPlaintiff Hoffmann-La Roche, Inc., (“Roche”) appeals from the decision of the United States District Court for the District of New Jersey granting the defendant generic drug companies summary judgment of invalidity as to claims 1-8 of U.S. Patent No. 7,718,634 (“the ’634 patent”) and claims 1-10 of U.S. Patent No. 7,410,957 (“the ’957 patent”).
Hoffmann-La Roche, Inc. at *4.
Legal Reasoning (Lourie, Bryson)
Representative Claim 11. A method for treating or inhibiting postmenopausal osteoporosis in a postmenopausal woman in need of treatment or inhibition of postmenopausal osteoporosis by administration of a pharmaceutically acceptable salt of ibandronic acid, comprising:

(a) commencing the administration of the pharmaceutically acceptable salt of ibandronic acid […], wherein the tablet comprises an amount of the pharmaceutically acceptable salt of ibandronic acid that is equivalent to about 150 mg of ibandronic acid; and

(b) continuing the administration by orally administering, once monthly on a single day, a tablet comprising an amount of the pharmaceutically acceptable salt of ibandronic acid that is equivalent to about 150 mg of ibandronic acid.

Hoffmann-La Roche, Inc. at *5-6.
Analysis on "monthly" dosing
Evidence of Monthly DosesFirst, an article in the trade journal Lunar News entitled Update: Bisphosphonates (“Lunar News”) stated that “[r]esearchers are seeking solutions for better compliance,” including approaches that “use bisphosphonates with high potency yet low irritability, such as . . . ibandronate (Roche). Oral agents could be given intermittently (once/month, for example) and still be quite potent.” Second, a 2001 article by Carey Krause in Chemical Market Reporter (“Krause”) disclosed that Roche would likely seek FDA approval of an “oral once-monthly” formulation of ibandronate in 2003. Finally, United States Patent No. 6,468,559 (“Chen”) […] disclosed a preferred embodiment in which “a dosage form of the invention is administered to a patient . . . preferably once a month.”
Hoffmann-La Roche, Inc. at *8-9
Evidence of Teaching Away Unpersuasive
Flawed Recker Study unpersuasiveThe Recker study […] showed a 26% reduction in vertebral fractures with intravenous ibandronate administered once every three months. The study was a “failure” only in the sense that the 26% reduction was statistically insignificant given the large number of patients that would have been required to reach a statistically significant conclusion about the relative rates of fractures in the control and subject groups. […] Recker’s failure to generate statistically significant results points to a fault in the study; it does not teach that infrequent ibandronate dosing is ineffective in treating osteoporosis.
Id. at *10
Subsequent Riis Study Trumps Support of Flawed StudySchnitzer speculated that the long drug-free interval [in Recker] was to blame for the inconclusive results and that dosing intervals longer than one or two weeks would be ineffective.[…] [However,] [a]ny doubt about the efficacy of oral ibandronate dosing that may have been created by Schnitzer’s speculation was put to rest by an article published in 2001 by Riis et al. entitled Ibandronate: A Comparison of Oral Daily Dosing Versus Intermittent Dosing in Postmenopausal Osteoporosis (“Riis”). […] Riis’s teaching that a dose-free interval of more than two months did not impact the BMD efficacy of ibandronate was directly contrary to Schnitzer’s speculation that such a dosing regimen would not be effective.
Id. at *10-11 (text added).
Proof of efficacy is not necessary to show obviousnessConclusive proof of efficacy is not necessary to show obviousness. All that is required is a reasonable expectation of success. […] Riis—along with other prior art that used BMD improvement as the primary efficacy marker for treating osteoporosis—established at least a reasonable expectation that once monthly dosing of ibandronate could successfully treat osteoporosis and reduce fracture risk.
Id. at *12 holding.
Analysis on selecting "150 mg" per month Dose
RavnA 1996 article by Ravn et al. (“Ravn”) reported the results of a study that measured BMD improvements and bone-turnover markers for daily ibandronate doses of 0.25 mg, 0.5 mg, 1.0 mg, 2.5 mg, and 5 mg. […] Of the five daily doses tested in Ravn, only the 2.5 and 5 mg doses “showed positive outcome in all regions.” Even though the 5 mg dose did not demonstrate greater efficacy than the 2.5 mg dose, it was still deemed an equivalently effective dose so that someone scaling it to a single monthly dose of 150 mg (5 mg/day x 30 days/month) would have anticipated equivalent success in raising BMD and limiting bone turnover, based on Riis.
Hoffmann-La Roche, Inc. at *12-13.
FDA Findings Must concern Value at IssueRoche contends that findings by the FDA taught away from further development of the 5 mg daily dose (and its total-dose equivalents) because the FDA approved a 2.5 mg daily dose of ibandronate instead of a 5 mg daily dose. But the FDA never made any findings contrary to the 5 mg daily dose, because it was never asked to approve that dose.
Id. at *13-14.
Total Dose concept equivalent to scaling daily doseThe Riis study, in particular, established that the total dose concept can reliably predict that the efficacy of an ibandronate treatment depends on the total dose administered to a patient over a given period, not on the amount administered at any single point in time. In light of that evidence, it was reasonable to expect that a once monthly dose of 150 mg would have roughly the same efficacy as a daily dose of 5 mg.
Id. at 14-15.
Analyis of Unexpected Results
Superior Efficacy of claimed dose over prior art dose does not rebut clear obviousness finding
MOBILE StudyRoche’s MOBILE study, published in 2005, demon- strated that a 150 mg monthly dose is more effective than a 2.5 mg daily dose with respect to BMD improvement in the lumbar spine and most hip sites. The MOBILE study demonstrated, for example, a mean BMD improvement in the lumbar spine of 4.9% after one year for patients taking the 150 mg monthly dose and 3.9% after one year for patients taking the 2.5 mg daily dose.
Hoffmann-La Roche, Inc. at *17.
Insufficientto Rebut Clear 103While the evidence would support a finding of superi- or efficacy of the 150 mg monthly dose in raising BMD levels, as compared to a 2.5 mg daily dose, that improved efficacy does not rebut the strong showing that the prior art disclosed monthly dosing and that there was a reason to set that dose at 150 mg. See In re Merck & Co., 800 F.2d 1091, 1099 (Fed. Cir. 1986). The evidence of superior efficacy does nothing to undercut the showing that there was a reasonable expectation of success with the 150 mg monthly dose, even if the level of success may have turned out to be somewhat greater than would have been expected.
Id. at *17.
Accordingly, we uphold the judgment of the district court that claims 1-8 of the ’634 patent and claims 1-10 of the ’957 patent would have been obvious in light of the prior art and are therefore invalid.
Hoffmann-La Roche, Inc. at *18.
NEWMAN, Circuit Judge, dissenting. Hoffmann-La Roche, Inc. at *3.
General Grounds for DissentHoffmann-LaRoche’s once-a-month Boniva® ibandro- nate medication for osteoporosis required twelve years of research and clinical testing and evaluation to demonstrate its efficacy when dosed once a month and its safety at this high monthly dosage. The prior investigations of intermittent dosing, and the publications describing protocols of lesser success, missed the protocol that produced this successful method. Indeed, this prior art weighs heavily against obviousness, for despite extensive exploration, this successful protocol was not discovered.
Hoffmann-La Roche, Inc. at *3.
Multiple Doses per Month not Equivalent to Single Dosis per MonthThe prior art shows intermittent therapies ranging from every other day to once a week to twice a week to twice a month to every three months plus varying initial loading periods, in a wide range of dosages. The prior art is replete with warnings of toxicity and patient non-compliance. The panel majority acknowledges that Roche’s MOBILE study and the nonlinear bioavailability data (discussed infra) demonstrate that the 150 mg monthly treatment produced unexpected results, but deems this irrelevant; the court now, with knowledge of Roche’s success, deems Roche’s successful method to have been obvious all along.
Id. at *4-5.
On the Prior Art
Riis ArticleThe court relies on the Riis article, which shows dosing patients with 20 mg of ibandronate every other day for twenty-four days, followed by a 9-week period of no treatment, then returning to 20 mg every other day for twenty-four days, and a 9-week period of no treatment, etc. The court characterizes this as definitive proof of the “total dosing concept.” However, Riis makes no suggestion that the once-a-month dosing at the high dosage used by Roche could replace Riis’ elaborate procedure.
Id. at *8.
RavnRavn tested daily treatment using a range of dosages and concluded that 2.5 mg per day is the most effective dose. Yet the court selects Ravn’s 5.0 mg dose, despite its increased toxicity and Ravn’s preference for the lower dose, to scale up to Roche’s 150 mg dose. Ravn does not suggest a once- monthly dose of 150 mg. It is also noteworthy that the Riis publication, which is later in time than Ravn, selected the 2.5 mg dosage, not the 5.0 mg dosage, as a framework for intermittent dosing.
Id. at *9.
 Image Attribution Statement: Thomas Hunt Morgan, “Critique of the Theory of Evolution Fig 076,” available under Project Gutenberg archives from “A Critique of the Theory of Evolution” whose Copyright has expired, http://commons.wikimedia.org/wiki/File:Critique_of_the_Theory_of_Evolution_Fig_076.jpg (last visited April 11, 2014).
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