BONIVA dosing regimen patent held obvious in summary judgment motion

On May 7, 2012, the United States District Court for the District of New Jersey granted a summary judgment motion holding that claims 1 to 8 of US Patent No. 7,718,634 were invalid for obviousness.  The decision is notable in that the Plaintiff, Roche, was not able to demonstrate the existence of a genuine issue as to a material fact on the issue of obviousness.

The ‘634 patent is generally directed to a once-monthly dosing regimen of 150 mg of ibandronic acid and its pharmaceutically acceptable salts Claim 1 of the ‘634 patent reads as follows:

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 by orally administering to the postmenopausal woman, on a single day, a first dose in the form of a tablet, 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.

The Defendants (Apotex, Dr. Reddy’s, Watson, Orchid and Mylan) had argued that claims 1 to 8 were obvious in light of a collection of prior art documents that taught:

  • “Another approach is to use bisphosphonates with high potency yet low irritability, such as zolendronate (Novartis) and ibandronate (Roche) [29, 30]. Oral agents could be given intermittently (once/month, for example) and still be quite potent. The projected mode for ibandronate is injection once every three months.” [Lunar News]
  • a 2.5 mg daily dose of ibandronate was the most effective for women with postmenopausal osteoperosis, but that positive outcomes were found in both the 2.5 and 5.0 groups [Ravn, 1996]
  • “preclinical data with ibandronate provided evidence that a total dose administered over a defined period provides equivalent results irrespective of the dosing schedule, providing that the dose used is efficacious”  [Riis 2001]
  • that certain bisphosphonates, including ibandronate, have high potency as inhibitors of osteoclastic bone resorption, and that other treatment methods utilize a cyclic regimen of treatment and rest periods, including the treatment method involving weekly dosing of ibandroinate [Daifotis, US 6,432,932]
  • the use of oral ibandronate to treat osteoporosis with a single dose should be in the range of 0.1 to 250 mg [Möckel US 6143326]
  • “The oral unit dosage forms of the bone-active phosphonate for the maintenance dose preferably contains from about 2.5 to about 15 mg per day from about 5 to about 10….Equivalent doses can be given every other day, twice a week, weekly, biweekly or monthly.”[Schofield; US 2003/0118634]
  • “It should be emphasized, however, that because the present dosage forms provide for substantially improved drug absorption relative to conventional formulations, it may not be necessary to administer the drug more than once every two to twelve weeks. Thus, in a preferred embodiment, a dosage form of the invention is administered to a patient every two weeks, preferably once a month, more preferably once every twelve weeks.” [Chen, US 6,468,559]
  • “Roche is expected to file ibandronate in a once-daily formulation . . . say analysts. More competitive formulations, an oral once-monthly and a quarterly IV, may be filed in 2003, with a 2004 launch.” [Krause 2001]
  • That bisphosphonate must be administered on at least one day out of every 30 day treatment. [Geddes  US 5,616,560]

Genuine issue of material fact

In response to the summary judgment motions, Roche offered four expert reports. The Court held that the Plaintiff’s expert evidence, which made assertions unsupported by analysis in respect of the Schofield, Riis and Möckel references, did not amount to a material factual dispute.

Teaching away

Roche had also submitted that another reference, Schnitzer 2001, dealing with alendronate taught away from the invention.  The Court held that whatever Schnitzer taught in September 2001, the “game changed”  with the publication of the Riis ibandronate paper in October of that year.  A skilled person would have understood the Riis reference to supercede the views about intermittent dosing with ibandronate expressed in Schnitzer 2001.  In the alternative, the Court concluded that the Schnitzer 2001 reference viewed in the broadest way was directed not to the claimed invention, but to a prior art combination, and that Schnitzer merely observes the inferiority of the existing device. The prior art did not suggest that once monthly oral ibandronate would not be effective for the treatment or inhibition of osteoporosis, but rather that it might not do it as well as some regimens with stronger dosing intervals.

The Court did not accept that Chen `559 taught away from using tablets, characterizing the notion as “outlandish” and “borders on frivolous” and concluding that “[n]o reasonable trier of fact could read this reference and conclude that Plaintiff’s reading is correct” .The Court also did not accept that the Lunar News reference teaches away from the oral administration of ibandronate.

Obvious to try

The options of using 75 and 150 mg doses were not “shots in the dark” but were the products of the application of reasoning empirical research.  The Court, following In re O’Farrell, held that all that is required is that the skilled person have a reasonable expectation of success. The Court concluded that based on the prior art, the skilled person would have a good reason to expect success with either 75 mg or 150 mg doses.  The development of the 150 mg dose appeared to be the product of ordinary skill and common sense not innovation. The Court concluded:

Applying KSR to the instant case leads to the conclusion that demonstrating that it was obvious to try once-monthly oral administration of ibandronate at doses of 75 mg and 150 mg is legally sufficient to prove obviousness. There is no dispute that, in 2002, there was market pressure to solve the problem of finding an osteoporosis treatment with reduced gastrointestinal side effects and improved patient compliance. Based on the reasoning explained above, the combination of Ravn 1996, Lunar News Spring 1996, and Riis 2001 suggests two possible treatments: once-monthly oral administration of ibandronate at doses of 75 mg and 150 mg. The set of these two options contains a finite number of identified solutions.

Objective considerations of non-obviousness

The Court did not accept that the objective considerations of nonobviousness, including commercial success, long felt but unresolved need and skepticism, failures of others, licensing of the ‘938 patent, copying, and unexpected results could overcome the clear and convincing evidence of obviousness.

A copy of the district Court’s Opinion may be found here.