Somewhat unexpected results yield to strong evidence of obviousness to try

John M. Wang | August 8, 2014

Roche and Genentech v. Apotex Inc; Roche and Genentech v. Dr. Reddy’s laboratories; Roche and Genentech v. Watson etc.; Roche and Genentech v. Orchid chemicals & pharmaceuticals etc; and Genentech v. Mylan etc.

April 11, 2014

Before  Newman, Lourie, and Bryson.  Opinion by Bryson. Dissent by Newman

Summary

Plaintiff Roche appeals from the decision of the U.S. District Court for the District of New Jersey granting the defendant generic drug companies summary judgment of invalidity of Roche’s two patents related to Boniva®, a commercial drug for the treatment of osteoporosis. CAFC affirms.

 Details

Ibandronate, one of a class of compounds known as bisphosphonates, has been used to treat osteoporosis, a disease characterized by abnormal bone resorption. Due to the low bioavilability and some adverse side effects of ibandronate in the past, patients need to adhere to a dosing regimen that requires a tablet containing about 2.5 mg of ibandronate to be taken daily in a fasting state at least 30 minutes before eating or drinking. This rigid dosing regimen caused a lot of patient compliance problems.

In 2005, Roche developed Boniva®, a once-monthly tablet containing a 150 mg dose of ibandronate. Roche owns U.S. Patents Nos. 7,718,634 (the ‘634 patent) and 7,410,957 (the ‘957 patent, the parent of the ‘634 patent), which are directed to methods of treating osteoporosis through the once-monthly administration of Boniva®. Claim 1 of the ‘634 patent is shown below:

1.  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 court divided the subject matter of claim 1 into two-parts: whether it would have been obvious at the time of invention (1) to select a once monthly oral dosing regimen of ibandronate to treat osteoporosis, and (2) to set that dose at 150 mg.

First, regarding monthly dosing, the court cited the following references:

1.  An article in the trade journal Lunar News and an article in Chemical Market Reporter (2001): These articles basically reported that Roche was developing an “oral-monthly” formulation of ibandronate.

2.  US Patent No. 6,468,559 (“Chen”): It discloses coated-dosage forms of bisphosphonic acids and methods for orally administering those dosage forms. Ibandronic acid was identified as one of many known bisphosphonic acids. It further states that oral dosages may be administered anywhere between once every two weeks and once every twelve weeks, and a preferred embodiment in which “a dosage form of the invention is administered to a patient… preferably once a month.” However, Chen does not provide any examples using ibandronate.

3.  The Riis Article: It discloses an elaborate program which requires 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 article also concludes that it is the total dose over a predefined period and not the dosing regimen that is the determining factor for successful ibandronate treatment, which the court characterizes as the total dosage concept.

The court held that the above references collectively established at least a reasonable expectation that once monthly dosing of ibandronate could be used to treat osteoporosis successfully.

Second, regarding selecting the 150 mg dose, the court cited the following references:

1.  Ravn article: It discloses that the 2.5 mg dose per day is deemed the most effective dose, and the 5 mg dose per day is as effective as the 2.5 mg dose per day. Then the court developed an idea that 5 mg/day multiplies 30 days/month equals 150 mg/month, which would have rendered Boniva® obvious.

2.  Daifotis patent: It discloses weekly doses of ibandronate “from the group consisting of 35 mg, 40mg, 45 mg, or 50 mg.” The 35 mg weekly dose corresponds to the same total dose as a 5mg daily dose. The court held that this prior art indirectly validates the total dosage concept in the Riis Article.

The court then held that it was obvious to try 150 mg of ibandronate once per month, because there was a market need for this type of dosage form and there were only a finite number of identified, predictable solutions.

Next, the court cited another reference to address the safety concern.

1.  US Patent No. 6,143,326 (Mockel): It is directed to a coated tablet formulation. Mockel provides specific examples containing a maximum dose of 50 mg, but it also recites that the formulations could contain up to 250 mg. Furthermore, Mockel states that rapid-release ibandronate formulations showed “no significant side effects … in clinical studies using ibandronate even at high dosages,” but does not state that “high” exceeds his preferred upper limit, for at that time, the FDA had determined that a single oral dose of 100 mg is the maximum tolerable dose of ibandronate.

The court held that Mockel showed that doses higher than 150 mg were considered safe.

Finally, Roche argued that the 150 mg dosage form produced an unexpected result because of the ibandronate’s nonlinear increase in bioavailability at the 150 mg, as shown below:

 

 

 

 

 

 

 

The court acknowledged that there was“somewhat greater than would have been expected” result in terms of bioavailability at 150 mg dosage level (the court did not directly use the term “unexpected results”). However, the court held that it was so obvious to try a once monthly dose of 150 mg of ibandronate that the somewhat unexpected result did not rebut the prima facie showing of obviousness.

Dissent: First, Judge Newman argued that the majority failed to consider other secondary evidence including commercial success, failure of others, and long-felt need. Roche’s once-a-month Boniva® ibandronate medication for osteoporosis was developed after almost twelve years of research and clinical testing, and has been very commercially successful. Then, Judge Newman rebutted all the references individually, and argued that the majority invoked judicial hindsight to reconstruct the patented subject matter from a number of different references to support its ruling of obviousness. “Only with knowledge of Roche’s success, can one reconstruct that which is not suggested in the prior art.”

Take Away

Somewhat unexpected results are not dispositive in proving nonobviousness of a patent application, especially when there is a strong showing of “obvious to try.”

Applicants should avoid any publicity of the subject matter of the patent application before filing it. Some of prior art in this case are of Roche’s own making.  A patent drafter should always keep a defensive mindset in drafting claims. If possible, claiming a range in an independent claim, followed by specific values in a series of dependent claims is usually more effective in protecting an invention than just claiming a single value in an independent claim.

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