Alza Corp. appealed a district court’s finding of noninfringement and invalidity of claims 1-3, 11, 13 and 14 of U.S. Patent No. 6,124,355 for a generic version of the once-a-day extended release formulation of the anti-incontinence drug oxybutynin, which Alza has been marketing as Ditropan XL®. Alza had sued after Mylan and Impax filed ANDAs for generic once-daily, controlled-release oxybutynin formulations.

The ‘355 patent claims:

A sustained-release oxybutynin formulation for oral administration to a patient in need of treatment for urge incontinence comprising a therapeutic dose of an oxybutynin selected from the group consisting of oxybutynin and its pharmaceutically acceptable salt that delivers from 0 to 1 mg in 0 to 4 hours, from 1 mg to 2.5 mg in 0 to 8 hours, from 2.75 to 4.25 mg in 0 to 14 hours, and 3.75 mg to 5 mg in 0 to 24 hours for treating urge incontinence in the patient.

The district court found that Alza had failed to meet its burden of proof on infringement. The district court also found the asserted claims of the ‘355 patent to be invalid as both anticipated and obvious in light of the prior art. The Federal Circuit agreed in Alza v. Mylan (Fed. Cir. 2006, 06–1019).

The standard for obviousness is that a claimed invention is unpatentable if the differences between it and the prior art are “such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.” 35 U.S.C. § 103(a) (2000); In re Kahn, 441 F.3d 977, 985 (Fed. Cir. 2006) (citing Graham v. John Deere Co., 383 U.S. 1, 13-14, (1966)).

Obviousness is a question of law, reviewed de novo, based upon underlying factual questions while the presence or absence of a motivation to combine references in an obviousness determination is a question of fact.

The “motivation to combine” requirement prevents hindsight reasoning when determining the obviousness of an invention. The CAFC pointed out that according to the “motivation-suggesting-teaching” test, a court must ask “whether a person of ordinary skill in the art, possessed with the understandings and knowledge reflected in the prior art, and motivated by the general problem facing the inventor, would have been led to make the combination recited in the claims.” Kahn, 441 F.3d at 988 (citing Cross Med. Prods., Inc., v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1321-24 (Fed. Cir. 2005)).

The CAFC repeated the analysis in Kahn:

A suggestion, teaching, or motivation to combine the relevant prior art teachings does not have to be found explicitly in the prior art, as “the teaching, motivation, or suggestion may be implicit from the prior art as a whole, rather than expressly stated in the references. . . . The test for an implicit showing is what the combined teachings, knowledge of one of ordinary skill in the art, and the nature of the problem to be solved as a whole would have suggested to those of ordinary skill in the art.” However, rejections on obviousness grounds cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness. This requirement is as much rooted in the Administrative Procedure Act [for our review of Board determinations], which ensures due process and non-arbitrary decision-making, as it is in § 103.

In the present case, the patent at issue is directed to an extended release form of oxybutynin. After roughly 8-12 hours a typical drug dosage form will reach the colon. If, hypothetically, a particular drug is simply not absorbed from the colon into the bloodstream, then it may make little sense to develop an extended-release dosage form that is capable of “withholding” the release of some fraction of that drug until it reaches the colon. In other words, under these hypothetical conditions, there may be little motivation to design an oral dosage form capable of releasing drug more slowly than over an approximately 8-12 hour time course, because such drug would be released in the colon, where it is (hypothetically) not absorbed.

The ‘355 patent claims an extended release oxybutynin formulation, which Alza argued one of ordinary skill in the art would not have believed that oxybutynin could be absorbed in the colon. Absent such absorption, Alza contends that one of ordinary skill in the art lacked the motivation to make the claimed extended release formulation.

The CAFC was not persuaded. Although the district court based its invalidity holding both on anticipation and obviousness grounds, the CAFC affirmed based only on obviousness.

Because Alza’s argument was that no one of ordinary skill in the art would have been motivated to adapt the known technology to oxybutynin in the first place, because a person of ordinary skill in the art would have had no reason to expect that such an extended release oxybutynin formulation would have therapeutic value, the CAFC merely looked at whether one of ordinary skill in the art in 1995 would have had a reasonable expectation that oxybutynin would be colonically absorbed and therefore would have been motivated to produce the claimed extended release formulation.

Alza argued that the district court erred when it concluded that the evidence established that a person of ordinary skill in the art in 1995 would reasonably expect oxybutynin to absorb in the colon and have a reasonable expectation of success of producing a 24 hour oxybutynin formulation meeting the claims of the ‘355 patent. Alza argued that there was no contemporaneous documentation supporting the view that any one factor—lipophilicity or anything else—existed to identify successful candidates for once-a-day delivery.

The CAFC set out that:

As an initial matter, it is essential to recognize that, as we have explained above, under our non-rigid “motivation-suggesting-teaching” test, a suggestion to combine need not be found in the prior art. See Cross Med. Prods., 424 F.3d at 1322 (“[T]he motivation to combine need not be found in prior art references, but equally can be found in the knowledge generally available to one of ordinary skill in the art . . . .”). Accordingly, where the testimony of an expert witness is relevant to determining the knowledge that a person of ordinary skill in the art would have possessed at a given time, this is one kind of evidence that is pertinent to our evaluation of a prima facie case of obviousness. We now turn to consider whether the relevant evidence, including the expert testimony and the prior art, when viewed as a whole supports the findings of the district court. We conclude that the findings of the district court were not clearly erroneous.

Mylan’s expert, Dr. Amidon, testified that based on its lipophilicity, he would “expect oxybutynin to be a highly permeable” compound that is “rapidly absorbed” along the length of the GI tract, including the colon.

In looking at the references cited by Alza to refute the testimony, the Court concluded that:

Far from teaching away or detracting from the weight of Dr. Amidon’s testimony, these prior art references, taken as a whole, are entirely consistent with the finding that in 1995 a person of ordinary skill in the art would have expected a general, albeit imperfect, correlation between a drug’s lipophilicity and its colonic absorptivity. Accordingly, we cannot perceive clear error in the district court’s factual findings that while colonic absorption was not guaranteed, the evidence, viewed as a whole, is clear and convincing that a person of ordinary skill in the art would nonetheless have perceived a reasonable likelihood of success and that she would have been motivated to combine prior art references to make the claimed invention.

Likewise, we find no error in the district court’s consideration of secondary indicia of obviousness. We therefore affirm its legal conclusion of obviousness, finding the district court to have correctly held that Mylan met its burden of overcoming the presumption of validity that attaches to an issued patent.

See also Alza v. Impax (Fed. Cir. 2006, 06–1047)

  Print This Post Print This Post  

Comments are closed.