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Motivation to Combine Prior Art Teachings Need Not Be Found in the Art

September 06, 2006

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Last Month at the Federal Circuit - October 2006

Judges: Gajarsa (author), Clevenger, Prost

[Appealed from: N.D. W. Va., Judge Keeley]

In Alza Corp. v. Mylan Laboratories, Inc., No. 06-1019 (Fed. Cir. Sept. 6, 2006), the Federal Circuit affirmed the district court’s holding that the asserted claims of U.S. Patent No. 6,124,355 (“the ’355 patent”) were invalid under 35 U.S.C. § 103(a) and not infringed.

Alza Corporation (“Alza”) owns the ’355 patent, which discloses an oral once-a-day extendedrelease oxybutynin formulation for the treatment of urinary incontinence. In describing the technology, the Court noted that an oral drug dissolves in the gastrointestinal (“GI”) tract and is absorbed into the bloodstream. A drug formulation may be released in the stomach, or it may have an extended release such that it is released slowly as it passes through the GI tract, resulting in the release of some of the drug in the colon. The Court explained that if the colon cannot absorb a particular drug, then there would be no reason to develop such an extended-release formulation. Claim 2, which is representative of the ’355 patent, is directed to “a sustained-release oxybutynin formulation,” which delivers specified amounts of the drug over specified periods of time for up to twenty-four hours. Alza markets the patented formulation as Ditropan XL®. Mylan Laboratories, Inc. and Mylan Pharmaceuticals, Inc. (collectively “Mylan”) filed two ANDAs for a generic version of Ditropan XL®, and Alza sued.

In its Markman Order, the district court construed the term “deliver” to refer to the rate of in vivo release of oxybutynin in the GI tract. To prove that Mylan’s ANDA formulation infringed the ’355 patent, Alza presented evidence showing (1) the rate at which Mylan’s formulation released oxybutynin in an in vitro dissolution apparatus, and (2) the rate at which Mylan’s formulation resulted in the accumulation of oxybutynin in the bloodstream. Alza, however, did not provide any direct evidence that Mylan’s formulation released oxybutynin in the GI tract at the claimed rates. Thus, the district court found that Alza failed to meet the burden of proof for infringement. Additionally, the district court found that the asserted claims of the ’355 patent were both obvious over and anticipated by the prior art. Alza appealed.

The Federal Circuit first addressed obviousness, noting that obviousness is a question of law based on underlying factual questions. These underlying factual inquiries, as set forth in Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966), include the scope and content of the prior art, the level of ordinary skill in the prior art, and the difference between the claimed invention and the prior art.

The Court reiterated that hindsight reasoning, based on the teachings of the invention at issue, may not enter an obviousness analysis. The secondary indicia of nonobviousness discussed in Graham serves to prevent such improper hindsight reasoning. Similarly, the “motivation to combine” analysis prevents improper hindsight reasoning by requiring that a court consider “whether a person of ordinary skill in the art, possessed with the . . . problem facing the inventor, would have been led to make the combination recited in the claims.” Slip op. at 5 (citation omitted). Thus, the “motivationsuggestion- teaching” test incorporates both the “scope and content of the prior art” and the “level of ordinary skill in the pertinent art,” as required by Graham. Id. Nevertheless, the Court emphasized that its “motivation-suggestion- teaching” test does not require an actual teaching in the prior art in order to establish that one of ordinary skill in the art would have known to combine references. Rather, “[t]here is flexibility in our obviousness jurisprudence because a motivation may be found implicitly in the prior art.” Id. at 6 (emphasis in original).

On appeal, the Federal Circuit affirmed the district court’s holding of invalidity on obviousness grounds, and did not reach the issue of anticipation. The Court rejected Alza’s argument that one of ordinary skill in the art would not have been motivated to adapt the prior art teachings to the oxybutynin because no one would expect that an extended-release formulation of oxybutynin would have any therapeutic value, in particular because nothing in the prior art references supported the idea that lipophilicity of a drug correlated to its colonic absorptivity. Instead, the Court emphasized that the motivation to combine references for a finding of obviousness can be found in the knowledge of one of ordinary skill in the art, and relied on the testimony of Mylan’s expert, Dr. Amidon, that at the time of the invention, he would have expected oxybutynin to be rapidly absorbed in the colon based on its lipophilicity. The Court explained that expert testimony may establish the knowledge of one of ordinary skill in the art at the time of the invention.

The Federal Circuit further rejected Alza’s contention that two additional prior art references negated Dr. Amidon’s testimony regarding knowledge in the art. The Court explained that at best, the references Alza presented suggested that other factors, in addition to lipophilicity, affect a drug’s absorption behavior in the colon. Thus, the Court found no clear error in the district court’s findings. Additionally, the Court agreed with the district court’s conclusion that one of ordinary skill in the art would have had a reasonable expectation of success in combining the prior art teachings. Finally, the Federal Circuit found no clear error in the district court’s finding that Alza failed to establish secondary indicia of nonobviousness.

Despite its invalidity holding, the Federal Circuit analyzed Alza’s infringement. The Court noted that Alza provided no direct evidence at trial on the rate of release of the accused product in vivo. The Federal Circuit explained that Alza had “failed to credibly link [the indirect evidence it offered] with the relevant pharmacokinetic parameter—the rate of in vivo dissolution in the GI tract.” Id. at 16. At trial, Alza attempted to equate the oxybutynin blood plasma concentrations with the claimed in vivo dissolution rates, but the only evidence in support of this contention was a statement by Dr. Amidon, which he had promptly recanted. Thus, the Federal Circuit agreed with the district court that the plasma concentration data failed to establish the in vivo release rate of the ANDA formulation. Alza’s in vitro dissolution rate data was similarly inadequate. The district court had relied on Dr. Amidon’s testimony that the in vitro experiments did not reflect the in vivo behavior of the drug. Thus, the Federal Circuit concluded that the in vitro dissolution rates were not relevant to infringement.

Finally, the Federal Circuit “explicitly reject[ed]” Alza’s argument that the district court erred because it did not expressly state that not only was the in vitro and blood plasma data insufficient on its own, but the combination of data was also insufficient to establish infringement. The Court noted that in this case, each piece of evidence was “severely inadequate” and, therefore, the combination of the two pieces of evidence was likewise insufficient to establish infringement. Thus, Alza had failed to establish infringement.