IP Law Daily Bayer’s patent for erectile dysfunction drug Staxyn was obvious
Wednesday, November 1, 2017

Bayer’s patent for erectile dysfunction drug Staxyn was obvious

By Peter Reap, J.D., LL.M.

The federal district court in Wilmington, Delaware, committed clear errors in finding that drug company Watson Laboratories failed to show that competitor Bayer’s asserted claims of its patent for the erectile dysfunction treatment drug Staxyn were obvious, the U.S Court of Appeals for the Federal Circuit has decided. The lower court erred in rejecting each of Watson’s arguments based on a motivation to combine, the use of mannitol and sorbitol, and that the prior art taught away from the asserted claims. Considering the district court’s errors with the remainder of its fact findings, claims 9 and 11 of Bayer’s patent would have been obvious, and the ruling of the district court was reversed (Bayer Pharma AG v. Watson Laboratories, Inc., November 1, 2017, Moore, K.).

In 2003, the Food & Drug Administration ("FDA") granted Bayer Pharma AG approval to market vardenafil hydrochloride trihydrate to treat erectile dysfunction ("ED") under the name Levitra. Vardenafil belongs to a class of ED drugs called phosphodiesterase inhibitors. When the FDA approved Levitra, two other phosphodiesterase inhibitors were already on the market: Pfizer launched sildenafil under the name Viagra in 1998, and Eli Lilly launched tadalafil under the name Cialis in 2003. Levitra, Viagra, and Cialis are each formulated as immediate-release tablets that are swallowed whole.

Bayer’s U.S. Patent No. 8,613,950 ("the ’950 patent") issued on December 24, 2013. It is directed to a formulation of vardenafil "in the form of an uncoated tablet which disintegrates rapidly in the mouth," commonly referred to as an oral disintegrating tablet ("ODT"). Bayer markets a commercial embodiment of the ’950 patent, vardenafil ODT, under the name Staxyn.

Watson filed an Abbreviated New Drug Application with the FDA seeking approval to market a generic version of Staxyn. Bayer filed the instant case asserting infringement of the ’950 patent. Claims 9 and 11, both of which depend from claim 8, were the only claims at issue.

Watson argued the claimed formulation of vardenafil would have been obvious to a person of ordinary skill in the art based on multiple exemplary references showing a motivation to: (1) create an ODT formulation of vardenafil; (2) select mannitol and sorbitol as sugar alcohols; and (3) make the ODT formulation immediate-release. The district court rejected each of Watson’s arguments. It found a person of ordinary skill in the art would not have been motivated to create an ODT formulation of vardenafil and would not have used mannitol and sorbitol as excipients. It found the prior art taught away from formulating vardenafil ODT as immediate-release. Watson appealed.

Vardenafil ODT limitation. The district court determined that Watson failed to meet its burden of proving by clear and convincing evidence that there would have been a motivation to formulate vardenafil as an ODT formulation. This determination rested largely on the court’s finding the testimony of Bayer’s expert, Dr. Wicks, more persuasive than the testimony of Watson’s expert, Dr. Jacobs. The district court found it important that, according to Dr. Wicks, no ED ODT drug was on the market as of the ’950 patent’s priority date.

The clear error in the district court fact finding that there was no motivation to formulate ED drugs in ODTs, was that it concluded that the record did not contain an indication that ED drugs would be good candidates for ODT formulations, according to the appellate court. Watson relied on nine prior art references to support its assertion that there would have been a motivation to create an ODT formulation of vardenafil. Six of the references cited by Watson—Chang, Boolell, Fryburg, Bell-Huff, Furitsu, and Chen—were absent from the district court’s decision. While it is certainly not necessary for a district court to evaluate all references presented to it, nowhere did the district court mention these key references in analyzing whether the prior art taught vardenafil ODT or whether a skilled artisan would have been motivated to formulate vardenafil ODT. These references were highly relevant to whether a person of ordinary skill in the art would have been motivated to formulate ODT vardenafil. Their express disclosures cause the district court fact finding regarding motivation to combine to be clear error, the Federal Circuit explained. All six of the prior art references disregarded by the district court identify ED drugs as ODT formulations.

Dr. Wicks’ testimony did not cast doubt on the weight of Watson’s evidence regarding the vardenafil ODT limitation. It is well within the district court’s discretion to credit one expert’s competing testimony over another. But a district court cannot, through a credibility determination, ignore the wealth of evidence, especially as in this case where the expert did not even address it, the Federal Circuit reasoned. The district court’s finding that ODTs were not considered applicable to ED drugs was clearly erroneous in light of Watson’s evidence.

Further, it was unclear why the district court found it important that no ODT ED drug had gained FDA approval as of ’950 patent’s priority date. The motivation to combine inquiry is not limited to what products are forthcoming or currently available on the market, the appellate court noted.

Sorbitol and mannitol limitation. The district court found a person of ordinary skill in the art would not have been motivated to use mannitol and sorbitol in an ODT formulation. The district court’s analysis for the sorbitol and mannitol limitation again focused on the commercial availability of products while failing to address relevant prior art. Upon consideration of the entire record, the district court clearly erred in finding a person of ordinary skill in the art would not have been motivated to formulate an ODT with sorbitol and mannitol, the appellate court held.

The parties did not dispute that as of the ’950 patent’s priority date, a company named SPI Pharma marketed an off-the-shelf ODT excipient product called Pharmaburst. The parties agreed that Pharmaburst existed in three different forms: two using only mannitol and a third, Pharmaburst B2, containing mannitol and sorbitol. The ’950 patent specification uses Pharmaburst B2 in an example. Thus there could be no question that it was known as of the ’950 patent’s priority date to use sorbitol and mannitol in ODT formulations. The district court clearly erred when it found "there was nothing in the prior art that would have given the [person of ordinary skill in the art] a reason to use sorbitol in addition to mannitol in an ODT."

The district court’s remaining findings on the motivation to use sorbitol and mannitol in an ODT formulation focused solely on the ODT market as of the ’950 patent’s priority date. Although FDA approval may be relevant to the obviousness inquiry, a lack of FDA approval cannot negate an otherwise apparent motivation to formulate a product, the court noted.

Immediate-release limitation. The district court found, based again on expert testimony, that a person of ordinary skill in the art would have expected vardenafil ODT to have a bitter taste, which would have discouraged him from creating a formulation that releases vardenafil in the mouth. It also found a person of ordinary skill in the art would have been concerned with using an immediate-release formulation because it would be expected to increase bioavailability, and Levitra’s label suggested an increase in vardenafil blood levels would be a problem for older men. The district court found these two concerns would have taught away from an immediate-release formulation.

The district court erred when it elevated its bitter taste and bioavailability findings to teaching away, the Federal Circuit determined. "A reference teaches away when it suggests that the line of development flowing from the reference’s disclosure is unlikely to be productive of the result sought by the applicant." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012). The district court did not find that a person of ordinary skill in the art would have believed vardenafil’s expected bitter taste and increased bioavailability would have likely rendered an immediate-release formulation unproductive. Instead, the district court’s analysis focused on whether a person of ordinary skill in the art would "necessarily have made an immediate-release ODT rather than a delayed-release ODT." The teaching away inquiry does not focus on whether a person of ordinary skill in the art would have merely favored one disclosed option over another disclosed option. When there are only two possible formulations and both are known in the art at the time, the fact that there may be reasons a skilled artisan would prefer one over the other does not amount to a teaching away from the lesser preferred but still workable option.

Objective evidence. The district court found Watson’s copying of the claimed invention and Staxyn’s unexpected increased duration of action compared to Levitra supported its conclusion of nonobviousness. Both Bayer’s evidence of copying and unexpected results weigh in favor of the nonobviousness of the claimed combination, according to the Federal Circuit.

Obviousness. Weighing all four of the Graham obviousness factors, claims 9 and 11 of the ’950 patent would have been obvious, the Federal Circuit decided. The repeated suggestion in the prior art to make an ODT formulation of an ED drug and the suggestion to use the combination of sorbitol and mannitol as excipients were strong evidence of a motivation to make the claimed combination. A skilled artisan motivated to formulate vardenafil ODT would have been faced with a design need for its release profile, and an immediate-release formulation would have been one of two options. While a skilled artisan may have preferred a delayed-release formulation over the claimed immediate-release formulation, all of the evidence together, along with the objective evidence of unexpected results and copying, a skilled artisan would have found the claimed combination obvious, the Federal Circuit ruled.

The case is No. 2016-2169.

Attorneys: David I. Berl (Williams & Connolly LLP) for Bayer Pharma AG, Bayer Intellectual Property GMBH and Bayer Healthcare Pharmaceuticals, Inc. Elizabeth Holland (Goodwin Procter LLP) for Watson Laboratories, Inc. and Actavis Pharma, Inc.

Companies: Bayer Pharma AG; Bayer Intellectual Property GMBH; Bayer Healthcare Pharmaceuticals, Inc.; Watson Laboratories, Inc.; Actavis Pharma, Inc.

MainStory: TopStory Patent FedCirNews

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