Bayer Pharma AG v. Watson Labs. Inc. United States Court of Appeals of the Federal Circuit,2017 No. 2016-2169,2017 WL 4929904

A. 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. It credited Dr. Wicks' testimony that a person of ordinary skill in the art would not have focused on an ODT formulation of vardenafil “because of the rarity of ODT formulations.”

The district court cited the absence of any other ODT formulations of ED drugs 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 is that it concluded that the record did not contain an indication that ED drugs would be good candidates for ODT formulations. This is simply not accurate. 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. Dr. Jacobs testified that the Chang reference states “drugs for [ED] would be good candidates for ODT formulation.” He testified the Boolell and Fryburg references each disclose formulating vardenafil as an ODT. He testified that numerous companies had already begun formulating ODT versions of ED drugs: Pfizer filed the Bell-Huff patent application directed to sildenafil ODT; Eisai filed the Furitsu patent application claiming an ODT formulation of phosphodiesterase inhibitors; and Lavipharm filed the Chen international patent application, identifying ODT versions of sildenafil.

These six references—Chang, Boolell, Fryburg, Bell-Huff, Furitsu, and Chen—are 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 here does it 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 are highly relevant to whether a person of ordinary skill in the art would have been motivated to formulate ODT vardenafil. And their express disclosures cause the district court fact finding regarding motivation to combine to be clear error.

All six of the prior art references disregarded by the district court identify ED drugs as ODT formulations. Chang identifies ED drugs as one of five drug classes considered candidates for fast-dissolving tablets. Boolell states ED drugs such as sildenafil and vardenafil can be “administered orally, buccally or sublingually in the form of tablets” and “may also be administered as fast-dispersing or fast-dissolving dosage forms.” Fryburg provides the same disclosure, limited to vardenafil. Bell-Huff, Furitsu, and Chen show that between 1999 and 2001, more than one company sought patent protection on ODT formulations of ED drugs. Bell-Huff is directed to “rapidly disintegrating oral dosage forms which contain sildenafil.” Furitsu is titled “Tablets Immediately Disintegrating in the Oral Cavity” and is directed to phosphodiesterase inhibitors, the class in which vardenafil, sildenafil, and tadalafil belong. And Chen is directed to sildenafil formulations, one example of which includes a “fast dissolving tablet.” All of these references indicate a person of ordinary skill in the art would have considered ODT formulations applicable to ED drugs. And several of these references indicate a person of ordinary skill in the art would have considered ODT formulations to be applicable to vardenafil in particular.

The remainder of the district court's findings underlying the motivation to formulate vardenafil ODT focused too heavily on the commercial availability of ODT formulations of ED drugs as of the ’950 patent's priority date. It is 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. Particularly given the lengthy FDA approval process, the pharmaceutical industry is no exception. Any motivation, whether articulated in the references themselves or supported by evidence of the knowledge of a skilled artisan, is sufficient. Here, the motivation to formulate an ODT version of vardenafil is plainly evident from the face of multiple prior art references disclosing ODT formulations of ED drugs. No further rationale for developing vardenafil ODT was necessary. On review of the entire record evidence before the district court, we are left with the definite and firm conviction that the district court clearly erred when it found there would not have been a motivation to formulate vardenafil ODT.

B. Sorbitol and mannitol limitation

Claim 9 requires the vardenafil ODT formulation to contain a mixture of sorbitol and mannitol, and claim 11 more generally requires that the ODT formulation contain at least two sugar alcohols, one of which must be sorbitol. Neither party disputes that it was known—if not necessary—to include a sugar alcohol in ODT formulations. The parties' dispute rests on whether a person of ordinary skill in the art would have been motivated to select the claimed combination of sugar alcohols, sorbitol and mannitol.

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, finding Dr. Wicks' testimony on this limitation more credible than Dr. Jacobs'.

We do not question the district court's credibility determinations. However, 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 and under a proper analysis, we conclude that 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 parties do 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 agree 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 can be no question that it was known as of the ’950 patent's priority date to use sorbitol and mannitol in ODT formulations.

Dr. Jacobs testified that the Norman reference, not addressed by the district court, discloses examples of ODT formulations using sorbitol and mannitol created by SPI Pharma. The district court mentioned Dr. Jacobs relied on the Sparks reference, but did not explain why Sparks' examples using sorbitol and mannitol in ODT formulations were not relevant to whether a skilled artisan would have used sorbitol and mannitol in vardenafil ODT, or give any reason why that reference would not inform the obviousness analysis. Dr. Wicks likewise provided no rebuttal testimony regarding these references. Other than critiquing its lack of examples or experimental data, the district court's decision does not otherwise mention the Pharmaburst advertisement, or its disclosure that it is “an ‘off the shelf’ excipient which allows you to develop your own quick dissolve formulations in-house quickly and much more cost effectively.” Its decision does not mention Ghosh's similar disclosure that Pharmaburst “is a highly flexible, rapidly disintegrating excipient that imparts a smooth creamy mouth feel, and is manufactured under cGMPs.”

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 Joshi reference states using sorbitol with mannitol in ODTs is advantageous because it “enable [s] strong binding and result[s] in a more robust tablet at low compression forces.” It explains that, “[i]n addition to contributing to the robustness of tablets, the sorbitol also imparts a sweet taste and a unique texture to the mannitol, thereby improving the ODT formulation's mouthfeel” without affecting pharmacopeial conformity standards. Particularly in light of the district court's finding that a person of ordinary skill in the art “would have expected a vardenafil ODT to have a bitter taste,” these disclosures are relevant to whether a skilled artisan would have been motivated to use sorbitol and mannitol in vardenafil ODT. The district court's finding that nothing in the prior art provided a reason to use sorbitol in addition to mannitol in an ODT is clearly erroneous in light of Watson's evidence.

C. Immediate-release limitation

The district court found that even if a skilled artisan would have been motivated to make an ODT formulation of vardenafil, the prior art taught away from formulating vardenafil ODT as immediate release. The parties agree that only two types of ODT formulations were known in the art: immediate-release ODTs, which are released in the mouth, and delayed-release ODTs, which are released in the stomach. 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.

We do not disturb the district court's findings relating to vardenafil's expected bitter taste and increased bioavailability, but the district court erred when it elevated those findings to teaching away. “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.” 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.” But 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. In assessing whether prior art teaches away, that “better alternatives exist in the prior art does not mean that an inferior combination is inapt for obviousness purposes.” 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. The district court's finding that a person of ordinary skill in the art would have first pursued a delayed-release formulation over an immediate-release formulation is insufficient to support a finding of teaching away.

The evidence before the district court supports its finding that a person of ordinary skill in the art may have preferred a delayed-release formulation over immediate release—not that an immediate-release formulation was unlikely to be productive in vardenafil ODT. Rather than testify that a skilled artisan would have believed the taste of vardenafil is too bitter to formulate as an immediate-release ODT, Dr. Wicks merely testified that “the consideration would lead them to a delayed-release ODT.” Nor did Dr. Wicks point to prior art suggesting vardenafil would have tasted too bitter. Dr. Wicks conceded “[t]he taste of vardenafil was not reported in the literature” and disclaimed that a person of ordinary skill in the art “would have assumed that vardenafil was as bitter as sildenafil.” When asked about bioavailability concerns due to Levitra's label, Dr. Wicks again focused on why those concerns would have caused a skilled artisan to prefer a delayed-release formulation. This testimony supports the district court's finding that the taste and bioavailability of vardenafil raised concerns, and that a skilled artisan may have preferred a delayed-release formulation, but it does not support a finding of teaching away.

While the district court did not clearly err in its fact finding that a skilled artisan would have had concerns over an immediate-release formulation due to vardenafil's expected bitter taste and bioavailability, obviousness “does not require that the motivation be the best option, only that it be a suitable option from which the prior art did not teach away.”

D. 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. We do not disturb these findings. Copying is one of the objective indicia we have held is probative of nonobviousness. Both Bayer's evidence of copying and unexpected results weigh in favor of the nonobviousness of the claimed combination.

E. Legal conclusion of obviousness

We consider whether the claimed invention would have been obvious de novo based on underlying findings of fact. Watson demonstrated by clear and convincing evidence that there would have been a motivation to formulate an ODT version of vardenafil. In fact, the prior art was explicit in the suggestion to make such a combination and the district court clearly erred in its fact finding to the contrary. The prior art of record expresses a clear motivation to formulate ODT versions of ED drugs and that multiple companies were formulating ODT versions of ED drugs. Watson also demonstrated by clear and convincing evidence that there was an express motivation in the prior art to use sorbitol and mannitol as the excipients in the ODT formulation of the ED drug and the district court clearly erred in its fact finding to the contrary. Pharmaburst B2 was a known, off-the-shelf ODT excipient product that permitted formulation of ODT products “in-house quickly and much more cost effectively.” The district court did not clearly err in its fact finding that a person of ordinary skill in the art would have had concerns using an immediate-release formulation due to vardenafil's expected bitter taste and bioavailability; however, it clearly erred when it concluded that those findings taught away from the immediate release. Bayer presented evidence of copying and unexpected results that weigh in favor of a conclusion of nonobviousness.

Weighing this evidence together with the objective evidence of unexpected results and copying, we conclude that a skilled artisan would have found the claimed combination obvious. The district court's final judgment is reversed.