Rotigotine - USA

On Jun 24, 2019, Federal Circuit affirmed district court’s decision that Actavis infringed the valid patent of Neupro® patch.

This appeal concerns UCB’s Patent Nos. US 6,884,434 and US 8,232,414. The ’434 patent claims a transdermal therapeutic system comprising rotigotine, a drug used for the treatment of Parkinson’s disease. The ’414 patent claims a polymorph of rotigotine. Delaware court found that Watson / Actavis’s generic products infringed the ’434 patent under the doctrine of equivalents & also upheld the validity of the ’434 patent over Actavis’s obviousness and anticipation challenges. Actavis appeals the district court’s infringement and validity judgments. UCB cross-appeals the district court’s invalidation of the ’414 patent under 35 U.S.C. § 102(a) as known and used by others in the United States before the date of invention.

A. Infringement of the ’434 Patent:

The only asserted independent claim reads:

1. A transdermal therapeutic system comprising a self-adhesive matrix layer containing the free base [rotigotine] in an amount effective for the treatment of the symptoms of Parkinson’s syndrome, wherein the matrix is based on an acrylate-based or silicone-based polymer adhesive system having a solubility of ≧5% (w/w) for the free base [rotigotine], all of said free base being present in the matrix in the absence of water; a backing layer inert to the components of the matrix layer; and a protective foil or sheet covering the matrix layer to be removed prior to use.

Actavis’s product contains polyisobutylene adhesive, which is different from the claimed acrylate-based or silicone-based polymer adhesives. But UCB argued that, under the doctrine of equivalents, polyisobutylene-based adhesives are interchangeable with the claimed adhesives. Actavis argued that UCB was “barred” from asserting the doctrine of equivalents here because of prosecution history estoppel, intentional narrow claiming, vitiation, or ensnarement.

a. Prosecution History Estoppel –

Actavis argued that UCB’s election of the Group I claims (limited to silicone- and acrylate-based polymer adhesive) after the examiner issued a restriction requirement should prevent UCB from now asserting infringement under the doctrine of equivalents. The Group II claims were not limited to silicone- and acrylate-based polymer adhesive systems. In Actavis’s view, because UCB withdrew those claims, it gave up claim scope of adhesives that are not silicates or acrylates and should not be allowed to recapture that subject matter through the doctrine of equivalents. Federal Circuit, however, sided with District court & said that here the examiner’s restriction requirement did not relate to polyisobutylene, and the examiner was not communicating anything about the patentability of polyisobutylene-based adhesive systems. UCB never added a polyisobutylene-excluding limitation by amendment, and its election cannot be read as such. Court concluded that UCB did not make a narrowing amendment in respect to the restriction requirement. Therefore,  court found no good basis in the prosecution history to bar the application of the doctrine of equivalents to polyisobutylene-based polymer adhesive systems.

b. Narrow Claiming –

Actavis argued that UCB had chosen to draft narrow claims and should not be permitted to expand the scope of those claims through the doctrine of equivalents. Specifically, Actavis argued that Dr. Mueller, an inventor of the ’434 patent, knew that polyisobutylene was a polymer that could be used in transdermal patches but chose not to prosecute a claim broad enough to cover polyisobutylene. Court said that ’434 patent’s specification does not rely on any unique characteristics of acrylate or silicone-based polymer adhesive systems that would not be present in a polyisobutylene-based system. And the fact that the specification repeatedly recites acrylate- and silicone-based polymers is irrelevant to the issue of whether it describes those polymers in a manner that would suggest to a skilled artisan that polyisobutylene is not an equivalent. There is not enough indication from the patent specification, claims, or the record evidence of the inventor’s knowledge here to conclude that UCB surrendered polyisobutylene as a possible equivalent. In the absence of such facts, Federal Circuit agreed with the district court that UCB’s claiming of acrylates and silicates does not bar treating polyisobutylenes as an equivalent for infringement purposes.

c. Vitiation -

Actavis argued that UCB’s doctrine of equivalents infringement theory should fail because it vitiates the “acrylate-based or silicone-base polymer adhesive system” limitation of claim 1. Federal Circuit did not agree with finding that polyisobutylene to be an equivalent gives the element “an acrylate-based or silicone-based polymer adhesive system” such broad play that the element would disappear entirely. The district court did not broaden the right to exclude so widely as to cover all adhesive systems and vitiate the “acrylate-based or silicone-based” claim language.

d. Ensnarement –

Actavis argued that a hypothetical claim including polyisobutylene-based polymers would ensnare the prior art. Court said that Actavis offers no examples of prior art that would be ensnared by the addition of polyisobutylene to the claim, in contrast to the claim as is. Federal Circuit said that District court correctly found that there is no an ensnarement issue here and found that “UCB’s equivalence theory does not ensnare the prior art.”

e. Doctrine of Equivalents – Merits

Court applied the insubstantial difference test here because it may be more suitable . . . for determining equivalence in the chemical arts,” and identified “structural equivalen[cy]” as particularly relevant when comparing chemical equivalents. Mylan Institutional LLC v. Aurobindo Pharma Ltd., 857 F.3d 858, 869 (Fed. Cir. 2017). The district court found that, at the time the ’434 patent was filed, silicates, acrylates, and polyisobutylenes were the most commonly used pressure-sensitive adhesives in transdermal patches. The district court then identified a set of properties that silicates, acrylates, and polyisobutylenes share: they are pressure-sensitive, adhesive, biologically inert, non-irritating, and non-toxic. Thus, the district court found that a skilled artisan “would recognize that polyisobutylene is not substantially different from the classes of adhesives literally within the scope of the claims.” The district court also made fact findings as to the differences between polyisobutylene and silicates/acrylates (e.g., lack of heteroatoms and functional groups, different polarity, etc.). But these differences do not matter for how the claimed invention works. The district correctly concluded that “[t]hese results show that the polyisobutylene-based polymer adhesive system did not alter the way rotigotine is transdermally delivered compared to a silicone-based polymer adhesive system,” nor did it “alter rotigotine transdermal delivery rates,” showing that “polyisobutylene is interchangeable with silicone in the claimed polymer adhesive system.” Therefore, polyisobutylene-based adhesive system is an insubstantial modification of the claimed invention.

B. Validity of the ’434 Patent:

The district court found that Cygnus prior art did not disclose a crucial element of claim 1: a patch containing rotigotine in free base form. On appeal, Actavis points to Cygnus’s Example 15 as teaching a patch with some rotigotine in free base form. But Actavis’s argument is flawd because there is nothing in Cygnus that teaches a water-free patch with rotigotine in free base form. All the patches in Cygnus’s examples— including those with rotigotine—contain significant amounts of water (10–15% w/w). Other prior arts, Lipp & Pfister  did not fill this gap. Both disclose transdermal patches containing PVP, but neither discloses any anti-Parkinson’s drugs, much less rotigotine free base in the absence of water.

The district court also rejected Actavis’s argument that the asserted claims of the ’434 patent would have been obvious in light of Miranda combined with Timmerman. Miranda discloses most of the things but does not specifically name rotigotine as a suitable drug for its patches. Timmerman is a 1988 study in which rats were treated transdermally on the skin of their necks with a solution containing rotigotine free base. On appeal, Actavis argues that the district court failed to find obviousness over this combination only because it applied an “unduly rigid” analysis in concluding that Actavis had not shown a motivation to combine or reasonable expectation of success. Federal Circuit said that even accepting Actavis’s argument that a skilled artisan would start with Timmerman, there is still an evidentiary gap as to why a skilled artisan would think of using a transdermal patch, as taught in Miranda, based on Timmerman’s “transdermal administration” disclosure of applying a liquid dose of the drug on the hairless skin on the neck of a rat. As to lack of reasonable expectation of success, Federal Circuit affirmed the district court’s finding.  Court said that based on the disclosures, it was reasonable to conclude that Miranda is less of a “recipe” for the claimed rotigotine transdermal patch and more of a list of thousands of possibilities out of which a skilled artisan would have to select the claimed combination as one to try. Miranda does not provide a reasonable expectation of success for making a transdermal patch of rotigotine without undue experimentation, and Timmerman cannot fill in this gap, as it does not contemplate using a patch to administer rotigotine transdermally. Also transdermal patch field was not a common, widespread one during the relevant time, and that of the drugs available as patches, rotigotine was the only active ingredient that was introduced as a patch without first being available in a different type of formulation.

Thus, Federal Circuit affirmed the district court’s findings upholding the validity of the asserted ’434 patent claims.

C. Invalidity of the ’414 Patent:

On cross-appeal, UCB asked court to reverse the district court’s invalidation of the asserted ’414 patent claims due to prior public use under § 102(a) because the record evidence allegedly did not support the district court’s inferences as to how UCB’s Form II invention was in actual use before the correct invention date. The district court reasonably found that a patient in the United States used Neupro patches that contained Form II rotigotine before November 28, 2007—the ’414 patent’s filing date—and that therefore, the ’414 patent claims were invalid under § 102(a). In November 2007, one female patient patient purchased Neupro patches that were from lot 47808—one of the lots later discovered to have contained Form II rotigotine. While using these lot 47808 patches, the patient began “clearly back-sliding, experiencing previous [Parkinson’s] symptoms of losing mobility, shaking and freezing.” The patient experienced the adverse event two days after the priority date of the ’414 patent, but she had been using the patches for “one week,” necessarily implying that she was using the patches before the ’414 patent’s priority date of November 28, 2007. Federal Ciruit rejected UCB’s arguments & said that there is plenty of evidence that most, if not all, of the patches in lot 47808 contained crystals, and that those crystals contained Form II. There is also evidence that the patient, who reported backsliding only after one week of using lot 47808 patches and who reported improvement (even if short-lived) when a new set of patches was used thereafter, used patches with Form II and that her symptoms matched up with use of Form II. Therefore court fond no clear error in the district court’s finding that Actavis presented clear and convincing evidence of public use before the date of invention under § 102(a). Thus it affirmed the district court’s invalidation of the asserted ’414 patent claims.

In conclusion, Federal Circuit affirmed the district court’s judgment of infringement and validity of the asserted ’434 patent claims, as well as invalidity of the asserted ’414 patent claims.