UCB, Inc. v. Watson Laboratories Inc.

          Appeals from the United States District Court for the District of Delaware in No. 1:14-cv-01083-LPS-SRF, Chief Judge Leonard P. Stark.

          Jack B. Blumenfeld, Morris, Nichols, Arsht & Tun-nell LLP, Wilmington, DE, argued for plaintiffs-cross-appellants. Also represented by Derek J. Fahnestock, Maryellen Noreika; James Trainor, Robert Counihan, Adam Gahtan, Kevin McGann, Silvia Medina, Fenwick & West LLP, New York, NY.

          John C. O'Quinn, Kirkland & Ellis LLP, Washington, DC, argued for defendants-appellants. Also represented by William H. Burgess, Calvin Alexander Shank; Leora Ben-Ami, Thomas F. Fleming, Christopher T. Jagoe, New York, NY.

          Before Taranto, Schall, and Chen, Circuit Judges.

          Chen, Circuit Judge.

         This appeal concerns UCB, Inc., UCB Manufacturing Ireland Limited, UCB Pharma GmbH, and LTS Lohman Therapie-Systeme AG (UCB)'s U.S. Patent Nos. 6, 884, 434^[1]and 8, 232, 414.^[2] 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. The United States District Court for the District of Delaware found that Watson Laboratories Inc. and Actavis Laboratories UT, Inc. (Actavis)'s generic products infringed the '434 patent under the doctrine of equivalents. The district court 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. For the reasons articulated below, we affirm.

         Technical Background

         The technology at issue relates to a transdermal (via the skin) form of delivering a drug that treats Parkinson's disease. Parkinson's is a degenerative neurological condition linked to reduced dopamine levels in the brain, caused by degeneration and death of "dopaminergic" neurons. The '434 and '414 patents relate to the compound rotigotine, a dopamine receptor stimulator, that has been used to treat Parkinson's since the 1990s. Rotigotine comes in two forms: free base form and hydrochloride salt form.

         Cygnus Therapeutic Systems conducted early attempts at transdermal rotigotine formulation circa 1994. J.A. 118-19. Its system is described in patent application WO 94/07468 (Cygnus) and a 1995 article entitled "A Two-Phase Matrix for the Delivery of N-0923, a Dopamine Agonist" by Chiang et al. (Chiang). Rotigotine in the Cygnus system is present in the hydrochloride salt form, which is dissolved in water to create an aqueous phase in the patch's matrix. Preliminary clinical trials using patches manufactured by Cygnus demonstrated proof of concept that a sufficient amount of rotigotine can be transdermally delivered for treatment of Parkinson's. No commercial product resulted from Cygnus's work.

         UCB developed a rotigotine transdermal patch without using water and filed the '434 patent to cover such a patch. The patent is entitled "Transdermal therapeutic system which contains a d2 agonist and which is provided for treating Parkinsonism, and a method for the production thereof." The only asserted independent claim reads:

1. A transdermal therapeutic system comprising a self-adhesive matrix layer containing the free base [rotigotine^[3] 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.

'434 patent, col. 7 ll. 55-67 (emphasis added). The claim covers administration of rotigotine through a transdermal patch made of three layers, the most relevant for this appeal being an adhesive layer in which an effective amount of the free base form of rotigotine is dissolved in an acrylate- or silicone-based polymer adhesive so that there is no water and at least 5% rotigotine by weight in the layer. Dependent claims cover use of polyvinylpyrrolidone (PVP), a solubility enhancer, as part of the adhesive system to achieve the claimed solubility.

         The FDA approved UCB's rotigotine transdermal patches in May 2007, and UCB has been selling the product under the brand name Neupro since July 2007. Neupro's polymer adhesive system is silicone-based and contains PVP.

         Relevant to the other UCB patent in this appeal-the '414 patent-in June and July 2007, batches of rotigotine patches were manufactured for distribution in the United States. Of particular relevance to the alleged public use of the '414 patented product before its date of invention, laminate lot 47808 was produced during this period.

         Until August 2007, UCB manufactured Neupro patches by dissolving rotigotine in ethanol, among other steps, to create a rotigotine solution. It then prepared a coating mass from this solution and other components (including a silicone-based polymer), which, after drying, produced a matrix. The matrix did not contain crystalline rotigotine, and the rotigotine in the resulting patches, pre-distribution, was non-crystalline.

         On August 7, 2007, an unknown solid precipitated during the dissolution step, causing UCB to halt manufacture of Neupro patches. Over the next few months, UCB investigated and determined that the solid was a polymorph of rotigotine, characterized by unique single-crystal X-ray diffraction parameters. Polymorphs are different three-dimensional, solid-state, crystalline structures of the same chemical compound.

         UCB filed a patent application to cover the newly discovered Form II polymorph of rotigotine. This resulted in the '414 patent, entitled "Polymorphic form of rotigotine and process for production," with a priority date of November 28, 2007. The claims read:

1. A polymorphic form of rotigotine characterized by at least one parameter selected from the group consisting of:

(a) a powder X-ray diffraction spectrum comprising at least one peak at the following °2θ angles (± 0.2): 12.04, 13.68, 17.72, and 19.01;

(b) a Raman spectrum comprising at least one peak at the following (±3 cm-1): 226.2, 297.0, 363.9, 737.3, 847.3, 1018.7, and 1354.3 cm-1

(c) a DSC peak with a Tonset at 97°C. ± 2°C. measured with a heating rate of 10°/min; and

(d)a melting point of 97°C. ± 2°C.

2. The polymorphic form of rotigotine of claim 1, wherein the polymorphic form of rotigotine is characterized by at least the following powder X-ray diffraction peaks at °2θ angles (± 0.2): 12.04, 13.68, 17.72 and/or 19.01.

3. A polymorphic form of rotigotine having a powder X-ray diffraction spectrum substantially as shown in FIG. 1.

'414 patent, col. 8 ll. 48-64.

         On November 12, 2007, UCB submitted a Field Alert Report to the FDA, alerting the FDA that "small crystalline structure (snowflakes)" had been observed on the active surface of Neupro patches that had already been manufactured and distributed. J.A. 4833-34. UCB informed the FDA that "testing confirmed on November 7, 2007 that the snowflakes contain crystalline structures of a polymorph variant (Form 2) of the active ingredient Rotigotine." J.A. 4833. According to its report, many of the examined patches contained snowflakes; of 29 batches of product, only one did not have any patches containing visible snow-flakes. J.A. 4838. For batches manufactured for distribution in the United States, over 90% of the examined patches contained crystals by November 12, 2007. J.A. 6144.

         On November 30, 2007, two days after the priority date of the '414 patent, a female patient experienced an adverse event while being treated with Neupro. J.A. 5965. An Alert Report submitted by UCB states that the patient received samples of Neupro in September 2007 and "responded well" to treatment. Id. In November 2007, she purchased Neupro patches that were from lot 47808. Id. While using these patches, the patient began "clearly backsliding, experiencing previous symptoms of losing mobility, shaking and freezing." J.A. 5966. The Report indicated that the patient used the lot 47808 patches for "one week," implying that she was using the patches before the '414 patent's priority date of November 28, 2007. After experiencing this back-sliding, the patient "was reverted to the samples of the newer lot number" and "an improvement in the patient was noted." Id.

         Procedural History

         Actavis filed an Abbreviated New Drug Application (ANDA) for generic versions of transdermal rotigotine patches, and UCB filed suit for infringement of the '434 and '414 patents under 35 U.S.C. § 271(e)(2). The case proceeded to a four-day bench trial on the validity and infringement of claims 1, 5, 7, and 14-15 of the '434 patent, and the validity of claims 1-3 of the '414 patent.^[4]

         The district court found infringement of all the asserted '434 patent claims by Actavis's ANDA products (the Accused Products) under the doctrine of equivalents. Actavis's products use a polyisobutylene adhesive, rather than the claimed acrylate-based or silicone-based polymer adhesives, but the district court found the adhesives in this context to be substantially similar and that nothing in this case barred application of the doctrine of equivalents. J.A. 138-54.

         The district court then upheld the validity of claims 1, 5, 7, 14, and 15 of the '434 patent, rejecting, in relevant part, Actavis's arguments of anticipation under 35 U.S.C. § 102 by the Cygnus prior art reference and obviousness under 35 U.S.C. § 103 over Cygnus with Lipp^[5] or Pfister, ^[6]and over Timmerman^[7] with Miranda.^[8] J.A. 154-62.

         The district court also found the '414 patent claims invalid under § 102(a) because the Form II polymorph of rotigotine was used by others in the United States before the invention date-Neupro patches with Form II crystals were administered to at least one patient before November 28, 2007. J.A. 180-84.

         Actavis appeals the district court's infringement and above-listed validity findings on the '434 patent. UCB cross-appeals the district court's invalidation of the '414 patent. We have jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).

         Discussion

         A. Infringement of the '434 Patent

         The only infringement issue relevant to this appeal is whether the Accused Products have a "matrix . . . based on []an acrylate-based or silicone-based polymer adhesive system." '434 patent, col. 7 ll. 59-61. Actavis does not dispute that its Accused Products literally meet every other element of the asserted claims. The Accused Products use a polyisobutylene adhesive, which is different from the claimed acrylate-based or silicone-based polymer adhesives. But UCB ...