UCB, INC., UCB MANUFACTURING IRELAND LIMITED, UCB PHARMA GMBH, LTS LOHMANN THERAPIE-SYSTEME AG, Plaintiffs-Cross-Appellants
WATSON LABORATORIES INC., ACTAVIS LABORATORIES UT, INC., Defendants-Appellants
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.
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.
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.
Taranto, Schall, and Chen, Circuit Judges.
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, 434and 8, 232,
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.
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.
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
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 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
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.
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.
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.
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
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.
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.
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
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.
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.
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
or Pfister, and over Timmerman with Miranda. J.A. 154-62.
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.
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.
Infringement of the '434 Patent
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 ...