Appeals from the United States District Court for the
Northern District of Illinois in Nos. 1:16-cv-00651,
1:17-cv-07903, Judge Rebecca R. Pallmeyer.
G. Unikowsky, Jenner & Block LLP, Washington, DC, argued
for plaintiff-appellant. Also represented by Bradford Peter
Lyerla, Aaron A. Barlow, Yusuf Esat, Ren-How Harn, Sara
Tonnies Horton, Chicago, IL.
T. Aly, Schiff Hardin LLP, Chicago, IL, argued for
defendant-appellee. Also represented by Kevin Michael Nelson,
Joel M. Wallace; Ahmed M.T. Riaz, New York, NY.
Lourie, Dyk, and Moore, Circuit Judges.
Lourie, Circuit Judge.
Inc. ("Hospira") appeals from the judgment of the
United States District Court for the Northern District of
Illinois that claim 6 of U.S. Patent 8, 648, 106 ("the
'106 patent") is invalid as obvious. Hospira,
Inc. v. Fresenius Kabi USA, LLC, 343 F.Supp.3d 823 (N.D.
Ill. 2018) ("Opinion"). Because we find
that the district court's factual findings were not
clearly erroneous and that those findings support a
conclusion of obviousness, we affirm.
makes and sells dexmedetomidine products under the brand name
Precedex, including a ready-to-use product known as Precedex
Premix. Hospira owns a number of patents that cover its
Precedex Premix product. Fresenius Kabi USA LLC
("Fresenius") filed an Abbreviated New Drug
Application ("ANDA") seeking approval to enter the
market with a generic ready-to-use dexmedetomidine product.
Hospira sued for infringement of five patents and eventually
dropped all but two claims, one of which was claim 6 of the
'106 patent. Fresenius stipulated to infringement of
claim 6, and the district court held a bench trial on its
Prior Art Dexmedetomidine
is a chemical compound that is effective as a sedative.
'106 patent col. 1 ll. 36-37. Dexmedetomidine was first
developed and patented by Farmos Yhtyma Oy
("Farmos") in the 1980s. Farmos was issued U.S.
Patent 4, 910, 214, which disclosed the dexmedetomidine
compound and its use as a sedative.
1989, Farmos submitted an Investigational New Drug
application ("the Farmos IND") to the U.S. Food and
Drug Administration ("FDA") seeking approval to
begin safety testing dexmedetomidine formulations in humans.
Farmos conducted at least two human safety studies using
intravenous administration of 20 µg/mL dexmedetomidine
hydrochloride but subsequently abandoned its safety testing
after the studies showed adverse effects.
1994, Farmos's successor granted Abbott Laboratories
(Hospira's predecessor-in-interest) an exclusive license
to make, use, and sell dexmedetomidine for human use in the
United States. In 1999, Abbott Laboratories received FDA
approval to market a 100 µg/mL dexmedetomidine
hydrochloride formulation known as "Precedex
Concentrate." Precedex Concentrate is supplied in 2 mL
clear glass vials and 2 mL clear glass ampoules made from
Type IA sulfur-treated glass sealed with coated rubber
stoppers. The 100 µg/mL concentration of Precedex
Concentrate is too strong to be directly administered to
patients, and thus the label provides instructions for
diluting the drug to a concentration of 4 µg/mL before
is also available as a sedative for commercial veterinary
use. In 2002, the European Medicines Evaluation Agency
authorized use of a product called Dexdomitor, which is a
ready-to-use 500 µg/mL formulation of dexmedetomidine
hydrochloride. Dexdomitor is stored in a 10 mL glass vial
sealed with a coated rubber stopper and has a two-year shelf
'106 patent is entitled "Dexmedetomidine Premix
Formulation" and is directed to pharmaceutical
compositions comprising dexmedetomidine (or a
pharmaceutically acceptable salt of dexmedetomidine)
formulated as a liquid for parenteral administration to a
patient, "wherein the composition is disposed within a
sealed container as a pre-mixture." '106 patent at
Abstract; see also '106 patent col. 1 ll. 19-20
("The present invention relates to patient-ready,
premixed formulations of dexmedetomidine, or a
pharmaceutically acceptable salt thereof . . . ."). The
'106 patent describes the alleged problems associated
with prior art dexmedetomidine formulations that the patented
invention was intended to solve:
To date, dexmedetomidine has been provided as a concentrate
that must be diluted prior to administration to a patient.
The requirement of a dilution step in the preparation of the
dexmedetomidine formulation is associated with additional
costs and inconvenience, as well as the risk of possible
contamination or overdose due to human error. Thus, a
dexmedetomidine formulation that avoids the expense,
inconvenience, delay and risk of contamination or overdose
would provide significant advantages over currently available
Id. col. 1 l. 61-col. 2 l. 3.
address the perceived shortcomings of the prior art, the
'106 patent states that its invention relates to
"pre-mixed pharmaceutical compositions of
dexmedetomidine, or a pharmaceutically acceptable salt
thereof, that are formulated for administration to a patient,
without the need to reconstitute or dilute the composition
prior to administration." Id. col. 2 ll. 7-11.
The patent specifies that the invention can be formulated as
a "ready to use" composition, which is a premixed
dexmedetomidine composition that is "suitable for
administration to a patient without dilution."
Id. col. 3 l. 66-col. 4 l. 2.
the '106 patent states that "[t]he present invention
is based in part on the discovery that dexmedetomidine
prepared in a premixed formulation that does not require
reconstitution or dilution prior to administration to a
patient, remains stable and active after prolonged
storage." Id. col. 3 ll. 6-10 (emphasis
added). The patent describes "stability studies"
that were conducted to measure the loss in potency of the
drug over time. Id. col. 13- col. 25 (Examples 1, 2,
4, and 6, which describe studies of dexmedetomidine potency
over time under different conditions). For instance, Example
1 describes a study of potency of a 4 µg/mL
dexmedetomidine hydrochloride formulation over time when
stored in different storage containers, and Example 4
describes testing under different stresses and concludes that
"[u]nder oxidative conditions, the sample showed highest
amount of degradation." Id. col. 17 ll. 25-26.
Example 5, the patent describes a process by which a 4
µg/mL dexmedetomidine hydrochloride formulation
"can be manufactured." Id. col. 17 ll.
57-58. That example manufacturing process includes
"[n]itrogen sparging . . . throughout the manufacturing
process." Id. col. 17 ll. 60-62. At the
conclusion of the process, "[a]n atmosphere of filtered
nitrogen gas is maintained in the head-space of the surge
bottle," and "the headspace of the container is