United States District Court, D. Delaware
PAR PHARMACEUTICAL, INC., PAR STERILE PRODUCTS, LLC, and ENDO PAR INNOVATION COMPANY, LLC, Plaintiffs,
HOSPIRA, INC., Defendant.
FINDINGS OF FACT AND CONCLUSIONS OF LAW
F. Bataillon, Senior United States District Judge.
matter is before the Court after a bench trial from June 28,
2019, to July 3, 2019. This is a patent infringement action
brought under the Hatch-Waxman Act, 21 U.S.C. § 355,
et seq. Defendant Hospira Inc.
(“Hospira”) filed an Abbreviated New Drug
Application ("ANDA"), No. 208908, with the Food and
Drug Administration (“FDA”), seeking approval to
engage in the manufacturing and sale of a generic version of
the plaintiffs' Adrenalin® brand epinephrine
injection 1 mg/mL product, which is indicated for emergency
treatment of allergic reactions, including anaphylaxis. The
plaintiffs, Par Pharmaceutical, Inc. (“Par
Pharm”), Par Sterile Products, LLC (“Par
Sterile”), and Endo Par Innovation Company, LLC
(“EPIC”) (collectively, "Par") allege
that Hospira's ANDA infringes its patents, United States
Patent Nos. 9, 119, 876 (“the '876 Patent”)
and 9, 295, 657 (“the '657 Patent”). Hospira
challenges the validity of Par's patents.
Hatch-Waxman Act was passed in 1984 to respond to two
problems created by the statutes that then regulated patents
and pharmaceuticals. Eli Lilly and Co. v. Medtronic,
Inc., 496 U.S. 661, 669 (1990). The first arose from the
fact that inventors ordinarily applied for patent protection
for newly discovered drugs well before securing regulatory
approval, even though marketing was prohibited until
regulatory approval was obtained. Warner-Lambert Co. v.
Apotex Corp., 316 F.3d 1348, 1357 (Fed. Cir. 2003).
Because the FDA generally took much longer to approve a New
Drug Application (“NDA”) than the Patent and
Trademark Office (“PTO”) took to grant a patent,
the seventeen-year patent term was substantially eroded by
the time the patentee could market its product obtain the
benefit of his invention. Id.
second problem was the requirement that a generic
manufacturer obtain its own NDA-providing its own safety and
efficacy data-if it wanted to market a product. Id.
At that time, manufacturing or using a patented product
solely for the purpose of conducting tests and developing the
necessary information to apply for regulatory approval later
was an act of infringement under 35 U.S.C. § 271(a).
Id. Because it took a substantial amount of time for
a generic manufacturer to obtain data and secure regulatory
approval, requiring those manufacturers to wait until after
the patent expired to begin testing and other pre-approval
activities resulted in a de facto extension of the
patent term. Id.
Hatch-Waxman Act was designed to address both of these
problems by restoring time lost to innovators during
pre-patent testing and regulatory approval, while at the same
time enabling generic manufacturers to be ready to enter the
market once the patents expired. Id. To further the
overall goal of getting generics to market faster,
Hatch-Waxman authorized the filing and approval of
Abbreviated New Drug Applications and provided a mechanism
through which patent-holders could adjudicate patent
infringement claims prior to a product coming on the market.
Id.; Sunovion Pharm., Inc. v. Teva Pharm. USA,
Inc., 731 F.3d 1271, 1279 (Fed. Cir. 2013) (noting that
the Hatch-Waxman framework envisions resolution of the
infringement issue earlier, and generally before ANDA
approval). Under Hatch-Waxman, generic manufacturers had to
show bioequivalence to a patented drug, but no longer had to
prove the safety and efficacy of a generic version of a drug,
they could effectively “piggy-back” on the patent
holder's showing of safety and efficacy. Generic
manufacturers are also allowed to test and seek approval to
market the generic formulation during the patent term.
the infringement adjudication mechanism of the Act, patentees
and NDA holders are required to list patents that claim the
approved drug or its approved use in the FDA's
Approved Drug Products with Therapeutic Equivalence
Evaluations publication (the “Orange Book”).
Id.; see21 U.S.C. § 355(b)(1). ANDA
applicants are required to either certify that no unexpired
patent is listed for its proposed generic formulation, or
that the listed patent is either invalid or would not be
infringed by the manufacture, use, or sale of the drug by the
ANDA applicant (“a paragraph IV certification”).
Id.; 21 U.S.C. § 355(j)(2)(A)(I-IV).
filing of an ANDA with a paragraph IV certification
constitutes an act of artificial patent infringement under 35
U.S.C. § 271(e)(2)(A), which allows litigation to
commence before actual sale of an accused product has
occurred. Vanda Pharm. Inc. v. West-Ward Pharm. Int'l
Ltd., 887 F.3d 1117, 1126 (Fed. Cir. 2018); see also
Sunovion, 731 F.3d at 1279 (“Although no
traditional patent infringement has occurred until a patented
product is made, used, or sold, under the Hatch-Waxman
framework, the filing of an ANDA itself constitutes a
technical infringement for jurisdictional purposes”).
Patent holders benefit from the Act because the patent term
was extended for products subject to a regulatory review
before commercial marketing or use, if the permission for the
commercial marketing or use of the product after such
regulatory review period was the first permitted commercial
marketing or use of the product. Id. at 1358.
FINDINGS OF FACT
following facts are gleaned from the parties' agreed
facts in the Pretrial Order and from the evidence adduced at
trial. (D.I. 192-1, Pretrial Order, Exhibit
(“Ex.”) 1, Statement of Uncontested Issues of
Fact (“Agreed Facts”); D.I. 223 to D.I. 226,
Trial Transcript (“Tr.”)).
dispute between the parties involves injectable epinephrine
formulations and long-standing problems of stability and
shelf-life. Epinephrine is a well-known drug used to treat
allergic reactions and anaphylaxis for over 100 years. Joint
Trial Exhibit (“JTX”) 48; D.I. 225, Tr. at 452.
Older epinephrine formulations, including Par's original
Adrenalin® formulation and Hospira's ampoule and
Abboject® products, pre-date the current FDA regulatory
regime and were sold without FDA approval under statutory
“grandfather” provisions. D.I. 225, Tr. at 527.
Although the “grandfathered” drugs had been sold
for many years, they did not meet modern pharmaceutical
standards in terms of quality, stability, and absence of
impurities. D.I. 223, Tr. at 159.
2006, the FDA began a drug safety initiative regarding the
marketing of unapproved drugs. D.I. 224, Tr. at 215-16;
Filing No. 225, Tr. at 527. Under the initiative, the FDA
required registration of unapproved products for listing in
the Orange Book. Id. Accordingly, the scientists at
Par's predecessor company, JHP Pharmaceuticals LLC
(“JHP”), began working to develop a product that
would meet the FDA's new requirements. Plaintiff's
Trial Exhibit (“PTX”) 1, '876 Patent, col.1,
ll. 53 to 62. Par's Adrenalin® was the first
epinephrine injection product approved by the Food FDA for
use in a clinical setting available in the United States.
D.I. 192-1, Agreed Facts ¶ 3. Par's NDA No. 204200
was approved by FDA on December 7, 2012 (Id.).
it approved the product, the FDA asked JHP for a post
marketing commitment that it would try to reduce the levels
of impurities in Adrenalin®. PTX 191 at 3. The impurities
were the result of degradation, a process whereby the amount
of the active ingredient, and thereby the potency, of the
product decreases and the amount of potentially toxic
compounds increases. The primary degradants in epinephrine
products are epinephrine sulfonic acid (ESA) and
D-epinephrine, an enantiomer of the active ingredient
L-Epinephrine. PTX 1, '876 Patent at col. 1,
record shows there are three epinephrine degradation
pathways-oxidation, racemization, and sulfonation. D.I. 223,
Tr. at 165, 173, 179. Patrick Irish, a scientist at JHP,
testified it was very difficult to come up with a set of
components in a formulation that could minimize one
degradation pathway without exacerbating another degradation
pathway. D.I. 223, Tr. at 163. The difficulty was that there
were unintended consequences of the experiments-solving one
issue would create another problem. D.I. 225, Tr. at 452-56.
efforts to improve the 2012-FDA-approved product eventually
led to a supplemental NDA, No. 204200-04, that was approved
on September 12, 2016, and to the two patents that are the
subject of this case. D.I. 223, Tr. at 69; D.I. 192-1, Agreed
Facts ¶ 2-3. Par's predecessor, JHP, filed
Application Serial No. 14/657, 990 with the PTO on March 13,
2015, and it issued as the '876 Patent on September 1,
2015. D.I. 192-1, Agreed Facts ¶ 2. JHP filed
Application Serial No. 14/818, 121 with the PTO on August 4,
2015, and it issued as the '657 Patent on March 29, 2016.
Id. at 3. The '657 Patent is a continuation of
the application that issued as the '876 Patent.
Id. at 2-3. Both patents are titled
“Epinephrine Formulations.” Id. The
'657 Patent and the '876 Patent share a common
specification. Id. Vinayagam Kannan, Patrick Irish,
and Michael Bergren are the named inventors of the '657
and '876 Patents. Id. The '876 Patent covers
the composition of the inventive formulations and the
improved impurity profile (JTX 1). The '657 Patent covers
using those formulations to treat patients (JTX 2).
improved formulation of Adrenalin® is the embodiment of
the asserted claims of the patents at issue and has a shelf
life of twenty-four months. D.I. 192-1, Agreed Facts ¶
3; JTX 7, FDA correspondence at 2. The '876 and '657
Patents are listed in the Orange Book for the listing for
Adrenalin® brand epinephrine injection. Id. at
had also committed to the FDA in 2007 that it would remediate
its unapproved products-Epinephrine Injection USP Ampul and
Epinephrine Injection USP Abboject. JTX 95, 2015 Epinephrine
Injection USP Project Technical Review (“2015
PTR”) at 2. Dr. Zhang was the main formulation
scientist responsible for the generic product and he
testified that Hospira began developing its ANDA Product
sometime in 2009. D.I. 223, Tr. at 215, 318: JTX 95, 2015 PTR
at 6. After several unsuccessful efforts, Hospira submitted
ANDA No. 208908 to the FDA in 2017, seeking approval to
engage in the commercial manufacture and sale of a generic
version of Adrenalin® epinephrine injection, 1 mg/mL
(“Hospira's ANDA Product”) prior to the
expiration of the '876 and '657
Patents. D.I. 192-1, Agreed Facts ¶ 5.
asserts that Hospira's ANDA product infringes claims 1-3,
5, and 10-19 of each patent (“the asserted
claims”) Independent claim 1 of the '876 Patent
1. A composition comprising:
in the range of about 0.5 to 1.5 mg/mL of epinephrine and/or
in the range of about 6 to 8 mg/mL of a tonicity regulating
in the range of about 2.8 to 3.8 mg/mL of a pH raising agent,
in the range of about 0.1 to 1.1 mg/mL of an antioxidant,
in the range of about 0.001 to 0.010 mL/mL of a pH lowering
agent, and in the range of about 0.01 to 0.4 mg/mL of a
transition metal complexing agent, wherein the antioxidant
comprises sodium bisulfite and/or sodium meta bisulfite.
D.I. 1-1, '876 Patent, col. 28, ll. 1-14. The remaining
asserted claims are dependent claims.
claim construction, the parties agreed to the following claim
construction: the word “about” should be given
its ordinary meaning, which is “approximate.”
D.I. 67, Joint Claim Construction Chart, Appendix A. A
“pH raising agent” is a “component to raise
the composition's pH, which may comprise a buffer
system.” Id. A “buffer system” is
a “component present in a composition or solution which
may provide a resistance to significant change in pH caused
by a strong acid or base; may comprise a single agent or more
than one agent, such as a weak acid and its conjugate
base.” Id. A pH lowering agent” is a
“component to lower the composition's pH.”
Id. A “transition metal complexing
agent” is a “component to complex with transition
metals, such as a chelating agent.” Id.
parties agree that Hospira's ANDA Product is a
composition and is indicated for emergency treatment of
allergic reactions (Type 1), including anaphylaxis. D.I.
192-1, Agreed Facts ¶ 6. Hospira's ANDA describes
the composition of Hospira's ANDA Product, including the
target amounts of each component and Hospira's stated
function of each component. Id. at 4-5. The parties
also agree that Hospira's ANDA Product contains: in the
range of about 0.5 to 1.5 mg/mL of epinephrine and in the
range of about 0.1 to 1.1 mg/mL of sodium metabisulfite.
Id. at 5. Further, they agree that sodium
metabisulfite is an antioxidant; sodium chloride is a
tonicity regulating agent; citric acid and sodium citrate are
a pH raising agent; citric acid and sodium citrate are a
buffer system; hydrochloric acid is a pH lowering agent; and
water for injection is a solvent. Id. Also, the
parties agree that Hospira's ANDA Product contains a
solvent comprising water and contains about 11% or less of
ESA after 18 months of storage at 23° C to 32° C and
55% to 70% relative humidity and about 3% or less of
D-Epinephrine after 18 months of storage at those temperature
and humidity levels. Id. at 6.
contends that Hospira's ANDA product contains amounts of
the specified agents in the ranges that are claimed in at
least one asserted claim in each of the patents at issue.
Hospira contends that its ANDA product does not infringe
Par's patents, arguing that Par and Hospira took
fundamentally different approaches to remediating their
is no dispute that Hospira's ANDA product contains the
active ingredient epinephrine and an antioxidant wherein the
antioxidant comprises sodium bisulfite and/or sodium
metabisulfite. D.I. 192-1, Agreed Facts ¶ 5, Table 13.
There is also no dispute that Hospira's ANDA product
meets the improved impurity profile that is specified in the
claims. In support of its contention of noninfringement,
Hospira points to different concentrations of 1) a tonicity
regulating agent; 2) a pH raising agent and 3) absence of a
transition metal complexing agent in its proposed product.
trial, Dr. Edmund Elder testified on behalf of Par (D.I. 223,
Tr. at 59 to 149). He has a Ph.D. in Pharmaceutical Sciences,
spent 16 years in the pharmaceutical industry, and is an
expert in pharmaceutical formulations, including injectables.
Id. at 63; JTX 113, Curriculum Vitae
("C.V."). He is director of the Zeeh Pharmaceutical
Experiment Station in the School of Pharmacy, University of
Wisconsin-Madison, where he oversees formulation development
activities, including for injectable products. Id.
at 60. Dr. Elder teaches drug development and formulation and
sits on a committee that oversees the University's
FDA-regulated research. Id. at 60-61. He also sits
on the compounding expert committee of the United States
Pharmacopeia and is an editor for peer-reviewed journals.
Id. at 62-63.
Elder reviewed Hospira's ANDA submission. D.I. 223, Tr.
at 70-71; JTX 110, Hospira ANDA, overall summary; JTX 50,
specification; and JTX 86, PTX 387, PTX 388, PTX 389, batch
records. He testified that Hospira's ANDA product
infringes claim 1 of the '876 Patent, both literally and
under the doctrine of equivalents. Id. at 90-91. He
first stated that Hospira's ANDA product contains 8.55 to
9 mg/mL of sodium chloride, which is a tonicity regulating
agent. D.I. 223, Tr. at 73-74.
record shows that the target amount of sodium chloride in
Hospira's ANDA Product is 9 mg/mL. JTX 110, Hospira ANDA
at 18. The amount of sodium chloride in commercial batches of
Hospira's ANDA Product will vary from the target
concentration of 9 mg/mL. Id. at 72. The release
specification for the first three exhibit batches was as low
as 8.55 mg/mL. Id. at 75. The measured amount in the
exhibit batches was between 8.91 and 9.27 mg/mL. Id.
at 75; JTX 86 at 13, 19, 24; PTX 387 at 13, 19, 24; PTX 388
at 10, 17, 22. Dr. Elder expressed the opinion that the
amount of sodium chloride in Hospira's ANDA product
literally meets the claim limitation of “about 8
mg/mL.” Id. at 77-78.
patent specification describes the purpose of the tonicity
regulating agent is to “maintain the tonicity of the
composition in a physiologically acceptable range.”
D.I. 223, Tr. at 77; JTX 1, '847 Patent at col. 8, ll.
46-53. “Physiologically acceptable” means that
the product will not have a negative impact on the cells that
are exposed to it-it will be in an isotonic range. D.I. 223,
Tr. at 79; PTX 165 at 3, PTX 173 at 6. Dr. Elder stated that
tonicity is osmotic pressure, explaining that when a blood
cell is in an isotonic environment, the concentration of
dissolved species in solution matches that inside the cell,
creating an equilibrium of water exchange between the cell
and the solution. Id. In a hypertonic solution, a
higher concentration of dissolved particles in the
surrounding solution causes water to flow out of the cell,
resulting in cell shrinkage. Id. In a hypotonic
solution, the fluid surrounding the cell has a lower
concentration of dissolved particles, causing water to move
into the cell, resulting in cell swelling and eventually
bursting. Id. at 78-79. He also testified that a
physiologically acceptable range of tonicity reported in the
literature is between 225 and 350 milliosmoles per kilogram
(mOsm/kg.) and formulations within that range are considered
isotonic. Id. at 79.
ANDA similarly states that the purpose of the 9 mg/mL sodium
chloride in Hospira's ANDA Product is to provide
“isotonicity” to the composition. Id. at
80. That function is identical to the function for the claim
limitation of “about 6 to 8 mg/mL of a tonicity
regulating agent” in the patents in suit. Id.
Also, Dr. Elder testified that the osmolality of
Hospira's ANDA Product with 8.55 mg/mL sodium chloride
would be slightly lower than the 323 or 324 mOsm/kg reported
for the target of 9 mg/mL, which would also be well within
the physiological acceptable range. Id. at 81-82. He
concluded that Hospira's ANDA product, which contains
8.55 mg/mL to 9 mg/mL of sodium chloride as a tonicity
regulating agent, meets the claimed limitation of
about 6 to 8 milligrams per milliliter. Id.
Elder also testified that 8.55 to 9 mg/mL sodium chloride
meets the limitation “about 8 mg/mL” in the
'847 Patent under the doctrine of equivalents.
Id.at 84. He evaluated the amount of sodium chloride
in Hospira's ANDA Product under the function-way-result
test and found it was equivalent: the function of the claimed
range of tonicity regulating agent is to regulate tonicity;
the way it does that is by providing dissolved particles; and
the result is a physiologically acceptable tonicity.
Id. at 83-85. He concluded that the sodium chloride
concentration in the product is insubstantially different
from the claimed range, because both provide a physiological
acceptable tonicity. Id. at 83-84.
Elder also noted that Hospira represented to FDA that the
“calculated osmolality of 308 mOsm/kg for the
reformulated Adrenalin is comparable to the measured values
for the proposed product . . . the minor differences are not
expected to affect safety and efficacy of epinephrine
injection.” Id. at 81; JTX 49 at 16.
Hospira's lead chemist on its ANDA project, Dr. Eric
Zhang, confirmed Hospira's representations as to the
osmolality of Hospira's ANDA product. D.I. 224, Tr. at
record also shows that during the development of its ANDA
product, Hospira varied the sodium chloride concentration
between 6 and 9 mg/mL without ever testing its impact. D.I.
224, Tr. at 262; Tr. at 82; (JTX 94, 2014 Hospira Product
Technical Review at 18. Hospira never measured the osmolality
of its formulations with 6 mg/mL sodium chloride and did not
test for any difference between 6 and 9 mg/mL concentrations.
D.I. 224, Tr. at 270. There was no suggestion or discussion
within Hospira or Pfizer that such a variation would affect
the safety of the drug product. Id. at 265.
respect to the limitations “a pH raising agent, ”
“a pH lowering agent” and “a transition
metals complexing agent, ” Hospira acknowledged to the
FDA that Par's reformulated Adrenalin and Hospira's
ANDA product have a difference in pH buffer, noting that the
reformulated Adrenalin® includes a pH buffer formed by
tartaric acid and sodium hydroxide, whereas the pH buffer in
the Hospira's proposed drug contains sodium citrate and
citric acid. JTX 49 at 15. Par argues that functionally
Hospira's ANDA product meets the limitations of
“about 2.8 to 3.8 mg/mL of a pH Raising Agent, ”
and “about 0.001 to 0.010 mL/mL of a pH Lowering
Agent” in Par's '876 Patent.
Francisco Dean Toste testified on behalf of Par. D.I. 224,
Tr. 319-423. He is the Gerald E. K. Branch Distinguished
Professor at the University of California, Berkeley.
Id. at 320. His research focuses on transition metal
catalysts used in chemistry and pharmaceuticals. Id.
at 320-21. Dr. Toste has consulted with pharmaceutical
companies for 15 years. Id. at 321-22. Dr. Toste is
a fellow of the American Academy of Arts and Sciences and the
Royal Society of Canada. Id. at ...