Sandoz Inc.v.EKR Therapeutics, LLC

Patent Trial and Appeal Board

Apr 24, 2015

12971084 (P.T.A.B. Apr. 24, 2015)

Trials@uspto.gov Paper No. 20
571-272-7822 Entered: April 24, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

SANDOZ INC.,
Petitioner,

v.

EKR THERAPEUTICS, LLC,
Patent Owner.
____________

Case IPR2015-00005
Patent 8,455,524 B2
____________

Before JACQUELINE WRIGHT BONILLA, SHERIDAN K. SNEDDEN,
and ZHENYU YANG, Administrative Patent Judges.

YANG, Administrative Patent Judge.

DECISION
Denying Institution of Inter Partes Review
37 C.F.R. § 42.108

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INTRODUCTION
Sandoz Inc. (“Petitioner”) filed a Petition for an inter partes review of
claims 1–28 of U.S. Patent No. 8,455,524 B2 (Ex. 1001, “the ’524 patent”).
Paper 1 (“Pet.”). EKR Therapeutics, LLC (“Patent Owner”) filed a
Preliminary Response. Paper 8 (“Prelim. Resp.”). We have jurisdiction
under 35 U.S.C. § 314.
For the reasons provided below, we determine Petitioner has not
established a reasonable likelihood that it would prevail in showing the
unpatentability of at least one challenged claim. Therefore, we deny the
Petition for an inter partes review.

Related Proceedings
According to the parties, Patent Owner previously asserted the ’524
patent against Petitioner in Chiesi USA, Inc., et al. v. Sandoz Inc. et al., Case
No. 1:13-cv-5723 (D.N.J.). Pet. 3; Paper 4, 1.
Petitioner concurrently filed Petitions for inter partes review of claims
in several other patents owned by Patent Owner, including IPR2015-00006
(US 7,612,102 B2), IPR2015-00007 (US 7,659,290 B2), and IPR2015-
00008 (US 7,659,291 B2).

The ’524 Patent
The ’524 patent relates to “ready-to-use premixed pharmaceutical
compositions of nicardipine or a pharmaceutically acceptable salt and
methods for use in treating cardiovascular and cerebrovascular conditions.”
Ex. 1001, Abstract. According to the ’524 patent, before its invention,
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nicardipine hydrochloride was sold in capsule form and in an injectable
intravenous form. Id. at 1:24–25. The injectable intravenous form,
CARDENE® I.V., marketed in glass ampuls in a concentration of
2.5 mg/mL, must be diluted in a compatible intravenous fluid before
administration. Id. at 1:28–32.
The requirement for diluting CARDENE® I.V. before use is
associated with a number of disadvantages, the most significant of which is
that the diluted solution is only stable for 24 hours at room temperature. Id.
at 1:44–47. Other disadvantages include variable pH levels, potential for
contamination, dosage errors, and safety hazards associated with the use of
glass ampuls. Id. at 1:47–55. The ’524 patent describes its invention as
overcoming these disadvantages. Id. at 1:56–62.

Illustrative Claims
Claims 1–3 and 8 are independent claims. Claims 1 and 3 are
representative. They read as follows:
1. A method for treating acute elevations of blood pressure
in a human subject in need thereof, said method comprising
parenterally administering a pre-mixed aqueous solution
comprising from about 0.1 to 0.4 mg/mL nicardipine or a
pharmaceutically acceptable salt thereof; a tonicity agent; and a
buffer; wherein the aqueous solution requires no dilution before
administration and has a pH from about 3.6 to about 4.7, the
aqueous solution stored in a container such that the aqueous
solution is in contact with non-polar polymers, the aqueous
solution when stored in the container for at least three months at
room temperature exhibiting (i) less than a 10% decrease in the
concentration of nicardipine or pharmaceutically acceptable salt
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thereof and (ii) a total impurity formation of less than about
3%.
3. A method for treating acute elevations of blood pressure
in a human subject in need thereof, said method comprising
parenterally administering to a subject in need thereof, a pre-
mixed aqueous solution with a pH from about 3.6 to about 4.7
comprising: from about 0.1 to 0.4 mg/mL nicardipine
hydrochloride; a tonicity agent selected from (i) about 4.5% to
about 5% dextrose or (ii) about 0.8% to about 0.9% sodium
chloride; and a buffer; the aqueous solution contained in a
pharmaceutically acceptable container such that the aqueous
solution is in contact with non-polar polymers, the aqueous
solution when stored in the container for at least three months at
room temperature exhibiting (i) less than a 10% decrease in the
concentration of nicardipine or pharmaceutically acceptable salt
thereof and a total impurity formation of less than about 3%.
Claim 2 is similar to claim 1, and claim 8 is similar to claim 3.
The only difference is that the methods of claims 2 and 8 are “for
inducing hypotension,” whereas the methods of claims 1 and 3 are
“for treating acute elevations of blood pressure.”

Asserted Grounds of Unpatentability
Petitioner asserts the following grounds, each of which challenges the
patentability of claims 1–28:

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Basis References
§ 103 Cardene PDR1 and JP ’3642
§ 103 Cardene PDR, JP ’364, Baaske,3 and the ’405 patent4
The earliest asserted priority date of the challenged claims is April 18,
2006. Ex. 1001, 1:8–15. Thus, each asserted reference qualifies as prior art
under 35 U.S.C. § 102(b).
In support of its patentability challenge, Petitioner relies on the
Declaration of Dr. Alpaslan Yaman (Ex. 1002).

ANALYSIS
Claim Construction
In an inter partes review, the Board interprets a claim term in an
unexpired patent according to its broadest reasonable construction in light of
the specification of the patent in which it appears. 37 C.F.R. § 42.100(b); In
re Cuozzo Speed Techs., LLC, 778 F.3d 1271, 1279–81 (Fed. Cir. 2015).
Under that standard, absent any special definitions, we assign claim terms
their ordinary and customary meaning, as would be understood by one of
ordinary skill in the art at the time of the invention, in the context of the

1 Cardene® I.V., Physicians’ Desk Reference, 2004 WL 2459623
(Ex. 1005, “Cardene PDR”).
2 Kenichi et al., Japanese Patent Publication JP 2002-177364, published on
June 25, 2002 (Ex. 1004, “JP ’364”)
3 Baaske et al., Stability of nicardipine hydrochloride in intravenous
solutions, Am. J. Health Syst. Pharm. 53: 1701–05 (1996) (Ex. 1006,
“Baaske”).
4 McFarlane et al., U.S. Patent No. 5,164,405, issued November 17, 1992
(Ex. 1003, “’405 patent”).
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entire patent disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
(Fed. Cir. 2007).
The parties dispute the construction of the term “a pre-mixed aqueous
solution,” as recited in each independent, challenged claim. See Pet. 6–8;
Prelim. Resp. 20–23. We determine that, for purposes of this Decision, it is
unnecessary to expressly construe the term.
Petitioner also asks us to construe “a total impurity formation,” as
recited in each independent, challenged claim. Petitioner proposes, and
Patent Owner does not object, that we construe this term to mean “a total
nicardipine-related impurity formation.” Pet. 8–9. For purposes of this
Decision, we adopt Petitioner’s construction.

Real Party in Interest
Patent Owner urges that we deny the Petition because Petitioner fails
to identify Sandoz AG and ACS Dobfar Info S.A. (“Dobfar”) as real parties
in interest with respect to the Petition. Prelim. Resp. 6–16. With the panel’s
authorization, Petitioner filed a Reply (Paper 13), and Patent Owner filed a
Sur-reply (Paper 17), addressing this issue.
Because we deny the Petition as Petitioner has not established a
reasonable likelihood that it would prevail in showing the unpatentability of
at least one challenged claim, we need not reach the real-party-in-interest
issue.

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Patentability Analysis
Prior Art Teachings
Cardene PDR teaches that CARDENE® I.V., available for
intravenous administration, is indicated for the short-term treatment of
hypertension when oral therapy is not feasible or not desirable. Ex. 1005, 4.
Each ampul contains 25 mg nicardipine hydrochloride in 10 mL solution
(i.e., at a concentration of 2.5 mg/mL) and should be diluted with 240 mL of
compatible intravenous fluid before infusion, resulting in a solution at a
concentration of 0.1 mg/mL. Id. at 1, 9.
JP ’364 teaches “a prefilled syringe having little adsorption of a drug.”
Ex. 1004, 2. Such a syringe is filled with a drug liquid or an injection liquid
before transporting. Id. at 3. According to JP ’364,
A prefilled syringe has many advantages, such as being very
simple to operate, allowing correct dosing without dose error
because the drug liquid and dose have already been set, and
avoiding bacterial infection because the drug does not need to
be prepared, even in an emergency.
Id. JP ’364 specifically teaches nicardipine hydrochloride as a
pharmacologically effective substance in the liquid. Id. at 3, 4.
The ’405 patent teaches “a stable pharmaceutical composition
containing nicardipine hydrochloride, a non-chloride isotonicity agent, a
buffering agent and a pharmaceutically acceptable aqueous vehicle for
parenteral administration.” Ex. 1003, Abstract. According to the ’405
patent, controlling the pH level of the formulation is essential to maintain the
aqueous solubility of the nicardipine salts. Id. at 4:26–30. Specifically, the
’405 patent teaches using citrate buffer to maintain “the pH of the
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composition in the range of about 3.5–4.5.” Id. at 4:42–46. In addition, the
’405 patent teaches that solutions containing either 1 mg/mL or 2.5 mg/mL
nicardipine hydrochloride showed “substantially identical” and “excellent
stability for up to 3 years at 25°C., with no significant loss in potency.” Id.
at 7:11–17, 7:28–31, Table 7.
Baaske teaches that solutions containing nicardipine hydrochloride at
concentrations of 0.05 mg/mL and 0.5 mg/mL are stable in glass containers
for up to seven days. Ex. 1006, 1, 3. In contrast, according to Baaske,
“[c]oncentrations of nicardipine hydrochloride slowly decreased in PVC
containers, sometimes to less than 85% of the initial drug concentration
within 24 hours.” Id. at 3.

Obviousness over Cardene PDR and JP ’364
Petitioner asserts that claims 1–28 would have been obvious over the
combination of Cardene PDR and JP ’364. Pet. 12–34. We determine that
Petitioner has not established a reasonable likelihood it would prevail on this
basis. We conclude so for at least two independent reasons.
First, all challenged claims recite, either directly or through their
dependency, a nicardipine solution with “a pH from about 3.6 to about 4.7.”
Petitioner, relying on Dr. Yaman’s Declaration, argues that
A POSA [person of ordinary skill in the art] would have
recognized that the dilution of concentrated Cardene® I.V.
having a pH of 3.5 in accordance with the Cardene PDR
instructions would provide solutions with a pH falling within
the range of, or a pH at least significantly overlapping with,
“about 3.6 to about 4.7.” A POSA would have been motivated
to select such a pH range in a pre-mixed nicardipine 0.1 mg/mL
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solution. Further optimization of the pH to maintain the
solubility and stability of parenteral formulations would have
been a routine step for a POSA.
Pet. 19 (internal citations omitted); Ex. 1002 ¶¶ 129–31. We are not
persuaded.
Cardene PDR teaches that the commercially available, concentrated
nicardipine hydrochloride (2.5 mg/mL) has a pH of 3.5. Ex. 1005, 1.
Neither party contends that Cardene PDR expressly discloses the pH of a
diluted solution having 0.1 to 0.4 mg/mL nicardipine hydrochloride. Citing
Dr. Yaman’s testimony, Petitioner argues that diluting the concentrated
nicardipine hydrochloride of Cardene PDR “would provide solutions with a
pH falling within the range of, or a pH at least significantly overlapping
with, ‘about 3.6 to about 4.7.’” Pet. 19 (citing Ex. 1002 ¶¶ 129–30). As
noted by Patent Owner, however, evidence of record indicates that diluting a
concentrated nicardipine hydrochloride can yield pH levels outside the
claimed range of “about 3.6 to about 4.7.” Prelim. Resp. 29. For example,
Patent Owner refers to Baaske for teaching that the pH levels of diluted
nicardipine hydrochloride can be as high as 5.9, notably higher than 4.7, the
highest pH in the recited pH range. Id. (citing Ex. 1006, 3). Such evidence
on the pH levels does not support Dr. Yaman’s opinion. The Petition and
evidence cited therein do not establish sufficiently that Cardene PDR
teaches, expressly or inherently (i.e., as necessarily present or a natural result
of dilution), a composition comprising from about 0.1 to 0.4 mg/mL
nicardipine and having a pH from about 3.6 to about 4.7, as required in the
challenged claims.
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In addition, Petitioner does not rely on JP ’364 to support its argument
regarding the pH levels. In fact, as Patent Owner points out, JP ’364 does
not discuss the pH of any nicardipine solutions. Prelim. Resp. 29. We are
not persuaded that a skilled artisan, knowing the teachings of Cardene PDR
and JP ’364, would have been motivated to select the pH range for a pre-
mixed nicardipine solution as claimed.
Second, all challenged claims recite, either directly or through their
dependency, an impurity-formation limitation, requiring the nicardipine
solution “when stored in the container for at least three months at room
temperature exhibiting . . . (ii) a total impurity formation of less than about
3%.” Petitioner argues that “[t]otal impurity formation over time is an
inherent property of the nicardipine hydrochloride solution and the container
within which it is stored.” Pet. 24. According to Petitioner, “[b]y merely
choosing to follow the teachings of the Cardene PDR and JP ’364, a POSA
would obtain a pre-mixed nicardipine hydrochloride solution” satisfying the
recited impurity-formation limitation. Id. We are not persuaded.
“[I]nherency may supply a missing claim limitation in an obviousness
analysis.” PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1194–95
(Fed. Cir. 2014) (citations omitted). The Federal Circuit has cautioned,
however, that the use of inherency doctrine “must be carefully circumscribed
in the context of obviousness.” Id. at 1195. Inherency “may not be
established by probabilities or possibilities.” Bettcher Indus., Inc. v. Bunzl
USA, Inc., 661 F.3d 629, 639 (Fed. Cir. 2011) (citing In re Oelrich, 666 F.2d
578, 581 (CCPA 1981)). Instead, “the limitation at issue necessarily must be
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present, or the natural result of the combination of elements explicitly
disclosed by the prior art.” PAR Pharm., 773 F.3d at 1196.
For purposes of this Decision, we assume, without deciding, that one
of ordinary skill in the art would have had a reason to combine the teachings
of the prior art. Even so, it still “matters greatly whether anything the skilled
artisan would be prompted by the prior art to do is in fact within the scope of
the . . . claim.” In re Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). Thus,
Petitioner must present sufficient evidence, either from the prior art or
through its own testing data, to show that nicardipine hydrochloride
solutions prepared as suggested in the prior art, in fact, would satisfy the
recited impurity-formation limitation, when stored in a container taught by
JP ’364. This, Petitioner has failed to do.
As Patent Owner correctly points out, Cardene PDR states that the
diluted nicardipine hydrochloride solution is stable only for 24 hours at room
temperature, and JP ’364 does not include any teaching of impurity
formation. See Prelim. Resp. 30, 31. Nor does Petitioner provide any
independent testing data to support its inherency theory on the impurity-
formation limitation. Thus, we are not persuaded that the impurity-
formation limitation is necessarily present in, or is the natural result of, the
combined teachings of Cardene PDR and JP ’364.
In sum, because Petitioner fails to sufficiently account for at least the
pH levels and the impurity-formation limitation in the challenged claims, we
conclude that Petitioner has not established a reasonable likelihood it would
prevail in showing that claims 1–28 would have been obvious over the
combination of Cardene PDR and JP ’364.
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Obviousness over Cardene PDR, JP ’364, Baaske, and the ’405 Patent
Petitioner asserts that claims 1–28 would have been obvious over the
combination of Cardene PDR, JP ’364, Baaske, and the ’405 Patent. Pet.
34–57. We determine that Petitioner has not established a reasonable
likelihood it would prevail on this basis. We conclude so because the
teachings of Baaske and the ’405 patent do not remedy the deficiency of
Cardene PDR and JP ’364 regarding the impurity-formation limitation, as
discussed above.
According to Petitioner, the ’405 patent teaches that “no more than
1.5% of the nicardipine hydrochloride could have formed impurities during
12 months at room temperature.” Pet. 45 (citing Ex. 1002 ¶ 204; Ex. 1003,
6:42–60, Example IIC, Table 7). Petitioner also refers to Baaske for
teaching nicardipine solutions remain stable in glass containers. Id. (citing
Ex. 1006, 3). In view of these teachings, Petitioner concludes, “a POSA
would have reasonably expected that a nicardipine hydrochloride solution
stored in a non-polar container would have had both the stability and purity
levels claimed.” Id. (citing Ex. 1002 ¶ 205). We are not persuaded.
As Petitioner acknowledges, the ’405 patent reports stability data for
1.0 mg/mL and 2.5 mg/mL nicardipine hydrochloride solutions, both of
which are outside of the concentration range of “from 0.1 to 0.4 mg/mL,” as
recited in the challenged claims. See Pet. 45; Ex. 1003, 6:46–60, 7:11–17.
The ’405 patent also shows data of nicardipine hydrochloride solutions
“using a 1:10 dilution.” Ex. 1003, 9:40–41. The dilution results in
nicardipine hydrochloride solutions of 0.1 mg/mL and 0.25 mg/mL, within
the claimed concentration range. The data of the diluted nicardipine
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hydrochloride solutions, however, relate to the compatibility with buffered
formula, and not stability or purity. Id. at 9:38–45. Indeed, the diluted
solutions were examined only for appearance “after mixing,” and not for any
prolonged period of time, certainly not the “at least three months” as
required in the challenged claims. Id. at 9:46–47, Tables 9 and 10.
Similarly, the concentrations of the nicardipine hydrochloride
solutions studied in Baaske are 0.5 mg/mL and 0.05 mg/mL, both of which
are outside of the claimed concentration range. Ex. 1006, 1. Furthermore,
Baaske only reports that the nicardipine hydrochloride solutions are stable
for up to seven days, significantly shorter than the recited “at least three
months.” Id.
Petitioner, again, resorts to an inherency argument. Pet. 46. But, as
explained above, neither the prior art nor any other evidence of record
addresses adequately the impurity formation of “from about 0.1 to 0.4
mg/mL” nicardipine solutions over “at least three months,” as recited in the
challenged claims. For example, Petitioner does not provide any
independent testing data to support the inherency theory. Thus, we are not
persuaded that the impurity-formation limitation is necessarily present, or is
the natural result of the combination of the teachings of Cardene PDR, JP
’364, Baaske, and the ’405 Patent.
In sum, because Petitioner does not sufficiently explain how the
combined prior art teachings would have suggested the impurity-formation
limitation, we conclude that Petitioner has not established a reasonable
likelihood it would prevail in showing that claims 1–28 would have been
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obvious over the combination of Cardene PDR, JP ’364, Baaske, and the
’405 Patent.

CONCLUSION
For the foregoing reasons, the information presented in the Petition
and accompanying evidence do not establish a reasonable likelihood that
Petitioner would prevail in showing the unpatentability of any one of claims
1–28 of the ’524 patent.

ORDER
Accordingly, it is
ORDERED that Petitioner’s request for an inter partes review of
claims 1–28 of the ’524 patent is denied.

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For PETITIONER:

Matthew Kreeger
Matthew D’Amore
Elizabeth Cary Miller
David J. Austin
MORRISON & FOERSTER LLP
mkreeger@mofo.com
mdamore@mofo.com
emiller@mofo.com
daustin@mofo.com

For PATENT OWNER:

Edgar H. Haug
Nicholas F. Giove
FROMMER LAWRENCE & HAUG LLP
ehaug@flhlaw.com
ngiove@flhlaw.com