Fresenius-Kabi USA LLCv.Cubist Pharmaceuticals LLC

Patent Trial and Appeal Board

May 12, 2016

09406568 (P.T.A.B. May. 12, 2016)

Trials@uspto.gov Paper 45
Tel. 571-272-7822 Entered: May 12, 2016

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

FRESENIUS-KABI USA LLC
Petitioner,
v.

CUBIST PHARMACEUTICALS, INC.
Patent Owner.
_______________

Case IPR2015-00227
Patent 6,468,967 B1
_______________

Before LORA M. GREEN, TINA E. HULSE, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.

PAULRAJ, Administrative Patent Judge

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

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I. BACKGROUND
Fresenius-Kabi USA LLC (“Petitioner”) filed a Petition for inter
partes review of claims 1–7, 12–28, and 32–45 of U.S. Patent No. 6,468,967
B1 (Ex. 1001, “the ’967 patent”). Paper 1 (“Pet.”). Cubist Pharmaceuticals,
Inc. (“Patent Owner”) filed a Preliminary Response to the Petition. Paper 10
(“Prelim. Resp.”). Taking into account the Petition and Patent Owner’s
Preliminary Response, we determined that there was a reasonable likelihood
that challenged claims 1–7, 12–28, and 32–45 are unpatentable. Pursuant to
35 U.S.C. § 314, we instituted inter partes review, on May 14, 2015, as to
claims 1–7, 12–28, and 32–45 of the ’967 patent. Paper 13 (“Dec.”).
After institution, Patent Owner filed a Patent Owner Response. Paper
24, “PO Resp.”. Petitioner filed a reply to the Patent Owner Response.
Paper 32 (“Pet. Reply”).
On August 20, 2015, the parties filed joint motions to seek to remove
from consideration claims 1–7, 12–15, 18–28, 32–33, and 36–45 of the ’967
patent, and thereby to limit the Petition to claims 16, 17, 34, and 35 pursuant
to a Joint Stipulation and Agreement between the parties. See Paper 25; Ex.
1023 (unredacted version); Ex. 1024 (redacted version). The parties also
filed joint motions to treat the Stipulation and Agreement as business
confidential information, to be kept separate from the files of the involved
patents. See Paper 26. These motions were granted on September 18, 2015.
See Paper 28. The scope of this inter partes review is therefore limited to
claims 16, 17, 34, and 35 of the ’967 patent.
A hearing was held on February 8, 2016, a transcript of which appears
in the record. Record of Oral Hearing, Paper 42 (“Tr.”).

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We have jurisdiction under 35 U.S.C. § 6(c). This is a Final Written
Decision under 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73 as to the
patentability of the challenged claims. For the reasons discussed below, we
determine that Petitioner has shown by a preponderance of the evidence that
claims 16, 17, 34, and 35 are unpatentable.
A. Related Proceedings
In addition to this proceeding, we have instituted an inter partes
review of a related patent, US Patent No. 6,852,689 B2 (“the ’689 patent”)
based on a petition filed by the same Petitioner. See IPR2015-00223,
Decision on Institution of Inter Partes Review (PTAB May 14, 2015) (Paper
13). A Final Written Decision in that proceeding has issued concurrently
with this Decision.
Further, in Cubist Pharmaceauticals, Inc. v. Hospira, Inc., No. 12‐cv‐
00367 (D. Del.), the U.S. District Court for the District of Delaware held
that claims 16, 17, 35, and 35 of the ’967 patent were obvious over the same
prior art considered in this proceeding. Ex. 1021. The U.S. Court of
Appeals for the Federal Circuit affirmed the holding of obviousness on
November 12, 2015. See Cubist Pharms., Inc. v. Hospira, Inc., 805 F.3d
1112 (Fed. Cir. 2015). On January 22, 2016, the court denied Patent
Owner’s Petition for Panel Rehearing and Rehearing En Banc. Ex. 1036.
Although Patent Owner emphasizes that the Hospira case “is a separate
proceeding based on a different record, [with] different experts testifying”
(Tr. 27:2–12), we find that the arguments and evidence presented in this
proceeding are largely duplicative of what the district court and Federal
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Circuit have already considered in Hospira.1 Moreover, the “preponderance
of the evidence” standard for determining unpatentability in an inter partes
review is lower than the “clear and convincing evidence” standard for
proving invalidity in district court litigation. See 35 U.S.C. § 316(e);
Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 95 (2011). Nonetheless,
while we have taken the Federal Circuit’s Hospira decision into account, we
have independently considered the patentability of the challenged claims
based on the specific evidence of record before us and the legal standards
applicable to an inter partes review.2
B. The ’967 Patent
The ’967 patent relates to methods for administering a therapeutically
effective amount of the antibiotic daptomycin in a manner that minimizes
skeletal muscle toxicity. Ex. 1001, 3:17–20. Daptomycin has potent
bactericidal activity against Gram-positive bacteria that cause serious and
life-threatening diseases. Id. at 1:25–28. Prior clinical trials and toxicology
studies in animals found that skeletal muscle was the primary target tissue of
daptomycin toxicity. Id. at 2:21–23. Although low doses of daptomycin do
not cause muscle toxicity, certain types of Gram-positive bactericidal
infections, such as deep-seated infections, or those caused by antibiotic-
resistant bacterial strains, may require higher doses of daptomycin for

1 In addition to the same prior art, the evidence of record before us includes
certain testimony from the Hospira litigation. See, e.g., Ex. 1033 (testimony
of Drs. Zeckel and Eisenstein); Ex. 1034 (testimony of Dr. Guglielmo, S.
Murray, and Dr. Rausser).
2 Patent Owner has represented that the only basis for continuing to proceed
with this inter partes review is that it is seeking Supreme Court review of
the Federal Circuit’s Hospira decision. Tr. 25:18–26:6; see Ex. 1037
(Petition for a Writ of Certiorari).
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effective treatment. Id. at 2:30–35. Thus, according to the Specification,
“there is a great need to develop methods for administration of effective
amounts of daptomycin that will also minimize adverse skeletal muscle
effects.” Id. at 2:40–43.
The Specification discloses the results of several studies that suggest
that daptomycin-associated skeletal muscle toxicity is not related to the peak
concentration of drug that occurs in the bloodstream after administration. Id.
at 4:36–39. Nor does toxicity appear to relate to the total concentration of
daptomycin in the bloodstream for 24 hours (i.e., the AUC24h). Id. at 4:39–
42. Instead, the Specification states that “the data suggest that the dosing
interval is the key determinant of muscle toxicity, rather than just the
magnitude of the dose itself.” Id. at 4:46–48. Accordingly, the
Specification discloses methods of providing daptomycin at a dosing interval
of 24 hours or greater to minimize skeletal muscle toxicity and allow for
higher peak concentrations of daptomycin. Id. at Abstract.
C. Illustrative Claims
Challenged claims 16 and 17 ultimately depend on independent claim
12. Challenged claims 34 and 35 ultimately depend on independent claim
26. Independent claims 12 and 26 are reproduced below:
12. A method for administering daptomycin, comprising the
step of administering to a human patient in need thereof a
therapeutically effective amount of daptomycin at a dose of 3 to 75
mg/kg of daptomycin at a dosage interval that minimizes skeletal
muscle toxicity, wherein the daptomycin dose is repeatedly
administered at a dosage interval of once every 24 hours.

26. A method for treating or eradicating a bacterial infection
in a human patient in need thereof, comprising the step of
administering a therapeutically effective amount of daptomycin in a
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dose of 3 to 75 mg/kg to the patient at a dosage interval that
minimizes skeletal muscle toxicity, wherein the daptomycin dose is
repeatedly administered at the dosage interval of once every 24 hours
to once every 48 hours until said bacterial infection is treated or
eradicated.

Claims 16 and 34 limit the dose of daptomycin to 4 mg/kg, and claims
17 and 35 limit the dose to 6 mg/kg.
D. Grounds for Unpatentability
In view of our Decision to Institute (Paper 13) and our Order on the
Motion to Limit the Petition (Paper 28), the following grounds of
unpatentability are before us in this inter partes review:
A. Anticipation of claims 16, 17, 34, and 35 by the ’226
patent;3

B. Anticipation of claims 16, 17, 34, and 35 by
Woodworth;4

C. Obviousness of claims 16, 17, 34, and 35 over the ’226
patent and Woodworth.

3 Baker et al., US 5,912,226, issued June 15, 1999 (Ex. 1008). We refer to
this reference as “the ’226 patent” because that is how it is identified by both
Petitioner and Patent Owner.
4 J. R. Woodworth et al., Single-dose Pharmacokinetics and Antibacterial
Activity of Daptomycin, a New Lipopeptide Antibiotic, in Healthy
Volunteers, 36 ANTIMICROB. AGENTS & CHEMOTHER. 318–325 (1992) (Ex.
1009).
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II. DISCUSSION
A. Claim Construction
We interpret claims using the “broadest reasonable construction in
light of the specification of the patent in which [they] appear[].” 37 C.F.R.
§ 42.100(b); see also In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278–
79 (Fed. Cir. 2015) (“Congress implicitly approved the broadest reasonable
interpretation standard in enacting the AIA,” 5 and “the standard was
properly adopted by PTO regulation.”), cert. granted sub nom. Cuozzo
Speed Techs., LLC v. Lee, 136 S. Ct. 890 (mem.) (2016). Under the broadest
reasonable construction standard, claim terms are given their ordinary and
customary meaning, as would be understood by one of ordinary skill in the
art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d 1249,
1257 (Fed. Cir. 2007).
1. “at a dosage interval that minimizes skeletal muscle toxicity”
In our Decision to Institute, we interpreted the term “at a dosage
interval that minimizes skeletal muscle toxicity,” which is recited in
independent claim 47, as not requiring anything beyond administering
daptomycin at the express dosage intervals recited in the claim. As we
noted, the requirement of “minimiz[ing] skeletal muscle toxicity” would be
understood as nothing more than the intended result or consequence of
administering daptomycin at the specifically recited dosage interval. Dec. 6.
Our interpretation is consistent with the Specification, which repeatedly
indicates that lengthening the dosing interval is what minimizes skeletal
muscle toxicity. The Specification does not indicate that the minimization

5 The Leahy-Smith America Invents Act, Pub. L. No. 11229, 125 Stat. 284
(2011) (“AIA”).
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of skeletal muscle toxicity is due to any variable other than extending the
dosage interval to once every 24 hours or more. See, e.g., Ex. 1001, 5:16–19
(“Without wishing to be being bound by any theory, these results may be
explained by the hypothesis that skeletal muscle toxicity is related to time
between doses for repair of skeletal muscle damage.”).
Patent Owner has sought reconsideration of our claim construction on
the grounds that the Examiner, during prosecution, considered minimizing
skeletal muscle toxicity to be an “essential element of the invention.” PO
Resp. 5–6 (citing Ex. 2013, 3; Ex. 2014, 2–3, 9, 11–12; Ex. 2016, 2; Ex.
2017, 1; Ex. 2018, 2, 4, 9, 13, 18; Ex. 2019, 2). Patent Owner argues that
these statements in the prosecution cannot be ignored, even under the
broadest reasonable interpretation standard. Id. at 6 (citing Microsoft Corp.
v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015)).
We find nothing in the prosecution history, however, to suggest
clearly that either the examiner or the applicants considered a “dosage
interval that minimizes skeletal toxicity” to require anything beyond
administering daptomycin at the expressly recited dosage interval required
by claim 47 (i.e., once every 48 hours). Indeed, in amending then pending
claim 32 in response to the Examiner’s § 112, ¶ 2 rejection on the grounds
that the claims do not recite an “essential element of the invention,” the
applicants added the entirety of the language “wherein said single dose is
formulated for administration to a human patient at a dosage interval of once
every 24 hours to once weekly and that does not result in muscle toxicity.”
Ex. 2013, 3; Ex. 2014, 3. Thus, Patent Owner plainly equated a dosage
interval that does not result in muscle toxicity to once every 24 hours to once
weekly. Patent Owner has not pointed to any other intrinsic or extrinsic
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evidence to indicate what else might be required for a dosage interval that
minimizes skeletal muscle toxicity. Accordingly, we maintain our claim
construction for purposes of this Final Decision.6
2. Remaining Claim Terms
We determine that, for purpose of this Final Written Decision, none of
the other terms in the challenged claims requires express construction.
B. Overview of the Prior Art
Petitioner relies upon the following prior art references in its
patentability challenges.
1. The ’226 Patent (Ex. 1008)
The ’226 patent relates to an antibacterial drug, designated as
LY146032 in the reference, which is acknowledged to be daptomycin. Ex.
1008, Abstract; Ex. 1005 ¶ 19. The ’226 patent discloses methods of
treating infections caused by gram-positive bacteria by administering an
effective dose of daptomycin. Ex. 1008, 10:46–48. The ’226 patent states
an effective dose is generally between about 0.1 and about 100 mg/kg of the
drug, with the preferred dose from about 1 to about 30 mg/kg. Id. at 10:53–
57. The ’226 patent also states that a typical daily dose for an adult human
is from about 100 mg to about 1.0 g. Id. at 10:57–58.
In practicing the method, the ’226 patent discloses that the antibiotic
compound can be administered “as a single daily dose or in multiple doses

6 Our construction is applicable under either the broadest reasonable
interpretation standard or the claim construction standard articulated in
Phillips v. AWH Corp., 415 F. 3d 1303 (Fed. Cir. 2005) (en banc). Indeed,
we note that our construction is consistent with the Federal Circuit’s
interpretation and treatment of the claims in Hospira. Ex. 1031, 17
(affirming district court’s finding that minimizing skeletal muscle toxicity
was a “necessary accompaniment to the other disclosed claim limitations”).
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per day.” Id. at 10:59–61. The ’226 patent discloses further that the
treatment regime may require administration over extended periods of time,
such as for several days or two to four weeks. Id. at 10:62–64. According to
the ’226 patent, “[t]he amount per administered dose or the total amount
administered will depend on such factors as the nature and severity of the
infection, the age and general health of the patient, the tolerance of the
patient to the antibiotic and the microorganism or microorganisms involved
in the infection.” Id. at 10:64–11:2.
2. Woodworth (Ex. 1009)
Woodworth describes three studies to define the disposition and
pharmacokinetics of daptomycin in healthy volunteers. Ex. 1009, Abstract.
Woodworth generally discloses that “[o]n the basis of the drug’s
pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day,
possibly in divided doses, are predicted to be effective.” Id. In one study,
Woodworth administered successive single doses of 2, 3, 4, and 6 mg/kg
intravenously with at least 72 hours separating each dose. Id. at 319.
Woodworth found that daptomycin exhibits extensive protein binding. Id. at
320. Woodworth also found that “[n]o adverse events were reported or
observed during the course of these studies. All doses were well tolerated.”
Id. at 321.
C. Obviousness of Claims 16, 17, 34, and 35 over the ’226 Patent and
Woodworth
Petitioner asserts that claims 16, 17, 34, and 35 are obvious over the
combination of the ’226 patent and Woodworth. See Pet. 48–56 (as
applicable to the remaining challenged claims). Petitioner relies upon the
Declaration of Dr. Alexander Shepherd, M.D., Ph.D., FRCP to support its
arguments. Ex. 1005. We determine that Petitioner has demonstrated, by a
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preponderance of the evidence, that claims 16, 17, 34, and 35 would have
been obvious over the combination the ’226 patent and Woodworth. We are
unpersuaded by Patent Owner’s arguments to the contrary.
1. Prima Facie Obviousness
Claims 16 and 17 are directed to a dosing regimen where daptomycin,
an antibiotic drug known in the prior art, is repeatedly administered to a
human patient in need thereof at a dose of 4 mg/kg or 6 mg/kg and at a
dosage interval of once every 24 hours. Claims 34 and 35 require a dosage
interval of once every 24 hours to once every 48 hours.
Petitioner asserts that administration of daptomycin at the specifically
claimed doses of 4 and 6 mg/kg would have been obvious because the ’226
patent discloses the use of the daptomycin at a “typical daily dose” in
humans of “from about 100 mg to about 1.0 g,” and “[a]ssuming an average
adult human weighs 70 kg, this range corresponds to 1.4 mg/kg to 14
mg/kg.” Pet. 14 (citing Ex. 1008, 10:46–58; Ex. 1005 ¶ 41). Petitioner
further points to Woodworth’s teaching that administering daptomycin at
doses of 4 and 6 mg/kg caused no adverse effects and were “well tolerated,”
and its conclusion that “doses of 4 to 6 mg/kg/day, possibly in divided
doses, are predicted to be effective.” Id. at 49–50 (citing Ex. 1009, Abstract,
319, 321). Petitioner further asserts that administration of daptomycin at the
claimed dose interval of once every 24 hours would have been obvious
because the ’226 patent and Woodworth both teach once-daily dosing. Id. at
51. In addition to these prior art teachings, Petitioner asserts that the skilled
artisan would have been motivated to use the claimed dosing regimen in
light of daptomycin’s similarity to other antibiotic dosing regimens. Id. at
42–43. In particular, Petitioner asserts that the skilled artisan would have
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known that aminoglycosides have properties that are similar to daptomycin,
namely, concentration-dependent killing and a potential toxicity that is
reversible. Id. at 43 (citing Ex. 1005 ¶¶ 65–71).
Patent Owner argues that “[t]he teachings of the ’226 patent and
Woodworth are broad and generic, and merely an invitation to investigate
what dosing regimens might be therapeutically effective.” PO Resp. 30.
Patent Owner asserts that the ’226 patent “discloses practically all possible
dosing regimens, and does not direct a skilled artisan toward any of them—it
certainly does not teach which would be therapeutically effective.” Id. at 31.
Relying upon the Declaration of its expert, Dr. Hartmut Derendorf, Ph.D., as
well as alleged admissions by Petitioner’s expert, Dr. Shepherd, Patent
Owner contends that a skilled artisan would not limit the dosing range
disclosed in the ’226 patent to only integer values. Id. at 13–14 (citing Ex.
2028 (Derendorf Decl.) ¶¶ 73–74; Ex. 2027 (Shepherd Depo.), 61:24–62:2,
83:16–19). Similarly, Patent Owner contends that “Woodworth provides an
“infinite” number of dosing regimens . . . , and does not guide one skilled in
the art to any one in particular as safe and effective.” Id. at 34 (citing Ex.
2027, 60:3–6; Ex. 2028 ¶¶ 96–98, 116–117).
We find that the teachings of the ’226 patent and Woodworth, when
considered together and in their entirety, would have guided the skilled
artisan to once-daily administration of daptomycin at doses of 4 mg/kg and 6
mg/kg. Contrary to Patent Owner’s arguments, the fact that an infinite
number of values can fall within the prior art’s non-integer range does not
necessarily render its disclosure boundless or otherwise meaningless. We
recognize that the ’226 patent discloses a broader dosing range than what it
claimed, calculated as between 1.4 and 14 mg/kg, which is not limited to
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only integer values falling within that range. Nonetheless, we find that the
’226 patent would sufficiently suggest to the skilled artisan that daptomycin
can be administered at dosage amounts falling within the disclosed range as
a “single daily dose” (i.e., a dosing interval of once every 24 hours) over
extended time periods. Ex. 1008, 10:59–63. Moreover, as noted by the
Federal Circuit in the Hospira decision, Woodworth more specifically
discloses once-daily administration of daptomycin at doses falling within the
narrower range of 4 to 6 mg/kg. Ex. 1031, 20. We reach the same
conclusion based on our own review of Woodworth. In particular, the
endpoints of the range disclosed in the abstract and conclusion of
Woodworth, as well as the specific dosages of 4 mg/kg and 6 mg/kg used in
the single-dose studies described therein, would have led a skilled artisan to
try the claimed dosage amounts for a daptomycin dosing regimen. See Ex.
1009, Abstract (“doses of 4 to 6 mg/kg/day, possibly in divided doses, are
predicted to be effective”), 319 (“volunteers were administered daptomycin
in successive single doses of 2, 3, 4, and 6 mg/kg”), 324 (“our data suggest
that good antibacterial activity would be produced from single doses of 4 to
6 mg/kg”).
With respect to Woodworth, Patent Owner argues that the reference
discloses only “single dose studies in healthy volunteers.” PO Resp. 35. As
such, Patent Owner asserts that “[a] skilled artisan simply would not be able
to reach a conclusion based on Woodworth’s single dose studies and limited
predictions regarding the safety or efficacy of the claimed dosage regimen.”
Id. at 36. Patent Owner further asserts that Woodworth teaches away from
the claimed once-daily or extended dosing regimen by “concluding that due
to daptomycin’s high protein binding, the dose required for an effective once
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a day regimen would ‘correspond to a dose of 20–25 mg/kg, which is
presently an unrealistic dose.’” Id. at 35 (citing Ex. 1009, 324, Ex. 2028
¶ 118).
We are unpersuaded by these arguments, as Woodworth plainly
concludes, based on the single dose studies described therein, that
daptomycin “doses of 4 to 6 mg/kg/day, possibly in divided doses, are
predicted to be effective.” Ex. 1009, Abstract. We agree with the Federal
Circuit that, “[w]hile it is true that the Woodworth reference is predictive in
nature, it is based on extensive laboratory research, and its predictions of the
efficacy of a dosage regimen of 4 mg/kg to 6 mg/kg at daily intervals give
rise to a reasonable expectation that dosages in that amount would be
effective in patients.” Ex. 1031, 21. We do not consider Woodworth’s
description of a simulation that required an “unrealistic dose” of 20 to 25
mg/kg based on certain assumptions to teach away from the claimed doses
of 4 mg/kg and 6 mg/kg because it does “not criticize, discredit, or otherwise
discourage investigation into the invention claimed.” Galderma Labs., L.P.
v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013). Indeed, Patent Owner
fails to mention in its briefing that Woodworth also describes “[a]nother
simulation [that] used concentrations closer to those anticipated from
multiple dosing of 6 mg/kg.” Reply 14; Ex. 1009, 324.
Moreover, we are unpersuaded by Patent Owner’s arguments that the
prior art did not recognize daptomycin’s toxicity problem, and thus would
not have provided a reasonable expectation of success in achieving a safe
and therapeutically effective dosing regimen of the drug. See, e.g., PO Resp.
31, 34. As discussed above, we have construed the claim term “at a dosage
interval that minimizes skeletal muscle toxicity” to be non-limiting, as as the
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condition is necessarily satisfied by administration of daptomycin at the
specifically recited dosage interval of once every 24 hours. Accordingly, the
prior art need not have recognized daptomycin’s toxicity problem in order to
render the claimed methods obvious. Here, Woodworth suggests
administration of a daily dose of daptomcyin (but only “possibly” in divided
doses), and the ’226 patent further teaches that daptomycin can be
administered as a “single daily dose.” Ex. 1008, 10:59–60; Ex. 1009, 324.
We find these teachings provide sufficient motivation to administer the drug
at a dosage interval of once every 24 hours with a reasonable expectation of
success. The skilled artisan need not have predicted the efficacy or safety of
such a dosing regimen with absolute certainty in order to render the claimed
invention obvious. See In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)
(“Obviousness does not require absolute predictability of success.”).
Patent Owner also argues that the pharmacokinetic and
pharmacodynamics properties of daptomycin cited by Petitioner do not
render the claimed invention obvious. PO Resp. 40–44. We disagree. The
evidence of record supports Petitioner’s contention that daptomcyin exhibits
concentration-dependent killing and the potential to induce a reversible
toxicity, similar to aminoglycosides that were administered once daily. See,
e.g., Ex. 1005 ¶¶ 69–71 (comparing properties of daptomycin to
aminoglycosides), 65–67 (concluding, based on Woodworth’s concentration
studies, that the skilled artisan “would have increased the dose of
daptomycin—if treating a more severe infection—with a reasonable
expectation of success given the [minimum inhibitory concentration (MIC)]
and pharmacokinetic profile of daptomycin”). As did the the Federal Circuit
in the Hospira decision, we find that these “characteristics . . . would have
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led one of skill in the art to believe that increasing the dosage intervals for
daptomycin would give rise to a reasonable expectation of increased efficacy
while minimizing the toxic side effects of the drug.” Ex. 1031, 22.
2. Secondary Considerations
In an obviousness analysis, we must consider any objective evidence
of nonobviousness (“secondary considerations”) that is presented. See
Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). The totality of the
evidence submitted may show that the challenged claims would not have
been obvious to one of ordinary skill in the art. In re Piasecki, 745 F.2d
1468, 1471–72 (Fed. Cir. 1984). To be relevant, evidence of
nonobviousness must be reasonably commensurate in scope with the
claimed invention. In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011).
Furthermore, there must be a nexus between the merits of the claimed
invention and the evidence of secondary considerations. In re GPAC Inc.,
57 F.3d 1573, 1580 (Fed. Cir. 1995).
Patent Owner asserts that evidence of long-felt need, failure of others,
initial skepticism, unexpected results, and commercial success support the
non-obviousness of the claimed invention. PO Resp. 48–60. We have
considered the secondary considerations evidence presented by Patent
Owner, but do not find them sufficient, individually or in combination, to
“overcome the strong prima facie case of obviousness” made of record. See
Wyers v. Master Lock Co., 616 F.3d 1231, 1246 (Fed. Cir. 2010).
The underlying facts that Patent Owner relies upon to support its
secondary considerations arguments are set forth primarily in the
Declaration of Michael Zeckel, M.D., a Senior Medical Fellow in global
patient safety at Eli Lilly and Company (“Lilly”) who was responsible for
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daptomycin’s clinical development. Ex. 2030. In his Declaration, Dr.
Zeckel recounts Lilly’s attempts to develop a therapeutically effective
regimen for daptomycin, which began around 1983. Id. ¶ 11. As part of
early human clinical trials, Lilly administered daptomycin to healthy
volunteers at dosages of 2 mg/kg every 24 hours, “which appeared to be safe
and achieved plasma daptomycin concentrations believed at that time to be
sufficient to inhibit Gram-positive organisms.” Id. ¶ 14. After completing
these initial studies, however, Lilly conducted a Phase II clinical study of
daptomycin at 2 mg/kg/24h, which was voluntarily terminated in June of
1988 due to a lack of proven efficacy in treating more serious infections. Id.
¶ 15.
Lilly hypothesized that the concentrations of unbound daptomycin
were not exceeding the MIC (minimum inhibitory concentration required to
prevent bacterial growth) throughout the 24-hour dosing interval, resulting
in a failure to effectively treat more serious Gram-positive infections. Id.
¶ 16; see also Ex. 2045 (“Lee 1991a”) (describing clinical failures with 2
mg/kg/24h dosage regimen). Based on the theory that sufficiently high
trough concentrations could be maintained by administering larger doses of
daptomycin more frequently, Lilly conducted a Phase II clinical trial with a
dosing regimen of 3 mg/kg/12h in patients with Gram-positive bacteremia
and endocarditis (i.e., bacterial infection in the heart). Ex. 2030 ¶ 17; Ex.
1015 (“Lee 1991”). Dr. Zeckel states that “Lilly considered this study a
failure, because even though daptomycin at 3 mg/kg/12h worked to treat
bacteremia, it did not work for endocarditis.” Ex. 2030 ¶ 19. After this
study, Lilly conducted a Phase I dose escalation study in healthy volunteers,
with a plan to escalate the dose to 4 mg/kg/12h and then 5 mg/kg/12h. Id.
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¶ 22. However, the results at 4 mg/kg/12h showed “significant skeletal
muscle toxicity” based on elevated creatine phosphokinase (CPK) levels. Id.
Lilly subsequently notified the FDA of these CPK elevations, and the FDA
responded by placing all daptomycin studies on clinical hold. Id. ¶ 24; see
also Ex. 2041; Ex. 2042.
Dr. Zeckel states that “Lilly did not continue developing daptomycin
after this, because we did not have a theory for what property of daptomycin
had caused the CPK elevations, or how to dose daptomycin safely and
effectively to treat a full range of infections.” Ex. 2030 ¶ 25. According to
Dr. Zeckel, a once-daily administration was not considered as a potential
solution to the dosing problem because, after observing failures at
2 mg/kg/24h, it was thought that 12-hour dosing was “needed to maintain
free (not protein boound) plasma concentrations throughout the dosing
interval and provide an effective dose.” Id. ¶ 26.
a. Long-Felt Need/Failure of Others/Skepticism
Patent Owner asserts that, at the time of the invention, there was a
long-felt but unsolved need for new antibiotics to treat S. aureus and
methicillin-resistant S. aureus (“MRSA”) infections due to concerns that
vancomycin did not work for all patients, and antibiotic resistance to
vancomycin was likely to develop. PO Resp. 49–51. Patent Owner asserts
that the non-obviousness of the ’967 patent is also confirmed by the attempt
and failure of others to develop the same invention. Id. at 52–57.
Specifically, Patent Owner points to Lilly’s attempts and failure to find a
daptomycin dosing regimen that would be safe and effective in the treatment
of a full range of infections, as summarized above and set forth in the Zeckel
Declaration (Ex. 2030). Additionally, Patent Owner asserts that skilled
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artisans at the time of the invention believed that daptomycin would never
be a viable treatment for a full range of MRSA and S. aureus infections, and
instead recommended developing daptomycin analogs. PO Resp. 57–58
(citing Ex. 2027 ¶ 162; Ex. 2044; Ex. 2043; Ex. 2010).
We have considered the evidence of record, but find that Patent
Owner has not demonstrated that any long-felt need, failure of others, or
skepticism associated with the development of daptomycin is reasonably
commensurate in scope with or has a sufficient nexus to the claimed
invention. Patent Owner asserts that there was a long-felt need to replace
vancomycin for certain bacterial infections (S. aureus and MRSA), and
skepticism that daptomycin could satisfy that need. But even assuming that
daptomycin administered according to the claimed method satisfied any such
need, the claims are not limited to the treatment of only those particular
infections. See Therasense, Inc. v. Becton, Dickinson & Co., 593 F.3d 1325,
1336 (Fed. Cir. 2010) (finding no long-felt need because the claims were
broad enough to cover devices that did not solve the problem). Likewise,
Patent Owner has not shown how Lilly’s alleged failure to develop a
successful daptomycin dosing regimen for more serious Gram-positive
bacterial infections is commensurate in scope with the claimed invention
insofar as the claimed invention is not limited to the treatment of more
serious infections. Moreover, the evidence of record in this proceeding,
which was also considered in the Hospira litigation, supports the same
conclusion reached by the Federal Circuit. That is, Lilly’s decision to
discontinue its daptomycin trials was due, at least in part, to economic
considerations., i.e., the desire to avoid cannabilizing sales of its own
market-leading drug, vancomycin. See Ex. 1031, 24; see also Ex. 1033,
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569:19–22 (Zeckel testimony in Hospira litigation), 667:19–668:6
(Eisenstein testimony in Hospira litigation).
b. Commercial Success
Patent Owner further asserts that the commercial success of its
daptomycin formulation CUBICIN®, with net revenues totaling over
$5 billion, further supports the non-obviousness of the claims. PO Resp.
59–60. Patent Owner asserts that the dosing regimen claimed in the ’967
patent, along with the related ’689 patent, reflect the only FDA-approved
dosing regimen for CUBICIN®. Id. at 60 (citing Ex. 2032 (Hall Decl.) ¶¶ 2–
3; Ex. 2001, 1 (CUBICIN® label).
“Commercial success is relevant because the law presumes an idea
would successfully have been brought to market sooner, in response to
market forces, had the idea been obvious to persons skilled in the art.”
Merck & Co. v. Teva Pharm. USA, Inc., 395 F.3d 1364, 1376 (Fed. Cir.
2005). “Thus, the law deems evidence of (1) commercial success, and (2)
some causal relation or ‘nexus’ between an invention and commercial
success of a product embodying that invention, probative of whether an
invention was non-obvious.” Id.
We have considered the evidence presented, but determine that Patent
Owner has not established that the commercial sales of CUBICIN® have a
sufficient nexus to the claims of the ’967 patent. That the FDA approved a
dosing regimen covered by the claims of the ’967 patent does not necessarily
mean that CUBICIN®’s sales are due to the claimed invention as opposed to
other factors. Other than summarily relying upon its sales numbers, Patent
Owner has not shown how the specifically claimed dosing regimen, as
opposed to other features of daptomycin, have driven the commercial sales
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of the drug. See Ex. 1034, Tr. 1106:14–1109:3 (Patent Owner’s witness,
Mr. Stuart Murray, testifying in Hospira litigation that Cubist does not have
any way to assess how any sales could be attributed to once-daily dosing as
opposed to any of the other marketed attributes of CUBICIN®).
c. Unexpected Results
Patent Owner asserts that, at the time of the invention, a skilled artisan
would not have expected that giving large doses of daptomycin less often
would decrease daptomycin’s skeletal muscle toxicity while maintaining its
efficacy. PO Resp. 58–59. As such, Patent Owner argues that unexpected
results support the non-obviousness of the claims.
We are not persuaded by this contention. As discussed above, even
though the prior art did not discuss skeletal muscle toxicity, Woodworth and
the ’226 patent specifically suggested a once-daily dosing regimen for
daptomycin. The fact that the inventors recognized another benefit of the
dosing regimen otherwise rendered obvious by this prior art is not sufficient
to impart patentability. See In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir.
1990) (“It is a general rule that merely discovering and claiming a new
benefit of an old process cannot render the process again patentable. . . .
While the processes encompassed by the claims are not entirely old, the rule
is applicable here to the extent that the claims and the prior art overlap.”)
(citations omitted).
Moreover, in view of the background knowledge of the skilled artisan
that daptomycin exhibits similar properties to aminoglycosides (Ex. 1005 ¶¶
69–71, 89), we do not find that any reduction in skeletal muscle toxicity
(while maintaining efficacy) associated with the claimed dosing regimen
was necessarily “unexpected.”
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We, therefore, find that Patent Owner’s evidence of alleged
unexpected results is not sufficient to overcome the showing of obviousness.
D. Anticipation Challenges
We also instituted an inter partes review based on Petitioner’s
anticipation challenges relying upon the ’226 patent and Woodworth. Dec.
16. However, in light of our determination that claims 16, 17, 34, and 35 are
rendered obvious by the combination of the ’226 patent and Woodworth, we
take no position in this Final Written Decision on whether the same claims
are also anticipated by the references individually.
III. CONCLUSION
We conclude that Petitioner has demonstrated by a preponderance of
the evidence that claims 16, 17, 34, and 35 are rendered obvious under 35
U.S.C. § 103 by the combination of the ’226 Patent and Woodworth.
This is a Final Written Decision of the Board under 35 U.S.C.
§ 318(a). Parties to the proceeding seeking judicial review of this Decision
must comply with the notice and service requirements of 37 C.F.R. § 90.2.
IV. ORDER
Accordingly, it is
ORDERED that claims 16, 17, 34, and 35 of U.S. Patent 6,468,967 are
held to be unpatentable;
FURTHER ORDERED that because this is a Final Written Decision,
parties to the proceeding seeking judicial review of the Decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

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For PETITIONER:

Imron T. Aly
Jason G. Harp
SCHIFF HARDIN LLP
ialy@shiffhardin.com
jharp@schiffhardin.com

For PATENT OWNER:

Emily R. Whelan
Heather M. Petruzzi
WILMER CUTLER PICKERING HALE AND DORR LLP
emily.whelan@wilmerhale.com
heather.petruzzi@wilmerhale.com

Gerard M. Devlin
gerard_devlin@merck.com