Anders Falk. Vikbjerg et al.

Patent Trials and Appeals Board

Jan 14, 2020

12994031 - (D) (P.T.A.B. Jan. 14, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/994,031 07/28/2011 Anders Falk Vikbjerg 51181-005001 1217
21559 7590 01/14/2020
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON, MA 02110
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
01/14/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patentadministrator@clarkelbing.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte ANDERS FALK VIKBJERG,
SUNE ALLAN PETERSEN, FREDRIK MELANDER,
JONAS ROSAGER HENRIKSEN, and KENT JØRGENSEN
__________

Appeal 2018-009053
Application 12/994,031
Technology Center 1600
__________

Before FRANCISCO C. PRATS, JEFFREY N. FREDMAN, and
MICHAEL J. FITZPATRICK, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1, 4, 5, 7, 9, 10, 13–15, 18–22 and 26–
29. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant states that “[t]he real party in interest for this
appeal is LiPlasome Pharma APS.” Appeal Br. 4.
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STATEMENT OF THE CASE
Appellant identifies Application 13/497,031 (Appeal 2018-008985) as
an appeal which “may directly affect or be directly affected by the Board’s
decision in this appeal.” Appeal Br. 4; see also Application 13/497,031
(Decision affirming Examiner entered January 23, 2019).
In the present appeal, the following rejections are before us for
review:
(1) Claims 1, 4, 5, 7, 9, 10, 13–15, 18–22 and 26–29, under 35 U.S.C.
§ 103(a) as being unpatentable over Andresen,2 Eriguchi,3 and Murakami4
(Ans. 2–4);
(2) Claims 1, 4, 5, 7, 9, 10, 13–15, 18–22 and 26–29, under 35 U.S.C.
§ 103(a) as being unpatentable over Andresen, Eriguchi, Murakami, and
Lakkaraju5 (Ans. 4–5), and
(3) Claims 1, 4, 5, 7, 9, 10, 13–15, 18–22 and 26–29, under 35 U.S.C.
§ 103(a) as being unpatentable over Andresen, Eriguchi, Murakami,
Lakkaraju, Melvik,6 and Jamil7 (Ans. 5–6).

2 Thomas L. Andresen et al., Advanced strategies in liposomal cancer
therapy: Problems and prospects of active and tumor specific drug release,
44 PROGRESS IN LIPID RESEARCH 68–97 (2005).
3 US 2004/0022842 A1 (published Feb. 5, 2004).
4 Makoto Murakami et al., Cellular components that functionally interact
with signaling phospholipase A2s, 1488 BIOCHIMICA BIOPHYSICA ACTA 159–
166 (2000).
5 US 2003/0026831 A1 (published Feb. 6, 2003).
6 US 2008/0085295 A1 (published Apr. 10, 2008).
7 WO 2005/000266 A2 (published Jan. 6, 2005).
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Claim 1, the sole independent claim on appeal, is representative and
reads as follows:
1. A therapeutic secretory phospholipase A2 (sPLA2)
hydrolyzable liposome comprising
• about 25% to 45% (mol/mol) of phosphatidyl glycerol
[PG];
• about 50% to 70% (mol/mol) of phosphatidyl choline
[PC];
• less than 1% cholesterol (mol/mol); and
• oxaliplatin
wherein about 0.1 mM to 1 mM of Ca2+ is encapsulated within
the liposome and the counterion of Ca2+ is selected from the
group consisting of gluconate, propionate or lactate.
Appeal Br. 14.
OBVIOUSNESS—
ANDRESEN, ERIGUCHI, AND MURAKAMI
The Examiner’s Prima Facie Case
The Examiner cited Andresen as disclosing cholesterol-free liposomes
capable of hydrolysis by sPLA2, as recited in Appellant’s claim 1, the
liposomes containing both phosphatidyl glycerol (PG) and phosphatidyl
choline (PC), as required by claim 1. See Ans. 2 (citing Andresen as
disclosing sPLA2-hydrolyzable liposomes composed of DSPC (distearoyl
PC), DSPG (distearoyl PG), DSPE-PEG 2000 (distearoyl
phosphatidylethanolamine polyethylene glycol 2000), and cisplatin).
The Examiner conceded that Andresen differed from Appellant’s
claim 1 in that Andresen did not expressly state that its liposomes contained
the amounts of PG and PC recited in claim 1. See id. (“[I]t is unclear as to
the percentages of the lipids in Andresen . . . .”).
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The Examiner noted, however, that Andresen taught that the degree to
which the liposomes were hydrolyzed by sPLA2 was affected by the
proportions of the lipids in the liposomes:
Andresen on page 82 teaches that the degree of hydrolysis is
increased by increasing amounts of PEG-lipids and that sPLA2
activity is dependent upon calcium concentration. Andresen
further teaches on pages 85 and 86 that sPLA2 displays higher
activity towards higher amounts of anionic
phosphatidylglycerol and by adjusting proAEL[pro(anticancer
ether lipid]-PG and proAEL PC composition it is possible to
fine-tune and optimize the liposomal lability with respect to
sPLA2 (3.3.1 ).
Ans. 2–3.
Based on these teachings the Examiner reasoned that it would have
been obvious to adjust the amounts of the lipids in Andresen’s liposomes to
achieve optimal hydrolysis by the sPLA2 enzyme. See id. at 3 (“It would
have been obvious to one of ordinary skill in the art to adjust the amounts of
PEG-lipids, neutral phospholipids and negatively charged PG in order to
obtain the best possible results based on Andresen’s teachings.”).
As to the calcium ions (Ca+2) required by Appellant’s claim 1 to be
encapsulated in the liposomes, the Examiner noted Andresen’s teaching
“that sPLA2 activity is dependent upon calcium concentration” (id. at 2),
and reasoned, therefore, that “[t]o encapsulate appropriate amounts of
calcium would have been obvious to one of ordinary skill in the art since
sPLA2 activity is dependent on calcium ions” (id. at 3).
The Examiner cited Murakami as additional evidence that sPLA2 was
known to require calcium ions as a cofactor. See id.; see also id. at 4 (“One
of ordinary skill in the art would be motivated to include calcium ions in the
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composition since sPLA2 activity is dependent upon the calcium ions as
taught by both Andresen and also Murakami.”).
As to the requirement in claim 1 for the liposome-encapsulated
calcium ions to have gluconate, propionate or lactate as counterion, the
Examiner reasoned that “sPLA2 activity is dependent on the calcium[;]
therefore, it is within the skill of the art to use an appropriate calcium salt in
the composition.” Id. at 4.
As to the oxiplatin required by claim 1 to be encapsulated in the
liposomes, the Examiner cited Eriguchi as teaching that oxiplatin possesses
therapeutic efficacy similar to the cisplatin used in Andresen’s liposomes,
but that oxiplatin has reduced side effects when compared to cisplatin. See
id. at 3. The Examiner reasoned, therefore, that a skilled artisan would have
considered it obvious to use oxiplatin instead of cisplatin in Andresen’s
liposomes “since oxaliplatin has the same therapeutic efficacy but without
toxicity associated with cisplatin.” Id. at 3–4.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Having carefully considered the evidence and arguments advanced by
Appellant and the Examiner, Appellant does not persuade us that the
preponderance of the evidence fails to support the Examiner’s conclusion of
obviousness as to representative claim 1 over Andresen, Eriguchi, and
Murakami.
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Andresen describes a sPLA2-hydrolyzable liposome that undisputedly
has both of the lipid components required by Appellant’s claim 1,
phosphatidyl glycerol (PG) and phosphatidyl choline (PC). See Andresen 88
(“We have analyzed liposomes with different DSPC/DSPG/DSPE-PEG2000
lipid composition[s] loaded with doxorubicin for in vitro serum stability and
found that the drug is successfully retained in the liposomes in compositions
that can be degraded by human sPLA2 type IIA.”); id. at 89 (“We have
encapsulated cisplatin in sPLA2 degradable liposomes and tested these
against a series of cancer cell lines. We have found that sPLA2 triggers the
release of cisplatin from sPLA2 degradable liposomes . . . resulting in a
pronounced cytotoxic effect . . . .”).
Andresen explains that, because sPLA2 is overexpressed in tumor
tissues, encapsulating chemotherapeutic agents such as doxorubicin or
cisplatin in liposomes that are hydrolyzable by sPLA2 provides localized
release of the therapeutic anti-tumor agents at the tumor site. See id. at 79
(“Our own work has been focused on utilizing secretory phospholipase A2
(sPLA2), which is over-expressed in inflammatory and tumor tissue, as a
site-specific trigger of long circulating liposomes. The liposomes can entrap
and transport conventional chemotherapeutics such as doxorubicin and
cisplatin.”) (Citations omitted); id. at 86 (“Both in vivo and in vitro studies
have been reported, describing significantly elevated levels of sPLA2 in
several human carcinomas of different origin including hepatocellular,
colorectal, breast, gastric and pancreatic carcinomas. In addition, sPLA2 has
been identified in tumor infiltrating macrophages and in the invading zone of
the tumors.”) (Citations omitted).
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Although Andresen does not disclose the specific amounts of the
lipids in its liposomes, Andresen teaches that the proportions of the lipid
components of the liposomes affect the degree to which sPLA2 hydrolyzes
the liposomes (and releases the drugs contained therein), as the Examiner
found. See id. at 82 (describing results of study that “not only illustrated that
sPLA2 could reach the surface of pegylated liposomes, they also
demonstrated that there was increased sPLA2 hydrolysis of pegylated
liposomes and that the degree of hydrolysis increased with increasing
amounts of PEG-lipids.”) (Citations omitted); id. at 86 (“By adjusting the
proAEL[pro(anticancer ether lipid]-PG:proAEL-PC composition . . . it is
possible to fine-tune and optimize the liposomal lability with respect to
sPLA2 levels in the tumor tissue.”) (Citations omitted; emphasis added).
As our reviewing court’s predecessor explained, “[w]here the general
conditions of a claim are disclosed in the prior art, it is not inventive to
discover the optimum or working ranges by routine experimentation.” In re
Aller, 220 F.2d 454, 456 (CCPA 1955); see also E.I. DuPont de Nemours &
Company v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018) (citation
omitted) (“[A] recognition in the prior art that a property is affected by the
variable is sufficient to find the variable result-effective.”).
In the present case, as noted above, Andresen discloses that the
general conditions of chemotherapeutic drug-delivering sPLA2-hydrolyzable
liposomes are that the liposomes contain three lipids, DSPC, DSPG, and
DSPE-PEG2000. Andresen 88. DSPC and DSPG are undisputedly species of
the two lipids (PC and PG) recited in Appellant’s claim 1, and DSPE-
PEG2000 is undisputedly encompassed by Appellant’s claim 4, which
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depends from claim 1 and expressly recites an additional lipid in Appellant’s
claimed liposome. See Appeal Br. 14 (claim 4).
And, as also noted above, Andresen discloses that the liposomes’
sPLA2 hydrolyzability can be optimized by varying the amounts of the
lipids in the liposome. See Andresen 82, 86.
Thus, based on the teachings of Andresen, a skilled artisan knew the
criterion for optimization (sPLA2 hydrolysis), and also knew that, as to the
lipid component of the liposomes, only three variables required optimization
(the amounts of DSPC, DSPG, and DSPE-PEG2000). We are not persuaded,
therefore, that Andresen failed to provide a skilled artisan with sufficient
guidance for optimizing the amounts of the lipids in its drug-delivering
liposomes. See Appeal Br. 7–8; Reply Br. 3–4. Nor are we persuaded that
determining suitable amounts of the lipids would have involved an infinite
number of options, given Andresen’s teaching that only three types of lipids
need be present in the liposomes to achieve drug delivery to cancer cells.
We acknowledge that Appellant’s claim 1 also requires the liposomes
to contain about 0.1 mM to 1 mM of calcium ions encapsulated within the
liposome, with the counterion of calcium being either gluconate, propionate
or lactate. Appeal Br. 14.
As the Examiner found, however, both Andresen and Murakami teach
that sPLA2 activity is dependent on calcium ions. See Andresen 82 (“sPLA2
activity is dependent on calcium concentration”) (citations omitted);
Murakami 160 (“sPLA2 comprises Ca2+ -dependent interfacial enzymes”).
We acknowledge, as Appellant contends, that none of the cited
references expressly teaches encapsulating calcium inside liposomes. See
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Appeal Br. 7 (noting that the sPLA2 enzyme secreted by cancer cells would
be on the exterior of the liposomes); Reply Br. 2–3.
As the Supreme Court has explained, however, in determining
whether the prior art supplied a reason for practicing the claimed subject
matter, the analysis “need not seek out precise teachings directed to the
specific subject matter of the challenged claim, for a court can take account
of the inferences and creative steps that a person of ordinary skill in the art
would employ.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007);
see also id. at 421 (“A person of ordinary skill is . . . a person of ordinary
creativity, not an automaton.”).
In the present case, based on teachings in Andresen, the Examiner
posits that a skilled artisan would have reasonably inferred that sPLA2 had
at least some hydrolytic activity toward the liposomes without exogenously
added calcium. Ans. 7 (citing Andresen 82). Therefore, the Examiner
reasons, including calcium ions inside the liposomes would ensure the
presence of the required cofactor of sPLA2, at the desired location, as
liposome hydrolysis progressed. See id. at 8 (“[O]ne of ordinary skill in the
art would be motivated to encapsulate calcium to be released at the intended
site and enhance the sPLA2 activity. If calcium ions are present in the
liposomal exterior, it would only get diluted in blood when administered.”).
Thus, Appellant does not persuade us that the Examiner failed to
provide an evidence-based explanation why a skilled artisan would have
considered it obvious to encapsulate calcium ions inside Andresen’s
liposomes, as recited in Appellant’s claim 1. Indeed, Appellant does not
explain specifically why the Examiner erred in determining, based on the
cited teachings in Andresen, that a skilled artisan would have reasonably
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inferred it would be useful to encapsulate calcium ions inside Andresen’s
liposomes, in order to ensure the presence of the required cofactor of sPLA2,
at the desired location therapeutic drug delivery.
And, having determined from the cited references that it would be
useful to encapsulate calcium ions inside Andresen’s liposomes, we agree
with the Examiner that a skilled artisan would have considered it a routine
matter of obvious optimization to determine suitable concentrations of the
calcium ions. See In re Aller, 220 F.2d at 456 (“[W]here the general
conditions of a claim are disclosed in the prior art, it is not inventive to
discover the optimum or workable ranges by routine experimentation.”).
Moreover, having determined from the cited references that it would
be useful to encapsulate calcium ions inside Andresen’s liposomes, we agree
with the Examiner that a skilled artisan would have considered it an obvious
matter to select a useful pharmaceutically acceptable calcium salt for that
purpose, including for example the gluconate, propionate, or lactate salts
recited in Appellant’s claim 1. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1368–69 (Fed. Cir. 2007) (holding obvious the selection of a known
counterion/salt for a known drug where no unexpected results were shown
for claimed combination); id. at 1368 (“We find this case analogous to the
optimization of a range or other variable within the claims that flows from
the ‘normal desire of scientists or artisans to improve upon what is already
generally known.’”) (Quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir.
2003)).
In addition to the lipids and calcium discussed above, the liposome of
Appellant’s claim 1 also includes oxaliplatin. See Appeal Br. 14. As the
Examiner found, however, oxaliplatin was known in the art to be a
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chemotherapeutic alternative to the cisplatin used in Andresen’s liposomes,
providing similar cytotoxic efficacy, but reduced adverse side effects. See
Eriguchi ¶ 2 (“The present invention relates to a liposome preparation for
use as an anti-tumor agent.”); id. ¶ 4 (“Oxaliplatin exerts therapeutic
activities similar to those of cisplatin and has relatively low nephrotoxicity
and emetogenicity.”); id. ¶ 7 (“The present invention provides a formulation
of liposomes containing oxaliplatin contained within the liposomes.”).
Given these teachings, we agree with the Examiner that a skilled artisan had
a good reason for, and a reasonable expectation of success in, using
oxaliplatin in Andresen’s liposomes, rather than cisplatin.
In sum, as evidenced by the teachings discussed above in Andresen,
Murakami, and Eriguchi, Appellant’s claim 1 recites an sPLA2-hydrolyzable
liposome that contains four ingredients known or expected to be useful in
sPLA2 hydrolyzable liposomes: (1) PG, (2) PC, (3) calcium ions provided as
calcium gluconate, calcium propionate, or calcium lactate, and (4)
oxaliplatin. As discussed above, the fact that the cited references might not
expressly disclose the specific amounts of PG, PC, and calcium ions recited
in claim 1 does not persuade us that the Examiner erred in determining that
the claimed concentrations of those ingredients would have been determined
through routine optimization, and therefore obvious.
Accordingly, Appellant does not persuade us that the evidence of
record fails to support the Examiner’s prima facie case of obviousness. See
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (“[W]hen a patent
‘simply arranges old elements with each performing the same function it had
been known to perform’ and yields no more than one would expect from
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such an arrangement, the combination is obvious.”) (Quoting Sakraida v. Ag
Pro, Inc., 425 U.S. 273, 282 (1976)).
As our reviewing court has pointed out, in situations such as the
present one, “[w]here ‘the difference between the claimed invention and the
prior art is some range or other variable within the claims . . ., the [applicant]
must show that the particular range is critical, generally by showing that the
claimed range achieves unexpected results.’” Iron Grip Barbell Co. v. USA
Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (quoting In re Woodruff,
919 F.2d 1575, 1578 (Fed. Cir. 1990)).
Appellant does not persuade us that it has advanced objective
evidence of nonobviousness, such as evidence of unexpected results,
sufficient to outweigh the prior art evidence of obviousness presented by the
Examiner. See Appeal Br. 5 (citing Examples 3, 6, and 7–9 of the
Specification as evidence that encapsulating calcium gluconate, propionate,
and lactate significantly improves liposome stability); Appeal Br. 10–11
(citing Example 3 and Tables 28 and 3 of the Specification as evidence that
calcium ion concentration is a result effective variable that unexpectedly
increases liposome stability); Reply Br. 3 (characterizing enhanced stability
resulting from encapsulating calcium ions in liposomes as “surprising
result”); Reply Br. 5 (citing Example 3 in Specification); Reply Br. 7–8
(citing Table 2 as showing that “liposome stability increases with increasing
amount of calcium gluconate between 0 and 1 mM, but that a liposome with
5 mM calcium gluconate exhibits decreased stability relative to a liposome
with 1 mM calcium gluconate”).

8 We note that Appellant’s Specification contains two tables designated as
Table 2, one on page 18 and one on page 25.
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We first note that it is well settled that, by themselves, assertions in
briefing by counsel as to the unexpectedness of experimental results are of
little probative value toward nonobviousness, absent some evidence, beyond
the assertions in the briefs, that a skilled artisan actually would have
considered the results to be unexpected. See In re Geisler, 116 F.3d 1465,
1470–71 (Fed. Cir. 1997) (finding arguments of unexpected results
unpersuasive “naked attorney argument” because applicant “did not offer
evidence of unexpected results in the form of a statement to that effect from
the inventors or any third party, or any objective evidence from a respected
source” nor did applicant make any statements of unexpectedness in its
specification or in an affidavit under 37 C.F.R. § 1.132).
In the present case, other than the assertions in briefs, Appellant does
not identify, nor do we discern, any statements in the Specification, or
elsewhere in the record, suggesting that the experimental results shown in
the Specification actually would have been unexpected by a skilled artisan.
Appellant’s assertions of unexpectedness are, therefore, of little probative
value.
It is also well settled that “[e]vidence of secondary considerations
must be reasonably commensurate with the scope of the claims.” In re Kao,
639 F.3d 1057, 1068 (Fed. Cir. 2011).
In the present case, Appellant’s claim 1 recites that calcium ions at
concentrations of from 0.1 mM to 1 mM are encapsulated within the
liposome, with the counterion of calcium being either gluconate, propionate
or lactate. Appeal Br. 14. We are not persuaded, however, that Appellant
explains with adequate specificity how or why any of the portions of the
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Specification cited as showing unexpectedness are commensurate in scope
with claim 1.
In that regard, we note in particular the disclosure in Appellant’s
Example 3 that when calcium gluconate was included in the interior of the
liposome, but not on the exterior, little improvement in stability was seen,
directly contrary to Appellant’s contention that encapsulating calcium ions
in the liposomal interior improves stability:
It was furthermore examined how the liposome formulation
was affected by the presence of calcium gluconate on interior or
exterior only. As demonstrated in [Table 4], it was quite
evident that liposome formulation containing calcium on the
interior only is not very good at stabilizing the liposome
oxaliplatin formulation. Having calcium on the exterior only
was demonstrated to stabilize the liposome formulation quite
well.
Spec. 20–21 (emphasis added); see also id. at 21 (Table 4 showing liposome
formulation with 1 mM calcium gluconate only in interior of liposome
exhibited 22% oxaliplatin leakage after 24 hours, whereas liposome with
calcium on the liposome exterior only exhibited 4% leakage after 24 hours,
and liposome with calcium on both the liposome exterior and interior
exhibited 1% leakage after 24 hours).
Thus, Appellant’s own Specification shows that 1 mM calcium
gluconate only in the interior of the liposome, an embodiment clearly
encompassed by Appellant’s claim 1, does not prevent oxaliplatin leakage,
i.e., does not improve the liposome’s stability. We are not persuaded,
therefore, that Appellant has shown unexpected results commensurate in
scope with the subject matter recited in claim 1.
We acknowledge the disclosure in Appellant’s Table 2 on page 18 of
the Specification that, when calcium gluconate concentration is either
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0.10 mM or 1.00 mM in a “liposomal oxaliplatin formulation,” the
oxaliplatin content in the formulation is 0.82 mg/ml and 1.24 mg/ml
respectively, whereas when the calcium gluconate concentration is raised to
5.00 mM, the oxaliplatin content is only 1.01 mg/ml. Spec. 18. Appellant
does not direct us, however, to any supporting disclosure as to Table 2 on
page 18 of the Specification suggesting that the data presented therein relates
in any way to an experimental determination of liposomal stability,
unexpected or otherwise.
We acknowledge that Appellant’s Table 3 on page 20 of the
Specification shows the results of experiments in Example 3 in which
calcium lactate and calcium propionate were included in the formulation
used to prepare the liposome. See Spec. 20. Although not entirely clear
from the disclosure in the Specification, and not explained by Appellant in
the briefs, the results shown in Table 3 on page 20 of the Specification are
apparently from experiments in which the calcium ions were present both on
the exterior and in the interior of the liposomes.
Although 1 mM calcium lactate and 1 mM calcium propionate in the
particular lipid formulation used in that experiment yielded only 1%
oxaliplatin leakage (see Spec. 20), Appellant’s claim 1 also encompasses
significantly lower concentrations of those compounds (as low as 0.1 mM;
see Appeal Br. 14), and Appellant has only provided data at that lower
concentration for calcium gluconate, but not for calcium lactate or calcium
propionate. See Appellant’s Fig. 3B. And again, Appellant’s claim 1
encompasses the situation in which calcium gluconate is present only in the
liposome’s interior, a situation which Appellant’s Specification expressly
states does not result in improved liposome stability. We are not persuaded,
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therefore, that Example 3 in the Specification is commensurate in scope with
representative claim 1.
Appellant’s Example 6 provides data only for calcium gluconate, but
not for calcium lactate and propionate, both of which are expressly recited in
claim 1. See Spec. 22–23. Moreover, Example 6 relates only to liposomes
that contain cisplatin, not oxaliplatin as recited in representative claim 1.
See id. We are not persuaded, therefore, that Appellant has explained
adequately how Example 6 in the Specification shows unexpected results
commensurate in scope with the liposomes recited in claim 1.
Appellant’s Example 7 describes experiments in which a “[l]iposome
encapsulated oxaliplatin formulation was prepared without calcium (10%
sucrose on interior and exterior)” (Spec. 23 (emphasis added)), and then
tested for particle size and stability after being stored in various
concentrations of calcium gluconate for 24 hours at room temperature (see
id. at 23–24 (data shown in Tables 1 and 2). Because the liposomes were
prepared without calcium, and therefore did not contain calcium
encapsulated in the liposomes’ interiors as recited in Appellant’s
representative claim 1, we are not persuaded that Appellant has explained
how or why Example 7 is commensurate in scope with claim 1.
Appellant’s Example 8 similarly “examine[d] the effect of only
having calcium on the exterior water phase of various liposomal
formulations containing DSPC, DSPG and DSPE-PEG2000 in terms of
particle size, total Pt, DOE [degree of encapsulation], and stability.” Spec.
25 (emphasis added). Because the liposomes did not contain calcium
encapsulated in the liposomes’ interiors, we are not persuaded that Appellant
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has explained how or why Example 8 is commensurate in scope with
Appellant’s representative claim 1.
Appellant’s Example 9 “examine[d] the effect of having calcium on
both the interior and exterior of various liposomal formulations containing
DSPC, DSPG and DSPE-PEG2000 in terms of particle size, total Pt, DOE,
and stability.” Spec. 30. The formulations contained 1 mM calcium
gluconate. See id.
In relation to the results obtained in the experiments described in
Example 9, the Specification discloses that “[f]or all the formulations
prepared there was observed higher Pt/P-ratio when calcium gluconate was
included on the interior.” Spec. 32. Although not explained by Appellant in
its briefs, Pt/P ratio is apparently a measure of oxaliplatin loss. See id. at 28
(“There is practically no loss of oxaliplatin between 1st and 2nd dialysis if
the dialysis solution is 10% sucrose in both dialysis steps (based on Ion
count ratio (Pt195 /P31)).”).
Because Appellant’s Example 9 only tested a single concentration of a
single calcium salt (1 mM calcium gluconate), whereas Appellant’s
representative claim 1 encompasses concentrations significantly lower than
tested in Example 9 (0.1 mM), and recites additional calcium salts not tested
in Example 9 (lactate and propionate), we are not persuaded that Appellant
has explained adequately why Example 9 is commensurate in scope with
representative claim 1. And again, Appellant’s claim 1 encompasses the
situation in which calcium gluconate is present only in the liposome’s
interior, a situation which Appellant’s Specification expressly states does not
result in improved liposome stability.
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In sum, given the absence of any non-attorney-argument assertion of
unexpectedness, and given the fact that claim 1 is not commensurate in
scope with the alleged evidence of unexpected results, particularly given the
Specification’s direct assertion that encapsulation of calcium in the interior
of the liposomes does not improve the liposomes’ stability (see Spec. 20–
21), we are not persuaded that Appellant has advanced objective evidence of
nonobviousness sufficient to outweigh the prior art evidence of obviousness
advanced in the Examiner’s prima facie case. Accordingly, we affirm the
Examiner’s rejection of claim 1 over Andresen, Eriguchi, and Murakami.
Because they were not argued separately, claims 4, 5, 7, 9, 10, 13–15, 18–22
and 26–29 fall with claim 1.
OBVIOUSNESS—
ANDRESEN, ERIGUCHI, MURAKAMI, AND LAKKARAJU
The Examiner’s Prima Facie Case
In the second rejection for obviousness, the Examiner cited Andresen,
Eriguchi, and Murakami for the teachings discussed above, and cited
Lakkaraju as additional evidence that it would have been obvious to include
the PG and PC lipids recited in claim 1, and the calcium ions recited in
claim 1, at the concentrations required by claim 1. See Ans. 4–5.
In particular, the Examiner reasoned that a skilled artisan would have
considered it obvious “to vary the amounts of phosphatidylcholine [PC] and
phosphatidylglycerol [PG] in Andersen since Lakkaraju teaches amounts
similar to [the claimed] instant amounts in liposomes containing
antineoplastic agents.” Id. at 5.
Analysis
Having carefully considered the evidence and arguments advanced by
Appellant and the Examiner, Appellant does not persuade us that the
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preponderance of the evidence fails to support the Examiner’s conclusion of
obviousness as to representative claim 1 over Andresen, Eriguchi,
Murakami, and Lakkaraju.
As discussed above, we find that the preponderance of the evidence
supports the Examiner’s conclusion that the liposome recited in Appellant’s
claim 1 would have been obvious in view of Andresen, Eriguchi, and
Murakami. We agree with the Examiner, moreover, that Lakkaraju provides
additional evidence that it would have been obvious to include the
proportions of PG and PC recited in claim 1, as well as the claimed
concentration of calcium ions, in a liposome for delivering a
chemotherapeutic agent.
Specifically, Lakkaraju discloses “methods of using anionic liposomes
to deliver bioactive agents, including oligonucleotides, plasmid
DNA, RNA, proteins, and drugs, to non-dividing cells.” Lakkaraju ¶ 3.
Lakkaraju discloses that drug-delivering liposomes can contain various
lipids, including the PG and PC lipids recited in Appellant’s claim 1, in
wide-ranging proportions:
The anionic liposome can include individual
phospholipids in any suitable, effective, and appropriate
amount. For example, the anionic liposome can include any
combination of DOPC, DOPG, DOPS, and DOPA; wherein the
amount of any one of DOPG, DOPS, and DOPA is up to about
100% of the anionic liposome and wherein the amount of
DOPC is up to about 99%; provided the combined amount of
each equals 100% of the anionic liposome, or less.
Lakkaraju ¶ 87.
In one embodiment, Lakkaraju discloses that drug-delivering
liposomes can contain the same two lipids as recited in Appellant’s claim 1,
PG (about 5% to about 20%) and PC (about 80% to 95%). See Lakkaraju
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¶ 87 (“[T]he amount of DOPC can be about 80% of the anionic liposome to
about 95% of the anionic liposome and the amount of DOPG can be about
5% of the anionic liposome to about 20% of the anionic liposome.”)
(Emphasis added).
As noted above, the liposome of Appellant’s claim 1 contains “about
25% to 45% (mol/mol) of [PG].” Appeal Br. 14 (emphasis added). The
liposome of Appellant’s claim 1 contains “about 50% to 70% (mol/mol) of
[PC].” Id. (emphasis added).
Thus, although the ranges of PG and PC taught in Lakkaraju do not
overlap the ranges of those lipids recited in Appellant’s claim 1, the prior art
ranges and the claimed ranges closely abut each other, given the “about”
language used both in Lakkaraju and in claim 1. We therefore agree with
the Examiner that, viewing Lakkaraju alongside the teachings of Andresen
discussed above, a skilled artisan would have considered the proportions of
the lipids recited in Appellant’s claim 1 obvious. In re Peterson, 315 F.3d at
1329 (“[A] prima facie case of obviousness exists when the claimed range
and the prior art range do not overlap but are close enough such that one
skilled in the art would have expected them to have the same properties.”).
Appellant does not persuade us, moreover, that the Examiner erred in
interpreting the “about” language in representative claim 1 as distinguishing
or teaching away from the ranges of PG and PC taught in Lakkaraju. See
Reply Br. 5–6.
It might be true, as Appellant contends, that each of Appellant’s
examples uses a liposome with lipid proportions falling within the ranges of
PG and PC recited in representative claim 1. Nonetheless, absent some
specific language in the Specification expressly prescribing a narrow
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interpretation of “about,” we are not persuaded that the examples in the
Specification mandate a reading of claim 1 that excludes the ranges of PG
and PC taught in Lakkaraju. See In re Trans Texas Holdings Corp., 498
F.3d 1290, 1299 (Fed. Cir. 2007) (“[W]hile ‘the specification [should be
used] to interpret the meaning of a claim,’ courts must not ‘import[ ]
limitations from the specification into the claim.’ . . . [I]t is improper to
‘confin[e] the claims to th[e] embodiments’ found in the specification . . . .”)
(quoting Phillips v. AWH Corp., 415 F.3d 1303, 1323 (Fed. Cir. 2005)
(citations omitted, bracketed text in internal quotes in original)).
Turning to the calcium ions recited in Appellant’s claim 1, Lakkaraju
discloses that drug-delivering liposomes can contain “one or more (e.g., 1, 2,
3, or 4) suitable, appropriate, and effective cations. It is appreciated that
those of skill in the art understand that when a cation is present in the
pharmaceutical composition, the counter ion (i.e., the anion) will also be
present in the pharmaceutical composition.” Lakkaraju ¶ 119.
As recited in Appellant’s claim 1, Lakkaraju discloses that “[t]he
cation can be a monovalent cation or a divalent cation. Specifically, the
cation can be a divalent cation, e.g., Mg2+ or Ca2+.” Id. ¶ 120.
Lakkaraju discloses that the cation may be present in the liposomes in
widely varying amounts, including concentrations “below about 25 mM”
and “up to about 5 mM.” Id. ¶ 121.
Because Lakkaraju’s cation concentration ranges of below about 25
mM and up to about 5 mM entirely overlap the range of 0.1 mM to 1 mM
calcium concentration range recited in Appellant’s claim 1, we agree with
the Examiner that, viewing Lakkaraju alongside the teachings of Andresen
and Murakami discussed above, a skilled artisan would have considered the
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concentration of calcium ions recited in Appellant’s claim 1 obvious. In re
Peterson, 315 F.3d at 1329 (“A prima facie case of obviousness typically
exists when the ranges of a claimed composition overlap the ranges
disclosed in the prior art.”).
We note in particular that Lakkaraju uses the language “up to about 5
mM” in describing the concentration of cations useful in its liposome
formulations. Lakkaraju ¶ 121 (emphasis added). That is, Lakkaraju
expressly describes a range that includes 5 mM as its upper endpoint for
suitable cation concentrations. Appellant does not persuade us, therefore,
that Lakkaraju only teaches or suggests cation concentrations 5 to 100 times
greater than recited in representative claim 1. See Appeal Br. 10; Reply Br.
4–5.
In sum, for the reasons discussed, Appellant does not persuade us that
that evidence of record fails to support the Examiner’s determination that the
combined teachings of Andresen, Eriguchi, Murakami, and Lakkaraju would
have suggested an sPLA2-hydrolyzable liposome having each of the
ingredients recited in representative claim 1, in the amounts required by the
claim. As discussed above, moreover, the current record lacks any specific
non-attorney-argument assertion of unexpectedness. And, as also discussed
above, claim 1 is not commensurate in scope with the alleged evidence of
unexpected results, particularly given the Specification’s direct assertion that
encapsulation of calcium in the interior of the liposomes does not improve
the liposomes’ stability. See Spec. 20–21. We are not persuaded, therefore,
that Appellant has advanced objective evidence of nonobviousness sufficient
to outweigh the prior art evidence of obviousness advanced in the
Examiner’s prima facie case.
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Accordingly, we affirm the Examiner’s rejection of claim 1 over
Andresen, Eriguchi, Murakami, and Lakkaraju. Because they were not
argued separately, claims 4, 5, 7, 9, 10, 13–15, 18–22 and 26–29 fall with
claim 1.
OBVIOUSNESS—ANDRESEN, ERIGUCHI,
MURAKAMI, LAKKARAJU, MELVIK, AND JAMIL
The Examiner’s Prima Facie Case
In the third rejection for obviousness, the Examiner cited Andresen,
Eriguchi, Murakami, and Lakkaraju for the teachings discussed above, and
cited Melvik and Jamil as additional evidence that it would have been
obvious to select gluconate, propionate, or lactate, as recited in Appellant’s
claim 1, as the counterion of the calcium ions included in Andresen’s
liposomes. See Ans. 5–6.
Analysis
We affirm this rejection as well. As discussed above, Appellant does
not persuade us that the Examiner erred in concluding that the liposome of
Appellant’s claim 1 would have been obvious in view of the combined
teachings of Andresen, Eriguchi, Murakami, and Lakkaraju. That is, for the
reasons discussed above, we find no deficiencies in the teachings of
Andresen, Eriguchi, Murakami, and Lakkaraju in relation to representative
claim 1.
Accordingly, even if we were to agree with Appellant that the
teachings of Melvik and Jamil failed to supplement the teachings of
Andresen, Eriguchi, Murakami, and Lakkaraju (an issue we do not reach),
that fact does not negate our determination that Appellant failed to show
error in the Examiner’s conclusion of obviousness as to claim 1 over
Andresen, Eriguchi, Murakami, and Lakkaraju. We, therefore, affirm the
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Examiner’s rejection of claim 1 over Andresen, Eriguchi, Murakami,
Lakkaraju, Melvik, and Jamil. Claims 4, 5, 7, 9, 10, 13–15, 18–22 and 26–
29 fall with claim 1.

CONCLUSION
In summary:
Claims Rejected 35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 4, 5, 7, 9, 10,
13–15, 18–22, 26–
29
103(a) Andresen, Eriguchi,
Murakami
1, 4, 5, 7, 9, 10,
13–15, 18–22,
26–29

1, 4, 5, 7, 9, 10,
13–15, 18–22, 26–
29
103(a) Andresen, Eriguchi,
Murakami,
Lakkaraju
1, 4, 5, 7, 9, 10,
13–15, 18–22,
26–29

1, 4, 5, 7, 9, 10,
13–15, 18–22, 26–
29
103(a) Andresen, Eriguchi,
Murakami,
Lakkaraju, Melvik,
and Jamil
1, 4, 5, 7, 9, 10,
13–15, 18–22,
26–29

Overall Outcome 1, 4, 5, 7, 9, 10,
13–15, 18–22,
26–29

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED