Ex Parte Petersen et al

Patent Trial and Appeal Board

Jan 18, 2019

13497031 (P.T.A.B. Jan. 18, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/497,031 03/19/2012
21559 7590
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON, MA 02110
01/23/2019
FIRST NAMED INVENTOR
Morten Just Petersen
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
51181-003001 8426
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
01/23/2019 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 MORTEN JUST PETERSEN,
FRED RIK MELANDER, ANDERS FALK VIKBJERG,
SUNE ALLAN PETERSEN, and MOGENS WINKEL MADSEN
Appeal2018-008985 1
Application 13/497,031
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREY N. FRED MAN, and
MICHAEL J. FITZPATRICK, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a liposome that
contains cisplatin and a specific mixture of lipids. The Examiner rejected
the claims for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 Appellants state that "[t]he real parties in interest for this appeal are
Bio-Bedst ApS and LiPlasome Pharma." Appeal Br. 4.
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Application 13/497,031
STATEMENT OF THE CASE
The following rejections are before us for review:
(1) Claims 11, 13, 15, 17, 26, and 30-46, under 35 U.S.C. § I03(a) as
being unpatentable over Takagi,2 Tardi '250, 3 Lim, 4 and Ansell5 (Ans. 2-3);
(2) Claims 11, 13, 15, 17, 26, and 30-46, under 35 U.S.C. § I03(a) as
being unpatentable over Tardi '945, 6 Takagi, Tardi '250, Lim, and Ansell
(Ans. 3-5); and
(3) Claims 11, 13, 15, 17, 26, and 30-46, under 35 U.S.C. § I03(a) as
being unpatentable over Andresen, 7 Takagi, Tardi '250, Lakkaraju, 8 Lim,
and Ansell (Ans. 5-7).
Claim 11, the sole independent claim on appeal, is representative, and
reads as follows:
11. A secretory phospholipase A2 (sPLA2) hydrolyzable
liposome comprising distearoyl phosphatidyl glycerol (DSPG)
in an amount of about 25% (mol/mol), distearoyl phosphatidyl
choline (DSPC) in an amount of about 70% (mol/mol),
[poly( ethylene glycol) ]-distearoyl phosphatidyl ethanolamine
(DSPE-PEG) in an amount of about 5% (mol/mol), less than
1 % cholesterol, and cisplatin.
Appeal Br. 22.
2 US 2007/0286898 Al (published Dec. 13, 2007).
3 US 2005/0118250 Al (published June 2, 2005).
4 US 5,858,397 (issued Jan. 12, 1999).
5 US 6,027,726 (issued Feb. 22, 2000).
6 US 2003/0147945 Al (published Aug. 7, 2003).
7 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).
8 US 2003/0026831 Al (published Feb. 6, 2003).
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OBVIOUSNESS-
TAKAGI, TARDI '250, LIM, AND ANSELL
The Examiner's Prima Facie Case
The Examiner cited Takagi as disclosing "liposomal compositions
containing DSPC, DSPG and PEG-lipid in percentages which fall within the
claimed percentages. The amounts of neutral lipids, anionic lipid and
polymer conjugated lipids are 72 %, 22 % and 5.4 % respectively." Ans. 2.
The Examiner cited Takagi as disclosing cisplatin as an active agent suitably
contained within the liposomes, as recited in Appellants' claim 11. Id.
The Examiner conceded, however, that Takagi's liposomes differ
from the liposome recited in claim 11 in that "Takagi' s liposomes ...
contain cholesterol in more than [the] claimed amounts and PEG in Takagi
is complexed with cholesterol and not with DSPE." Id.
As evidence that the liposome recited in claim 11 would nonetheless
have been obvious, the Examiner cited Tardi '250 as teaching that "the
presence of ... negatively charged phospholipids increase[s] the blood
stability of liposomes and decreased concentration of cholesterol in PG
containing liposomes increases the retention of antineoplastic agent." Id.;
see also id. at 3 ( citing Examples 1-3 of Tardi '250). The Examiner also
cited Tardi '250 as disclosing the use of PEG-conjugated phospholipid in its
liposomes, including in its examples. Id. at 3.
The Examiner cited Lim and Ansell as evidence that, in liposomal
drug delivery formulations, "PEG-cholesterols and PEG-
phosphatidylethanolamine are both suitable steric barriers." Id.
Based on the references' combined teachings, the Examiner
concluded that it would have been obvious to decrease the amount of
cholesterol in Takagi's liposomes "since the negatively charged
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phospholipid in Takagi's liposomes would by itself increase the blood
stability and decreased amounts of cholesterol would enable the liposome to
retain the anti-neoplastic agent more within the liposomes as taught by Tardi
['250]." Id.
The Examiner also concluded that the "use of PEG-DSPE instead of
PEG-cholesterol taught by Takagi would have been obvious to one of
ordinary skill in the art because Lim and Ansell teach that both PEG-
derivatives are steric barriers." Id.
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
Appellants and the Examiner, Appellants do not persuade us that the
preponderance of the evidence fails to support the Examiner's conclusion of
obviousness as to representative claim 11 over Takagi, Tardi '250, Lim, and
Ansell.
As the Supreme Court explained in KSR Int 'l Co. v. Teleflex Inc.,
550 U.S. 398 (2007), "when 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 such an arrangement, the combination
is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282
(1976)).
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In the present case, claim 11 recites a liposome that contains less than
1 % cholesterol. Appeal Br. 22. The liposome of claim 11 must contain four
ingredients: (1) DSPG in an amount of "about 25%" (mol/mol), (2) DSPC
in an amount of "about 70%" (mol/mol), (3) DSPE-PEG in an amount of
"about 5%" (mol/mol), and ( 4) cisplatin. Id. ( emphasis added).
As Appellants acknowledge (Appeal Br. 8), Example 1 of Tardi '250,
expressly cited by the Examiner (Ans. 3), discloses a liposome that contains
no cholesterol, daunorubicin as the active agent contained within the
liposome, 20 mole% DSPG, and 80 mole% DSPC. Tardi '250 ,r 102.
Example 1 of Tardi also discloses a liposome having the same ingredients,
but with the DSPG and DSPC at a 30:70 molar ratio. See id.
In analyzing the in vivo properties of the liposomes prepared in
Example 1, Tardi '250 discloses that the "[ r ]esults depicted in FIG. lB
indicate that plasma blood levels of daunorubicin also increased with
increasing levels of DSPG. This data thus demonstrates that in addition to
decreasing the elimination of liposomes from the blood compartment, the
DSPG containing liposomes exhibit excellent drug retention properties in
vivo." Id. ,r 106 ( emphasis added); see also id. ,r 107 ("DSPG was
incorporated into DSPC liposomes at 20 mole % as this level of PG was
found to confer to the liposomes optimal circulation longevity as
demonstrated in Example 1.").
We note, moreover, that Figure lB of Tardi '250 shows similar in vivo
drug retention properties of the cholesterol-free 30% DSPG/70% DSPC
liposomes, as compared to the "optimal" cholesterol-free 20% DSPG/80%
DSPC liposomes. Id. ,I 107; id. at Fig. lB.
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Rather than requiring precise amounts of DSPG and DSPC,
Appellants' claim 11 requires only that the claimed liposomes contain
"about 25%" (mol/mol) DSPG and "about 70%" (mol/mol) DSPC. Appeal
Br. 22 (emphasis added). Given Tardi '250's teaching that its cholesterol-
free 30% DSPG/70% DSPC liposomes and cholesterol-free 20% DSPG/80%
DSPC liposomes "exhibit excellent drug retention properties in vivo" (Tardi
'250 ,r 106), as well as Tardi '250's teaching that its cholesterol-free 20%
DSPG/80% DSPC liposomes possess "optimal circulation longevity" in vivo
(id. ,r 107), Appellants do not persuade us (see Appeal Br. 7-12; Reply Br.
2--4) that the Examiner erred in finding that an ordinary artisan had a good
reason for, and a reasonable expectation of success in, preparing cholesterol-
free liposomes having molar percentages of DSPG and DSPC encompassed
by Appellants' claim 11.
Although the liposomes in Tardi '250 described as having
advantageous circulation properties contain daunorubicin rather than the
cisplatin required by Appellants' claim 11, Tardi '250 discloses that a
variety of therapeutic compounds, including anti-neoplastic agents, may be
incorporated into its liposomes (Tardi '250 ,r 72), and the remaining
references cited in this rejection provide evidence that it was desirable to
incorporate cisplatin, a known anti-neoplastic agent, into liposomes of the
type described in Tardi '250. See Takagi ,r 34; Lim at 6: 17-31; Ansel at
8:23-36.
As to the DSPE-PEG recited in Appellants' claim 11, required to be
present in the claimed liposome at a molar percentage of about 5% (Appeal
Br. 22), both Lim and Ansell disclose that polyethylene glycol lipid
conjugates function as steric barrier components which inhibit liposome-to-
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liposome interaction and aggregation, as the Examiner found. See Ans. 3;
see also Lim at 7 :33--41 ("The purpose of steric barrier components is to
inhibit liposome-liposome interactions and thereby reduce aggregation of the
liposome systems formed. Suitable steric barrier components are modified
derivatives of lipids and cholesterol, such as polyethylene glycol derivatives
of cholesterol (PEG-cholesterols) and PEG-lipids (e.g.,
phosphatidylethanolamine-polyoxyethylene conjugates and phosphatidic
acid-polyoxyethylene conjugates)." (emphasis added)); Ansell at 6:54--58
("Suitable steric barrier components are modified derivatives of lipids and
cholesterol, such as polyethylene glycol derivatives of cholesterol (PEG-
cholesterols) and PEG-lipids (e.g., phosphatidylethanolamine-
polyoxyethylene conjugates ... )." (emphasis added)).
Tardi '250, moreover, discloses that including 5% DSPE-PEG2000,
encompassed by Appellants' claim 11, in DSPC-containing liposomes,
inhibits liposome aggregation, measured as freezing-induced size increase, a
desirable property not exhibited by similar cholesterol-containing liposomes.
See Tardi '250 ,r 128 ("[A]s exemplified in FIG. 14, pH gradient liposomes
consisting of DSPC/DSPE-PEG2000 (95:5 mol %) did not demonstrate
changes in size subsequent to freezing whereas DSPC/cholesterol/DSPE-
PEG2000 liposomes did."). Thus, Tardi '250, particularly when viewed
alongside Lim and Ansell, suggests not only that it would have been
desirable to incorporate the amount of DSPE-PEG recited in Appellants'
claim 11 into agents carrying therapeutic agents such as cisplatin, but also
provides an additional teaching suggesting that it would have been desirable
to exclude cholesterol from such liposomes.
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In sum, given the teachings discussed above in the cited references,
Appellants do not persuade us that the Examiner erred in finding that an
ordinary artisan had a good reason for, and a reasonable expectation of
success in, preparing a liposome having all of the ingredients required by
Appellants' claim 11, in amounts encompassed by the claim.
We acknowledge, as Appellants contend (Appeal Br. 7-8; Reply Br.
2-3), that Takagi is directed to the use of a PEG cholesterol ether as a lipid
component in liposomes to enhance drug delivery, rather than the DSPE-
PEG recited in Appellants' claim 11, and that Takagi uses cholesterol in its
liposomes at molar concentrations higher than the 1 % recited in claim 11:
[T]he present inventors have conducted extensive studies on the
method for improving delivery of a drug encapsulated in a
liposome into a target organ or cell, and found as a result that
polyethylene glycol cholesteryl ether, whose action has so far
been revealed only about its retention in the circulating blood,
has the effect to improve drug efficacy in the target organ and
cell.
Takagi ,r 20; see also id. ,r 50 (Example 1 ).
We acknowledge also that Lim and Ansell disclose the desirability of
using amounts of cholesterol higher than the 1 % limit recited in Appellants'
claim 11. See Lim at 3 :41--48 ( disclosing preferred liposomes as containing
about 30% to 50% cholesterol); Ansell at 6:47--49 (disclosing preferred
liposomes as containing phospholipid and cholesterol, at molar ratios of
from 0.1 to 1.0 ( cholesterol: phospholipid)).
It is well settled, however, that "[ n ]on-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references. . . . [The reference] must
be read, not in isolation, but for what it fairly teaches in combination with
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the prior art as a whole." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir.
1986).
As discussed above, Tardi '250 teaches that cholesterol-free
liposomes having DSPG: DSPC in molar percentages encompassed by claim
11 have excellent in vivo drug retention properties. Tardi '250 ,r 106. As
discussed above, Tardi '250 also teaches that including 5% DSPE-PEG in
DSPG liposomes confers anti-aggregation properties to the liposomes (id.
,r 128), as suggested by both Lim and Ansell (see Lim at 7:33--41; Ansell at
6:54--58). And Tardi '250 teaches that the anti-aggregation properties
conferred by DSPE-PEG are not present when cholesterol is present in the
liposomes in a significant amount. See Tardi '250 ,r 128.
In the present case, Appellants' consideration, in isolation, of the
disclosures of Takagi, Lim, and Ansell regarding the use of cholesterol in
liposomes improperly fails to take into account the disclosures in Tardi '250
identified by the Examiner teaching that, as an alternative to cholesterol-
containing liposomes, a cholesterol-free liposome containing DSPG, DSPC,
and DSPE-PEG, in amounts encompassed by Appellants' claim 11, would
be useful as a carrier for a therapeutic agent such as the cisplatin recited in
claim 11. Appellants do not persuade us, therefore, that when the cited
references are properly viewed in combination, an ordinary artisan lacked
motivation for, or a reasonable expectation of success in, preparing a
liposome encompassed by representative claim 11, or that the claimed
combination of elements would have been arrived at solely through
improper hindsight.
Appellants argue:
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None of the cited publications describe sPLA2-mediated
hydrolysis of lipids, nor do they provide any reason to expect
that certain lipids or lipid amounts would produce a liposome
exhibiting release of cisplatin at the site of sPLA2-expressing
tumors. Thus, one of skill in the art would have had no
reasonable expectation of success in improving retention and
sPLA2-targeted delivery of cisplatin to tumors by modifying
the lipid content and/ or ratio of Takagi, Tardi, Lim, or Ansell's
liposomes.
Appeal Br. 10.
To establish obviousness, however, the prior art need only provide a
reasonable expectation of practicing the subject matter actually recited in the
claim at issue. See Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
821 F.3d 1359, 1367 (Fed. Cir. 2016) ("[O]ne must have a motivation to
combine accompanied by a reasonable expectation of achieving what is
claimed in the patent-at-issue.") (emphasis added).
In the present case, Appellants' claim 11 does not expressly recite a
liposome that exhibits release of cisplatin at the site of sPLA2-expressing
tumors, nor does claim 11 recite a liposome that exhibits improved retention
and sPLA2-targeted delivery of cisplatin to tumors as compared to some
other liposome. Rather, Appellants' claim 11 recites only an sPLA2-
hydrolyzable liposome composed of the four ingredients discussed above,
and containing less than 1 % cholesterol.
As discussed above, the combined teachings of the cited references
provide a reasonable expectation of preparing a cholesterol-free liposome
containing those four ingredients in the claimed amounts. Appellants
identify no persuasive evidence of record suggesting that, following the cited
references' teachings, an ordinary artisan lacked a reasonable expectation of
preparing a liposome having the ingredients recited in claim 11.
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And, Appellants identify no persuasive evidence of record suggesting
that the recitation in claim 11 's preamble regarding sPLA2-hydrolyzability
requires the presence of any ingredients other than those recited in claim 11.
See Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997) ("[W]here a patentee
defines a structurally complete invention in the claim body and uses the
preamble only to state a purpose or intended use for the invention, the
preamble is not a claim limitation.").
To the contrary, on the current record, as discussed above, claim 11
recites a liposome containing ingredients known in the prior art to be
suitable for use in therapeutic liposomes, in amounts known to be useful in
such liposome formulations. As noted above, "when 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 such an
arrangement, the combination is obvious." KSR, 550 U.S. at 417 (quoting
Sakraida v. Ag Pro, 425 U.S. at 282).
In the present case, we are not persuaded that Appellants have shown
that the claimed combination of prior art elements provides unexpected
results sufficient to outweigh the evidence of obviousness in the prior art,
discussed above, advanced by the Examiner. See Appeal Br. 20 ( citing
Spec. 8; also citing Spec. 21-29 (Example 6) ).
As to unexpected results, Appellants state:
As is shown in Example 6 of Appellant's specification,
the Maximum Tolerated Dose (MTD) of cisplatin increased
when cisplatin was administered to rats and mice encapsulated
within a liposome within the scope of the claims (LiPlaCis ).
These results demonstrate that LiPlaCis releases cisplatin at the
tumor site and not at a non-tumor site, because of the
liposome's sPLA2 hydrolyzable properties and stability in vivo.
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Appeal Br. 20.
Appellants' Example 6 appears at pages 21-29 of the Specification,
and appears to be a proposal for a human clinical trial, as opposed to an
experiment showing selective release of cisplatin at a tumor site in rats
and/or mice. See Spec. 21-29. Although some results in human patients
appear to be presented for the study described in Appellants' Example 6,
none of those disclosures mentions anything about results in mice or rats,
nor do the disclosures include any statement alleging that the human results
obtained were unexpected or surprising. See Spec. 29 (citing Figs. 8-16).
Other than the unpersuasive citations to the Specification, Appellants
point to no other evidence to support their assertion that the liposome
formulation of representative claim 11 provided unexpected results. It is
well settled that unsupported assertions in a party's briefing regarding the
unexpectedness of results is insufficient to show nonobviousness. See In re
Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997). Thus, on the current record,
Appellants do not persuade us that the results disclosed in Example 6 are
sufficient to show that the liposome of Appellants' claim 11 provides
unexpected benefits.
We acknowledge, consistent with Appellants' argument, that the rat
experiment described in Appellants' Example 3 "revealed that LiPlaCis [ a
liposome encompassed by claim 11] is a long-circulating liposomal form of
cisplatin with a Tl/2 of about 20-23 h compared to the 15 minutes for free
cisplatin. The area under the curve (AUC) for LiPlaCis was at least 50 times
that of cisplatin." Spec. 19.
We acknowledge also the disclosure in Appellants' Example 4 of an
experiment in which cisplatin-containing liposomes were administered to
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mice with induced tumors. See id. at 19--20. Consistent with Appellants'
argument, the Specification discloses that "LiPlaCis is long-circulating
liposomal form of cisplatin. LiPlaCis accumulates in tumors and also in
kidneys and spleen. Cisplatin can be released from LiPlaCis in the tumor
microenvironment." Id. at 20.
Again, however, neither Example 3 nor Example 4 includes any
statement or assertion alleging that the results presented therein would have
been unexpected. As noted above, the unsupported assertions in Appellants'
briefing regarding the unexpectedness of those results are insufficient to
show nonobviousness. See In re Geisler, 116 F.3d at 1471.
It is well settled, moreover, that "when unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art." In re Baxter Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991). In the present case, Appellants do not identify in
the record any comparison of the properties of the liposome of representative
claim 11 to any prior art liposome formulation, much less one identified as
being the closest prior art.
We acknowledge the disclosures on page 25 of the Specification
identified by Appellants regarding the conversion factor for cisplatin
dosages in rats as compared to humans. Appeal Br. 20 ( citing Spec. 25).
We acknowledge the statement in the Specification identified by Appellants
(see id.) that "[t]he MTD (maximum tolerated dose) of LiPlaCis [a liposome
encompassed by claim 11] given every 3 weeks was determined to be above
80 mg per treatment cycle, which is surprising in view of the MTD predicted
from animal experiments." Spec. 8.
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Appellants, however, fail to explain specifically which animal
experiments were used to demonstrate the allegedly unexpected MTD, and
more importantly, whether those animal experiments involved the use of
prior art liposomes in any of the cited prior art, or in the closest prior art. In
the absence of identifying a suitable specific comparative basis for
establishing unexpectedness, we are not persuaded that the assertion
regarding an unexpected MTD in the Specification is sufficient to show that
the liposome of Appellants' claim 11 possesses unexpected properties
sufficient to demonstrate nonobviousness. See In re Baxter-Travenol Labs.,
952 F.2d at 392.
In sum, for the reasons discussed, Appellants do not persuade us that
the preponderance of the evidence shows that Examiner erred in concluding
that the liposome recited in Appellants' claim 11 would have been obvious.
We, therefore, affirm the Examiner's rejection of claim 11 over Takagi,
Tardi '250, Lim, and Ansell. Because they were not argued separately,
claims 13, 15, 17, 26, and 30-46 fall with claim 11. 37 C.F.R.
§ 4I.37(c)(l)(iv).
OBVIOUSNESS-
TARDI '945, TAKAGI, TARDI '250, LIM, AND ANSELL
The Examiner's Prima Facie Case
In rejecting claims 11, 13, 15, 17, 26, and 30-46 over Tardi '945,
Takagi, Tardi '250, Lim, and Ansell, the Examiner cited Tardi '945 as
disclosing "various liposomal preparations containing cisplatin, a neutral
phospholipid (DSPC) an anionic lipid (DSPS) and PEG-DSPE (Examples).
The amounts of DSPC: Chol:DSPS: DSPE-PEG-2000 in Example 19 are
35:45: 10: 10." Ans. 4.
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The Examiner conceded that Tardi '945's liposomes differed from
the claimed liposomes in that the "amounts of anionic lipid taught by Tardi
['945] are lower than the claimed amounts." Id.
As evidence that the claimed liposomes nonetheless would have been
obvious, the Examiner again cited Takagi and Tardi '250 as evidence that it
would have been desirable to prepare cholesterol-free, cisplatin-containing
liposomes having the claimed combination of lipid components, in the
claimed amounts. Id.
In particular, the Examiner reasoned:
To use anionic lipid, DSPG in instant amounts with a
reasonable expectation of success would have been obvious to
one of ordinary skill in the art since the inclusion of amounts of
22 % of the anionic lipid in liposomes is a common practice in
the art for the encapsulation of cisplatin as taught by Takagi.
To decrease the amount of cholesterol in the liposomes would
have also been obvious to one of ordinary skill in the art since
the negatively charged phospholipid in liposomes would by
itself increase the blood stability and decreased amounts of
cholesterol would enable the liposome to retain the anti-
neoplastic agent more within the liposomes as taught by Tardi.
Id. at 5.
Analysis
Having carefully considered the evidence and arguments advanced by
Appellants and the Examiner, Appellants do not persuade us that the
preponderance of the evidence fails to support the Examiner's conclusion of
obviousness as to representative claim 11 over Tardi '945, Takagi, Tardi
'250, Lim, and Ansell.
We acknowledge, as Appellants contend (Appeal Br. 13-14; Reply
Br. 4--5), that Tardi '945's Example 19 uses a significant percentage of
cholesterol, and also that Tardi '945 discloses that including cholesterol in
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liposomes used as vehicles for therapeutic agents such as cisplatin can be
advantageous in certain circumstances. See Tardi '945 ,r 286 (Tardi '945's
Example 19 using 45 mole % cholesterol); id. ,r 150 ("[I]mproved
pharmacokinetics may be achieved by encapsulating the second drug in a
liposome composition with lipids of increased acyl chain length (e.g.,
DSPC/Chol).").
As discussed above, however, Tardi '250 teaches that cholesterol-free
liposomes having DSPG: DSPC in molar percentages encompassed by claim
11 have excellent in vivo drug retention properties. Tardi '250 ,r 106. As
also discussed above, Tardi '250 also teaches that including 5% DSPE-PEG
in DSPG liposomes confers anti-aggregation properties to the liposomes (id.
,r 128), as suggested by both Lim and Ansell (see Lim at 7:33--41; Ansell at
6:54--58). And Tardi '250 teaches that the anti-aggregation properties
conferred by DSPE-PEG are not present when cholesterol is present in the
liposomes in a significant amount. See Tardi '250 ,r 128.
Thus, similar to the position advanced by Appellants in the rejection
discussed above, Appellants' consideration of the isolated disclosures of
Tardi '945, Takagi, Lim, and Ansell regarding the use of cholesterol in
liposomes improperly fails to take into account the disclosures in Tardi '250
identified by the Examiner teaching that, as an alternative to cholesterol-
containing liposomes, a cholesterol-free liposome containing DSPG, DSPC,
and DSPE-PEG, in amounts encompassed by Appellants' claim 11, would
be useful as a carrier for a therapeutic agent such as the cisplatin recited in
claim 11. Appellants do not persuade us, therefore, that when the cited
references are properly viewed in combination, an ordinary artisan lacked
motivation for, or a reasonable expectation of success in, preparing a
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liposome encompassed by representative claim 11, or that the claimed
combination of elements would have been arrived at solely through
improper hindsight.
As discussed above, we are also not persuaded that Appellants have
shown sufficiently that the liposome recited in representative claim 11
exhibits unexpected properties sufficient to establish the claimed liposome' s
nonobviousness when weighed against the disclosures in the cited
references.
In sum, for the reasons discussed above, Appellants do not persuade
us that the preponderance of the evidence shows that Examiner erred in
concluding that the liposome recited in Appellants' claim 11 would have
been obvious. We, therefore, affirm the Examiner's rejection of claim 11
over Tardi '945, Takagi, Tardi '250, Lim, and Ansell. Because they were
not argued separately, claims 13, 15, 17, 26, and 30-46 fall with claim 11.
37 C.F.R. § 4I.37(c)(l)(iv).
OBVIOUSNESS-ANDRESEN, TAKAGI,
TARDI '250, LAKKARAJU, LIM, AND ANSELL
The Examiner's Prima Facie Case
In rejecting claims 11, 13, 15, 17, 26, and 30-46 over Andresen,
Takagi, Tardi '250, Lakkaraju, Lim, and Ansell, the Examiner cited
Andresen as disclosing "sPLA2 hydrolysable liposomes containing
DSPC/DSPG/DSPE-PEG 2000 and cisplatin (3.4)," that is, liposomes
containing each of the ingredients required by representative claim 11. Ans.
5.
The Examiner conceded, however, that Andresen's liposome differs
from the liposome recited in Appellants' claim 11 in that Andresen "is
unclear as to the percentages of the lipids in [the disclosed liposomes]." Id.
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The Examiner reasoned, nonetheless, based on teachings in Andresen,
that "[i]t 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 And[re]sen's teachings."
Id. at 6.
The Examiner cited Lakkaraju as disclosing cholesterol-free "anionic
liposomes containing phosphatidylcholine and phosphatidylglycerol and
containing active agents such as anti-neoplastic agents," including lipids
similar to those recited in Appellants' claim 11, in amounts comparable to
those recited in the claim. Id.
The Examiner found that an ordinary artisan would have been
motivated to "use the percentages of neutral lipids, anionic lipid and
polymer conjugated lipid in [Appellants'] claimed amounts since these
amounts are routinely used in the art for the encapsulation of cisplatin as
taught by Takagi." Id.
The Examiner concluded:
To increase the amount of negatively charged liposome and
decrease the cholesterol in the liposomes would have been
obvious to one of ordinary skill in the art since the negatively
charged phospholipid in Takagi' s liposomes would by itself
increase the blood stability and decreased amounts of
cholesterol would enable the liposome to retain the anti-
neoplastic agent more within the liposomes as taught by Tardi
250. Although Takagi teaches PEG-cholesterol and not PEG-
DSPE, one of ordinary skill in the art would be motivated to use
PEG-DSPE because Lim and Ansell teach that both PEG-
derivatives are steric barriers.
Id. at 6-7.
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Analysis
Having carefully considered the evidence and arguments advanced by
Appellants and the Examiner, Appellants do not persuade us that the
preponderance of the evidence fails to support the Examiner's conclusion of
obviousness as to representative claim 11 over Andresen, Takagi, Tardi
'250, Lakkaraju, Lim, and Ansell.
Andresen discloses that cholesterol-free liposomes containing each of
the three lipids recited in representative claim 11 are hydrolyzed by tumor
cells expressing sPLA2 in vitro, releasing the drug contained within the
liposomes at the cells' location, while also exhibiting drug-retention stability
in the absence of the tumor-specific enzyme:
We have encapsulated doxorubicin and cisplatin in liposomes
and found that we can obtain a sPLA2 generated drug release
through enzymatic hydrolysis of the liposomal membrane in
vitro.
We have analyzed liposomes with different
DSPC/DSPG/DSPE-PEG2000 lipid composition 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. We have
furthermore found that it is possible to release doxorubicin from
liposomes incubated with media from sPLA2 secreting colon
cancer cells to a high degree within a few hours as shown in
Fig. 8. In contrast, the clinically used liposomal doxorubicin
formulation, Doxil®, does not release doxorubicin, clearly
illustrating that the sPLA2 mediated drug release does not occur
for this formulation.
Andresen 87-88.
Andresen discloses that targeted delivery results similar to
those described for doxorubicin were also observed in relation to
cisplatin:
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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 (Fig. 9(b)) resulting in a pronounced
cytotoxic effect in contrast to cisplatin encapsulated in Stealth®
liposomes (SPI-077) . . . . We have furthermore investigated
the cisplatin loaded sPLA2 degradable liposomes in preclinical
studies. Improved drug efficacy was obtained in a mouse breast
cancer model (MT-3) (Fig. 10) .... We are currently
optimizing drug dose and liposome formulation to improve this
drug delivery system for specific triggering and release of
cisplatin at the tumor target site.
Id. at 8 9--90 ( citation omitted).
Andresen, thus, suggests that cholesterol-free liposomes having each
of the four ingredients recited in Appellants' claim 11 are advantageous in
that the liposomes can provide targeted delivery of the drug to certain tumor
cells, thereby improving drug efficacy. Although Andresen differs from
claim 11 in not disclosing the specific amounts of the lipids recited in the
claim, Tardi '250, as discussed above, teaches that cholesterol-free
liposomes having DSPG: DSPC in molar percentages encompassed by claim
11 have excellent in vivo drug retention properties. Tardi '250 ,r 106. As
discussed above, Tardi '250 also teaches that including 5% DSPE-PEG in
DSPG liposomes confers anti-aggregation properties to the liposomes (id.
,r 128), as suggested by both Lim and Ansell (see Lim at 7:33--41; Ansell at
6:54--58). And Tardi '250 teaches that the anti-aggregation properties
conferred by DSPE-PEG are not present when cholesterol is present in the
liposomes in a significant amount. See Tardi '250 ,r 128.
Given the teachings in Tardi '250 that a cholesterol-free liposome
containing DSPG, DSPC, and DSPE-PEG, in amounts encompassed by
Appellants' claim 11, would be useful as a carrier for a therapeutic agent
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such as the cisplatin recited in claim 11, Appellants do not persuade us (see
Appeal Br. 15-20; Reply Br. 6-8) that an ordinary artisan, informed by
Andresen's teachings regarding the advantageous properties of cholesterol-
free liposomes composed ofDSPG, DSPC, and DSPE-PEG, lacked a good
reason for, or a reasonable expectation of success in, using the amounts of
DSPG, DSPC, and DSPE-PEG taught in Tardi '250 in Andresen's
liposomes.
It might be true, as Appellants contend (Appeal Br. 17-18; Reply Br.
7-8), that the cited references provide multiple different potential liposome
formulations that would be useful for delivering cisplatin. Given Andresen's
disclosure of the advantageous properties of the claimed combination of
ingredients, however, particularly when viewed in light of the teachings in
Tardi '250 regarding the advantageous properties obtained when using the
amounts of the claimed lipids recited in claim 11, it is evident that an
ordinary artisan would have recognized that the specific combination of
ingredients recited in representative claim 11, in the claimed amounts, would
be useful for delivering cisplatin. See KSR, 550 U.S. at 417 ("[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 such an arrangement, the combination is obvious.") ( quoting
Sakraida v. Ag Pro, 425 U.S. at 282).
As to Appellants' contention that Tardi '250 teaches that "suboptimal
results were observed with a liposome containing greater than 20%
(mol/mol) of a PG lipid and less than 80% of a PC lipid" (Appeal Br. 18),
we first note that Appellants' claim 11 recites DSPG and DSPC in amounts
of "about 25% (mol/mol)" and "about 70% (mol/mol)" (Appeal Br. 22
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(emphasis added)), and therefore encompasses the 20:80 DSPG: DSPC
combination described in Tardi '250 as having "optimal circulation
longevity" (Tardi '250 ,r 107).
As noted above, moreover, the 30:70 DSPG: DSPC combination
described in Tardi '250 has circulation properties similar to the optimal
20:80 combination (see id. at Fig. lB), and regarding the results shown in
Figure lB, Tardi '250 discloses more generally that its "DSPG containing
liposomes exhibit excellent drug retention properties in vivo." Id. ,r 106.
Thus, that Appellants' claim 11 might not recite the DSPG: DSPC
ratio described by Tardi '250 as being the most preferred does not persuade
us that an ordinary artisan nonetheless would not have recognized the ratio
of lipids recited in claim 11 as being useful when preparing a cisplatin-
delivering liposome. See In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004)
("[O]ur case law does not require that a particular combination must be the
preferred, or the most desirable, combination described in the prior art in
order to provide motivation for the current invention.").
In sum, for the reasons discussed, Appellants do not persuade us that
the Examiner erred in finding, based in particular on the teachings in
Andresen and Tardi '250, that an ordinary artisan had a good reason for, and
a reasonable expectation of success in, preparing a liposome having the
ingredients required by Appellants' claim 11, in the amounts required by the
claim 11. For reasons similar to those discussed above, we are also not
persuaded that Appellants have shown sufficiently that the liposome recited
in representative claim 11 exhibits unexpected properties sufficient to
establish the claimed liposome 's nonobviousness when weighed against the
disclosures in the cited references, particularly in view of Andresen's
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teachings regarding the advantageousness of the claimed combination of
ingredients.
Accordingly, for the reasons discussed above, Appellants do not
persuade us that the preponderance of the evidence shows that Examiner
erred in concluding that the liposome recited in Appellants' claim 11 would
have been obvious. We, therefore, affirm the Examiner's rejection of claim
11 over Andresen, Takagi, Tardi '250, Lakkaraju, Lim, and Ansell. Because
they were not argued separately, claims 13, 15, 17, 26, and 30-46 fall with
claim 11. 37 C.F.R. § 4I.37(c)(l)(iv).
SUMMARY
For the reasons discussed, we affirm each of the Examiner's
obviousness rejections.
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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