Weiping Yu et al.

Patent Trials and Appeals Board

Aug 9, 2019

11508324 - (D) (P.T.A.B. Aug. 9, 2019)

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.
11/508,324 08/23/2006 Weiping Yu 2437.0070001/JMC/JGM 1844
26111 7590 08/09/2019
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
1100 NEW YORK AVENUE, N.W.
WASHINGTON, DC 20005
EXAMINER
GREENE, IVAN A
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
08/09/2019 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):
e-office@sternekessler.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte WEIPING YU and JOHN MON 1
____________

Appeal 2019-001234
Application 11/508,324
Technology Center 1600
____________

Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and
DEBORAH KATZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The claims in this appeal are directed to a method of storing a frozen
liposome formulation, where the liposomes comprise doxorubicin. The
Examiner rejected the claims under 35 U.S.C. § 112 as indefinite and 35
U.S.C. § 103 as obvious. Pursuant to 35 U.S.C. § 134, Appellant appeals the
Examiner’s determination that the claims are unpatentable. We have
jurisdiction for the appeal under 35 U.S.C. § 6(b).
The Examiner’s decision is AFFIRMED.

1 The Appeal Brief, filed Jul. 25, 2018 (“Appeal Br.”), lists Celsion
Corporation as the real party in interest. Appeal Br. 3.
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STATEMENT OF THE CASE
The claims stand finally rejected by the Examiner as follows:
Claims 7, 8, 10–13, 39, 40, 47, 48, 50–53, 62 and 63 under 35 U.S.C.
§ 112(b) or 35 U.S.C. § 112 (pre-AIA), second paragraph, as indefinite for
failing to particularly point out and distinctly claim the subject matter which
the inventor or a joint inventor regards as the invention. Ans. 3.
Claims 7, 8, 10–13, 39, 40, 47, 48, 50–53, 62, 63, and 68 under 35
U.S.C. § 103(a) as obvious in view of Abra et al. (WO 2001/05372 A2;
published, January, 2001) (“Abra”); Needham (US 6,726,925 B1, issued
April, 2004) (“Needham”); Huang et al. (US 4,927,571; published May 22,
1990) (“Huang”); as evidenced by:
Mihalko et al. (US 5,340,587, issued Aug. 23, 1994) (“Mihalko”):
Avanti, Hydro Soy PC-Avanti Number 840058,
http://www.avantilipids.com/index.php?, last visited June 2019 (“Avanti”);
LECITHIN, Kirk-Othmer Encyclopedia of Chemical Technology, 1–17
(2000) John Wiley & Sons, Inc. (“Lecithin”); and product information for
Phospholipon 90H (Phospholipid GmBH) (“Phospholipon”). Ans. 8–9.
Independent claim 7, which is reproduced below, is illustrative of the
claimed subject matter:
7. A method of storing a frozen liquid suspension liposome
formulation having
a) at least one phospholipid,
at least one lysolipid chosen from monopalmitoyl
phosphatidyl choline (MPPC), monolauryl phosphatidyl
choline (MLPC), monomyristoyl phosphatidylcholine
(MMPC), monostearoyl phosphatidylcholine (MSPC), and
mixtures thereof, and
at least one hydrophilic polymer chosen from DSPE-
mPEG-2000, DSPE-mPEG-5000, and mixtures thereof,
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wherein the phospholipid is at least one phosphatidyl
choline, and wherein the molar ratio of phospholipid to
lysolipid is from about 80:20 to about 90:10, and wherein
the hydrophilic polymer is an amount of 3 to 13 molar
percent of total liposome lipids; and
b) an encapsulated active agent that is doxorubicin,
which method comprises freezing the liquid suspension
liposome formulation to form a frozen liquid suspension
liposome formulation and storing said frozen liquid
suspension liposome formulation for at least one month,
wherein % encapsulation of said active agent is
substantially maintained over the period, and wherein there
is no significant change in the liposome size of the
formulation after thawing compared to the formulation prior
to freezing.

SECTION 112 REJECTION
The Examiner found the following phrase in claim 7 to be indefinite:
wherein % encapsulation of said active agent is substantially
maintained over the period, and wherein there is no significant
change in the liposome size of the formulation after thawing
compared to the formulation prior to freezing.

Substantially maintained
Claims 7, 39, 40, 47, 62, and 63 recite that the percent encapsulation
of the active agent is “substantially maintained” over the recited storage
period. The Examiner found that the phrase is “indefinite” under pre-AIA
35 U.S.C. § 112, second paragraph and § 112(b) because the “metes and
bounds” of the claims cannot be determined. Final Act. 3.
Appellants contend: 1) that the term “substantially” has been found to
be definite by the Federal Circuit Court of Appeals in numerous cases in
which the term has been construed (Appeal Br. 8–9); 2) the term
“substantially maintained” would be understood by one of ordinary skill in
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the art when read in the light of the Specification (Appeal Br. 7–9); and 3)
the Specification “discloses methods for measuring the degree of
encapsulation.” Appeal Br. 9.
We have considered these arguments and do not find them persuasive.
During patent examination proceedings, claim terms are given “the
broadest reasonable meaning . . . in their ordinary usage as they would be
understood by one of ordinary skill in the art, taking into account whatever
enlightenment by way of definitions or otherwise that may be afforded by
the written description contained in the applicant’s specification.” In re
Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997). Thus, while the term
“substantially” may have been found to be definite in Deere & Co. v. Bush
Hog, LLC, 703 F.3d 1349 (Fed. Cir. 2012) and Aventis Pharmaceuticals,
Inc. v. Amino Chemicals Ltd., 715 F.3d 1363, 1377 (Fed. Cir. 2013) as
asserted by Appellants (Appeal Br. 8), such determinations are not
dispositive in this appeal. Indeed, in Aventis, the court specifically held that
“same claim term can have different constructions depending upon the
context of how the term is used within the claims and specification.”
Aventis, 715 F.3d at 1373.
The Specification must first be consulted to determine whether
“substantially maintained” reasonably apprises the skilled worker of its
meaning.
The phrase “substantially maintained” does not appear in the
Specification as it was originally filed. However, the Specification discloses
that, in the past, “it has not been possible to effectively use freezing alone
for the purpose of storing liposomes.” Spec. 7 (second full paragraph). The
Specification states that “[a] formulation useful with the present invention
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can provide a composition wherein liposomes and nanoparticles can be
frozen without damaging the membrane integrity or the encapsulated
contents.” Id. The Specification further explains that the claimed
hydrophilic polymer (“DSPE-mPEG-2000, DSPE-mPEG-5000”) “affords
protection of the integrity of the liposome or nanoparticle membrane during
freezing” and “maintains the properties of any compound entrapped or
encapsulated within the nanoparticle or liposome.” Spec. 4 (last paragraph)
(emphasis added). Thus, the Specification explains that the hydrophilic
polymer recited in the claims protects the liposome during freezing and
maintains the properties of the compound present in the liposome. We note
that the term “maintains” is used in the Specification to describe the
properties of the compound trapped in the liposome, the claim uses the term
to describe how much of it is “maintained” in the liposome after freezing.
The claims do not disclose a precise numerical value for how much
“% encapsulation of said active agent” is necessary to meet the limitation
that it be “substantially maintained over the [freezing] period.” However as
explained in Sonix Technology Co., Ltd v. Publications International, Ltd.,
844 F.3d 1370, 1377 (Fed. Cir. 2017):
Because language is limited, we have rejected the proposition
that claims involving terms of degree are inherently indefinite.
Interval Licensing, 766 F.3d at 1370. Thus, “a patentee need
not define his invention with mathematical precision in order to
comply with the definiteness requirement.” Invitrogen Corp. v.
Biocrest Mfg., L.P., 424 F.3d 1374, 1384 (Fed. Cir. 2005)
(citation omitted). Indeed, “[c]laim language employing terms
of degree has long been found definite where it provided
enough certainty to one of skill in the art when read in the
context of the invention.” Interval Licensing, 766 F.3d at 1370.

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Based on the ordinary meaning of “substantially”2 and “maintained,” 3
and the Specification disclosure discussed above, one of ordinary skill in the
art would understand that the liposome is protected during freezing by
keeping it largely, but not wholly, in its existing state. However, this
meaning is not helpful by itself in apprising one of ordinary skill in the art of
what actual values fall within the scope of the claim.
The Specification provides examples of values that one of ordinary
skill in the art would understand to fall within the scope of a “substantially
maintained” percent encapsulation of doxorubicin. Specifically, the
Specification discloses examples in which the liposomes were “stable” over
a three-month period and “[n]o significant changes in . . . encapsulation
[was] . . . observed over this time frame.” Spec. 12. Table 2 shows that at
t=0, frozen liposomes showed 99.5% encapsulation of doxorubicin, and that
after being frozen and thawed three times it was 99.4% at t=0, 99.5% at one-
week, 99.5% at one-month, and 98.2% encapsulation at three-months. Spec.
13 (Table 2). While we do not limit the claims to these values,4 they do
provide guidance as to what values represent “% encapsulation of said active
agent is substantially maintained over the [storage] period.”

2 “[B]eing largely but not wholly that which is specified.”
https://www.merriam-webster.com/dictionary/substantial (last accessed July
19, 2019).
3 “[To] keep in an existing state.” https://www.merriam-
webster.com/dictionary/maintain (last accessed July 19, 2019).
4 Limitations from the Specification are not imported into the claims and “a
particular embodiment appearing in the written description may not be read
into a claim when the claim language is broader than the embodiment.”
SuperGuide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875 (Fed. Cir.
2004).
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As to values lower than those reported in Table 2, there is no helpful
guidance in the Specification. The Specification teaches that the invention
addresses “leakage problems” that occur during a freezing cycle. Spec. 2:1–
3; Appeal Br. 7–8. The Specification, however, does not teach unacceptable
levels of leakage of the active agents nor leakage amounts that would be too
high and not meet the limitation of “% encapsulation of said active agent is
substantially maintained over the [storage] period.” In other words, the
Specification does not compare the % encapsulation to liposomes with and
without the hydrophilic polymer to determine what one of ordinary skill in
the art would understand values of encapsulation when the liposomes are not
protected during freezing.
In the Reply Brief, Appellants argue that Abra “discloses methods for
freezing and storing liquid liposome suspensions which result in a change in
% encapsulation of 12% and 5% after only 1 month of storage at -20 °C.”
Reply Br. 4. Appellants contend that “the claimed methods result in at least
a 2-fold to 6-fold increase in storage stability.” Id. Thus, Appellants
apparently rely on Abra to define an amount of active agent leakage that
would not be considered by those skilled in the art to be a substantially
maintained amount of encapsulated agent over the storage period.
However, Appellants did not establish that the liposome formation in
Abra possessed the leakage problem described in the Specification, i.e., that
Abra’s liposomes are representative of the prior art liposomes that leaked
active agent upon freezing. Appellants attempt to fill this gap by citing to
the prior art “Doxil” formulation which Appellants contend has the same
components as Abra’s liposomes. Reply Br. 4. However, while Doxil is
disclosed in the Specification, and thus could be understood by one of
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ordinary skill in the art as possessing the stated leakage problem (Spec. 7
(second full paragraph)), Appellants did not provide adequate evidence that
the Doxil disclosed in the Specification is the same formulation as the one
described in Abra. Specifically, Abra discloses Doxil in its background
section as containing sucrose, a cryoprotectant, to protect against freezing
damage (Abra 2:16–20), but characterizes its own invention as liposomes
suspended in a medium comprising a “water soluble salt and a
cryoprotectant [such as sucrose], wherein the external medium has an outer
osmolarity higher than the inner liposome osmolarity thereby establishing a
lower inside/higher outside osmotic gradient across each liposome” (Abra
3:10–14; emphasis added). Appellants did not provide evidence that Doxil
is suspended in such a medium. To the contrary, it appears that Abra
considered its invention as a solution to the problem of prior art
formulations, such as Doxil.
Because Appellants did not establish by adequate evidence that the
claimed liposome formulation is an improvement over the formulation
described in Abra, we are not persuaded that the values described in Abra of
a 5% and 12% change in encapsulation of the active agent upon freezing are
necessarily excluded by the claims. We know that the values in Table 2 of
the Specification fall within the claim scope, but the Specification does not
apprise one of ordinary skill in the art how different the encapsulation values
can be from those reported in Table 2 and still be within the scope of the
claim, i.e., what is largely, but not wholly different from the values disclosed
in the table.
In sum, while we recognize that the phrase “substantially maintained”
is a term of approximation that does not by itself render the claim indefinite
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under 35 U.S.C. § 112, we find that Appellants did not establish by adequate
evidence how those of skill in the art would have construed the phrase in
light of the Specification of the application involved in this appeal.

No significant change
Claim 7 also recited that “there is no significant change in the
liposome size of the formulation after thawing compared to the formulation
prior to freezing.” Claims 39, 40, 47, 62, and 63 have a similar limitation.
The Examiner found the phrase to be indefinite because the phrase is
“unclear”, “subjective”, and does not “allow the public to determine the
scope of the claim.” Final Act. 4–5.
Appellants argue that “the specification sets forth examples
illustrating what constitutes a ‘significant change in liposome size of the
formulation after thawing compared to the formulation prior to freezing.’”
Appeal Br. 10. Appellants explain:
As shown in Table 1 of the specification, the size of the
doxorubicin loaded liposomes of the present invention (labeled
as “Liposome with MPEG”) changed from 107 nm to 105 nm
after 3 months, i.e., about 2% change in size, which is not a
significant change. In contrast, the size of the doxorubicin-
loaded liposomes that fall outside the claimed invention
(labeled as “Liposome without MPEG”) changed from 121 nm
to 137 nm after just 3 days, i.e., about 13% change in size.
Appeal Br. 10. Thus, a 13% change is considered to be a significant change
in size and excluded from the scope of the claim.
Appellants also cite the disclosure in Table 2 of the Specification to
support the interpretation of the disputed phrase:
In addition, Table 2 of the specification lists the size of
liposomes prior to freezing, thawed after 1 week of storage,
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thawed after 1 month of storage, thawed after 3 months of
storage, and subject to three freeze-thaw cycles, being 97.0 nm,
98.9 nm, 96.7 nm, 97.8 nm, and 98.3 nm, respectively. The
largest liposome size change is from 97.0 nm to 98.9 nm, i.e., a
size increase of about 2%, which is not a significant change.
Appeal Br. 10.
The` Specification referred to the results in Table 2 as showing “[n]o
significant changes in vesicle size, doxorubicin content, encapsulation or
lipids content were observed over this time frame.” Spec. 12.
Thus, based on the disclosure in the Specification showing values
which show no significant change in vesicle size and those that do, we agree
with Appellants that there is adequate evidence that the phrase “no
significant change in the liposome size” when read in the light of the
Specification reasonably apprises one of ordinary skill in the art of the scope
of the claim.
As to the Examiner’s objection to claim 47 because “(2) it is unclear
whether the claim requires ‘at least two freeze-thaw cycles’, and if so when
the ‘at least two freeze thaw cycles’ should be performed” (Final Act. 4), we
find it would be clear to one of ordinary skill based on the plain language in
the claim that the recited limitation is a property of the liposomes and does
not have to be performed as part of the method.

Summary
The rejection under 35 U.S.C. § 112 of claims 7, 39, 40, 47, 62, and
63 is affirmed because the phrase “wherein % encapsulation of said active
agent is substantially maintained over the period” does not reasonably
apprise of ordinary skill in the art of the scope of the claim. Separate
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arguments for claims 8, 10–13, 48, 50–53, and 68 were not provided.
Consequently, these claims fall as well. 37 C.F.R. 41.37(c)(iv)(1).

REJECTION BASED ON ABRA
Claim 7 is directed to a liposome formulation comprising a
phospholipid, a lysolipid selected from a list of specific lysolipids, and a
hydrophilic polymer selected from a list of specific polymers. Doxorubicin
is encapsulated in the liposome. The claim recites that “the molar ratio of
phospholipid to lysolipid is from about 80:20 to about 90:10, and wherein
the hydrophilic polymer is an amount of 3 to 13 molar percent of total
liposome lipid.”
The Examiner found that Abra discloses a liposome composition
having a resistance to freeze/thaw damage which comprises a phospholipid
(hydrogenated soy phosphatidyl choline (“HSPC”)) and a hydrophilic
polymer (mPEG-DSPE), meeting the corresponding limitations of claim 7.
Final Act. 10. While Abra does not expressly recite that the liposome
comprises a lysolipid, the Examiner provided evidence that a lysolipid is
present in HSPC in the amounts required by the claim. Id. at 11–13. The
Examiner also found that Abra also discloses that doxorubicin can be present
in its liposome formulation. Id. at 15.
The Examiner found that Needham discloses a liposome formulation
with all three of the recited component in the same ratio as claimed. Final
Act. 14 (citing Example 5 of Needham).
The Examiner determined it would have been obvious to apply Abra’s
freezing method to Needham’s liposome formulation because Abra disclose
that “it is important that liposome preparations be stored for extended
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periods of time under appropriate conditions.” Final Act. 15. The Examiner
found that “the low temperature would prevent the degradation of the
composition while in storage; furthermore, storing the composition would
provide a convenient means of managing the supply and demand of the
manufactured product.” Id. at 15–16.

Freezing
Appellants contend that “that Abra’s attempts to prepare liposomes
that are resistant to freezing damage were not successful.” Appeal Br. 17.
Appellants state that “[t]herefore, Abra does not enable a person of ordinary
skill in the art to successfully freeze and store liposomes, let alone liposomes
with a different bilayer composition and a different active agent.” Id. at 18.
Appellants state:
However, while Abra may have considered freezing liposomes
to be beneficial, a person of ordinary skill in the art would not
have been motivated to do so by Abra, because Abra was not
able to successfully freeze and store liposomes. As discussed
above, Abra discloses that its liposomes were less stable (more
leakage of cisplatin) when being stored at-20 °C as compared
to being stored at +20 °C, or at 2-8 °C.
Appeal Br. 19.
Appellants also argue:
Further, at the time of filing the present application, prolonged
freezing (more than 1 month) was warned to have a deleterious
effect on commercially available doxorubicin liposomes (see
DOXIL ® labeling, a copy of which was submitted in our
Reply and Amendment filed November 28, 2016 (Exhibit A)).
The DOXIL ®liposomes contain mPEG-DSPE, HSPC, and
cholesterol, the same components as Abra's liposomes. Thus,
not only does Abra demonstrate that the liposomes are not
stable for more than a month when frozen, a person of ordinary
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skill in the art would not have been motivated to store a frozen
liquid suspension liposome formulation of doxorubicin over a
prolonged period upon reading the DOXIL® labeling.
Appeal Br. 18.
This argument is not persuasive.
First, Appellants did not provide persuasive evidence that Abra does
not enable one of ordinary skill in the art to freeze and store liposomes. To
support their argument, Appellants identify the data disclosed in Table 10 of
Abra, stating that it “shows that the liposomes disclosed therein were less
stable (i.e., more leakage of cisplatin) when being stored at -20 °C as
compared to being stored at +20 °C or 2-8 °C.” Appeal Br. 15.
The data in Table 10, as discussed by Appellants, show that the
liposome stability at 20 °C and 2–8 °C is better than stability at freezing.
However, Appellants overlook the fact that Abra does not show the results
from the control which lacks the soluble salt and cryoprotectant said by
Abra to protect the liposomes from freeze damage. Abra 3:10–14.
Specifically, Abra lists a control in Table 9 which lacks sucrose, a
cryoprotectant, and NaCl (the soluble salt), but did not disclose the results of
freezing the control formulation in Table 10 which follows. Thus, it cannot
be determined from the table, alone, whether Abra’s formulation comprising
the cryoprotectant and salt in the disclosed concentrations is an improvement
over the control, which lacks these protective agents.
Appellants compare the room temperature results to the results
obtained after freezing, but the proper comparison is between a control and
the formulation comprising the salt and cryoprotectant, with both subjected
to freezing to show how Abra’s method protects against freezing. The
question is not whether the frozen liposomes are less stable than those at
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cold and room temperatures, but whether the salt and cryoprotectant protect
the liposome formulation during freeze-thaw. While the data is not shown in
Table 10, Abra makes numerous statements that a formulation comprising
the soluble salt and cryoprotectant is protective against freeze-thaw damage.
Following Table 10, Abra states:
The stability tests indicate that a liposome composition having
an osmotic gradient across the lipid bilayer, wherein the outer
liposome osmolarity is higher than the inner osmolarity,
provides additional protection from accidental freezing damage
during product shipment, with negligible effect on product
stability.
Abra 20:7–11.
The entire disclose of Abra is about resistance to freeze/thaw damage
and improved protection upon freezing and thawing. Abra is titled “A
liposome composition having resistance to freeze/thaw damage.” Abra 1:1–
2. See also 1:5–7; 2:23–26.
Abra also specifically discloses that a liposome formulation
comprising the salt and cryoprotectant showed improved freezing resistance
in comparison to formulation with the cryoprotectant alone:
In another aspect, the present invention provides a liposome
composition having improved protection from freeze/thaw
damage, as evidenced by a reduction in vesicle fusion and a
reduction in the loss of entrapped contents, when compared to
the protection provided by the presence of a cryoprotectant
alone.
Abra 2:27–3:2.
Based on the explicit disclosure in Abra that the salt and
cryoprotectant protect liposomes against freezing and Abra’s own comments
on the data in Table 10, we find Appellants’ argument that Abra does not
enable a liposome formulation to be protected against freeze-thaw to not be
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supported by the evidence in this record. Because this argument is the basis
for Appellants’ contention that there would have been no reason to apply
Abra’s method to Needham’s liposomes (Appeal Br. 15–16), we conclude
that Appellants did not demonstrate that the Examiner erred in finding a
reason to combine Abra and Needham.

Expectation of success
Appellants contend that a person of ordinary skill in the art would not
have had a reasonable expectation of success of achieving the claimed
invention. Appeal Br. 20.
First, Appellants argue that the cisplatin described in Abra is a
completely different molecule than doxorubicin recited in all the rejected
claims and “thus ha[s] different chemical and physical properties.” Appeal
Br. 20. Appellants state:
For example, cisplatin has a water solubility of about 2 mg/ml
at 37 °C, whereas doxorubicin has a water solubility of about
20 mg/ml at room temperature. As such, they have different
affinities to the lipid membranes, and are formulated
differently. Accordingly, a person of ordinary skill in the art
would not have expected doxorubicin-containing liposomes to
behave in the same manner as cisplatin-containing liposomes
when frozen.
Id.
This argument does not persuade us that the Examiner erred. Abra
expressly teaches that doxorubicin is an exemplary cytotoxic agent that can
be entrapped in a liposome. Abra 23:3–6. Thus, while Abra’s working
example is of a liposome with entrapped cisplatin (Abra 28:23), Abra
expressly contemplated that liposomes comprising doxorubicin and other
agents (id. at 23:4–29) would be protected against freeze-thawing utilizing a
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cryoprotectant and soluble salt. As explained by the Examiner, Abra
“teaches that it is the osmolarity gradient between the liposome contents
(inner medium) and the suspension medium (external medium) that is
important in forming freeze/thaw stable liposome compositions not the
active ingredient (abstract).” Ans. 19. Appellants did not provide adequate
evidence that the active agent, itself, when incorporated into a liposome
would change the ability of the cryoprotectant and salt to protect the
liposome against freeze-thaw damage.
Second, Appellants argue that Abra’s liposome formulations comprise
cholesterol “which are drastically different from Needham's cholesterol-free
liposome formulations.” Appeal Br. 20. Appellants provided a declaration
under 37 C.F.R. § 1.132, by Francis C. Szoka (filed July 6, 2010, “Szoka
Decl.”) “in which Dr. Szoka stated that the differences in chemical structure
between cholesterol and phospholipids affect the rigidity and the
permeability of liposome formulations containing them.” Appeal Br. 18.
Based on the difference in properties, Dr. Szoka states:
not only would a skilled scientist not have been able to predict
that the liposome formulations of Tagawa (having cholesterol)
and Needham (having phospholipids but no cholesterol) would
behave in exactly the same way after freeze-thaw, i.e., retain the
same amount of encapsulated drug, retain particle size, etc.,
he/she would not have been able to predict that the non-frozen
liposomes formulations of Tagawa and Needham would behave
in exactly the same way.
Szoka Decl. ¶ 11.
Dr. Szoka’s opinion is based a publication “Tagawa” which is not
cited in the rejection in this Appeal.
Dr. Szoka further states in his declaration that it was known that
freezing would have a deleterious effect on Doxil, a commercially available
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liposome formulation comprising doxorubicin. Szoka Decl. ¶ 13. Dr. Szoka
concludes that “skilled scientist would not have been motivated to freeze and
store nanoparticle formulations for more than one month without risking
adversely affecting the encapsulated drug product, based on the teachings of
this document.” Id. Dr. Szoka further states in his declaration, citing the
Fransen publication, that it is his opinion “that neither the cited references
nor the knowledge in the art at the time the application was filed provides
the skilled scientist with a reasonable expectation that one could successfully
freeze and stably store nanoparticle formulations with the ingredients listed
in the claims for a period of at least one month without adversely affecting
the encapsulated drug product and without inducing significant changes in
nanoparticle size and % of drug entrapment.” Id. ¶ 15.
Dr. Szoka’s declaration is not persuasive. Dr. Szoka does not state in
his declaration that the Abra publication was considered by him in making
these statements about a lack of reasonable expectation of success. Abra is
not listed in the publications said to have been considered by him in his
declaration. Szoka Decl. ¶¶ 2, 5, 12. Dr. Szoka did not address the issue in
the appealed rejection of whether Abra’s method of using a water soluble
salt and cryoprotectant to protect against freeze-thaw would have been
reasonably expected by one of ordinary skill in the art to protect Needham’s
liposomes which lack cholesterol. The Doxil formulation, described by Dr.
Szoka, is not cited in the current rejection. Consequently, Dr. Szoka’s
opinions about the lack of a reasonable expectation of success is not
persuasive because the actual prior art cited in the obviousness rejection in
this appeal was not addressed.
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Abra, itself, does not limit its liposomes to the components
exemplified in its examples, but refers generally to liposomes throughout its
disclosure without identifying the specific components of them. The
disclosure by Abra of its method of using protecting liposomes against
freeze-thaw damage contains no limitation as to the composition of the
liposomes. Abra 4:7–18. Rather, Abra describes its invention as relating to
liposome compositions having “an osmotic gradient across the liposome
lipid bilayer, wherein the suspension medium external to the liposome has a
higher osmolarity than the osmolarity of the medium entrapped within the
liposome.” Id. at 6:7–12. Thus, we find no evidence that a different
liposome formulation than the one exemplified in Abra, would not have
been reasonably expected to be protected against freezing utilizing Abra’s
method.
Unexpected results
Appellants argue that the inventors “unexpectedly discovered that by
practicing the claimed method, the encapsulation of doxorubicin (active
agent) was substantially preserved over 3 months.” Appeal Br. 18. Citing
Example 2 and Table 2 in the Specification, Appellants state that “after 3
months, the doxorubicin content of the liposomes only dropped from 99.5%
encapsulation (frozen at t=0) to 98.2% encapsulation. (Application as-filed,
pages 12-13, Table 2).” Id. Based on the labeling of Doxil, Appellants
contend that one of ordinary skill in the art would have expected prolonged
freezing to have a deleterious effect on a liposome preparation having the
same components present in Abra’s liposomes, namely mPEG-DSPE,
HSPC, and cholesterol. Id.
Appeal 2019-001234
Application 11/508,324

19
Doxil is not the same liposome formulation as described in Abra. As
discussed above, we have not been directed to evidence that Doxil contains
the salt and cryoprotectant described in Abra as conferring resistance to
freeze-thaw. To the contrary, it is disclosed in the background section of
Abra that Doxil has a sugar for protection against freezing damage, but
makes no mention of the soluble salt in the amounts necessary to achieve
freeze-thaw resistance. Abra 2:16–20. Thus, we are not persuaded that one
of ordinary skill in the art would have found it unexpected that liposomes
could resist freezing damage, particularly when Abra provides a method to
do so.
Example 2 in the Specification shows the effect of freezing on a single
liposome preparation comprising DPPC, MSPC, and DSPE-mPEG-2000.
Spec. 11 (Example 1), Spec. 12 (Example 2), Spec. 13 (Table 2). However,
there is no comparison to the closest prior art. When unexpected results are
used to demonstrate the non-obviousness of a claimed invention, the results
must be “surprising or unexpected” to one of ordinary skill in the art when
considered in the context of the closest prior art. See In re Soni, 54 F.3d
746, 750; see also Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d
1317, 1322 (Fed. Cir. 2004) (A showing of “new and unexpected results”
must be “relative to the prior art.”); In re Baxter Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence
of nonobviousness, the results must be shown to be unexpected compared
with the closest prior art.”). Thus, here, Appellants did not compare the
results to the closest prior art, namely, the Abra publication.
In addition to this, unexpected results must be “commensurate in
scope with the degree of protection sought by the claimed subject matter.”
Appeal 2019-001234
Application 11/508,324

20
In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). Appellants have only
shown the results from a single liposome preparation, but the scope of the
claim includes other liposome formulations that have have a different
phospholipid, lysolipid, and hydrophilic polymer. Appellants did not
demonstrate that the reported results would be obtained using other liposome
formulations within the scope of the claim.
Accordingly, we agree with the Examiner that Appellants’ evidence of
the unexpected results is insufficient to establish the nonobviousness of the
claimed subject matter.
Summary
The obviousness rejection of claim 7 is affirmed. Separate arguments
for claims 8, 10–13, 39, 40, 47, 48, 50–53, 62, 63, and 68 were not provided.
Consequently, these claims fall with claim 7. 37 C.F.R. 41.37(c)(iv)(1).

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)(1)(iv).

AFFIRMED