CuriNanoRx, LLC

Patent Trials and Appeals Board

Apr 12, 2021

2020005497 (P.T.A.B. Apr. 12, 2021)

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.
15/593,586 05/12/2017 Indu JAVERI 21562-0103 5211
164114 7590 04/12/2021
Verrill Dana, LLP
One Federal Street, 20th Floor
Boston, MA 02110
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
04/12/2021 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):
kwalmsley@verrilldana.com
lhymel@verrilldana.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte INDU JAVERI and
KALIAPPANADAR NELLAIAPPAN
Appeal 2020-005497
Application 15/593,586
Technology Center 1600
Before DONALD E. ADAMS, RYAN H. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims directed to a method of incorporating
hydrophobic therapeutic agents into preformed liposomes as being obvious.
Oral argument was heard on March 23, 2021. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.

1 We use the term “Appellant” to refer to “applicant” as defined in 37 C.F.R.
§ 1.42. Appellant identifies the real party in interest as CuriNanoRx, LLC.
Appeal Br. 3.
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STATEMENT OF THE CASE
“Liposomes are microscopic lipid vesicles that are composed of a
central aqueous cavity surrounded by a lipid membrane formed by
concentric bilayer(s) (lamellas).” (Spec. 1.) “Liposomes can be unilamellar
vesicles (“UMV”), having a single lipid bilayer[.]” (Id.) “The properties of
the liposomes depend, among other factors, on the nature of the
constituents.” (Id. at 2.) “There are numerous combinations of
phospholipids, optionally with other lipids or cholesterol, in an aqueous
medium to obtain liposomes. Depending on the method of preparation and
the lipids used, it is possible to obtain vesicles of different sizes, structures,
and properties.” (Id.)
“The bioavailability of a pharmaceutical drug depends largely in part
on the solubility and stability of the drug.” (Id. at 1.) It is known that
encapsulating drugs in a liposome bilayer can be accomplished to improve
its biovailability. (Id.; see also id. at 3–4 (citing prior art methods).)
Appellant’s invention is directed to methods for incorporating a hydrophobic
therapeutic agent into liposomes. (Id. at 5.)
Claims 1 and 25, reproduced below, are illustrative of the claimed
subject matter:
1. A method of incorporating a hydrophobic therapeutic agent
into preformed liposomes, the method comprising the steps of:
(a) providing (i) a liposome suspension comprising a
plurality of preformed unilamellar liposomes having an average
size less than about 100 nm suspended in an aqueous medium,
the liposomes comprising lipid forming a lipid bilayer phase, and
(ii) a solid form of a hydrophobic therapeutic agent;
(b) adding the solid form of the hydrophobic therapeutic
agent to the liposome suspension, thereby forming a liposome-
drug suspension;
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(c) homogenizing the liposome-drug suspension;
whereby the hydrophobic therapeutic agent is
incorporated into the lipid bilayer phase; and
(d) lyophilizing the homogenized liposome-drug
suspension;
wherein step ( c) is performed at a temperature at or below
ambient temperature; and
wherein steps (b) and (c) are performed in the absence of
solvent and in the absence of surfactant.

25. A method of incorporating a hydrophobic therapeutic agent
into preformed liposomes, the method comprising the steps of:
(a) providing (i) a liposome suspension comprising a
plurality of preformed unilamellar liposomes having an average
size less than 100 nm suspended in an aqueous medium, the
liposomes comprising lipid forming a lipid bilayer phase, and (ii)
a therapeutic agent concentrate comprising a hydrophobic
therapeutic agent dissolved in a liquid medium comprising or
consisting of solvent;
(b) adding the therapeutic agent concentrate to the
liposome suspension to form a liposome-drug suspension,
wherein the total concentration of solvent in the liposome-drug
suspension is not more than 10 weight percent;
(c) homogenizing the liposome-drug suspension;
whereby the hydrophobic therapeutic agent is incorporated into
the lipid bilayer phase; and
(d) lyophilizing the homogenized liposome-drug
suspension;
wherein step (c) is performed at a temperature at or below
ambient temperature; and
wherein steps (b) and (c) are performed in the absence of
surfactant.
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REFERENCES
The prior art relied upon by the Examiner is:
Name Reference Date
Hope US 2002/0094344 A1 July 18, 2002
Daftary et al. US 2005/0142178 A1 June 30, 2005
Desai et al. US 2007/0178147 A1 Aug. 2, 2007
Leigh et al. US 2008/0131499 A1 June 5, 2008
Haas et al. US 2011/0002851 A1 Jan. 6, 2011
Ali et al. WO 2008/127358 A22 Oct. 23, 2008

REJECTIONS
Claims 1, 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51 are
rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Leigh
alone or in combination with WO ’358. (Non-Final Action 2).
Claims 1, 4–8, 11–16, 18, 20–24 are rejected under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over Leigh, Desai, and Hass.
(Non-Final Action 4.)
Claims 1, 4–8, 11–31, 33–37, and 40–45, 47, 49–513 are rejected
under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over WO ’358
alone or in combination with Daftary and Leigh. (Non-Final Action 5.)
Claims 25–31, 33–37, 40–45, 47, and 49–51 are rejected under pre-
AIA 35 U.S.C. § 103(a) as being unpatentable over WO ’358 by itself or in
combination with Daftary, Leigh, and Hope. (Non-Final Action 8.)

2 Although the Examiner and Appellant have called it “WO,” “WO 2008,”
and “Jina,” herein we refer to this reference as “WO ’358.”
3 As claims 46 and 48 have been canceled and claims 52–54 are not of
record, we find the Examiner’s statement of rejection including those claims
to be an inadvertent error.
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Claims 25–31, 33–37, 40–45, 47, and 49–51 are rejected under pre-
AIA 35 U.S.C. § 103(a) as being unpatentable over Hope, Desai, and Hass.
(Non-Final Action 9.)
Claims 1, 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51 are
rejected on the ground of non-statutory double patenting as being
unpatentable over claims 1–5 of U.S. Patent No. 8,591,942. (Non-Final
Action 11.)
DISCUSSION
I. Obviousness Rejections Involving Independent Claim 1
The Examiner makes three separate rejections of claim 1 over varying
combinations of the prior art. However, two of the rejections rely on the
combination of Leigh and WO ’358 prior art. We address that combination
below.
Appellant’s claim 1 requires homogenization take place at or below
ambient temperature and that the addition of a hydrophobic agent to a
liposome suspension and homogenization take place in the absence of both a
solvent and a surfactant.
The Examiner finds that Leigh teaches a method of loading a
hydrophobic drug into preformed liposomes where the lipophilic drug may
be in solution such as ethanol or may be present as a lyophilized powder
which is added to a liposomal suspension to incorporate the drug compound
in the liposome. (Non-Final Action 2–3, 4 (citing Leigh “Examples, 7 and 8
in particular”); id. at 4 (“Leigh clearly teaches that the hydrophobic drug is
added as a solid”); Ans. 10 (citing Leigh ¶¶ 32, 49).) The Examiner notes
that Leigh teaches that liposomes sizes are less than 40 nm in diameter
(Non-Final Action 2) and teaches that preparation by high pressure
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homogenization or extrusion “implies small unilamellar liposomes” (Ans. 10
(citing Leigh ¶35)). The Examiner finds further that “[a]ssuming that the
gentle swirling of the liposomal mixture is not homogenization as argued by
applicant, one of ordinary skill in the art would use any suitable means such
as high pressure homogenization or extrusion which are also taught by Leigh
in paragraph 0035 to obtain the total incorporation of the hydrophobic
therapeutic agent into the lipid bilayer since these techniques are known in
the art to reduce the sizes of liposomes as evident from Leigh.” (Non-Final
Action 3; see also Non-Final Action 4–5; Ans. 10.)
According to the Examiner, “[w]hat is lacking in Leigh is the
lyophilization of liposomes.” (Non-Final Action 3, 4.) The Examiner finds,
however, that lyophilization of liposomes was common practice in the
liposomal art for storage purposes, citing as examples, WO ’358, Desai, and
Haas. (Non-Final Action 4, 5.) The Examiner concludes that it would have
been obvious to one having skill in the art to lyophilize the liposomes of
Leigh “since lyophilization of liposomes for storage purposes is a common
practice in the art as evident from WO [’358].” (Id.) Regarding Desai, the
Examiner finds that it teaches “that liposomes loaded with hydrophobic
drugs can be stored after a lyophilization for years or more.” (Id. at 5.) The
Examiner notes that Haas teaches lyophilization of a paclitaxel containing
liposome that has more than 18 month shelf-life. (Id.) The Examiner also
notes that Haas teaches that it was known in liposomal preparation art that
such preparations can be obtained by homogenizing the hydrophobic
compound, where homogenization includes “mechanical mixing, stirring,
[and] high-pressure homogenization.” (Id.)
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The Examiner finds that WO ’358 teaches encapsulation in liposomes
of at least one hydrophobic drug, such as amphotericin or paclitaxel, with or
without deoxycholate as a solvent, and subsequently lyophilizing the drug
loaded liposomes. (Id. at 6, 3.) The Examiner explains that the WO ’358
process in the examples involves suspension of the drug in an aqueous
medium and mixing that with cholesteryl sulfate and soya
phosphatidylcholine, which mixture is then subject to high pressure
homogenization and that the temperature is either room temperature or at a
desired temperature. (Id.) The Examiner finds that WO ’358 teaches that
cholesterol can be used as an alternative to cholesteryl sulfate (Ans. 10
(citing WO ’368 16:10–13).) Moreover, the Examiner finds that “[i]t is
well-known in the art that cholesterol is [a] liposomal membrane rigidifying
agent and therefore, it would have been obvious to one of ordinary skill in
the art that [WO ’358] is using cholesterol or its derivatives as a membrane
rigidifying agent.” (Id. at 10–11)
The Examiner states that the process of WO ’358 differs from the
claimed process in that the encapsulation of the hydrophobic drug and
hydration of phospholipid occurs simultaneously in WO ’358, when the
phospholipid is hydrated with an aqueous medium and the hydrophobic
active. (Non-Final Action 6.) The Examiner explains that the lipid bilayer
forms quickly when the phospholipid is hydrated. (Id. at 5–6.) And, in any
event, the Examiner finds that Leigh and Daftary teach that hydrophobic
active agents could be loaded into liposomes after the formation of those
liposomes. (Id. at 7.)
In light of the teachings of the references, the Examiner finds that one
of ordinary skill in the art would have found it obvious to use a high pressure
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homogenization technique to incorporate the hydrophobic drug compound in
Leigh because WO ’358 teaches using such a technique. (Id. at 3.) The
Examiner finds that it would have been obvious to add the hydrophobic drug
compound to preformed liposomes in WO’358 in light of the fact that both
Leigh and Daftary teach doing so is known in the art. (Id. at 7.)
We agree with the Examiner that Leigh in combination with WO’358
renders claim 1 obvious.
WO ’358 teaches that “there is a need for processes for preparation of
lipid based formulations without the need for . . . organic solvents.” (WO
’358 ¶ 2.) WO ’358 also teaches a method in which the active ingredient
can be added “after the preparation of the liposome system,” and that the
liposome formulation is prepared without using organic solvent. (Id. ¶¶ 13,
37 (“For example, in some embodiments, the active ingredient in dry form
may be dispersed or emulsified into an aqueous unloaded liposome
system”), 43 (“[t]he invention method is simple, rapid and less expensive
method to produce organic solvent-free aqueous liposome systems”).)
WO ’358 teaches that a suspension of phospholipid, active compound and
cholesteryl derivative in water or buffer is homogenized or sonicated at any
desired temperature range from 20–60 ºC. (Id. ¶¶ 114–116.)
Leigh teaches a “method of loading poorly soluble compounds into
previously formed, aqueous suspensions of lipid particles” where the
“average lipid particle size is below 1000 nm, preferably below 300 nm.”
(Leigh ¶ 69.) Indeed, Leigh further states that it is most preferred that the
phospholipid containing liposome be below 100 nm. (Id. ¶ 35.) Leigh notes
that:
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Surprisingly it has been found that an aqueous suspension
of finely divided lipid particles, i.e. preformed particles
comprising at least one membrane lipid as the major component
or constituent has a much higher capacity for solubilising
lipophilic compounds if the compound is added to already
formed lipid particles and not dissolved in a lipid solution
during formation of the particles, which is usually the case in
the prior art.
(Id. ¶ 33; see also id. ¶ 22.) Leigh further explains that “[b]ecause of the
lipophilicity of the compound and the extensive surface area presented by
the discrete lipid particles, the compound partitions preferentially into the
lipid and forms molecular associates.” (Id. ¶ 32 (emphasis added).)
Although Leigh teaches that the “fully loaded lipid suspension” may
be prepared just prior to use, it also discloses that for those “compounds that
are more stable,” “the lipid suspension may be lyophilised.” (Id. ¶ 36.)
Example 8 of Leigh describes the method generally whereby a dry
form of a lipophilic drug is mixed with an aqueous dispersion of lipid
particles to thereby “load the lipophilic drug” into the lipid particle. (Leigh
¶¶ 67–68 (Example 8).) Though the method is only generally described in
Example 8, we understand from the description at paragraphs 22 and 32–33
that the preferential partition of the lipophilic drug into a lipid particle
occurs “spontaneously and instantaneously” when the aqueous suspension of
finely divided preformed lipid particles comprising at least one membrane
lipid as the major component or constituent when the lipophilic drug is
added without first being dissolved in a lipid solution during formation of
the particles.
Although Leigh indicates that “[o]nly minimum agitation is required”
(Id. ¶ 69), we note that Leigh also teaches that association efficiency may
only be 80%. (Id. ¶ 36). Thus, we agree with the Examiner that it would
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have been obvious to homogenize the mixture such as was known to be done
for liposome drug loading (see, e.g., WO ’358 ¶ 114). We understand that
such homogenization, which involves shear stress, would facilitate
temporary disruption of the lipsome bilayer of the lipid particles. (See, e.g.,
Hope ¶ 7.) Moreover, we agree with the Examiner that it would have been
obvious to lyophilize the loaded liposome suspension as suggested in Leigh
(Leigh ¶ 36), and as taught by other prior art references, such as WO’358 for
longer term storage of the loaded liposome (WO ’358 ¶ 44).
Appellant argues that the Examiner’s rejection of claim 1 combining
Leigh and WO ’358 is in error because WO ’358 “requires the use of
cholesteryl sulfate, a surfactant, to disrupt lipid bilayer structure to aid the
incorporation of hydrophobic drugs” and that “the Examiner wrongly asserts
that cholesteryl sulfate is not a surfactant” when that compound “has a
negatively charged head group and a hydrophobic portion (acylated sterol
ring), which clearly fits the structural paradigm for surfactants.” (Appeal
Br. 9, 11, 12; Reply Br. 5, 6.) In addition, Appellant argues that Example 8
of Leigh, “[t]he only portion of Leigh that is marginally relevant” to the
claimed invention “which requires incorporation of drug into preformed
liposomes” (id. at 8), has “no details . . . revealed about the nature (e.g., size
and lamellarity) of the resulting liposomes” and it “lacks the homogenization
step of Appellant’s claims, instead performing ‘swirling’ (which the average
skilled person would not regard as homogenization)” (id.). Appellant also
argues that “Example 8 includes no specific protocols or method details, and
the entire approach is different from the methods described in the rest of
Leigh. Thus, the only relevant portion of Leigh lacks sufficient information
to provide an enabling disclosure of Appellant’s method of claim 1.” (Id. at
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8–9.) In light of the foregoing, Appellant argues that “Leigh alone fails to
teach or suggest every limitation of claim 1” and WO ’358 “does not cure
the defect of Leigh” because it only teaches the use of “surfactant-containing
liposomes which are excluded from claim 1.” (Id. at 11.) Moreover,
Appellant argues that “[o]nly Example 8 of Leigh suggests a method of
adding a solid drug to liposomes, but the liposomes are uncharacterized due
to lack of any detailed description” and thus claim 1 is not obvious over WO
’358 and Leigh. (Id. at 12.)
We do not find Appellant’s arguments persuasive to establish non-
obviousness of the method recited by claim 1. In particular, Appellant’s
argument rests on the false premise that “[i]t was expected at the time of
Leigh and at the time of the present invention that hydrophobic agents could
only be incorporated into lipid bilayer (liposomal) membranes by first
disrupting the bilayer structure using surfactants or solvents, or by pre-
mixing the lipid and hydrophobic agent in a solvent solution or in mixed
lipid-surfactant micelles prior to formation of the liposomes.” (Reply Br. 4
(emphasis added).) Appellant argues that prior to the claimed invention the
expectation was that hydrophobic drugs were not able to “overcome the
polar and charged bilayer surface and access the hydrophobic bilayer core
without surfactants and without the need to add the drug to the lipid-organic
solvent solution prior to liposome formation.” (Appeal Br. 5.) However,
Leigh teaches that it was found that the association of a lipophilic compound
(one with a low solubility in aqueous medium) with a liposome could be
accomplished by mixing it with the preformed and finely divided lipid
particles where the particles are in aqueous suspension and not dissolved in a
lipid solution during formation of the particles and the lipophilic compound
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is not in a solvent. (Leigh ¶¶ 22, 33.) In particular, as we have already
noted above, Leigh states:
Surprisingly it has been found that an aqueous suspension
of finely divided lipid particles, i.e. preformed particles
comprising at least one membrane lipid as the major component
or constituent has a much higher capacity for solubilising
lipophilic compounds if the compound is added to already
formed lipid particles and not dissolved in a lipid solution
during formation of the particles, which is usually the case in
the prior art.
(Leigh ¶ 33.) Leigh explains that “[b]ecause of the lipophilicity of the
compound and the extensive surface area presented by the discrete lipid
particles, the compound partitions preferentially into the lipid and forms
molecular associates,” a process which it calls “Instant Partition Loading.”
(Id. ¶ 32.) And Leigh teaches that this association is, upon mixing,
“spontaneous[] and instantaneous[].” (Id. ¶ 22:
Unexpectedly, it has been found that the present invention
allows compounds which have low solubility in aqueous media
to form molecular associates spontaneously and instantaneously
with membrane lipid suspensions comprising discrete particles
wherein the major constituent is at least one membrane lipid,
when they are mixed together.)
In short, Leigh specifically contradicts Appellant’s contention as to what the
scientific expectation was at the time of Appellant’s invention. And for this
reason, we disagree with Appellant’s characterization of Example 8 of Leigh
as being incomplete for failure to describe the use of solvents and surfactants
and that “the examples of Leigh confirm that [solvents and surfactants] are
not optional at all, as they are used in every example except the incomplete
Example 8.” (Reply Br. 3.)
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In addition, Leigh teaches, even apart from its own surprising
discovery, among the known “manufacturing procedures to associate the
lipophilic drug with the lipids [of a liposome] . . . included high shear and/or
high pressure homgenisation” aside from “controlled organic solvent
dilution, [and] cross flow filtration to produce aqueous liposomal
suspensions containing the drug.” (Leigh ¶ 6.) We note further that
WO ’358 confirms that it was known that homogenization can be used to
associate lipophilic drugs with phospholipid liposomes in an aqueous
solution. (WO ’358 ¶ 114.)
In light of the foregoing, the fact that Example 8 of Leigh does not
provide a specific protocol for combining a lyophilized lipophilic drug with
an aqueous dispersion to obtain a liposome having the lipophilic drug in
association with the membrane lipid does not persuade us that Leigh in
combination with WO ’358 does not render obvious the claimed process
wherein no solvent or surfactant is used in associating a lipophilic
therapeutic agent with a lipid of a liposome. Moreover, we conclude that the
addition of a homogenization step would have been obvious from the
teachings of Leigh and WO ’358 to ensure efficiency of loading into the
membrane over Leigh’s expected 80% efficiency by the “instant partition
loading.” (Leigh ¶ 36).
Moreover, the fact that Example 8 of Leigh does not describe a
liposome having the claimed liposome size and lamellarity (Appeal Br. 8)
does not persuade us that these features are not rendered obvious from the
teachings of the relied upon references. Leigh teaches that unilamellar
vesicles are known lipid particles that can be loaded by instant partition
loading. (Leigh ¶ 56.) Although Leigh specifically teaches using such
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vesicles with a lipophilic drug that is dissolved in PEG400/ethanol (id. ¶ 54),
Leigh does not teach this to be the only process in which such vesicles can
be used. Leigh, instead, particularly notes that where the low water soluble
compound to be associated with the lipid of the vesicle is lyophilized, the
compound does not need to be in a container that includes a solvent or
surfactant in order to take advantage of instant partition loading. (Id. ¶ 33.)
Leigh notes that use of excipients may “improve solubility and the loading
of the lipids” but they are not necessary. (Id. ¶ 49.) And, Leigh teaches that
the aqueous suspension of discrete lipid particles that may be used, taking
advantage of this surprising discovery with respect to instant partition
loading, “most preferably” has particle sizes of below 100 nm. (Id. ¶ 35.)
Thus, we agree with the Examiner that the prior art renders obvious the
claimed process wherein no solvent or surfactant is used in associating a
lipophilic therapeutic agent with a lipid of a liposome where the liposomes
are unilamellar and have an average size less than about 100 nm.
Moreover, regarding Appellant’s position that WO ’358 teaches a
method that requires the presence of a surfactant, for example, cholesteryl
sulfate (Appeal Br. 9, 12), we disagree. “It is well settled that a prior art
reference is relevant for all that it teaches to those of ordinary skill in the
art.” In re Fritch, 972 F.2d 1260, 1264 (Fed. Cir. 1992). Although
cholesteryl sulfate is used in every example where the liposome was
homogenized with the lipophilic drug in WO ’358, WO ’358 discloses that
cholesteryl sulfate is just one of a number of other lipids that may be
included, which list includes just using cholesterol itself. (WO ’358 ¶ 21.)
Moreover, WO ’358 teaches that formulations of amphotericin B
incorporated into unilamellar liposomes formed from soy
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phosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol are
known and that use of cholesteryl sulfate simply reduces the toxicity of
amphotericin B on use of the liposome by reducing hemolysis of
erythrocytes and binding to plasma protein. (WO ’358 ¶¶ 78, 80.)
Furthermore, we agree with the Examiner that it was known in the art
that cholesterol in combination with phospholipids in forming liposomes
was known to provide structural support to the liposome. (Hope ¶ 504.)
Thus, we conclude, like the Examiner, that WO ’358’s teaching regarding
the use of cholesterol lipids in the liposome composition is for its use in
structural support of a liposome that may be subject to homogenization, and
that a surfactant type cholesterol, therefore, is not required. That using
cholesteryl sulfate would not have been understood by one of ordinary skill
in the art to teach at the time of Appellant’s invention to be necessary to
incorporate a lipophilic into drug into the lipid bilayer of the liposome is also
supported by Leigh’s teaching just discussed: namely that, upon mixing,
lipophilic compounds that have a low solubility in aqueous media with
liposomes suspensions in aqueous media “spontaneously and
instantaneously” form molecular associates between the lipophilic
compound and liposomes due to preferential partitioning of the lipophilic
compound into the lipid of the aqueous suspension. (Leigh ¶¶ 22, 33.)

4 Hope states:
In membranes composed of unsaturated phospholipids, the presence
of cholesterol restricts acyl chain motion and increases membrane
thickness. On the other hand, the interaction of cholesterol with
saturated phospholipids prevents the formation of the gel state and
tends to eliminate the gel to liquid crystalline phase transition[.]
(Hope ¶ 50.)
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Consequently, we agree with the Examiner that the teachings of
WO ’358 and Leigh in combination would have made obvious the process
recited in Appellant’s claim 1. Appellant does not separately argue the
patentability of claims 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51,
and thus, they fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). We affirm the
Examiner’s rejection of claims 1, 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47,
and 49–51 as being unpatentable over Leigh in combination with WO ’358
and claims 1, 4–8, 11–31, 33–37, and 40–54 as being unpatentable over
WO ’358 in combination with Daftary and Leigh.
We need not, and do not address the Examiner’s rejection of claims 1,
4–8, 11–16, 18, and 20–24 as obvious over Leigh in combination with Desai
and Haas, because these came claims have also been rejected as obvious
over the combination of Leigh and WO ’358 alone, or also in combination
with Daftary, which, as just discussed, are rejections that we affirm.

II. Obviousness Rejections Involving Independent Claim 25
Appellant’s claim 25 differs from claim 1 in that the hydrophobic
therapeutic agent is said to be dissolved in a liquid-solvent-containing
medium, but requires that the addition of a hydrophobic agent to a liposome
suspension and homogenization take place in the absence of a surfactant.
The Examiner makes two different rejections of claims 25–31, 33–37,
40–45, 47, and 49–51, but both rely on the teachings of Hope.
According to the Examiner, Hope teaches loading drugs, including
hydrophobic drugs, into preformed liposomes where ethanol and solvents
“such as DMSO below a certain amount” are used to increase the
permeability of the liposome without vesicular collapse. (Non-Final Action
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8, 9.) The Examiner concludes that it would have been obvious to load the
liposomes of WO ’358 after the liposomes are formed “since Hope teaches
that preformed liposomes can be loaded with an active agent.” (Id. at 8.)
The Examiner also finds that it would have been obvious to lyophilize the
Hope liposomes loaded with drug for storage purposes as taught by Desai
and Haas. (Id. at 9.)
Appellant argues that the Examiner’s rejections of claim 25 involving
Hope are in error because “Hope discloses merely the entrapment of only
water-soluble drugs using organic solvent to destabilize the membrane, not
to deliver a hydrophobic drug.” (Appeal Br. 12.) According to Appellant,
Hope does not teach dissolving drugs in organic solvent, but rather
“discloses a drug trapping method in which organic solvent is added to
liposomes to permeabilize them, following which the organic solvent is
removed, allowing the liposomes to reseal and entrap a solute at the same
concentration at which it exists in the suspension.” (Id. at 10.) Appellant
argues that “it is doubtful that Hope’s method can work with a hydrophobic
drug, because it requires use of an aqueous solution of the drug, which
merely becomes entrapped in the liposomal lumen, not intercalated within
the lipid bilayer as in Appellant’s method.” (Id. at 11.)
We do not find Appellant’s argument persuasive. Hope teaches in the
abstract that loading of preformed liposomes of solutes that include “both
small nonpolar molecules and larger species, such as proteins and
carbohydrates.” (Hope Abstr.) Indeed, Hope indicates that the molecular
characteristic of the drug is irrelevant to whether or not the drug can be
loaded, stating:
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Generally, the loading of all drugs that can cross the vesicle
bilayer in the presence of up to 30% ethanol are contemplated
by this invention. Such drugs can be readily identified by
encapsulating the drug of interest and then adding ethanol to
see if the drug is released from the vesicle. One will recognize
that this method of loading and/or release is therefore
independent of any particular molecular characteristic of the
drug (e.g., charge, molecular weight, etc.).
(Id. ¶ 64.)
Moreover, Hope also teaches with respect to the solvent addition that
the molecule to be loaded can be suspended in organic solvent and added to
the liposome instead of the liposome being suspended in an organic solvent
with the molecule to be loaded added afterward. (Hope ¶ 62.) Hope
specifically states “the order of addition is unimportant.” (Id.)
Finally, Hope teaches that “[t]he alcohol temporarily enhances the
permeability of the vesicles, without substantially altering or changing their
size” and that the liposomal membrane retains its “structural integrity”
(Hope ¶ 46.) Hope explains that the solvent is generally a polar solvent. (Id.
¶ 52.)
In the face of the foregoing teachings in Hope, Appellant’s argument
that “it is doubtful that Hope’s method can work” (Appeal Br. 11) is not
supported by the evidence of record and is unpersuasive. “Attorney
argument is not evidence.” Icon Health & Fitness v. Strava, 849 F.3d 1034,
1043 (Fed. Cir. 2017) (citing Gemtron Corp. v. Saint-Gobain Corp., 572
F.3d 1371, 1380 (Fed. Cir. 2009) (“[U]nsworn attorney argument . . . is not
evidence and cannot rebut . . . other admitted evidence . . . .”); see also
Manual of Patent Examining Procedure § 2145 (9th ed. Nov. 2015)
(“Attorney argument is not evidence unless it is an admission, in which case,
an examiner may use the admission in making a rejection.”).
Appeal 2020-005497
Application 15/593,586

19
Furthermore, Leigh teaches that it was known at the time of the
invention, that where a lipophilic compound is added to a preformed
liposomal particles, either as a particulate or in a hydrophilic medium such
as ethanol, the compound partitions preferentially into the lipid to form
molecular associations. (Leigh ¶¶ 32, 33.) Consequently, Leigh supports a
conclusion that the use of a solvent as in Hope, which would assist in
permeabilizing the liposome membrane, thus facilitating entry of the
lipophilic compound into the lipid bilayer would also result in the
instantaneous and spontaneous partition loading of a lipophilic compound
into molecular association with the lipid of the liposome membrane.
For the foregoing reasons, we affirm the Examiner’s rejection of
claim 25 as being unpatentable over Hope, Desai, and Hass, or Hope, WO
’358, Leigh, and Daftary. Appellant does not separately argue the
patentability of claims 26–31, 33–37, 40–45, 47, and 49–51, and thus, they
fall with claim 25. 37 C.F.R. § 41.37(c)(1)(iv).

III. Non-statutory Double Patenting
Appellant does not contest the Examiner’s rejection of the claims for
non-statutory double patenting over claims 1–5 of U.S. Patent No.
8,591,942. (Appeal Br. 7.) Appellant also has not filed a terminal
disclaimer to obviate the rejection, and we therefore, summarily affirm the
Examiner’s rejection. Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir.
2008) (“When the appellant fails to contest a ground of rejection to the
Board, . . . the Board may treat any argument with respect to that ground of
rejection as waived.”).

Appeal 2020-005497
Application 15/593,586

20
DECISION SUMMARY
Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 4–8, 11–
16, 18, 20–
31, 33–37,
40–45, 47,
49–51
103(a) Leigh, WO’358 1, 4–8, 11–
16, 18, 20–
31, 33–37,
40–45, 47,
49–51

1, 4–8, 11–
31, 33–37,
40–54
103(a) WO’358, Daftary,
Leigh
1, 4–8, 11–
31, 33–37,
40–45, 47,
49–51

25–31, 33–
37, 40–45,
47, 49–51
103(a) WO’358, Daftary,
Leigh, Hope
25–31, 33–
37, 40–45,
47, 49–51

25–31, 33–
37, 40–45,
47, 49–51
103(a) Hope, Desai, Hass 25–31, 33–
37, 40–45,
47, 49–51

1, 4–8, 11–
16, 18, 20–
31, 33–37,
40–45, 47,
49–51
Non-statutory
Double Patenting
1, 4–8, 11–
16, 18, 20–
31, 33–37,
40–45, 47,
49–51

Overall
Outcome
1, 4–8, 11–
31, 33–37,
40–45, 47,
49–51

TIME PERIOD FOR RESPONSE
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