Ex Parte Zhang

Patent Trial and Appeal Board

Sep 28, 2016

13020730 (P.T.A.B. Sep. 28, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/020,730 02/03/2011
108547 7590 09/30/2016
McDermott Will & Emery LLP
500 North Capitol Street NW
Washington, DC 20001
FIRST NAMED INVENTOR
Yuanpeng Zhang
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.
091504-0013/8001.USOO 3030
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
09/30/2016 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):
mweipdocket@mwe.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YUANPENG ZHANG1
Appeal2014-007153
Application 13/020,730
Technology Center 1600
Before MELANIE L. McCOLLUM, JACQUELINE T. HARLOW, and
RYAN H. FLAX, Administrative Patent Judges.
McCOLLUM, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for making agent-entrapped liposomes. The Examiner has rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellant identifies the real party in interest as LivOn Laboratories (App.
Br. 1).
Appeal2014-007153
Application 13/020,730
STATEMENT OF THE CASE
Claims 1---6, 21, and 22 are on appeal (App. Br. 2-3).2 The claims
have not been argued separately and therefore stand or fall together. 37
C.F.R. § 41.37(c)(l)(iv). Claim 1 is representative and reads as follows:
1. A method of making liposomes with an entrapped agent,
compnsmg:
solubilizing at least about 10 w/w% of vesicle-forming lipids in about
1-12 w/w% of a solvent miscible with water at room temperature to form a
lipid solution;
separately solubilizing an amount of the agent in 0.005-0.01 w/w% of
EDT A at room temperature to form an agent containing solution;
filtering the agent containing solution;
injecting a stream of the lipid solution into the agent containing
solution while mixing; and
allowing the resulting lipid and agent containing solution to hydrate
for at least one hour with frequent mixing.
Claims 1---6, 21, and 22 stand rejected under 35 U.S.C. § 103(a) as
obvious over:
T
L Edgerly-Plug3 alone or in view of Ghyczy4 (Ans. 2);
II. Panzner5 alone or in view of Ghyczy (id. at 3);
III. Kirby6 in view of either Edgerly-Plug or Panzner and optionally
further in view of Ghyczy (id. at 4--5); and
2 Claims 7-19 are also pending but have been withdrawn from consideration
(Ans. 2).
3 Edgerly-Plug, US 6,596,305 Bl, issued July 22, 2003.
4 Ghyczy et al., US 5,711,965, issued Jan. 27, 1998.
5 Panzner, US 6,713,533 Bl, issued Mar. 30, 2004.
6 C. J. Kirby et al., Stabilization of Ascorbic Acid by Microencapsulation in
Liposomes, 26 INT'LJ. FOOD SCI. & TECH. 437--49 (1991).
2
Appeal2014-007153
Application 13/020,730
IV. Kirby in view of either Edgerly-Plug or Panzner, optionally
further in view of Ghyczy, and additionally in view of Morello 7 (id. at 6).
I
The Examiner relies on Edgerly-Plug for disclosing "a method of
preparation of ... liposomes wherein the vesicle forming lipid in ethanol is
added to the aqueous solution containing the hydrophilic active agent in an
aqueous phase containing EDTA" (Ans. 2). The Examiner finds that
Edgerly-Plug "teaches that the sizes of the liposomes depend upon the
amounts of ethanol added" (id.). The Examiner concludes that it would have
been obvious "to adjust the amounts of lipid( s) and the solvent to obtain the
desired sizes of the liposomes" (id.). In addition, the Examiner concludes
that "[ o ]ne of ordinary skill in the art would be motivated to use the claimed
amounts of solvent and lipid since Ghyczy teaches that one can obtain a
liposomal gel composition by using amounts of phospholipids and solvents
which are similar to claimed amounts for the encapsulation of active agents"
(id. at 3).
Findings of Fact
1. Edgerly-Plug discloses a "process for producing liposomes
having a desired mean particle size wherein the desired mean particle size is
obtained by varying the initial organic solvent concentration" (Edgerly-Plug,
Abstract).
2. Edgerly-Plug also discloses:
The process of forming liposomes ... depends in part on
whether a lipophilic or hydrophilic bioactive agent is to be
associated with the liposomes. For lipophilic associated
7 Morello et al., US 2003/0157220 Al, published Aug. 21, 2003.
3
Appeal2014-007153
Application 13/020,730
liposomes, an optional preservative such as BHT and the
bioactive agent (e.g. prostaglandin Ei) are dissolved in the
organic solvent and the solution is then added to an aqueous
medium, which may contain a buffer (e.g. citrate or phosphate)
and/or a drying protectant such as maltose.
If a hydrophilic bioactive agent such as gentamicin is to be
associated with the liposomes, then the gentamicin is added to
the aqueous phase (which may contain a buffer, a drying
protectant, and/or a preservative such as disodium EDTA) to
form a solution. The lipid dissolved in the organic solvent is
added to the aqueous solution. The resulting mixtures containing
either the lipophilic or hydrophilic bioactive agent are processed
in a conventional manner by vigorous mixing until a liposome
population is formed ....
(Id. at col. 5, 11. 21-39.)
3. In addition, Edgerly-Plug discloses:
The maximum ratio of lipid to organic solvent that may be
selected must be sufficient to produce liposomes, i.e. if too much
solvent is present liposomes will not form. The minimum ratio
is determined by the point at which the lipid will no longer
dissolve in the solvent. The ratio of the fixed amount of lipid to
organic solvent must fall within the minimum to maximum
ratios.
(Id. at col. 6, 11. 8-14.)
4. In Example 1, Edgerly-Plug discloses:
4.4 mg of egg phosphatidylcholine (EPC), 0.03 mg of
butylated hydroxytoluene (BHT) and 5.58 mL of ethanol were
combined and mixed until a homogenous mixture was formed.
100 g of maltose was mixed with 900 mL of water for injection
(WFI), sterilized by filtration, and added to a 3 liter jacketed
glass reactor equipped with one 3 inch R-100 impeller and the
reactor was maintained at ambient temperature. The impeller
was activated at 2,000 RPM at which time the EPC/BHT/ethanol
solution was added to the maltose solution contained within the
reactor. The impeller was maintained at 2,000 RPM for a total
4
Appeal2014-007153
Application 13/020,730
of 15 minutes. Upon completion of the mixing, the contents of
the reactor were brought to a final volume of one liter with water
for injection.
(Id. at col. 6, 11. 32--47.)
5. In Examples 2--4, Edgerly-Plug discloses that the "procedure
set forth in Example 1 was repeated using initial ethanol concentrations of
5.0%, 10.0% and 15.0% by volume, respectively, based on the total volume
contained in the reactor" (id. at col. 6, 11. 54--59).
6. Edgerly-Plug also discloses:
It has been found that for the formation of-liposomes using
egg phosphatidylcholine as the lipid and ethanol as the solvent,
there is a substantial continuous decrease in the mean particle
size of the resulting liposomes as the concentration of the organic
solvent increases from about 0.558% to 10.0% by volume ...
while the amount of lipid remains fixed ( 4.4 mg). As the
concentration of the organic solvent increases from about 10.0%
to 15.0% by volume ... , the mean particle size of the thus
formed liposomes increases.
Beyond about a 15.0% concentration of ethanol, the lipid
will not form liposomes, but instead will remain dissolved in the
ethanol. In accordance with this example, the lipid/solvent ratio
is at least 0.03 mg/mL, preferably 0.03 to 0.80 mg/mL. ...
(Id. at col. 7, 11. 12-25.)
7. In addition, Edgerly-Plug discloses that the "operable range of
the lipid to organic solvent ratio for the selected lipid and organic solvent
can be routinely determined" (id. at col. 8, 11. 5-7).
8. Ghyczy
relates to an alcoholic, aqueous gel-like phospholipid
composition which, as alcohol, contains ethanol, 1-propanol,
2-propanol or mixtures thereof, ... the phospholipid composition
[being] a liposomal gel of the following composition:
5
Appeal2014-007153
Application 13/020,730
15.00-30.00 parts by weight of a phospholipid
concentrate, ...
20.00-14.00 parts by weight of alcohol and
50.00-71.00 parts by weight of an aqueous solution.
(Ghyczy, col. 3, 11. 33--48.)
9. Ghyczy discloses that the amount of alcohol is "preferably
about 16 parts by weight, per 100 parts by weight of the phospholipid
composition" (id. at col. 4, 11. 58---61 ).
10. In Example 1, Ghyczy discloses:
10.48 g of the phospholipid concentrate (containing 10 g
of phospholipids) are dissolved in 8 g of ethanol with stirring .
. . . The solution is homogenized for 3 min. with 31.52 g of
demineralized water, a commercially available high-speed
laboratory stirrer being used. A transparent gel containing
20.96% by weight of phospholipid concentrate (20% by weight
of phospholipids) is obtained.
(Id. at col. 6, 11. 37--46.)
11. In Example 5, Ghyczy discloses:
The entire amount of the phospholipid gel (50 g) obtained
in Example 1 is mixed with 42 g of 0.2 molar phosphate buffer
solution of pH 7.4 and stirred for 4 min. The resulting highly
fluid dispersion is mixed with 8 g of ethanol and additionally
stirred for a further minute to give the ready-to-use final product.
(Id. at col. 7, 11. 9-16.)
Analysis
As determined by the Examiner, Edgerly-Plug discloses a method
having many of the features of claim 1 (see, in particular, Findings of Fact
(FF) 2 & 4). As acknowledged by the Examiner, Edgerly-Plug does not
specifically teach the amounts of lipids and solvent recited in claim 1
6
Appeal2014-007153
Application 13/020,730
(Ans. 3). However, Edgerly-Plug does disclose an ethanol concentration of
"from about 0.558% to ... 15.0% by volume," stating that, "[b]eyond about
a 15.0% concentration of ethanol, the lipid will not form liposomes" (FF 6).
In addition, to form a liposomal gel, Ghyczy discloses dissolving
"10.48 g of the phospholipid concentrate (containing 10 g of phospholipids)
... in 8 g of ethanol with stirring" (FF 10). Ghyczy also discloses that this
"solution is homogenized ... with 31.52 g of demineralized water" to obtain
a "transparent gel containing 20.96% by weight of phospholipid concentrate
(20% by weight of phospholipids)" and that "the phospholipid gel (50 g) ...
is mixed with 42 g of 0.2 molar phosphate buffer solution" and "with 8 g of
ethanol ... to give the ready-to-use final product" (FF 10-11). In view of
the disclosures in Ghyczy, we conclude that the Examiner has set forth a
prima facie case that it would have been obvious to include at least 10 w/w%
of vesicle-forming lipids in the process of Edgerly-Plug.
Appellant argues, however, that "[o]ne skilled in the art wouldn't
greatly adjust the ratio of lipid and ethanol as required to obtain the claimed
method due to a corresponding change in liposome size distribution
expected" (App. Br. 5; see also id. at 6 ("One skilled in the art would not
drastically increase the lipid amount as the lipid:solvent ratio would not lead
to liposomes of the desired size.")). We are not persuaded.
Edgerly-Plug discloses a "process for producing liposomes having a
desired mean particle size wherein the desired mean particle size is obtained
by varying the initial organic solvent concentration" (FF 1 ). In particular, as
noted above, Edgerly-Plug discloses an ethanol concentration of "from about
0.558% to ... 15.0% by volume" (FF 6). We conclude that Appellant does
7
Appeal2014-007153
Application 13/020,730
not adequately explain why this teaching fails to suggest "about 1-12 w/w%
of a solvent miscible with water," as recited in claim 1.
With regard to the claimed amount of lipid, we recognize that
Edgerly-Plug exemplifies a particular amount of lipid (FF 4---6). In addition,
Edgerly-Plug states that "the lipid/solvent ratio is at least 0.03 mg/mL,
preferably 0.03 to 0.80 mg/mL" (FF 6). However, this teaching relates to a
particular example (id. ("[i]n accordance with this example ... ")).
As noted by Appellant (App. Br. 5), Edgerly-Plug also discloses:
The maximum ratio of lipid to organic solvent that may be
selected must be sufficient to produce liposomes, i.e. if too much
solvent is present liposomes will not form. The minimum ratio
is determined by the point at which the lipid will no longer
dissolve in the solvent. The ratio of the fixed amount of lipid to
organic solvent must fall within the minimum to maximum
ratios.
(FF 3.) In addition, Edgerly-Plug discloses that the "operable range of the
lipid to organic solvent ratio for the selected lipid and organic solvent can be
routinely determined" (FF 7).
Moreover, Ghyczy discloses a composition containing at least about
10 w/w% of lipids (FF 8 & 10-11). In particular, like Edgerly-Plug, Ghyczy
discloses adding a lipid solution (dissolved in ethanol) to an aqueous
solution (FF 10 & 4). In addition, Ghyczy discloses that a relatively high
amount of lipid can be dissolved in a relatively low amount of ethanol
(FF 10). In view of these teachings, Appellant's argument does not persuade
us that it would not have been obvious to modify Edgerly-Plug's process to
include the claimed amount of lipid.
Appellant also argues: "In order for the gel of Ghyczy to form, the
alcohol content must be very high, at about 16% . . . . Ghyczy does not
8
Appeal2014-007153
Application 13/020,730
teach solubilizing the lipids in a lower amount of solvent and the present
method would not likely result in a stable gel as required by Ghyczy." (App.
Br. 5.) We are not persuaded.
We understand that Ghyczy discloses a composition containing
"20.00-14.00 parts by weight of alcohol" and that the composition
preferably contains 16 parts by weight of alcohol (FF 8-9). However, as
noted by Appellant, "[a]s the method of claim 1 does not require a stable gel,
the percentage of alcohol may be ... 15% or less" (App. Br. 5). Moreover,
as noted above, Edgerly-Plug discloses an ethanol concentration of "from
about 0.558% to ... 15.0% by volume" (FF 6).
In addition, Appellant argues that "the present rejection does not
provide sufficient rationale to support a conclusion that the present claims
are prima facie obvious in view of Edgerly-Plug alone or in combination
with Ghyczy" (App. Br. 6). In particular, Appellant argues that the
"Examiner merely states 'one of ordinary skill in the art would be motivated
to vary the amounts of the components in order to obtain the desired sizes of
the liposomes'" (id. at 6-7). We are not persuaded.
As noted above, Edgerly-Plug discloses a "process for producing
liposomes having a desired mean particle size wherein the desired mean
particle size is obtained by varying the initial organic solvent concentration"
(FF 1 ). In view of this disclosure, we agree with the Examiner that "one of
ordinary skill in the art would [have] be[ en] motivated to vary the amount[]
of [ethanol] in order to obtain the desired sizes of the liposomes" (Ans. 11 ).
Edgerly-Plug exemplifies a particular amount of lipid (FF 3).
However, Ghyczy discloses that higher amounts, including the claimed
amount, may be used (FF 8 & 10-11 ). Therefore, in view of Ghyczy, we
9
Appeal2014-007153
Application 13/020,730
agree with the Examiner that "[ o ]ne of ordinary skill in the art would [have]
be[ en] motivated to use the claimed amount[] of ... lipid" (Ans. 3). As
noted by the Supreme Court, the "combination of familiar elements
according to known methods is likely to be obvious when it does no more
than yield predictable results." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398,
416 (2007). Furthermore, "it is not inventive to discover the optimum or
workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456
(CCPA 1955).
Conclusion
The evidence supports the Examiner's conclusion that Edgerly-Plug
and Ghyczy suggest the method of claim 1. We therefore affirm the
obviousness rejection of claim 1 over these references. Claims 2---6, 21, and
22 fall with claim 1.
II
The Examiner relies on Panzner for teaching "a method of preparation
of liposomes by adding ethanolic solutions of phospholipid to an aqueous
medium containing EDT A for the encapsulation of active agents such as
vitamins" (Ans. 3). The Examiner finds that "Panzner does not teach [the]
instant amounts of the solvent and the lipid" (id. at 4). However, the
Examiner finds that, "since the preparation produced is a liposomal
preparation in both cases, in the absence of showing the criticality it is
deemed obvious to one of ordinary skill in the art to vary the amounts in
order to obtain the best possible results" (id.). In addition, the Examiner
concludes that "[ o ]ne of ordinary skill in the art would be motivated to use
the claimed amounts of solvent and lipid since Ghyczy teaches that one can
obtain a liposomal gel composition by using amounts of phospholipids and
10
Appeal2014-007153
Application 13/020,730
solvents which are similar to claimed amounts for the encapsulation of
active agents" (id.).
Findings of Fact
12. Panzner "relates to nanocapsules ... produced by covalently
cross-linking at least two different water-soluble polymers ... on the surface
of liposomes" (Panzner, Abstract).
13. Panzner discloses that the "nanocapsules can carry biologically
active compounds" (id).
14. In Example 5, Panzner discloses preparing liposomes as
follows: "400 mg of [phosphatidylcholine] and 7.5 mg of octadecyl-
mercaptane are dissolved in 1 ml of ethanol and subsequently placed in
40 ml of buffer (10 mM HEPES, 150 mM NaCl, 5 mM EDTA, pH 7.5) with
stirring." (Id. at col. 12, 11. 43--47, & col. 10, 1. 32.)
Analysis
Appellant argues that Panzner's "Examples 5-7 disclose 0.97 w/w%
lipids and 1.9 w/w% ethanol (solvent), which is outside the range of
claim 1" (App. Br. 8). In addition Appellant argues that Ghyczy does not
"add to the inquiry" (id.). In particular, Appellant argues that "one skilled in
the art wouldn't decrease the amount of solvent based on Ghyczy because
the reference is concerned with forming a liposomal gel, which wouldn't
likely form where the alcohol (solvent) content is below 15%" (id.). Thus,
Appellant argues that "Panzner, alone or in combination with Ghyczy, fails
to teach a method including the presently claimed amounts of lipid and
solvent" (id.). We are not persuaded.
11
Appeal2014-007153
Application 13/020,730
Appellant states that "Examples 5-7 disclose ... 1.9 w/w% ethanol
(solvent)" (id.). Appellant does not explain why this teaching is outside the
scope of claim 1.
In addition, Ghyczy discloses a composition containing at least about
10 w/w% of vesicle-forming lipids (FF 8 & 10-11). Appellant has not
adequately explained why it would not have been obvious to combine this
teaching with Panzner. We understand that Ghyczy teaches a higher amount
of alcohol (FF 8-11 ). However, this does not address the Examiner's
position that it would have been obvious to include a higher amount of lipid
in Panzner.
We note that Appellant additionally raises arguments regarding
Panzner's Example 1 (App. Br. 7-8). However, we are not relying on this
example. Therefore, we are not persuaded by these arguments.
Conclusion
The evidence supports the Examiner's conclusion that Panzner and
Ghyczy suggest the method of claim 1. We therefore affirm the obviousness
rejection of claim 1 over these references. Claims 2---6, 21, and 22 fall with
claim 1.
III
The Examiner relies on Kirby for teaching "liposomes containing
ascorbic acid" (Ans. 5), as recited in dependent claim 6. The Examiner finds
that Kirby teaches a different "method of preparation of liposomes" (id.).
However, the Examiner relies on Edgerly-Plug or Panzner and Ghyczy to
suggest the method as discussed above (id.).
12
Appeal2014-007153
Application 13/020,730
Analysis
Appellant argues: "[A]s noted above, Edgerly-Plug and Panzner each
fail to show or suggest the presently claimed method. Therefore, it cannot
be obvious to encapsulate ascorbic acid in liposomes using the presently
claimed method." (App. Br. 9.) We are not persuaded by this argument for
the reasons discussed above.
Conclusion
The evidence supports the Examiner's conclusion that Kirby, Edgerly-
Plug or Panzner, and Ghyczy suggest the method of claim 1. We therefore
affirm the obviousness rejection of claim 1 over these references. Claims 2-
6, 21, and 22 fall with claim 1.
IV
The Examiner relies on the teachings of Kirby, Edgerly-Plug,
Panzner, and Ghyczy as discussed above (Ans. 6). The Examiner relies on
Morello for teaching "that ascorbic acid shows discoloration after a period of
time and EDTA provides stability to color change" (id.). The Examiner
concludes that "[ o ]ne of ordinary skill in the art would be further motivated
to include EDT A especially when ascorbic acid is used as the active agent
since Morello teaches that ascorbic acid shows discoloration and EDT A
provides stability to color change" (id.).
Analysis
Appellant argues that "Morello does not add to the obviousness of a
method of forming liposomes at all" (App. Br. 9). In particular, Appellant
argues that, "[a]s Morello is not concerned with liposome formation, there is
no guidance provided in Morello as to the amounts that would render the
present method obvious over the cited references" (id.). However, we
13
Appeal2014-007153
Application 13/020,730
conclude that Appellant has not adequately explained why the amounts
would not have been obvious over Edgerly-Plug or Panzner in view of
Ghyczy. Thus, we are not persuaded by Appellant's argument.
Conclusion
The evidence supports the Examiner's conclusion that Kirby, Edgerly-
Plug or Panzner, Ghyczy, and Morello suggest the method of claim 1. We
therefore affirm the obviousness rejection of claim 1 over these references.
Claims 2---6, 21, and 22 fall with claim 1.
SUMMARY
We affirm the obviousness rejection of claims 1---6, 21, and 22 over
(I) Edgerly-Plug in view of Ghyczy, (II) Panzner in view of Ghyczy,
(III) Kirby in view of Edgerly-Plug or Panzner and further in view of
Ghyczy, and (IV) Kirby in view of Edgerly-Plug or Panzner and further in
view of Ghyczy and Morello.
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).
AFFIRMED
14