Ex Parte Lesieur nee Boivin et al

Patent Trial and Appeal Board

Jul 26, 2017

12299261 (P.T.A.B. Jul. 26, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/299,261 06/02/2009 Sylviane Lesieur nee Boivin 0512-1505 7410
466 7590 07/28/2017
YOUNG fr THOMPSON
EXAMINER
209 Madison Street KISHORE, GOLLAMUDI S
Suite 500
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1612
NOTIFICATION DATE DELIVERY MODE
07/28/2017 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):
DocketingDept@young-thompson.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SYLVIANE LESIEUR nee BOIVIN, VALERIE BERNAT,
GENEVIEVE LE BAS, and CATHERINE RINGARD nee LEFEBVRE
Appeal 2016-006393
Application 12/299,2611
Technology Center 1600
Before DONALD E. ADAMS, ULRIKE W. JENKS and DAVID COTTA,
Administrative Patent Judges.
COTTA, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a process
for preparing liposomes. The Examiner rejected the claims on appeal under
35 U.S.C. § 112(b) as indefinite and under 35 U.S.C. § 103(a) as obvious.
We affirm-in-part.
1 According to Appellants, the real parties in interest is Centre National de la
Reserche Scientfique. App. Br. 1.
Appeal 2016-006393
Application 12/299,261
STATEMENT OF THE CASE
Claims 25—34, 39, and 43—48 are on appeal. Claim 25 is illustrative
and reads as follows:
25. A process for preparing liposomes, said process
comprising the following steps:
encapsulating at least one ingredient in liposomes
comprising phospholipids, said liposomes being dispersed in an
aqueous medium;
bringing said liposomes comprising phospholipids, which
are dispersed in an aqueous medium, into contact with natural
a-cyclodextrins optionally modified with hydrophilic chemical
groups,
said a-cyclodextrins and said liposomes presenting a
ratio between the molar concentration of a-cyclodextrin in the
aqueous medium and the molar concentration of the
phospholipids constituting the liposomes in the aqueous
medium equal to at least 1;
forming liposomes-cyclodextrins aggregates, the formed
liposomes-cyclodextrins aggregates flocculating and
sedimenting in the aqueous medium to form a deposit, said
deposit of liposomes-cyclodextrins aggregates constituting a
concentrate of liposomes and encapsulating at least one
ingredient;
recovering said liposomes-cyclodextrins aggregates
encapsulating at least one ingredient; and
disintegrating the liposomes-cyclodextrins aggregates to
recover individual liposomes encapsulating said at least one
ingredient.
App. Br. 38—39 (emphasis added).
The claims stand rejected as follows:
Claims 25—34, 39, and 43—48 were rejected under 35 U.S.C. § 112(b)
as indefinite.
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Claims 25—34, 39, and 43—48 were rejected under 35 U.S.C. § 103(a)
as obvious over the combination of Nishijo,2 Oh,3 Pereswetoff-Morath4 and
Millan.5
Claim 31 was rejected under 35 U.S.C. § 103(a) as obvious over the
combination of Nishijo, Oh, Pereswetoff-Morath, Millan and Gregoriadis.6
INDEFINITENESS
Claims 25—31, 39, and 46-48 require a specific ratio between the
molar concentration of a-cyclodextrin and the molar concentration of the
phospholipids that make up the liposomes. Claims 32—34, and 43 similarly
require a specific ratio between the molar concentration of a-cyclodextrin
and the molar concentration of the liposomes. The Examiner found that it
was not clear which component of the claimed ratio was the antecedent and
which was the consequent. Ans. 6—7 (stating with respect to claim 25, “the
term, ‘at least’ [in the limitation “presenting a ratio . . . equal to at least 1”]
implies that one of the components could be higher than 1 and claim does
not clearly state which one is higher”); Final Act. 2—3 (“It is unclear as to
what applicant intends to convey by ‘molar concentrations between alpha-
2 Nishijo et al., Interactions of Cyclodextrines with DPPCLiposomes, 46(1)
Chem. Pharm. Bull 120-124 (1998) (“Nishijo”).
3 Oh et al., US Patent Publication No. 2006/0222694 Al, published Oct. 5,
2006 (“Oh”).
4 Pereswetoff-Morath et al., US Patent Publication No. 2007/0026058 Al,
published Feb. 1,2007 (“Pereswetoff-Morath”).
5 Millan et al., US Patent Publication No. 2005/0069533 Al, published Mar.
31,2005 (“Millan”).
6 Gregoriadis et al., US Patent Publication No. 2002/0041895 Al, published
Apr. 11, 2002 (“Gregoriadis”).
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Application 12/299,261
cyclodextrins and liposomes in aqueous medium is between 2 and 1,500’ in
claim 47? Which one is between 2 and 1,500.”).
We agree with the Examiner that, in the claims reciting a specific
molar ratio, it is not clear which of the components is the antecedent and
which the consequent. Moreover, Appellants do not present any argument
as to why the Examiner’s rejection is in error. Accordingly, we affirm the
Examiner’s rejection of claims 25—34, 39, 43, and 46-48 as indefinite on the
basis that the claimed ratio is unclear.
The Examiner also rejected claims 25—34, 39, and 43—48 on the basis
that the claims “should recite how the liposome-cyclodextrin aggregate is
disintegrated and liposomes recovered.” Ans. 6.7 While the Examiner is
correct that claim 25 does not specify a method by which the liposome-
cyclodextrin aggregate is disintegrated,8 we disagree that this renders the
claim indefinite. The scope of claim 25 is clear. It encompasses any method
by which the liposome-cyclodextrin aggregates can be disintegrated.
Accordingly, we reverse the Examiner’s rejection of claims 25—34, 39, and
43—48 as indefinite on the basis that they do not specify how the liposome-
cyclodextrin aggregate is disintegrated and liposomes recovered.
7 The Examiner’s explanation of this rejection references only claim 25,
however the indefmiteness rejection was made with respect to all of the
pending claims. See, Final Act. 2—3; Ans. 6—7.
8 We note that claims 44 and 45 specify a method of disintegration. Claim
44 requires “dialyzing said liposomes-cyclodextrins aggregates thereby
disintegrating the liposomes-cyclodextrins aggregates to recover individual
liposomes” and claim 45 requires “disintegrating the liposomes-
cyclodextrins aggregates through addition of an aqueous medium to recover
individual liposomes.”
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Application 12/299,261
OBVIOUSNESS9
Both of the Examiner’s obviousness rejections rely on the same
underlying combination of Nishijo, Oh, Pereswetoff-Morath, and Millan.
Accordingly, we will discuss both obviousness rejections together.
Findings of Fact
1. Nishijo discloses: “Multilamellar liposomes consisting of F-a-
dipalmitoylphosphatidylcholine (DPPC) were prepared, and the effects of
CDs [cyclodextrins] on the gel-to-liquid crystalline transition of DPPC were
studied by differential scanning calorimetry (DSC).” Nishijo 120.
2. Nishijo discloses: “it was found that. . . a-CD forms an
insoluble complex with DPPC liposomes.” Id. at Abstract.
3. Nishijo discloses:
From the calorimetric results presented here, the interaction
between a-CD and DPPC liposomes was assumed to be as
follows: In the presence of a-CD, the transition temperature
was not changed, and only AHt decreased. This suggests that a-
CD substracts DPPC molecules from the liposomes and forms
an inclusion complex with DPPC out of a membrane matrix;
therefore, the number of phospholipid molecules constituting
the membrane decreases, resulting in a decrease in AHx.
Id. at 121.
9 Although we have determined supra that these claims 25—34, 39, 43 and
46-48 are indefinite, we nonetheless use our discretion in this case to
address the prior art contentions raised by Appellants based on the
assumption that the claims encompass the molar concentration ratio used in
Nishijo. See, e.g., Supplementary Examination Guidelines for Determining
Compliance with 35 U.S.C. § 112 and for Treatment of Related Issues in
Patent Applications, 76 Fed. Reg. 7162, 7169 (Feb. 9, 2011) (advising
examiners to interpret the claim and apply art with an explanation of how an
indefinite term is interpreted under the principles of compact prosecution).
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4. Nishijo discloses: “Added a-CD reacted with DPPC liposomes
to form an insoluble complex with DPPC molecules constituting the
liposomes. . . . The insoluble complex formation was confirmed because the
production of a white precipitation was observed when a-CD and DPPC
liposomes were mixed.” Id. at 122.
5. Sylviane Lesieur testifies:
In the work reported by Nishijo et al, no investigation was undertaken
to identity the composition of the precipitate, especially no
experiment was performed to inquire about the liposome structure
after the addition of alpha-cyclodextrin, such as, for instance, light
scattering measurements which would have determined the size
distribution and stability of the vesicle structures. I think that the lack
of these investigations led Nishijo et al to propose a mistaken
interpretation.
Lesieur Deck 3.10
6. The Specification discloses:
The liposomes were brought to the final concentration selected
by adding the dispersant aqueous phase. An a-cyclodextrin (a-
CD) solution prepared in the same medium was subsequently
added in one go. At the end of a period of time of between 1 and
10 minutes, the liposomes flocculated in the form of a dispersion
of aggregates with diameters ranging between 800 nm and
several microns.
Spec. 14.
7. The Specification discloses: “A concentrate of liposomes and
cyclodextrins was obtained in the form of a white precipitate.” Id. at 17.
10 Declaration of Sylviane Lesieur under 37 C.F.R. § 1.132, signed July 30,
2014 (“Lesieur Dec!.”)-
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8. Millan discloses:
The preparation is made in equimolar proportions of cyclodextrin and
Ang-(l-7). In brief[], P-cyclodextrin and/or its derivatives is dissolved
in water using stirring and heating. Then the respective amount of
angiotensin-(l-7) is added to the aqueous solution. Following the
dissolution, the mixture is frozen in liquid nitrogen and submitted to the
lyophilization process, obtaining a dry solid.
Millan 163.
9. Oh discloses:
Another possible approach is to dehydrate the liposomes by
lyophilization. Lyophilization of such drug encapsulated
liposomal compositions, followed by reconstitution to form an
administerable dosage form has been attempted. However,
conventional lyophilization and reconstitution processes have
resulted in substantial release of free (unencapsulated) drug on
reconstitution. For example, conventional lyophilization and
reconstitution procedures result in a substantial release of
liposome entrapped drug, typically 20-30% of free
(unencapsulated) drug is detected in the reconstituted liposome
suspension.
Oh. 1 8.
10. Oh discloses:
During the lyophilization process, the liposome structure could
become damaged leading to leakge of the encapsulated
topotecan. Such damage can be prevented by the use of
cryoprotectants, which may be present in certain predetermined
ratios with respect to the lipid concentration. These
cryoprotectants are present both in the internal as well as
external medium of the liposomes.
These cryoprotectants may be selected from sugars such as
sucrose, trehalose, lactose, maltose, cyclodextrin and its
derivatives.
Id. at 1126-27.
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The Examiner’s rejection
The Examiner found that Nishino disclosed a process of mixing
liposomes and cyclodextrin in which, “at a certain concentration of
cyclodextrin, the cyclodextrin forms an insoluble complex with DPPC of the
liposomes [which is] seen as a white precipitate.” Ans. 3. The Examiner
acknowledge that Nishino did not teach the inclusion of an active agent in
the liposomes,11 separating the liposomes from the aggregates, and
lyophilizing and rehydrating the liposomal composition. Id.
The Examiner found that Pereswetoff-Morath disclosed that
“liposome-entrapped drug preparations are often provided in a dry (freeze-
dried) form, which is subsequently reconstituted with an aqueous solution
immediately prior to administration to minimize the possibility of leakage of
the drug” and that the liposome fraction can be separated from an aqueous
carrier by centrifugation, dialysis or ultrafiltration. Id. at 4.
The Examiner found that Milan taught that cyclodextrin complexes
can be subjected to lyopholization and that dialysis can be used to separate
unencapsulated compound from liposome formulations. Id.
The Examiner found Oh taught that “liposomes can be dehydrated by
lyophilization followed by reconstitution to form an administrable dosage
form and that the freeze-drying process can be performed in the presence of
cryoprotectants such as cyclodextrins.” Id.
11 The Examiner qualified this by noting that Nishijo’s disclosure of
ethylenediaminetetraacetic acid (EDTA) could be construed as an active
agent. Ans. 3.
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Application 12/299,261
Based on the combined teachings of Nishijo, Pereswetoff-Morath,
Millan, and Oh the Examiner concluded:
It would have been obvious to one of ordinary skill in the art to
. . . lyophilize the compositions of Nishijo if they contain a
drug with a reasonable expectation of success since ... the
formation of liposomes and lyophilization procedures are
known in the art as evident from Pereswetoff-Morath and
Millan. One of ordinary skill in the art would be motivated to
. . . lyophilize the cyclodextrin-liposomal complex since
cyclodextrin also serves as a cryoprotectant during the
lyophilization process as taught by Oh. One of ordinary skill in
the art would be motivated to subject the composition to
dialysis or filtration procedure if it is desirable to remove the
unencapsulated active agent or separate the liposomes
cyclodextrin as taught by Millan.
Ans. 4—5.
Claims 25—31, 33, 39, and 44-47
Each of claims 25—31, 33, 39, and 44-47 requires that after forming
liposome-cyclodextrin aggregates, the aggregates be disintegrated (claims
25—31, 39, and 44-48) and/or dialyzed (claims 33 and 44). Appellants
contend, inter alia, that Nishijo teaches that a-cyclodextrins subtract DPPC
molecules from the liposome creating an insoluble liposome-cyclodextrin
inclusion complex. App. Br. 12—14; Lesieur Decl. 3. Appellants thus argue,
“given that the complex of NISHIJO is insoluble, one of ordinary skill in the
art would not have expected to recover the liposomes from the complex.”
App. Br. 14. Accordingly, Appellants assert that the skilled artisan would
have had no reason to disintegrate Nishijo’s liposome-cyclodextrin inclusion
complex. Id.
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As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
“[T]he examiner bears the initial burden ... of presenting a prima facie case
of unpatentability.” Appellants have persuaded us that the Examiner has not
carried the burden of establishing that process of claims 25—31, 33, 39, and
44-47 would have been obvious over the cited art.
Nishijo teaches that a-cyclodextrin “substracts DPPC molecules from
the liposomes and forms an inclusion complex with DPPC out of a
membrane matrix” (FF3), thus forming insoluble complex. FF2 and FF4.
This teaching conflicts with the Examiner’s rationale that “[sjince
cyclodextrin is soluble in buffer (liposomes are not since they contain[]
amphipathic phospholipids), it would have been obvious to one of ordinary
skill in the art to separate the liposomes from cyclodextrin aggregates by
filtration techniques.” Ans. 9. As Appellants point out, “[tjhere is no
suggestion in NISHIJO that cyclodextrins are soluble in the insoluble
complex” and thus, “[a] skilled person had no technical teaching that
cyclodextrins could be separated from the insoluble complex.” Reply Br. 3.
While the Nishijo’s teachings may ultimately have proved incorrect (see
FF5), the Examiner must still articulate a rationale for disintegrating or
dialyzing Nishijo’s liposome-cyclodrextrin complex consistent with the state
of the art at the time the application was filed. Here, the Examiner has not
identified any teaching or suggestion in the art that would have caused the
skilled artisan to doubt Nishijo’s teaching that its liposome-cyclodextrin
complex was insoluble or that would otherwise have provided reason to
disintegrate or dialyze the Nishijo’s complex. Accordingly, we reverse the
Examiner’s rejection of claims 25—31, 33, 39, and 44-47 as obvious.
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Claim 43
Claim 43 requires, inter alia, that the “liposome molar concentration
is in a range of 0.05 mM to 5mM.” Appellants argue that Nishijo does not
disclose this limitation. App. Br. 25. The Examiner does not discuss this
limitation or make factual findings regarding the liposome molar
concentration in any of the prior art references. The Examiner has thus not
carried the initial burden of presenting a prima facie case of unpatentability
with respect to claim 43. In re Oetiker, 977 F.2d at 1445. Accordingly we
reverse the Examiner’s rejection of claim 43 as obvious.
Claims 32 and 34
Appellants assert that claims 32 and 34 differ from Nishijo in three
ways, App. Br. 16, and then argue that Pereswetoff-Morath, Millan and Oh
“fail to provide sufficient guidance to modify Nishijo to approach the
claimed invention.” Id. at 18. We address each of Appellants arguments in
turn.
First, Appellants argue that Nishijo “does not describe preparing
liposomes-cyclodextrins aggregates” instead disclosing “an insoluble
complex formed with a-cyclodextrins with DPPC liposomes.” Id. at 16. We
are not persuaded.
Nishijo describes a process that involves adding a-cyclodextrin to
liposomes to form an insoluble complex that precipitated out of solution.
FF4. The Examiner finds that this process was the same as that described in
the Specification (see FF6 and FF7). We agree with the Examiner that the
process described in Nishijo with respect to forming a liposomal-
cyclodextrin precipitate is, in material respect, substantially the same as that
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described in the Specification. Accordingly, the burden shifted to
Appellants to show differences between the claimed liposome-cyclodextrin
aggregate and Nishijo’s liposome-cyclodextrin inclusion complex. In re
Best, 562 F.2d 1252, 1255 (CCPA 1977)). The primary differences
identified by Appellants with respect to the claimed aggregate and Nishijo’s
complex are in how Nishijo characterized it complex, which the Lesieur
Declaration suggests are based on a “mistaken interpretation.” Lesieur Decl.
3. This is not a sufficient evidentiary basis to establish that the claimed
aggregate and Nishijo’s complex are, in fact, different.
Second, Appellants argue that Nishijo does not disclose the process
step of presenting a “ratio between the molar concentrations of a-
cyclodextrins in the aqueous medium and liposomes in the aqueous medium
equal to at least 1 and forming liposomes-cyclodextrins aggregates, the
formed liposomes-cyclodextrins aggregates flocculating and sedimenting in
the aqueous medium to form a deposit.” App. Br. 16—17. We note that we
have found that the claimed ratio is indefinite and that our analysis of
obviousness assumes that the claims encompass the molar concentration
ratio used in Nishijo. We are not persuaded that Nishijo fails to disclose the
step of forming liposome-cyclodextrin aggregates for the reasons discussed
in connection with Appellants first argument with respect to claims 32 and
34.
Third, Appellants argue that Nishijo does not teach lyophilizing and
rehydrating the liposome-cyclodextrin aggregates. Id. at 17—18. While
Appellants are correct that Nishijo does not teach lyophilizing its liposome-
cyclodextrin aggregates, Millan discloses that cyclodextrin complexes can
be subjected to lyophilization (FF 8) and Oh discloses lyophilization can be
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performed in the presence of cryoprotectants such as cyclodextrins. See FF
9 and FF 10. The art thus, discloses that lyopholization was known and that
the presence of cyclodextrins can prevent damage to the liposome structure.
FF8—FF10. We, thus, agree with the Examiner that it would have been
obvious to lyophilize Nishijo’s liposome-cyclodextrin complex.
Accordingly, we affirm the Examiner’s rejection of claims 32 and 34.
SUMMARY
For the reasons set forth herein and those set forth in the Examiner’s
Answer and Final Office Action, we affirm the Examiner’s rejection of
claims 25—34, 39, 43, and 46-48 as indefinite and the Examiner’s rejection
of claims 32 and 34 as obvious over the combination of Nishijo, Oh,
Pereswetoff-Morath and Millan.
For the reasons set forth herein, we reverse the Examiner’s rejection
of claims 44 and 45 under 35 U.S.C. § 112(b) as indefinite, the Examiner’s
rejection of claims 25—31, 33, 35, 36, 38, 39, and 42-48 as obvious over the
combination of Nishijo, Oh, Pereswetoff-Morath and Millan; and the
Examiner’s rejection of claim 31 as obvious over the combination of
Nishijo, Oh, Pereswetoff-Morath, Millan and Gregoriadis.
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).
AFFIRMED-IN-PART
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