Ex Parte Jensen et al

Board of Patent Appeals and Interferences

Jun 8, 2012

10723423 (B.P.A.I. Jun. 8, 2012)

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.
10/723,423 11/26/2003 Gerard M. Jensen 01992.005US1 6232
53137 7590 06/11/2012
VIKSNINS HARRIS & PADYS PLLP
7900 International Drive
Suite 670
Bloomington, MN 55425
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
MAIL DATE DELIVERY MODE
06/11/2012 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte GERARD M. JENSEN, NING HU, SU-MING CHIANG,
CRAIG SKENES, and RICHARD FAHRNER
__________

Appeal 2011-004529
Application 10/723,423
Technology Center 1600
__________

Before DONALD E. ADAMS, DEMETRA J. MILLS, and
LORA M. GREEN, Administrative Patent Judges.

Per curiam.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to formulations
comprising a lipophobic therapeutic agent encapsulated in a liposome. The
Examiner has rejected the claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification discloses formulations “comprising a lipophobic
therapeutic agent encapsulated in a liposome” (Spec. 3:28-29). The
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Specification discloses that the liposomal lipid layer typically includes at
least one phosphatidyl choline that may be, among others, “dielaidoyl
phosphatidyl choline (DEPC), dioleoyl phosphatidyl choline (DOPC) …
hydrogenated soybean phosphatidyl choline (HSPC) … and dimyristoyl
phosphatidyl choline (DMPC)” (id. at 6:1-6). The Specification discloses
that cholesterol “provides stability to the liposome” (id. at 6:21). The
Specification discloses that an anionic phospholipid such as distearoyl
phosphatidyglycerol (DSPG), among others, “can help stabilize the system
upon storage and can prevent fusion or aggregation or flocculation; it can
also facilitate or enable freeze drying” (id. at 7:20-29).
Claims 54-58 are on appeal. The appealed claims are directed to a
formulation comprising a lipophobic therapeutic agent encapsulated in a
liposome that comprises
HSPC:Cholesterol:DSPG in a ratio of about 4:1:0.1 (claim 54);
DEPC:Cholesterol in a ratio of about 2:1 (claim 55);
DEPC:Cholesterol:DSPG in a ratio of about 2:1:0.1 (claim 56);
DOPC:Cholesterol in a ratio of about 2:1 (claim 57);
DMPC:Cholesterol:DSPG in a ratio of about 2:1:0.1 (claim 58).
The claims stand rejected under 35 U.S.C. § 103(a) as follows:
• Claims 54-58 in view of Hersch,
1
Allen,
2
Fujii,
3
and O’Rear;
4

1
Hersch et al., US 5,759,571, issued Jun. 2, 1998.
2
T.M. Allen and L.G. Cleland, Serum-Induced Leakage of Liposome
Contents, 597 BIOCHIMICA ET BIOPHYSICA ACTA 418-426 (1980).
3
Fujii et al., US 5,328,678, issued Jul. 12, 1994.
4
O’Rear III et al., US 5,503,850, issued Apr. 2, 1996.
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• Claims 54-58 in view of Hersch, Allen, Fujii, O’Rear, and Lopez-
Berestein;
5

• Claims 55-56 and 58 in view of Hersch, Allen, Fujii, O’Rear, and
Hays;
6

• Claim 57 in view of Hersch, Allen, Fujii, O’Rear, Hays, and
Anaissie.
7

I. The combination of Hersch, Allen, Fujii, and O’Rear:
The Examiner finds that “Hersch discloses liposomes containing [the]
amino glycoside, amikacin. The liposomal formulations contain various
claimed neutral phospholipids,” including hydrogenated soy
phosphatidylcholine (HSPC) and dimyristoyl phosphatidylcholine (DMPC)
(Answer 5). The Examiner finds that the Hersch liposomes also contain
cholesterol and anionic phospholipids such as distearoyl
phosphatidyglycerol (DSPG) (id.). The Examiner finds that the Hersch
discloses that the “preferred ratio of HSPC: cholesterol and DSPG is
2:1:0.1” (id.). The Examiner finds that each of Allen, Fujii, and O’Rear
disclose that increasing the relative amount of cholesterol in the liposomal
formulation reduces leakage of active agent (id. at 5-6). The Examiner
concludes that “[t]o vary the cholesterol amounts in Hersch with respect to
other phospholipids would have been obvious to one of ordinary skill in the
art depending upon the type of release of the active agent (quicker or slower

5
Lopez-Berestein et al., US 5,032,404, issued Jul. 16, 1991.
6
Hays et al., US 5,869,092, issued Feb. 9, 1999.
7
Anaissie et al., US 4,999,199, issued Mar. 12, 1991.
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release of the active agent in the blood) based on the teachings of Allen,
Fujii and O'Rear” (id. at 6).
Issues
Does the preponderance of evidence on this record support the
conclusions that the cited references would have made obvious:
• the liposomal formulation of claim 54 with the claimed ratio of
components;
• the liposomal formulation of claim 58 with DMPC as the
phosphatidylcholine;
• the liposomal formulations of claims 55-57 with DEPC or DOPC as
the phosphatidylcholine.
Factual Findings (FF)
FF 1. The Specification discloses “a lipophobic therapeutic agent
encapsulated in a liposome” (Spec. 3:28-29).
FF 2. The Specification discloses that in “one embodiment the therapeutic
agent is an anti-cancer agent, an antibiotic (e.g. an aminoglycoside or a
glycopeptide) … . In yet another embodiment the therapeutic agent is …
amikacin” (id. at 8:28-9:1).
FF 3. Hersch discloses a “liposomal aminoglycoside formulation preferably
containing a neutral lipid such as a phosphatidylcholine, a
phosphatidylglycerol, cholesterol (CHOL) and amikacin” (Hersch, col. 5, ll.
48-51, Ans. 5).
FF 4. Hersch discloses that the “preferred neutral lipids are saturated lipids
such as hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soy
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phosphatidylcholine (HSPC), distearoyl phosphatidylcholine (DSPC), and
dipalmitoyl phosphatidylcholine (DPPC)” (id. at col. 5, ll. 52-56, Ans. 5).
FF 5. Hersch discloses that the neutral lipid may be dimyristoyl
phosphatidylcholine (DMPC) (id., col. 15-16, claim 4, Ans. 5).
FF 6. Hersch discloses that “[o]ther suitable phosphatidylcholines include
those obtained from egg or plant sources, or those that are partially or
wholly synthetic” (id. at col. 5, ll. 64-66, Ans. 6).
FF 7. Hersch discloses that the “preferred carbon chain lengths of the
neutral lipids are from C16-C18” (id. at col. 5, ll. 56-57, Ans. 15).
FF 8. Hersch discloses that one of the preferred negatively charged lipids is
distearoyl phosphatidylglycerol (DSPG) (id. at col. 5, ll. 58-61, Ans. 5).
FF 9. Hersch discloses that “[h]ydrogenated soy phosphatidylcholine
(HSPC), distearoylphosphatidylglycerol (DSPG) are the preferred lipids for
use in the invention” (id. at col. 5, ll. 62-64, Ans. 5).
FF 10. Hersch discloses that the “preferred ratio of HSPC:CHOL:DSPG is
about 2:1:0.1” (id. at col. 6, ll. 12-13, Ans. 5).
FF 11. Hersch discloses that “[o]ther preferred formulations include DSPG
in a molar amount of 0 to 20%” (id. at col. 6, ll. 13-15, Ans. 13).
FF 12. Allen discloses that the “[i]ncorporation of increasing molar ratios of
cholesterol into liposomes reduced leakage of calcein from liposomes
incubated with buffer and with serum” (Allen, abstract, Ans. 5).
FF 13. Allen discloses that “[l]iposomes were made from either egg
phosphatidylcholine, dipalmitoylphosphatidylcholine or
distearoylphosphatidylcholine. Liposome preparations were made
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containing 0, 0.1, 0.2 or 0.5 mol cholesterol/mol phosphatidylcholine” (id. at
420).
FF 14. Fujii discloses “a liposome formulation, encapsulating boron-
containing compounds, that has the properties of retaining concentrations of
said boron compounds inside the liposomes without significant breakage”
(Fujii, col. 2, ll. 32-36).
FF 15. Fujii discloses that “sterols such as cholesterol help stabilize the
bilayer toward leakage and destruction in blood plasma. A stable liposome
may be obtained by incorporating 5-50% cholesterol by weight of
phospholipid into the liposome” (id. at col. 3, ll. 6-11, Ans. 5).
FF 16. Fujii discloses liposomes made of DSPC and cholesterol (id. at col.
3, ll. 12-14).
FF 17. O’Rear discloses microcapsules that “comprise a plasminogen
activator-containing aqueous core and a biocompatible layer surrounding the
core … which permits controlled release of at least a portion of the core
plasminogen activator within the cardiovascular system” (O’Rear, col. 1, ll.
23-28).
FF 18. O’Rear discloses that the biocompatible layer “preferably comprises
a liposome” (id. at col. 3, ll. 46-48).
FF 19. O’Rear discloses that “solute retention by liposomes and their half-
life in the circulation can be controlled by appropriate manipulation of
liposomal membrane fluidity and composition” (id. at col. 3, ll. 62-65, Ans.
6).
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FF 20. O’Rear discloses that “[i]n the absence of cholesterol, liposomes
may leak substantially when introduced intravenously” (id. at col. 3, ll. 65-
67, Ans. 6).
FF 21. O’Rear discloses that “[c]holesterol alters the mechanical and
structural properties of the phospholipid bilayer of the liposome to cause
variable permeability and fragility” (id. at col. 4, ll. 3-5, Ans. 6).
Analysis
Claim 54:
Appellants argue that Hersch discloses a liposomal formulation
comprising HSPC:cholesterol:DSPG in a ratio of 2:1:0.1, while the claim 54
liposomal formulation comprises HSPC:cholesterol:DSPG in a ratio of about
4:1:0.1 (Appeal Br. 10). Appellants argue that the Examiner’s reliance on
the combination of Allen, Fujii, and O’Rear as rendering obvious the
modification of the Hersch liposomal component ratios to arrive at the
instantly claimed ratios is misplaced because the liposomes of Allen, Fujii,
and O’Rear are structurally and functionally distinguishable from the
claimed liposomes (id. at 11-12). Appellants argue that the liposomes of
Allen, Fujii, and O’Rear were made with phosphatidylcholines other than
the HSPC recited in claim 54 (id. at 11-12).
These arguments are not persuasive. All of Allen, Fujii, and O’Rear
disclose that liposomal membranes can be stabilized or, alternatively
rendered permeable, by varying the concentration of cholesterol in the
liposomal membrane (FF 12, 15, 20, 21). Further, Allen’s liposomes were
formulated with egg phosphatidylcholine or distearoyl phosphatidylcholine
(DSPC), among others (FF 13), and Fujii’s liposomes were formulated with
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distearoyl phosphatidylcholine (DSPC) (FF 16). Since Hersch discloses that
HSPC, DSPC, and egg phosphatidylcholine can all be used to make
liposomes, one of ordinary skill in this art would expect that the cholesterol
effect found in Allen and Fujii for DSPC and egg phosphatidylcholine would
also apply to HSPC.
Appellants also argue that Allen, Fujii, and O’Rear “do not speak to
the difference between the ratios of phosphatidylglycerol lipids to
phosphatidylcholine lipids … and thus do not remedy the deficiencies of
Hersch” (Appeal Br. 11).
This argument is not persuasive. The claimed ratio of
HSPC:cholesterol:DSPG of 4:1:0.1 has a
phosphatidylcholine:phosphatidylglycerol ratio of 4:0.1, or 40:1. Hersch
discloses that the ratio of HSPC:cholesterol:DSPG is 2:1:0.1, or 20:1.
However Hersch also discloses that “[o]ther preferred formulations include
DSPG in a molar amount of 0 to 20%” (FF 11). Thus, the claimed
phosphatidylcholine:phosphatidylglycerol ratio of 40:1 is within the range
suggested by Hersch.
Claim 58:
Appellants argue that “Hersch does not teach or suggest a formulation
of DMPC:Cholesterol in a ratio of about 2:1:0.1” (Appeal Br. 15).
This argument is not persuasive. Hersch expressly discloses an
HSPC:cholesterol:DSPG ratio of 2:1:0.1 (FF 10), and Hersch expressly
discloses that another option for the phosphatidylcholine in the liposomes is
DMPC (FF 5). Thus, Hersch would have made obvious the substitution of
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HSPC with DMPC to arrive at a DMPC:cholesterol:DSPG formulation with
a ratio of about 2:1:0.1.
Claims 55-57:
The Examiner finds that Hersch does not teach the phospholipids
(DEPC and DOPC), but “teaches that the preferred neutral phospholipids
have a chain length of 16 to 18 carbon atoms and other suitable
phosphatidylcholines include those obtained from egg or plant sources and
those that are partially or wholly synthetic” (Answer 6). The Examiner
concludes that “[t]herefore, it would have been obvious to one of ordinary
skill in the art to choose the appropriate phosphatidylcholine with a
reasonable expectation of success” (id.).
Appellants argue that none of the cited references teach or suggest the
phospholipids DEPC or DOPC and thus the combination of the cited
references would not have made obvious the liposomal formulations of
claims 55-57.
We agree with Appellants that the Examiner has not adequately
explained why it would have been obvious, in view of the cited references,
for one of skill in the art to formulate the Hersch liposomes with DEPC or
DOPC since these phosphatidylcholines are not discussed in the cited
references and the Examiner has not set forth a sufficient rationale as to why
one of skill in the art would choose these phosphatidylcholines.
Conclusion of Law
The preponderance of evidence on this record supports a conclusion
of obviousness for claims 54 and 58. Thus, the rejection of claims 54 and 58
under 35 U.S.C. § 103(a) as unpatentable over the combination of Hersch,
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Allen, Fujii, and O’Rear is affirmed. However, because our reasoning
differs from that of the Examiner, we designate our affirmance as a new
ground of rejection under 37 C.F.R. § 41.50(b).
The Examiner has not adequately explained how the cited references
support a conclusion of obviousness for claims 55-57. Thus, the rejection of
claims 55-57 under 35 U.S.C. § 103(a) in view of Hersch, Allen, Fujii, and
O’Rear is reversed.
II. The combination of Hersch, Allen, Fujii, O’Rear, and Lopez-Berestein:
Issues
Does the preponderance of evidence on this record support a
conclusion that the cited references would have made obvious:
• the liposomes of claims 55 and 56 with DEPC as the
phosphatidylcholine;
• the liposomes of claim 57 with DOPC as the phosphatidylcholine.
Additional Findings of Fact
FF 22. Lopez-Berestein discloses “the treatment of systemic fungal
infections by administration of liposome[ ]incorporated polyenes” (Lopez-
Berestein, col. 1, ll. 11-13).
FF 23. Lopez-Berestein discloses that polyene macrolide antibiotics have
“amphipathic properties (those relating to molecules containing groups with
different properties, for example, hydrophilic and hydrophobic)” (id. at col.
4, ll. 9-19).
FF 24. Lopez-Berestein discloses that “[l]iposome encapsulation has
markedly reduced the toxicity and enhanced the therapeutic index of polyene
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macrolide compounds. However, liposome formulations presently available
do not sufficiently reduce toxicity of several polyene macrolide compounds,
for example, hamycin, lucensomycin, and mepartricin” (id. at col. 5, ll. 20-
25).
FF 25. Lopez-Berestein discloses that “liposomes containing a large
percentage by weight of cholesterol, reduced the toxicity of polyene
macrolide compounds so that they may now be used relatively safely” (id. at
col. 5, ll. 35-39).
FF 26. Lopez-Berestein discloses a study of various lipid combinations in
buffering the toxic effects of mepartricin in a liposomal formulation,
including combinations that included the phospholipids egg
phosphatidylcholine (egg PC), distearoyl phosphatidylcholine (DSPC),
dipalmitoyl phosphatidylcholine (DPPC), dielaidyl phosphatidyl choline
(DEPC), and dideoyl phosphatidyl choline (DOPC), all in combination with
cholesterol (col. 14, l. 59 - col. 15, l. 55, Table 5, Fig. 8).
FF 27. Lopez-Berestein discloses that most of the lipid combinations
studied, including those containing egg PC, DSPC, DEPC, and DOPC were
able to increase the maximum tolerated dose of mepartricin (id.).
Analysis
Claims 55, 56 and 57:
Claims 55, 56, 57 are directed to formulations comprising a
lipophobic therapeutic agent encapsulated in a liposome that comprises:
DEPC:Cholesterol in a ratio of about 2:1 (claim 55); or
DEPC:Cholesterol:DSPG in a ratio of about 2:1:0.1 (claim 56),
DOPC:Cholesterol in a ratio of about 2:1 (claim 57).
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Hersch discloses a liposomal formulation that comprises an
aminoglycoside therapeutic, e.g. amikacin, a phosphatidylcholine,
cholesterol, and a phosphatidylglycerol (FF 3). Hersch also discloses that the
phosphatidylcholines include, among others, hydrogenated egg
phosphatidylcholine (HEPC), hydrogenated soybean phosphatidylcholine
(HSPC), and distearoyl phosphatidylcholine (DSPC) (FF 4). Hersch
discloses that other suitable phosphatidylcholines may be used (FF 6) and
discloses a ratio of a phosphatidylcholine:cholesterol:phosphatidylglycerol
of 2:1:0.1, e.g. HSPC:cholesterol:DSPG. Lopez-Berestein discloses a study
of the ability of various phospholipid/cholesterol liposomal formulations to
buffer the toxic effects of mepartricin (FF 26, 27). Some of the lipid
combinations in the mepartricin study that were able to increase the
maximum tolerated doses were those containing egg PC, DSPC, DEPC, and
DOPC (FF 26, 27). Since Hersch expressly discloses the
phosphatidylcholines HSPC, egg PC and DSPC and discloses that other
phosphatidylcholines may be used, and Lopez-Berestein discloses that
DEPC and DOPC may be used in a similar way as egg PC and DSPC, it
would have been obvious for one of skill in the art to use the DEPC and
DOPC of Lopez-Berestein in the Hersch formulations as an alternative.
Thus, the combination of Hersch, Allen, Fujii, O’Rear, and Lopez-Berestein
would have made obvious the liposomal formulations of claims 55-57.
Appellants argue that Lopez-Berestein discloses a hydrophobic
therapeutic agent (Appeal Br. 16).
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This argument is not persuasive since Lopez-Berestein is relied on
only to show that DEPC and DOPC can be used for the same purposes as the
HSPC, egg PC and DSPC of Hersch.
Appellants argue that Lopez-Berestein teaches away from the claimed
inventions because Lopez-Berestein teaches the phosphatidylglycerol
DMPG rather than DSPG (Appeal Br. 17).
This argument is not persuasive since Hersch teaches DSPG and
Lopez-Berestein is relied on only to show that DEPC and DOPC can be used
for the same purposes as the HSPC, egg PC and DSPC of Hersch.
Appellants argue that Lopez-Berestein does not teach the claimed
ratios of DEPC:cholesterol or DOPC:cholesterol (id. at 18-19).
This argument is not persuasive since Hersch teaches the claimed
ratios of phosphatidylcholine:cholesterol, i.e. an HSPC:cholesterol ratio of
2:1, and Lopez-Berestein is relied on only to show that DEPC and DOPC
can be used for the same purposes as the HSPC, egg PC and DSPC of
Hersch.
Claims 54 and 58:
We have affirmed the rejection of claims 54 and 58 as being obvious
in view of Hersch, Allen, Fujii, and O’Rear, as discussed above, and
therefore we also affirm the rejection of claims 54 and 58 in view of Lopez-
Hersch, Allen, Fujii, O’Rear, and Lopez-Berestein.
Conclusion of Law
The preponderance of evidence on this record supports a conclusion
of obviousness. The rejection of claims 54-58 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Hersch, Allen, Fujii, O’Rear, and
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Lopez-Berestein is affirmed. However, because our reasoning differs from
that of the Examiner, we designate our affirmance as a new ground of
rejection under 37 C.F.R. § 41.50(b).
III. The combination of Hersch, Allen, Fujii, O’Rear, and Hays and
the combination of Hersch, Allen, Fujii, O’Rear, Hays, and Anaissie.
Since the above stated conclusion is dispositive for all of the pending
claims, we vacate the rejections of claims 55-56 and 58 in view of Hersch,
Allen, Fujii, O’Rear, and Hays and of claim 57 in view of Hersch, Allen,
Fujii, O’Rear, Hays, and Anaissie.
SUMMARY
We affirm the rejection of claims 54-58 under 35 U.S.C. § 103(a).
TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to 37 CFR
§ 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12,
2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37 CFR §
41.50(b) provides “[a] new ground of rejection pursuant to this paragraph
shall not be considered final for judicial review.
37 CFR § 41.50(b) also provides that the appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new ground of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new evidence relating
to the claims so rejected, or both, and have the matter
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reconsidered by the examiner, in which event the proceeding
will be remanded to the examiner . . . .

(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same record . . . .

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, 37 C.F.R. § 41.50(b)

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