Ex Parte Helms et al

Patent Trial and Appeal Board

Feb 21, 2013

12074766 (P.T.A.B. Feb. 21, 2013)

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.
12/074,766 03/05/2008 Jill Helms STAN-542 8921
77974 7590 02/21/2013
Stanford University Office of Technology Licensing
Bozicevic, Field & Francis LLP
1900 University Avenue
Suite 200
East Palo Alto, CA 94303
EXAMINER
GAMETT, DANIEL C
ART UNIT PAPER NUMBER
1647
MAIL DATE DELIVERY MODE
02/21/2013 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 PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JILL HELMS, ROELAND NUSSE,
JAEBEOM KIM, and PHILIPP LEUCHT
__________

Appeal 2011-010610
Application 12/074,766
Technology Center 1600
__________

Before TONI R. SCHEINER, DEMETRA J. MILLS, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims directed to
pharmaceutical formulations containing Wnt proteins, as well as processes
of administering the formulations. The Examiner entered rejections for
anticipation and obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
“Wnt proteins form a family of highly conserved secreted signaling
molecules that regulate cell-to-cell interactions during embryogenesis”
(Spec. [0001]). “Wnt signaling is involved in numerous events in animal
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development, including the proliferation of stem cells and the specification
of the neural crest. Wnt proteins are therefore potentially important reagents
in expanding specific cell types, and in treatment of conditions in vivo” (id.
at [0004]).
The Specification explains that the inventors’ initial attempts to
deliver a Wnt protein, Wnt3a, to an injury site in vivo “were unsuccessful;
neither purified protein by itself nor protein combined with a fibrin glue
elicited any discernable [sic] effect in the wound environment. In sharp
contrast, Wnt3a liposomes were highly efficacious at enhancing bone
regeneration” (id. at [0096]).
To account for the difference in efficacy between liposomal delivery
of the Wnt protein, and methods not using liposomes, the Specification
posits:
Wnt3a is modified by a palmitate residue, which is essential for
its in vivo activity. The palmitate moiety itself has pronounced
lipid affinity and during fabrication of the Wnt3a liposomes, it
is probable that the palmitate associates with the liposome
membrane. Consequently, Wnt3a may be effectively tethered
to the liposome, which could prevent its clearance from the
injury site.

(Id.)
Appellants’ invention is thus directed to pharmaceutical compositions,
“where the Wnt protein is inserted in the non-aqueous phase of a lipid
structure, e.g. in the surface of a liposome, micelle, lipid raft, etc., in an
emulsion, and the like” (id. at [0006]).
Claims 1, 3, 5-9, and 11-19 stand rejected and appealed (App. Br. 2).
Claims 1, 7, and 11 illustrate the appealed subject matter and read as
follows:
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1. A method for the therapeutic delivery of a wnt protein to
an animal, the method comprising:
administering to said animal an effective dose of a mammalian
wnt protein comprising a lipid moiety, formulated in a liposome that
comprises an outer liposome membrane, wherein active wnt protein is
tethered to said outer liposome membrane.

7. A pharmaceutical formulation comprising an effective
dose of a mammalian wnt protein comprising a lipid moiety, wherein
the wnt protein is formulated in a lipid structure that comprises an
outer liposome membrane, wherein active wnt protein is tethered to
said outer liposome membrane; and a pharmaceutically acceptable
excipient.

11. A method of accelerating bone repair in a mammal, the
method comprising:
administering to a mammal having a bone injury an effective
dose of a wnt protein comprising a lipid moiety, formulated in a lipid
structure that comprises an outer liposome membrane, wherein active
wnt protein is tethered to said outer liposome membrane.

The following rejections are before us for review:
(1) Claims 1 and 5-8, under 35 U.S.C. § 102(b) as anticipated by
Matthews
1
(Ans. 3-4); and
(2) Claims 3, 8, 9, and 11-19, under 35 U.S.C. § 103(a) as obvious
over Matthews, Shaughnessy,
2
Larsen,
3
Perreault,
4
and Weissig
5
(Ans. 4-6).

1
U.S. Patent No. 5,851,984 (issued December 22, 1998).
2
U.S. Patent App. Pub. No. 2008/0193515 A1 (filed December 4, 2007).
3
U.S. Patent App. Pub. No. 2005/0261189 A1 (published November 24,
2005).
4
U.S. Patent App. Pub. No. 2006/0068494 A1 (published Mar. 30, 2006).
5
Volkmar Weissig et al., Accumulation of Protein-Loaded Long-Circulating
Micelles and Liposomes in Subcutaneous Lewis Lung Carcinoma in Mice,
15 PHARMACEUTICAL RESEARCH 1552-1556 (1998).
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ANTICIPATION
The Examiner found that Matthews described therapeutic Wnt
formulations that included liposomes and native forms of Wnt polypeptides
“produced in mammalian cells” (Ans. 3). The Examiner cited Willert
6
as
evidence that the therapeutically active Wnt proteins used in Matthews
inherently comprised the lipid moiety “which would partition [the Wnt
proteins] into the non-aqueous phase of a lipid structure” (id.), thus meeting
the claims’ requirement for the active Wnt protein to be tethered to the outer
liposome membrane.
Appellants argue the claims subject to this rejection in two groups, the
first group consisting of claims 1, 5, and 6, and the second group consisting
of claims 7 and 8 (App. Br. 4). We select claim 1 as representative of the
first group, and claim 7 as representative of the second group. See 37 C.F.R.
§ 41.37(c)(1)(vii).
Appellants argue, for a variety of reasons, that Matthews fails to
describe or enable liposomal formulations that meet the claims’ requirement
for an effective dose of an active Wnt protein to be tethered to the outer
liposome membrane (see App. Br. 5-8).
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. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

6
Karl Willert et al., Wnt proteins are lipid-modified and can act as stem cell
growth factors, 423 NATURE 448-452 (2003).

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Appellants’ arguments do not persuade us that a preponderance of the
evidence fails to support the Examiner’s prima facie case of anticipation as
to either claim 1 or claim 7.
Claim 1 recites a method for the therapeutic delivery of a Wnt protein
to an animal. The claim’s sole step requires the practitioner to administer to
the animal an effective dose of an active mammalian Wnt protein that has a
lipid moiety. Claim 1 requires the Wnt protein to be formulated in a
liposome that has an outer liposome membrane, with the active Wnt protein
being “tethered” to the outer liposome membrane (App. Br. 16 (claims 1 and
7)).
Claim 7 recites a pharmaceutical formulation that contains a
pharmaceutically acceptable excipient, a lipid moiety, and an effective dose
of a mammalian Wnt protein. Like claim 1, claim 7 requires the Wnt protein
to be tethered to an outer liposome membrane.
As noted above, the Specification explains that the active mammalian
Wnt protein Wnt3a has a palmitate residue that causes the protein to be
tethered to the outer membrane of liposomes when the protein is formulated
into liposome-containing compositions (see Spec. [0096]). The
Specification also explains that liposomes according to Appellants’
invention may be prepared by known prior art techniques (see id. at [0046]
(“The liposomes may be prepared by a variety of techniques, such as those
detailed in Szoka, F., Jr., et al., Ann. Rev. Biophys. Bioeng. 9:467
(1980).”)).
Turning to the art, Matthews discloses that “Wnts can be used to
stimulate proliferation and/or differentiation and/or maintenance of
hematopoietic stem/progenitor cells either in vitro or in vivo (e.g., for
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treating hematopoietic diseases or disorders)” (Matthews, col. 5, ll. 24-27).
Matthews discloses that “native,” i.e. naturally occurring, forms of Wnts are
suitable for use in its methods (id. at col. 7, ll. 55-57), and that native
polypeptides include Wnt3a (id. at col. 8, ll. 9-24).
Matthews discloses that a variety of administration routes and carriers
can be used (id. at col. 36, ll. 24-51). As required by claim 1, Matthews
discloses that “[f]or all administrations, conventional depot forms are
suitably used. Such forms include, for example, microcapsules, nano-
capsules, liposomes” (id. at col. 36, ll. 51-53 (emphasis added)).
Matthews later elaborates on the use of liposomes:
Sustained-release Wnt polypeptide compositions also
include liposomally entrapped polypeptides. Liposomes
containing the Wnt polypeptide are prepared by methods
known in the art, such as described in Eppstein et al., Proc.
Natl. Acad. Sci. USA 82:3688-3692 (1985); Hwang et al., Proc.
Nati.[sic] Acad. Sci. USA 77:4030 (1980); and U.S. Pat. Nos.
4,485,045 and 4,544,545. Ordinarily, the liposomes are the
small (about 200-800 Angstroms) unilamelar [sic] type in
which the lipid content is greater than about 30 mol.%
cholesterol, the selected proportion being adjusted for the
optimal Wnt polypeptide therapy. Liposomes with enhanced
circulation time are disclosed in U.S. Pat. No. 5,013,556.

(Id. at col. 37, ll. 20-31.)
Thus, as required by claim 1, Matthews describes administering a
liposome formulation containing an active Wnt protein to an animal. As
required by claim 7, the Wnt protein is present in a therapeutically effective
dosage. While Matthews discloses that its liposomes can be prepared using
known prior art methods, Matthews does not explicitly state that the Wnt
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protein in its liposome formulations is tethered to the outer liposome
membrane, as claims 1 and 7 require.
However, as the Examiner points out, Willert discloses that active
forms of Wnt proteins inherently contain a palmitate moiety, whereas
inactive forms do not (see Willert 448 (abstract) (“By mass spectrometry, we
found the proteins to be palmitoylated on a conserved cysteine. Enzymatic
removal of the palmitate or site-directed and natural mutations of the
modified cysteine result in loss of activity, and indicate that the lipid is
important for signaling.”)).
As the Examiner also points out, Appellants’ Specification
acknowledges that it is the presence of the palmitate moiety which causes
the Wnt proteins to be tethered to the outer membranes when included in a
liposome formulation (Spec. [0096]). Appellants’ Specification also
acknowledges that prior art techniques of preparing liposomes produce the
tethered arrangement recited in claims 1 and 7 (see id. at [0046]-[0048]).
Thus, because Matthews describes its therapeutic liposomal Wnt
formulations as being prepared using conventional prior art techniques, and
because the active Wnt proteins in Matthews’ formulations inherently
contain the palmitate moiety that causes the Wnt proteins to be tethered to
the outer liposomal membrane, we find that the Examiner had a reasonable
evidentiary basis for finding that the liposomal formulations described by
Matthews inherently included Wnt proteins tethered to the outer liposome
membrane, as required by claims 1 and 7.
As our reviewing court has pointed out, “when the PTO shows sound
basis for believing that the products of the applicant and the prior art are the
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same, the applicant has the burden of showing that they are not.” In re
Spada, 911 F.2d 705, 708 (Fed. Cir. 1990).
We are not persuaded that Appellants have advanced evidence
adequate to rebut the Examiner’s prima facie case of anticipation as to
claims 1 and 7.
Appellants argue that, as shown by the Helms Declaration,
7
liposome
formulations typically consist of one or more lipid bilayers that enclose an
aqueous core, with a drug or molecule of interest being disposed within the
aqueous core from which it is delivered (App. Br. 5 (citing Banerjee
8
and
Allen
9
)). In contrast, Appellants argue, because the claimed formulations
include active Wnt proteins tethered to the outer liposome membrane,
whereas Wnt proteins entrapped within the aqueous core of liposomes are
inactive, the claimed liposome formulations deliver the Wnt proteins in an
unexpected manner (see App. Br. 5-6 (citing Morrell
10
)).
As an initial matter, we note that evidence of unexpected results is not
relevant to whether Matthews anticipates claims 1 and 7. See In re Paulsen,
30 F.3d 1475, 1482 n.11 (Fed. Cir. 1994) (“[E]vidence of nonobviousness is
irrelevant for patentability purposes when an invention is anticipated under
section 102.”).

7
Declaration of Dr. Jill Helms under 37 C.F.R. § 1.132 (declaration
executed April 8, 2010).
8
R. Banerjee, Liposomes: Applications in Medicine, 16 JOURNAL OF
BIOMATERIALS APPLICATIONS 3-21 (2001).
9
Theresa M. Allen and Pieter R. Cullis, Drug Delivery Systems: Entering
the Mainstream, 303 SCIENCE 1818-1822 (2004).
10
Nathan T. Morrell et al., Liposomal Packaging Generates Wnt Protein
with In Vivo Biological Activity, 3 PLOS ONE 1-9 (2008).

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We also note that Matthews discloses compositions including
“liposomally entrapped [Wnt] polypeptides” (Matthews, col. 37, l. 21
(emphasis added)). As noted above, however, Appellants’ Specification
supports the Examiner’s finding that conventional liposome formation
techniques inherently produce the claimed tethered arrangement (see Spec.
[0046]-[0048]), and Matthews discloses that its liposome formulations are
prepared using conventional prior art techniques (see Matthews, col. 37, ll.
21-31).
We note the disclosures in the Helms Declaration and Morrell, that
actual entrapment of Wnt proteins within the liposomes’ aqueous core yields
a product with little or no activity (see Helms Declaration 1; Morrell 4).
However, this inactivating entrapment of the Wnt proteins within the
liposomes’ aqueous core requires enzymatic trypsin digestion of the
liposome preparation to remove the Wnt proteins that inherently become
tethered to the outer liposomal membrane upon liposome formation (see
Helms Declaration 2-4; Morrell 4).
Appellants point us to no clear or specific evidence of record
suggesting that an ordinary artisan using conventional techniques to prepare
liposomal Wnt formulations as taught by Matthews would have digested the
liposomal formulations with trypsin after preparing them. Thus, a
preponderance of the evidence supports the Examiner’s finding that, when
Matthews refers to liposomally entrapped therapeutically active Wnt
formulations, Matthews is not referring to trypsin-digested formulations
having no activity.
Appellants argue that Matthews does not enable preparing a
liposomal preparation with active Wnt proteins as claimed, because,
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although Matthews provides a laundry list of techniques for isolating Wnt
proteins, “no specific methods or results are provided with respect to this
goal” (App. Br. 6). However, as our reviewing court has explained, the fact
that Matthews did not prepare a working example of its liposomes does not
demonstrate that Matthews’ disclosure is non-enabling:
[F]ailures by those skilled in the art (having possession of the
information disclosed by the publication) are strong evidence
that the disclosure of the publication was nonenabling. By
contrast, the fact that the author of a publication did not
attempt to make his disclosed invention does not indicate one
way or the other whether the publication would have been
enabling.

In re Donohue, 766 F.2d 531, 533 (Fed. Cir. 1985) (emphasis added).
Appellants contend that the Austin reference, which Appellants assert
is the “corresponding journal article” published by the inventors of the
Matthews patent, demonstrates that the Wnt proteins of Matthews were not
isolated using techniques that employed detergent to maintain the protein’s
solubility (App. Br. 6).
However, while Appellants assert that a copy of the Austin article was
attached to the Appeal Brief (id.), the article does not appear to be cited in
the Appeal Brief’s Evidence Appendix, and our review of the application
file does not show that the Austin article has been made of record.
Nonetheless, it might be true, as Appellants assert (id. at 7), that Austin’s
purification methods do not use detergent, and that the affinity purified
protein did not exhibit “increased biological activity” as compared to the
pre-affinity-purified preparation.
As Appellants concede, however, the affinity purified Wnt protein
described by Austin exhibited “biological activity” (id.). Thus, the fact that
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11
the Wnt protein was active demonstrates that the protein possessed the
activity-conferring palmitate moiety (see Willert), which is also responsible
for the tethering arrangement recited in claims 1 and 7 (see Spec. [0096]).
Moreover, the test for public possession of subject matter described
in an allegedly anticipating reference is whether “one of ordinary skill in the
art could have combined the publication’s description of the invention with
his own knowledge to make the claimed invention.” In re Donohue, 766
F.2d. at 533.
As noted above, and as the Examiner points out, techniques of
preparing active Wnt proteins that possessed the activity-conferring
palmitate moiety were known in the art (see Willert generally). As it is the
activity-conferring palmitate moiety which inherently produces the claimed
tethered arrangement upon liposome formulation (see Spec. [0096]), we are
not persuaded that Matthews’ disclosure of therapeutically active Wnt-
containing liposome formulations proteins failed to place into the hands of
the public a formulation in which the Wnt protein inherently possessed the
tethered arrangement required by claims 1 and 7.
Accordingly, as Appellants’ arguments do not persuade us a
preponderance of the evidence fails to support the Examiner’s finding that
Matthews anticipates claims 1 and 7, we affirm the Examiner’s rejection of
those claims over that reference. Claims 5, 6, and 8 fall with claim 1. See
37 C.F.R. § 41.37(c)(1)(vii).
OBVIOUSNESS
In rejecting claims 3, 8, 9, and 11-19 as obvious, the Examiner cited
Matthews, Larsen, and Perreault, as evidence that liposomal Wnt protein
formulations were known in art, but conceded that those references did not
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describe administering the formulations to accelerate bone repair, as recited
in claims 11-19 (Ans. 4).
To address that deficiency, the Examiner cited Shaughnessy as
evidence that it was known in the art that Wnt proteins were useful for
preventing or reducing bone destruction, and reasoned, therefore, that an
ordinary artisan would have been “motivated and expect[ed] success in
modifying the bone treatment method of Shaughnessy to include the use of
liposomes, thereby arriving at the methods recited in claims 11-17” (id. at 5).
The Examiner also conceded that Matthews, Larsen, and Perreault,
differed from claims 3, 8, 9, 18, and 19, in that those references did not
describe using micelles as the lipid-based delivery vehicle for the Wnt
proteins (see id. at 4). To address that deficiency, the Examiner cited
Weissig for its disclosure that small sized micelles were more efficient than
liposomes for in vivo delivery of a model protein having a lipid moiety (id.
at 5). Based on these teachings, the Examiner found that
one of skill in the art (1) would expect that a protein that
comprises a lipid modification, such as a wnt protein, would
readily incorporate into either liposomes or micelles, (2) would
recognize liposomes and micelles as usable alternatives for in
vivo administration of proteins and, (3) would have reason to
expect that micelles may be advantageous over liposomes for
particular applications. Thus, the substitution micelles for
liposomes is at least a matter of substitution of one known
element for another to obtain predictable results and possibly
the use of a known technique to improve a similar method.

(Id.)
Appellants argue the claims subject to this ground of rejection in the
following groupings: Group III (claim 3), Group IV (claim 8), Group V
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(claim 9), Group VI (claims 11 and 16-19), and Group VII (claims 12-15)
(see App. Br. 4-5).
We have carefully reviewed Appellants’ arguments, but are not
persuaded that a preponderance of the evidence fails to support the
Examiner’s conclusion of obviousness.
Regarding claim 3, Appellants initially reiterate their arguments that
Matthews discloses Wnt proteins being entrapped in liposomes, which
would result in an inactive formulation, and note that Larsen contains a
similar disclosure regarding liposomal Wnt protein entrapment (App. Br. 8-
9). As to claims 8 and 9, Appellants argue that “the cited art does not teach
how to provide for an effective dose of a mammalian wnt protein, as the
liposome compositions of the cited art would generate biologically inactive
protein” (id. at 11).
For reasons similar to those discussed above, we do not find these
arguments persuasive.
Thus, we again note Matthews’ use of the term “entrapped” to
describe its Wnt liposomal formulations (Matthews, col. 37, l. 20), as well as
Larsen’s use of the same term (Larsen, [0492]). We also note Perreault’s
disclosure that its Wnt protein “may be provided in the form of a purified
protein, or in complex with another component such as a liposome or cell
membrane to maintain its activity and/or increase its solubility” (Perreault
[0013]).
However, both Matthews and Larsen disclose that their Wnt liposomal
formulations should be prepared using conventional liposome preparation
techniques (see Matthews, col. 37, l. 21-31; Larsen [0492]), whereas, as
Appellants point out, actual inactivating entrapment of Wnt proteins within
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liposomes requires the added step of digesting the liposome preparation with
trypsin after the liposomes are formed (see Helms Declaration; also
Morrell).
Appellants point to no clear or specific teaching in the cited
references, or elsewhere in the record, suggesting that an ordinary artisan
preparing Wnt liposomal preparations according to Matthews, Larsen, or
Perreault would have treated the liposomes with trypsin before administering
them for the therapeutic effects described in the references. We are
therefore not persuaded that the prior art would have suggested preparing
inactive Wnt formulations to an ordinary artisan.
Regarding the suitability of substituting the micelles recited in
Appellants’ claims 3, 8, and 9 for the liposomes of Matthews, Larsen, and
Perreault, as the Examiner pointed out, Weissig discloses that both
liposomes and micelles were recognized as lipid-based drug delivery
vehicles (see Weissig 1552 (“[L]ong-circulating liposomes and micelles gain
increasing recognition as drug carriers for intratumoral delivery . . . .”)).
As the Examiner also pointed out, Weissig found that micelles were
superior to liposomes at delivering a model therapeutic protein having a
hydrophobic moiety to experimental tumors in mice (see id. (abstract)
(“Small-sized long-circulating delivery systems, such as PEG-lipid micelles,
are more efficient in the delivery of protein to Lewis lung carcinoma than
larger long-circulating liposomes.”)).
We note, as Appellants argue, that Weissig’s study was directed to
evaluating suitable vehicles for delivery of therapeutic proteins to lung
carcinoma cells (see id. (“The purpose of our work was to compare the
biodistribution and tumor accumulation of a liposome- or micelle-
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incorporated protein in mice bearing subcutaneously-established Lewis lung
carcinoma.”)).
As the Supreme Court has pointed out, however, “the [obviousness]
analysis need not seek out precise teachings directed to the specific subject
matter of the challenged claim, for a court can take account of the inferences
and creative steps that a person of ordinary skill in the art would employ.”
KSR Int’l v. Teleflex Inc., 550 U.S. 398, 418 (2007). Thus, a “person of
ordinary skill is . . . a person of ordinary creativity, not an automaton.” Id. at
421.
Here, given the teachings in Matthews, Larsen, and Perreault of the
suitability of liposomes as vehicles for Wnt protein delivery, we agree with
the Examiner that an ordinary artisan, further advised by Weissig of the
suitability of micelles as delivery vehicles for a therapeutic protein having a
hydrophobic moiety, would have reasonably inferred that micelles would be
a suitable alternative to liposomes for delivering other therapeutic proteins,
such as Wnt, having hydrophobic residues, and therefore would have been
prompted to substitute micelles, such as those described in Weissig, for the
liposomal carriers of Wnt proteins described in Matthews, Larsen, and
Perreault.
As the Supreme Court also advised in KSR, “when a patent claims a
structure already known in the prior art that is altered by mere substitution of
one element for another known in the field, the combination must do more
than yield a predictable result.” KSR, 550 U.S. at 417.
Thus, as we agree with the Examiner that an ordinary artisan would
have been prompted to substitute micelles for the liposomes described in
Matthews, Larsen, and Perreault as the lipid-based delivery vehicle for
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therapeutic administration of Wnt proteins, and as Appellants do not argue
that the methods and compositions recited in claim 3, 8, and 9 produce
unexpected results, we affirm the Examiner’s obviousness rejection of
claims 3, 8, and 9.
As to claim 11, contrary to Appellants’ arguments (see App. Br. 12;
Reply Br. 3), we are not persuaded that Shaughnessy fails to suggest
administering Wnt proteins for the purpose of accelerating bone repair:
Additionally, it is also contemplated that the method can be
used to promote more rapid effective healing of bone fractures
in the elderly. Furthermore, although the present invention
demonstrated repairing the lytic lesions with Wnt-3a protein, it
is contemplated that other canonical Wnt ligands such as Wnt-l,
Wnt-2 or Wnt-10b will be equally effective. The Wnt-3a
protein may be directly administered at the site of a lytic lesion
to promote osteoblast differentiation and spontaneous healing.

(Shaughnessy [0030].)
In addition to describing administering at the site of injury as recited
in Appellants’ claim 12, Shaughnessy explicitly discloses the pulsed
administration technique Appellants urge is described in their examples (see
App. Br. 11; Reply Br. 2):
[T]here may be a reluctance to use Wnt-3a systemically
because of its putative tumor promoting effects. This
possibility may be eliminated by local use, ex-vivo exposure of
osteoblasts precursors and/or pulsing the compound for short
periods of time to avoid chronic exposure. Thus, pulsing Wnt-
3a for short periods of time in-vivo might eliminate the
unwanted pro-growth effects this molecule may have on cell
types sensitive to Wnt signaling perturbation in cancers.

(Shaughnessy [0030].)
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We note the Specification’s disclosure that administration to a bone
injury site of either purified Wnt3a protein or Wnt3a incorporated into fibrin
glue did not improve rates of bone regeneration (see Spec. [0087], [0096]).
We also note the Specification’s disclosure regarding the significant
difference in bone regeneration rates between control liposomes containing
only PBS and liposomes containing Wnt3a:
[I]njury sites that received a single injection of Wnt3a
liposomes were completely filled with mature bony trabeculae
(n=7; Fig. 5c). This dramatic effect was achieved in 72h, since
liposomes were injected on post-surgical d3 and histological
evaluations were carried out on post-surgical d6.
Histomorphometric analyses showed that injury sites treated
with Wnt3a liposomes had 350% more bone than control injury
sites (average number of pixels representing bone in Wnt3a
treated samples = 78146; PBS samples = 20615; Fig. 5d,e).

(Id. at [0091].)
As the Federal Circuit has pointed out, however, “any superior
property must be unexpected to be considered as evidence of non-
obviousness.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir.
2007).
Here, because Shaughnessy teaches that Wnt proteins enhance bone
repair rates, an ordinary artisan might have considered it unexpected that
purified Wnt3a protein and fibrin glue-incorporated Wnt3a protein did not
elicit improvement in bone repair in Appellants’ tests. However, in view of
Shaughnessy’s express disclosure that Wnt proteins “promote more rapid
effective healing of bone fractures in the elderly” (Shaughnessy [0030]), we
are not persuaded that the results Appellants obtained using liposomal
formulations would have been considered unexpected.

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Moreover, “when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991).
Also, “[m]ere improvement in properties does not always suffice to
show unexpected results. . . . [W]hen an applicant demonstrates substantially
improved results . . . and states that the results were unexpected, this should
suffice to establish unexpected results in the absence of evidence to the
contrary.” In re Soni, 54 F.3d 746, 751 (Fed. Cir. 1995).
Here, Shaughnessy describes obtaining significant results in a bone
tumor model using a non-liposomal Wnt formulation (see Shaughnessy
[0061] (Example 14)). In contrast, the Specification does not explain the
specific conditions of the experiments which produced negative results using
purified and fibrin glue-incorporated Wnt3a proteins (see Spec. [0087],
[0096]). Thus, we are not persuaded that Appellants have demonstrated that
Shaughnessy’s methods do not work, as Appellants argue.
Moreover, given that Shaughnessy’s non-liposomal preparations were
active, whereas Appellants’ non-liposomal preparations were not, it does not
appear that Appellants compared the liposomal compositions used in claim
11 to the closest functional non-liposomal compositions from the prior art.
Absent such a comparison, we are not persuaded that Appellants have
adequately demonstrated a substantial improvement over the prior art. See
In re Baxter Travenol Labs., 952 F.2d at 392.
Moreover, while Appellants’ briefs assert that the results obtained
using liposomal formulations show “a surprising effect [which] could not
have been predicted from the teachings of the cited art” (App. Br. 11; Reply
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Br 3), other than the briefs, Appellants point to no such assertion in the
Specification, or elsewhere in the record. It is well settled that argument by
counsel is no substitute for actual evidence of non-obviousness. See In re
Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997).
In sum, for the reasons discussed, Appellants’ arguments do not
persuade us that the Examiner erred in finding that an ordinary artisan would
have been prompted to accelerate bone repair in a mammal by administering
a Wnt liposomal formulation encompassed by claim 11. As we are also not
persuaded, for the reasons discussed, that Appellants have advanced
evidence of unexpected results sufficient to outweigh the evidence of prima
facie obviousness advanced by the Examiner, we affirm the Examiner’s
rejection of claim 11. As they were argued in the same group as claim 11
(App. Br. 5), claims 16-19 fall with claim 11.
As also discussed above, given Shaughnessy’s express disclosure that
“Wnt-3a protein may be directly administered at the site of a lytic lesion to
promote osteoblast differentiation and spontaneous healing” (Shaughnessy
[0030]), Appellants’ arguments do not persuade us that the Examiner erred
in finding that an ordinary artisan would have been prompted to administer
liposomal Wnt3a formulations, such as taught or suggested by Matthews,
Larsen, and Perreault, directly to the site of a bone injury, as recited in claim
12. We therefore affirm the Examiner’s obviousness rejection of that claim,
as well as claims 13-15, which were argued in the same claim grouping (see
App. Br. 5).

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Application 12/074,766

20
SUMMARY
We affirm the Examiner’s anticipation rejection of claims 1 and 5-8
over Matthews.
We also affirm the Examiner’s obviousness rejection of claims 3, 8, 9,
and 11-19 over Matthews, Shaughnessy, Larsen, Perreault, and Weissig.

TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

cdc