Ex Parte Rapraeger et al

Board of Patent Appeals and Interferences

Aug 27, 2012

11760594 (B.P.A.I. Aug. 27, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ALAN C. RAPRAEGER and DEANNALEE M. BEAUVAIS
__________

Appeal 2011-000199
Application 11/760,594
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, STEPHEN WALSH, and
JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

Dissenting opinion filed by WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to peptide
inhibitors of syndecan binding to integrins. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

Appeal 2011-000199
Application 11/760,594

2
Statement of the Case
Background
The Specification teaches “peptide segments from the extracellular
domain of syndecan-1 (Sdc-1) that can inhibit angiogenesis and can thus be
used to treat angiogenesis in pathologic conditions” (Spec. 2, ll. 11-13).
The Claims
Claims 1-5, 9, 20, and 81 are on appeal. Claim 1 is representative and
reads as follows:
1. An isolated and purified peptide or
polypeptide segment consisting of between 32 and
100 amino acid residues and comprising SEQ ID
NO:21 or SEQ ID NO:13, wherein the segment is
not SEQ ID NO:28 and said peptide or polypeptide
segment inhibits the binding of syndecan 1 to v3
or v5 integrin.

The issue
The Examiner rejected claims 1-5, 9, 20 and 81 under 35 U.S.C.
§ 103(a) as obvious over Beauvais1 (2004) and Beauvais2 (2003) (Ans. 3-7).
The Examiner finds that Beauvais (2004) “teaches that deletion of
regions of the syndecan-1 (S1) ectodomain (ED) block cell spreading” (Ans.
3). The Examiner finds that Beauvais (2004) “teaches that cells that express
a protein in which amino acids 122-252 are deleted retain function in a cell

1 Beauvais et al., The syndecan-1 ectodomain regulates v3
integrin activity in human mammary carcinoma cells, 167 J. CELL
BIOLOGY 171-181 (2004)
2 Beauvais et al., The syndecan-1 ectodomain is required for v3
integrin-dependent signaling in Human Mammary Carcinoma Cell
Spreading, 14 MOLECULAR BIOLOGY OF THE CELL 272A (2003).
Appeal 2011-000199
Application 11/760,594

3
spreading assay . . . that cells that express a protein lacking amino acids 88-
252 did not retain the function” (Ans. 4). The Examiner finds that Beauvais
(2004) teaches that “further experimentation will be necessary to identify the
active site, but a 34 amino acid stretch shares high identity and homology
between species” (Ans. 4).
The Examiner finds that Beauvais (2003) teaches “that analysis traces
syndecan-1s signaling activity to 35 amino acids unique to the central region
of the S1ED (third to last complete sentence). [Beauvais (2003)] does not
expressly recite the amino acids that make up the 35 amino acid sequence”
(Ans. 4).
The Examiner finds that since Beauvais (2004)
shows positions 88 and 121 as beginning and end points one
would be motivated to make various lengths overlapping a
few residues before and after each of these residues. As
such, one would be motivated to make numerous peptides
including peptides that correspond to residues 88-121, 87-
121,89-121, 88-120,87-120 and 89-120,etc. The peptide that
corresponds to amino acids 89-120 reads on claim 9 of the
instant invention.

(Ans. 6).
Appellants contend that “neither reference shows a peptide that
contains all of SEQ ID NO:21, but is less than 100 amino acids in length,
and that retains the ability to inhibit integrin-mediated attachment and cell
spreading” (App. Br. 4). Appellants contend that “even if the Beauvais et
al. papers had identified a structure in SED responsible for integrin
interaction (which is not the case . . .), that would not mean that the same
element would be sufficient for that function” (App. Br. 4-5).
Appeal 2011-000199
Application 11/760,594

4
Appellants contend that “not only would one be left to try numerous
lengths of peptide to determine the desired function is retained, one would
first have to answer the question of whether any peptide could block
syndecan-l binding to integrins. This is clearly an example of an improper
‘obvious to try’ approach” (App. Br. 6-7). Appellants also rely on the
Sanderson Declaration to support non-obviousness (App. Br. 7-8).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Beauvais (2004) and
Beauvais (2003) render obvious the peptide of claim 1?
Findings of Fact
The following findings of fact (“FF”) are supported by a
preponderance of the evidence of record.
1. Beauvais (2004) teaches that “S1 and the v3 integrin are
functionally coupled via the S1ED and that coupling is required for v3
integrin activation and signaling” (Beauvais (2004) 172, col. 2).
2. Beauvais (2004) teaches that to “identify the properties of S1
required to regulate v3 integrin activity, cells expressing mS1 mutants
were plated on a substratum of mAb 281.2. A mutant that lacks its HS
chains (mS1TDM) retains its ability to spread” (Beauvais (2004) 176, col. 1).
3. Beauvais (2004) teaches that “[c]ells expressing a S1 construct
that lacks either its cytoplasmic domain (mS1280-311) or both its TM and
cytoplasmic domains (GPI-mS1ED) retain their ability to spread, confirming
that activity resides in the S1ED” (Beauvais (2004) 176, col. 1).
4. Figure 6A of Beauvais (2004) is reproduced below:
Appeal 2011-000199
Application 11/760,594

5

“Graphic representation of S1 expression constructs transfected into MDA-
MB-231 cells and their relative expression levels as detected by FACS”
(Beauvais (2004) 175, col. 2, figure 6A legend).
5. Beauvais (2004) teaches that “[m]utants with progressively
larger ED deletions (mS1223-252, mS1202-252, and mS1147-252) all retain
activity (unpublished data) as does a S1 construct (mS1122-252) that lacks
131 amino acids located between the HS attachment sites and the TM
domain” (Beauvais (2004) 176, col. 1).
6. Beauvais (2004) teaches that, however, “cells expressing a
mutant (mS188-252) that lacks 34 additional amino acids, fail to spread; and
spreading cannot be rescued by treatment with mAb P5D2 . . . a treatment
that would have otherwise enhanced v3 integrin activation” (Beauvais
Appeal 2011-000199
Application 11/760,594

6
(2004) 176, col. 1). The “34 additional amino acids” corresponds to amino
acids 88-121 of the S1ED protein.
7. Beauvais (2004) teaches that:
Although further experimentation will be necessary to
identify the active site, a syndecan mutant lacking amino
acids 121–252 of the ED retains activity, whereas one
lacking an additional 34 amino acids (88–252) does not.
Importantly, within this 34–amino acid stretch mS1 and hS1
share 58% identity and 72% homology, indicating that
activity of the S1ED is likely conserved between the species.
This is also evidenced by the fact that overexpression of
either S1 species is sufficient to confer enhanced v3
activity.

(Beauvais (2004) 178, col. 2).
8. Beauvais (2004) teaches that “soluble recombinant S1ED,
which is not tethered to the membrane and unable to sense the mechanical
force imbued by an immobilized ligand, acts as a functional inbibitor of
v3” (Beauvais (2004) 179, col. 1).
9. Beauvais (2003) teaches “[a]ddition of recombinant murine S1
ectodomain (mS1ED), which is not recognized by mAb B-B4, has no effect
on cell adhesion but blocks cell spreading suggesting that mS1ED disrupts a
functional signaling complex involving syndecan-1 and v3 integrins”
(Beauvais (2003)).
10. Beauvais (2003) teaches that “[m]utational analysis traces
syndecan-1’s signaling activity to 35 amino acids unique to the central
region of the S1ED. These data suggest that syndecan-1 and v3 integrins
are functionally coupled via the S1ED and this coupling is required for both
syndecan-1 and v3 integrin signaling” (Beauvais (2003)).
Appeal 2011-000199
Application 11/760,594

7
Principles of Law
The admonition that “obvious to try” is not the standard
under § 103 has been directed mainly at two kinds of error.
In some cases, what would have been “obvious to try”
would have been to vary all parameters or try each of
numerous possible choices until one possibly arrived at a
successful result, where the prior art gave either no
indication of which parameters were critical or no direction
as to which of many possible choices is likely to be
successful. . . . In others, what was “obvious to try” was to
explore a new technology or general approach that seemed
to be a promising field of experimentation, where the prior
art gave only general guidance as to the particular form of
the claimed invention or how to achieve it.

In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988); see also Bayer Schering
Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1347 (Fed. Cir. 2009)
(quoting and citing O’Farrell, 853 F.2d at 903).
Analysis
This is a very close case. The teachings of Beauvais (2004) and
Beauvais (2003) reasonably direct the ordinary artisan to the 34 amino acid
region which was necessary for inhibiting the binding of syndecan to the
v3 integrin and which was identified by deletion analysis (FF 4-10).
Consequently, we conclude that selection of an isolated peptide consisting of
those 34 amino acids along with some additional amino acids would have
been “obvious to try”.
As we balance the teachings in Beauvais (2003) and Beauvais (2004),
we find that the “reasonable expectation of success” falls between the
situations outlined in Pfizer and Takeda. In Pfizer, the Federal Circuit found
that the besylate salt of a known compound was obvious because there was a
Appeal 2011-000199
Application 11/760,594

8
finite number of anions that were “obvious to try” and “ample motivation to
narrow the genus of 53 pharmaceutically-acceptable anions disclosed [in the
prior art] to a few.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1363 (Fed.
Cir. 2007). Distinguishing Pfizer, in Takeda the Federal Circuit found
the prior art disclosed a broad selection of compounds any
one of which could have been selected as a lead compound
for further investigation. Significantly, the closest prior art
compound (compound b, the 6-methyl) exhibited negative
properties that would have directed one of ordinary skill in
the art away from that compound. Thus, this case fails to
present the type of situation contemplated by the Court when
it stated that an invention may be deemed obvious if it was
“obvious to try.”

Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd, 492 F.3d 1350, 1359
(Fed. Cir. 2007).
We conclude that the instant situation is closer to Pfizer than to
Takeda in that there is a reasonable expectation of success, since neither of
the errors identified in O’Farrell apply. This is not a case where the prior
art gave no direction or indication of critical parameters. Indeed, Beauvais
(2004) directly identifies the 34 amino acid region between amino acids 88
and 121 as the active site, and recognizes substantial homology between
mice and humans in this region (FF 7).
This is also not a situation where only general guidance is provided.
Beauvais (2004) teaches that “soluble recombinant S1ED, which is not
tethered to the membrane and unable to sense the mechanical force imbued
by an immobilized ligand, acts as a functional inbibitor of v3” (Beauvais
(2004) 179, col. 1; FF 8). This is specific guidance that the entire protein
functions as an v3 inhibitor, which, along with the specific teaching of the
Appeal 2011-000199
Application 11/760,594

9
34 amino acid region, provides substantial guidance on the selection of the
34 amino acid region as being reasonably expected to function as an
inhibitor of v3 integrin binding to syndecan, as required by claim 1.
We have considered the Sanderson Declaration3, but find that it
supports a finding of reasonable expectation of success. Dr. Sanderson
acknowledges that “when a sequence such as SEQ ID NO:21 is recognized,
these of skill in the art would immediately apprehend that this sequence
could be linked to many other sequences with varying or no particular
functional attributes” (Sanderson Dec. 2 ¶ 4). We understand Dr. Sanderson
to be acknowledging that it is sufficient to identify the 34 amino acid region
as functional, and that additional surrounding amino acids may not impact
the peptides functional capacity.
Dr. Sanderson does contend that “even when an element has been
shown to be necessary for a given function, that does not mean that the same
element is sufficient for that function; nor that the element when provided as
an independent factor would inhibit that function” (Sanderson Dec. 4 ¶ 5).
However, Beauvais (2004) teaches that the entire protein serves to inhibit
the function (FF 4-8) and Beauvais (2003) teaches that “[m]utational
analysis traces syndecan-1’s signaling activity to 35 amino acids unique to
the central region of the S1ED. These data suggest that syndecan-1 and v3
integrins are functionally coupled via the S1ED and this coupling is required
for both syndecan-1 and v3 integrin signaling” (Beauvais (2003); FF 10).
Thus, while Dr. Sanderson suggests that there is no an absolute expectation
of success, the admission that the 35 amino acids are necessary for inhibitory

3 Declaration of Dr. Ralph Sanderson, filed Sep. 10, 2008.
Appeal 2011-000199
Application 11/760,594

10
activity as recognized by Beauvais (2003) provides a reasonably expectation
of success that these amino acids may also be sufficient for the inhibitory
activity.
We acknowledge the dissent’s point that there may have been some
uncertainty for the ordinary artisan since the three dimensional structure of
the protein will, in some cases, impact the function of the protein. Indeed, it
was serendipitous that the 34 amino acid deletion identified by Beauvais
(2004) fully encompassed the functional domain, and that the deletion did
not fall within the domain, requiring additional experimentation to identify
the metes and bounds of the functional domain. We conclude, however, that
neither of these factors alters the “reasonable expectation of success”
calculus in this situation.
The facts are similar to the situation outlined in Kubin, where
“artisans in this field . . . had every motivation to seek and every reasonable
expectation of success in achieving the sequence of the claimed invention”
In re Kubin, 561 F.3d 1351, 1361 (Fed. Cir. 2009). Appellants provide no
evidence that the 34 amino acid region identified by Beauvais (2004) would
not have been the first region an ordinary artisan would have found “obvious
to try” or that the ordinary artisan would have had no “reasonable
expectation of success”. Appellants also provide no evidence of any
secondary considerations which favor nonobviousness.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Beauvais (2004) and Beauvais (2003) render obvious the peptide of claim 1.
Appeal 2011-000199
Application 11/760,594

11
SUMMARY
In summary, we affirm the rejection of claims 1-5, 9, 20 and 81
under 35 U.S.C. § 103(a) as obvious over Beauvais (2004) and Beauvais
(2003).
AFFIRMED

WALSH, Administrative Patent Judge, dissenting.
I respectfully dissent. In my view the evidence does not
support finding a reasonable expectation of success that an isolated
peptide would inhibit binding of syndecan 1 to aVβ3 or aVβ5
integrin. The finding of a reasonable expectation of success is a
question of fact, Medichem v. Rolabo, 437 F.3d 1157, 1165-66
(Fed. Cir. 2006), and evidence supporting the finding must be in
the prior art, In re Vaeck, 947 F.2d 488, 493 (Fed. Cir. 1991); see
also, Velander v. Garner, 348 F.3d 1359, 1376 (Fed. Cir. 2003)
(reviewing the Board’s finding of a reasonable expectation of
success under a “substantial evidence” standard).
As explained in the majority opinion, Beauvais (2004)
taught a goal of identifying properties of S1 required to regulate
integrin activity, and that deletion of regions of the syndecan (S1)
ectodomain (ED) block cell spreading. Cells expressing a deletion
form of S1 lacking amino acids 122-252 retain function in a cell
spreading assay but cells expressing a deletion form of S1 lacking
amino acids 88-252 did not retain the function. The authors
indicated that further experimentation would be necessary to
Appeal 2011-000199
Application 11/760,594

12
identify the active site, and noted that a 34 amino acid stretch
shared high identity between species. It should be noted that the
experiments illustrated in Beauvais (2004) Figure 6 involved
expressing the deletion forms of S1 as transmembrane proteins,
that is, anchored on a cell surface. The authors did not explain the
nature of the further experimentation intended. Nevertheless, the
rejection finds a motivation to experiment with free peptides (not
bound to a cell surface, corresponding to the claimed “isolated and
purified peptide or polypeptide consisting of . . .”) and concludes
the result of experimenting with free peptides would have been
predictable.
Declarant Sanderson states:
Even if one were to assume that it was known that certain
regions of SED were required for integrin activation, that
does not answer the opposite question of how little of the
SED can serve to inhibit integrin activation. These are
distinct technical features, and one does not lead ipso facto
to the other. Put another way, even when an element has
been shown to be necessary for a given function, that does
not mean that the same element is sufficient for that
function; nor that the element when provided as an
independent factor would inhibit that function.
The additional consideration of Beauvais et al. (2004)
does not change my conclusions, set forth above. Beauvais
et al. (2004) is cited as identifying particular deletions of
SED which retain or lack integrin activating function,
including a 34 residue segment that when lost, results in loss
of integrin activation. From this, the examiner concludes
that “one would be motivated to remove additional amino
acids from either side ... of residues 88-121” and thus the
“removal of residues 88 and 121 would result in a peptide
Appeal 2011-000199
Application 11/760,594

13
consisting of residues 89-120,” which just happens to be
SEQ ID NO:21.
However, the examiner is relying on the same flawed
assumption as discussed above, namely, that a discrete
portion of the SED required for integrin activation would
also serve to inhibit integrin activation. Yet as already
stated, this is the difference between necessary and
sufficient sequences, and one does not lead ipso facto to the
other. An amino acid sequence could be critical to the
function of a native protein for many reasons, and could
disable that function if deleted; but it would not necessarily
be expected that a peptide based on that critical sequence
would actively inhibit that function.

(Decl. at ¶ 5.)
The presence of a reasonable expectation of success is
measured from the perspective of a person of ordinary skill in the
art at the time the invention was made. Life Techs., Inc. v.
Clontech Labs., Inc., 224 F.3d 1320, 1326 (Fed. Cir. 2000). A
person of ordinary skill in the art would have been aware of
general protein structure principles including: the activity of S1’s
ectodomain is dependent on the domain’s conformation, and the
conformation in turn is dependent on how the domain’s amino
acids, both adjacent and remote, interact with each other to form
the overall conformation. The conformation of the active site in S1
was unknown. An active site may be the product of different parts
of the sequence folding together, and it cannot be generally
assumed that an active site will be produced by whittling the
domain down to a contiguous string of amino acids. Put another
way, removing amino acids from either end of a peptide having an
Appeal 2011-000199
Application 11/760,594

14
unknown conformation is not analogous to cutting a block of wood
down to a baseball bat. The bulk properties of the wood substrate
remain the same as the mass is reduced, but not so for peptides.
The sum of interactions between constituent amino acids
determines the overall conformation of the peptide, and changing
the consitutent amino acids by deletion, may change the binding
properties of the peptide. Removing amino acids introduces
unpredictability as to conformation and function. Declarant
Sanderson criticizes the rejection’s assumption that removing
additional amino acids in that fashion would reasonably have been
expected to produce the claimed peptides as “flawed.” In my
view, Declarant Sanderson’s assessment is consistent with
generally accepted principles of protein folding.
Appellants argue that the rejection attempts to make out a
case of obviousness based on motivation alone. (App. Br. 8.)
According to Appellants, “both logic and science dictate that there
is a profound lack of predictability with respect to the claimed
peptides and their associated inhibitory functions. Without at
least some predictability, obviousness cannot stand.” (Id.)
The definition of “reasonable expectation” is “somewhat
vague,” Medichem, 437 F.3d at 1165, but evidence of
predictability can support the finding. KSR Int’l Co. v. Teleflex
Inc., 550 U.S. 398, 417 (2007) (“If a person of ordinary skill can
implement a predictable variation, § 103 likely bars its
Appeal 2011-000199
Application 11/760,594

15
patentability.”). Addressing the situation where something might
have been obvious to try, the KSR opinion explains:
When there is a design need or market pressure to solve a
problem and there are a finite number of identified,
predictable solutions, a person of ordinary skill has good
reason to pursue the known options within his or her
technical grasp. If this leads to the anticipated success, it is
likely the product not of innovation but of ordinary skill and
common sense. In that instance the fact that a combination
was obvious to try might show that it was obvious under §
103.

Id. at 421 (emphasis added). I conclude that on this record the two
Beauvais references do not provide sufficient evidence that a
solution was predictable, and that the rejection did not make up the
deficit with other evidence. I would reverse the rejection.

lp