Ex Parte Logtenberg

Board of Patent Appeals and Interferences

Apr 10, 2010

10184508 (B.P.A.I. Apr. 10, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte TON LOGTENBERG
__________

Appeal 2009-000090
Application 10/184,508
Technology Center 1600
__________

Decided: April 12, 2010
__________

Before JAMES T. MOORE, Vice Chief Administrative Patent Judge,
TONI R. SCHEINER and JEFFREY N. FREDMAN, Administrative Patent
Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the rejection of claims
11, 18-21, 25, and 26, directed to a method for obtaining a mutant antibody,
single chain Fv fragment, or Fab fragment. The claims have been rejected as
obvious under 35 U.S.C. §103. We have jurisdiction under 35 U.S.C.
§ 6(b).
We affirm.
Appeal 2009-000090
Application 10/184,508

2
STATEMENT OF THE CASE
Claims 11, 18-21, 25, and 26 are pending and on appeal.1 Appellant’s
arguments, for the most part, concern claim 11, the broadest claim on
appeal. However, Appellant also makes specific arguments concerning the
anti-Ep-CAM monoclonal antibody UBS-54 (App. Br. 16), a feature which
appears in dependent claim 26. Therefore, we select claims 11 and 26 as
representative of the subject matter on appeal (37 C.F.R. § 41.37(c)(1)(vii)
(2006)):
11. A method for obtaining a mutant derived from a parental
binding molecule, said parental binding molecule being selected from the
group consisting of an antibody, a single chain Fv fragment and a Fab
fragment, the method comprising:
generating a phage display library of mutants derived from the
parental binding molecule;
incubating the phage display library with a cell or a crude cellular
extract thereof, the cell or crude cellular extract thereof comprising an
epitope capable of being bound by the parental binding molecule;
selecting at least once for phages binding to the cell or crude cellular
extract thereof comprising the epitope;
separating, recovering and isolating the phages binding to the cell or
crude cellular extract thereof comprising the epitope; and screening for a
mutant having a higher affinity for the epitope compared to the parental
binding molecule.

26. The method according to claim 11, wherein the parental binding
molecule is UBS-54.

1 The cover sheet of the Final Office Action mailed September 26, 2006
listed claim 26 as objected to, but the office action itself included claim 26 in
the obviousness rejection. In responding to Appellant’s Brief, the Examiner
reiterated that claim 26 was included in the rejection (Ans. 2). Appellant
does not dispute this in his Reply Brief. Therefore, we consider claim 26 to
be subject to the outstanding obviousness rejection.
Appeal 2009-000090
Application 10/184,508

3

The Examiner rejected claims 11, 18-21, 25, and 26 under 35 U.S.C.
§ 103(a) as unpatentable over Yelton,2 Huls,3 Balzar,4 and Hoogenboom.5, 6

ISSUES
Claim 11
Claim 11 is directed to a method for obtaining a mutant antibody,
single chain Fv fragment, or Fab fragment derived from a parent binding
molecule comprising: generating a phage display library of mutants;
incubating the library with a cell or cell extract containing an epitope bound
by the parent molecule; selecting and isolating phages binding to the cell or
cell extract; and screening for a mutant with a higher affinity for the epitope
than the parent molecule.
Yelton discloses a method of obtaining “mutant BR96 antibodies and
functional equivalents thereof which exhibit higher and improved affinity to

2 European Patent Application No. EP 0,699,756 A1 of Yelton, published
March 6, 1996.
3 Gerwin Huls et al., Antitumor Immune Effector Mechanisms Recruited by
Phage Display-derived Fully Human IgG1 and IgA1 Monoclonal
Antibodies, 59 CANCER RESEARCH 5778-5784 (1999). This reference was
submitted with Appellant’s IDS filed July 13, 2006, and newly cited in the
Final Rejection mailed September 9, 2006. Appellant does not dispute this
reference in the Appeal or Reply Briefs.
4 M. Balzar et al., The Biology of the 17-1A Antigen (Ep-CAM), 77 J. MOL.
MED. 699-712 (1999).
5 Hennie R. Hoogenboom et al., Selection-Dominant and Nonaccessible
Epitopes on Cell-Surface Receptors Revealed by Cell-Panning with a Large
Phage Antibody Library, 260 EUR. J. BIOCHEM. 774-784 (1999).
6 A rejection of the claims under 35 U.S.C. § 112, first paragraph, was
withdrawn by the Examiner (Ans. 3).
Appeal 2009-000090
Application 10/184,508

4
. . . a BR96 antigen, than BR96” (Yelton 2: 9-10) by generating mutagenized
BR96 Fab phage display libraries, and screening the resultant Fab molecules
against cells expressing the BR96 antigen for Fab molecules with a higher
affinity for the BR96 antigen than the parent BR96 antibody (id., Examples
1 and 2).
Hoogenboom teaches that selection of phage antibodies to cell-surface
antigens can be accomplished by “[a]ny method that separates clones that
bind from those that do not” (Hoogenboom 774, col. 1), and discloses a
“direct cell-panning” method “us[ing] a large phage antibody fragment
library to select on cell transfectants expressing . . . chosen receptors” (id.,
Abstract).
The issue raised by this rejection with respect to claim 11 is: Does
the evidence of record support the Examiner’s conclusion that screening
Yelton’s mutagenized BR96 phage display library - rather than the isolated
Fab products of that library - with cells expressing the epitope recognized by
BR96, would have been obvious given Hoogenboom’s teaching that the
expression products of a library can be screened by incubating the library
with a cell expressing the epitope of interest?
Claim 26
Claim 26 depends from claim 11 and specifies that the parental
binding molecule is the antibody UBS-54.
Balzar teaches that Ep-CAM (Epithelial Cell Adhesion Molecule) “is
present on most carcinomas, which makes it an attractive target for
immunotherapy” (Balzar, Abstract), and the extracellular domain is one of
the most immuno-dominant epitopes at the cell surface (id. at 705).
Appeal 2009-000090
Application 10/184,508

5
Huls discloses phage-display derived human UBS-54 anti-Ep-CAM
monoclonal antibodies (Huls, Abstract).
The issue raised by this rejection with respect to claim 26 is: Does the
evidence of record support the Examiner’s conclusion that it would have
been obvious to generate a mutagenized phage display library of Huls’ UBS-
54 antibody, and to screen the library against a cell expressing Ep-CAM for
molecules with higher affinity for Ep-CAM than UBS-54?

FINDINGS OF FACT
FF1 Yelton discloses “mutant BR96 antibodies and functional
equivalents thereof which exhibit higher and improved affinity to . . . a
BR96 antigen, than BR96” (Yelton 2: 9-10).
FF2 The BR96 antigen is expressed on the surface of tumor cells
(Yelton 2: 53).
FF3 Yelton generated a phage display library containing “mutant
BR96 polypeptides . . . having a variable region comprising an amino acid
sequence substantially homologous to the variable region of BR96 . . .
[thereby] increasing the affinity of mutant BR96 to a BR96 antigen” (Yelton
3: 46-48).
FF4 Yelton analyzed “[p]urified mutant BR96 M1 IgG and mutant
BR96 M4 IgG . . . for binding specificity to tumor cells, tumor-derived cell
lines, and normal tissues” (Yelton 27: 12-13). Thus, Yelton screened the
isolated, purified products of the phage display library on cells expressing
the BR96 antigen, rather than screening the library directly, as required by
the claims on appeal.
Appeal 2009-000090
Application 10/184,508

6
FF5 Hoogenboom teaches that selection of phage antibodies to cell-
surface antigens can be accomplished by “[a]ny method that separates clones
that bind from those that do not” (Hoogenboom 774, col. 1). For example,
Hoogenboom discloses a direct cell-panning technique “for the isolation of
antibody fragments to predetermined cell-surface antigens from a naïve
scFV phage antibody library by selection and screening on live cells, which
express high levels of these antigens” (id., at 780, col. 2).
FF6 “By direct panning on cells expressing the rat or human CD36
antigens, 14 and 20 different antigen-binding antibodies were isolated,
respectively. These numbers compare positively with the yield of more
‘conventional’ selections on purified, immobilized antigens” (Hoogenboom
781, col. 1).
FF7 “Using the same methodology and starting with the same
[naïve] library . . . [was] not, however, successful in isolating antibody
fragments to one of the somatostatin receptors” (Hoogenboom 781-782).
FF8 Somatostatin is a member of the 7-transmembrane G-protein-
coupled receptor family (Hoogenboom 774).
These receptors bind their small peptide ligand within their
transmembrane helices, while on the extracellular side, they
display a short yet heavily glycosylated N-terminal region.
Antibodies that recognize the native receptor have been difficult
to raise, in part due to this membranous nature . . . and due to
the lack of immunogenicity. Despite extensive efforts using the
traditional hybridoma technique, no mAb are available to
extracellular epitopes present on any of the intact [somatostatin]
subtypes.

(Id. at 775.)
Appeal 2009-000090
Application 10/184,508

7
Hoogenboom suggests that “the failure to select receptor-specific
antibodies is due to the glycosylation of the extracellular N-terminus of the
receptor, which stops antibodies from reaching the peptide core of the
receptor” (id. at 783, col. 1-2).
FF9 Hoogenboom teaches that direct cell-panning is a particularly
effective technique “when using immune libraries in which the frequency of
irrelevant phage antibodies will be lower” (Hoogenboom 774, col. 2).
FF10 Yelton’s phage display library is an immune library, because it
contains mutants derived from, and homologous to, the monoclonal antibody
BR96 (Yelton 3: 46-48), rather than the diverse repertoire of a naïve (i.e.,
non-immune) library.
FF11 Balzar teaches that Ep-CAM (Epithelial Cell Adhesion
Molecule) “is present on most carcinomas, which makes it an attractive
target for immunotherapy” (Balzar, Abstract).
FF12 According to Balzar, “the extracellular domain of the Ep-CAM
molecule is one of the most immuno-dominant epitopes at the cell surface”
(Balzar 705).
FF13 Huls discloses “a human scFv antibody fragment specific for
human Ep-CAM” obtained by “subtractive phage selection on colon
carcinoma cells” (Huls 5778, col. 2). The V regions encoding the scFv
antibody fragment were recloned to generate fully human monoclonal
antibodies of the IgG1 and IgA1 isotypes: UBS-54/IgG1 and UBS-54/IgA1
(id.).
FF14 UBS-54/IgA1 is more effective in recruiting peripheral blood
PMNs for tumor cell killing than UBS-54/IgG1 (Huls 5780).

Appeal 2009-000090
Application 10/184,508

8
PRINCIPLES OF LAW
A reference must be read, not in isolation, but for what it fairly
teaches in combination with the prior art as a whole. In re Merck & Co.,
Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). “The combination of familiar
elements according to known methods is likely to be obvious when it does
no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550
U.S. 398, 416 (2007).

ANALYSIS
Claim 11
The evidence of record supports the Examiner’s conclusion that the
invention of claim 11 would have been obvious over the prior art, given
Yelton’s teaching that mutagenized phage display libraries can be used to
obtain mutant antibodies with increased affinity to a cell-surface antigen
than the parent antibody (FF3), and Hoogenboom’s teaching that direct cell
panning of a phage library is an effective technique for isolating antibodies
with desirable properties from the library (FF5, FF6).
Appellant contends that “Yelton discloses contacting individually
expressed Fab, scFv and antibody molecules” (App. Br. 15), rather than “a
phage display library” (id.), with “cells or fractions thereof” (id.), while
“Hoogenboom discloses the isolation of phage antibodies from a naive scFv
phage display library to predetermined cell-surface antigens” (id. at 16),
rather than a library of “mutants of a parental binding molecule” (id. at 16-
17). Appellant contends that “a person skilled in the art . . . would have
refrained from using cells or cellular extracts for selections of mutant
antibody libraries” because “no reasonable expectation of success exists”
Appeal 2009-000090
Application 10/184,508

9
(id. at 17), since “Hoogenboom discloses that CD36-specific phage
antibodies can be selected . . . by using cells carrying CD36, but that the
same methodology was unsuccessful when somatostatin was the antigen”
(id.) (emphasis omitted).
These arguments are not persuasive for several reasons. Hoogenboom
teaches that direct panning of a phage library on intact cells is an effective
technique for obtaining antibodies specific for cell-surface antigens, and
antibodies to CD36 were readily isolated from a naïve phage display library
using this technique (FF5, FF6). While it’s true that direct panning was
unsuccessful with native somatostatin (FF7), we don’t agree with Appellant
that this would have discouraged one skilled in the art from using the
panning technique for Yelton’s antigen. Native, undenatured somatostatin
was well known in the art as a particularly difficult antigen to raise
antibodies against because of its relatively small, highly glycosylated
extracellular domain - in fact, according to Hoogenboom, no monoclonal
antibodies specific for extracellular epitopes present on any intact subtype of
somatostatin had been made by any technique (FF8). Yelton, on the other
hand, provides evidence that BR96 antigen expressed on the surface of
tumor cells is readily accessible to BR96 and isolated mutants of BR96
(FF2, FF6). Appellant has not explained why one skilled in the art would
not have expected the BR96 antigen to be similarly accessible to BR96
mutants during direct panning of Yelton’s phage library.
Moreover, Yelton’s library is an immune library since all of the
antibodies in it are derived from, and homologous to, the parent BR96
antibody (FF10). Hoogenboom teaches that direct cell panning of phage
libraries is a particularly effective selection technique when screening
Appeal 2009-000090
Application 10/184,508

10
immune libraries, because of the low frequency of irrelevant phage
antibodies (FF9).
Claim 26
Claim 26 depends from claim 11 and specifies that the parental
binding molecule is the antibody UBS-54. Appellant contends that
[T]here is no motivation to combine the disclosure of Huls with
that of Yelton [to isolate mutants of UBS-54], because the focus
of Huls is on rapidly finding new clinically applicable human
monoclonal antibodies. For that purpose, Huls uses a
semisynthetic library having multiple specificities. Huls is not
interested in finding high affinity mutants of a single antibody.

(App. Br. 16.)
This argument is not persuasive. Huls used a phage display library to
construct and express a recombinant, fully human IgA1 antibody, USB-
54/IgA1, which had advantages over its IgG1 counterpart, USB-54/IgG1
(FF13, FF14). In other words, Huls used a phage display library to obtain a
new version of the USB-54 antibody with improved properties. Yelton
discloses an alternative method of obtaining an improved (i.e., mutant)
version of an antibody.

CONCLUSIONS OF LAW
The evidence of record supports the Examiner’s conclusion that
screening Yelton’s mutagenized BR96 phage display library with cells
expressing the epitope recognized by BR96 would have been obvious given
Hoogenboom’s teaching that the expression products of a library can be
screened by incubating the library with a cell expressing the epitope of
interest.
Appeal 2009-000090
Application 10/184,508

11
In addition, the evidence of record supports the Examiner’s
conclusion that it would have been obvious to generate a mutagenized phage
display library of Huls’ UBS-54 antibody, and to screen the library against a
cell expressing Ep-CAM.
The Examiner’s rejection of claims 11, 18-21, 25, and 26 under
35 U.S.C. § 103(a) as unpatentable over Yelton, Huls, Balzar, and
Hoogenboom is affirmed.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

dm

TRASKBRITT, P.C.
P.O. BOX 2550
SALT LAKE CITY, UT 84110