Ex Parte LogtenbergDownload PDFBoard of Patent Appeals and InterferencesApr 10, 201010184508 (B.P.A.I. Apr. 10, 2010) Copy Citation 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 Copy with citationCopy as parenthetical citation