DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
The amendment of 03 September 2025 has been entered in full. Claim 28 is amended. Claims 1-27 and 31 are cancelled.
Claims 28-30 and 32-35 are under consideration in the instant application.
Maintained Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1. Claims 33 and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
1a. Claim 33 recites that the core molecule of the multimeric complex of claim 28 is a liposome comprising antibodies that specifically bind the two or more fusion proteins. However, since the fusion proteins consist essentially of a variable region of the extracellular domain of human CD33 and an immunoglobulin Fc region, it is not clear what antigen the antibodies comprised in the liposome are directed against. For instance, are the antibodies anti-CD33 or anti-Fc? One skilled in the art would not be reasonably apprised of the scope the invention because the antibody selection affects how the fusion protein is oriented on the liposome.
1b. Claim 34 is rejected as being indefinite because lines 1-2 recite that the antibodies that bind the two or more fusion proteins and comprised in the liposome specifically bind a biotin acceptor peptide. However, claim 28, from which claim 34 ultimately depends, does not require that the recombinant fusion protein comprises a biotin acceptor peptide. Therefore, it is not clear how the antibodies recited in claim 34 would bind the two or more fusion proteins.
(i) At page 4 of the Response of 03 September 2025, Applicant states that without conceding to the merit of the rejection, and in an effort to advance prosecution, claim 28 has been amended to clarify that the recombinant fusion proteins consist essentially of: (a) a variable region of the extracellular domain of human CD33; (b) an immunoglobulin Fc region; and (c) an optional affinity tag.
Applicant’s arguments and claim amendment have been fully considered but are not found to be persuasive. Specifically, neither Applicant’s brief argument nor claim amendment has addressed the two issues set forth by the Examiner in the previous Office Action:
First, regarding claim 33, it is not clear what antigen the antibodies comprised in the liposome are directed against. For instance, are the antibodies anti-CD33 or anti-Fc? One skilled in the art would not be reasonably apprised of the scope the invention because the antibody selection affects how the fusion protein is oriented on the liposome.
Second, regarding claim 34, although claim 28 has been amended to recite an optional affinity tag, there is still no limitation recited in claims 28 or 33 that the optional affinity tag comprised in the fusion proteins is a biotin acceptor peptide. Many different affinity tags (other than biotin) were well known in the art at the time of filing the instant application (see for example, entirety of Kimple et al., Curr Protocol Prot Sci 9.9.1-9.9.23, 2013), so simply reciting the “optional affinity tag” limitation in claim 28 still lends to a gap to the antibodies that bind a biotin acceptor peptide recited in claim 34. In other words, since claims 28 and 33 do not require that the recombinant fusion protein comprises a biotin acceptor peptide it is not clear how the antibodies recited in claim 34 would bind the two or more fusion proteins. Please note that this second issue could be overcome by amending claim 34 to recite, for example, “The multimeric complex of claim 33, wherein the optional affinity tag is a biotin acceptor peptide and wherein the antibodies specifically bind [a] the biotin acceptor peptide”.
Maintained Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Wilson et al. and Czajkowsky et al.
2. Claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (WO 2012/083370; cited on the IDS of 22 May 2023) and Czajkowsky et al. (EMBO Mol Med 4(10): 1015-1028, 2012; cited on the IDS of 22 May 2023). The basis for this rejection is set forth at pages 3-6 of the previous Office Action of 03 March 2025.
(i) It is noted that at page 5 of the Response of 03 September 2025, Applicant cites pertinent case law reviewing the legal standard of obviousness. The Examiner takes no issue with Applicant's general comments regarding the legal standard for obviousness.
(ii) At the bottom of page 5, Applicant argues that the disclosure of Wilson et al. is aimed at providing an antibody with a modified IgG4 Fc region to improve the in vivo half-life of the constructs (page 1, lines 7-11). Applicant states that Wilson notes that the modified antibody can include an antibody that specifically binds to CD33 (huMab195). Applicant contends that although the Office points to Wilson’s purported description of a human CD33 extracellular domain including the same amino acid sequence of SEQ ID NOs: 3 & 4, Wilson does not utilize hCD33 ECD in the context of a fusion protein. Applicant argues that Wilson describes a DNA fragment encoding the hCD33 ECD is ligated with DNA encoding a (His)6 tag and a thrombin cleavage site before being ligated to an IgG1 Fc-encoding DNA fragment. Applicant asserts that the resulting protein sequence described in Wilson is subsequently treated with thrombin to remove the Fc potion and isolated before being used to coat an ELISA microwell to measure the half-life of Fc modified huMab195 antibodies (page 53, line 26 through page 54, line 28). Applicant concludes Wilson does not disclose a recombinant fusion protein consisting essentially of a variable region of the extracellular domain of human CD33; and an immunoglobulin Fc region, let alone provide sufficient motivation to modify the hCD33 ECD as described to be formed as a multimeric complex including two or more recombinant fusion proteins as presently claimed.
Applicant’s arguments have been fully considered but are not found to be persuasive. Contrary to Applicant’s arguments that Wilson et al. do not utilize human CD33 extracellular domain in the context of a fusion protein with Fc (and that the protein is instead treated with thrombin to remove the Fc), Applicant’s attention is directed to page 13, line 11 of Wilson et al., which states, “Figure 7 shows the sequence of the human CD33 extracellular domain-Fc fusion protein”.
Wilson et al. clearly teach a human CD33 extracellular domain-immunoglobulin Fc fusion protein (page 13, line 11; page 53, lines 26-34; Figure 7). It is noted that the CD33 extracellular domain-Fc fusion protein of Wilson et al. even comprises the variable region amino acid sequence of SEQ ID NO: 3 or 4 of instant claims 29 and 30 (see SEQ ID NO: 13 of Wilson et al.; see sequence alignments provided in the previous Office Action).
Although Wilson et al. disclose that the fusion protein may be treated with thrombin to remove the Fc region, Wilson’s disclosure of more than one alternative does not constitute a teaching away from any of the disclosed alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed (see MPEP 2123(II); In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Additionally, “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments” (see MPEP 2123(II); In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)).
The Examiner acknowledges that Wilson et al. do not teach a multimeric complex comprising two or more recombinant CD33 extracellular domain-Fc fusion proteins conjugated to a core molecule or particle.
However, Czajkowsky et al. review the engineering of the Fc-domain for specific applications (page 1015). Specifically, Czajkowsky et al. teach that although mass spectrometry and yeast-two-hybrid technologies are useful for investigating protein-protein interactions, they are hampered by their inability to detect low affinity binding events that are often observed during cell-cell or cell-matrix contact (page 1024, column 1, 1st full paragraph). Czajkowsky et al. indicate that Fc-fusion proteins have been assembled into multivalent complexes using scaffolds such as protein-G/A microbeads (page 1024, column 1, 1st full paragraph; Figure 2C (first panel)).
As discussed at page 6 of the previous Office Action of 03 March 2025, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the CD33 extracellular domain-Fc fusion protein as taught by Wilson et al. by conjugating two or more of the fusion proteins onto protein-G/A microbeads to generate a multivalent complex as taught by Czajkowsky et al. The person of ordinary skill in the art would have been motivated to make that modification to detect low affinity binding of anti-CD33 antibodies or a ligand (for example) in non-clinical applications, such as protein microarrays (see Czajkowsky et al., page 1023, column 2, last paragraph; page 1024, 1st full paragraph; Figure 2C;; see also, Wilson et al., page 45, lines 6-19; page 54, lines 16-28). The person of ordinary skill in the art reasonably would have expected success because similar multimeric complexes were already being generated with other Fc-fusion proteins at the time the invention was made (see Czajkowsky et al., page 1024, column 1). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Wilson et al., Cannon et al., and Sano et al.
3. Claims 28-30, 32, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (WO 2012/083370; cited on the IDS of 22 May 2023), Cannon et al. (Methods Mol Biol 748: 51-67, 2011; cited on the IDS of 22 May 2023) and Sano et al. (J Chromatogr B 715: 85-91, 1998). The basis for this rejection is set forth at pages 7-10 of the previous Office Action of 03 March 2025.
(i) At the bottom of page 6 of the Response of 03 September 2025, Applicant argues that as discussed above, Wilson does not disclose or suggest the subject matter of claim 28. Applicant submits that the combination of Cannon and Sano fails to remedy the deficiencies of Wilson.
Applicant’s arguments have been fully considered but are not found to be persuasive. Contrary to Applicant’s arguments that Wilson et al. do not utilize human CD33 extracellular domain in the context of a fusion protein with Fc (and that the protein is instead treated with thrombin to remove the Fc), Applicant’s attention is directed to page 13, line 11 of Wilson et al., which states, “Figure 7 shows the sequence of the human CD33 extracellular domain-Fc fusion protein”.
Wilson et al. clearly teach a human CD33 extracellular domain-immunoglobulin Fc fusion protein (page 13, line 11; page 53, lines 26-34; Figure 7). It is noted that the CD33 extracellular domain-Fc fusion protein of Wilson et al. even comprises the variable region amino acid sequence of SEQ ID NO: 3 or 4 of instant claims 29 and 30 (see SEQ ID NO: 13 of Wilson et al.; see sequence alignments provided in the previous Office Action).
Although Wilson et al. disclose that the fusion protein may be treated with thrombin to remove the Fc region, Wilson’s disclosure of more than one alternative does not constitute a teaching away from any of the disclosed alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed (see MPEP 2123(II); In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Additionally, “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments” (see MPEP 2123(II); In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)).
Wilson et al. do not teach a multimeric complex comprising two or more recombinant CD33 extracellular domain-Fc fusion proteins conjugated to a core molecule or particle. Wilson et al. also do not teach that the core molecule is streptavidin and that the two or more fusion proteins are biotinylated.
However, as discussed at page 8 of the previous Office Action of 03 March 2025, Cannon et al. teach that recombinant protein reagents in which a protein domain of interest has been fused to the Fc region of immunoglobulin have been used in diverse applications that require detection of binding of a receptor (or other) domain to target ligands (page 51, 1st paragraph). Cannon et al. state that the IgG Fc moiety confers an intrinsic dimerization and bivalent binding function to the protein, providing an increase in avidity of binding and that such an increase can be invaluable in the study of interactions of relatively low affinity (page 51, 1st paragraph). Cannon et al. also disclose that the widespread commercial availability of diverse, labeled secondary serological reagents capable of detecting the Fc region enhances experimental utility of such reagents (page 51, 1st paragraph). Cannon et al. review protocols for the generation of expression vectors that allow the subcloning of cDNA fragments encoding protein domains of interest to the Fc regions of human IgG1 (page 52, 1st paragraph). Cannon et al. indicate that the vectors also encode a C-terminal target sequence for E. coli biotin ligase, such that when included, this sequence allows the site-specific addition of a biotin tag to a specific residue near the C-terminus of the recombinant Fc fragment (page 52, 1st paragraph; Figure 1). Cannon et al. teach that expressed constructs can interact with either protein A or streptavidin for use in purification or affinity assays (page 55, 1st full paragraph).
Sano et al. teach that streptavidin is a stable tetrameric protein that binds up to four molecules of D-biotin with high affinity (page 85, columns 1-2). Sano et al. disclose that streptavidin can maintain its functional structure at high temperatures, extremes of pH, and in the presence of high concentrations of denaturants and organic solvents (page 85, column 2). Streptavidin is also stable against proteolysis (page 85, column 2). Sano et al. point out that these unique properties of streptavidin, along with the ability to biotin to be easily incorporated into various biological materials, allow streptavidin to serve as a versatile, powerful affinity tag in a variety of biological applications, including diagnostics (page 85, bottom of column 2 through page 86, column 1).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the CD33 extracellular domain-Fc fusion protein as taught by Wilson et al. by biotinylating the fusion protein and conjugating four of the fusion proteins onto a core streptavidin molecule to generate a multimeric complex as taught by Cannon et al. and Sano et al. The person of ordinary skill in the art would have been motivated to make those modifications to detect or capture low affinity binding of anti-CD33 antibodies or a ligand (for example) in biological applications such as microtiter plates, gel matrices, and microbeads (see Cannon et al., pages 51-52, top of page 55; Sano et al., page 87, column 1; Wilson et al., page 45, lines 6-19). The person of ordinary skill in the art reasonably would have expected success because streptavidin complexes were already being successfully generated with other biotinylated proteins at the time the invention was made (see Sano et al., page 86, top of column 1). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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BEB
Art Unit 1647
17 November 2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647