DETAILED ACTION
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/Claims
Applicant’s response filed on 3/9/2026 has been considered.
Claims 5 and 8 have been canceled. Claim 7 has been amended. Claims 1, 3-4, 7 and 9-20 are pending. Claims 15-16 and 18-20 are withdrawn from further consideration, without traverse, pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 3-4, 7, 9-14 and 17 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/061,339 filed on 2/3/2017 and DIV of 15/424,372, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 2/4/2016.
Claim Interpretation
Applicants use of the terms “immunoglobulin-binding peptide” and “cell surface tether protein” will be given their broadest reasonable interpretation in light of the specification. It is noted that although these terms are broad, they are considered functionally defined.
“Large-scale” as recited in claim 17 is interpreted broadly as the production of more than 10 antibody secreting cells.
“Derived from” as described in claim 10 is interpreted broadly as any peptide or mutated peptide thereof sharing sequence or functional homology to the recited list of peptides to any degree.
Maintained Claim Rejection - 35 USC § 112b
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.
Claim 7 is 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 pre-AIA the applicant regards as the invention. This rejection is maintained with respect to the Office action mailed on 12/9/2025. A response to applicant’s traversal follows the reiterated rejection below.
Claim 7 describes “promoters” selected from B Lymphocyte-Induced Maturation Protein 1, Syndecan 1, Tumor Necrosis Factor Receptor Superfamily Member 17, or Fucosyltransferase 1 genes. Applicants’ amendments specify that the promoter is selected from a promoter that drives expression of said genes. Claim 7 is an improper Markish form; a Markush group should be in the for “a promoter selected from the group consisting of A, B and C”. Currently, it is not clear which species are included in the Markush group listing.
Response to Traversal
Applicant traverses the rejection by pointing to amendments to claim 7 which describe promoters that drive expression of a selected gene.
This argument has been fully considered, but is not found persuasive since it is still unclear which specific promoter the claims are referencing.
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 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.
Claims 1, 4, 7, 9, 12-14 and 17 stand rejected under 35 U.S.C. 103 as being unpatentable over Ait-Azzouzene et al. "An immunoglobulin Cκ-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system." The Journal of experimental medicine 201.5 (2005): 817-828 (hereinafter Azzouzene, reference of record) in view of Meagher et al. US 2003/0162947, published 8/28/2003 (hereinafter Meagher, reference of record). This rejection is maintained with respect to the Office action mailed on 12/9/2025. A response to applicant’s traversal follows the reiterated rejection below.
Claim 1: Ait-Azzouzene teaches the expression of a membrane-tethered anti-Igk-reactive single chain antibody which was generated by assembling a single chain Fv (scFv) from the variable genes of a rat anti-mouse hybridoma (Ait-Azzouzene, pg 818). This scFv was engineered to be expressed as a membrane protein on the surface of all cells in a mouse model, including B cells using a nucleic acid vector comprising a promoter operably linked to a nucleic acid sequence coding for the immunoglobulin-binding peptide and a nucleic acid coding for a surface tether peptide (Ait-Azzouzene, abstract, pg 818, 819 and Fig 3). The scFv specifically recognizes and binds to the constant region of the mouse k light chain immunoglobulin (Ait-Azzouzene, pg 818). Ait-Azzouzene uses a ubiquitin C promoter which would drive expression in all cell types including immature B cells and antigen-inexperienced mature B cells.
Claim 4: Ait-Azzouzene describes expression in all cells in a mouse model, including B cells using a nucleic acid vector comprising a promoter operably linked to a nucleic acid sequence coding for the immunoglobulin-binding peptide and a nucleic acid coding for a surface tether peptide (Ait-Azzouzene, abstract, pg 818, 819 and Fig 3).
Claim 9: Ait-Azzouzene describes a membrane-tethered anti-Igk-reactive single chain antibody which contains a transmembrane and intracytoplasmic region derived from the H-2Kb gene (Ait-Azzouzene, pg 818)
Although Ait-Azzouzene uses the use of a ubiquitin C promoter, the prior art teaches other promoters which allow for selective expression in mature antibody-secreting cells as well as reporter constructs thereof.
Claim 1: Meagher describes myeloma cells which are transfected with an expression vector comprising a promoter operably linked to Igα (CD79A) and Igβ (CD79B) to form a hybridoma antibody-secreting cell (Meagher, para 25, 39, 144). With respect to the limitations describing a promoter which is expressed in antibody-secreting cells but not immature B cells, it is emphasized that Meagher describes the use of inducible promoter systems including tetracycline-responsive promoters and syndecan-1 promoters (Meagher, para 230). According to applicants’ specification and the limitations set forth in claim 7, syndecan-1 promoters fit this functional definition since they are preferentially expressed in antibody-secreting cells.
Claim 7: Meagher describes the use of constitutive or inducible promoters (Meagher, para 164). Meagher describes the use of inducible promoter systems including tetracycline-responsive promoters and syndecan-1 promoters (Meagher, para 230). According to applicants’ specification, the specific promoters listed by Meagher are preferentially expressed in antibody-secreting cells.
Claims 12-14: Meagher describes the use of nucleic acid vectors comprising fluorescent reporter peptides liked to IRES sequences which can be used for quantification via FACS (Meagher, para 40-42, 241 and claims 78-79, 85, 114 and Figs 6-7).
Claim 17: Meagher describes methods for large scale and rapid production of antibodies by generating hundreds of antibody secreting cells (Meagher, claim 138, 147).
It would have been prima facie obvious to one of ordinary skill in the art to use the inducible tetracycline-responsive promoters or syndecan-1 promoters described by Meagher in the expression vector for generating the antibody-secreting cells described by Ait-Azzouzene rather than the constitutive ubiquitin C promoter. It would have been a matter of simple substitution of one known promoter type for another to obtain predictable results (constitutive for inducible). One of ordinary skill would have been motivated to make this substitution since the inducible tetracycline-responsive promoter would allow for temporal control of gene expression and is well known in the art. Furthermore, the membrane-tethered anti-Igk-reactive single chain antibody would help in purifying the antibody-secreting cells because the tethered molecule can act as a specific cell-surface marker for fluorescence-based flow cytometry or magnetic-based sorting. One would have a reasonable expectation of success given that the substitution of known promoters is fundamental and routine using predictable molecular biology techniques. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1, 4, 7, 9, 12-14 and 17 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that a person of skill in the art would have no reason to look to Meagher to modify the method of Ait-Azzouzene because the methods of producing hybridomas described in Meagher are distinct from studying the mechanisms of B cell tolerance. Applicant argues that the Office has not provided a reason that would have led a person of ordinary skill to generate an ASC expressing a membrane-bound immunoglobulin-capturing molecule as claimed. Applicant argues that it would have been a matter of simple substitution for a person of skill in the art to select the promoter described by Meagher.
This argument has been fully considered, but is not found persuasive. Although it is acknowledged that Ait-Azzouzene is mainly focused on the use of a ubiquitin C promoter, the prior art teaches other promoters which allow for selective expression in mature antibody-secreting cells as well as reporter constructs thereof. For example, Meagher describes the use of constitutive or inducible promoters like inducible promoter systems including tetracycline-responsive promoters and syndecan-1 promoters, which according to applicants’ specification, are preferentially expressed in antibody-secreting cells (Meagher, para 230). Thus, it would have been a matter of simple substitution of one known promoter for another to obtain predictable results. One of ordinary skill would have been motivated to make this substitution since the inducible tetracycline-responsive promoter would allow for temporal control of gene expression, enabling expression specifically after B cells have matured into antibody-secreting cells, thereby avoiding any developmental effects in immature B cells. It is emphasized that the motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their commonly known purpose, see MPEP 2144. The rationale to modify or combine prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles or legal precedence established by case law, see MPEP 2144.
Applicant further argues that Ait-Azzouzene teaches away from expressing the Igk-macroself antigen in B cells by using a model wherein the Igk-macroself antigen is expressed in all cells except for the bone marrow. Applicant argues that the temporal limitation on expression is important because premature expression of the immunoglobulin capturing molecule in immature B cells disrupts normal B cell differentiation into plasma cells and would not have been obvious.
This argument has been fully considered, but is not found persuasive since the membrane-tethered anti-Igk-reactive single chain antibody would help in purifying the antibody-secreting cells because the tethered molecule can act as a specific cell-surface marker for fluorescence-based flow cytometry or magnetic-based sorting. With respect to the temporal limitation on expression, the inducible tetracycline-responsive promoter would allow for temporal control of gene expression, enabling expression specifically after B cells have matured into antibody-secreting cells, thereby avoiding any developmental effects in immature B cells. Thus, one would have a reasonable expectation of success given that the substitution of known promoters is fundamental and routine using predictable molecular biology techniques.
Claims 1, 3-4, 7, 9-14 and 17 stand rejected under 35 U.S.C. 103 as being unpatentable over Ait-Azzouzene (supra) and Meagher (supra) as applied to claims 1, 4, 7, 9, 12-14 and 17 above in further view of Cheng et al. "Membrane‐tethered proteins for basic research, imaging, and therapy." Medicinal Research Reviews 28.6 (2008): 885-928 (hereinafter Cheng, reference of record). This rejection is maintained with respect to the Office action mailed on 12/9/2025. A response to applicant’s traversal follows the reiterated rejection below.
A description of Ait-Azzouzene and Meagher can be found above. Neither Ait-Azzouzene nor Meagher describe an immunoglobulin-binding peptide derived from a bacterial Protein A or G, a transmembrane peptide derived from human lymphocyte activation gene 3, human CD58, rat CD2, human CD7 or a C-terminal peptide sequence that mediates glycosylphosphatidylinositol linkage to the plasma membrane. However, it is noted that Meagher does describe the use of Protein A-Sepharose as a means for conventional immunoglobulin purification (Meagher, para 72).
Claim 3: Cheng describes how chimeric proteins can be retargeted and tethered on the surface of mammalian cells (Cheng, pg 2 and Fig 1). In table I, Cheng provides a list of membrane-anchored chimeric proteins and methods to achieve efficient surface expression (Cheng, Table 1, Fig 2-3 and section 3). Taken together with the disclosure of Meagher using Protein A-Sepharose as a means for conventional immunoglobulin purification, one of ordinary skill could readily conceive of using Protein A to generate tethered immunoglobulin-binding peptides based on Protein A.
Claim 10: In Table III, Cheng describes membrane-anchored antibodies including transmembrane domains from CD58 with an anti-human CD28 scFv functional extracellular domain (Cheng, Table III).
Claim 11: Cheng describes glycosylphosphatidylinositol (GPI) anchored proteins (Cheng, section 2). In Fig 1, Cheng shows C-terminal peptide sequences that mediates glycosylphosphatidylinositol linkage to the plasma membrane.
It would have been prima facie obvious to one of ordinary skill in the art to select the immunoglobulin-binding peptide derived from a bacterial Protein A and cell surface tether peptide derived from human CD58 in which the C-terminal peptide sequence is used to mediate glycosylphosphatidylinositol linkage to the plasma membrane as described by Cheng in the methods for generating antibody-secreting cells as described by Ait-Azzouzene in view of Meagher. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Cheng offers a reliable mechanism for achieve efficient membrane-anchored expression of known chimeric proteins and antibodies. Furthermore, it is emphasized that although specific peptides are described in claims 3 and 10, the language of “derived from” reads on a broad range of possible peptides which correspond to those embodiments disclosed by Cheng in Tables 1-3 and the Protein A-Sepharose use case described by Meagher. One of ordinary skill would have been motivated to make this combination in order to more efficiently produce monoclonal antibodies with specificity for an antigen of interest. One would have a reasonable expectation of success given the predictable mechanism shown by Cheung in expressing chimeric membrane-tethered proteins in antibody secreting cells. Furthermore, Cheng states that the modular nature of antibodies means that antigen-binding can be reconstituted in small scFv molecules, thus increasing the range of vectors that can be employed to express membrane-tethered antibodies (Cheng, pg 23). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by pointing to previous arguments and stating that Cheng does not cure the deficiencies of Meagher and Ait-Azzouzene.
This argument has been fully considered, but is not found persuasive and applicant is invited to review previous arguments.
Conclusion
No claims allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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