DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The examiner of this application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Sharon Wen, Group Art Unit 1641, Technology Center 1600.
Applicant’s amendment, filed 12/01/2025, has been entered.
Claims 1-25 are pending.
Election/Restrictions
Applicant’s election of Group I in the reply filed on 05/12/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The previous Species Election requirement has been withdrawn.
Claims 8-24 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Inventions, there being no allowable generic or linking claim.
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.
Claims 1-7 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Hong et al. (J Immunother 2017 40:201-210; reference of record) in view of Scheinberg et al. (US 2019/0227063 A1), further in view of Guasp et al. (Molecular & Cellular Proteomics 2019, 18(8):1491–1510; cited in IDS), and further in view of Oliveira et al. (Journal of Immunology 2013, 191:4020-4028).
Hong et al. teach genetically engineering human cells by multiplex CRISPR/Cas9-mediated disruption of the endogenous HLA-A, HLA-B, and HLA-C genes to generate an HLA class I-null human cell line (see entire document, in particular, see, e.g., Summary). Hong further teaches introducing an individual HLA class I allele into the engineered HLA-null cells, thereby generating an antigen-presentation platform in which peptides are presented exclusively by the introduced HLA allele (see Discussion). Hong explains that elimination of endogenous HLA class I molecules prevents competing peptide presentation and permits accurate evaluation of HLA-restricted antigen presentation and T-cell responses (Summary).
Accordingly, Hong teaches an isolated engineered human cell: 1) lacking expression of HLA-A, HLA-B and HLA-C and 2) expressing a single HLA allele. Hong does not expressly disclose disruption of TAP1, TAP2, ERAP1, ERAP2, HM13, or ER-targeted expression of candidate epitope peptides.
Scheinberg et al. teaches engineered antigen-presentation systems for identifying MHC class I peptide epitopes (see entire document, in particular, see, e.g., paragraph 0052, claim 37). Scheinberg teaches recombinant nucleic acids comprising an endoplasmic reticulum (ER) signal sequence operably linked to a candidate epitope peptide, whereby the peptide is directed into the ER for loading onto HLA class I molecules (see, e.g., Claims 1-3).
Scheinberg further teaches use of T2 cells, which are deficient in TAP-mediated peptide transport, thereby minimizing endogenous peptide loading and permitting controlled presentation of experimentally introduced peptides (see, e.g., paragraph 0014).
Scheinberg additionally teaches that the ER-targeting sequence may comprise the MMTV gp70 signal peptide, including modified MMTV gp70 leader sequences for directing candidate peptides into the ER (see, e.g., paragraphs 0018 and 0051).
Accordingly, Scheinberg teaches: 1) TAP-deficient antigen-presentation cells;
2) expression of candidate epitope peptides; 3) trafficking of candidate peptides into the ER; and 4) use of the MMTV gp70 signal peptide. Scheinberg does not expressly disclose disruption of ERAP1, ERAP2, or HM13.
Guasp et al. teach CRISPR/Cas9-mediated disruption of ERAP1, ERAP2, and combined ERAP1/ERAP2 in engineered human cells expressing a single HLA class I allele (see entire document, in particular, see, e.g., Abstract). Guasp explain that ERAP1 and ERAP2 are the principal aminopeptidases responsible for trimming peptides within the endoplasmic reticulum before loading onto HLA class I molecules and demonstrate that elimination of these aminopeptidases alters the repertoire of peptides presented by HLA class I molecules (see Discussion).
Accordingly, Guasp teach engineered antigen-presentation cells lacking expression of 1) ERAP1; 2) ERAP2; and 3) both ERAP1 and ERAP2.
Oliveira et al. teach that HM13, also known as signal peptide peptidase (SPP), is an intramembrane aspartyl protease that cleaves signal peptides within the endoplasmic reticulum membrane to generate C-terminal peptide fragments suitable for presentation by MHC class I molecules (see entire document). Oliveira demonstrates that this antigen-processing pathway is independent of TAP activity, thereby establishing HM13 as an alternative source of endogenous MHC class I ligands (page 4026, first paragraph).
Importantly, Oliveira further demonstrates that silencing HM13 results in a general reduction of surface peptide-MHC class I complexes, thereby establishing that HM13 contributes directly to endogenous HLA class I peptide presentation. Oliveira conclude that HM13 is involved in antigen processing and presentation and constitutes a significant source of endogenous peptide ligands presented by MHC class I molecules (Discussion).
Accordingly, Oliveira teaches that HM13 is a known component of the endogenous antigen-processing machinery whose activity contributes to background HLA class I peptide presentation.
One of ordinary skill in the art would have been motivated to combine the teachings of Hong and Scheinberg because both references are directed to engineering cells that provide simplified and reproducible HLA class I antigen presentation. Hong teaches eliminating endogenous HLA-A, HLA-B, and HLA-C expression while expressing only a single HLA allele to eliminate competing HLA presentation. Scheinberg teaches TAP-deficient antigen-presentation cells together with direct ER delivery of candidate epitopes using an ER-targeting signal peptide to minimize endogenous peptide loading. Combining these teachings would have predictably produced an antigen-presentation platform having reduced background peptide presentation and improved specificity for evaluating peptide-HLA interactions.
One of ordinary skill in the art further would have been motivated to incorporate the teachings of Guasp because ERAP1 and ERAP2 were well known to trim peptides before HLA class I loading. Eliminating ERAP1 and ERAP2 would have predictably further reduce endogenous peptide processing and standardize the peptide repertoire presented by the engineered single-HLA cells, thereby improving the reproducibility and sensitivity of peptide-screening assays.
Furthermore, Oliveira demonstrates that HM13 generates TAP-independent endogenous MHC class I ligands and that silencing HM13 reduces surface peptide-MHC class I complexes. Thus, the prior art recognized that elimination of TAP-dependent peptide transport alone does not eliminate endogenous peptide presentation because HM13 continues to generate endogenous signal peptide-derived ligands through an alternative antigen-processing pathway. Since the objective of both Hong and Scheinberg is to minimize endogenous peptide presentation while maximizing presentation of experimentally introduced candidate epitopes, one of ordinary skill in the art would have recognized HM13 as another known contributor to endogenous peptide generation whose elimination would further reduce background peptide presentation. Therefore, it would have been obvious to incorporate HM13 disruption into the engineered antigen-presentation platform as a predictable optimization to further suppress endogenous HLA class I peptide presentation and improve the fidelity, specificity, and reproducibility of peptide screening. The proposed combination merely combines known genetic modifications that each reduce endogenous antigen processing or simplify HLA class I peptide presentation, thereby predictably improving the specificity, fidelity, and reproducibility of engineered antigen-presentation platforms for evaluation of peptide-HLA interactions. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (when there is a known problem and a finite number of identified, predictable solutions, pursuing the known options is likely the product of ordinary skill rather than innovation).
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention as evidenced by the combined teachings of Hong et al., Scheinberg et al., Guasp et al., and Oliveira et al., especially in the absence of evidence to the contrary.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
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/SHARON X WEN/Primary Examiner, Art Unit 1641
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