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 .
This action is in response to the papers filed August 20, 2025.
Election/Restrictions
Applicant’s election without traverse of inventive Group I, claims 1-5, 8-9, 11, 14, 19-25, 28-29, and 31-40 in the reply filed on March 7, 2025 is acknowledged.
Applicant’s election without traverse of “sequencing mRNA or genomic DNA” as a species of methods of detecting aberrant proteins in the reply filed on March 7, 2025 is acknowledged.
Applicant’s election without traverse of “Immunotherapy comprising administering to the subject an antibody that binds to a fragment of a protein, wherein the fragment comprises an aberrant amino acid sequence presented by an MHC molecule on a surface of the cell” as a species of “administering to the subject an immunotherapy” in the reply filed on March 7, 2025 is acknowledged.
Priority/Effective Filing Date
The present application, filed on May 24, 2022 is a 371 of PCT/US2020/62495, filed on November 27, 2020 and claims priority to 62/942,728, filed on December 2, 2019.
Claim Status and Action Summary
Claims 1-5, 8-9, 11, 14, 19-25, 29, 31-40 and 44 are pending in this application.
Claim 44 is withdrawn as directed to a non-elected invention.
Claim 14 is withdrawn as directed to a non-elected species “performing mass spectrometry of proteins…”
Claims 34-37 are withdrawn as directed to non-elected species of “administering to the subject an immunotherapy”.
Claim 28 was canceled by applicant.
Claims 1-5, 8-9, 11, 19-25, 29, 31-33 and 38-40 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections to the claims have been withdrawn in view of the claim amendments.
The rejections of record under 35 U.S.C. 112 have been withdrawn in view of the claim amendments.
The rejection of record under 35 U.S.C. 102 over Incyte WO2003/062391 A2 has been withdrawn in view of the claim amendments comprising incorporating the limitations of claim 28, now canceled, into claim 1.
Claim Rejections - 35 USC § 103
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 1-3, 5, 8-9, 11, 19-25, 29, 31-32 and 38-40 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Vasserot et al., US 2019/0201510 A1, (Published July 4, 2019) in view of Casella et al., “Transcriptome signature of cellular senescence” Nucleic Acids Research, 2019, Vol 47, No. 14. (Published June 28, 2019).
This rejection has been updated as necessitated by claim amendments.
Regarding claim 1, Vasserot et al. teaches methods comprising detecting senescent cells in tissue samples (i.e. aberrant cells) by detecting aberrant expression of senescence cell associated polypeptides by immunohistochemistry or by quantitative PCR of mRNA from the sample (Vasserot et al., paragraphs 0012-0013) and administering antibodies that bind to specific cell-surface antigens on senescent cells (i.e. aberrant proteins associated with senescence) to a subject to clear senescent cells from a tissue of a subject (i.e. administering an immunotherapy) (Vasserot et al., paragraphs 0145-0146).
Vasserot et al., does not teach that the aberrant proteins are selected using a machine learning model or that the mRNA encoding the aberrant protein is detected by sequencing mRNA or genomic DNA.
However, Casella et al. teaches methods of detecting mRNAs encoding senescent cell associated proteins by RNA sequencing (Casella et al., abstract) and machine learning (Casella et al., page 7302, column 1, paragraph 3) (i.e. selecting senescence associated aberrant proteins). Casella et al. teaches that the senescent cell associated protein-coding RNAs can be used to target senescent cells therapeutically (Casella et al., abstract), including for “senolytic interventions” (Casella et al., page 7304, column 1, paragraph 2). Casella et al. expressly teaches using statistical modeling to find a minimum number of transcripts needed to achieve a discriminatory pattern between senescent and non-senescent cells. Casella et al. teach using supervised logarithmic regression with LASSO “a powerful machine learning and statistical method that is applicable for performing dimensional reduction … to help in feature selection and in revealing hidden biological information” (i.e. Casella et al. teach obtaining a machine learning model that selects features associated with senescence from transcriptomic data) (Casella et al., page 7302, column 1, paragraph 3).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to combine the method of treating a subject with antibodies that bind to cell-surface antigens on senescent cells and clear the senescent cells from a tissue, taught by Vasserot et al., with the method of detecting and selecting mRNAs encoding senescence-associated proteins comprising RNA sequencing and machine learning, taught by Casella et al. The ordinary artisan would have been motivated to combine the methods of clearing senescent cells from a subject’s tissues by administration of an antibody that selectively binds to the surface and facilitates clearance of senescent (i.e. aberrant) cells taught by Vasserot et al., with the method of identifying senescence-associated protein-coding mRNAs by RNA sequencing and machine learning, taught by Casella et al. because of the suggestion of Casella et al. that the senescence-associated mRNA discovery method would be useful in targeting senescent cells in senolytic (i.e. senescent cell killing) therapies (Casella et al., page 7304, column 1, paragraph 2). The methods taught by Vasserot et al. comprising administering antibodies that bind to specific cell-surface antigens on senescent cells (i.e. aberrant proteins associated with senescence) to a subject to clear senescent cells from a tissue of a subject (i.e. administering an immunotherapy) (Vasserot et al., paragraphs 0145-0146) are senolytic therapies. The ordinary artisan would have been reasonably confident that the mRNA sequencing and machine learning method taught by Casella et al. would have successfully detected and selected mRNAs encoding senescence-associated proteins (i.e. aberrant proteins) useful for designing senolytic antibodies suitable for administration in the method taught by Vasserot et al. because of the suggestion of Casella and the demonstrated senescent cell clearing (i.e. senolytic) antibodies taught by Vasserot et al.
Regarding claim 2, Vasserot et al. teaches a senescent cell-associated antigen is mutant beta-actin (i.e. an aberrant structural protein). (Vasserot et al., page 34, table 1, line 1)
Regarding claim 3, Vasserot et al. teaches a senescent cell-associated antigen is mutant beta-actin (gi|28336) (i.e. the aberrant protein is a genetic variant) (Vasserot et al., page 34, table 1, line 1).
Regarding claim 5, Vasserot et al. teaches a senescent cell-associated antigen is mutant beta-actin (gi|28336) (i.e. the aberrant protein is a housekeeping protein) (Vasserot et al., page 34, table 1, line 1). It is noted that the instant specification provides that housekeeping genes include… genes encoding structural proteins (e.g. cytoskeletal) (specification, paragraph 0027).
Regarding claim 8, Vasserot et al. teaches the subject is a human (Vasserot et al., paragraph 0166).
Regarding claim 9, Vasserot et al. teaches the presence of senescent cells can be observed and analyzed by several methods to determine whether the senescent cells have been cleared from a tissue (Vasserot et al., paragraphs 0111-0114) (i.e. the tissue sample prior to administration comprises a preponderance of senescent cells).
Regarding claim 11, Vasserot et al. teaches the sample is a solid tissue biopsy specimen, a bone marrow biopsy sample, or a liquid biopsy sample (Vasserot et al., paragraph 0160).
Regarding claim 19, Vasserot et al. teaches detecting aberrant forms of a plurality of proteins (Vasserot et al., tables 1-3).
Regarding claims 20-21, Vasserot et al. teaches determining the expression of p16 mRNA (a senescence associated aberrant protein) by quantitative PCR (i.e. a measure of the aberrant protein in the sample).
Regarding claims 22-23, Vasserot et al. teaches determining p16INK4a (a senescence associated protein) is undetectable until adulthood (i.e. is above a threshold in adulthood) and expression increases with age (i.e. the measure is a function of the subject’s chronological age) (Vasserot et al., paragraph 0036).
Regarding claim 24, Vasserot et al. teaches the presence of senescent cells can be observed and analyzed by several methods to determine whether the senescent cells have been cleared from a tissue (Vasserot et al., paragraphs 0111-0114) comprising statistical analyses such as ANOVA (i.e. determining a fraction of cells in the tissue expressing the aberrant protein).
Regarding claim 25, Vasserot et al. teaches methods comprising clearing senescent cells can be used in conjunction with chemotherapy (i.e. removing malignant cells in a tissue) (Vasserot et al., paragraph 0168-0170) Therefore it would be obvious that the method comprises sampling tissue biopsies in which a tumor has been removed or successfully treated (i.e. there are not malignant cells present).
Regarding claim 29, Vasserot et al. teaches the sample can be a blood sample (Vasserot et al., paragraph 0160) (i.e. the subject has aberrant cells in organ systems including the circulatory system).
Regarding claim 31, Vasserot et al. teaches the sample is a solid tissue biopsy specimen, a bone marrow biopsy sample, or a liquid biopsy sample (Vasserot et al., paragraph 0160 (i.e. a biopsy sample from the subject detects the presence of aberrant cells expressing the aberrant protein).
Regarding claim 32, Vasserot et al. teaches that a senescence associated aberrant protein may be displayed on the surface of senescent cells in complexes with MHC class 1 molecules (Vasserot et al., paragraph 0036) (i.e. the senolytic antibody binds to a fragment of the aberrant protein presented by an MHC molecule on the surface of a cell).
Regarding claim 38, Vasserot et al. teaches the aberrant cell is a senescent cell (Vasserot et al., paragraphs 0111-0114).
Regarding claim 39, Vasserot et al. teaches the aberrant cell may be senescent cells associated with neurological diseases such as Alzheimer’s disease or Parkinson’s disease (i.e. the aberrant cell is not a malignant cell) (Vasserot et al., paragraph 0171-0174) Furthermore, Vasserot et al. claims a method of removing senescent cells that are not cancer cells (Vasserot et al., claim 5).
Regarding claim 40, Vasserot et al. teaches a senescent cell-associated antigen is mutant beta-actin (gi|28336) (i.e. the aberrant protein is not a transmembrane protein, a membrane-anchored protein, or a protein encoded by an oncogene or a tumor suppressor gene) (Vasserot et al., page 34, table 1, line 1).
Response to arguments
Applicant’s response traverses the rejection of the claims under 35 U.S.C. 103 on the grounds that Casella does not teach or suggest “obtaining a machine learning model that predicts a biological age or senescence of a sample and identifying protein features used by the machine learning model to predict biological age or senescence, thereby identifying aberrant proteins…”. This argument has been thoroughly reviewed and is not persuasive. The 103 rejection as updated more clearly points out the sections of Casella that explicitly teach using a machine learning model trained on expression data from senescent and non-senescent cells to extract features (i.e. expressed genes) that are predictive of the senescent state. Furthermore, emphasis has been added to the sections of Casella that explicitly suggest that senescence-associated gene products would be useful targets for senolytic (i.e. aged-cell killing) therapies. As described above, these teachings and suggestions of Casella would have motivated the ordinary artisan to combine the senescent-cell signature identifying method of Casella with the senescent-cell detecting and eliminating methods comprising senolytic antibodies taught by Vasserot et al.
Claim 4 is/remains rejected under 35 U.S.C. 103 as being unpatentable over Vasserot et al., US 2019/0201510 A1, (Published July 4, 2019) in view of Casella et al., “Transcriptome signature of cellular senescence” Nucleic Acids Research, 2019, Vol 47, No. 14. (Published June 28, 2019) as applied to claims 1-3, 5, 8-9, 11, 19-25, 29, 31-32 and 38-40, and as evidenced by Ohmori et al., 1992.
Regarding claim 4, Vasserot et al. teaches a senescent cell-associated antigen is mutant beta-actin (gi|28336) Ohmori et al. teaches the nucleotide sequence encoding gi|28336 differs from wild type actin by two single nucleotide polymorphisms (i.e. the aberrant protein is a genetic variant; a single nucleotide polymorphism) (Ohmori et al., figure 1).
Response to arguments
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claim 33 is/remains rejected under 35 U.S.C. 103 as being unpatentable over Vasserot et al., US 2019/0201510 A1, (Published July 4, 2019) in view of Casella et al., “Transcriptome signature of cellular senescence” Nucleic Acids Research, 2019, Vol 47, No. 14. (Published June 28, 2019) as applied to claims 1-3, 5, 8-9, 11, 19-25, 29, 31-32 and 38-40 above, and further in view of Squires, US 2016/0166718 A1 (Published June 16, 2016).
Regarding claims 28 and 32, upon which claim 33 depends, and as discussed in the 103 rejection above, Vasserot et al. in view of Casella et al. teaches methods of selecting subjects having senescent (i.e. aberrant) cells that express aberrant proteins in a tissue sample (Vasserot et al., paragraphs 0012-0013), wherein nucleic acids encoding the aberrant proteins are detected by RNA sequencing (Casella et al., abstract) and are selected as being associated with senescence by a machine learning algorithm (Casella et al., page 7302, column 1, paragraph 3). Vasserot et al. in view of Casella et al. further teaches methods comprising administering antibodies that bind to specific cell-surface antigens on senescent cells (i.e. aberrant proteins associated with senescence) to a subject to clear senescent cells from a tissue of a subject (i.e. administering an immunotherapy) (Vasserot et al., paragraphs 0145-0146), wherein the senescence associated aberrant protein may be displayed on the surface of senescent cells in complexes with MHC class 1 molecules (Vasserot et al., paragraph 0036) (i.e. the senolytic antibody binds to a fragment of the aberrant protein presented by an MHC molecule on the surface of a cell).
Vasserot et al. in view of Casella et al. does not teach that the antibody is an antibody-drug conjugate.
However, Squires teaches methods of eliminating senescent cells comprising administering antibodies coupled to a therapeutic or cytotoxic agent (i.e. a drug) that specifically binds to senescent cells (Squires, abstract and paragraph 0122). Squires further teaches that the therapeutic or cytotoxic agents may further include lytic peptides, anti-cancer drugs, anti-depressants, and other drugs (Squires, paragraph 0106-0122).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method of eliminating senescent cells comprising administering senolytic antibodies capable of binding to senescence-associated aberrant proteins presented on an MHC molecule on the surface of senescent cells, taught by Vasserot et al. in view of Casella et al. such that the senolytic antibodies are conjugated to drugs, as taught by Squires. The ordinary artisan would have been reasonably confident that the antibody-drug conjugates, taught by Squires, would have successfully cleared senescent cells from a tissue because of the teaching of Squires that “when coupled to a therapeutic or cytotoxic agent, specific targeting by the agents of the invention (e.g., peptides, polypeptides, proteins, small molecules, antibodies, or antibody fragments that target senescent cells) allows selective destruction of senescent cells… in a human” (Squires, paragraph 0122).
Response to arguments
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682