DETAILED ACTION
Claims 1, 3-4, 6, 10, 12-16, 20-21, 24-28, 30, and 38 are pending.
Status of Claims
Claims 1, 3-4, 6, 10, 12-16, 20-21, 24-28, 30, and 38 are pending. Claims 1, 3-4, 12-13, 15, 20-21, 24, and 26 have been amended. Claim 38 has been newly added. Claims 1, 3-4, 6, 10, 12-16, 20-21, 24-28, 30, and 38 are under examination.
Withdrawn Claim Objections and/or Rejections
The objection of claims 1, 12, and 24-26 for minor informalities as set forth on pp. 2 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended claims (filed on 03/29/2026).
The rejection of claims 4, 15, 21, and 23-24 under 35 USC 112(b) as being indefinite as set forth on p. 2-5 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended and cancelled claims (filed on 03/29/2026).
The rejection of claims 1, 6, 10, and 16 under 35 USC 102 as being anticipated by Wright et al., as set forth on pp. 5-6 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended claims (filed on 03/29/2026).
The rejection of claims 2-3 and 4 under 35 USC 103 as being unpatentable over Wright and Repasky et al., as set forth on p. 7 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended and cancelled claims (filed on 03/29/2026).
The rejection of claims 12-14 under 35 USC 103 as being unpatentable over Wright and Gustafson et al., as set forth on pp. 8-9 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended claims (filed on 03/29/2026).
The rejection of claim 15 under 35 USC 103 as being unpatentable over Wright and Wu et al., as set forth on pp. 9-10 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended claims (filed on 03/29/2026).
The rejection of claims 24-25 under 35 USC 103 as being unpatentable over Wright and Kyogoku et al., as set forth on pp. 10-11 of the previous office action (mailed on 01/21/2026) has been withdrawn in view of the amended claims (filed on 03/29/2026).
Claim Objections
1.Claims 3 is objected to because of the following informalities:
Claims 3 recites abbreviations and/or acronyms. The biomarkers should be spelled out at their first usage followed by the abbreviation/acronym in parenthesis.
Claim 3 recites “PD-L2” and “anti-CTLA4” but does not spell out the name of the biomarkers.
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed 03/29/2026 have been fully considered but they are not persuasive.
On p. 6 applicant argues that all claims have been amended to fully spell out the name of the proteins when they first appear in the claims.
However, claim 3 depends on claim 1. PD-L2 and anti-CTLA4 are not fully spelled out in claims 1 or 3. Therefore, the objection still stands.
Claim Rejections - 35 USC § 103-Necessitated by Amendments
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
2.Claims 1, 3-4, 6, 10, 16, 20-21, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al., “Neutrophil biomarkers predict response to therapy with tumor necrosis factor inhibitors in rheumatoid arthritis.” Journal of leukocyte biology vol. 101,3 (2017): 785-795. doi:10.1189/jlb.5A0616-258R (IDS filed on 05/26/2024), Pfaender et al., “LY6E impairs coronavirus fusion and confers immune control of viral disease”. Nat Microbiol 5, 1330–1339 (2020). https://doi.org/10.1038/s41564-020-0769-y, in view of Repasky et al., (US20180051084A1) (effectively filed on 03/14/2016), as evidenced by Al-Hossiny et al., “Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance”. Cancer Res. 2016 Jun 1;76(11):3376-86. doi: 10.1158/0008-5472.CAN-15-2654. Epub 2016 Apr 11. PMID: 27197181; PMCID: PMC4910623.
Instant claim 1 recites “a method of treating a subject suffering from cancer with an immunotherapy, the method comprising determining suitability of the subject to be treated with the immunotherapy by receiving a sample from the subject, and measuring lymphocyte antigen 6E (Ly6E} expression in individual neutrophils in said sample, wherein the presence in said sample of neutrophils expressing Ly6E above a predetermined threshold indicates said subject is suitable to be treated with said immunotherapy, wherein said immunotherapy comprises an immune checkpoint inhibitor (ICI) and wherein the method further comprises administering the immunotherapy to the suitable subject”.
Wright teaches measuring a neutrophil biomarkers (such as LY6E) in a subject in order
to predict the response to TNFi therapy (a known immunotherapy) (see abstract, see table 1
on page 788, see table 2 on page 792). Wright teaches that there is a threshold used for each
biomarker in order to predict “responders” and “nonresponsers” for TNFi therapy (see page 787
under statistical analysis) (instant claims 1 and 24-25). Wright teaches administering TNFi therapy and measuring the response after 12 weeks (see figure 3, see page 791) (instant claim 1). Wright teaches taking a sample before the subject receives immunotherapy (see figure 3) (instant claim 10) and the sample being a bodily fluid (blood) (see abstract) (instant claim 6). Wright teaches wherein said measuring comprises measuring Ly6E mRNA expression (see pages 787, 789, and 792) (instant claim 16).
While Wright does not explicitly teach the neutrophils expressing LY6E above a predetermined threshold that is making up greater than 30% and 70% of all neutrophils to indicate the subject is suitable to be treated with immunotherapy, Wright does teach a threshold for each biomarker and correlating the threshold to predicting responders and non-responders (see page 787 under statistical analysis). It would have been obvious to one of ordinary skill in the art to perform routine optimization of determining the level of LY6E in neutrophils and comparing it to a predetermined threshold of LY6E and correlating the predetermined threshold to the suitability of the subject for immunotherapy. Comparing levels of a biomarker to a pre-determined level of said biomarker is a common practice in the art of diagnostics and treatments. Absent evidence of the contrary, it would have been obvious to one of ordinary skill in the art to routinely optimize the level of neutrophils expressing LY6E to be 30-70+% of all neutrophils (instant claims 20-21).
Wright does not teach measuring LY6E in individual neutrophils, the subject having cancer, nor does Wright teach the immunotherapy comprising an immune checkpoint inhibitor (ICI).
Pfaender teaches measuring lymphocyte antigen 6E (Ly6E) expression in individual neutrophils in a sample (see page 1330 “To confirm the presence of LY6E in respiratory cells that are targeted by human CoVs, we examined expression in primary human airway epithelial cells (hAECs) by single-cell RNA sequencing (scRNA-seq). LY6E was widely expressed in all cell types, with the greatest levels observed in goblet cells (Fig. 1i).”) (instant claim 1). Pfaender teaches measuring LY6E and STAT1 (see figures 1c-1h) (instant claims 24-25).
Pfaender does not teach wherein said immunotherapy comprises an immune checkpoint inhibitor (ICI).
Repasky teaches administering immunotherapy with the immune checkpoint inhibitor
anti-PD-1 to breast cancer subjects (see [0006], see [0029]) (instant claims 1 and 3-4).
Al-Hossiny teaches that increased expression in LY6E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes (see abstract). Al-Hossiny teaches that Ly6E expression is present in all breast cancer cell line with higher levels in ER positive breast cancer cell lines (see page 5). Al-Hossiny further teaches that Ly6E correlates specifically with breast cancer subset with increase PDL1 and CTLA-4 (see page 7). Thus, Ly6E was a known cancer biomarker at the time of the instant application.
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to combine Wrights teachings of treating a subject with cancer an immunotherapy
with Pfaender’s methods of measuring LY6E in individual neutrophils, with Repasky’s teachings of administering immunotherapy with the immune checkpoint inhibitor anti-PD-1 to cancer subjects, with Al-Hossiny’s teaching of Ly6E in cancer. Pfaender provides motivation by teaching that single cell RNAS sequencing (scRNA-seq) detects the expression of LY6E in individual cells (see page 1330), thus at the time of the instant application measuring a biomarkers expression in individual cells (such as neutrophils) was a known and used technique at the time. Repasky provides motivation by teaching that the use of checkpoint inhibitors can inhibit the growth of the cancer (see [0009]). Repasky further provides motivation by teaching that anti-PD-1 will bind to PD-1 molecules, which is expressed on the surface of activated immune cells (cytotoxic T lymphocytes) and prevent ligation by tumor expressed PD-L1 which would otherwise lead to CTL (cytotoxic T lymphocyte) inhibition, thus preventing the immune- check point (see [0033]). Al-Hossiny provides motivation by teaching that Ly6E is present in all subtypes of breast cancer (see page 5). Thus, it would have been obvious for one of ordinary skill in the art to use Ly6E as a cancer diagnosis, prognosis, and treatment guidance biomarker. The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
3.Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Wright, Pfaender, Repasky, and Al-Hossiny et al., as applied to claims 1, 3-4, 6, 10, 16, 20-21, and 24-25 above, in view of Gustafson et al. “A method for identification and analysis of non-overlapping myeloid immunophenotypes in humans.” PloS one vol. 10,3 e0121546. 23 Mar. 2015, doi:10.1371/journal.pone.0121546 (Notice of References Cited filed on 01/21/2026).
The teachings of Wright, Pfaender, Repasky, and Al-Hossiny as it pertains to claims 1, 3-4, 6, 10, 16, 20-21, and 24-25 are discussed in the 35 USC 103 rejection above.
Wright teaches treating a subject with an immunotherapy when the biomarkers are above a predetermined threshold (see page 787 under statistical analysis) (instant claims 12-13).
Wright does not teach the neutrophils being CD45+, HLA-DR-, Lin-, CD11b+, CD33+, CD14-, and CD15+ cells, and the neutrophils being granulocytic MDSCs.
Gustafson teaches the neutrophils being CD45+ (see figure 3A, see page 17 “The data generated from our protocols will permit detection of well over 120 immunophenotypes but could potentially reach 2.9 x 106 (9! x 8 for each protocol) for CD45+ cells.”), HLA-DR- (see page 2 “In general, human MDSCs comprise a diverse group of CD33+HLA-DR- cells that includes cells granulocytic cells (CD15+ or CD66b+), monocytes that have lost or diminished HLA-DR expression (CD14+HLA-DRlo/neg monocytes or monocytic MDSCs)”), Lin- (see page 2 “immature myeloid cells (Lineage-), although many other cell surface markers have been used
to identify these cells”, see figure 5, see page 13 “As basophils have also been shown to
express CD123[25], and can also be defined as LIN-CD33+HLA-DR-“), CD11b+ (see table 2,
see page 16 “Since granulocytes from healthy individuals are CD33+CD11b+HLA-DR- and do
express Arginase-I[30], additional phenotypic markers and/or functional assays are needed to
further define granulocytic MDSCs.”), CD33+ (see page 2 “general, human MDSCs comprise a
diverse group of CD33+HLA-DR- cells that includes cells granulocytic cells (CD15+ or
CD66b+)”, see page 16), CD14- (see page 6 “and lineage negative cells that are CD14-CD3-
CD19-CD16-CD56… The CD14- cells contain a mixture of lymphocytes and immature cells. For
simplicity, we denoted the CD14- gate “Lymphocytes” (colored orange)”, see figure 2A, see
table 2), and CD15+ (see table 2, see page 2 “In general, human MDSCs comprise a diverse
group of CD33+HLA-DR- cells that includes cells granulocytic cells (CD15+ or CD66b+)”, see
page 6 “Granulocytes gated by high side scatter were assessed for CD15 and CD16 to enumerate neutrophils (CD15+CD16+)”) (instant claim 12). Gustafson teaches wherein the
neutrophils are myeloid derived suppressor cells (MDSCs) that are granulocytic MDSCs (see
page 2 “In general, human MDSCs comprise a diverse group of CD33+HLA-DR- cells that
includes cells granulocytic cells (CD15+ or CD66b+)”, see page 11 “LIN2negHLA-DRneg cells
include both immature MDSCs and granulocytes/granulocytic MDSCs as previously defined”)
(instant claims 13-14).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to combine Wrights teachings of treating a subject with an immunotherapy with Pfaender’s methods of measuring LY6E in individual neutrophils, with Repasky’s teachings of administering immunotherapy with the immune checkpoint inhibitor anti-PD-1 to cancer subjects, with Al-Hossiny’s teaching of Ly6E in cancer, with Gustafsons teachings of specialized types of neutrophils. Gustafson provides motivation by teaching that in genera human MDSCs comprise a diverse group of CD33+ HLA- DR- cells that include granulocytic cells (CD15+ or CD66v+), monocytes that have lost or diminished HLA-DR expression (CD14+HLA-DR lo/neg monocytes or monocytic MDSCs), and immature myeloid cells (lineage -) (see page 2). Grustafson provides motivation by teaching that MDSCs are of great interest due to their role in tumor-mediated immune suppression (see page 16). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
4.Claims 15 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Wright, Pfaender, Repasky, Al-Hossiny, and Gustafsons et al., as applied to claims 12-14 above, in view of Wu et al., “Distinct Role of CD11b+Ly6G- Ly6C- Myeloid-Derived Cells on the Progression of the Primary Tumor and Therapy-Associated Recurrent Brain Tumor.” Cells vol. 9,1 51. 24 Dec. 2019, doi:10.3390/cells9010051”.
The teachings of Wright, Pfaender, Repasky, Al-Hossiny, and Gustafsons as it pertains to claims 12-14 are discussed in the 35 USC 103 rejection above.
Wright does not teach the the G-MDSC being polymononuclear (PMN)-MDSC.
Wu teaches wherein said G-MDSC is a polymononuclear (PMN)- MDSC (see abstract) (instant claim 15) and wherein said PMN-MDSCs are CD45+/CD11b+/ Ly6CLow/Ly6G+/Ly6E+ cells (see abstract, see page 13) (instant claim 38).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to combine Wrights teachings of treating a subject with an immunotherapy with Pfaender’s methods of measuring LY6E in individual neutrophils, with Repasky’s teachings of administering immunotherapy with the immune checkpoint inhibitor anti-PD-1 to cancer subjects, with Al-Hossiny’s teaching of Ly6E in cancer, with Wu’s teaching of polymorphonuclear myeloid-derived suppressor cells. Wu provides motivation by teaching that myeloid-derived suppressor cells (MDSCs) are involved in the promotion of rapid tumor proliferation and create a microenvironment that supports tumor survival by stimulating angiogenesis, promoting tumor invasion, and suppressing the anti-tumor immunity (see page 1). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Response to Arguments
Applicant's arguments filed 03/29/2026 have been fully considered but they are not persuasive.
On pp. 8-9 applicant argues that Wright does not teach the new limitations of measuring Ly6E expression in individual neutrophils and the subject having cancer and that a skilled artisan would not have any expectation of success in taking a biomarker from one disease and brining it to another.
Wright teaches measuring neutrophil biomarkers in a subject in order to predict the subjects response to immunotherapy. Applicant is correct that Wright does not teach measuring individual neutrophils and the subject having cancer.
However, Pfaender teaches the use of scRNA-seq to measure LY6E in individual cells. Repasky teaches the subject having cancer and being treated with an immunotherapy with immune checkpoint inhibitor anti-PD-1.
It would have been obvious to one of ordinary skill in the art to combine Wright, Pfaender, and Repasky. Wright and Repasky both teach treating a suitable subject with immunotherapy. Pfaender teaches the ability to measure LY6E in individual neutrophils. While Pfaender does not teach the subject having cancer, it would have been obvious to one of ordinary skill in the art to use the methods of measuring biomarkers in individual neutrophils in a subject who has cancer, because as Pfaender teaches it is a widely known and used technique in the art and the artisan would have a reasonable expectation of success. Repasky teaches using ICI immunotherapy to treat a breast cancer subject (see [0006], see [0029]). Al-Houssiny teaches that LY6E is a biomarker found in all breast cancer subtypes (see page 5). Thus, it would have been obvious to one of ordinary skill in the art to determine the suitability of a subject to be treated with ICI immunotherapy by receiving a sample from the subject, measuring a known cancer biomarker in the sample, determining the presence of the biomarker in the sample, then treating the subject with an ICI immunotherapy if the expression of the biomarker is above a predetermined threshold.
Further, in regards to the argument that one would not expect success in taking a biomarker from one disease and bringing it into another. Al-Hossiny teaches that LY6E is used as a cancer biomarker (see page 5). Al-Hossiny provides motivation for using Ly6E as a biomarker for a subject suffering from cancer. Al-Hossiny teaches that Ly6E is a marker found in all breast cancer subtypes (see page 5). Al-Hossiny teaches that increased expression in LY6E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes (see abstract). Al-Hossiny further teaches that Ly6E is required for the growth of human breast cancer cells (see page 7). Thus, at the time of the instant application, one of ordinary skill in the art would have expectation of success in measuring Ly6E for cancer, because as Al-Hossiny teaches it was a known cancer biomarker at the time of the instant application.
Allowable Subject Matter
Claims 26-28 and 30 are allowed.
Conclusion
Claims 1, 3-4, 6, 10, 12-16, 20-21, 24-25, and 38 are not allowed. Claims 26-28 and 30 are 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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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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