DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s reply filed on 2/18/2026 is acknowledged. Claims 1-62 are pending. Claims 8, 9, 19 and 29-62 are withdrawn from consideration. Claims 1, 4, 6, 12, 21-26 and 28 have been amended. Applicant elected species of (i) a marker for bone marrow derived antigen presenting cells, (ia) a marker for M2 macrophages, (ii) CD155, (iii) an antibody and (iv) CD40 in the reply filed on 10/14/2025.
3. Claims 1-7, 10-18 and 20-28 are under examination.
Objections Withdrawn
4. The objection to claims 21 and 28 for informalities is withdrawn in view of applicant’s amendments.
Rejections Withdrawn
5. All rejections except those maintained below are withdrawn in view of applicant’s amendments.
Rejections Maintained
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 1-4, 10-13, 15 and 25 remain rejected under 35 U.S.C. 103 as being unpatentable over Soon-Shiong (WO 2017/223186A1, pub. date: 12/28/2017, PTO 892 dated 9/3/2025), in view of Liang et al. (WO 2018/220446A1, pub. date: 12/6/2018).
Note: the rejection has been modified in view of applicant’s amendments to the claims.
Regarding claims 1 and 2, Soon-Shiong teaches a method for monitoring treatment of a patient, the method comprising
determining a presence and/or quantity of a patient-specific disease associated protein in a first exosome obtained from a biological fluid of the patient prior to a treatment,
wherein the treatment targets the patient-specific disease associated protein;
determining a presence and/or quantity of the patient-specific disease associated protein in a second exosome obtained from a biological fluid of the patient during or after the treatment,
updating a patient record based on the determination of the presence and/or quantity of the patient-specific disease associated protein in the second exosome,
wherein the step of updating the patient record comprises a recommendation to modify the treatment (claims 1 and 15).
Soon-Shiong teaches exosomes may be isolated using non-specific entrapment and/or antibody-mediated capture, and biological fluid typically include whole blood, serum, plasma or urine ([0013]). The first biological sample, e.g. blood would comprise a first total extracellular vesicle population and the second biological sample would comprise a second total extracellular vesicle population. Soon-Shiong teaches that exosomes can also be further enriched for those originating from a specific cell type and exosomes originating from distinct cell populations can be analyzed for their protein and/or nucleic acid content, e.g. example, tumor (malignant and non-malignant) exosomes will carry tumor-associated or tumor specific surface antigens and may be detected, isolated and/or enriched via these antigen ([0046]). Suitable antigens include EpCAM, CD70, CEA, EGFR, Fas ligand, TRAIL ([0046]). These antigens meet the limitation of a source specific marker. Therefore, Soon-Shiong teaches the new limitations: capturing a first target extracellular vesicle population in a first biological sample from the patient before treatment, and capturing a second target extracellular vesicle population in a second biological sample from the patient after the treatment, the first target extracellular vesicle population comprises a source-specific marker, and the second target extracellular vesicle population comprises the source-specific marker.
Soon-Shiong teaches that the disease associated protein is preferably the target of the treatment and therefore will provide direct and specific insight into the treatment efficacy ([0020]), the target includes cancer specific genes, a target that is specific to a diseased cell or organ, and checkpoint inhibitor ligands e.g. PD-L1 ([0058]). PD-L1 reads on a first checkpoint protein.
Soon-Shiong teaches that the target can be detected in conjunction with one or more proteins including CTLA-4, LAG3, CD80 and CD86 ([0059]).
Regarding claims 4 and 12, Soon-Shiong teaches that exosomes can also be further enriched for those originating from a specific cell type and exosomes originating from distinct cell populations can be analyzed for their protein and/or nucleic acid content, e.g. example, tumor (malignant and non-malignant) exosomes will carry tumor-associated or tumor specific surface antigens and may be detected, isolated and/or enriched via these antigen ([0046]). Suitable antigens include EpCAM, CD70, or EGFR ([0046]), which meets the limitation of a marker for cancer cells.
Regarding claim 10, Soon-Shiong teaches that the target (disease associated protein) is checkpoint inhibitor ligands e.g. PD-L1 and the disease associated protein is preferably the target of the treatment ([0058]). Thus the first checkpoint inhibitor therapy would be an inhibitor of PD-L1.
Regarding claim 25, Soon-Shiong teaches detecting the disease associated protein including PD-L1 by western blot, ELISA, and FACS, which would use a labeled antibody.
Regarding claim 1, Soon-Shiong teaches that the method comprise a recommendation to modify the treatment based on the presence and/or quantify of the patient-specific disease associated protein in the second exosome, Soon-Shiong does not specifically teach treating the patient with a modified treatment (alternative treatment) when the amount of the first checkpoint protein in the second sample is elevated above the amount of that in the first sample.
However, these deficiencies are made up for in the teachings of Liang et al.
Regarding claim 1, Liang et al. teaches that the presence of PVR (CD155) and PVRL2 (CD112) contribute to suppressing immune responses independently of PD-L1 and that inhibitors of PVRIG (CD112R) and TIGIT could be of particular importance in patients that are non-responders/progressors to PD-1 inhibitors ([00661]). Liang et al. teaches a treatment comprising a combination of anti-TIGIT antibodies, anti-PVRIG antibodies, and anti-PD-1 antibodies for targeting tumor cells with high PD-L1 expression ([00527]). Liang et al. teaches that a combination of anti-TIGIT antibodies, anti-PVRIG antibodies and anti-PD-1 antibodies can be used to treat cancer patient whose tumor expresses PD-L1 and/or who is refractory to anti-PD-1 therapeutics ([00527]). Liang et al. teaches that PVR (CD155) is broadly expressed in tumors ([0003]).
Regarding claim 3, Liang et al. teaches treating cancer patient whose tumor highly expresses PD-L1 and/or who is refractory to anti-PD-1 therapeutics with a combination of anti-TIGIT antibodies, anti-PVRIG antibodies and anti-PD-1 antibodies (page 142, para 1, [00598]). A treatment comprising an anti-TIGIT antibody meets the limitation of an alternative treatment comprising a second checkpoint inhibitor therapy.
Regarding claim 11, Liang et al. teaches atezolizumab is one of three approved anti-PD-L1 antibodies ([00175]).
Regarding claim 13, Liang et al. teaches that the (second) checkpoint protein is TIGIT ([0003]).
Regarding claim 15, Liang teaches second checkpoint protein TIGIT, which differs from a source-specific marker e.g. EpCAM, CD70, or EGFR taught by Soon-Shiong.
Regarding claim 25, Liang teaches detecting PD-L1, PVR (CD155), PD-1, TIGIT, PVRL2, and PVRIG using labeled antibodies that bind PD-L1, PVR (CD155), PD-1, TIGIT, PVRL2, and PVRIG, respectively ([0027]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Soon-Shiong to treat the patient having PD-L1 expression level in the second sample higher than in the first sample (i.e. patients who are resistant to anti-PD-1 therapeutics) with an alternative treatment comprising a combination of anti-TIGIT antibodies, anti-PVRIG antibodies, and anti-PD-1 antibodies in view of Soon-Shiong and Liang. Soon-Shiong teaches that tumor cells shed substantial quantities of exosomes, and that the changes in the tumor cell are directly reflected by the corresponding changes in the exosomes ([0025]). One of ordinary skill in the art would have been motivated to do so because Liang et al. teaches that the presence of PVR (CD155) and PVRL2 (CD112) contribute to suppressing immune responses independently of PD-L1 and that inhibitors of PVRIG (CD112R) and TIGIT could be of particular importance in patients whose tumor has high PD-L1 expression and who are non-responders/progressors to PD-1 inhibitors ([00661]). One of ordinary skill in the art would have had a reasonable expectation of success because Liang et al. teaches that a combination of anti-TIGIT antibodies, anti-PVRIG antibodies and anti-PD-1 antibodies can be used to treat cancer patient whose tumor has high PD-L1 expression and who is refractory to anti-PD-1 therapeutics ([00527]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Soon-Shiong to use atezolizumab as the inhibitor of PD-L1 in view of Liang. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Liang et al. teaches that atezolizumab is one of three approved anti-PD-L1 antibodies ([00175]).
8. Claims 1-4, 10-13, 15-18, 20 and 25 remain rejected under 35 U.S.C. 103 as being unpatentable over Soon-Shiong (WO 2017/223186A1, pub. date: 12/28/2017, PTO 892 dated 9/3/2025), in view of Liang et al. (WO 2018/220446A1, pub. date: 12/6/2018), further in view of Sabzevari et al. (WO 2017/048824A1, pub. date: 3/23/2017).
The teachings of Soon-Shiong and Liang have been set forth above as they apply to claims 1-4, 10-13, 15 and 25.
Sabzevari et al. teaches treating cancer using a CD155/TIGIT antagonist, wherein the CD155/TIGIT antagonist is an anti-CD155 antibody or an anti-TIGIT antibody (claims 54, 60 and 61).
Regarding claim 16, Liang teaches that second checkpoint protein is TIGIT ([0027]). An anti-CD155 antibody targets the CD155 (a ligand of TIGIT receptor).
Regarding claims 17 and 20, Sabzevari teaches that the CD155/TIGIT antagonist is an anti-CD155 antibody or an anti-TIGIT antibody (claims 54, 60 and 61). According to Sabzevari, the second checkpoint protein may be CD155 (a ligand of TIGIT receptor). An anti-TIGIT antibody targets TIGIT (a receptor of CD155).
Regarding claim 18, CD155 is a ligand as well as a receptor.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted an anti-CD155 antibody for the anti-TIGIT antibody in the alternative treatment comprising anti-TIGIT antibodies, anti-PVRIG antibodies and anti-PD-1 antibodies as suggested by Liang in view of Sabzevari et al. One of ordinary skill in the art would have been motivated to do so because both anti-CD155 and anti-TIGIT antibodies inhibit CD155/TIGIT interaction. One of ordinary skill in the art would have had a reasonable expectation of success because Sabzevari et al. teaches treating cancer using a CD155/TIGIT antagonist, wherein the CD155/TIGIT antagonist is an anti-CD155 antibody or an anti-TIGIT antibody (claims 54, 60 and 61).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Soon-Shiong to further detect CD155 (PVR) on the exosomes in the first and second samples and treat the patient having high CD155 expression level in the second sample with an alternative treatment comprising a combination of anti-TIGIT or anti-CD155 antibodies, anti-PVRIG antibodies, and anti-PD-1 antibodies in view of Soon-Shiong, Liang and Sabzevari. One of ordinary skill in the art would have been motivated to do so for purpose of identifying patients who would be responsive to the treatment that targets TIGIT-CD155 interaction. One would have had a reasonable expectation of success because Liang et al. teaches how to detect CD155 using a labeled antibody that binds CD155. Liang et al. further teaches that a combination of anti-TIGIT antibodies, anti-PVRIG antibodies and anti-PD-1 antibodies can be used to treat cancer patient whose tumor has high PD-L1 expression and who is refractory to anti-PD-1 therapeutics ([00527]) and expresses CD155 ([0003]).
9. Claims 1-4, 10-13, 15, 25 and 28 remain rejected under 35 U.S.C. 103 as being unpatentable over Soon-Shiong (WO 2017/223186A1, pub. date: 12/28/2017, PTO 892 dated 9/3/2025), in view of Liang et al. (WO 2018/220446A1, pub. date: 12/6/2018), further in view of Frendewey et al. (US 2014/0308370A1, pub. date: 10/16/2014).
The teachings of Soon-Shiong and Liang have been set forth above as they apply to claims 1-4, 10-13, 15 and 25.
Regarding claim 28, Frendewey et al. teaches that depending on the selected marker, absence of an increase or an absence of a decrease in the level of a tumor-responsive biomarker after administration of an anti-tumor drug can indicate that the administration of the anti-cancer drug was not therapeutically effective. An increase or decrease can be a one-fold, a two-fold, a three-fold, a four-fold, a five-fold, a six-fold, a seven-fold, an eight-fold, a nine-fold, or a ten-fold or more increase or decrease in the amount of biomarker after administration of an anti-tumor drug as compared to the amount of a biomarker before anti-tumor drug administration ([0048]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Soon-Shiong and Liang to treat the patient having at least 1, 2, 3, 4 or 5 fold increase in PD-L1 expression level in the second sample as compared to that in the first sample with an alternative treatment comprising a combination of anti-TIGIT antibodies, anti-PVRIG antibodies, and anti-PD-1 antibodies in view of the cited reference. One would have been motivated to do so because Liang et al. teaches that the presence of PVR (CD155) and PVRL2 (CD112) contribute to suppressing immune responses independently of PD-L1 and that inhibitors of PVRIG (CD112R) and TIGIT could be of particular importance in patients whose tumor has high PD-L1 expression and who are non-responders/progressors to PD-1 inhibitors ([00661]) and Frendewey teaches that an increase or decrease can be a one-fold, a two-fold, a three-fold, a four-fold, a five-fold, a six-fold, a seven-fold, an eight-fold, a nine-fold, or a ten-fold or more increase or decrease in the amount of biomarker after administration of an anti-tumor drug as compared to the amount of a biomarker before anti-tumor drug administration ([0048]). One of ordinary skill in the art would have had a reasonable expectation of success because Liang et al. teaches that a combination of anti-TIGIT antibodies, anti-PVRIG antibodies and anti-PD-1 antibodies can be used to treat cancer patient whose tumor has high PD-L1 expression and who is refractory to anti-PD-1 therapeutics ([00527]).
New Grounds of Rejection
Claim Rejections - 35 USC § 112
10. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
11. Claims 21-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 21 has been amended to recite “the first level and the second level are normalized based on a difference between an amount of extracellular vesicles in the first total extracellular vesicle population and an amount of extracellular vesicles in the second total extracellular vesicle population.” (emphasis added)
Claim 24 has been amended to recite “wherein the first level and the second level are relative levels, and wherein the relative levels comprises ratios between a total amount of the checkpoint protein in the first/second target extracellular vesicle population and a total amount of checkpoint protein in the first/second total extracellular vesicle population.” (emphasis added)
There is no support for amended claims 21 and 24 in the specification, claims and drawing as filed. The application as filed only has support for normalizing for total exosome levels (page 4 and 46). The specification discloses that normalization may be accounted for by dividing the amount of the checkpoint protein on the exosomes having the source-specific protein by the variable being normalized (e.g. the total number of exosomes). The specification discloses the level of the extracellular-bound checkpoint protein may be divided by the level of the marker for the extracellular vesicle from the subject (page 53).
If applicant believes that support for the above-mentioned phrases or terms is present in the specification, claims or drawing as originally filed, applicant must, in responding to this action, point out with particularity, where such support may be found.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
12. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
13. Claim 23 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 23 is drawn to the method of claim 21, wherein in the normalizing, a total amount of the checkpoint protein in the total amount of extracellular vesicles is obtained for each of the first and second biological samples. Claim 23 does not further limit claim 21 because claim 21 requires detecting the first level and second level in the first and second total extracellular vesicle population.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
14. 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.
15. Claims 1-4, 10-13, 14-15 and 21-25 are rejected under 35 U.S.C. 103 as being unpatentable over Soon-Shiong (WO 2017/223186A1, pub. date: 12/28/2017, PTO 892 dated 9/3/2025), in view of Liang et al. (WO 2018/220446A1, pub. date: 12/6/2018), further in view of Lyden et al. (US 2014/0038901A1, pub. date 2/6/2014) and Spetzler et al. (US 2014/0141986A1, pub. date: 5/22/2014), and Lee et al. (US 2019/0346434A1, pub. date: 11/14/2019)
The teachings of Soon-Shiong and Liang have been set forth above as they apply to claims 1-4, 10-13, 15 and 25.
Soon-Shiong teaches isolating exosomes by immune precipitation of magnetic separation using exosome specific surface markers, including CD9, CD63, CD81 and detecting the disease associated proteins ([0044]). Liang et al. teaches detecting CD155 (PVR) and TIGIT ([0027]) and treating cancer expressing PVR (CD155) using a combined therapy comprising anti-TIGIT antibody that target TIGIT/PVR interaction ([0003]).
Soon-Shiong and Liang does not specifically teach claims 21-24 and 14.
Regarding claims 21-23, Lyden et al. teaches a method of monitoring metastatic disease treatment in a subject, comprising:
obtaining first and second samples, at different points in time, from the subject being treated for a metastatic disease and measuring the exosome level and the exosomal expression levels of one or more protein biomarkers of metastatic disease in each sample,
comparing the exosome level and the exosomal expression levels of the one or more protein biomarkers of metastatic disease in the first sample to corresponding levels in the second sample, and
determining whether the subject is responding to the metastatic disease treatment based on this comparison ([0014)].
Lyden et al. teaches that the exosome level is the total number of exosomes (e.g. total exosomes per ml plasma), total exosome protein (i.e. total protein per exosome or total exosome protein per ml patient plasma ([0086]). Lyden teaches detecting the total number of exosomes by flow cytometry using anti-CD9 and anti-CD63 antibodies ([0134]).
Regarding claim 22, Spetzler et al teaches detecting total number of vesicles by flow cytometry using anti-CD9, ant-CD63 and anti-CD81 antibodies ([0136]).
Regarding claim 23, Spetzler et al. teaches detecting biomarkers (miR) in EpCAM, CD63 and B7-H3 positive subpopulations of vesicles as well as in total populations ([1545]).
Regarding claim 24, Spetzler et al. teaches comparing the levels of biomarkers detected in EpCAM, CD63 and B7-H3 positive subpopulations of vesicles to the levels of the biomarkers detected in total populations ([1545]). By comparing the biomarker levels in subpopulation of vesicles and total vesicles, the ratio between them becomes apparent.
Regarding claim 14, Spetzler et al. teaches that markers including CD155 can be used for capture and/or detecting of vesicles ([0447]). When CD155 is used for capture of vesicles, the limitation of claim 14, i.e. the second checkpoint protein and the source specific marker are same is met.
Lee et al. teaches that for each target marker (M), a pair of magnetic beads: one conjugated with antibodies against CD63 (CD63-beads) and the other with antibodies against iso-type matched IgG (IgG-beads) were prepared. Exosomes were mixed with each bead-type and subsequently labeled with antibodies against a target marker; the net signal difference ΔIM (=ICD63+M−IIgG+M; see FIG. 18) was then obtained. ΔICD63 was used to estimate the total exosome load, and defined a normalized metric TM (=ΔIM/ΔICD63) as the expression level of a target marker (M) (page 43, lines 17-24) (i.e. the expression level of a target marker is normalized to the total exosome number). Lee et al. teaches that such scaling would compensate for variations in exosome numbers among samples (page 43, lines 17-24).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Soon-Shiong to detect the total amount of exosomes in the first and second samples by flow cytometry using antibodies that bind CD9, CD63 and CD81 and normalize the level of the patient-specific disease associated proteins such as PD-L1 to the total amount of exosomes in view of Lyden, Spetzler, and Lee. One of ordinary skill in the art would have been motivated to do so because Lee et al. teaches using a normalized metric (i.e. the expression level of a target marker is normalized to the total exosome number) would compensate for variations in exosome numbers among samples (page 43, lines 17-24). One would have had a reasonable expectation of success because Lyden and Spetzler teach how to detect total amount of exosomes and Spetzler teaches detecting a total amount of exosomes in a sample by flow cytometry using antibodies that bind CD9, CD63 and CD81([0136]) ([0136]), and Lee et al. teaches obtaining a level of a target marker that is normalized to the total amount of exosomes in the sample.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used CD155 as a source specific marker to isolate CD155+ exosomes in view of Liang, Spetzler and Soon-Shiong. One of ordinary skill in the art would have been motivated to do so for purpose of identifying patients who would be responsive to the treatment that targets TIGIT-CD155 interaction and because Spetzler et al. teaches that markers including CD155 can be used for capture and/or detecting of vesicles ([0447]). One would have had a reasonable expectation of success because Soon-Shiong teaches that exosomes can also be further enriched for those originating from a specific cell type and exosomes originating from distinct cell populations can be analyzed for their protein and/or nucleic acid content, e.g. tumor (malignant and non-malignant) exosomes will carry tumor-associated or tumor specific surface antigens and may be detected, isolated and/or enriched via these antigen ([0046]), Spetzler et al. teaches that markers including CD155 can be used for capture and/or detecting of vesicles ([0447]), and Liang et al. teaches how to detect CD155 using a labeled antibody that binds CD155.
16. Claims 1-7, 10-13, 15 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Soon-Shiong (WO 2017/223186A1, pub. date: 12/28/2017, PTO 892 dated 9/3/2025), in view of Liang et al. (WO 2018/220446A1, pub. date: 12/6/2018), further in view of Wang et al. (Oncogenesis , 2018, 7:41, pages 1-11).
The teachings of Soon-Shiong, and Liang have been set forth above as they apply to claims 1-4, 10-13, 15 and 25.
Soon-Shiong teaches that exosomes can also be further enriched for those originating from a specific cell type and exosomes originating from distinct cell populations can be analyzed for their protein and/or nucleic acid content, e.g. tumor (malignant and non-malignant) exosomes will carry tumor-associated or tumor specific surface antigens and may be detected, isolated and/or enriched via these antigen ([0046]).
Soon-Shiong, and Liang do not teach obtaining exosomes using source specific markers for tumor-associated macrophages (TAMs).
Regarding claims 5-7, Wang et al. teaches that macrophages constitute a major component of tumor-infiltrating immune cells and M2 macrophages have been reported to promote tumor progression through promoting tumor angiogenesis and metastasis and regulating T-cell function (abstract). Moreover, PD1+ tumor-associated macrophages (TAMs) exhibited an M2-like surface profile and can suppress CD8+ T-cell function and this immunosuppressive activity can effectively be enhanced upon triggering PD1 signal (abstract). Wang et al. teaches that gastric cancer (GC)-derived exosomes effectively educated monocytes to differentiate into PD1+ TAMs with M2 phenotypic and functional characteristics.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Soon-Shiong and Liang to obtain exosomes using source specific markers for tumor-associated macrophages and further detect PD-1 on the exosomes in view of Wang. One of ordinary skill in the art would have been motivated to do so because Wang et al. teaches that M2 macrophages have been reported to promote tumor progression through promoting tumor angiogenesis and metastasis and regulating T-cell function and gastric cancer (GC)-derived exosomes effectively educated monocytes to differentiate into PD1+ TAMs with M2 phenotypic and functional characteristics. One of ordinary skill in the art would have had a reasonable expectation of success because Wang teaches assessing TAMs using markers including CD11b and further analysis PD1 expression on macrophages (Fig. 1).
17. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Chen et al. “Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response:, Nature, 2018, 560: 382-386, IDS filed on 2/24/2023.
Conclusion
18. No claims 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.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646