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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 19, 2026 has been entered.
3. Claims 10, 12, 13 and 21-29 are pending.
Claims 14-20 have been cancelled.
Claims 10, 12, 13, 21, 26 and 28 have been amended.
Claims 10, 12, 13 and 21-29 are examined on the merits.
4. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 112
5. Claims 13 and 28 no longer recite the limitation "the tumor", hence the rejection is withdrawn, see Amendments to the Claims submitted March 19, 2026, pages 3 and 4.
6. Claim 28 no longer recite the limitation "the repolarized macrophage phenotype", hence the rejection is withdrawn, see Amendments to the Claims submitted March 19, 2026, page 4.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
7. 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.
8. 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.
9. The rejection of claim(s) 10, 12, 13 and 21-29 under 35 U.S.C. 103 as being unpatentable over Yuan et al. (Scientific Reports 5, Article number 14273, pages 1-12 published 24 September 2015 with Supplementary Data, pages 1-14), and further in view of Sophia N. Karagiannis et al. (Cancer Research 77(11): 2779-2783, June 1, 2017/ IDS reference #1 on sheet 5 submitted March 1, 2023) denoted herein as S.N.Karagiannis, Karagiannis et al. (Cancer Immunol. Immunother. 61: 1547-1564, 2012/ IDS reference #15 on sheet 4 submitted March 1, 2023), Josephs et al. (Frontiers in Bioscience, Elite, 7: 334-351, January 1, 2015) and Tarique et al., (American Journal of Respiratory Cell and Molecular Biology 53(5): 676-688, November 2015) is maintained. Claims 14-20 have been cancelled.
Applicant argues they have “…identified a previously unidentified macrophage phenotype…”, which “…is distinct from the M1 or “M1-like” phenotypes…”, see Remarks/ Arguments submitted March 19, 2026, page 7, 1st full paragraph (para.).
Applicant further argues the cited prior art “does not teach or suggest selecting a subject having a M0 or M2a (as opposed to M2) macrophage phenotype in a tumor sample, administering IgE to the subject, and…the IgE produces macrophages having a newly polarized macrophage phenotype charactered by expression TNFa, IFNg, IL-1B, IL-6, RANTES, and IL-10.”, see page 7 of the Remarks, 2nd para. “[O]ne of ordinary skill in the art would not have been motivated to administer IgE as a cancer treatment to the selected patient class because one of ordinary skill in the art would not have had any reasonable expectation that administering lgE would repolarize quiescent or anti-inflammatory macrophages into cancer-fighting cells expressing TNFa, IFNy, IL-1B, IL-6, RANTES, and IL-10.”, see 3rd para. on page 7.
Applicant follows the said arguments with the teachings of the prior art references in an attempt to distinguish them from the claimed invention, see pages 7-10.
Applicant concludes these arguments stating “it [was] not known how to promote the anti-cancer action of IgE antibodies in the most effective manner." Application at page 4, second complete paragraph. “Specifically, an M0 and/or M2a macrophage phenotype were not previously known to provide patient selection criteria for IgE therapy. Thus, one of ordinary skill in the art would not have considered using an M0 and/or M2a macrophage phenotype to select a patient class that is particularly suited for a successful cancer treatment with IgE.
Further, it was not known or predictable that IgE therapy exerted particular effects on M0 and/or M2a macrophages to produce a new macrophage phenotype expressing TNFa, IFNg, IL- 1b, IL-6, RANTES, and IL-10 and having anticancer activity in the patient tumor. Patients having other phenotypes (i.e., not the recited M0/M2a phenotype) would not have been expected to benefit in the same way from IgE treatment because the new macrophage phenotype expressing TNFa, IFNg, IL-1b, IL-6, RANTES, and IL-10 would not have been produced. Similarly, patients having the MO/M2a phenotype and treated with other treatments (i.e., not the recited IgE treatment) would also not have been expected to benefit in the same way.
Accordingly, Applicant respectfully asserts that the cited art, alone or in combination, does not teach or suggest all claim features because the cited art, alone or in combination, does not teach or suggest all of: 1) selecting a subject having a macrophage phenotype having one or both of a quiescent (MO) and/or an anti-inflammatory (M2a) macrophage phenotype; 2) administering IgE to the subject; and 3) producing in the patient a new macrophage phenotype characterized by expression of TNFa, IFNy, IL-1B, IL-6, RANTES, and IL-10. The Office's rejection requires a person of ordinary skill in the art to independently select the M0/M2a phenotype for patient stratification, choose IgE as the therapeutic agent for those particular patients, and then expect that IgE treatment would produce a new macrophage phenotype, i.e., not the M1 phenotype described in the cited art, expressing the specific six-marker profile recited by the claims. None of the cited references, alone or in combination, teaches or suggests the conjunction of all three steps, and one of ordinary skill in the art would not have arrived at this combination absent the benefit of Applicant's disclosure.”, see pages 10 and 11.
Applicant’s arguments and points of view have been carefully considered but fail to persuade.
Foremost, to arrive at a proper determination under 35 U.S.C. 103, the Examiner must undertake the role of the person of ordinary skill in the art utilizing factual information and arriving at a legal conclusion based on the facts, devoid impermissible hindsight and rationale for making a proper case of prima facie of obviousness. The Examiner has provided articulated reasoning with rational underpinning to support the legal conclusion of obviousness. In summary, there must be some suggestion or motivation; a reasonable expectation of success; and the prior art references must teach or suggest all the claim limitations. The Examiner’s obviousness conclusion is based on sufficiently articulated reasoning that overcomes any concerns about hindsight bias. See KSR, 550 U.S. at 418.
Applicant is correct in the fact, S.N. Karagiannis does not describe detecting macrophage phenotypes, macrophage quiescent (M0), nor anti-inflammatory (M2a) within a tumor sample from a cancer patient and subsequent treatment with the administration of IgE. However, S.N. Karagiannis is replete with teachings, the administration of IgE will render recruitment, reprogramming, repolarization to a new macrophage phenotype see Figure 1, particularly Figure 1D. The state of the art, prior to Applicant’s effective filing year of 2019 has provided incentive to implement IgE therapies in an approach to target macrophages and alter the tumor microenvironment (TME), see page 2781, 2nd column (col.), Reprogramming…segment.
The science has provided “…administration of therapeutic IgE antibodies may re-direct macrophage functions, evolved to neutralize parasites, against cancer cells. TNFa, MCP-1, nitric oxide, and IL10 are all upregulated during parasiticidal activities of macrophages …Upregulation of TNFa and MCP-1 is detected in tumors in response to IgE therapy, but the classical Th2 cytokine IL4 is notably absent.”, see page 2781, 2nd col., last 10 lines. Therein, there are at least three of the cytokines expressed by a newly polarized macrophage phenotype.
Both Karagiannis documents are rife with teachings (from one of the articles available) as early as 2012, IgE is able “…to mount superior immune response against tumours…”, “…[kills] tumour cells by mechanisms such as ADCC and ADCP”, increases survival expectancy, as well as offers “…enhanced immune surveillance…, superior effector cell potency against cancer cells”, “monocyte and macrophage activation and recruitment to tumors”, “antibody-mediated tumor cell cytoxicity and phagocytosis” and “repolarisation to an M1-like phenotype”, see S.N. Karagiannis’ abstract on page 2779, Figure 1 on page 2782, and entire document; and Karagiannis, Abstract on page 1547, entire document. Given the impetus to repolarization to an M1-like phenotype, which is art known to exhibit antitumor activity, proinflammatory activity, suppress tumor proliferation and cell viability, it would be obvious to one of ordinary skill in the art to assess the patient’s TME and tumour-associated macrophages (TAM) via a tumor sample, see Yuan, para. bridging pages 9 and 10; Figure 4 on page 6.
Yuan teaches the M0 macrophage subtype exhibits increased cell viability, tumor proliferation and invasiveness, increased tumor volume and tumor weight and tumor promoting activity, see page 2. And the M2a macrophage subtype has the propensity for the tumor to demonstrate invasiveness and increased tumor growth, see Yuan in its entirety, particularly page 2. The two subtypes, “…M2a… and M0 have similar effects on the biological functions of cancer cells.”, see para. bridging pages 8 and 9; and pages 9 and 10. Given such, one of ordinary skill in the art would have the motivation to assay a tumor sample for those negative factors contributory to TME.
Moreover, with the teachings of Tarique one of ordinary skill in the art would be able to discern and distinguish between macrophage subtypes, thereby indicative of those with a “negative” profile, for instant, either M0 or M2a macrophages. Based on the knowledge of these subtypes, one of ordinary skill in the art would have the impetus to treat these individuals with a therapeutic agent known to have demonstrated re-educate and repolarize the M0 and/or M2a macrophage phenotype(s). With the repolarization of the macrophages with the IgE antibody a particular cytokine/ chemokine signature would be expressed and it would naturally flow, immunostimulatory and anti-tumor activities would commence and/or be restored, see all references in their entireties.
This modification of the primary reference in light of the secondary reference is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. Accordingly, the rejection is maintained.
Yuan teaches “M2 macrophages have been considered to exert a tumor-promoting influence. In basal cell carcinoma and breast cancer, M2 macrophages have been reported to mediate angiogenesis by inducing or releasing pro-angiogenic factors. In [the Yuan] study, M2a and M2c subtypes could enhance cell invasion and tumor growth compared with A549 cells (Fig. 3 and Supplementary Fig. 1) but not angiogenesis (Fig. 4). These different effects might be attributed to different cancer cell types or the microenvironments in distinct organs.”, see paragraph (para.) bridging pages 6 and 7.
“M0 or/and M2 promoted tumorigenesis in human-original and mouse-original lung cancer models.”, page 7, lines 8 and 9. Specifically, the M2a subtype is able to promote “…A549 invasion and xenograft tumor growth”, see abstract.
“In [Yuan’s] previous studies, PMA-activating M0 macrophages could enhance cancer cell invasiveness.”, see page 9, lines 2 and 3.
Yuan’s current “…data showed that M0 and M2 macrophages increase cancer invasion ability (Supplementary Fig. 1), but M1 macrophages contribute to the suppression of tumor growth and angiogenesis (Figs. 3 and 4) and enhance their sensitivity to chemotherapy agents (Fig. 2F).”, see page 9, 1st full para.
Yuan does not teach selecting a subject having either the quiescent (M0) macrophage phenotype and/or anti-inflammatory (M2a) macrophage phenotype detected in macrophages associated with an obtained tumor sample and the subsequent administration of immunoglobulin E (IgE) to the subject.
Yuan also does not teach the detection and expression of newly polarized macrophage phenotypes characterized by the expression of TNF-a, IFN-g, IL-1b, IL-6, RANTES, IL-10, MCP-1, IL-12 and CXCL11 after administering IgE.
However, S.N.Karagiannis teaches IgE activates macrophages, which mediates a TNFa/MCP-1 axis and reprograms macrophages “…to a new macrophage phenotype, macrophage recruitment, repolarization to an M1-like phenotype, activation to trigger antibody-mediated tumor cell death (e.g. by ADCC, ADCP, immunoactivatory cytokines), and reduced immunosuppressive tumor-associated macrophage survival.”, see page 2782, Figure 1 and specifically Figure 1D caption. As seen in Figure 1D, there is the increase of cytokines and mediators, including TNF-a, MCP-1, IFNg, IL-10, IL-12, see page 2782.
Karagiannis teaches treating “…human xenograft models of [tumour antigen folate receptor a] FRa-expressing ovarian carcinoma grown in [SCID] immunodeficient mice” with mouse/human chimaeric antibody (Mov18 IgE) and human peripheral blood mononuclear cells (PBMC), see, Efficacy…section beginning in column 2 of page 1552; Figure 3 on page 1553. “Chimaeric MOv18 IgE was…engineered by switching the human g1-constant regions for human e constant regions.”, see page 1552, col. 1, last sentence in 2nd para.
“IgE can bind to different Fc receptors than IgG resulting in activation of different immune cell populations known to be present in many solid tumours such as monocytes, macrophages, basophils, eosinophils and mast cells.”, see page 1554, 1st column, Immune…section, last sentence of 1st para.
Likewise, Karagiannis teaches “[c]ross-linking of IgE bound to FceRI causes receptor aggregation and downstream signalling through a Syk-dependent pathway. The net result of this is degranulation by mast cells and the release of inflammatory mediators (histamine, leukotrienes and proteases) and cytokines (IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, GM-CSF and TNF-a) that recruit T cells, monocytes, basophils, APCs and eosinophils to the site of inflammation, resulting in an enhancement of the response to the allergen or parasite. The same mediators also activate infiltrating cells in situ to induce ADCC through release of pro-inflammatory cytokines, enzymes and other cytotoxic mediators (e.g., TNF-a, lysozyme, nitric oxide, H2O2 and other reactive oxygen species). IgE binding to CD23 promotes macrophage/ monocyte activation via the adhesion molecules CD11bCD18.“, see page 1549, 2nd col., 1st para.
Moreover, Josephs teaches “macrophages participate in the inflammatory infiltrate of solid tumours”, see page 334, section 2. “Recruitment and regulation of TAMs in tissues occurs in response to a number of factors including CCL2 (MCP-1), VEGF, PDGF, TGF-β, CSF-1, MIP-1a, complement component C5a, [regulated on activation normal T cell expressed and secreted] RANTES, and TNF-a, all of which can be produced by cancer cells.”, see sentence bridging pages 1 and 2.
Josephs further teaches a therapeutic approach utilizing monoclonal antibodies of the IgE class to in the repolarization of TAMs towards an immunosupportive M1-like phenotype, which produce inflammatory cytokines and exert anti-tumour activities including elimination of tumour cells, killing by ADCC and ADCP, see entire document in particular segments, 6.3-6.5 spanning pages 4-6.
Tarique teaches obtaining buffy coats containing monocytes and monocyte-derived macrophages (MDMs) from eight healthy blood donors, see page 677, 3rd column (col.), 1st sentence. Tarique teaches assaying macrophage surface markers in order to distinguish between populations of macrophages, see page 677, col. 3, last two sentences before Materials…section; and entire document. Tarique teaches the phenotypic features of macrophages based on surface receptors utilizing flow cytometry, PCR analysis and Western blotting, see Abstract on page 676; Figure 1, Gene…section and M1 Cells…section beginning on page 678; page 679, Figure 2; Figure 3 on page 681; and page 686, Table 2.
The quiescent or uncommitted macrophages (M0) can be differentiated from other subtypes such as activated macrophages (M2) including the M2a phenotype, see Tarique Abstract on page 676; page 677, 1st column; page 678, Phenotypic… and M1…sections; Figure 2 on page 679; page 680, Table 1, 1st and 2nd paragraphs (paras.) in column 1 and Stability…section in column 3; page 681, 1st and 2nd columns; paragraph (para.) bridging columns 2 and 3 on page 683; para. bridging pages 683 and 684; para. bridging pages 685 and 686; and page 686, Table 2.
These taught methods also are able to quantify a host of cytokines and chemokines, IL-1b, TNF-a, IFN-g, RANTES, IL-6, IL-10 and CXCL11, see page 678, Quantification…section; page 680, Unique…section; page 683, Discussion, 1st sentence; para. bridging pages 684 and 685; and page 685, Figure 7.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to obtain a tumor sample from a patient to assay their macrophage phenotype for one or both, M0 and/or M2 and commence with an anti-tumor treatment regimen, as these particular phenotypes have been shown to demonstrate cell invasion enhancement, promote tumor growth and activity, significantly increase tumor volume and weight, and increase cancer invasion, see Yuan, page 2, last full para.; para. bridging pages 6 and 7; para. bridging pages 7 and 8; page 9; and Supplementary Figure 1; and the entireties of S.N. Karagiannis, Karagiannis, Josephs and Tarique.
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat the cancer patient with IgE, especially once identifying the said patient had either the M0 phenotype, M2a phenotype or both, knowing as taught in Yuan they have the increased propensity to attribute to tumorigenicity.
One of ordinary skill in the art would have been motivated to sample a cancer patient’s tumor to perform detection assays in an effort to identify these particular phenotypes of macrophages, before and after IgE treatment to determine if the newly repolarized macrophages were producing and expressing cytokines, see all references in their entirety. The information gained from these detection assays allows one of ordinary skill in the art to monitor monocyte/macrophage polarization or activatory signatures in patients with the administered IgE to measure macrophage growth, determine proliferative status and differentiation, thereby monitoring the status of the cancer and evaluate treatment as the IgE antibodies are known to activate the Syk-dependent pathway resulting in enhancement of a therapeutic immune response, see all references in their entirety.
One of ordinary skill in the art would have been motivated to treat the cancers that have either macrophage phenotype, M0 and/or M2a because the bevy of references teach administered IgE activates macrophages, which participates in the recruitment and regulation of immune cells that work in concert to eliminate the cancer and is able to reprogram macrophages toward a tumoricidal function, as well as recruit them and activate them, see the entireties of S.N.Karagiannis, Karagiannis, Josephs and Tarique.
Conclusion
10. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
11. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
30 April 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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