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 .
Application Status
The Response to the Non-Final Office Action, filed April 10, 2026, is acknowledged. Claims 3 and 5 are amended. Claims 16-17 are newly added.
Claims 1-10, 13, and 15-17 are pending and under examination herein.
WITHDRAWN OBJECTIONS AND REJECTIONS
The objection to the specification is withdrawn in view of Applicant's amendments filed April 10, 2026.
The objection to claim 5 is withdrawn in view of Applicant's amendments to said claim.
The rejection of claims 3 and 5 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's amendments to said claims.
MAINTAINED REJECTIONS
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.
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.
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.
(1)
Claims 1-6, 8-10, 13, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Terman (US Patent No. 6,126,945; published October 3, 2000) in view of Van Eenennaam (US 2019/0135933 A1) and Rosenberg (The Journal of Immunology (2014) 192(12): 5451-5458). This rejection has been updated to reflect Applicant's newly filed claims.
Terman describes the use of Staphylococcal enterotoxins (A, B, C, D, E) in treatment of cancer as tumoricidal agents (e.g., Abstract). The SEB can be administered “intravenously, subcutaneously, as in adjuvant form, or used extracorporeally in free or bound form to stimulate immunocytes which are subsequently infused into tumor bearing hosts” (col 1). Terman discloses a method of treating a cancer, comprising the step of administering to a patient or subject in need thereof a tumoricidally effective amount of Staphylococcal enterotoxin B or a biologically active fragment thereof (e.g., col 23, 35; claims 1-14), relevant to claims 1, 3-4, 9, and 16. Terman discloses that enterotoxins are heat stable and resistant to trypsin digestion, and that enterotoxins have distinct advantages over previously described Staphylococcal Protein A plasma perfusion systems (e.g., col 2-3).
However, Terman does not expressly teach a combination treatment method further comprising administering an anti-PD-1 antibody, or further administering an anti-PD-1 antibody and one or more further drugs.
Van Eenennaam discloses methods of treating conditions (e.g., solid tumors) ameliorated by stimulation of an immune response via stimulation of CD27 immune cells and/or by inhibition of an immune checkpoint protein such as PD-1, PD-L1, CTLA-4, and others (e.g., Abstract; ¶ 0004, 0080-0087). Van Eenennaam teaches that immune checkpoint inhibitors against the PD-1/PD-L1 pathway and CTLA-4 are in clinical development and have shown promising results in clinical studies (e.g., ¶ 0009). Van Eenennaam teaches that their invention is based on the surprising discovery that the combination of an agonistic anti-CD27 antibody and an immune checkpoint inhibitor result in immune stimulation to an unexpected level (¶ 0014). Van Eenennaam discloses methods that comprise administering the combination of an anti-human CD27 agonist antibody of the invention and an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) (e.g., ¶ 0014-0021), relevant to claims 1, 5-6, 10, and 17. Van Eenennaam discloses that the combination of an anti-CD27 agonist antibody and anti-PD-1 antibody enhances Staphylococcal enterotoxin B-induced T-cell activation in human PBMCs and in human whole blood compared to either treatment alone (e.g., Figure 1A, Figure 2A, Figure 3).
Relevant to claims 2 and 9, Van Eenennaam discloses that suitable routes of administration for antibodies of the invention include systemic administration (e.g., intramuscular, intravenous, subcutaneous, or intraperitoneal injection) or local administration (injection) directly into the site of action (e.g., ¶ 0099-0100).
Relevant to claim 8, Van Eenennaam discloses a confirmatory experiment in Example 2 wherein human PBMCs isolated from the blood of healthy donors were first combined with antibody treatment (anti-CD27 monotherapy, anti-PD-1 monotherapy, or anti-CD27/anti-PD-1 combination therapy) followed by addition of SEB to effect superantigen-induced IL-2 secretion (¶ 0132-0134; Figure 3).
Rosenberg teaches that IL-2 is a cytokine produced by antigen-stimulated CD4+ T cells, CD8+ cells, and activated dendritic cells (page 5451). IL-2 plays a prominent role in the maintenance of CD4+ regulatory T cells and differentiation of CD4+ T cells into a variety of subsets with different T cells functions. In CD8+ cells, IL-2 stimulates cell growth as well as differentiation into memory and more terminally differentiated lymphocytes (page 5451). Rosenberg describes how early observations that administration of IL-2 promoted durable and curative tumor regression in patients with metastatic melanoma and renal cancer paved the way for later use of IL-2 to grow T cells in vitro that can be used for adoptive cell therapy for cancer, as lymphocytes expanded long-term in IL-2 could retain specific antigen reactivity (e.g., pages 5451-5454). Rosenberg notes that tumors do not express IL-2 receptors and thus the anti-tumor activity of IL-2 administration is the result of IL-2 stimulation of immune cells (page 5453).
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of treating cancer in a subject having a tumor that comprises administering the combination of SEB (or a biologically active fragment thereof) and an anti-PD-1 antibody. The skilled artisan would have been motivated to do so because Terman teaches that SEB has tumoricidal properties and that enterotoxins have several advantages (e.g., ease of use/administration, safety, efficacy) compared to previously disclosed systems. Further, SEB promotes IL-2 production (as taught by Van Eenennaam), which Rosenburg notes is beneficial in the treatment of cancer since IL-2 stimulates immune cells (with said effect being desired by Van Eenennaam). In addition, Van Eenennaam teaches that immune checkpoint inhibiting antibodies against PD-1, CTLA-4, and CD27 likewise display efficacy in the treatment of solid cancers, and that the combination of an anti-PD-1 antibody with an anti-CD27 antibody enhances SEB-induced IL-2 secretion. There would have been a reasonable expectation of success because, as set forth in MPEP § 2144.06(I), “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Those of ordinary skill in the art would recognize that SEB and anti-PD-1 antibodies are both suitable for the purpose of treating cancer, and their combined use for the same purpose (treating cancer) would not be considered inventive in view of the state of the prior art.
Furthermore, with respect to the schedule of treatment regimens recited in claim 8, there are a finite number of timeframes at which a combination of potential treatments may be administered to a patient, and one of ordinary skill in the art has good reason to pursue known options within his or her technical grasp in order to arrive at an optimal treatment regimen through the process of routine optimization.
With respect to the pharmaceutical composition recited in claim 13, it would be obvious to formulate a pharmaceutical composition comprising the combination of both SEB and an anti-PD-1 antibody, configured for use in the treatment of cancer. One of ordinary skill in the art would recognize that such a formulation could be more conveniently and comfortably administered to a patient by requiring a single administration of drug instead of two separate administration events, and it is within the skill of one of ordinary skill in the art to prepare a pharmaceutical composition comprising more than one therapeutically active ingredient. Furthermore, Terman and Van Eenennaam teach that each of SEB and anti-PD-1 antibodies can be administered intravenously (i.e., in the same manner).
(2)
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Terman (US Patent No. 6,126,945; supra) in view of Van Eenennaam (US 2019/0135933 A1; supra) and Rosenberg (The Journal of Immunology (2014) 192(12): 5451-5458; supra) as applied to claims 1-6, 8, and 10 above, and further in view of Bonaventura (Frontiers in Immunology (2019) 10: Article 168; cited in IDS) and Ayers (Journal of Clinical Investigation (2017) 127(8): 2930-2940).
The teachings of Terman are recited in the 35 U.S.C. § 103 rejection above.
However, Terman does not teach treating a tumor characterized by a low IFN-γ response signature, a low BATF3 response signature, and/or a low tumor infiltration signature.
The teachings of Van Eenennaam and Rosenberg are disclosed in the 35 U.S.C. § 103 rejection above.
Bonaventura teaches that while therapeutic antibodies targeting immune checkpoint proteins have been effective for some patients, non-response to treatment is observed in many cases (page 1). Bonaventura teaches that a major factor involved in initial resistance to immune checkpoint protein inhibitors is lack or paucity of tumor T cell infiltration, leading to “non-inflamed” or “cold tumors” (page 1). By contrast, lymphocyte infiltration and IFN-γ status may be key factors for effective anti-PD-1 therapy by defining a “T cell inflamed” phenotype (“hot tumors”) (page 1). Bonaventura teaches that defects in antigen-presenting cells (APCs; which activate T cells) and absence of T cell activation/co-stimulation are among the possible factors that could lead to “cold tumors” (pages 1-3; Figure 1).
Ayers sought to determine whether quantifying a T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed anti-tumor therapy. Per Ayers, “Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab” (Abstract). Ayers notes, “Elucidation of the underlying immunologic characteristics of the tumor microenvironment associated with response and resistance will improve the identification of patients who will derive the most benefit from anti–PD-1 monotherapy and might reveal additional immunologic determinants that could be targeted in combination with PD-1 checkpoint blockade” (Introduction). Ayers analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients (e.g., Abstract). Ayers identified several IFN-γ-related genes that are involved in T cell cytolytic activity, antigen presentation, and chemokine production were predictive of PD-1 blockade treatment response across different tumor types, including a preliminary 10-gene signature and an expanded 28-gene gene signature that correlated with the preliminary 10-gene signature (e.g., Results; Figure 1). The “expanded” gene signature described by Ayers includes IL2Rg (which encodes IL2Rγ) (e.g., Table 2). Ayers further noted a general pattern of a lack of objective response in patients whose tumors showed low expression levels across the genes, “assumed to represent tumors without a T cell-inflamed phenotype” (page 2934).
In view of these teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a combination treatment method based on the collective teachings of Terman, Van Eenennaam, and Rosenberg, in a patient having a tumor with a low interferon-γ response signature. The skilled artisan would have been motivated to do so because, as taught by Ayers and Bonaventura, cancer patients having “cold” tumors are less likely to respond to anti-PD-1 blockade monotherapy, and targeting additional immunological determinants in combination with PD-1 blockade could improve therapeutic response. Increasing T cell costimulation or activation, e.g., by increased IL-2 production via administration of SEB, would be expected to promote a more inflamed or “hot” tumor phenotype and thus increase the likelihood of response to anti-PD-1 blockade. There would have been a reasonable expectation of success because SEB promotes IL-2 production, and IL2Rg (a receptor for IL-2) was among the genes identified by Ayers as having a tight correlation to the preliminary 10-gene IFN-γ gene signature that predicts anti-PD-1 blockade responsiveness.
Response to Arguments (Combined)
Applicant's combined arguments for the 35 U.S.C. § 103 rejections of record, filed April 10, 2026, have been fully considered but they are not persuasive.
Applicant disagrees with the rejections and states that “The invention is focused on ‘non-inflamed’ or ‘cold tumors’, which … are tumors that display a lack of or reduced T cell infiltration” (emphasis added by Applicant). Remarks at page 9. Citing Mellman (Immunity (2023) 56: 2188-2205), Applicant asserts that contrary to the Examiner’s statement in the previous Office action, “a more inflamed or ‘hot’ tumor phenotype is not what would have been expected in the prior art. The hot phenotype does not depend on more proliferation, which is what is shown in the prior art; rather it depends on- if not entirely on- homing into the tumor and local re-stimulation”. Remarks at pages 9-10. Applicant submits that none of the cited prior art documents teach or suggest increased T cell proliferation on tumors.
Further, Applicant submits that the data in the present application show for the first time that “intratumoral SEB injection led to ‘high’ T cell infiltration in multiple tumors” in mice (e.g., Figure 1C). Further, Applicant submits that administration of SEB + anti-PD-1 “led to complete disappearance of the melanotic part of the SEB-injected tumors” (e.g., Figure 2B) and that SEB + anti-PD-1 + anti-CTLA-4 doubled the amount of mice that rejected the tumor (e.g., Figure 3B). Remarks at pages 9-10. Applicant states that the cited prior art documents that show proliferation or activation/stimulation of T cells (i.e., Van Eenennaam and Rosenberg) “are silent about infiltration”, which is “useful for cold tumors”. Remarks at pages 9-10. Applicant further argues that the cited documents that relate to “cold tumors” (Bonaventura and Ayers) “do not propose or suggest using toxins to increase T cell infiltration”. Remarks at page 10.
In response, it is first noted that the claims are broadly drawn to the treatment of a generic tumor (which need not be a cold tumor) by administering any species of S. enterotoxin and any “immune checkpoint modulator” (e.g., an agonist or antagonist of any immune checkpoint molecule). While dependent claim 6 does recite “a cold or low immune cell infiltrated tumor”, it is one of several alternative options that further include “primary tumors” or “solid tumors”, which are rendered obvious by the methods previously disclosed by at least Van Eenennaam (e.g., ¶ 0087).
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the feature upon which Applicant relies (i.e., T cell infiltration) is not a required feature of the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). While Applicant defines “non-inflamed” or “cold” tumors as those displaying a lack of or reduced T cell infiltration, Bonaventura provides that this was a known feature of cold tumors at the time of filing of the instantly claimed invention. Bonaventura also provides that absence of T cell activation/co-stimulation was among the possible factors that could lead to “cold tumors” (pages 1-3; Figure 1). See non-final Office action at page 9. A person of ordinary skill in the art, understanding the teachings of Van Eenennaam and Rosenburg, would recognize that SEB-induced IL-2 secretion serves to increase T cell activation/co-stimulation. By further applying these teachings to those of Bonaventura, such a manipulation could be used to treat or reduce incidence of cold tumors. Even if it was not recognized in the prior art that cold tumors display reduced T cell infiltration or that SEB administration increases T cell infiltration in tumors, it is noted that MPEP § 2145 (Il) sets forth, “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. Furthermore, MPEP § 2112.02(II) states that “when the claim recites using an old composition or structure and the ‘use’ is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01. The SEB administered in the methods of the prior art, having materially the same composition and the inherent properties thereof, does not differ from that administered in the instant claims.
With respect to Applicant's arguments regarding the teachings of Bonaventura and Ayers (relevant to claim 7), it remains held that one of ordinary skill in the art would be motivated to co-administer a Staphylococcal enterotoxin (e.g., SEB) and an immune checkpoint modulator (e.g., an inhibitory anti-PD-1 antibody) for the treatment of a tumors characterized by a low IFN-γ response signature or a low IFN-γ response expanded signature. As taught by Bonaventura, IFN-γ status is predictive of response to anti-PD-1 therapy. As taught by Ayers, several IFN-γ-related genes involved in regulating the activity of T cells are predictive of PD-1 blockade treatment response, among them the receptor for IL-2 (IL2Rg). As noted above, IL-2 secretion is increased by SEB administration. Thus, co-administration of SEB would be expected to increase activation of IL2Rg and promote more favorable treatment outcomes.
For these reasons, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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