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 .
Response to Amendment
The amendment filed 5 June 2026 is acknowledged. Claims 20, 22, 25, 28, 30, and 43 are currently amended. Claims 26, 33, and 44 are newly cancelled.
Formal Matters
The Examiner notes that the amendment to claim 25 is improperly marked. Claim 25 in the claim set dated 1/5/2026 and examined in the Non-Final office action dated 2/5/2026 reads:
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As amended, claim 25 reads:
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Therefore, the deletion of “by virtue of the presence of allergies” is removed without being properly marked. Applicant is advised to follow the rules of MPEP 714 (in particular section (II)(C)) in future amendment submissions. For the purposes of expedited prosecution, claim 25 will be examined as currently amended.
Election/Restrictions
As previously described, Applicant’s election of Group I, claims 20-26, 28, 30, 32, 33, 43-45, and 48 in the reply filed on 5 January 2026 is acknowledged. Applicant further elects i) melanoma cancer, ii) detecting elevated levels of histamine, iii) anti-PD-1, and iv) fexofenadine. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 23, 34, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (claim 23) and invention (claims 34 and 37), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5 January 2026.
Due to the amendment of claim 25 described in the formal matters section above, the claims currently require a non-elected species of detecting plasma levels of IgE. Therefore, claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Claim Status
Claims 20-25, 28, 30, 32, 34, 37, 43, 45, and 48 are pending. Claims 23, withdrawn from further consideration as described in the Election/Restriction section above. Claims 26, 33, and 44 are newly cancelled. Claims 20-22, 24, 28, 30, 32, 43, 45, and 48 are under examination in the instant office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawal of Objections
The objection to the specification for reference to Figures in provisional applications is withdrawn in view of the amendments to the specification.
Withdrawal of Rejections
The rejection of claims 28, 43-45, and 48 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendments to the claims.
The rejection of claims 20-22, 24, 26, 30, 32 under 35 U.S.C. 102(a)(1) as being anticipated by Li, Hongzhong, et al. "The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1." Cancer cell 40.1 (2022): 36-52 published 24 November 2021 (Of record, cited on IDS dated 6/25/2024) is withdrawn in view of the disqualification of the reference as prior art in the declaration under 37 C.F.R. §1.130 filed 5 June 2026.
The rejection of claims 25, 43-45 and 48 under 35 U.S.C. 103 as being unpatentable over Li, Hongzhong, et al. "The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1." Cancer cell 40.1 (2022): 36-52 published 24 November 2021 (Of record, cited on IDS dated 6/25/2024) is withdrawn in view of the disqualification of the reference as prior art in the declaration under 37 C.F.R. §1.130 filed 5 June 2026.
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 48 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 48 is indefinite for the recitation of “wherein a biological sample from the subject has histamine in an amount greater than 0.3 ng/mL” (claim 43 lines 4-5) “wherein the biological sample is a tumor sample, and wherein the level of histamine and/or HRH1 signaling activation is determined by detecting […] HDC mRNA, HDC protein, mast cells, HRH1 mRNA, HRH1 protein, HRH1+ macrophages, VISTA+ macrophages, PI3K-gamma+ macrophages, and/or TIM-3+ macrophages in the sample” (claim 48 lines 2-5). The claim is unclear because, other than by detecting histamine, it is unclear how a person of ordinary skill in the art could determine that the level of histamine is in an amount greater than 0.3ng/mL by the detecting “HDC mRNA, HDC protein, mast cells, HRH1 mRNA, HRH1 protein, HRH1+ macrophages, VISTA+ macrophages, PI3K-gamma+ macrophages, and/or TIM-3+ macrophages in the sample”. Additionally, the claim is unclear because it is uncertain how the units of histamine measured for a solid tumor sample may be displayed in amounts of 0.3ng/mL. A person of ordinary skill in the art would not be able to determine what solute or what weight of tumor is equivalent to 0.3ng/mL because tumors vary in density.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement- New/Maintained, modifications necessitated by amendment
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.
Claims 20-22, 24 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating:
i) a subject with melanoma, lung cancer, breast cancer, or colon cancer (regarding claim 43 and dependents),
ii) wherein the subject has elevated levels of histamine or HRH1 signaling activation with elevated histamine, HDC mRNA, HDC protein, mast cells, HRH1 mRNA, HRH1 protein, or HRH1+ macrophages (regarding claims 20 and dependents and 43 and dependents);
iii) comprising administering to the subject a therapeutically effective amount of an anti-PD-1, anti-PD-L1, or an anti-CTLA4 checkpoint inhibitor (regarding claims 20 and dependents); and
iv) wherein the level of histamine and/or HRH1 signaling is determined by detecting histamine, HDC mRNA, HDC protein, mast cells, HRH1 mRNA, HRH1 protein, HRH1+ macrophages, VISTA+ macrophages, PI3K-gamma+ macrophages, and/or TIM-3+ macrophages in the sample wherein the tumor sample has histamine in an amount greater than 0.3ng/mL (regarding claim 48)
does not reasonably provide enablement for a method of treating:
i) any cancer;
ii) via any method of determining that the subject has an elevated level of HRH1 signaling activation (claim 20) or wherein a biological sample from the subject has histamine in an amount greater than 0.3ng/mL (claim 43) based on a detection level of any downstream target of HRH1 signaling activation in a subject
iii) comprising administering any generic checkpoint inhibitor; and
iv) wherein the subject has a tumor sample with histamine in an amount greater than 0.3ng/mL, because a tumor is not
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the method of the invention commensurate in scope with these claims.
Scope of the claims and nature of the invention
Instant claim 20 is directed towards a method of treating colorectal cancer, breast cancer, lung cancer, or malignant melanoma in a subject, comprising obtaining a biological sample from the subject, measuring the levels of histamine in the biological sample, determining that the subject has at least one of an elevated histamine or HRH1 signaling activation, wherein the subject is classified as having elevated levels of histamine if histamine is present in an amount greater than 0.3ng/mL and administering to the subject an H1-antihistamine in conjunction with any generic immunotherapy comprising the administration of a checkpoint inhibitor. The claim preamble must be read in the context of the entire claim. 'The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966." In this case, the preamble is interpreted to limit the method to “treating cancer in a subject” because the recitation of administering to the subject means the preamble is giving limiting structure to the claim. Regarding the determining or identifying HRH1 signaling activation, the instant claims encompass indirect means of determining HRH1 activation including indirect measures of downstream process elevated levels of VISTA+ macrophages, PI3K-gamma+ macrophages, and/or TIM-3+ macrophages. The limitation “wherein the subject is classified as having elevated levels of histamine if histamine is present in an amount greater than 0.3ng/mL” does not recite or require an active method step of measuring histamine, only the mental step of classification, and histamine may be present at any amount greater than 0.3ng/mL. Regarding H1 antihistamines, the art teaching that an H1 histamine is an antagonists or inverse agonists of the histamine receptors H1 (Faustino-Rocha, Ana I., et al. "Antihistamines as promising drugs in cancer therapy." Life Sciences 172 (2017): 27-41 p. 33 right column, ¶3; Of record IDS dated 6/25/2024). Regarding checkpoint inhibitors, the specification states “in some embodiments, the checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4” [0007] but does not provide a closed definition of checkpoint inhibitors. Although PD-1, PD-L1, and CTLA-4 are the checkpoint inhibitor targets with the most clinically validated antagonist monoclonal antibody therapies, there are many other immune checkpoints encompassed by the scope of the claim.
Instant claim 43 is directed towards a method of treating a subject with cancer, the method comprising selecting a subject having cancer, wherein the subject previously failed to respond to a checkpoint inhibitor consisting of an anti-PD-1, PD-L1, or CTLA-4, and wherein the biological sample from the subject has histamine in an amount greater than 0.3ng/mL. This is not an active method step, but requires selection of a subject based on the properties of checkpoint inhibitor resistance and the property of having a biological sample with histamine in an amount greater than 0.3ng/mL.
Although claims 21-22, 24, 28, 30, 32 do in some cases narrow the claims (e.g. to a particular biological sample, claim 22), none of the dependent claims is sufficiently narrow is scope to resolve the enablement issues as described for claims 20 and 43.
State of the Relevant Art; level of ordinary skill; and level of predictability in the art
Histamine levels and histamine signaling have known links to the pathogenesis of cancer, but the pathways and mechanisms are not predictable in the art. Nguyen, Phuong Linh, and Jungsook Cho. "Pathophysiological roles of histamine receptors in cancer progression: implications and perspectives as potential molecular targets." Biomolecules 11.8 (2021): 1232 (PTO-892 2/5/2026) teaches that the histamine released into the tumor microenvironment (TME) increased tumor growth and moderately increased metastatic colony-forming potential (p. 9 ¶2). Nguyen et. al. further teaches that the expression of H1R has been observed in a variety of cancer cell lines including in melanoma. H1R was found to be associated with cancer prognosis in some but not all different types different types of cancers (p. 9 ¶5). Nguyen et. al. teaches that studies of H1R in hepatocellular carcinoma, oral squamous cell carcinoma, and basal and HER2-breast cancer found mechanistic links between H1R upregulation and cancer progression and that “These data suggest that H1R in tumor cells may be a potential oncoprotein, and it is associated with a poor prognostic value in cancer” (p. 9 ¶5-p. 10 ¶1). Nguyen et. al. teach that several H1R antagonists have been show to inhibit tumor progression (p. 10 ¶2-3).
Sarasola, María de la Paz, et al. "Histamine in cancer immunology and immunotherapy. Current status and new perspectives." Pharmacology Research & Perspectives 9.5 (2021): e00778 (PTO-892 2/5/2026) teaches “Extraordinary advances in the understanding of the interactions between the immune system and cancer cells have been made in the last decade, which led to the development of effective and promising immunotherapies targeting different tumor molecules and their interaction with the tumor microenvironment (TME). Consequently, immune checkpoint inhibitors were developed to successfully enhance anti-tumor T-cell features but resulted in durable responses only in a fraction of patients. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer and it can be reshaped by cancer immunotherapies. One of the most important topics in cancer immunology research today is to understand the characteristics and profiles of immune cells in the TME to design new immunomodulatory strategies that can boost the immune system to fight cancer. Even though histamine has been the first inflammatory biogenic amine to be characterized, novel functions of histamine are still being described […] Immune cells that are key participants in the TME can synthesize, release and respond to histamine” (p. 2 left column-right column ¶2). Sarasola et. al. teaches “Histamine is considered one of the most important mediators that orchestrate inflammatory responses, and it plays a central role in numerous pathological conditions, including cancer” (p. 2 right column, ¶5). Sarasola et. al. review the different effects of histamine on immune cells in the tumor microenvironment such as T cells and that “Systemic treatment with histamine (10 mg/kg, twice a day for 21 days beginning the day of tumor implantation) increased Colon 38 tumor growth implants in syngeneic mice by an indirect effect associated with a reduction in the anti-tumor cytokines expression in the TME, dysregulating the balance between Th1 and Th2 cells.139 Reynolds et al reported the levels of histamine content in 31 colorectal cancer specimens and indicated that they were sufficient to inhibit lymphocyte activity.140 Lactobacillus rhamnosus-derived histamine promotes a regulatory Foxp3-T cell response profile in intestinal Peyer patches while altering Th1 polarization through the H2 receptor.141 The infiltrating cytotoxic cells, mainly CD8+ T lymphocytes and NK cells, are responsible for killing cancer cells. Therefore, immunosuppressive cells’ infiltrate such as Tregs and MDSCs, is usually associated with a worse prognosis in cancer patients” (p. 9 left column ¶2-3). Sarasola et. al. teaches that the effects of histamine through the H4 receptor can have a dual anti-tumoral and immunosuppressive effect depending on the stage and tumor condition (Fig. 2). Sarasola et. al. teaches “However, the benefit of histamine does not apply to all tumors and depends on its type and origin.163” (p. 10 right column ¶3). Sarasola et. al. teaches: “Differences in the levels of histamine, the composition of TME, or histamine receptor subtypes present in tumor cells and immune cells could ultimately determine the biological effects of histamine and pharmacological agents targeting histamine receptors. Therefore, these facts help to understand the controversial studies in cancer research” (p. 17 ¶1).
Lastly Sarasola teaches “Immunotherapy is now a mainstay of cancer treatment. The success in targeting immunologic checkpoints, including the PD-1/PD-L1 blockade in different solid tumors, has revived the interest in immunotherapies and in combinatorial strategies to achieve additive or synergistic clinical benefits. One obstacle in the effectiveness of immunotherapy is the complexity and the dynamic nature of immune-related responses. In this line, novel immunotherapy combinations seek immunomodulatory agents capable of manipulating the signals in the TME to boost the immune system against cancer, targeting T cells and other components including myeloid cells. Considering the promising preclinical and clinical data using the combination of histamine with immunotherapies, future clinical trials should be developed to evaluate the efficacy and safety of the combined therapy of immune checkpoint inhibitors and histamine receptor ligands” (p. 17, left column). Sarasola therefore indicates that response to therapy would have been unpredictable depending on the cancer subtype, the histamine ligand, and the tumor microenvironment, and the tumor microenvironment.
Regarding the methods of identifying or determining HRH1+ activation, some of these are known in the art and largely the scope of the claims is directed towards direct regulators of histamine or H1HR levels (histidine decarboxylase, which produces histamine, histamine protein itself, HRH1 protein or mRNA levels). However, the art teaches other mechanisms of the downstream effectors such as TIM3+ macrophages; Maksimova, Aleksandra, Tamara Tyrinova, and Elena Chernykh. "TIM-3+ Macrophages: Insights into Their Role in Cancer and Inflammation." International Journal of Molecular Sciences 27.2 (2026): 840 (PTO-892 2/5/2026) teaches that although there has been a link described between the M1 or M2 polarization state and the expression of TIM-3, research demonstrated that neither TIM-3+ nor TIM-3- cells belonged exactly to the M1 or M2 phenotype and that the M1/M2 polarization depends on the localization of cells and the microenvironment (p. 4 ¶3). TIM-3 expression has been linked to monocyte-derived macrophages polarized with IL-4 and IL-4/STAT6 signals may promote TIM-3 activation (M2 and M2-like) but increased M1 polarization during intracerebral hemorrhage (p. 4 ¶2-3). Maksimova et. al. concludes “it is not possible to unambiguously associate TIM-3 with a pro- or anti-inflammatory macrophage phenotype” (p. 4 ¶3). Thus, it would not have been predictable from the state of the art whether the TIM-3+ macrophages and other downstream markers instantly claimed are able to predictably determine HRH1 activation.
Regarding checkpoint inhibitor therapies, although monoclonal antibodies antagonizing PD-1, PD-L1, and CTLA-4 are well known, there are still lots of novel immune checkpoints being investigated such as VISTA; ectonucleotidases CD39, CD73, and CD38; LAG-3; IDO-1; CD27; CD70; TIM-3; CD47; CD93; CD161; BTLA; VTCN1; B7-H3; and TIGIT (reviewed in Wang, Y., Zhang, H., Liu, C. et al. Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts. J Hematol Oncol 15, 111 (2022). https://doi.org/10.1186/s13045-022-01325-0, see Table 1; PTO-892 2/5/2026). These checkpoints are all mechanistically distinct checkpoint with different pathways, effects, and cellular targets, some of which have not been identified or which have not been well characterized in clinical trials and have heterogenous responses in different target cancers (Wang et. al. Conclusion p. 46-48).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification teaches a method of overcoming resistance to anti-PD-1, anti-PD-L1, and anti-CTLA-4 monoclonal antibody checkpoint immunotherapy due to increase histamine signaling via HRH1 in the tumor microenvironment by treating with known H1 antagonist antihistamines such as fexofenadine. The instant specification teaches a reduced risk of death in checkpoint immune blockade patients taking PD-1 or PD-L1 monoclonal antibody checkpoint therapies for lung cancer compared to other medicines such as antibiotics (Fig. 1). Further, in another cohort of ICB (anti-PD-1/PD-L1) treated melanoma patients, there decreased risk of death in those taking H1-antihistamines, but not in a cohort of patients treated with chemotherapy and taking H1-antihistamines (Fig. 1C).
The specification shows that HRH1 but not the other histamine receptors is associated with more dysfunctional tumor T-cells in many cancer subtypes (Fig. 1F) and particularly validated in triple negative breast cancer and melanoma (Fig. 1G-H). HRH1 expression was strongest in M2 macrophages by both gene expression and IHC of TNBC tissue (Fig. 2). Inhibition of HRH1 on macrophages using HRH1 knockout or the H1 antihistamine fexofenadine was associated with increased T cell activation and anti-tumor cytotoxicity in vitro (Figs. 3 and 10). The specification teaches that in vivo in syngeneic E0771 and B16-GM models in HRH1-/- or WT C57BL/6 mice where Enhanced MHCII:CD206 ratio in the TAMs, increased numbers of IFN-g+ and reduced tumor growth were found in HRH1-/- mice and FEXO-treated mice compared with WT mice and vehicle treated mice, respectively (FIGS. 3C-3E). The inhibition of tumor growth was T-cell dependent and was blocked by CD8-T cell depletion or anti-CD8 antibodies (Fig. 3F and 10L). The tumor-associated immune cells in HRH1-/- mice had fewer M2-like macrophages and increased CD8 T cells and other cytotoxic immune cells (Fig. 11C).
Regarding specific methods of treatment, the specification teaches two methods of treating two syngeneic mouse models of cancer with CT26 (colon cancer) or B16-GM (murine melanoma), which express GM-CSF and recruit suppressive myeloid cells, and is therefore more resistant to CTLA-4 and PD-1 checkpoint inhibitors than the parental B16-F10 cell model (De Henau, Olivier, et al. "Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells." Nature 539.7629 (2016): 443-447; IDS dated 6/25/2026). In both of these models, there was a partial but incomplete response of CTLA-4 checkpoint monotherapy or PD-1/CTLA-4 combination therapy which was similar to fexofenadine alone, with some improvement from the combination.
The specification also teaches two tumor models, EMT6 and CT26 concurrent with an allergy model (Fig. 7A) which became resistant two checkpoint immunotherapy except when co-treated with fexofenadine (Fig. 7E-F). In retrospective human trial data, allergy status and histamine expression were also associated with respond to PD-1/PD-L1 checkpoint treatment (Fig. 7G-J).
Regarding macrophage expression of other downstream markers of HRH1 activation, the specification teaches that HRH1 regulates VISTA and TIM3 expression on macrophages [0135], Fig. 4B, Fig. 13B and that treatment with fexofenadine decreased VISTA expression on tumor-associated macrophages (Fig. 13F).
Regarding the type and level of the biological samples for determining increased levels of histamine, the specification describes plasma levels of histamine of low (<0.3ng/mL), medium (0.3ng/mL-1ng/mL), and high (1 ng/mL) (e.g. Fig. 7I, p. 10 ¶1); tumor tissue levels are reported in ng/ml/mg tissue from culture medium of tumors. There are no measurements of histamine in ng/mL in tumor samples.
There is no evidence in the specification of methods of treating a cancer subtype that has not previously had some approval of PD-1/PD-L1/CTLA-4 checkpoint immunotherapies; there are no examples of correlating downstream markers of HRH1 signaling with solely with HRH1 activation in all cancers, or demonstrations that all VISTA+, TIM3+, or PI3K-gamma+ macrophages are evidence of HRH1 activation; there are no checkpoint inhibitors other than the traditional antagonists of PD-1, PD-L1, or CTLA-4 tested in combination with an antihistamine (anti-VISTA is tested, but only in combination with a second checkpoint inhibitor and not with an antihistamine).
All of the instant methods are directed at the effects of elevated histamine and HRH1 signaling; there are no examples where the identification of resistance to immunotherapy is based on a decrease of histamine levels or signaling compared to control, although decreases in histamine compared to control have been described in the art.
Conclusion
The Applicant does not have enablement for the method of treating any generic cancer in a subject comprising administering any antihistamine and any checkpoint inhibitor in the subject and detecting or identifying an elevation of histamine or HRH1, or any difference in histamine or HRH1 activation compared to a control that would respond to checkpoint inhibitors, wherein HRH1 activation is detected by any downstream effector of HRH1. It would take undue experimentation to determine how to practice the scope of the method as claimed. Dependent claims are rejected for failing to completely resolve the scope of enablement issues, as described.
Response to Arguments
Applicant’s arguments dated 6/5/2026 have been fully considered but are not persuasive.
Applicant argues first that the amendment of claim 20 to recite specific types of cancers obviates the scope of enablement as described by the office (Remarks 6/5/2026 p. 12 ¶2). This is partially unpersuasive because independent claim 43 does not also include this amendment, as described in the modified scope of enablement rejection, necessitated by amendment, above.
Applicant further argues that the specification provides sufficient description of how to determine the elevated level of histamine and HRH1 signaling and claims “The specification also describes how to measure HRH1 signaling activation, e.g., by detecting HRH1 expression and/or the number of HRH1+ macrophages, HDC expression, mast cells, VISTA+ macrophages, PI3K-gamma+ macrophages TIM-3+ macrophages in a tumor sample” (Remarks 6/5/2026 p. 12 ¶3). This is not persuasive because, as described in the modified scope of enablement rejection, above, Applicant merely prophetically recites all of these biomarkers of histamine and/or HRH1 signaling; there is no particular guidance showing that high histamine levels are necessary and sufficient for M2-like TIM-3+ macrophages in tumors and that, in a method of treating a human subject, these alternate biomarkers that are downstream of and affected by many other pathways that histamine are sufficient to allow a person of ordinary skill in the art to determine which subject would be determined to have an elevated level of histamine or HRH1 signaling. What level of VISTA+ macrophages indicates an elevated level of histamine or HRH1 signaling? There is no guidance, and no particular level or even direction of change is required by the claims, and therefore a person of ordinary skill in the art would have to perform undue experimentation in order to practice the instant methods as claimed.
The Applicant further argues that the instant specification provides a clear and enabling disclosure of immune checkpoint blockade agents and that a person of ordinary skill in the art “would understand how to select a suitable checkpoint inhibitor for treating a particular cancer” (Remarks p. 13 ¶1). This is not persuasive because the instant invention is a method of treating cancer in a particular population comprising administering to the subject both an H1 antihistamine in conjunction with an immunotherapy comprising a checkpoint inhibitor, not merely whether a method of treatment with a checkpoint inhibitor is enabled. All of the checkpoint inhibitors mentioned have distinct mechanisms and distinct effects on the immune system, and there is no guidance offered by the specification that would allow a person of ordinary skill in the art to determine what the expected interaction of an H1 antihistamine would be with these alternate immune checkpoint inhibitors. Even within these classes of immune checkpoint inhibitors, there was vast variation that was not known at the time of filing in the cancer response that would have prevented a person of ordinary skill in the art from reliably determining the method of treatment as claimed. For example, Sen, Shiraj, et al. "Initial results from a first-in-human phase 1 study of SNS-101 (pH-selective anti-VISTA antibody) alone or in combination with cemiplimab in patients with advanced solid tumors." (2024): 2600-2600 teaches that a pH-selective anti-VISTA antibody alone and in combination with cemiplimab can be safely administered at doses ~50x higher than doses where severe CRS was observed with prior VISTA agents”. This teaches that the effective dose and the effect of the treatment with cancer, especially in combination with a second immunomodulatory drug H1 antihistamine. As an additional example, Yang, Xuan, and Lieping Chen. "Why has immune “checkpoint” therapy failed in most clinical trials?." Journal for Immunotherapy of Cancer 13.8 (2025): e012457 teaches that “most clinical trials for other “checkpoint inhibitors have shown disappointing response rates, leading to significant doubts about the path forward for this field” (p. 1 left column, “Introduction”) and “for checkpoint blockade to be effective and safe, the target may need to be deeply embedded in the unique immune architecture of the TME” (p. 2 left column, ¶2). Additionally, the claims do not recite that the tumor or the tumor microenvironment expresses the target of the checkpoint, and a person of ordinary skill in the art would not be able to determine, without undue experimentation, which cancers and patients as claimed may be treated by the active steps of the instant methods.
Therefore, as described in the 112(a) scope of enablement rejection above, a person of ordinary skill in the art would require undue experimentation to practice the instant combination method as claimed in the scope as claimed and the rejection is maintained/modified as necessitated by amendment.
Claim Rejections - 35 USC § 102- New, necessitated by amendment
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 43 and 45 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO2016069727 to Wong et. al. published 6 May 2016.
Claim interpretation: Claim 43 recites a method of treating a subject with cancer, the method comprising (a) selecting a subject having cancer, wherein the subject previously failed to respond to a checkpoint inhibitor consisting of an anti-PD-1, PD-L1, or CTLA-4, and “wherein a biological sample from the subject has histamine in an amount greater than 0.3ng/mL”. The phrase starting with “wherein a biological sample form the subject” recites a property of the subject, but is not an active method step, and therefore does not require the measurement of histamine. The broadest reasonable interpretation of the claim is, therefore, that the subject must have the properties of 1) having previously failed to response to a checkpoint inhibitor therapy consisting of an anti-PD-1, anti-PD-L1, or anti-CTLA-4 and 2) the subject has the property that a biological sample from the subject has histamine in an amount greater than 0.3ng/mL.
Wong et. al. teaches a method of treatment of a subject with cancer comprising administering a combination of anti-CSF1R and anti-PD-1/PD-L1 therapy (Abstract) wherein some of the patients have PD-1 resistant NSCLC or melanoma (See e.g. [0280], Appendix B part j). Wong et. al. teaches that for Grade 2 symptoms the patient will be administered diphenhydramine 50 mg IV and that prophylactic pre-infusion medications including diphenhydramine 50 mg should be administered prior to all subsequent nivolumab infusions ([0512-0515]). Regarding “wherein a biological sample from the subject has histamine in an amount greater than 0.3ng/mL”, a subject having a grade 2 infusion reaction to nivolumab would inherently have the property that a biological sample from the subject would have histamine in an amount greater than 0.3ng/mL because, as evidenced by Vadas et. al., serum histamine in reactions in response to drugs was elevated by the standard of >10nmol/L (equivalent to 1.1 ng/mL) in 57% of patients and was above 3nmol/L (0.3ng/mL is equivalent to 2.7 nmol/L) in every patient that had an allergic response to a drug (See Fig. 3B, column B; the very lowest response appears to be about 5 nmol/L). Therefore, all of the patients of Wong et. al. that have a Grade 2 response to the combination of nivolumab and anti-CSF1R antibody would have the characteristic of having a plasma histamine level of greater than 0.3ng/mL.
Regarding claim 45, the therapy is in combination with anti-PD-1/PD-L1 therapy or particularly nivolumab (Abstract, [0512-0515]).
Claim Rejections - 35 USC § 103- New, modifications necessitated by amendment
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.
Claims 20-22, 24, 28, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Labella, Marina, and Mariana Castells. "Hypersensitivity reactions and anaphylaxis to checkpoint inhibitor–monoclonal antibodies and desensitization." Annals of Allergy, Asthma & Immunology 126.6 (2021): 623-629 published June 2021 (PTO-892 2/5/2026) as evidenced by Davis, Steven C., et al. "Up-regulation of histidine decarboxylase expression and histamine content in B16F10 murine melanoma cells." Inflammation Research 60.1 (2011): 55-61 (PTO-892 2/5/2026), and further in view of Vadas, Peter, Boris Perelman, and Gary Liss. "Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis." Journal of Allergy and Clinical Immunology 131.1 (2013): 144-149 (PTO-892 2/5/2026).
Regarding claims 20, 21, Labella et. al. teach a method of treating cancer with checkpoint inhibitor antibodies against PD-1, CTLA-4, and PD-L1 (p. 624). Labella et. al. teaches skin testing to diagnose type I hypersensitivity reaction and anaphylaxis and that the testing “provides evidence of IgE and mast cell involvement” (p. 626, right column). Hypersensitivity reactions and anaphylaxis therefore would both be considered allergic reactions. Labella et. al. teaches drug desensitization of a patient receiving Nivolumab (anti-PD-1; instant claim 21) for the treatment of melanoma with a 3 bag, 12 step protocol (Table 3) wherein the protocol comprises administration of the H1 antihistamine dexchlorpheniramine in conjunction with the infusion of Nivolumab (p. 628, left column). Labella teaches that drug desensitization have been successfully applied to checkpoint inhibitor drugs to allow patients to receive first-line therapies to improve cancer outcomes (Abstract: Results and Conclusion sections).
Regarding claim 28, the dexchlorpheniramine is administered intravenously (p. 628, left column).
Regarding claim 30, the H1 antihistamine dexchlorpheniramine is an H1 antihistamine, which are, by definition, antagonists of histamine receptor 1 (HRH1) and therefore inhibits the downstream effectors of HRH1 activation.
Regarding claim 32, although Labella et. al. does not explicitly teach that melanoma is associated with high levels of histamine production, HRH1 signaling activation, and/or plasma histamine, association of melanoma upregulation of histamine is an inherent property because melanoma cells have been shown to upregulated histamine as evidenced by Davis, Steven C., et al. "Up-regulation of histidine decarboxylase expression and histamine content in B16F10 murine melanoma cells." Inflammation Research 60.1 (2011): 55-61, see Figure 2.
Labella et. al. further teaches that some infusion reactions are anaphylactic (p. 626) and that clinical management and prevention of anaphylaxis rely on its rapid recognition and diagnosis based on clinical phenotype, underlying endotype, and biomarkers.
Labella et. al. does not teach explicitly teach the method comprising obtaining a biological sample from the subject and measuring the levels of histamine in the biological sample wherein the subject is determined to have an elevated level of histamine if histamine is present in an amount greater than 0.3ng/mL (instant claim 20) by detecting plasma histamine concentrations (instant claim 22) in a sample obtained by the subject or wherein the level of histamine is detected by IHC, flow cytometry, or ELISA (instant claim 24).
This deficiency is resolved by Vadas et. al.
Vadas et. al. teaches that in patients undergoing anaphylactic reactions, including anaphylaxis related to medicine, histamine levels were of grade 1-3 anaphylaxis were significantly different when untransformed and were of borderline significance when log-transformed (p. 145 right column). 70% of patients with grade 3 anaphylaxis had serum levels >10nmol/L (Fig 1B) (equivalent to 1.1 ng/mL, reads on greater than 0.3ng/mL). Vadas et. al. teaches that histamine was measured in blood plasma by ELISA (p. 145 left column ¶4)(reads on obtaining a biological sample, wherein the sample is plasma, from a subject and measuring the levels of histamine in the sample; claims 20, 22, and 24). Vadas et. al. teaches that histamine levels correlated better with clinical signs than did tryptase levels (p. 148 left column ¶2). --
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method comprising 1) measuring histamine from a plasma sample by ELISA to detect high-grade anaphylactic reactions with histamine >1.1ng/mL in a patient that has been administered Nivolumab in order to benefit from the correlation of histamine with anaphylaxis as taught by Vadas et. al. as a biomarker and in order to benefit from a biomarker for the diagnosis of anaphylactic response to checkpoint inhibitor administration as taught by Labella et. al and 2) subsequently administering Nivolumab in conjunction with the H1 antihistamine dexchlorpheniramine in order to benefit from a desensitization protocol and continued Nivolumab treatment for cancer immunotherapy as taught by Labella. This would have a predictable effect because Vadas et. al. teaches that there is correlation with histamine in anaphylactic reaction to medication and Labella et. al. teaches that it is important to detect anaphylactic reaction to the checkpoint inhibitor antibodies; therefore, an artisan would expect to be able to apply detection of histamine as one biomarker to determine the treatment course to an adverse immune reaction to a checkpoint inhibitor antibody infusion; and further, Labella et. al. teaches that drug desensitization with a protocol including an H1 antihistamine is a way to successfully allow patients with cancer to receive first-line therapies.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over WO2016069727 to Wong et. al. published 6 May 2016 in view of Agis, H., et al. "Clinical and prognostic significance of histamine monitoring in patients with CML during treatment with imatinib (STI571)." Annals of oncology 18.11 (2007): 1834-1841.
The teachings of Wong et. al. in regards to claim 43 are in the 102 rejection above and are incorporated by reference herein.
Claim interpretation: As described in the 112(b) rejection above, it is unclear how the level of histamine of 0.3ng/mL is determined by detecting any of the recited components (e.g. how a person of ordinary skill in the art could determine that histamine was greater than 0.3ng/mL from VISTA+ macrophages, and further because 0.3 ng/mL is not a clear unit of measurement for a solid tumor sample, which would have variable density. For the purposes of expedited prosecution, the claim will be interpreted to read on detecting histamine greater than 0.3ng/mL in a tumor sample, wherein the tumor is a blood cancer.
Wong et. al. further teaches that the methods include liquid cancers such as leukemia [095], [0232].
Wong et. al. does not teach a method of treating a subject with cancer, the method comprising selecting a subject having cancer wherein a tumor sample from the subject has histamine in an amount greater than 0.3ng/mL and wherein the level of histamine is determined by detecting histamine.
This deficiency is resolved by Agis.
Agis teaches that CML is a cancer of the blood wherein histamine is highly upregulated, in part do to clonal expansion of basophils (). Agis teaches that 97 CML patients has median peripheral blood histamine of 4618, 11242, or 5563 ng/mL divided by phase of the cancer (Table 1A) compared to age-matched controls who had average peripheral blood histamine of 55ng/ml. Agis et. al. teaches that during treatment, histamine levels decreased and returned to normal in those achieving a complete cytogenic response.
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to perform the method of detecting histamine in a CML tumor sample in combination with the method of treating leukemia with a combination of nivolumab, an anti-CSFIR antibody, and an H1 antihistamine as taught by Wong et. al. to benefit from a method of measuring cancer progression for CML as taught by Agis. This would have a predictable effect because a person of ordinary skill in the art would expect the detection of histamine correlating with clonal basophils to be effective at measuring the cancer treatment effectiveness for CML as taught by Agis regardless of the different type of cancer treatment (a checkpoint inhibitor nivolumab for combined with anti-CSFIR antibody for Wong et. al.).
Response to Arguments
The arguments dated 6/5/2026 have been fully considered but are not persuasive.
Regarding the rejection of claims 20-22, 24, 26, 30, and 32 under 35 U.S.C. 102(a)(1) as anticipated by Li et. al, this argument is persuasive and the rejection is withdrawn in view of the declaration under 37 C.F.R §1.130(a) filed 6/5/2026.
Regarding the rejection of claims 20, 21, 25, 26, 28, 30, 32, and 33 under 35 U.S.C. 102(a)(1) as anticipated by Labella et. al. as evidenced by Davis, Applicant argues that amended claim 20 recites “determining that the subject has at least on of an elevated of histamine or HRH1 signaling activation, wherein the subject is classified as having elevated levels of histamine if histamine is present in an amount great than 0.3 ng/mL” (Remarks 6/5/2026 p. 14). These arguments are partially moot due to the withdrawal of the rejection and the new 103 rejection, necessitated by amendment, above. Applicant argues that “Labella does not teach measuring the level of histamine in a biological sample from a patient prior to treatment”; however, this limitation is not recited in the claims. As described in the 103 rejection above, Labella teaches detection of an allergic reaction to administration of a checkpoint inhibitor followed by subsequent treatment with a H1 antihistamine in conjunction with a checkpoint inhibitor. First, the examiner notes that the method “comprises” each step, and that other than steps (a) and (b) which are required to be performed in order to provide antecedent basis for the biological sample, none of the steps require any particular sequencing or order (See MPEP 2111.01.II). Indeed, it would be improper to read a requirement that a patient be checkpoint inhibitor naïve onto the instant claims because it is clear from both the claims and the specification that the inventors have contemplated patients that have received a checkpoint inhibitor prior to receiving a checkpoint inhibitor in conjunction with an H1 antihistamine (e.g. see Specification [0056]).
Regarding the 103 rejection of claims 25, 43-45, and 48 under 35 U.S.C. 103 as being unpatentable over Li et. al., this argument is persuasive and the rejection is withdrawn in view of the declaration under 37 C.F.R §1.130(a) filed 6/5/2026.
Regarding the 103 rejection of claims 22 and 24 under 35 U.S.C. 103 as being unpatentable over Labella in view of Vadas, these arguments are partially moot in view of the new 103 rejection, necessitated by amendment, as unpatentable in view of Labella as evidenced by Davis in view of Vadas. To the extent the arguments still apply to the new rejection, they are unpersuasive. Applicant argues first that because Labella does not anticipate claim 20, claims 22 and 24 cannot be obvious over Labella in view of Vadas. This is not persuasive in view of the new obviousness rejection, necessitated by amendment, of claim 20 as described in the 103 rejection and arguments above.
Applicant argues that “The cited references do not disclose or suggest each and every limitation of the claims. For example, neither of the references disclose or suggest testing a biological sample from a subject before the subject has been treated with a checkpoint inhibitor” (Remarks 6/5/2026 p. ). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., testing a biological sample before the subject has been treated with a checkpoint inhibitor) are not recited in the rejected claim(s). 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). As described in the arguments above, there is no particular order required by the treatment steps of claim 20. Further Labella does suggest a method of treating comprising administering an H1 antihistamine and a checkpoint immunotherapy subsequent to testing a biological sample for histamine because Labella teaches the subsequent desensitization combination treatments after the initial reaction.
Applicant argues “a person of ordinary skill in the art would not have been motivated to combine the references with any reasonable expectation of achieving the same technical effects of the present application […] Thus, Labella is merely focused with controlling adverse drug reactions following administration of the checkpoint inhibitor, of which is a fundamentally different technical problem and solution than the Published Application” (Remarks p. ). Again, these limitations are not recited in the claims.
Regarding Vadas, applicant argues that “Neither histamine nor tryptase showed as good correlations with severity scores as did PAF”. MPEP 2145 states “Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)”. As described in the 103 rejection above, Labella in view of Vadas teaches a method comprising measuring histamine from a serum sample (Vadas), using biomarkers to measure allergic reaction to drug administration (both Vadas and Labella), and a method of administration of an H1 antihistamine in conjunction with an anti-PD-1 checkpoint inhibitor in order to benefit from the 1) measurement of a biomarker that correlates with allergy as taught by Labella and Vadas and 2) the desensitization protocol that allows first-line treatment as taught by Labella. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Thus, as noted above in the arguments and the 103 rejection, although Vadas does not teach all of the instant limitations, the combination of Labella in view of Vadas makes obvious the instant claims.
Applicant argues that the present Applicant is directed to a method of treating cancer by first determining if the subject has high levels of histamine and subsequently administering an immune checkpoint inhibitor in combination with an H1 antihistamine, and that the specification describes a correlation between the levels of histamine in a subject and the likelihood of cancer treatment success (Remarks p. 18). Additionally, Applicant argues that the inhibition of production or expression of histamine enhances an antimetastasis immune response (Remarks p. 18). Applicant states “Thus, the methods of the Published Application are not directed to desensitizing a subject to immune checkpoint inhibitor treatment or reducing anaphylaxis, but rather meticulously downregulating the expression of histamine in a subject in combination with administering an immune checkpoint inhibitor to ameliorate the cancer” (Remarks p. 18 ¶2). As described in the 103 rejection and the arguments above, these limitations are not recited in the 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). Even if, en arguendo, there was an unexpected technical effect of administering an H1 antihistamine in combination with the immune checkpoint inhibitor (see Remarks p. 18 ¶2, last sentence), MPEP 2145 states “ the evidence must be reasonably commensurate in scope with the claimed invention” and “in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention”. The scope of the instant claims is much broader than the scope for which there may be an unexpected technical effect as demonstrated by the application because the technical effect is limited to a method of treating comprising administering certain H1 antihistamines (e.g. fexofenadine) to particular patients (e.g. patients with a baseline plasma histamine level of medium between 0.3-0.6 ng/mL or high >0.6ng/mL), with particular checkpoint inhibitor targets. There is no ceiling on plasma histamine recited by the claims, and a person of ordinary skill in the art would have immediately understood, as taught by Labella in view of Vadas, the a patient is more likely to have a favorable response to an immune checkpoint inhibitor if they are not having a allergic response to the checkpoint inhibitor itself. There is no timing, order of steps, or dosage required by the instant claims. Indeed, the BRI of instantly amended claim 43 could even extend to a patient cancer patient who previously failed to respond to a checkpoint inhibitor continuing to take their routine seasonal allergy medication; a patient with seasonal allergies would certainly be expected to have higher levels of histamine and in would not typically be expected that a patient undergoing therapy for cancer discontinue their other routine medications. As such, the instant claims are much broader in scope than any technical effect that could be considered unexpected.
Conclusion
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.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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