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 .
Election/Restrictions
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Claims 23, 34, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (claim 23) and invention (claims 34 and 37), there being no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.
Claim Status
Claims 20-26, 28, 30, 32-34, 37, 43-45, and 48 are pending. Claims 23, 34, and 37 are withdrawn from further consideration as described in the Election/Restriction section above. Claims 20-22, 24-26, 28, 30, 32, 33, 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.
Specification
The disclosure is objected to because of the following informalities: The specification makes reference to Figures in provisional applications that will not be published ([127], [129], [133], [138]). Because the content is therefore unclear and cannot be understood from the specification, it is informal.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 28, 43-45, and 48 are 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 28 recites the limitation "the derivative" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 43 is directed towards a method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a checkpoint inhibitor and of an antihistamine, wherein “the subject has been identified as unlikely to respond to an immunotherapy comprising the checkpoint inhibitor based upon a detection of levels of histamine and/or HRH1 signaling activation in a biological sample obtained from the subject, wherein the identification of the subject as unlikely to respond to the immunotherapy is based on a difference in the level of histamine and/or HRH1 signaling activation in the biological sample as compared to the level in a biological sample obtained from an individual known to be responsive to the immunotherapy”. This is unclear for several reasons. The terms “unlikely to respond to an immunotherapy comprising the checkpoint inhibitor” and “difference in the level” are relative terms that are not sufficiently defined by the specification. While the specification does indicate that the presence of allergies (Fig. 7G) and that patients with high plasma histamine levels (>0.6ng/ml) correlate with progressive disease and less tumor reduction (Fig. 7H and 7I) and reduced objective response rates and disease control rates, it is unclear what the bounds of “unlikely to respond” would be because there are patients that respond to disease in every group even though they are correlated. Would the medium histamine group be considered unlikely to respond because they have a reduction in response rate compared to the highest responses? Further, the scope of the claim says that “as compared to the level in a biological sample obtained from an individual known to be responsive to immunotherapy”. Since both the high histamine, medium histamine, and low histamine populations in the study have individuals that are known to respond to the checkpoint immunotherapy, the metes and bounds of the controls are also unclear. Thus, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Additionally, the claim recites that the subject is unlikely to respond to an immunotherapy comprising the checkpoint inhibitor, but the method is administering an immunotherapy comprising the checkpoint inhibitor. It would not make sense to treat someone with a therapy they have been identified as unlikely to respond to, and the claim does not make clear whether the patient is unlikely to respond to all therapies including combination therapies or just checkpoint inhibitor monotherapies. Therefore, an artisan would not be able to define the metes and bounds of the instantly claimed method.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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, 24-26, 28, 30, 32, 33, 43-45, and 48 are 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,
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;
iii) comprising administering to the subject a therapeutically effective amount of an anti-PD-1, anti-PD-L1, or an anti-CTLA4 checkpoint inhibitor; and
iv) administering an H1 antihistamine wherein the subject has been identified as at risk of a poor or reduced response to the checkpoint inhibitor
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 identifying a subject as unlikely to respond to an immunotherapy comprising the checkpoint inhibitor (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) administering any generic antihistamine.
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 any generic cancer in a subject, comprising determining that the subject has at least one of an elevated histamine or HRH1 signaling activation and administering to the subject any generic 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. Regarding the scope of a generic antihistamine, the instant specification does not offer a definition of antihistamine. The art recognizes two definitions of antihistamines: one is specific to H1 antihistamines (and particularly refers to H1 antagonists or inverse agonists) and the second is antagonists or inverse agonists of any of the histamine receptors H1, H2, H3, or H4 (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 administering to the subject a therapeutically effective amount of a checkpoint inhibitor and of an antihistamine wherein the subject has been identified as unlikely to respond to an immunotherapy comprising the checkpoint inhibitor based on a detection of levels of histamine and/or HRH1 signaling activation in a biological sample obtained from the subject, wherein the identification of the subject as unlikely to respond to the immunotherapy is based on a difference in the level of histamine and/or HRH1 signaling activation in the biological sample obtained from the subject as compared to the level in a biological sample obtained from an individual known to be responsive to immunotherapy. As described above for claim 20, the claims is broadly directed towards any checkpoint inhibitor, any antihistamine, and based on detection of HRH1 signaling activation which includes downstream biological targets that are also regulated by other signaling mechanisms.
Although claims 21-22, 24-26, 28, 30, 32 do in some cases narrow the claims (e.g. to a particular cancer, claim 33; or to H1-antihistamine, claim 26), 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 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 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 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). 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). 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).
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). There are no examples of the effects of antihistamines other than H1 antagonist antihistamines, and all of the instant guidance is directed at effect of histamine through the H1 receptor.
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.
Claim Rejections - 35 USC § 102
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.
Claims 20-22, 24, 26, 30, 32 are rejected 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).
Li et. al. teaches a method of treating cancer in two mouse tumor cell transplantation models, EMT6 (murine mammary carcinoma) and CT26 (murine colon cancer) wherein allergic sensitization to OVA increases tumor size (Fig. 7C) and total blood histamine levels (Fig. 7B) compared to non-allergic mice (reads on determining that the subject has elevated level of histamine). Li et. al. teaches treatment of the mice the allergic model, which causes resistance to anti-PD-1 and anti-CTLA-4 antibody therapy, by treatment with a combination of fexofenadine and dual anti-PD-1/anti-CTLA-4 therapy (Fig. 7E and F).
Regarding claim 22 and 24, Li et. al. teaches the mice are determined to have a high levels of histamine by detecting histamine in a tumor sample obtained from the subject (p. 46 right column ¶3 , Fig. S7G) by ELISA (Figure S7G, caption).
Regarding claim 26, fexofenadine is a H1-antihistamine (p. 40 right column, ¶2).
Regarding claim 30, fexofenadine is an H1-antihistamine which means it inhibits the histamine receptor H1 (HRH1). An inhibitor of HRH1 would by definition inhibit a downstream effector of HRH1 activation, because inhibiting an upstream activator would also inhibit the activation of downstream effectors.
Regarding claim 32, the CT26 tumors have high histamine (Fig. S7G) (reads on “associated with high levels of histamine production”).
Claims 20, 21, 25, 26, 28, 30, 32, and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by 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 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 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.
Claim interpretation: Instant claim 20 is directed towards a method of treating cancer in a subject comprising determining that the subject has at least one of an elevated level of histamine or HRH1 signaling activation, and administering to the subject an antihistamine in conjunction with an immunotherapy comprising the administration of a checkpoint inhibitor. First, the examiner would like to note that the steps of determining and administering need not occur in order because no order has been specified. Second, the “determining that the subject has at least one of an elevated level of histamine or HRH1 signaling activation” is a mental process that occurs broadly and does not require a measurement of any type of elevated level of histamine or HRH1 signaling activation. This is clarified further by claim 25, where “the subject is determined to have an elevated level of histamine or HRH1 signaling activation by virtue of the presence of allergies and/or by detection of plasma IgE levels in the subject”. It is therefore understood in the art that the presence of an allergic reaction is sufficient for a person of ordinary skill in the art to determine that histamine is elevated.
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, and, as described above, reads on “detecting elevated levels of histamine”. Labella et. al. teaches drug desensitization of a patient receiving Nivolumab (anti-PD-1) 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).
Regarding claim 28, although it is indefinite as described in the 112(b) rejection above, for the purposes of expedited prosecution, the dexchlorpheniramine is administered intravenously (p. 628, left column).
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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 25, 43-45 and 48 are rejected 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).
The teachings of Li et. al. in regards to claim 20 are above.
Regarding claim 25, Li et. al. does not explicitly teach the method wherein the subject is determined to have an elevated level of histamine (elected species) by virtue of the presence of allergies and/or by detection of plasma IgE levels in the subject.
Li et. al. teaches that the blood and tumor histamine levels are elevated in the allergic mouse models (Fig. 7B, S7G) compared to non-allergic and that the allergy model causes resistance to checkpoint immunotherapy (Fig. 7E-F). Li et. al. further teaches that in human patients’ allergy was associated with increased mortality (Fig. 7G). Li et. al. teaches that the differences in outcome correlate with the plasma histamine levels in patients (Fig. 7H-J).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use allergy status to determine the blood levels of histamine in the cancer patients because Li et. al. teaches that allergy status causes worse outcomes from checkpoint immunotherapy (p. 49 left column ¶2) and that the mechanism is related to high histamine levels in the tumor. An artisan would understand that determining of allergy status of the patient in order to determine histamine levels has the benefit of not requiring additional blood or tumor tests, but rather can be taken with the patient history. Further, Li et. al. teaches that co-administration of fexofenadine H1-antihistamine with anti-PD-1/anti-CTLA-4 checkpoint immunotherapy improves the anti-cancer response in an allergic mouse model. This would have a reasonable expectation of success because Li et. al. teaches that high histamine allergy increases mortality risk and during immunotherapy in cancer patients and that administering fexofenadine in addition to the immunotherapy improves tumor treatment in the mouse model.
Regarding claims 43, 45, and 48, as described in the 102 above for claim 20 Li et. al. teaches a method of treating cancer in two mouse tumor cell transplantation models, EMT6 (murine mammary carcinoma) and CT26 (murine colon cancer) wherein allergic sensitization to OVA increases tumor size (Fig. 7C) and total blood histamine levels (Fig. 7B) compared to non-allergic mice (reads on determining that the subject has elevated level of histamine). Li et. al. teaches treatment of the mice the allergic model, which causes resistance to anti-PD-1 and anti-CTLA-4 antibody therapy, by treatment with a combination of fexofenadine and dual anti-PD-1/anti-CTLA-4 therapy (Fig. 7E and F).
Li et. al. does not explicitly teach the method wherein the subjects have been identified as unlikely to respond to an immunotherapy comprising the checkpoint inhibitor based on a detection of levels of histamine and wherein the identification of unlikely to respond to immunotherapy is based on a different in the level of histamine in a biological sample obtained from the subject as compared to the level in a sample obtained from an individual known to be responsive to the immunotherapy.
Li et. al. teaches that the blood and tumor histamine levels are elevated in the allergic mouse models (Fig. 7B, S7G) compared to non-allergic and that the allergy model causes resistance to checkpoint immunotherapy (Fig. 7E-F). Li et. al. further teaches that in human patients’ allergy was associated with increased mortality (Fig. 7G). Li et. al. teaches that the differences in outcome correlate with the plasma histamine levels in patients (Fig. 7H-J). Li et. al. teaches “our finding that plasma histamine levels of, and uptake of antihistamines by, cancer patients are associated with their response to immunotherapy strongly supports using antihistamines to treat cancer patients who have allergy with high levels of plasma histamine” (p. 50 left column ¶4-right column ¶1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to identify a subject as unlikely to respond to an immunotherapy comprising the checkpoint inhibitor based on a detection of levels of histamine in order to benefit from the relationship disclosed by Li et. al. of increased histamine causing less response and increased mortality in response to anti-PD-1 checkpoint therapy in order to benefit from improving cancer therapy by being able to administer the patients with increased histamine an anti-histamine in order to overcome the immunotherapy resistance as taught by Li et. al. This would have a predictable effect because an artisan would understand that in order to get the most benefit from the combination therapy the determination of resistance to checkpoint immunotherapy must occur prior to the administration step.
Regarding claim 44, Li et. al. does not explicitly teach the method wherein identification of the subject as unlikely to respond to immunotherapy comprises the calculation of a response score is based on the levels of histamine in the biological sample obtained from the subject.
As described above, Li et. al. teaches that different cancer responses correlated with the plasma histamine levels of the patients. Li et. al. teaches that Low (<0.3 ng/ml), Medium (0.3-0.6 ng/ml), and High (>0.6ng/mL) plasma histamine lead to different best % change in target legion size (Fig. 7I) and different percent of patients with objective response rate and disease control rate (Fig. 7J).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the clinical data that correlates histamine level with responses to anti-PD-1 treatment in cancer patients with melanoma or lung cancer to calculate a response score in order to describe the mathematical relationship detected by Li et. al. between histamine plasma levels and the likelihood of response to anti-PD-1 treatment in order to benefit from a way to predict the most beneficial treatment for the particular cancer patient. This would have a reasonable expectation of success because an artisan would expect to be able to use the different response shown for the Low, Medium, and High histamine patients in order to predict potential histamine-mediated resistance to checkpoint immunotherapy as taught by Li et. al.
Claims 22 and 24 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 as applied to claim 20 above, 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.
The teachings of Labella et. al. in regards to claim 20 are in the 102 rejection above.
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 the method wherein the subject is determined to have an elevated level of histamine by detecting plasma histamine concentrations in a sample obtained by the subject (claim 22) or wherein the level of histamine is detected by IHC, flow cytometry, or ELISA.
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). Vadas et. al. teaches that histamine was measured in blood plasma by ELISA (p. 145 left column ¶4). 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 measure histamine by ELISA to detect high-grade anaphylactic reactions in order to benefit from the correlation of histamine with anaphylaxis as taught by Vadas et. al. as a biomarker in order to benefit from a biomarker for the diagnosis of anaphylaxis as taught by Labella et. al. 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.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678