DETAILED ACTION
Applicant’s amendment of 10/17/2025 has been entered and is considered below. Claims 77-84 were pending.
Claims 77 and 78 are amended.
Claims 77-84 are the Subject of the Office Action below.
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 .
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 10/17/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statement is being considered by the Examiner.
Claim Rejections - 35 USC § 112
(NEW Rejection)
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 77-84 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.
Applicant’s claim 77 is directed towards a method of inhibiting recurrence of cancer or formation of distant metastases of primary tumor cells in a subject, the method comprising administering a therapeutic agent that decreases the level or ROS-forming activity of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-positive, CD11b-positive myeloid cells in the subject thereby inhibiting recurrence of cancer or formation of distant metastases of primary tumor cells in the subject.
Applicant has not defined any therapeutic agents that decrease the level or how the level is decreased. “CD11b” is only mentioned 3 times in the Specification, and at no point is the level in the subject ever discussed, measured, or decreased. Applicant has shown an influx of the CD11b+ cells [0106] in the lungs, but has never shown the subject’s level, measuring the level, or decreasing the level. As such it is unclear the metes and bounds of the limitation to “ a therapeutic agent that decreases the level… in the subject.”
Claim 78 states, “wherein the level of NOX2-positive, CD11b-positive myeloid cells is decreased by an antibody.” Applicant has not provided any examples of “an antibody” in the Specification that decreases the level of NOX2-positive, CD11b-positive myeloid cells. Applicant hasn’t shown an antibody to anything in the pathway of NOX2+/CD11b+ myeloid cells. Moreover Applicant hasn’t defined “an antibody” in the Specification. There are no examples provided and “an antibody” is not defined in the Specification. While the general structure of an antibody is known in the art, an antibody capable of this function in not known, and Applicant has not defined one, as such the metes and bounds of the limitation is indefinite.
Claim Rejections - 35 USC § 103
(MAINTAINED Rejection)
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 77 and 79-84 are rejected under 35 U.S.C. 103 as being unpatentable over
Yang et al. “Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells,” Nature Medicine Vol 17, No 1, January 2011;
Martner et al. “Histamine Promotes the Development of Monocyte-Derived Dendritic Cells and Reduces Tumor Growth by Targeting the Myeloid NADPH Oxidase,” J Immunol (2015) 194 (10): 5014–5021;
Hellstrand WO 1991/004037 A1 published April 1991;
Donskov et al. “Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma,” British Journal of Cancer (2005) 93, 757 – 762;
Agarwala et al. (“Results From a Randomized Phase III Study Comparing Combined Treatment With Histamine Dihydrochloride Plus Interleukin-2 Versus Interleukin-2 Alone in Patients With Metastatic Melanoma’, Journal of Clinical Oncology, Vol. 20(1), pp. 125-133 (2002); Abstract only);
Martner et al.”Martner II”) (“Immunotherapy with histamine dihydrochloride for the prevention of relapse in acute myeloid leukemia’, Expert Rev. Hematol., Vol. 3(4), pp. 381-391, 2010).
Claim 77 is directed towards a method of inhibiting recurrence of cancer or formation of distant metastases of primary tumor cells in a subject, the method comprising administering a therapeutic agent that decreases the level or ROS-forming activity of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-positive, CD11b-positive myeloid cells in the subject thereby inhibiting recurrence of cancer or formation of distant metastases of primary tumor cells in the subject.
Yang teaches CD11b-positive myeloid cells an increased accumulation of immature CD11b+/Gr1+ myeloid cells during cancer progression in HDC-/- mice compared with HDC-sufficient mice and reported that HDC-/- mice were strikingly susceptible to chemically induced cancer. Yang reported that the exogenous administration of histamine to HDC-/- mice prevented the accumulation of immature myeloid cells. Thereby showing that histamine “decreased the level” of CD11b+ myeloid cells. Yang doesn’t discuss NOX2-positive, though NOX2 is expressed in all “wild” animals.
Martner teaches histamine-induced inhibition of lymphoma growth is NADPH oxidase/NOX2 dependent. Thereby noting that NOX2 “positive” is required for the drug, histamine, to work in inhibition of growth of lymphoma.
Now looking to the art we see the use of the combination of histamine and IL-2 (an NK cell activating agent for the treatment of many types of cancer. Given the teaching of Yang and Martner, one would realize that the administration of histamine to the cancer patient would expect a decrease in NOX2+, CD11b+ myeloid cells during the administration of the drug combination.
Hellstrand teaches the anti-tumor therapy by the coadministration of the IL-2 (an NK cell activating agent, instant claims 79-81) with an agent such as histamine or analogs thereof (a NOX2 inhibitor). Hellstrand states “[t]his invention relates to a preparation or system for inhibiting tumor growth and the formation of metastases of malignant tumor cells.” Hellstrand is teaching this invention for all malignant tumor cells. Hellstrand goes on to test the combination for melanoma cells (skin, instant claims 82-83) that metastasize to the lungs (instant claims 82-83). Hellstrand shows the combination, the same combination as the instant invention, is effective in the specific cancer melanoma, and the invention is taught to be effective in any and all malignant tumor cells. This is understood as Hellstrand states, “Unexpectedly, a combined histamine/IL-2-treatment completely prevented metastases of malignant tumor cells when the compounds were given as a single dose 24 hrs prior to and one week after tumor cells inoculation.” Taking this reference as a whole one would be motivated to use the combination of drugs, IL-2 with histamine, in any malignant tumor regardless of tissue type.
The following references will discuss the combination in other cancers, Donskov teaches metastatic renal cell carcinoma. Agarwala teaches metastatic melanoma. Martner II teaches acute myeloid leukemia.
Donskov teaches treating metastatic renal cell carcinoma with histamine dihydrochloride (HDC) (the NOX2 inhibitor required by instant claim 3) and IL-2 (the NK cell activating agent required by instant claims 9-11). Donskov teaches the metastatic site can be lung, lymph, liver, or bone in Table 1 (required by instant claim 19). Instant claim 21 requires NOX2 is inhibited in “a cell” wherein the cell is a hematopoietic cell or a myeloid cell, since the drugs are systemic any and all cells having NOX2 will see some inhibition therefore this inhibition is inherent and at once envisaged. Instant claims 26 and 27 have different wrding, but the scope includes treating treating metastatic renal cell carcinoma with histamine dihydrochloride (HDC) and IL-2.
Agarwala teaches histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients.” The study was a “phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m2 bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m2 bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat–overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate.” [Emphasis added.] The results of the study demonstrated that “[c]ombined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P = .004) and showed a trend for improved survival in the ITT population (P= .125)”. Agarwala concluded that the “[u]se of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement.” See the entire Abstract.
Martner II teaches (at page 395, left column, section titled “Improving IL-2 efficacy by use of ROS inhibitors”) that “a conceivable explanation to the insufficient clinical efficacy of IL-2 monotherapy in AML is that the patients’ lymphocytes are in a suppressed state and, therefore, fail to mount an anti-leukemic response during IL-2 therapy . The evaluation of this hypothesis comprises the co-administration of a ROS inhibitor to tumor-bearing animals during IL-2 therapy; if myeloid cell-derived ROS significantly dampen the efficacy of IL-2, an inhibitor of ROS production (such as HDC) or a scavenger of ROS would be expected to improve the immunostimulation by IL-2 in vivo, and improve the antitumor efficacy of IL-2 therapy. [emphasis added]” This theory is confirmed by the following disclosure (id.): “In tumor-bearing mice, treatment with IL-2 in combination with HDC was more efficient than either treatment alone in reducing the formation of lung metastases from NK cell-sensitive melanoma cells in mice in vivo, and similar results have been obtained in rodents carrying YAC-1 lymphoma or prostate adenocarcinoma cells [emphasis added].” Martner also teaches (at page 384, left column) that “HDC protected NK cells from myeloid cell-induced inactivation, an effect that was strictly mediated by histamine H2-receptors on myeloid cells. Although Martner teaches that HDC inhibits NOX, it does not teach inhibition of NOX2. However, since Martner teaches administering the same compound (HDC), to the same target population, it would be expected to inhibit NOX2.
Therefore the art shows the teaching of the combination as a treatment for the entire genus of malignant tumors and specifically the combination was used in metastatic renal cell carcinoma, metastatic melanoma, and acute myeloid leukemia.
A person of ordinary skill in the art would look to treat all malignant cells of any type based on the teaching of Hellstrand, and based on the art one would be motivated to specifically use the drugs in combination in renal cell carcinoma (Donskov), metastatic melanoma (Agarwala), and acute myeloid leukemia (Martner). One would expect this treatment to be efficacious as the art clearly recognized this treatment in many cancers. As such the instant claims were obvious at the time of filing.
While the references are not explicit on “decreasing the level of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-positive, CD11b-positive myeloid cells in the subject thereby inhibiting recurrence of cancer or formation of distant metastases of primary tumor cells in the subject,” the references teach the using the same compounds in combination as the instant Specification. Moreover Applicant has not shown any methods, compounds, or “ways” in which this is done in the Specification, and as such this limitation is indefinite and impossible to search as claimed.
Response to Arguments: Applicant gives two facts. One, that Yang (the first reference) is mainly discussing primary cancer in early cancer development, and two, PHOSITA “would understand that different mechanisms are involved in early cancer development and cancer recurrence/metastases and that events occurring at one stage are not necessarily predictive of events at the other stage.” That these 2 facts make Yang deficient according to Applicant in context of the instant claims directed to “method of inhibiting recurrence of cancer or formation of distant metastases of primary tumor cells in a subject.” In response to applicant's arguments against the references individually, one cannot show non-obviousness 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). While Yang does discuss early cancer development, the other references teach metastatic cancer, thereby this argument is unpersuasive.
Applicant also contents that the other references discussing metastatic disease aren’t curative to the “deficiency” of Yang, as they do not discuss the cells Yang discusses. Again, this is simply looking at the individual references in isolation and thereby this argument is unpersuasive. Taking all the art as a whole one would look to use the coadministration of the IL-2 (an NK cell activating agent) with an agent such as histamine or analogs thereof (a NOX2 inhibitor) for the treatment of many types of cancer is all stages of the disease.
Applicant next argues there are unexpected results of the instantly claimed invention. Stating, “reduction of NOX2 has the unexpected ability to inhibit recurrence of cancer or formation of distant metastases of primary tumor cells.” Applicant doesn’t point to any specific evidence to interrogate this position. Applicant just states this is unexpected.
Applicant does provide several references stating interesting facts about NOX2. The problem is while this may be true, the art still shows that the coadministration of the IL-2 (an NK cell activating agent) with an agent such as histamine or analogs thereof (a NOX2 inhibitor) for the treatment of many types of cancer is all stages of the disease. This combination meets the limitation to a therapeutic agent that decreases decreasing the level or ROS-forming activity of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-positive, CD1lb-positive myeloid cells (histamine) and to a therapeutic agent is a NK cell activating agent (IL-2). While the art may not appreciate the mechanism of action of the combination, the art does clearly teach this combination for treating many types of cancer is all stages of the disease. Therefore this argument is unpersuasive.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached M-F 8-6 MidDay Flex.
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/MICHAEL J SCHMITT/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629