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 without traverse of Group I, drawn to a method of treating cancer in a subject in need thereof; and the following species:
Axelopran as the elected species of MOR antagonist;
Pembrolizumab as the elected species of checkpoint inhibitor; and
Colon cancer as the elected cancer species;
in the reply filed on July 30, 2026 is acknowledged.
Claims 69, 98, 104-105 and 107-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 30, 2026.
Please note claim 108 recites “[t]he method” but depends on claim 98, drawn to a combination rather than a method; therefore, based on its dependency on a withdrawn claim, the Examiner has determined said claim is drawn to a nonelected invention.
Please note applicant elects bevacizumab as a species of inhibitor of VEGF in the reply filed on July 30, 2026; However, said species is not recited in the instant claims, and only recites “an anti-VEGF antibody” in claim 62, which encompasses bevacizumab according to paragraph [0083] of the specification; therefore, the claims are under examination to the extent that the anti-VEGF antibody is drawn to “an inhibitor of VEGF”. To the extent that applicant amends the claims to include said species, it would require further search and consideration. Additionally, applicant indicates 61-62 does not read on the elected species; However, the Examiner determined these claims are under examination.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Kwatra et al. that anticipates the claimed invention, wherein the prior art teaches
naloxone as the MOR antagonist and lung adenocarcinoma with bony metastasis as the cancer; However, it is noted that the prior art does not teach the elected species of MOR antagonist and cancer. In light of this discovery, the search is expanded to the subject matter of the MOR antagonist to include naloxone in addition to the elected axelopran, and expanded to include lung adenocarcinoma with bony metastasis as the cancer in addition to the elected colon cancer, such that it does not encompass the full scope of the claims.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment filed on April 24,
2025, wherein claims 44-47, 49-51, 54, 61 and 62 are amended; claims 48 and 52-53 are unchanged; claims 1-43, 56-60, 63-68, 70-97 and 99-102 are canceled; and claims 103-108 are newly added.
Claims 44-55, 61-62, 69, 98 and 103-108 are pending.
Claims 69, 98, 104-105 and 107-108 are withdrawn.
Claims 44-55, 61-62, 103 and 106 are under examination in accordance with the elected species.
Priority
The instant application 18/845,283 filed on September 9, 2024 is a 371 of PCT/US2023/064088 filed on March 10, 2023, which claims priority to, and the benefits of U.S. Provisional Application No.
63/318,465 filed on March 10, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 9/9/2024, 10/25/2024, 4/24/2025, 2/26/2026, and 7/30/2026 are in compliance with the provisions of 37 CFR 1.97 unless otherwise noted. Accordingly, the information disclosure statements are being considered by the examiner.
The information disclosure statement (IDS) submitted on 2/26/2026 contains duplicate references that has been cited in the prior-filed information disclosure statement dated 4/24/2025. Specifically, US7622508 (cited under “U.S. Patent Documents”, cite no. AA), WO2016/061531-A1, WO2023/173055A2 (cited under “Foreign Patent Documents”, cite no. BA-BB, respectively), Feng et al. and Marin-Acevedo et al. (cited under “Non-Patent Literature Documents”, cite no. CA and CD); Thus, these references have been line through in the IDS as they have already been considered by the Examiner.
Drawings
The drawings are objected to because of the following informalities:
Figure 3A: the text on the top of the phrase “(Exogenous TILS)” appears to be faded and unreadable.
Figure 4A-B: the numerical numbers, units and symbols illustrated therein are blurry and unreadable (e.g., see
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). It is not clear which symbol corresponds to which treatment group as they appear to have similar color and shape. The lines in Figure 4A also appear to be faded and unreadable.
Figure 12A: “AX-Mean”, “PD-1 Mean” and “AxPD-1 Mean” are each represented by the same circular symbol with same shade; therefore, it is not clear which circle in the graph is corresponding to which group.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
The claimed term “treating”, when reasonably construed in view of the special definition provides in paragraph [0055] of the specification, shown below:
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, is taken to include prophylactic and suppression of the disease or disorder.
The claimed term “MOR antagonist”, when reasonably construed in view of the definition provides in paragraph [0044] of the specification, refers to Mu opioid receptor antagonist.
Claim Rejections - 35 USC § 112
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 44-55, 61-62, 103 and 106 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 treating melanoma, pancreatic cancer, colon cancer, or breast cancer to the extent that the term “treating” excludes preventing and curing, does not reasonably provide enablement for treating the full scope of cancer to the extent the term “treating” includes preventing and curing. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
Instant claim 44 broadly recites a method of treating cancer in a subject in need thereof, the method comprising administering to the subject: i. a MOR antagonist; and ii. a checkpoint inhibitor.
The claimed term, when reasonably construed in view of the special definition provides in paragraph [0055] of the specification, shown below:
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, is taken to include prophylactic, curation, and suppression of the disease or disorder.
Therefore, the breadth of the clams covers the administration of the full scope of Mu opioid receptor antagonist and the full scope of checkpoint inhibitor for treating the full scope of cancer, such that the term “treating” also includes prophylactic, curation and suppressive measure of cancer.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the
art would have known, at the time the application was filed, about the subject matter to which the
claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art
refers to the skill of those in the art in relation to the subject matter to which the claimed invention
pertains at the time the application was filed.”
According to Moss et al. (US 2017/0202832 A1), one skilled in the art would have known that mu opiate receptor (MOR) antagonist methylnaltrexone is known to lower the percentage of subject deaths in these five cancers, including lung, breast, prostate, pancreatic, and colon cancer (see e.g., [0397])(see e.g., [0408]); and further according to Trafton (“Study explains why certain immunotherapies don’t always work as predicted”, MIT News on campus and around the world. [Online]), one of ordinary skilled in the art would have also known that immune checkpoint therapies are not effective for all cancer patients (see e.g., p. 2, line 15-16), and this lack of response appears to be the result of a phenomenon known as intratumoral heterogeneity. Therefore, the state of the art with regard to using the full scope of immune checkpoint therapies and the full scope of mu opiate receptor for the treatment of the full scope of cancer is still underdeveloped based on the unpredictability surrounding the cancer treatment.
Additionally, the relative skill of those in the art with respect to preventing the full scope of cancer would have been low. For instance, one skilled in the art would have known most pancreatic
cancer cannot be prevented, because some pancreatic cancer can be genetic driven by four major genes, including KRAS, P53, P15 and SMAD4, according to He (“Pancreatic Cancer: Experts Answer 10 Commonly Asked Questions” [Online]. John Hopkins Medicine). In other words, there is lack of predictability surrounding preventing the full scope of cancer.
The relative skilled on those in the art with respect to curing the full scope of cancer would have also been low. For instance, one skilled in the art would have known multiple myeloma, a rare blood cancer that affects plasma cell, currently has no cure, according to Cleveland Clinic ("Multiple Myeloma" [Online]. Published on August 18, 2025). In other words, there is lack of predictability surrounding curing the full scope of cancer.
Therefore, it is uncertain whether administering the full scope of MOR antagonist and the scope of checkpoint inhibitor at any amount can successfully treat the full scope of cancer to the extent that the treatment includes prophylactic/preventing and curing.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all the foregoing, at the time the application was filed, it would have required undue experimentation to practice the entire scope of the claimed invention. In this case, the instant specification tested the effect of axelopran in combination with pembrolizumab against the following cancer, including i) M-001 melanoma tumor progression in Zebra fish larvae (see e.g., Table 2-1); 2) MDA-MB-231 breast tumor progression in chicken egg (see e.g., [0135]-[0140]; Table 2-2); 3) MC39 mouse colon tumor progression in a mouse model without a gut microbiome (see e.g., [0141]-[0146]); and PAN02 mouse pancreatic tumor progression in a mouse model (see e.g., [0147]). In sum, while the specification disclosed the biological activities of axelopran and pembrolizumab against melanoma, breast cancer, colon cancer and pancreatic cancer, the specification does not demonstrate their prophylactic activities against any cancer nor the curative effect against any cancer. One of the relative skill in the art could not reasonably predict which of the hundreds or thousands of cancers encompassed by the claims could be prevented or cured by administering the full scope of MOR antagonist and the full scope of checkpoint inhibitor at any amount based on the limited disclosure provided. Therefore, it would require an undue experimentation as it is highly unpredictable that the administration of any amount of any MOR antagonist and any amount of any checkpoint inhibitor would, in fact, be usable for treating the full scope of cancer, to the extent that the claimed term “treating” includes prophylactic/preventing and curing.
Accordingly, while axelopran in combination with pembrolizumab can treat melanoma, breast cancer, colon cancer and pancreatic cancer to the extent that the treatment does not includes preventing and curing, the method drawn to the full scope of “treating” cancer, including prophylactic/preventing and curing, in a subject in need thereof is not enabled by the instant specification. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
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 49 and 50 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.
Regarding claims 49 and 50, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). In this case, the term “axelopran” in these claims, when reasonably construed in light of the special definition provides in paragraph [0045]-[0046] of the specification, is used by the claim to mean “axelopran, pharmaceutically acceptable salts of axelopran, stereoisomers of axelopran, and derivatives of axelopran, while the general accepted meaning is just “axelopran”. The “derivatives of axelopran” embraced by the claimed term “axelopran” is indefinite, because the definition provides in the specification does not clearly set forth the boundaries for the derivatives. In other words, it is not clear what is considered to fall within the scope of “derivatives of axelopran”; and therefore, one of the ordinary skill in the art cannot reasonably determine the metes and bounds of the “derivatives of axelopran” embraced by the claimed term.
Claim Rejections - 35 USC § 102
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 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.
Claims 44-48 and 51-55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kwatra et al. (The New England Journal of Medicine, 2018. Vol. 379(16): 1578–1579).
Kwatra et al. teaches a patient with lung adenocarcinoma with bony metastasis received an immune checkpoint inhibitor pembrolizumab developed an acute flare in the pruritic rash (see e.g., p. 1578, left column, 2nd paragraph; p. 1578, right column, 2nd paragraph); and was started on a continuous infusion of 1000 mL of naloxone, a competitive antagonist at the mu-opioid receptor (see e.g., p. 1578, right column, 3rd paragraph), in addition to topical and intravenous glucocorticoids and antihistamines that reduce the severity of pruritus within 1 hour (see e.g., p. 1578, right column, 2nd paragraph); and concludes that mu-opioid receptor antagonism may prevent patients with clinically significant pruritus caused by PD-1 blockade therapy from discontinuing treatment (see e.g., p. 1567, right column, last paragraph to p. 1579, left column, line 2). Kwatra et al. teaches antibodies such as pembrolizumab that block programmed death 1 (PD-1) protein are immune checkpoint inhibitors that are approved for the treatment of various cancers (see e.g., p. 1578, left column, left column, 1st paragraph).
In this case, even though Kwatra et al. is silent regarding the technical feature of “improves an immune response to a tumor” in claim 45, “increases infiltration of NK cells, lymphocytes and/or monocytes/macrophages into the tumor” in claim 46, “increases infiltration of CD3+, CD244+, and MMD+ immune cells into the tumor” in claim 47, and “the MOR antagonist and the checkpoint inhibitor synergistically improve the immune response to the tumor” in claim 48, the prior art clearly teaches an immune checkpoint inhibitor pembrolizumab is administered to a patient with lung adenocarcinoma with bony metastasis for the treatment of said cancer, and the administration of a mu-opioid receptor (MOR) antagonist naloxone is also initiated for treating pruritus caused by anti-PD-1 therapy. According to MPEP 2112.01, II, “’[p]roducts of identical chemical composition cannot have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable”. In other words, the administration of naloxone and pembrolizumab taught by Kwatra et al., which reads on the administration of MOR antagonist and a checkpoint inhibitor instantly claimed, would naturally result in these properties whenever the compounds are administered to the same patient population under the same or similar circumstances.
Therefore, the claimed invention is being anticipated by Kwatra et al.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 44-55, 61-62, 103 and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Moss et al. (US 2017/0202832 A1; cited in the IDS filed on September 9, 2024), Weinstein et al. (US 2019/0240293 A1; cited in the IDS on September 9, 2024), Stackhouse et al. (Cancer Immunology Research, 2020. Vol. 8 (4 Suppl): B81), Prasetya et al. (Eur J Pharmacol, 2021. Vol. 906:174284), Singleton et al. (Cancer, 2015. Vol. 121(16): 2681-2688).
Moss et al. teaches an exemplary method of treating a subject suffering from cancer (see e.g., (see e.g., [0015]; claim 4), in which the example demonstrates a composition comprising a mu opioid receptor (MOR) antagonist (e.g., PAMORA, naloxone, or naltrexone) is administered to a subject diagnosed with colon cancer; and as a result of said administration, the subject experiences attenuation of further disease progression, remission of the cancer and/or prolonged survival (see e.g., Example 27); wherein the MOR antagonist includes a peripherally acting mu opioid receptor antagonist (PAMORA) selected from, inter alia, axelopran (see e.g., [0027]). Moss et al. further teaches in one embodiment, the subject is also administered a cancer or an anti-tumor therapy that does not include a mu opioid receptor antagonist (see e.g., [0047]); wherein the cancer or anti-tumor therapy includes anti-angiogenic agent (see e.g., [0050]) and that is, inter alia, anti-VEGF antibody (see e.g., [0052]); wherein the cancer is selected from, inter alia, colon or lung (see e.g., [0058]). Moss et al. further teaches the acquired ability of a localized tumor to metastasize is a multistep process involving many pathways, including those involved in angiogenesis, focal adhesion, invasion and eventually colonization of a distant site; and vascular endothelial growth factor (VEGF) is a pivotal component of both normal and malignant angiogenesis, and it has been validated as a clinical target in many tumor (see e.g., [0410]). Moss et al. further teaches the provided compound or composition disclosed therein are also useful in the treating of conditions including cancers involving, inter alia, angiogenesis and immune suppression (see e.g., [0319]). Moss et al. further teaches additional advantageous uses of the provided compound or composition include treatment of opioid-induced immune suppression (see e.g., [0317]).
Moss et al. does not teach the elected checkpoint inhibitor (pembrolizumab).
Stackhouse et al. teaches the efficacy of pembrolizumab was evaluated against MC38 colon cancer expressing human PD-1 in transgenic C57BL/6 mice expressing human PD-1 and PD-L1 checkpoint genes (see e.g., “title”); the tumor-implanted mice treated with pembrolizumab (100 μg per animal) caused tumor regression by Day 17 and growth inhibition was 94% on Day 17 compared to the control animals; and concludes both PD-1 and PD-L1 inhibitors are effective in treating genetically modified MC38 colon tumors in transgenic mice (see e.g., abstract).
Weinstein et al. teaches a method of treating a subject with cancer, including colon cancer (see e.g., [0319]), the method comprising administering to the subject an effective amount of neuromodulating agent selected from, inter alia, a neuropeptide signaling modulator, including opioid antagonist (see e.g., claims 8 and 91); and further teaches axelopran is an antagonist of μ-opioid receptor and a neuropeptide antagonist (see e.g., p. 50, Table 2L, “μ-opioid receptor”, “antagnoist”). Weinstein et al. teaches further teaches one type of agent that can be administered in combination with a neuromodulating agent described herein is a checkpoint inhibitor, including agent such as antibodies that block an inhibitory pathway directly on T cell or natural killer (NK) cells (e.g., PD-1 targeting anti-bodies such as nivolumab and pembrolizumab)(see e.g., [0332]). Weinstein et al. further teaches the neuromodulating agents described herein may be administered in combination with one or more additional therapies (e.g., 1, 2, 3 or more additional therapeutic agents), because the effect of the two or more treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic)(see e.g., [0361]). Weinstein et al. further teaches modulation of neurological signaling pathways can modulate an immune response and, e.g., can be used to modulate an anti-cancer immune response (see e.g., [0002]).
Prasetya et al. further teaches monoclonal antibodies have been indicated as a blockade to immune checkpoint pathways, including PD-1 (pembrolizumab and nivolumab)(see e.g., p. 2, left column, 1st paragraph). Prasetya et al. et al. teaches immune checkpoint inhibitor (ICI) therapy’s success relies on patients’ immunity response, other substances that intervene in the immune system could hamper ICI effectiveness, such as drugs to alleviate symptoms like pain (see e.g., p. 3, left column, 2nd paragraph); and further teaches opioids may hamper immune checkpoint inhibitors (ICIs) within the immune system in many ways, such as reducing T cell function through the overexpression of MOR or downregulation of MHC class II, increasing immunosuppressor Treg cells, directly promoting tumor cell proliferation and invasion, and interrupting the gut microbiome composition leading to disruption of gut homeostasis and the whole immune system (see e.g., p. 5, right column, 1st paragraph under “4. Drug interaction between analgesics and ICIs”). Prasetya et al. further teaches from the other perspective, there is an opportunity to develop adjunctive therapy using antagonists targeting peripheral opioid receptors (see e.g., p. 4, right column, “3.2 Opioids directly affect cancer cells” section).
Singleton et al. teaches the mu opioid receptor is a potential target for cancer therapy (see e.g., abstract); and in the preclinical studies, MOR-deficient mice inoculated with B16 melanoma cells that secrete endogenous mu-opioid peptides demonstrated a marked reduction in tumor growth and significantly higher infiltration of immune cells into the tumors (see e.g., Table 1, “Effective of the Mu Opioid Receptor and Cancer Progression”).
According to MPEP 2144.06, "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Same logic is applicable to instant process claims, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by combining the mu opioid receptor antagonist axelopran of Moss et al. and pembrolizumab of Stackhouse et al. that are individually taught by the prior art to be useful for treating colon cancer, because one would have been motivated to combine them in order to form another method useful for the same purpose. One would have a reasonable expectation of success to arrive at the claimed invention, because Moss et al. teaches a list of mu opioid receptor antagonist, including axelopran, that can be administered for treating colon cancer and Stackhouse demonstrate effective treatment of colon cancer by administering pembrolizumab; and therefore, one would have expected both method shown useful separately for the exact purpose would be expected to be similar useful when used together.
In the alternative, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by combining the mu opioid receptor antagonist axelopran of Moss et al. and pembrolizumab of Stackhouse et al. that are individually taught by the prior art to be useful for treating colon cancer, because Weinstein et al. teaches axelopran is a neuropeptide signaling modulator and neuromodulating agent that can be combined with a checkpoint inhibitor, including pembrolizumab, for treating a subject with cancer, including colon cancer; and further teaches the combination with one or more additional therapies can create effect that is partially additive, wholly additive, or great than additive such as synergistic. One would have a reasonable expectation of success to arrive at the claimed invention, because Moss et al. teaches a list of mu opioid receptor antagonist, including axelopran, that can be administered for treating colon cancer and Stackhouse demonstrate effective treatment of colon cancer by administering pembrolizumab; and therefore, one would have expected both method shown useful separately for the exact purpose would be expected to be similar useful when used together as well as providing additional effect.
Regarding the limitation of “improves an immune response to a tumor” in claim 45, “increases infiltration of NK cells, lymphocytes and/or monocytes/macrophages into the tumor” in claim 46, “increases infiltration of CD3+, CD244+, and MMD+ immune cells into the tumor” in claim 47, and “the MOR antagonist and the checkpoint inhibitor synergistically improve the immune response to the tumor” in claim 48, each of these limitations is drawn to the properties or the outcome of the method steps positively recites. In this case, Weinstein et al. clearly teaches the mu opioid receptor antagonist, including axelopran, is a neuromodulating agent can be combined with checkpoint inhibitor, including pembrolizumab, for treating a subject with cancer, including colon cancer; and said neuromodulating agent can be used to modulate an anti-cancer immune response to create effect that is partially additive, wholly additive, or great than additive such as synergistic; Prasetya et al. suggests the development of adjunctive therapy using antagonists targeting peripheral opioid receptors, because opioids may hamper immune checkpoint inhibitors, such as pembrolizumab, by reducing T cell function, increasing immunosuppressor Treg cells and the whole immune system; and Singleton teaches MOR-deficient mice demonstrates significantly higher infiltration of immune cells into the tumors. In view of the foregoing, one of ordinary skill in the art would have reasonably expected that the administration of axelopran, a peripherally acting mu opioid receptor antagonist, is particularly useful in treating cancers as well as modulating anti-cancer immune response; and antagonizing the peripheral opioid receptor would have been expected to reverse opioid-induced immune suppression, which is known to hamper the effect immune checkpoint inhibitors such as pembrolizumab, to increase infiltration of immune cells into the tumor, and to create additional effect, such as synergistic. Accordingly, one would have reasonably expected that the administration of axelopran and pembrolizumab would have successfully reversed opioid-induced immune suppression, improving immune response, increasing infiltration of immune cells into the tumor, restoring the effect of checkpoint inhibitor, and creating additional effects, such as synergistic. Therefore, by practicing the method made obvious by the prior arts for treating colon cancer set forth above, one would naturally result in these properties, and that renders obvious the limitation(s) instantly claimed.
Regarding the limitation of “wherein the method further comprises administering an inhibitor of VEGF” in claim 61, and the limitation of “wherein the inhibitor of VEGF is an anti-VEGF antibody” in claim 62, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the method set forth above to further administering an anti-VEGF antibody, because Moss et al. teaches the method can also include administration of anti-angiogenic agent, including anti-VEGF antibody, in which VEGF has been validated as a clinical target in many tumor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of anti-angiogenic agent in addition to the axelopran and the pembrolizumab set forth above would have successfully target angiogenesis of the cancer.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 44-55, 61-62, 103 and 106 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 19/599,919 (reference application), in view of Moss et al. (US 2017/0202832 A1; cited in the IDS filed on September 9, 2024) and Stackhouse et al. (Cancer Immunology Research, 2020. Vol. 8 (4 Suppl): B81).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of reference application is drawn to a method comprising administering a peripherally active mu-opioid receptor antagonist (PAMORA), which is selected from, inter alia, axelopran, to a patient diagnosed with a cancer and has cancer-associated pain; and the patient is treated with a primary treatment including a checkpoint inhibitor, including pembrolizumab, and/or an inhibitor of VEGF. The claims of reference application also teach a method of treating cancer, comprising administering axelopran and a PD-1/PD-L1 anti-cancer therapy, wherein the threshold concentration of axelopran synergizes the PD-1/PD-L1 anti-cancer therapy.
The claims of reference application do not teach the elected cancer (colon cancer). The claims of reference application do not teach anti-VEGF antibody as claimed in claim 62.
Moss et al. teaches an exemplary method of treating a subject suffering from cancer (see e.g., (see e.g., [0015]; claim 4), in which the example demonstrates a composition comprising a mu opioid receptor (MOR) antagonist (e.g., PAMORA, naloxone, or naltrexone) is administered to a subject diagnosed with colon cancer; and as a result of said administration, the subject experiences attenuation of further disease progression, remission of the cancer and/or prolonged survival (see e.g., Example 27); wherein the MOR antagonist includes a peripherally acting mu opioid receptor antagonist (PAMORA) selected from, inter alia, axelopran (see e.g., [0027]). Moss et al. further teaches in one embodiment, the subject is also administered a cancer or an anti-tumor therapy that does not include a mu opioid receptor antagonist (see e.g., [0047]); wherein the cancer or anti-tumor therapy includes anti-angiogenic agent (see e.g., [0050]) and that is, inter alia, anti-VEGF antibody (see e.g., [0052]); wherein the cancer is selected from, inter alia, colon or lung (see e.g., [0058]). Moss et al. further teaches the acquired ability of a localized tumor to metastasize is a multistep process involving many pathways, including those involved in angiogenesis, focal adhesion, invasion and eventually colonization of a distant site; and vascular endothelial growth factor (VEGF) is a pivotal component of both normal and malignant angiogenesis, and it has been validated as a clinical target in many tumor (see e.g., [0410]). Moss et al. further teaches the provided compound or composition disclosed therein are also useful in the treatment of conditions including cancers involving, inter alia, angiogenesis and immune suppression (see e.g., [0319]). Moss et al. further teaches additional advantageous uses of the provided compound or composition include treatment of opioid-induced immune suppression (see e.g., [0317]).
Stackhouse et al. teaches the efficacy of pembrolizumab was evaluated against MC38 colon cancer expressing human PD-1 in transgenic C57BL/6 mice expressing human PD-1 and PD-L1 checkpoint genes (see e.g., “title”); the tumor-implanted mice treated with pembrolizumab (100 μg per animal) caused tumor regression by Day 17 and growth inhibition was 94% on Day 17 compared to the control animals; and concludes both PD-1 and PD-L1 inhibitors are effective in treating genetically modified MC38 colon tumors in transgenic mice (see e.g., abstract).
Even though the claims of reference application is silent regarding the technical feature of “improves an immune response to a tumor” in claim 45, “increases infiltration of NK cells, lymphocytes and/or monocytes/macrophages into the tumor” in claim 46, “increases infiltration of CD3+, CD244+, and MMD+ immune cells into the tumor” in claim 47, the prior art clearly teaches a checkpoint inhibitor, including pembrolizumab, and a PAMORA, including axelopran, is administered to a patient with cancer. According to MPEP 2112.01, II, “’[p]roducts of identical chemical composition cannot have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable”. In other words, the administration of axelopran and pembrolizumab taught by Kwatra et al., which reads on the administration of MOR antagonist and a checkpoint inhibitor instantly claimed, would naturally result in these properties whenever the compounds are administered to the same patient population under the same or similar circumstances.
Regarding “colon cancer” recites in claims 103 and 106, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the method of reference application for treating colon cancer as the cancer, because the mu opioid receptor antagonist of Moss et al., including axelopran, and pembrolizumab of Stackhouse et al. that are individually taught by the prior art to be useful for treating colon cancer. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have expected both methods shown useful separately for treating colon cancer would be expected to be similar useful when used together in the method of reference application.
Regarding the limitation of “wherein the inhibitor of VEGF is an anti-VEGF antibody” in claim 62, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the method of reference application to select anti-VEGF antibody of Moss et al. as the inhibitor of VEGF, because Moss et al. mu opioid receptor antagonist, including axelopran, can also include administration of anti-VEGF antibody as the anti-angiogenic agent, because VEGF has been validated as a clinical target in many tumor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of anti-VEGF antibody in addition to the axelopran and the pembrolizumab set forth above would have successfully target angiogenesis of cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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