DETAILED ACTION
All rejections and objections not mentioned below are withdrawn.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/25/2026 has been entered.
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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/049,556, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. A claim by claim analysis failed to find support for myeloid-derived suppressor cell (claim 85) and the compounds of claim 80. Thus a priority date of 7/7/2021 was used for claims 80 and 85. The remaining claims received a priority date of 07/08/2020.
Specification
The disclosure is objected to because of the following informalities: The structures on pages 97, 104, 106 are of poor image resolution and should be replaced with higher definition structures.
Appropriate correction is required.
Claim Objections
Claim 89 is objected to because of the following informalities: the structures of claim 89 are of poor image resolution. New, higher definition larger structures are requested. Appropriate correction is required.
Claim 63 is objected to because of the following informalities: the phrase "the cancer lung cancer" should be "the cancer is lung cancer" . Appropriate correction is required.
Claims 40, 51, 59, 61, 65 are objected to because of the following informalities: these claims depend from a later claim and should be reordered. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 3, 7-8, 11, 40, 51, 59, 61, 63, 65, 73-86 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.
Independent claim 1 is indefinite in scope due to having two conflicting definitions of R2x. It is unclear if the variable of R2x can be selected from either or both of these groups. Claims 3, 7-8, 11, 40, 51, 59, 61, 63, 65, 73-86 are dependent on claim 1 and thus have the same issue.
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 80 and 85 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by LOW (LOW et al., WO2022147576A1, effective filing date 2021-01-04).
The references Low teaches “Methods are provided for reprogramming M2 -like macrophages to Ml -like macrophages, which reverses the proinflammatory to anti-inflammatory shift observed during the course of certain cancers, co-administered with one or more types of engineered cells such as, without limitation, CAR T-cells, engineered natural killer cells, engineered stem cells or the like. The compounds comprise an immune modulator that targets a pattern recognition receptor of a cell and are specific to the cells of interest through the incorporation of a targeting moiety (e.g., folate or a functional fragment or analog thereof). Releasable and/or non-releasable linkers can be included and engineered to facilitate the optimal delivery of the immune modulator. The compounds and compositions can be employed in one or more methods of treatment for cancers”(abstract).
Claims 80 and 85 have a later priority date and thus are anticipated by the reference Low. The references Low teaches the instant compound of claim 75 [00021]:
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Instant claim 89 includes this exact compound so the application acknowledges this as a compound of claim 75. This anticipates claim 80.
The references Low teaches “Accordingly, the present combinations, compounds, and methods provide for a cancer prevention and treatment that is not only effective against solid tumors, but can also selectively target an agonist (i.e. immune modulator) to a receptor on tumor-associated macrophages (TAMs) and/or myeloid-derived suppressor cells (MDSCs) inside a cancerous tumor such that systemic and/or off-target toxicity is avoided”[000124].
This anticipates claim 85.
The applied reference has a common inventor and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim(s) 80 and 85 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Luo (Luo et al., WO 2022115711 A1, effective filing date 20201130).
The reference Luo teaches “The present disclosure relates to small molecule drug conjugates (SMDCs), chimeric antigen receptor (CAR)-expressing cytotoxic lymphocytes, compositions comprising a combination of the same, and methods of use thereof to treat cancer”[0002].
The reference Luo teaches (compound 2 figure 1):
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Instant claim 89 includes this exact compound so the application acknowledges this as a compound of claim 75. This anticipates claim 80.
The reference Luo teaches “ In view of the above, it is an object to provide materials and methods to render TAMs and MDSCs in the TME tumoricidal. This and other objects and advantages, as well as inventive features, will become apparent from the detailed description provided herein”[0007].
This anticipates claim 85.
The applied reference has a common inventor and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
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.
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.
Claim(s) 1, 3, 7, 8, 11, and 73 is/are rejected under 35 U.S.C. 103 as being unpatentable over KREPSKI (KREPSKI et al., WO 2005/051317, 2005-06-09, IDS) and further in view of Barillari (Barillari et al., Classical Bioisosteres, Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown _ 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA).
The reference KREPSKI teaches the lead compound similar to compounds of formula I (example 25, page 108), wherein, R3=H, R2=NH2, X3=X2=N, R1=alkyl, X1=N, R4= R5=alkyl or H, n=1, Y=H or COCH3(instant claim 11), COR2x, R2x=alkyl. This helps to teach claims 1, 3, 7, 8, 11, 73.
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The reference KREPSKI teaches “Imidazo ring systems substituted at the 1-position, pharmaceutical compositions containing the compounds, intermediates, methods of making the compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed”(abstract). This helps to teach claims 1, 3, 7, 8, 11, 73.
The reference KREPSKI does not teach the correct compounds of instant Formula (I) and instead requires the exchange of the CHO group to COOH group.
The reference Barillari teaches that(abstract):
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The reference Barillari teaches the following bioisosteres(page 17):
This helps to teach claims 1, 3, 7, 8, 11, 73.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified KREPSKI with Barillari to get the compounds of the instant claims because KREPSKI teaches lead compounds that are useful in treatment of diseases and Barillari teaches it is common practice to replace functional groups with bioisosteres to see if small modifications improve properties, such as pharmacological activity, selectivity, and pharmacokinetics. One would be motivated to do so to see if any of these properties would improve. One would have a reasonable expectation of success because methyl to OH is a classical bioisostere replacement and because the replacement is a small changes in the overall structure of the molecules.
Claim(s) 1, 7, 8, 11, 73 is/are rejected under 35 U.S.C. 103 as being unpatentable over THOMPSON (THOMPSON et al., WO-2017100305-A2, 2017, previously presented) and further in view of Barillari (Barillari et al., Classical Bioisosteres, Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown _ 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA) as evidenced by CAS SciFinder (imiquimod and S 34240, 2025, previously presented).
The reference Thompson teaches lead compounds similar to compounds of formula I “In some aspects, said immune-stimulatory compound is a damage-associated molecular pattern molecule or a pathogen associated molecular pattern molecule In some aspects, said immune-stimulatory compound is a toll-like receptor agonist, STING agonist, or RIG-I agonist. In some aspects, said immune-stimulatory compound is a TLR1 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a TLR10 agonist. In some aspects, said immune-stimulatory compound is selected from a group consisting of: S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, and CL663” [0011]. The Scifinder references provide evidence that the compounds taught by Thompson have the structure that follow.
S-34240
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Wherein, R3=H, R2=NH2, X3=X2=N, R1=alkyl or H, X1=N, R4= R5=alkyl or H, n=1, Y=H or COCH3(instant claim 11), COR2x, R2x=alkyl. This helps to teach claims 1, 7, 8, 11, 13, 73.
The reference Thompson does not teach the correct compounds of instant Formula (I) and instead requires the addition of two methyl groups to Imiquimod (see figure below) or the exchange of the CHO group on S-34240 to COOH group (see figure below).
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The reference Barillari teaches that(abstract):
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The reference Barillari teaches the following bioisosteres(page 17):
This helps to teach claims 1, 7, 8, 11, 73.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Thompson with Barillari to get the compounds of the instant claims because Thompson teaches lead compounds that are useful as immune-stimulatory compounds and Barillari teaches it is common practice to replace functional groups with bioisosteres to see if small modifications improve properties, such as pharmacological activity, selectivity, and pharmacokinetics. One would be motivated to do so to see if any of these properties would improve. One would have a reasonable expectation of success because H to methyl and methyl to OH are classical bioisostere replacements and because these replacements are small changes in the overall structure of the molecules. Further, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the H group for a Me. 2144.08(II)(A)(4)(c). Since it is a simple substitution of H for methyl one would have a reasonable expectation of success even when it is two hydrogens for two methyls.
Claim(s) 1, 7, 8, 11, 40, 51, 59, 61, 63, 65, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 is/are rejected under 35 U.S.C. 103 as being unpatentable over THOMPSON (THOMPSON et al., WO-2017100305-A2, 2017, previously presented) in view of Kurahara (Kurahara et al,. Clinical Significance of Folate Receptor b–expressing Tumor-associated Macrophages in Pancreatic Cancer, Ann Surg Oncol (2012) 19:2264–2271, previously presented) and further in view of Gabrilovich ( Gabrilovich et al., Myeloid-Derived Suppressor Cells, Cancer Immunol Res; 5(1) January 2017, previously presented) and further in view of Barillari (Barillari et al., Classical Bioisosteres, Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown _ 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA) as evidenced by CAS SciFinder (imiquimod and S 34240, 2025, previously presented).
The reference Thompson teaches lead compounds similar to compounds of formula I “In some aspects, said immune-stimulatory compound is a damage-associated molecular pattern molecule or a pathogen associated molecular pattern molecule In some aspects, said immune-stimulatory compound is a toll-like receptor agonist, STING agonist, or RIG-I agonist. In some aspects, said immune-stimulatory compound is a TLR1 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a TLR10 agonist. In some aspects, said immune-stimulatory compound is selected from a group consisting of: S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, and CL663” [0011]. The Scifinder references provide evidence that the compounds taught by Thompson have the structure that follow.
S-34240
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Wherein, R3=H, R2=NH2, X3=X2=N, R1=alkyl or H, X1=N, R4= R5=alkyl or H, n=1, Y=H or COCH3(instant claim 11), COR2x, R2x=alkyl. This helps to teach claims 1, 5, 6, 7, 8, 11, 13, 73, and 75.
The reference teaches “The composition described herein relates to different embodiments of a conjugate. In various embodiments, a conjugate comprises a) an immune-stimulatory compound; b) an antibody construct comprising an antigen binding domain and an Fc domain, wherein said antigen binding domain binds to a first antigen and wherein a Kd for binding of said Fc domain to an Fc receptor in the presence of said immune-stimulatory compound is no greater than about 100 times a Kd for binding of said Fc domain to said Fc receptor in the absence of the immune stimulatory compound; and c) a linker, wherein said linker attaches said antibody construct to said immune-stimulatory compound”[004] This helps to teach claims 75 and 51.
The reference teaches “In addition to the development of antibodies against tumor antigens for cancer treatment, antibodies that target immune cells to boost the immune response have also been developed. For example, an anti-CD40 antibody that is a CD40 agonist can be used to activate dendritic cells to enhance the immune response. [0150] Cluster of Differentiation 40 (CD40) is a member of the Tumor Necrosis Factor Receptor (TNF-R) family. CD40 can be a 50 kDa cell surface glycoprotein that can be constitutively expressed in normal cells, such as monocytes, macrophages, B lymphocytes, dendritic cells, endothelial cells, smooth muscle cells, fibroblasts and epithelium, and in tumor cells, including B-cell lymphomas and many types of solid tumors. Expression of CD40 can be increased in antigen presenting cells in response to IL-1βp, IFN-γ, GM-CSF, and LPS induced signaling events” [0149-150]. This helps to teach claim 75, 77, 83, 84, 86.
The reference Thompson teaches “A linker is linked with an antibody, in which the linker is a pegylated linker…”[0407]. This helps to teach claim 76.
The reference Thompson teaches “In some aspects, said antigen binding domain recognizes a single antigen. In some aspects, said antigen binding domain recognizes two or more antigens. In some aspects, said first antigen is a tumor antigen. In some aspects, said first antigen that is at least 80% homologous to CD5, CD19, CD20, CD25, CD37, CD30, CD33, CD45, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC, HLD-DR, carcinoembryonic antigen, TAG-72, EpCAM, MUC1, folate-binding protein…”[0008]. This helps to teach claim 78 and 80.
The reference Thompson teaches “Immune-stimulatory molecular motifs, such as Pathogen-Associated Molecular Pattern molecules, (PAMPs) can be recognized by receptors of the innate immune system, such as Toll- like receptors (TLRs), Nod-like receptors, C-type lectins, and RIG-I-like receptors”[0158]. This helps to teach claim 81.
The reference Thompson teaches “By way of example and not limitation, some cleavable and noncleavable linkers that may be included in the antibody construct immune-stimulatory compound conjugates described herein are described below” [0306]. This helps to teach claim 40.
The reference Thompson teaches “The compositions and methods described herein can be considered useful as pharmaceutical compositions for administration to a subject in need thereof. Pharmaceutical compositions can comprise at least the compositions described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents” [0381]. This helps to teach claim 59.
The reference Thompson teaches “In some embodiments, a method for treating a subject in need thereof, comprises administering a therapeutic dose of said conjugate of any one of the preceding embodiments or said pharmaceutical composition of any of the preceding embodiments. In some aspects, said subject has cancer. In some aspects, said composition is administered intravenously, cutaneously, subcutaneously, or injected at a site of affliction” [0021]. This helps to teach claim 61.
The reference Thompson teaches “Non-limiting examples of cancers can include Acute lymphoblastic leukemia (ALL); Acute myeloid leukemia; Adrenocortical carcinoma; Astrocytoma, childhood cerebellar or cerebral; Basal-cell carcinoma; Bladder cancer; Bone tumor, osteosarcoma/malignant fibrous histiocytoma; Brain cancer; Brain tumors, such as, cerebellar astrocytoma, malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma; Brainstem glioma; Breast cancer; Bronchial adenomas/carcinoids; Burkitt's lymphoma; Cerebellar astrocytoma; Cervical cancer; Cholangiocarcinoma; Chondrosarcoma; Chronic lymphocytic leukemia;
Chronic myelogenous leukemia; Chronic myeloproliferative disorders; Colon cancer; Cutaneous T-cell lymphoma; Endometrial cancer; Ependymoma; Esophageal cancer; Eye cancers, such as, intraocular melanoma and retinoblastoma; Gallbladder cancer; Glioma; Hairy cell leukemia; Head and neck cancer; Heart cancer; Hepatocellular (liver) cancer; Hodgkin lymphoma; Hypopharyngeal cancer; Islet cell carcinoma (endocrine pancreas); Kaposi sarcoma; Kidney cancer (renal cell cancer); Laryngeal cancer; Leukaemia, such as, acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myelogenous and, hairy cell; Lip and oral cavity cancer; Liposarcoma; Lung cancer…”[0403]. This helps to teach claims 82 and 63.
The reference Thompson teaches “Non-limiting examples of cancers can include Acute lymphoblastic leukemia (ALL); Acute myeloid leukemia; Adrenocortical carcinoma; Astrocytoma, childhood cerebellar or cerebral; Basal-cell carcinoma; Bladder cancer; Bone tumor, osteosarcoma/malignant fibrous histiocytoma…”[0403]. This helps to teach claim 65.
The reference Thompson does not teach Folate Receptor b or radical (claims 79-80), myeloid-derived suppressor cells (claim 85) or the radicals (all claims).
The reference Thompson does not teach the correct compounds of instant Formula (I) and instead requires the addition of two methyl groups to Imiquimod (see figure below) or the exchange of the CHO group on S-34240 to COOH group (see figure below).
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The reference Barillari teaches that(abstract):
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The reference Barillari teaches the following bioisosteres(page 17):
This helps to teach claims 1, 7, 8, 11, 73, 74.
The reference Kurahara teaches “Clinical Significance of Folate Receptor b–expressing
Tumor-associated Macrophages in Pancreatic Cancer” (title) and “ FRb macrophages are a novel subset of tumor-associated macrophages in pancreatic cancer and may play an important role in the tumor microenvironment in association with systemic metastasis through the interaction with tumor cells and vessels. FRb macrophages may be promising a targeting therapy for pancreatic cancer”(Conclusions). Thus it would be obvious to use a folate radical as a binding moiety. This helps to teach claims 79 and 80.
The reference Gabrilovich teaches “Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master—tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC).
These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer and in pathologic conditions associated with chronic inflammation or stress. These cells have emerged as an important contributor to tumor progression. Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases. MDSCs have a fascinating biology and are implicated in limiting the effects of cancer immunotherapy. Therefore, targeting these cells may represent an attractive therapeutic opportunity” (abstract). This helps to teach claim 85.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Thompson with Barillari to get the compounds of the instant claims because Thompson teaches lead compounds that are useful as immune-stimulatory compounds and Barillari teaches it is common practice to replace functional groups with bioisosteres to see if small modifications improve properties, such as pharmacological activity, selectivity, and pharmacokinetics. One would be motivated to do so to see if any of these properties would improve. One would have a reasonable expectation of success because H to methyl and methyl to OH are classical bioisostere replacements and because these replacements are small changes in the overall structure of the molecules. Further, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the H group for a Me. 2144.08(II)(A)(4)(c). Since it is a simple substitution of H for methyl one would have a reasonable expectation of success even when it is two hydrogens for two methyls. Since the compounds are obvious in view of the art so to is a radical of the compounds (claim 74) because this would be simply a portion of the obvious compound. This is the same use of the word radical as made in the argument on 08/25/2026: the defined molecular portion incorporated into a larger compound. In this case the larger compound can be the addition of a hydrogen.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Thompson with Kurahara because Thompson teaches folate-binding protein and cancer treatment and Kurahara teaches FRb macrophages may be promising a targeting therapy for pancreatic cancer. Thus one would have a reasonable expectation of success and be motivated to treat cancer by targeting the folate binding receptor beta because it is suggest as a good target for cancer treatment. Furthermore, it would have been obvious to modify Thompson with Gabrilovich because Thompson teaches cancer treatment of myeloid related cancers and Gabrilovich suggests MDSC as a good target. Thus one would have a reasonable expectation of success and be motivated to treat myeloid related cancers via targeting MDSC cells because it is a suggested target. It would have been prima facie obvious to one of ordinary skill in the art that Thompson’s molecule contains a radical, in the conjugate connected to linker, because the molecule need not be a radical as a whole to fit the instant claims but simply contain (comprise) a radical (a portion of the molecule would be considered a radical if not taken as a whole).
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 7, 8, 11, 40, 51, 59, 61, 63, 65, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87-92 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9, 11, 14, 27-30 of copending Application No. 17/625,461, over claims 1-26 of copending Application No. 19/264,776, over claims 1-25, 31, 37-41 of copending Application No. 18/260,273 over claims 1-6, 8-9, 12, 15-19, 21-23, 25, 28, 30-33 of copending Application No. 18/687,785 in view of THOMPSON (THOMPSON et al., WO-2017100305-A2, 2017) in view of Kurahara (Kurahara et al,. Clinical Significance of Folate Receptor b–expressing Tumor-associated Macrophages in Pancreatic Cancer, Ann Surg Oncol (2012) 19:2264–2271) and further in view of Gabrilovich ( Gabrilovich et al., Myeloid-Derived Suppressor Cells, Cancer Immunol Res; 5(1) January 2017) as evidenced by CAS SciFinder (imiquimod and S 34240, 2025) .
The application ‘461 claims:
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417
654
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675
695
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113
695
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403
622
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90
717
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The application also teaches:
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97
633
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A compound claim can be used to reject a method claim if the utility is disclosed in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1385 (CAFC 2010). See also MPEP § 804(II)(B)(2)(a).
This helps to teach all claims.
Application ‘461 doesn’t teach the cells (claim 81-85), lung cancer (claim 63) or a specific example of a lead compound (all claims).
The application ‘776 claims:
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646
702
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219
712
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344
688
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244
703
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151
691
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80
717
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This helps to teach all claims.
Application ‘776 doesn’t teach the cells (claim 81-85), lung cancer (claim 63) or a specific example of a lead compound (all claims).
The application ‘273 claims:
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278
697
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800
687
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125
682
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657
712
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343
708
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804
686
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109
767
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193
694
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Application ‘273 doesn’t teach the cells (claim 81-85), lung cancer (claim 63) or a specific example of a lead compound (all claims).
The application ‘785 claims:
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628
687
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518
714
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103
674
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202
704
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72
672
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78
670
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698
689
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Application ‘785 doesn’t teach the cells (claim 81-85) or lung cancer (claim 63) or the folate receptor or targeting moiety is specific (claims 77-80).
The secondary references further teach that all needed changes would be obvious as outlined in the 103 rejection (which is incorporated herein by reference).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the applications ‘461, ‘776, ‘785 and ‘273 with the reference THOMPSON because all references teach TLR agonist of similar structure conjugated to a linker to a targeting moiety for cancer treatment. Thus one would have reasonable expectation of success and motivation to do so to treat cancer as suggested by both references having similar compounds for a similar purpose. Additionally it would have been obvious to modify Thompson and the applications with Kurahara because Thompson teaches folate-binding protein and cancer treatment and Kurahara teaches FRb macrophages may be promising a targeting therapy for pancreatic cancer. Thus one would have a reasonable expectation of success and be motivated to treat cancer by targeting the folate binding receptor beta because it is suggest as a good target for cancer treatment. Furthermore, it would have been obvious to modify Thompson and the applications with Gabrilovich because Thompson teaches cancer treatment of myeloid related cancers and Gabrilovich suggests MDSC as a good target. Thus one would have a reasonable expectation of success and be motivated to treat myeloid related cancers via targeting MDSC cells because it is a suggested target.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 08/25/2026 have been fully considered but they are not persuasive.
103 Rejections
The applicants argued that the amendments to the structure of the compounds of the instant claims made the instant claims unobvious over the structures of Imiquimod and S-34240. Due to the amendments a new 103 argument has been added to account for these amendments.
The applicant also argues unexpected results. However, the applicant only tests compounds 1-5 while the claims cover a broad scope of compounds with various structures that may or may not share the unexpected results. In fact, the courts have made a distinction between mechanical elements, which function the same in different circumstances, yielding predictable results, and chemical and biological compounds, which often react unpredictably under different circumstances. Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ 95, 105(M.D. Fla. 1976); Aff’d 584 F.2d 714, 200 USPQ 257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970). Thus, the physiological activity of a chemical or biological compound is considered to be an unpredictable art. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F .2d 731,741,218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). Since there is a large number of structures not tested it is unlikely the claimed range is commensurate in scope with the unexpected results. It is also clear from figure 2 that even with the compounds of the instant claim tested (compound 3) some performed worse than the benchmark compound and some performed better (compound 1). Having some compounds that perform worse and some that perform better is not unexpected.
The applicant also argues that neither reference discloses all the components of the conjugates. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Thompson teaches folate-binding protein and cancer treatment and Kurahara teaches FRb macrophages may be promising a targeting therapy for pancreatic cancer. Thus one would combine the two based on knowledge of folate-binding protein and cancer treatment. Thus one would have a reasonable expectation of success and be motivated to treat cancer by targeting the folate binding receptor beta because it is suggest as a good target for cancer treatment. "Obviousness does not require absolute predictability of success.” Id. at 903, 7 USPQ2d at 1681".
The applicant also argues that the claimed architecture is functional. This is not a persuasive argument. The claims being functional does not make them less obvious.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Double Patenting Rejections
Additionally, the applicant argues that the double patenting rejections should be withdrawn because the instant claims cite limitations that are not found in the references, however, no specific examples of these differences are given. For example the applicant argues generic differences in specific compound structure or technical problems but no specific examples are given. This is unpersuasive because for instance instant claim 89 and co-pending application ‘273 teach the same exact compound. An additionally, example is the compounds of application ‘785 fall within the generic formula of instant claim 1 – since no structural difference were identified the applicants argument is unpersuasive. A claim that recites a compound for use in a method makes the compound obvious. Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Conclusion
Claims 1, 3, 7, 8, 11, 15, 40, 51, 59, 61, 63, 65, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87-92 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALISON AZAR HASTINGS whose telephone number is (703)756-4584. The examiner can normally be reached Mon-Thurs 7:30am-5pm EST Friday 7:30-4pm EST (every other Friday off).
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
Prosecution Insights