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 .
1. The response filed on November 14, 2025 to the restriction requirement of July 31, 2025 has been received. Applicant has elected for examination the species of:
A. Tubulin binding agent plinabulin;
B. Farnesyl pyrophosphate synthase (FPPS) inhibitor zoledronate;
C. Immune checkpoint inhibitor anti-PD-1 antibody nivolumab;
D. One checkpoint inhibitor administered; and
E. Cancer is a lung cancer: NSCLC.
Because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)). Claims 1-32 are pending. Claims 6, 10, 19, 23, 25, 28-30, and 33 are withdrawn as being drawn to non-elected species. Claims 1-5, 7-9, 11-18, 20-22, 24, 26, 27, 31, and 32 are currently under prosecution as drawn to the elected species.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
2. Claim(s) 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018.
Huang teaches a pharmaceutical composition comprising:
(i) an immune checkpoint inhibitor that is an anti-PD-1 antibody and is nivolumab;
(ii) T-cell activator plinabulin ([24-30]; claims 1-3, 18-20); and
(iii) one or more chemotherapeutics including zoledronic acid (zoledronate, a nitrogen-containing bisphosphonate compound) ([56]; [74]); and
(iv) pharmaceutically acceptable excipient (claim 18; [18]; [31-35]).
Huang teaches a method of treating cancer in a subject, the method comprising administering the pharmaceutical composition stated above ([34]; [57-65]; [71-74]; claims 20-27, 30, 31, 38, 39, and 44-46);
wherein the cancer is NSCLC ([65]; [67]; [70]; claim 27).
3. Claim(s) 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application Publication 2025/0073230, Huang et al, claiming priority to November 2015 (Application #18/952,618).
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.
US Patent Application Publication 2025/0073230, Huang claims priority to US Patent Application Publication 2018/0028531, Huang cited above therefore comprises the same disclosure as stated above for US Patent Application Publication 2018/0028531 and anticipates the rejected claims for the reasons stated above in section 3.
4. Claim(s) 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by each of:
US Patent 11,875,522 (Mohanlal); and
US Patent 10,912,748 (Mohanlal),
each US Patent claiming priority to February 2016.
These two US Patents share priority and comprise the same disclosure.
The applied references have 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.
Mohanlal teaches a pharmaceutical composition comprising:
(i) an immune checkpoint inhibitor that is an anti-PD-1 antibody and is nivolumab;
(ii) T-cell activator plinabulin; and
(iii) one or more chemotherapeutics including zoledronic acid (zoledronate, a nitrogen-containing bisphosphonate compound); and
(iv) pharmaceutically acceptable excipient (see US Patent 11,857,522 at abstract, col. 4-7; col. 10-16; col. 26-29; claims 1-10).
Mohanlal teaches a method of treating cancer in a subject, the method comprising administering the pharmaceutical composition stated above; wherein the cancer is NSCLC (see US Patent 11,857,522 at col. 16-17; col. 26-29; claims 11-26).
Claim Rejections - 35 USC § 103
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.
5. Claim(s) 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018; in view of ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018.
Huang teaches a pharmaceutical composition comprising:
(i) an immune checkpoint inhibitor that is an anti-PD-1 antibody and is nivolumab;
(ii) T-cell activator plinabulin; and
(iii) one or more chemotherapeutics including zoledronic acid (zoledronate, a nitrogen-containing bisphosphonate compound) ([56]; [74]); and
(iv) pharmaceutically acceptable excipient (claim 18; [18]; [31-35]).
Huang teaches a method of treating cancer in a subject, the method comprising administering the pharmaceutical composition stated above ([57-65]; [71-74]);
wherein the cancer is NSCLC ([65]; [67]).
In Example 7, Huang demonstrates the combination of plinabulin with anti-PD-1 antibody (Group 4) or the combination of plinabulin+ PD-1 antibody +CTLA-4 antibody (Group 6) resulted in synergy in inhibiting tumor growth of MC-38 mouse tumor models (Figure 4). Huang demonstrates FACS analysis of the treated tumors demonstrated that treatments of Plinabulin alone, Plinabulin and the immune checkpoint inhibitors (e.g., plinabulin with PD-1 antibody, Plinabulin with PD-1 antibody and CTLA-4-antibody) were associated with a decreased percentage of Regulatory T cells (Treg cells), a decreased percentage of macrophage stained cells, and a concomitant increase in the ratio of CD8+/Treg cells. Huang teaches: The decrease of the Treg cells percentage and macrophage stained cells and the increase in the ratio of CD8+/Treg cells were more significant in the treatment groups with plinabulin and immune checkpoint inhibitors than the group with plinabulin alone or antibody (antibodies) alone. These data has demonstrated the synergistic immuno-oncology properties of the combined treatment using Plinabulin and the immune checkpoint inhibitors (e.g., PD-1 antibody and CTLA-4-antibody) (Figure 5; [91]).
Huang teaches, but does not demonstrate, adding bisphosphonate zoledronate to plinabulin and PD-1 antibody as a composition to treat cancer or NSCLC.
NCT02812667 teaches clinically treating metastatic NSCLC patients by administering a combination of plinabulin and anti-PD-1 antibody nivolumab (Arms and Interventions; Eligibility). NCT02812667 teaches plinabulin inhibits tumor growth by targeting both new and existing blood vessels going to the tumor as well as killing tumor cells (Study Description). NCT02812667 teaches the known anti-cancer function of plinabulin and nivolumab and suggested synergic anti-tumor effect when combining the two agents (Study Description, Detailed Description):
“Plinabulin is a microtubule destabilizing agent (MDA) that inhibits the polymerization of tubulin monomers with resultant vascular disrupting properties. Plinabulin inhibits tumor growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing apoptosis via the Ras-JNK pathway. It also may activate anti-tumor immunity via inducing maturation of dendritic cells (DC) and triggering release of pro-inflammatory cytokines. Plinabulin could therefore have a synergic anti-tumor effect when combined with immune-checkpoint inhibitors. This hypothesis has been confirmed in a murine model bearing subcutaneous MC38 colon cancers using other MDAs, including ansamitocin P3, which induces DC maturation similar to that of plinabulin. Plinabulin has been tested in a randomized phase 2 trial in combination of docetaxel and showed similar response rate to that of docetaxel alone, but with a significantly longer duration of response.
Nivolumab is an inhibitor of the programmed cell death receptor-1 checkpoint pathway (PD-1) that has superior activity in NSCLC, regardless of tumor histology, comparing to standard of care.”
Akoury teaches and demonstrates that zoledronate has antitumor effects on primary NSCLC tumor and metastatic cells. Zoledronate impaired the ability of lung cancer cells and spine metastasis cells to proliferate, migrate, and invade 3D matrix and enhanced apoptosis (p. 2 of Introduction; sections 2.2-2.6). Akoury teaches administering zoledronate to impede the development of bone metastasis in NSCLC (p. 10).
Lopez-Olivo studies the effects of bisphosphonates, including zoledronate, on treatment of lung cancer patients with bone metastases. Lopez-Olivo teaches bisphosphonates are already known to prevent skeletal related events (SREs) in advanced breast cancer, prostate cancer, and multiple myeloma (abstract; Table 1). Lopez-Olivo concludes that treatment with bisphosphonates reduced SREs, improved pain control, and showed a trend to increased survival. Bisphosphonates should be used in the treatment of patients with lung cancer and bone metastases (abstract). In summary, bisphosphonates (zoledronic acid, pamidronate, and clodronate) reduced SREs and when added to other treatment modalities (e.g., chemotherapy, radiation therapy, and radioisotope therapy) resulted in better pain control, quality of life, and less progression of bone lesions than the other therapies alone. Our findings suggest that bisphosphonate therapy is indicated in the treatment of patients with lung cancer and metastatic bone disease (p. 2993, col. 2 last paragraph).
Zhang teaches they demonstrate bisphosphonates, including zoledronate, have direct antitumor effects, induce tumor cell immunogenic cell death, induce the immune response of the body, inhibit lung metastasis of different cancers, and directly promote the immunity of the host body, and exert better antitumor effects in combination with antitumor drugs (such as immune checkpoint inhibitors such as PD-1 antibodies, nucleoside chemotherapeutics such as 5-FU) and radiation therapy ([6]; [8]; Figures 8-18). Zhang demonstrated that combination treatment of tumors with zoledronate and anti-PD-1 antibody had a synergistic antitumor effect (Example 4; Figure 14; [203]) and combination treatment of tumors with zoledronate and chemotherapy (5-Fu) had a synergistic antitumor effect (Figure 18; Example 6; [210]; [213]). Zhang teaches nivolumab is a known anti-PD-1 antibody clinically treating cancers including NSCLC ([81]; Table 1).
Zhang teaches ([6]) it is known that bisphosphonate, zoledronic acid for example, has direct or indirect antitumor effects, and its antitumor effects are mainly manifested in promoting tumor cells apoptosis, inhibiting the extracellular matrix adhesion of tumor cells, inhibiting tumor metastasis and invasion, resisting angiogenesis, activating and amplifying γδ T of the host, and so on. The research is mainly focused on breast cancer, prostate cancer, lung cancer, and multiple myeloma, etc. In addition, data from multiple meta-analysis found that taking bisphosphonate can reduce the risk of occurrence of various tumors such as breast cancer and the bone metastasis, prostate cancer, lung cancer, etc.
Zhang concludes ([9]) bisphosphonates have the following antitumor mechanisms:
induce tumor cell immunogenic cell death (ICD), thereby activating the immune system of the host: promoting tumor cells membrane to express the “eat me” signaling molecules, calreticulin and ERp57, making the tumor cell easier for priming T cells after phagocytosed by DC cells; promoting tumor cells to express type I interferon (IFN-I) and type I interferon-activated gene ISG; increasing the number of tumor-infiltrating CD8+ T cells, CD4+ T cells, and DC cells in mouse tumor models of homologous transplantation; and using drug-treated tumor cells as tumor vaccines to protect the body against the re-challenge of tumor cells;
directly promote DC immune response: statins and bisphosphonates promote the cross-priming of T cells by DC cells; promote adoptive DC cells infusion to treat tumors; and
have a synergistic antitumor effect when combined with PD-1 antibody, chemotherapeutic drug 5-FU and the radiation therapy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine zoledronate with plinabulin and anti-PD-1 antibody as cancer-treating composition and administered for the treatment of cancer including NSCLC. One would have been motivated to, and have a reasonable expectation of success to because: (1) Huang suggests doing so; (2) NCT02812667, Akoury, Lopez-Olivo, and Zhang teach that any of zoledronate, plinabulin, and anti-PD-1 antibody nivolumab are already administered clinically for the same purpose to treat cancer and NSCLC, and their anti-tumor functions are known and established; (3) NCT02812667 teaches plinabulin and anti-PD-1 antibody preclinically demonstrated synergistic antitumor effects when combined, and teach administering the combination to NSCLC patients; and (4) Zhang demonstrates the combination of zoledronate with anti-PD-1 antibody or chemotherapy resulted in synergistic antitumor effects.
As stated in the above rejection, each of the three agents, zoledronate, plinabulin and anti-PD-1 antibody, had been taught by the prior art to be effective in treating cancer, including NSCLC, wherein the subcombinations of plinabulin + anti-PD-1 antibody and zoledronate + anti-PD-1 antibody demonstrated synergistic antitumor effects, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It 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 which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the three agents, each of which is taught by the prior art to be useful for the same purpose, and wherein subcombinations demonstrate synergistic antitumor effects, in order to form a combined composition of the three agents which is to be used for the very same purpose of treating cancer including NSCLC.
6. Claim(s) 22 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; as applied to claims 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 above, and further in view of Vansteenkiste et al (Annals of Oncology, 2019, 30:1244-1253).
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang (the combined references) teach a method of treating NSCLC cancer comprising administering a combination of zoledronate, plinabulin, and anti-PD-1 antibody, wherein each of zoledronate, plinabulin, and anti-PD-1 antibody have known mechanisms of enhancing anti-tumor immunity, as set forth above.
The combined references do not teach treating low grade (early stage) immunogenic NSCLC.
Vansteenkiste teaches early stage NSCLC is in need of cancer treatment and teaches such patients are being clinically treated with anti-PD-1 antibody or immune checkpoint inhibition therapy, and in combination with other anticancer therapies, to enhance antitumor immune responses (abstract; p. 1245, Tables 1-4; Figure 2 and 3; p. 1248-1249; p. 1251).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat early stage immunogenic NSCLC in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references recognize NSCLC patients need immunotherapeutic treatment and teach each of the agents in the composition treat NSCLC and enhance anti-tumor immune responses; (2) Vansteenkiste teaches that NSCLC patients at early stages need treatment with immunotherapy; and (3) Vansteenkiste teaches early stage NSCLC patients are already being clinically treated with immunotherapy including anti-PD-1 antibody combined with chemotherapy and other anti-cancer agents.
7. Claim(s) 21 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; as applied to claims 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 above, and further in view of Lin et al (Biochemical and Biophysical Research Communications; Volume 496, Issue 2, 5 February 2018, Pages 536-541).
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang (the combined references) teach a method of treating NSCLC cancer comprising administering a combination of zoledronate, FPPS inhibitor plinabulin, and anti-PD-1 antibody, wherein each of zoledronate, plinabulin, and anti-PD-1 antibody have known mechanisms of enhancing anti-tumor immunity, as set forth above. Zhang further teaches the importance of inhibiting the mevalonic acid (mevalonate) pathway to treat cancer, that FPPS catalyzes mevalonate, and teaches zoledronate is an effective mevalonate pathway inhibitor acting as a FPPS inhibitor ([3-6]).
The combined references do not teach the NSCLC treated expresses FPPS.
Lin teaches NSCLC tumors express FPPS and expression is significantly correlated with tumor stage and metastasis (Highlights; section 3.1). Lin teaches Farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, has been shown to play a role in cancer progression (abstract; section 4). Lin demonstrates that FPPS contributes to NSCLC cell invasion and EMT process, and inhibition of FPPs blocked cell invasion and EMT process (Figure 1; section 3.2 and 3.4).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat NSCLC expressing FPPS by the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references teach treating patients diagnosed with NSCLC by administration of zoledronate, plinabulin, and anti-PD-1 antibody; (2) Lin teaches NSCLC expresses FPPS and FPPS contributes to cell invasiveness and metastasis; (3) Lin teaches inhibiting FPPS successfully inhibited cell invasiveness and EMT; and (4) Lin and Zhang recognize inhibiting the mevalonate pathway with a FPPS inhibitor treats cancer, wherein Zhang teaches zoledronate is a known FPPS inhibitor.
8. Claim(s) 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2025/0073230, Huang et al, claiming priority to Nov. 2015; in view of ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018.
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. 103 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); 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 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. See generally MPEP § 717.02.
US Patent Application Publication 2025/0073230, Huang claims priority to US Patent Application Publication 2018/0028531, Huang cited above, therefore comprises the same disclosure as stated above for US Patent Application Publication 2018/0028531.
Huang teaches, but does not demonstrate, adding bisphosphonate zoledronate to plinabulin and PD-1 antibody as a composition to treat cancer or NSCLC.
NCT02812667; Akoury; Lopez-Olivo; and Zhang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine zoledronate with plinabulin and anti-PD-1 antibody as cancer-treating composition and administered for the treatment of cancer including NSCLC. One would have been motivated to, and have a reasonable expectation of success to because: (1) Huang suggests doing so; (2) NCT02812667, Akoury, Lopez-Olivo, and Zhang teach that any of zoledronate, plinabulin, and anti-PD-1 antibody nivolumab are already administered clinically for the same purpose to treat cancer and NSCLC, and their anti-tumor functions are known and established; (3) NCT02812667 teaches plinabulin and anti-PD-1 antibody preclinically demonstrated synergistic antitumor effects when combined, and teach administering the combination to NSCLC patients; and (4) Zhang demonstrates the combination of zoledronate with anti-PD-1 antibody or chemotherapy resulted in synergistic antitumor effects.
As stated in the above rejection, each of the three agents, zoledronate, plinabulin and anti-PD-1 antibody, had been taught by the prior art to be effective in treating cancer, including NSCLC, wherein the subcombinations of plinabulin + anti-PD-1 antibody and zoledronate + anti-PD-1 antibody demonstrated synergistic antitumor effects, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It 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 which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the three agents, each of which is taught by the prior art to be useful for the same purpose, and wherein subcombinations demonstrate synergistic antitumor effects, in order to form a combined composition of the three agents which is to be used for the very same purpose of treating cancer including NSCLC.
9. Claim(s) 22 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2025/0073230, Huang et al, claiming priority to Nov. 2015; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; as applied to claims 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 above, and further in view of Vansteenkiste et al (Annals of Oncology, 2019, 30:1244-1253).
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. 103 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); 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 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. See generally MPEP § 717.02.
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang (the combined references) teach a method of treating NSCLC cancer comprising administering a combination of zoledronate, plinabulin, and anti-PD-1 antibody, wherein each of zoledronate, plinabulin, and anti-PD-1 antibody have known mechanisms of enhancing anti-tumor immunity, as set forth above.
The combined references do not teach treating low grade (early stage) immunogenic NSCLC.
Vansteenkiste teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat early stage immunogenic NSCLC in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references recognize NSCLC patients need immunotherapeutic treatment and teach each of the agents in the composition treat NSCLC and enhance anti-tumor immune responses; (2) Vansteenkiste teaches that NSCLC patients at early stages need treatment with immunotherapy; and (3) Vansteenkiste teaches early stage NSCLC patients are already being clinically treated with immunotherapy including anti-PD-1 antibody combined with chemotherapy and other anti-cancer agents.
10. Claim(s) 21 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2025/0073230, Huang et al, claiming priority to Nov. 2015; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; as applied to claims 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 above, and further in view of Lin et al (Biochemical and Biophysical Research Communications; Volume 496, Issue 2, 5 February 2018, Pages 536-541).
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. 103 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); 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 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. See generally MPEP § 717.02.
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang (the combined references) teach as set forth above.
The combined references do not teach the NSCLC treated expresses FPPS.
Lin teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat NSCLC expressing FPPS by the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references teach treating patients diagnosed with NSCLC by administration of zoledronate, plinabulin, and anti-PD-1 antibody; (2) Lin teaches NSCLC expresses FPPS and FPPS contributes to cell invasiveness and metastasis; (3) Lin teaches inhibiting FPPS successfully inhibited cell invasiveness and EMT; and (4) Lin and Zhang recognize inhibiting the mevalonate pathway with a FPPS inhibitor treats cancer, wherein Zhang teaches zoledronate is a known FPPS inhibitor.
11. Claim(s) 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over each of
US Patent 11,875,522 (Mohanlal); and
US Patent 10,912,748 (Mohanlal);
each US Patent claiming priority to February 2016;
each US Patent in view of ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018.
The two US Patents 11,875,522 and 10,912,748 share priority and comprise the same disclosure.
The applied references, 11,875,522 and 10,912,748 (Mohanlal), have 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. 103 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); 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 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. See generally MPEP § 717.02.
Mohanlal teaches a pharmaceutical composition comprising:
(i) an immune checkpoint inhibitor that is an anti-PD-1 antibody and is nivolumab;
(ii) T-cell activator plinabulin; and
(iii) one or more chemotherapeutics including zoledronic acid (zoledronate, a nitrogen-containing bisphosphonate compound); and
(iv) pharmaceutically acceptable excipient (see US Patent 11,857,522 at abstract, col. 4-7; col. 10-16; col. 26-29; claims 1-10).
Mohanlal teaches a method of treating cancer in a subject, the method comprising administering the pharmaceutical composition stated above; wherein the cancer is NSCLC (see US Patent 11,857,522 at col. 16-17; col. 26-29; claims 11-26).
Mohanlal teaches, but does not demonstrate, adding bisphosphonate zoledronate to plinabulin and PD-1 antibody as a composition to treat cancer or NSCLC.
NCT02812667; Akoury; Lopez-Olivo; and Zhang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine zoledronate with plinabulin and anti-PD-1 antibody as cancer-treating composition and administered for the treatment of cancer including NSCLC. One would have been motivated to, and have a reasonable expectation of success to because: (1) Mohanlal suggests doing so; (2) NCT02812667, Akoury, Lopez-Olivo, and Zhang teach that any of zoledronate, plinabulin, and anti-PD-1 antibody nivolumab are already administered clinically for the same purpose to treat cancer and NSCLC, and their anti-tumor functions are known and established; (3) NCT02812667 teaches plinabulin and anti-PD-1 antibody preclinically demonstrated synergistic antitumor effects when combined, and teach administering the combination to NSCLC patients; and (4) Zhang demonstrates the combination of zoledronate with anti-PD-1 antibody or chemotherapy resulted in synergistic antitumor effects.
As stated in the above rejection, each of the three agents, zoledronate, plinabulin and anti-PD-1 antibody, had been taught by the prior art to be effective in treating cancer, including NSCLC, wherein the subcombinations of plinabulin + anti-PD-1 antibody and zoledronate + anti-PD-1 antibody demonstrated synergistic antitumor effects, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It 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 which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the three agents, each of which is taught by the prior art to be useful for the same purpose, and wherein subcombinations demonstrate synergistic antitumor effects, in order to form a combined composition of the three agents which is to be used for the very same purpose of treating cancer including NSCLC.
12. Claim(s) 22 is rejected under 35 U.S.C. 103 as being unpatentable over each of
US Patents 11,875,522 or 10,912,748 (Mohanlal); and ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; as applied to claims 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 above, and further in view of Vansteenkiste et al (Annals of Oncology, 2019, 30:1244-1253).
The applied Mohanlal references have 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. 103 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); 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 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. See generally MPEP § 717.02.
Mohanlal; NCT02812667; Akoury; Lopez-Olivo; and Zhang (the combined references) teach a method of treating NSCLC cancer comprising administering a combination of zoledronate, plinabulin, and anti-PD-1 antibody, wherein each of zoledronate, plinabulin, and anti-PD-1 antibody have known mechanisms of enhancing anti-tumor immunity, as set forth above.
The combined references do not teach treating low grade (early stage) immunogenic NSCLC.
Vansteenkiste teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat early stage immunogenic NSCLC in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references recognize NSCLC patients need immunotherapeutic treatment and teach each of the agents in the composition treat NSCLC and enhance anti-tumor immune responses; (2) Vansteenkiste teaches that NSCLC patients at early stages need treatment with immunotherapy; and (3) Vansteenkiste teaches early stage NSCLC patients are already being clinically treated with immunotherapy including anti-PD-1 antibody combined with chemotherapy and other anti-cancer agents.
13. Claim(s) 21 is rejected under 35 U.S.C. 103 as being unpatentable over each of
US Patents 11,875,522 or 10,912,748 (Mohanlal); and ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; as applied to claims 1-5, 7-9, 11-18, 20, 24, 26, 27, 31, and 32 above, and further in view of Lin et al (Biochemical and Biophysical Research Communications; Volume 496, Issue 2, 5 February 2018, Pages 536-541).
The applied Mohanlal references have 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. 103 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); 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 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. See generally MPEP § 717.02.
Mohanlal; NCT02812667; Akoury; Lopez-Olivo; and Zhang (the combined references) teach as set forth above.
The combined references do not teach the NSCLC treated expresses FPPS.
Lin teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat NSCLC expressing FPPS by the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references teach treating patients diagnosed with NSCLC by administration of zoledronate, plinabulin, and anti-PD-1 antibody; (2) Lin teaches NSCLC expresses FPPS and FPPS contributes to cell invasiveness and metastasis; (3) Lin teaches inhibiting FPPS successfully inhibited cell invasiveness and EMT; and (4) Lin and Zhang recognize inhibiting the mevalonate pathway with a FPPS inhibitor treats cancer, wherein Zhang teaches zoledronate is a known FPPS inhibitor.
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.
14. Claims 1-5, 7-9, 11-18, 20-22, 24, 26, 27, 31, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,377,094 in view of US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; Vansteenkiste et al (Annals of Oncology, 2019, 30:1244-1253) and Lin et al (Biochemical and Biophysical Research Communications; Volume 496, Issue 2, 5 February 2018, Pages 536-541).
The US patent claims a method of treating cancer resistant to or progressed after prior treatment with one or more immune checkpoint inhibitor, the method comprising:
identifying a subject as having been resistant to or progressed after prior treatment with a PD-1 or PD-L1 inhibitor; and administering to the subject:
(i) a PD-1 or PD-L1 inhibitor; and
(ii) plinabulin;
the method further comprising administering a chemotherapeutic agent, wherein the agent is docetaxel, oxaliplatin, carboplatin, or cisplatin;
wherein the PD-1 inhibitor is nivolumab;
wherein the cancer is NSCLC.
The US Patent does not claim additionally administering zoledronate or the treatment composition comprises all of PD-1 inhibitor, plinabulin, and zoledronate and a pharmaceutically acceptable carrier.
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang teach a method of treating a patient having NSCLC comprising administering a pharmaceutical composition comprising a combination of zoledronate, plinabulin, anti-PD-1 antibody, and pharmaceutical carrier, as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine zoledronate with the plinabulin and anti-PD-1 antibody as cancer-treating composition for the treatment of NSCLC claimed by the US Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) Huang suggests doing so; (2) The US Patent claims, and Huang, NCT02812667, Akoury, Lopez-Olivo, and Zhang teach that any of zoledronate, plinabulin, and anti-PD-1 antibody nivolumab are already administered clinically for the same purpose to treat cancer and NSCLC, and their anti-tumor functions are known and established; (3) NCT02812667 teaches plinabulin and anti-PD-1 antibody preclinically demonstrated synergistic antitumor effects when combined, and teach administering the combination to NSCLC patients; and (4) Zhang demonstrates the combination of zoledronate with anti-PD-1 antibody or chemotherapy resulted in synergistic antitumor effects.
With regard to claim 22, the US Patent does not claim treating low grade (early stage) immunogenic NSCLC.
Vansteenkiste teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat early stage immunogenic NSCLC in the method of the US Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) the US Patent claims treating NSCLC, and the combined secondary references recognize NSCLC patients need immunotherapeutic treatment and teach each of the agents in the composition treat NSCLC and enhance anti-tumor immune responses; (2) Vansteenkiste teaches that NSCLC patients at early stages need treatment with immunotherapy; and (3) Vansteenkiste teaches early stage NSCLC patients are already being clinically treated with immunotherapy including anti-PD-1 antibody combined with chemotherapy and other anti-cancer agents.
With regard to claim 21, the US Patent does not claim the NSCLC treated expresses FPPS.
Lin teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat NSCLC expressing FPPS by the method of the US Patent and combined secondary references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the US Patent claims treating NSCLC, and the combined secondary references teach treating patients diagnosed with NSCLC by administration of zoledronate, plinabulin, and anti-PD-1 antibody; (2) Lin teaches NSCLC expresses FPPS and FPPS contributes to cell invasiveness and metastasis; (3) Lin teaches inhibiting FPPS successfully inhibited cell invasiveness and EMT; and (4) Lin and Zhang recognize inhibiting the mevalonate pathway with a FPPS inhibitor treats cancer, wherein Zhang teaches zoledronate is a known FPPS inhibitor.
15. Claims 1-5, 7-9, 11-18, 20-22, 24, 26, 27, 31, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,857,522 (Mohanlal) in view of US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; Vansteenkiste et al (Annals of Oncology, 2019, 30:1244-1253) and Lin et al (Biochemical and Biophysical Research Communications; Volume 496, Issue 2, 5 February 2018, Pages 536-541).
The US patent claims a pharmaceutical composition comprising an immune checkpoint inhibitor of PD-1 that is an antibody, plinabulin and an additional chemotherapeutic agent; and a method of treating cancer, the method comprising
administering the composition to a subject in need thereof; wherein the cancer is NSCLC; wherein the immune checkpoint inhibitor antibody is nivolumab.
The US Patent does not claim additionally administering zoledronate or the treatment composition comprises all of PD-1 inhibitor, plinabulin, and zoledronate and a pharmaceutically acceptable carrier.
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang teach a method of treating a patient having NSCLC comprising administering a pharmaceutical composition comprising a combination of zoledronate, plinabulin, anti-PD-1 antibody, and pharmaceutical carrier, as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine zoledronate with the plinabulin and anti-PD-1 antibody as cancer-treating composition for the treatment of NSCLC claimed by the US Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) Huang suggests doing so; (2) The US Patent claims, and Huang, NCT02812667, Akoury, Lopez-Olivo, and Zhang teach that any of zoledronate, plinabulin, and anti-PD-1 antibody nivolumab are already administered clinically for the same purpose to treat cancer and NSCLC, and their anti-tumor functions are known and established; (3) NCT02812667 teaches plinabulin and anti-PD-1 antibody preclinically demonstrated synergistic antitumor effects when combined, and teach administering the combination to NSCLC patients; and (4) Zhang demonstrates the combination of zoledronate with anti-PD-1 antibody or chemotherapy resulted in synergistic antitumor effects.
With regard to claim 22, the US Patent does not claim treating low grade (early stage) immunogenic NSCLC.
Vansteenkiste teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat early stage immunogenic NSCLC in the method of the US Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) the US Patent claims treating NSCLC, and the combined secondary references recognize NSCLC patients need immunotherapeutic treatment and teach each of the agents in the composition treat NSCLC and enhance anti-tumor immune responses; (2) Vansteenkiste teaches that NSCLC patients at early stages need treatment with immunotherapy; and (3) Vansteenkiste teaches early stage NSCLC patients are already being clinically treated with immunotherapy including anti-PD-1 antibody combined with chemotherapy and other anti-cancer agents.
With regard to claim 21, the US Patent does not claim the NSCLC treated expresses FPPS.
Lin teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat NSCLC expressing FPPS by the method of the US Patent and combined secondary references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the US Patent claims treating NSCLC, and the combined secondary references teach treating patients diagnosed with NSCLC by administration of zoledronate, plinabulin, and anti-PD-1 antibody; (2) Lin teaches NSCLC expresses FPPS and FPPS contributes to cell invasiveness and metastasis; (3) Lin teaches inhibiting FPPS successfully inhibited cell invasiveness and EMT; and (4) Lin and Zhang recognize inhibiting the mevalonate pathway with a FPPS inhibitor treats cancer, wherein Zhang teaches zoledronate is a known FPPS inhibitor.
16. Claims 1-5, 7-9, 11-18, 20-22, 24, 26, 27, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No.18/952,618 in view of US Patent Application Publication 2018/0028531, Huang et al, published February 1, 2018; ClinicalTrials.gov NCT02812667 (Record History, Version 5, published August 5, 2018); Akoury et al (Journal of Clinical Medicine, 2019, 8:1212, internet pages 1-16); Lopez-Olivo et al (Supportive Care Cancer, 2012, 20:2985-2998); and US Patent Application Publication 2021/0008084, Zhang et al, claiming priority to 2018; Vansteenkiste et al (Annals of Oncology, 2019, 30:1244-1253) and Lin et al (Biochemical and Biophysical Research Communications; Volume 496, Issue 2, 5 February 2018, Pages 536-541).
The copending application claims a method of treating NSCLC in a human subject comprising administering to the subject:
(i) an inhibitor of PD-1 that is nivolumab;
(ii) plinabulin; and
(iii) chemotherapeutic docetaxel or platinum-based agent.
The copending application does not claim additionally administering zoledronate or the treatment composition comprises all of PD-1 inhibitor, plinabulin, and zoledronate and a pharmaceutically acceptable carrier.
Huang; NCT02812667; Akoury; Lopez-Olivo; and Zhang teach a method of treating a patient having NSCLC comprising administering a pharmaceutical composition comprising a combination of zoledronate, plinabulin, anti-PD-1 antibody, and pharmaceutical carrier, as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine zoledronate with the plinabulin and anti-PD-1 antibody as cancer-treating composition for the treatment of NSCLC claimed by the copending application. One would have been motivated to, and have a reasonable expectation of success to because: (1) Huang suggests doing so; (2) The copending application claims, and Huang, NCT02812667, Akoury, Lopez-Olivo, and Zhang teach that any of zoledronate, plinabulin, and anti-PD-1 antibody nivolumab are already administered clinically for the same purpose to treat cancer and NSCLC, and their anti-tumor functions are known and established; (3) NCT02812667 teaches plinabulin and anti-PD-1 antibody preclinically demonstrated synergistic antitumor effects when combined, and teach administering the combination to NSCLC patients; and (4) Zhang demonstrates the combination of zoledronate with anti-PD-1 antibody or chemotherapy resulted in synergistic antitumor effects.
With regard to claim 22, the copending application does not claim treating low grade (early stage) immunogenic NSCLC.
Vansteenkiste teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat early stage immunogenic NSCLC in the method of the copending application. One would have been motivated to, and have a reasonable expectation of success to because: (1) the copending application claims treating NSCLC, and the combined secondary references recognize NSCLC patients need immunotherapeutic treatment and teach each of the agents in the composition treat NSCLC and enhance anti-tumor immune responses; (2) Vansteenkiste teaches that NSCLC patients at early stages need treatment with immunotherapy; and (3) Vansteenkiste teaches early stage NSCLC patients are already being clinically treated with immunotherapy including anti-PD-1 antibody combined with chemotherapy and other anti-cancer agents.
With regard to claim 21, the copending application does not claim the NSCLC treated expresses FPPS.
Lin teaches as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat NSCLC expressing FPPS by the method of the copending application and combined secondary references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the copending application claims treating NSCLC, and the combined secondary references teach treating patients diagnosed with NSCLC by administration of zoledronate, plinabulin, and anti-PD-1 antibody; (2) Lin teaches NSCLC expresses FPPS and FPPS contributes to cell invasiveness and metastasis; (3) Lin teaches inhibiting FPPS successfully inhibited cell invasiveness and EMT; and (4) Lin and Zhang recognize inhibiting the mevalonate pathway with a FPPS inhibitor treats cancer, wherein Zhang teaches zoledronate is a known FPPS inhibitor.
This is a provisional nonstatutory double patenting rejection.
17. Conclusion: No claim is allowed.
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/Laura B Goddard/ Primary Examiner, Art Unit 1642