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 .
Claim Status
Claims 1, 4, 7, 8, 10-12, and 15-16 are currently pending and subject to examination.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim 9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
The rejection of claims 1, 4, 10, and 17-20 under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017) is withdrawn.
The rejection of claim(s) 1-2, 4-5, 10, and 17-20 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17), as applied to claims 1, 4, 10, and 17-20 above, and further in view of Fayzullina et al. (Front. Oncol., 09 February 2022, Sec. Molecular and Cellular Oncology, Volume 12 – 2022, p. 1-8) is withdrawn.
The rejection of claims 1-2, 4-5, 10 and 17-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,268,702 B2 (herein the ‘702 patent), citing to Ahlmann & Hempel (Cancer Chemotherapy and Pharmacology, Review Article, Published: 19 September 2016, Volume 78, pages 661–671, (2016)), Javeed et al. (European Journal of Pharmaceutical Sciences, Volume 38, Issue 4, 5 November 2009, Pages 283-290) and Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17) is withdrawn.
The rejection of claims 1-2, 4-5, 10 and 17-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,878,028 B1 (herein the ‘028 patent) in view of Liang and Liu (Oncology Letters, May-2022, Volume 23, Issue 5, p. 1-7) and Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17) is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
Claim Rejections - 35 USC 103 – Previously Presented
35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
“A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of claim(s) 1, 4, 7-8, and 10 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17), and Fayzullina et al. (Front. Oncol., 09 February 2022, Sec. Molecular and Cellular Oncology, Volume 12 – 2022, p. 1-8) and further in view of Panda et al. (JCI Insight, 2018 Aug 23;3(16):e121522, p. 1-12) is maintained.
The rejection of claim(s) 11-12 and 15 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17) and further in view of Wan Zhang et al. (J Cancer, 2019 Jun 2;10(11):2578–2587 is maintained.
The rejection of claim(s) 10-12 and 15-16 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17), and Wan Zhang et al. (J Cancer, 2019 Jun 2;10(11):2578–2587, as applied to claims 11-12 and 15 above, and further in view of Castelli et al. (Cells, 2021, 10(9), 2227, p. 1-10) is maintained.
Response to Arguments
The Applicant argues that Zhang and Fayzullina do not specifically teach the combination of azvudine and an anti-PD-1 or anti-PD-L1 antibody and that they do not specifically test and show that the combination works better than either drug alone (Remarks, p. 5-6). These arguments were fully considered but are not persuasive. The Applicant has not shown an effect greater than the additive effect of both drugs. Furthermore, Fayzullina specifically suggests that the immunomodulator should proceed through an immune checkpoint pathway (PD-1 and PD-L1 are immune checkpoint therapies). One of ordinary skill in the art would have a reasonable expectation of success to combine azvudine with an immune checkpoint therapy such as anti-PD-1 or anti-PD-L1 because Fayzullina specifically teaches azvudine in combination with immunotherapies such as immune checkpoint therapies:
Retroviruses’ activity and metabolites, secreted by tumor microenvironment, inducing immunosuppressive activity along with other properties of the stem of cancer cells (10). HERVs also induces local immune checkpoint activation (19). Therefore, suppression of retroviral activity by FNC can lead to an increase in the effectiveness of immunotherapeutic strategies. Actually, targeting of the HERV-K envelope protein by CAR-T cells has already been reported as a potential immunotherapeutic approach for melanoma and other tumors (52).
Fayzullina, col. 1, p. 5.
While Fayzullina does not teach the specifically claimed PD-1 antibodies, the Applicant has not demonstrated that any particular anti-PD-1 exhibits superior properties and the anti-PD-1 and anti-PD-L1 antibodies claimed by the applicant are commonly known immune checkpoint therapies as demonstrated by Panda.
Reiterated Rejection
The rejection of claim(s) 1-4, 7-8, and 10 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17), and Fayzullina et al. (Front. Oncol., 09 February 2022, Sec. Molecular and Cellular Oncology, Volume 12 – 2022, p. 1-8) and further in view of Panda et al. (JCI Insight, 2018 Aug 23;3(16):e121522, p. 1-12) is maintained.
Claim 1 recites:
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Pharmaceutical compositions comprising azvudine are well known in the art. For example, Zhang teaches an intravenous formulation comprising azvudine (FNC): “For in vivo experiments, FNC and Ara-C were dissolved in 0.9% sodium chloride.” (Zhang, p. 2).
Immunomodulation is an inherent property of compositions comprising azvudine. ("[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas
Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). MPEP § 2112). Nonetheless, Zhang teaches that the pharmaceutical composition comprising azvudine has immunomodulatory effects:
Pathway analysis of the microarray data revealed that the most significant pathways were involved in the immune system and cell cycle. The most significantly enriched terms such as “immune system process”, “cellular process” and “death” were selected by GO enrichment analysis. Therefore, FNC may affect the occurrence and development of tumors through multiple molecular pathways… This finding suggests that modulating the immune system may be another important antitumor mechanism of FNC.”
Zhang, p. 14.
Zhang teaches that compositions comprising azvudine (FNC) treated tumors in mice and that regulation of the immune system played an important role in this effect:
FNC, 2’-deoxy-2’-β-fluoro-4’-azidocytidine, is a novel cytidine analogue, that has shown strong antiproliferative activity in human lymphoma, lung adenocarcinoma and acute myeloid leukemia. In this study, we investigated the effects of FNC on mantle cell lymphoma (MCL) and the underlying mechanisms. In in vitro experiments, cell viability was detected by the CCK8 assay, and cell cycle progression and apoptosis were assessed by flow cytometry, and the expression of relative apoptosis proteins were detected by Western Blot. The in vivo antitumor effect of FNC was investigated in a SCID xenograft model. Finally, the mechanisms of action of FNC were assessed using a whole human genome expression profile chip. The data showed that FNC inhibited cell growth in a dose- and time-dependent manner, and FNC could induce apoptosis by the death recepter pathways in JeKo-1 cells and arrest the cell cycle in the G1/S or G2/M phase. Notably, FNC showed in vivo efficacy in mice bearing JeKo-1 xenograft tumors. Gene expression profile analysis revealed that the differentially expressed genes were mainly focused on the immune system process, cellular process and death. These findings implied that FNC may be a valuable therapeutic in mantle cell lymphoma and provided an experimental basis for the early clinical application of FNC.
Zhang, Abstract;
Pathway analysis of the microarray data revealed that the most significant pathways were involved in the immune system and cell cycle. The most significantly enriched terms such as “immune system process”, “cellular process” and “death” were selected by GO enrichment analysis. Therefore, FNC may affect the occurrence and development of tumors through multiple molecular pathways… This finding suggests that modulating the immune system may be another important antitumor mechanism of FNC.”
Zhang, p. 14.
Zhang teaches to administer FNC at doses of 1-3 mg/kg to subjects with cancer, and that at these doses, FNC inhibits tumor growth and upregulates genes associated with activation of the immune system:
To evaluate the antitumor activity of FNC in vivo, JeKo-1-bearing SCID/Beige mice were injected with FNC via the caudal vein. When administered at a dose of 1, 2 or 3 mg/kg for eight consecutive days, the inhibitory rates were 37.9%,75.8% and 82.1%, respectively. At the end of the experiment, tumor volume was 1857.73 ± 326.51 mm3 in the control group, while tumor volume in the treatment groups was 1089.35± 267.14 mm3 , 452.65 ± 96.38 mm3 and 274.40± 77.26 mm3 at FNC doses of 1 mg/kg, 2 mg/kg and 3 mg/kg, respectively. The tumor volume in cytarabine group was 553.61 ± 123.85 mm3 . Our results showed that the tumor growth in the FNC-treated group was markedly inhibited compared with that of the negative control group, and FNC significantly suppressed tumor growth in a dose-dependent manner (Fig 4A and 4B).
Zhang, p. 8.
While Zhang does not teach that azvudine is in a pharmaceutical composition with an anti-PD-1 /PD-L1 antibody, one of ordinary skill in the art would have a reasonable expectation of success to combine azvudine with an anti-PD-1/PD-L1 antibody because Fayzullina teaches that FNC could increase the effectiveness of immunotherapeutic strategies, particularly targeting altered immune checkpoints in cancer:
Modulating the immune system may be another important anti-tumor mechanism of FNC and should be investigated. In a study comparing the gene-expression profiles with and without FNC treatment, significant changes in the expression of several genes associated with immunity were shown. The co-stimulatory signal during T-cell activation and genes associated with IL-2, IL-4, IL-7, IL-10 pathways has been shown based on Biocarta (4). In addition, some HERVs have proven effects on the immune system too: protein products of the translation of retroviral sequences, for example, the Gag of the HERV-K gene, affect the interaction of cancer cells with the immune system (14, 19). Retroviruses’ activity and metabolites, secreted by tumor microenvironment, inducing immunosuppressive activity along with other properties of the stem of cancer cells (10). HERVs also induces local immune checkpoint activation (19). Therefore, suppression of retroviral activity by FNC can lead to an increase in the effectiveness of immunotherapeutic strategies. Actually, targeting of the HERV-K envelope protein by CAR-T cells has already been reported as a potential immunotherapeutic approach for melanoma and other tumors (52).
Fayvullina, col. 1, p. 5 (emphasis added).
For example, Fayzullina cites to Panda (19), who teaches that tumors in patients that express endogenous retroviruses (ERVs) respond to immune checkpoint blockade (ICB), e.g. PD-1/ PD-L1 antibodies:
These results demonstrate that elevated expression of a set of πERVs is associated with gene expression based evidence of ICA in several solid cancers and particularly strikingly in ccRCC. This finding suggests that broad transcriptional activation of πERVs, present in a subset of tumors, may induce antitumor immune response and subsequent upregulation of immune checkpoint pathways, making such tumors sensitive to ICB. Expression of 7 members of the ERVK family has previously been reported to be correlated with the expression of cytotoxins GZMA and PRF1 in ccRCC (18), and we found an association between ERV3-2 expression and response to ICB in a small cohort of 24 metastatic ccRCC patients. Although πERV high tumors in ccRCC have poor prognosis under standard therapy, such tumors may have significantly improved outcomes with ICB.
Panda, p. 8.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 7 is directed towards the method of claim 6, wherein the PD-1 antibody is selected from the group consisting of pembrolizumab, nivolumab, sintilimab, toripalimab, RMVP1-14, camrelizumab, tislelizumab, cemiplimab and a combination thereof. Claim 8 is directed towards the method of claim 6, wherein the PD-L1 antibody is selected from the group consisting of avelumab, atezolizumab, durvalumab and a combination thereof.
One of ordinary skill in the art would have a reasonable expectation of success to use the PD-1 antibody such as nivolumab or pembrolizumab or the PD-L1 antibody such as atezolizumab because these antibodies are commonly known in the art for treating tumors that express ERVs. For example, Panda teaches nivolumab, pembrolizumab and atezolizumab:
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Panda, p. 5.
Therefore, claims 7-8 were prima facie obvious at the time of filing.
The rejection of claim(s) 11-12 and 15 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17) and further in view of Wan Zhang et al. (J Cancer, 2019 Jun 2;10(11):2578–2587 is maintained.
Claim 11 is directed towards a method for enhancing immune response, comprising obtaining a sample from a subject; isolating immune cells from the sample; culturing the immune cells with the pharmaceutical composition according to claim 1; expanding the immune cells and reintroducing the cells into the subject; and enhancing the immune response.
Zhang teaches that administering azvudine to tumor bearing mice enhances the immune response and modulates the release of cytokines in the tumor tissue as several interleukin signaling pathways were upregulated:
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Zhang, p. 11.
While Zhang does not teach that the method for enhancing the immune response involves obtaining a sample from a subject; isolating immune cells from the sample; culturing the immune cells with the pharmaceutical composition according to claim 1; expanding the immune cells and reintroducing the cells into the subject; and enhancing the immune response, one of ordinary skill in the art would have a reasonable expectation of success to isolate immune cells from a subject, culture them with the pharmaceutical composition of claim 1, expand the immune cells, and reintroduce the cels to the subject to enhance the immune response because it is commonly known in the art to isolate immune cells, treat them with immunostimulatory agents such as interleukins, and reintroduce them into the subject to enhance the immune response.
For example, Wan Zhang teaches adoptive immunotherapy, which involves taking a patient's own immune cells, growing them in a laboratory, treating with cytokines and an anti-PD-1 antibody, and then reintroducing them into the patient's body to enhance their ability to target and destroy cancer cells, with dendritic stimulated cytokine induced killer cells (DC-CIK cells):
We generated CIK cells by culturing isolated PBMCs with recombinant IL-2, IFN-γ, and anti-CD3. The CIK cells expanded by several hundred-fold and the proportion of effector cells, including CD3+CD56+ cells and CD8+ cells, increased during the culture period (Fig. 1A-C). After 7 days of culture, the subset of CD3+CD56+CIK cells was 9.7%, and it increased to 30.8% and 53.5% after 14 and 21 days of culture, respectively. Morphologically, the expanded CIK cells formed cell colonies. During the cultures, the cell colonies became larger and more numerous (Fig. 1D). We detected PD-1 expression on the DC-CIK cells from all donors; on average 11%, ranging from 4% to 21%, of DC-CIK cells expressed PD-1 (Fig. 1E). We found that anti-PD-1 (20 μg/mL) treatment increased DC-CIK cell proliferation over that observed in the PBS-treated control group (Fig. 1F).
Wan Zhang, p. 2580-2581.
Our study demonstrated the efficacy of an immunotherapy that enhances the anti-tumor activity of DC-CIK cells using only a small quantity of PD-1 inhibitor, thereby avoiding the high cost and severe adverse reactions typically associated with pembrolizumab. We identified a prospective modality for the treatment of hepatocellular carcinoma. Our results encourage further study into the efficacy of patient-derived DC-CIK cells combined with anti-PD-1 antibody for treatment of hepatocellular carcinoma, especially as the expression of PD-1 on DC-CIK cells differs among individuals. Although it was beyond the scope of our study to investigate the specific pathways related to the anti-tumor activity of DC-CIK cells, it is critical to identify these pathways in future studies, in order to determine the biomarkers for tumor patients who are susceptible to the therapy. In the future, we will conduct clinical trials of DC-CIK cells combined with a PD-1 inhibitor or with other treatment methods, like RFA and TACE, as immunotherapy is most effective when combined with traditional therapeutic approaches.
Wan Zhang, col. 2, p. 2586.
As such, it is well within the level of ordinary skill to isolate immune cells from a subject, treat them with a known immunostimulatory compound such as FNC as taught by Zhang, expand the cells, reintroduce them into the subject, and thereby enhance the immune response of the patient.
Therefore, claim 11 was prima facie obvious at the time of filing.
Claim 12 is directed towards the method according to claim 11, wherein the immune cell is selected from the group consisting of an antigen-presenting cell, a T cell, a B cell and a natural killer cell.
One of ordinary skill in the art would have a reasonable expectation of success to use an antigen-presenting cell, a T cell, a B cell or a natural killer cell because Wan Zhang teaches cytokine killer cells (CIKs), which are a mixed population of natural killer cells and T cells.
Therefore, claim 12 was prima facie obvious at the time of filing.
Claim 15 is directed towards the method according to claim 11, wherein the PD-1 antibody is selected from the group consisting of pembrolizumab, nivolumab, sintilimab, toripalimab, camrelizumab, tislelizumab, cemiplimab and a combination thereof.
One of ordinary skill in the art would have a reasonable expectation of success to use a second immunoregulatory substance in the pharmaceutical composition for cell treatment, in particular pembrolizumab, because Wan Zhang teaches to use immunostimulatory compounds such as cytokines in combination with pembrolizumab during the treatment of cells for adoptive immunotherapy, as shown in the rejection of claim 11 above.
Therefore, claim 15 was prima facie obvious at the time of filing.
The rejection of claim(s) 10-12 and 15-16 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Plos ONE, Vol. 12, no. 3, e0174112, published March 23, 2017, p. 1-17), and Wan Zhang et al. (J Cancer, 2019 Jun 2;10(11):2578–2587, as applied to claims 11-12 and 15 above, and further in view of Castelli et al. (Cells, 2021, 10(9), 2227, p. 1-10) is maintained.
The rejection of claims 11-12 and 15 as obvious over Zhang in view of Wan Zhang is incorporated herein by reference.
Claim 16 is directed towards the method according to claim 14, wherein the PD-L1 antibody is selected from the group consisting of avelumab, atezolizumab, durvalumab and a combination thereof.
Wan Zhang teaches blockade of the PD-1/PD-L1 axis in DC-CIK cells prior to infusion is a promising therapeutic strategy against HCC. While Wan Zhang does not teach PD-L1 antibodies for the blockade of the PD-1/PD-L1 axis, one of ordinary skill in the art would have a reasonable expectation of success to select a PD-L1 antibody such as avelumab, atezolizumab, or durvalumab because the antibodies are commonly known in the art for the blockade of the PD-1/PD-L1 axis.
For example, Castelli teaches that atezolizumab, avelumab, and durvalumab are all approved treatments for targeting the PD-1/PD-L1 pathway:
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Castelli, p. 2, Table 1.
Therefore, claim 16 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
