Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on Jan. 14, 2026 and July 8, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Priority
This Application is a 371 of PCT/US2021/065059, filed Dec. 23, 2021 and claims priority benefit of U.S. Provisional Application No. 63129911, filed Dec. 23, 2020.
Claim Status – Response to Restriction/ Election Requirement
Claims 1-20 are pending.
Applicant’s election of Group I, claims 1-14, and (i) Vinblastine-Nb’-oxide, (ii) ipilimumab, and (iii) melanoma, claims 1-4, 7, 13 and 14, in the reply filed on Jan. 14, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The Applicant argued that there is not search burden because a search concerning the patentability of Group I would uncover art of interest in Group II, and similarly that a search for the elected species would uncover art interest to the other species (Remarks, p. 2). These arguments are not specific and distinct because the Applicant did not explain why art of interest would be uncovered by the search for the elected invention. The Applicant did not specifically and distinctly argue why there is unity of invention: the Applicant did not argue that there is a special technical feature and/or that the inventions are obvious variants.
Claims 1-4, 7, 13 and 14 are active and subject to examination. Claims 5-6, 8-12 and 15-20 are withdrawn.
Claim Rejections – 35 USC § 112(b)
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 14 is 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.
Claim 14 is directed towards the method of claim 1, wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status. The language “HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status” renders the metes and bounds of the claim unclear for at least the following reasons:
The term “differentially present” is unclear. The term “differentially present” fails to inform a person of ordinary skill in the art with reasonable certainty as to the scope of the claimed method. The claim does not specify: (a) the direction of differential expression (i.e. whether HIF1a expression is upregulated or downregulated; (b) the magnitude of the difference required to constitute “differential” presence; or (c) the method or threshold measure by which differential presence is measure or determined. The Specification fails to clarify this ambiguity and does not provide any guidance as to the term “differentially present.” Without such parameters, one of ordinary skill in the art cannot determine with reasonable certainty where the boundary of the claimed method lies.
The term “another phenotypic status” is indefinite. The claim further fails to inform a person of ordinary skill in the art what constitutes “another phenotypic status.” The specification and claims do not define what phenotypic statuses are contemplated, nor do the identify a reference phenotypic status for a patient such that “another” status can be understood relative to it. The term “phenotypic status” is broad enough to encompass any observable biological or clinical characteristic, and the claim provides no limiting principle to resolve the ambiguity. A person of ordinary skill in the art would not know with reasonable certainty what types of subjects qualify as having “another phenotypic status.”
The interaction between the two indefinite terms compounds the indefiniteness of the claims because both “differentially present” and “another phenotypic status” are independently indefinite. It is impossible to determine he outer bounds of a comparison (differential expression) when the identity of the comparator (a subject of another phenotypic status) is itself undefined.
Appropriate correction is required.
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.”
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.
Claim(s) 1-4 and 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Orecchioni et al. (American Association for Cancer Research, Vol. 79, Issue 13 Supplement, 1 July 2019, Abstract 3948) in view of Shah et al. (Journal of Controlled Release, Vol. 253, 10 May 2017, p. 37-45) (of record, IDS July 8, 2025, NPL24).
Claim 1 recites:
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Orecchioni teaches a method of treating a patient having cancer, the method comprising administering to the patient in need thereof a therapeutically effective amount of a vinca alkaloid (vinblastine and vinorelbine) and an anti-PD-L1 immune checkpoint inhibitor:
Checkpoint inhibitors (CIs) have shown an unprecedented clinical activity in a large variety of cancer types, but only in a fraction of patients. To increase the number of responders, preclinical models are studied to define effective combinatorial regimens and the best window of therapeutic opportunities. We recently described a synergy between anti-PD-1 and -PD-L1 CIs and several types and dosages of chemotherapy in immunocompetent models of triple negative breast cancer (TNBC), likely due to unique effects of chemotherapeutics over circulating and tumor-infiltrating, suppressive, antigen-presenting and effector immune cell populations (Orecchioni et al, Br J Cancer 2018). To find a high-order drug combination, we have further studied by multiparametric flow cytometry and single-cell transcriptomic a panel of different chemotherapy drugs (including microtubular poisons, alkylating agents, topoisomerase inhibitors and antimetabolites) used in vivo at different dosages and schedule. Our aim was to define a combination, dose and schedule able to promote a) dendritic cell maturation, b) release and c) uptake of cancer-associated antigens from targeted neoplastic cells, d) cross-priming between antigen-presenting cells (APCs) and T cells, e) NK cell activation, and f) inhibition of suppressor immune cell populations. Vinca alkaloids vinblastine and vinorelbine (V), at low-medium dosages, were the most effective in a), b), c) and d). After V administration, Tregs were reduced, and circulating and tumor-infiltrating APCs showed a “maturation to activation” program with increased expression of several antigens including CD40, CD80, and CD86. The alkylating agent cyclophosphamide (CTX) targeted Tregs, mobilized APC progenitors, activated and increased the number of circulating and intratumoral NK cells. These effects were significantly increased when CTX was administered in an intermittent fashion (every 6 days) at low-medium doses. As the APC-NK cell axis has been recently found to be pivotal in CI-mediated, anti-tumor cell immunity, our data suggested a preclinical trial in immunocompetent orthotopic models of metastatic (post-mastectomy) BALB mice injected with 4T1 or EMT-6 TNBC cells. Among a large panel of different combinations and dosages, the sequential administration of V, intermittent CTX and anti-PD-L1 was the only able to completely abrogate TNBC local and metastatic growth, and this effect was not observed in T and NK cell-depleted mice. Taken together with recent data from randomized, combinatorial studies in TNBC patients (Schmid et al, NEJM 2018), our findings suggest that CIs might be included in future combinatorial regimens aimed at improving the percentage of patients receiving a clinical benefit and prolonging the duration of this benefit.
Orrechioni, Abstract (emphasis added).
While Orrechioni does not teach that the vinca alkaloid is a vinca alkaloid n-oxide, one of ordinary skill in the art would have a reasonable expectation of success to substitute a vinca alkaloid n-oxide for a traditional vinca alkaloid because it is commonly known in the art that vinca alkaloid n-oxides are prodrugs of vinca alkaloids with improved exposure and efficacy.
For example, Shah teaches liposome encapsulated CPD100, a prodrug of vinblastine that is vinblastine-Nb’-oxide, for the treatment of cancer with improved properties as compared to the parent drug:
Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi). We evaluated the antiproliferative effect of CPD100 and the two formulations against A549 non-small lung cancer cell. A549 cell line showed to be sensitive to CPD100 and the two formulations displayed a higher hypoxic: air cytotoxicity ratio compared to the pro-drug. CPD100 elimination from the circulation after injection in mouse was characterized by a very short circulation time (~ 0.44 h), lower area under the curve (AUC) (33 μg h/mL) and high clearance (916 mL/h/kg) and lower volume of distribution (17.4 mL/kg).Total drug elimination from the circulation after the administration of liposomal formulation was characterized by prolonged circulation time (5.5 h) along with increase in the AUC (56 μg h/mL) for CPD100 Li and (9.5 h) with AUC (170 μg h/mL) for CPD100PEGLi. This was observed along with increase in volume of distribution and decrease in clearance for the liposomes. The systemic exposure of the free drug was much lower than that achieved with the liposomes. When evaluated for the efficacy in A549 xenograft model in mice, both the liposomes demonstrated excellent tumor suppression and reduction for 3 months. The blood chemistry panel and the comprehensive blood analysis showed no increase or decrease in the markers and blood count. In summary, the pharmacokinetic analysis along with the efficacy data emphasis on how the delivery vehicle modifies and enhances the accumulation of the drug and at the same time the increased systemic exposure is not related to toxicity.
Shah, Abstract;
Hypoxia is a hallmark of many cancers including NSCLC. However, to date no therapies or formulations exist to target this inherent property of the cancerous tissues. To exploit the hypoxic property of the tumor cells, Cascade Prodrug Inc. has developed a prodrug of vinblastine labelled vinblastine-N-oxide (CPD100) [39], where the prodrug undergoes reduction in the hypoxic tumor environment to the active moiety. This strategy allows for high concentrations of the vinblastine to be present in the hypoxic regions of the tumor tissue.
Shah, p. 37, col. 2.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 is directed towards the method of claim 1, wherein the vinca alkaloid N-oxide, or a pharmaceutically acceptable salt or solvate thereof, is administered to the patient encapsulated in a liposome.
While Orrechioni does not teach a vinca alkaloid N-oxide encapsulated in a liposome, one of ordinary skill in the art would have a reasonable expectation of success to employ a vinca alkaloid N-oxide encapsulated in a liposome in a method for treating cancer because this drug delivery method is commonly known in the art. For example, see the teachings of Shah in the rejection of claim 1, incorporated herein by reference.
Therefore, claim 2 was prima facie obvious at the time of filing.
Claim 3 is directed towards the method of claim 2, wherein the liposome comprises sphingomyelin and cholesterol. Claim 4 is directed towards the method of claim 2, wherein the liposome comprises sphingomyelin, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000].
While Orrechioni does not teach a vinca alkaloid N-oxide encapsulated in a liposome, wherein the liposome comprises sphingomyelin, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000], one of ordinary skill in the art would have a reasonable expectation of success to employ such a liposome in a cancer treatment because this his drug delivery method is commonly known in the art.
For example, Shah teaches a liposome comprising a vinca alkaloid N-oxide, sphingomyelin, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000]:
2.1. Materials
CPD100 was obtained from Cascade Prodrug Inc. (OR., USA). Egg- Sphingomyelin (SPM) and 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethyleneglycol) (DSPE-PEG2000) was obtained from NOF America Corporation (N.Y., USA). Cholesterol (Chol) and A23187 were obtained from Alfa Aesar (MA., USA). Adenocarcinomic human alveolar basal epithelial cells (A549) [1], [9] cells were purchased from American Type Culture Collection (Manassas, VA). Roswell Park Memorial Institute (RPMI) medium and Dulbecco's phosphate buffered saline (DPBS) were acquired form Mediatech (Manassas, VA). Cell culture reagents and disposables were purchased from VWR (Radnor, PA), Thermo Scientific (Fairlawn, NJ). Cell Titer-Blue® Cell Viability Assay kit was obtained from Promega Inc. (Madison, WI).
2.2. Liposomal preparation
Sphingomyelin cholesterol (55:45) and sphingomyelin cholesterol DSPE-PEG (55:40:5) (PEGylated) liposomes are prepared by thin-film hydration method. The final lipid concentration is fixed at 50 mg/mL. Lipids are solubilized in a chloroform: methanol (70:30) solution and evaporated under vacuum conditions to yield a homogeneous thin lipid film. The lipid solution is hydrated using 300 mM MgS04 solution (pH 4). Multilamellar vesicles (MLV) are obtained by hydrating the lipid mixture in 300 mM MgSO4 at 65 °C. The resulting colloidal solution of MLV's is reduced to large unilamellar vesicle (LUV) by extruding 20 times by forcing the lipid emulsion (MLV) through a mini-extruder (Avanti Polar Lipids, Alabaster, AL) with polycarbonate filters of 0.1 μm pore size at 60–65 °C. The extruded liposomes are passed through a Sephadex G-50 column (GE Healthcare Life Sciences) equilibrated with the external buffer SHE (300 mM sucrose, 3 mM EDTA, 20 mM HEPES) at pH 7.5 to establish the primary ion gradient. The liposomes are stored at 4 °C until drug loading is initiated. CPD100 is loaded into the liposomes using the A23187-ionophore loading method which establishes the secondary ion gradient [10]. Briefly, CPD100 is dissolved at 10 mg/mL in 300 mM sucrose buffer. Both the drug and the liposome suspension are pre-heated at 60 °C before being mixed together. After 15 min of incubation, EDTA (30 mM) and A23187 (2 μg/mg of lipid) are added to the drug-liposome mixture. The liposome along with the drug and ionophore are allowed to mix in a water bath at 60 °C for 60 min. The drug-loaded liposome mixture is cooled in ice for 15 min. Unencapsulated drug, EDTA and ionophore are removed by purification using Sephadex G-50 columns.
Shah, p. 38, col. 1-2.
Therefore, clams 3-4 were prima facie obvious at the time of filing.
Claim 13 is directed towards the method of claim 1, wherein the cancer is selected from a long list of tumors including breast cancer.
As shown in the rejection of claim 1, Orrechioni teaches breast cancer.
Therefore, claim 13 was prima facie obvious at the time of filing.
Claim 14 is directed towards the method of claim 1, wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status.
While Orrechioni does not teach that hypoxia inducible factor 1-alpha (HIF-1a) expression is differentially present in a sample taken from the patient, one of ordinary skill in the art would have a reasonable expectation of success to apply the method to a patient wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status because it is commonly known in the art that vinblastine-N-oxide is hypoxia activated.
For example, see the teachings of Shah in the rejection of claim 1.
Therefore, claim 14 was prima facie obvious at the time of filing.
Claim(s) 1-4 and 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bloom et al. (Oncoimmunology, Vol. 8, no. 10, e1625687, 2019 Jul 16, p. 1-15) in view of Shah et al. (Journal of Controlled Release, Vol. 253, 10 May 2017, p. 37-45) (of record, IDS July 8, 2025, NPL24).
Claim 1 recites:
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Bloom teaches a method of treating cancer in patient, comprising administering to the patient a combination of vinblastine and cisplatin (INT230-6) combined with either anti-PD-1 or anti-CTLA-4. Bloom demonstrates significant synergistic effects with the combination of INT230-6 and anti-CTLA-4:
In this study, INT230-6, a formulation that consists of fixed concentrations of widely used agents, cisplatin and vinblastine, and the cell penetration enhancer IT-006, is utilized as a model therapeutic (Bender et al. 2018 submitted). Bender et al. demonstrated that intratumorally delivered INT230-6 diffused throughout the tumor tissue and was taken up quickly by cells within the tumor, resulting in regression with complete response of Colon26 (C26) tumors and limited toxicity. We show here that INT230-6 turns tumors into in situ vaccines by relying on CD4+ and CD8+ T cells for its efficacy in the C26 colon and orthotopic 4T1 breast cancers, inducing long-term immunological memory, reducing burden of distant micrometastases and synergizing with checkpoint inhibitors to induce systemic immunity and regression of distant tumors.
Bloom, p. 2, col. 2;
In Figure 5e studying anti-CTLA-4, contralateral tumors were 30% larger than in Figure 5a as C26 cells were inoculated seven days before treatment onset. Mice that received vehicle treatment had a shorter survival than in Figure 5b due to the larger tumor burden at the contralateral site. Again, INT230-6 treatment alone resulted in a significant response at the primary tumor site. Anti-CTLA-4 monotherapy significantly reduced tumor sizes in the primary site (Figure 5g), although none of the mice had a complete response. Anti-CTLA-4 also had a significant impact on contralateral tumors compared to vehicle and untreated contralateral tumors alone by inducing the complete response of contralateral tumors in 3 out of 10 mice (Figure 5h). Anti-CTLA-4 synergized with INT230-6, resulting in significantly improved survival over INT230-6 or anti-CTLA-4 monotherapy (Figure 5f). The combination significantly increased the number of complete responses on both primary (9/10) and contralateral (6/10) tumors compared with either treatment alone. This suggests that CTLA-4 may be a more critical checkpoint in T cell responses to these distant untreated tumors, at least under these conditions, and rejuvenation of intra-tumor antigen-specific CD8+ T cells (as expected to be mediated by anti-PD-1) may be less critical than enhanced activation of T cells and promotion of T cell entry into the tumor microenvironment by anti-CTLA-4. Thus, although both checkpoint inhibitors showed some activity in combination with INT230-6, the effect was more pronounced with anti-CTLA-4, especially on the contralateral tumors.
Bloom, p. 5, 7 (emphasis added);
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Bloom, Fig. 5, p. 8.
As mentioned above, Bloom utilized a proprietary vehicle, the cell penetration enhancer IT-006, to deliver vinblastine to the tumor (the pharmaceutical composition INT230-6). While Bloom does not teach vinblastine-N-oxide, one of ordinary skill in the art would have a reasonable expectation of success to substitute liposome encapsulated vinblastine N-oxide for INT230-6 because it is commonly known in the art that liposome encapsulated vinblastine N-oxide can be used to selectively and efficiently deliver vinblastine to tumors.
For example, Shah teaches liposome encapsulated CPD100, a prodrug of vinblastine that is vinblastine-Nb’-oxide, for the treatment of cancer with improved properties as compared to the parent drug:
Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi). We evaluated the antiproliferative effect of CPD100 and the two formulations against A549 non-small lung cancer cell. A549 cell line showed to be sensitive to CPD100 and the two formulations displayed a higher hypoxic: air cytotoxicity ratio compared to the pro-drug. CPD100 elimination from the circulation after injection in mouse was characterized by a very short circulation time (~ 0.44 h), lower area under the curve (AUC) (33 μg h/mL) and high clearance (916 mL/h/kg) and lower volume of distribution (17.4 mL/kg). Total drug elimination from the circulation after the administration of liposomal formulation was characterized by prolonged circulation time (5.5 h) along with increase in the AUC (56 μg h/mL) for CPD100 Li and (9.5 h) with AUC (170 μg h/mL) for CPD100PEGLi. This was observed along with increase in volume of distribution and decrease in clearance for the liposomes. The systemic exposure of the free drug was much lower than that achieved with the liposomes. When evaluated for the efficacy in A549 xenograft model in mice, both the liposomes demonstrated excellent tumor suppression and reduction for 3 months. The blood chemistry panel and the comprehensive blood analysis showed no increase or decrease in the markers and blood count. In summary, the pharmacokinetic analysis along with the efficacy data emphasis on how the delivery vehicle modifies and enhances the accumulation of the drug and at the same time the increased systemic exposure is not related to toxicity.
Shah, Abstract (emphasis added);
Hypoxia is a hallmark of many cancers including NSCLC. However, to date no therapies or formulations exist to target this inherent property of the cancerous tissues. To exploit the hypoxic property of the tumor cells, Cascade Prodrug Inc. has developed a prodrug of vinblastine labelled vinblastine-N-oxide (CPD100) [39], where the prodrug undergoes reduction in the hypoxic tumor environment to the active moiety. This strategy allows for high concentrations of the vinblastine to be present in the hypoxic regions of the tumor tissue.
Shah, p. 37, col. 2.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 is directed towards the method of claim 1, wherein the vinca alkaloid N-oxide, or a pharmaceutically acceptable salt or solvate thereof, is administered to the patient encapsulated in a liposome.
While Bloom does not teach a vinca alkaloid N-oxide encapsulated in a liposome, one of ordinary skill in the art would have a reasonable expectation of success to employ a vinca alkaloid N-oxide encapsulated in a liposome in a method for treating cancer because this drug delivery method is commonly known in the art. For example, see the teachings of Shah in the rejection of claim 1, incorporated herein by reference.
Therefore, claim 2 was prima facie obvious at the time of filing.
Claim 3 is directed towards the method of claim 2, wherein the liposome comprises sphingomyelin and cholesterol. Claim 4 is directed towards the method of claim 2, wherein the liposome comprises sphingomyelin, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000].
While Bloom does not teach a vinca alkaloid N-oxide encapsulated in a liposome, wherein the liposome comprises sphingomyelin, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000], one of ordinary skill in the art would have a reasonable expectation of success to employ such a liposome in a cancer treatment because this his drug delivery method is commonly known in the art.
For example, Shah teaches a liposome comprising a vinca alkaloid N-oxide, sphingomyelin, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000]:
2.1. Materials
CPD100 was obtained from Cascade Prodrug Inc. (OR., USA). Egg- Sphingomyelin (SPM) and 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethyleneglycol) (DSPE-PEG2000) was obtained from NOF America Corporation (N.Y., USA). Cholesterol (Chol) and A23187 were obtained from Alfa Aesar (MA., USA). Adenocarcinomic human alveolar basal epithelial cells (A549) [1], [9] cells were purchased from American Type Culture Collection (Manassas, VA). Roswell Park Memorial Institute (RPMI) medium and Dulbecco's phosphate buffered saline (DPBS) were acquired form Mediatech (Manassas, VA). Cell culture reagents and disposables were purchased from VWR (Radnor, PA), Thermo Scientific (Fairlawn, NJ). Cell Titer-Blue® Cell Viability Assay kit was obtained from Promega Inc. (Madison, WI).
2.2. Liposomal preparation
Sphingomyelin cholesterol (55:45) and sphingomyelin cholesterol DSPE-PEG (55:40:5) (PEGylated) liposomes are prepared by thin-film hydration method. The final lipid concentration is fixed at 50 mg/mL. Lipids are solubilized in a chloroform: methanol (70:30) solution and evaporated under vacuum conditions to yield a homogeneous thin lipid film. The lipid solution is hydrated using 300 mM MgS04 solution (pH 4). Multilamellar vesicles (MLV) are obtained by hydrating the lipid mixture in 300 mM MgSO4 at 65 °C. The resulting colloidal solution of MLV's is reduced to large unilamellar vesicle (LUV) by extruding 20 times by forcing the lipid emulsion (MLV) through a mini-extruder (Avanti Polar Lipids, Alabaster, AL) with polycarbonate filters of 0.1 μm pore size at 60–65 °C. The extruded liposomes are passed through a Sephadex G-50 column (GE Healthcare Life Sciences) equilibrated with the external buffer SHE (300 mM sucrose, 3 mM EDTA, 20 mM HEPES) at pH 7.5 to establish the primary ion gradient. The liposomes are stored at 4 °C until drug loading is initiated. CPD100 is loaded into the liposomes using the A23187-ionophore loading method which establishes the secondary ion gradient [10]. Briefly, CPD100 is dissolved at 10 mg/mL in 300 mM sucrose buffer. Both the drug and the liposome suspension are pre-heated at 60 °C before being mixed together. After 15 min of incubation, EDTA (30 mM) and A23187 (2 μg/mg of lipid) are added to the drug-liposome mixture. The liposome along with the drug and ionophore are allowed to mix in a water bath at 60 °C for 60 min. The drug-loaded liposome mixture is cooled in ice for 15 min. Unencapsulated drug, EDTA and ionophore are removed by purification using Sephadex G-50 columns.
Shah, p. 38, col. 1-2.
Therefore, clams 3-4 were prima facie obvious at the time of filing.
Claim 13 is directed towards the method of claim 1, wherein the cancer is selected from a long list of tumors including colorectal cancer.
One of ordinary skill in the art would have a reasonable expectation of success to apply the combination therapy to colorectal cancer because Bloom demonstrates the efficacy of the drug combination in a mouse model of colorectal cancer using transplanted Colon26 (C26) tumors (Bloom, p. 2, col. 1).
Therefore, claim 13 was prima facie obvious at the time of filing.
Claim 14 is directed towards the method of claim 1, wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status.
While Bloom does not teach that hypoxia inducible factor 1-alpha (HIF-1a) expression is differentially present in a sample taken from the patient, one of ordinary skill in the art would have a reasonable expectation of success to apply the method to a patient wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status because it is commonly known in the art that vinblastine-N-oxide is hypoxia activated.
For example, see the teachings of Shah in the rejection of claim 1.
Therefore, claim 14 was prima facie obvious at the time of filing.
Claim(s) 1-4, 7 and 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bloom et al. (Oncoimmunology, Vol. 8, no. 10, e1625687, 2019 Jul 16, p. 1-15) in view of Shah et al. (Journal of Controlled Release, Vol. 253, 10 May 2017, p. 37-45) (of record, IDS July 8, 2025, NPL24), as applied to claims 1-4 and 13-14 above, and further in view of Intensity Therapeutics (“Intensity Therapeutics Doses First Patient with Combination of INT230-6 and Bristol Myers Squibb’s Yervoy® in a Phase 2 Study”, BusinessWire, Sep. 17, 2020, p. 1-8).
The rejection of claims 1-4 and 13-14 above as obvious over Bloom in view of Shah is incorporated herein by reference.
Claim 7 is directed towards the method of claim 1, wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.
As shown in the rejection of claim 1, Bloom teaches to administer the vinca alkaloid vinblastine in combination with anti-CTLA-4 or anti-PD-1 antibodies. Bloom demonstrates a synergistic effect with vinblastine in combination with anti-CTLA-4 or anti-PD-1 antibodies in a mouse model.
While Bloom does not teach a specific anti-CTLA-4 antibody for use in human subjects, one of ordinary skill in the art would have a reasonable expectation of success to substitute this antibody with ipilimumab for human patients because this is a commonly known commercially available anti-CTLA-4 antibody with demonstrated safety in combination with vinblastine.
For example, Intensity Therapeutics teaches that they are launching a phase 2 study of the combination of INT230-6 in combination with ipilimumab, after preclinical and clinical data demonstrated favorable safety and efficacy for INT230-6 in combination with immunotherapies:
Intensity Therapeutics, Inc., a clinical-stage biotechnology company developing proprietary technology and products to kill tumors and increase immune system recognition of the cancer, today announced that the first patient has been dosed with a combination of INT230-6, the Company’s lead investigational product, and Yervoy® (ipilimumab), Bristol Myers Squibb’s (BMS) Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) immune checkpoint inhibitor therapy in Phase 2. The combination is being studied in a series of phase 2 expansion cohorts within IT-01, Intensity’s ongoing international clinical study (NCT03058289), which evaluates the safety and efficacy of the combination in patients with three different types of cancer (breast cancer, liver cancer, and sarcoma).
“Bringing INT230-6 into phase 2 human testing in combination with Yervoy is an important achievement for Intensity Therapeutics,” commented Lewis H. Bender, President and Chief Executive Officer of Intensity Therapeutics. “Our preclinical and clinical data have resulted in favorable safety for INT230-6 as a single agent or in combination with immunotherapies. The phase 1 escalation portion of our INT230-6 development program is complete. We are excited about starting the phase 2 portion of our trial using INT230-6 at proper doses early in the treatment process especially in combination with Yervoy.”…
INT230-6, Intensity’s lead proprietary product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRxSM technology platform. The drug is comprised of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule that helps disperse the drugs throughout tumors for diffusion into cancer cells. In preclinical studies, INT230-6 eradicated tumors by a combination of direct tumor killing, release of tumor antigens and recruitment of immune cells to the tumor. Results generated by both the Company and the National Cancer Institute (NCI) showed treatment with INT230-6 in in vivo models of severe cancer resulted in substantial improvement in overall survival compared to standard therapies. Further, INT230-6 provided complete responses in animals with long-term protection from multiple re-challenges of the initial cancer and resistance to other cancers. The Company’s research published in the International Journal of Molecular Sciences earlier this year and published jointly with the NCI as part of Intensity’s collaborative research, published in July 2019 in the Journal OncoImmunology, also showed strong synergy when INT230-6 was combined with anti-PD-1 and anti-CTLA-4 antibodies. INT230-6 is being evaluated in a Phase 1/2 clinical study (NCT03058289) in patients with various advanced solid tumors. There have been no dose limiting adverse events observed in patients to date, even when dosing into deep tumors in the lung and liver. Several patients demonstrated tumor shrinkage, symptomatic improvement, and evidence of cancer cell death and immune cell activation on tumor biopsy. In the combination cohort with pembrolizumab the Company reported the safety of the combination was comparable to INT230-6 monotherapy.
Intensity Therapeutics, p. 1-2 (emphasis added).
Therefore, claim 7 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.
Nonstatutory 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).
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Claims 1-4, 7 and 13-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 8,883,775 B2 (herein “the ‘775 patent”) in view of Intensity Therapeutics (“Intensity Therapeutics Doses First Patient with Combination of INT230-6 and Bristol Myers Squibb’s Yervoy® in a Phase 2 Study”, BusinessWire, Sep. 17, 2020, p. 1-8) and Shah et al. (Journal of Controlled Release, Vol. 253, 10 May 2017, p. 37-45) (of record, IDS July 8, 2025, NPL24).
Although the claims at issue are not identical, they are not patentably distinct because the instant claims are directed towards a method of treating a patient having cancer comprising administering to a patient in need thereof a combination of a vinca alkaloid n-oxide and an immune checkpoint inhibitor (instant and the ‘775 patent claims a method of treating cancer in an animal comprising administering to the animal in need thereof a therapeutically effective amount of a vinca alkaloid n-oxide as in the instant claims . The ‘775 patent also claims a method of treating cancer, further comprising administering one or more other active agents (claim 18). While the ‘775 patent does not claim immune checkpoint inhibitors as the additional active agent, one of ordinary skill in the art would have a reasonable expectation of success to combine the vinca alkaloid n-oxide with an immune checkpoint inhibitor because it is commonly known in the art to administer vinca alkaloids in combination with immune checkpoint inhibitors. For example, see the teachings of Intensity Therapeutics:
Intensity Therapeutics, Inc., a clinical-stage biotechnology company developing proprietary technology and products to kill tumors and increase immune system recognition of the cancer, today announced that the first patient has been dosed with a combination of INT230-6, the Company’s lead investigational product, and Yervoy® (ipilimumab), Bristol Myers Squibb’s (BMS) Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) immune checkpoint inhibitor therapy in Phase 2. The combination is being studied in a series of phase 2 expansion cohorts within IT-01, Intensity’s ongoing international clinical study (NCT03058289), which evaluates the safety and efficacy of the combination in patients with three different types of cancer (breast cancer, liver cancer, and sarcoma).
“Bringing INT230-6 into phase 2 human testing in combination with Yervoy is an important achievement for Intensity Therapeutics,” commented Lewis H. Bender, President and Chief Executive Officer of Intensity Therapeutics. “Our preclinical and clinical data have resulted in favorable safety for INT230-6 as a single agent or in combination with immunotherapies. The phase 1 escalation portion of our INT230-6 development program is complete. We are excited about starting the phase 2 portion of our trial using INT230-6 at proper doses early in the treatment process especially in combination with Yervoy.”…
INT230-6, Intensity’s lead proprietary product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRxSM technology platform. The drug is comprised of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule that helps disperse the drugs throughout tumors for diffusion into cancer cells. In preclinical studies, INT230-6 eradicated tumors by a combination of direct tumor killing, release of tumor antigens and recruitment of immune cells to the tumor. Results generated by both the Company and the National Cancer Institute (NCI) showed treatment with INT230-6 in in vivo models of severe cancer resulted in substantial improvement in overall survival compared to standard therapies. Further, INT230-6 provided complete responses in animals with long-term protection from multiple re-challenges of the initial cancer and resistance to other cancers. The Company’s research published in the International Journal of Molecular Sciences earlier this year and published jointly with the NCI as part of Intensity’s collaborative research, published in July 2019 in the Journal OncoImmunology, also showed strong synergy when INT230-6 was combined with anti-PD-1 and anti-CTLA-4 antibodies. INT230-6 is being evaluated in a Phase 1/2 clinical study (NCT03058289) in patients with various advanced solid tumors. There have been no dose limiting adverse events observed in patients to date, even when dosing into deep tumors in the lung and liver. Several patients demonstrated tumor shrinkage, symptomatic improvement, and evidence of cancer cell death and immune cell activation on tumor biopsy. In the combination cohort with pembrolizumab the Company reported the safety of the combination was comparable to INT230-6 monotherapy.
Intensity Therapeutics, p. 1-2 (emphasis added).
Therefore, claim 1 is rejected on the grounds of obviousness type nonstatutory double patenting.
The dependent claims 2-4 further limit the method to a specific liposomal formulation. While the ‘775 patent does not claim the liposomal formulation, one of ordinary skill in the art would have a reasonable expectation of success to use this specific formulation because it is commonly known in the art. For example, see the teachings of Shah:
Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi). We evaluated the antiproliferative effect of CPD100 and the two formulations against A549 non-small lung cancer cell. A549 cell line showed to be sensitive to CPD100 and the two formulations displayed a higher hypoxic: air cytotoxicity ratio compared to the pro-drug. CPD100 elimination from the circulation after injection in mouse was characterized by a very short circulation time (~ 0.44 h), lower area under the curve (AUC) (33 μg h/mL) and high clearance (916 mL/h/kg) and lower volume of distribution (17.4 mL/kg).Total drug elimination from the circulation after the administration of liposomal formulation was characterized by prolonged circulation time (5.5 h) along with increase in the AUC (56 μg h/mL) for CPD100 Li and (9.5 h) with AUC (170 μg h/mL) for CPD100PEGLi. This was observed along with increase in volume of distribution and decrease in clearance for the liposomes. The systemic exposure of the free drug was much lower than that achieved with the liposomes. When evaluated for the efficacy in A549 xenograft model in mice, both the liposomes demonstrated excellent tumor suppression and reduction for 3 months. The blood chemistry panel and the comprehensive blood analysis showed no increase or decrease in the markers and blood count. In summary, the pharmacokinetic analysis along with the efficacy data emphasis on how the delivery vehicle modifies and enhances the accumulation of the drug and at the same time the increased systemic exposure is not related to toxicity.
Shah, Abstract;
Hypoxia is a hallmark of many cancers including NSCLC. However, to date no therapies or formulations exist to target this inherent property of the cancerous tissues. To exploit the hypoxic property of the tumor cells, Cascade Prodrug Inc. has developed a prodrug of vinblastine labelled vinblastine-N-oxide (CPD100) [39], where the prodrug undergoes reduction in the hypoxic tumor environment to the active moiety. This strategy allows for high concentrations of the vinblastine to be present in the hypoxic regions of the tumor tissue.
Shah, p. 37, col. 2.
2.1. Materials
CPD100 was obtained from Cascade Prodrug Inc. (OR., USA). Egg- Sphingomyelin (SPM) and 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethyleneglycol) (DSPE-PEG2000) was obtained from NOF America Corporation (N.Y., USA). Cholesterol (Chol) and A23187 were obtained from Alfa Aesar (MA., USA). Adenocarcinomic human alveolar basal epithelial cells (A549) [1], [9] cells were purchased from American Type Culture Collection (Manassas, VA). Roswell Park Memorial Institute (RPMI) medium and Dulbecco's phosphate buffered saline (DPBS) were acquired form Mediatech (Manassas, VA). Cell culture reagents and disposables were purchased from VWR (Radnor, PA), Thermo Scientific (Fairlawn, NJ). Cell Titer-Blue® Cell Viability Assay kit was obtained from Promega Inc. (Madison, WI).
2.2. Liposomal preparation
Sphingomyelin cholesterol (55:45) and sphingomyelin cholesterol DSPE-PEG (55:40:5) (PEGylated) liposomes are prepared by thin-film hydration method. The final lipid concentration is fixed at 50 mg/mL. Lipids are solubilized in a chloroform: methanol (70:30) solution and evaporated under vacuum conditions to yield a homogeneous thin lipid film. The lipid solution is hydrated using 300 mM MgS04 solution (pH 4). Multilamellar vesicles (MLV) are obtained by hydrating the lipid mixture in 300 mM MgSO4 at 65 °C. The resulting colloidal solution of MLV's is reduced to large unilamellar vesicle (LUV) by extruding 20 times by forcing the lipid emulsion (MLV) through a mini-extruder (Avanti Polar Lipids, Alabaster, AL) with polycarbonate filters of 0.1 μm pore size at 60–65 °C. The extruded liposomes are passed through a Sephadex G-50 column (GE Healthcare Life Sciences) equilibrated with the external buffer SHE (300 mM sucrose, 3 mM EDTA, 20 mM HEPES) at pH 7.5 to establish the primary ion gradient. The liposomes are stored at 4 °C until drug loading is initiated. CPD100 is loaded into the liposomes using the A23187-ionophore loading method which establishes the secondary ion gradient [10]. Briefly, CPD100 is dissolved at 10 mg/mL in 300 mM sucrose buffer. Both the drug and the liposome suspension are pre-heated at 60 °C before being mixed together. After 15 min of incubation, EDTA (30 mM) and A23187 (2 μg/mg of lipid) are added to the drug-liposome mixture. The liposome along with the drug and ionophore are allowed to mix in a water bath at 60 °C for 60 min. The drug-loaded liposome mixture is cooled in ice for 15 min. Unencapsulated drug, EDTA and ionophore are removed by purification using Sephadex G-50 columns.
Shah, p. 38, col. 1-2.
Therefore, claims 2-4 are rejected on the grounds of obviousness type nonstatutory double patenting.
Dependent claim 7 limits the immune checkpoint inhibitor to ipilimumab or tremelimumab. As shown in the rejection of claim 1, intensity therapeutics teaches ipilimumab. Therefore, claim 7 is rejected on the grounds of obviousness type double patenting.
Dependent claim 13 limits the cancer to a long list of cancers, which are commensurate in scope with claim 1 of the ‘775 patent. Therefore, claim 13 is rejected on the grounds of obviousness type double patenting.
Dependent claim 14 is directed towards the method of claim 1, wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status.
While the ‘775 patent does not teach that hypoxia inducible factor 1-alpha (HIF-1a) expression is differentially present in a sample taken from the patient, one of ordinary skill in the art would have a reasonable expectation of success to apply the method to a patient wherein HIF-la expression is differentially present in a sample taken from the patient as compared with a biological sample taken from a subject of another phenotypic status because it is commonly known in the art that vinblastine-N-oxide is hypoxia activated.
For example, see the teachings of Shah in the rejection of claim 1.
Therefore, claim 14 is rejected on the grounds of obviousness type double patenting.
Given the above teachings, at the time of filing, the invention as a whole was obvious over the claims of the ‘775 patent in view of Intensity Therapeutics and Shah.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629