Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
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
Claims 1-4, 7, 13, and 21-28 are currently pending.
Applicant’s election of Group I, claims 1-14, drawn to a method of treating cancer comprising administering an effective amount of (a) a vinca alkaloid N-oxide and (b) an immune checkpoint inhibitor; 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. Newly added claim 21 reads on the elected invention. Newly added claims 22-28 are withdrawn.
Claim 22 is directed towards the method of claim 21, wherein the melanoma is uveal melanoma. The Applicant previously elected “melanoma as the single indication” (Remarks filed Jan. 14, 2026, p. 2). One of ordinary skill in the art would understand “melanoma as the single indication” to refer to cutaneous melanoma, a skin cancer. For example, Bhatia et al. (Oncology (Williston Park), 2009 May; 23(6): 488–496), uses melanoma as synonymous with cutaneous melanoma, citing the staging system for cutaneous melanoma in an article about treating metastatic melanoma. Therefore, claim 22 is withdrawn as being directed towards the non-elected invention (uveal melanoma as the single indication).
Claim 23 is directed towards the pharmaceutically acceptable salt of vinblastine V-oxide. The applicant elected vinblastine N-oxide as the species. Therefore, claim 23 is withdrawn.
Claim 24 is directed towards a kit, which lacks unity of invention with the method which was originally elected. Therefore, claim 24 is withdrawn. Claims 25-28 are directed towards tremelimumab as the CTLA-4 antibody, which is not the ipilimumab which was originally elected. Therefore, claims 25-28 are withdrawn.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim 14 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The rejection of claim(s) 1-4 and 13-14 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) is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims. The rejections of claim 14 are withdrawn as moot because claim 14 was cancelled.
Claim Rejections – 35 USC § 103 – Previously Presented
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.
The rejection of claim(s) 1-4, 13 and 21 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) is maintained.
The rejection of claim(s) 1-4, 7, 13 and 21 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) is maintained.
Claim 21 is newly added but is rejected over the art of record.
Response to Arguments
The Applicant argues that there is no reasonable expectation of success to substitute vinblastine N-oxide for vinblastine in the method of Bloom because INT230-6 is comprised of vinblastine and cisplatin and the office suggests that the cytotoxic activity is due to vinblastine alone (Remarks, p. 9-10). These arguments were fully considered but are not persuasive. The presently claimed method does not require the administration of vinblastine N-oxide and a CTLA-4 antibody alone. The claimed method comprises administering vinblastine N-oxide and a CTLA-4 antibody. As such, the method still encompasses a method wherein cisplatin is also administered (see MPEP § 2111.03 (explaining that the transitional term “comprising” is open ended and does not exclude additional, unrecited elements or method steps).
The Applicant argues that claim 1 as amended requires the intravenous administration of vinblastine N-oxide and Bloom’s INT230-6 was specifically formulated for intratumoral administration (Remarks, p. 10). These arguments were fully considered but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). One of ordinary skill in the art would have a reasonable expectation of success to administer vinblastine n-oxide intravenously because Shah teaches that vinblastine N-oxide is administered intravenously:
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Shah, p. 43, Fig. 9;
When the primary tumor volume reaches 30–50 mm3 (approximately 7–14 days), animals are randomized into 5 groups (n = 20; 4/group). Each group is treated by lateral tail vein injections with the control (normal saline), vehicle (empty liposomes), CPD100, CPD100 Li, CPD100 PEGLi at a dose of 40 mg/kg. The volume of injection ranges between 100 and 200 μL based on the weight of each mouse to ensure identical doses. An i.v. dosing schedule every 7 days for 2 cycles is utilized. Each cycle consists of weekly treatment for 3 weeks followed by a rest phase for 3 weeks. The tumor growth is assessed using a vernier caliper every 3 to 4 days.
Shah, p. 40, col. 2.
The Applicant argues that a skilled person would have no reason to separate the components of INT230-6 and intravenously administer only vinblastine to a patient because INT230-6 is designed for direct intratumoral injection and comprised of both cisplatin and vinblastine (Remarks, p. 11). These arguments were fully considered but are not persuasive. One of ordinary skill in the art would have a reasonable expectation of success to substitute vinblastine N-oxide for vinblastine 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, see the teachings of Shah.
Reiterated Rejection
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 intravenously administered liposome encapsulated vinblastine N-oxide for INT230-6 (intratumorally delivered vinblastine) because it is commonly known in the art that intravenously administered 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;
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Shah, p. 43, Fig. 9;
When the primary tumor volume reaches 30–50 mm3 (approximately 7–14 days), animals are randomized into 5 groups (n = 20; 4/group). Each group is treated by lateral tail vein injections with the control (normal saline), vehicle (empty liposomes), CPD100, CPD100 Li, CPD100 PEGLi at a dose of 40 mg/kg. The volume of injection ranges between 100 and 200 μL based on the weight of each mouse to ensure identical doses. An i.v. dosing schedule every 7 days for 2 cycles is utilized. Each cycle consists of weekly treatment for 3 weeks followed by a rest phase for 3 weeks. The tumor growth is assessed using a vernier caliper every 3 to 4 days.
Shah, p. 40, 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(s) 1-4, 7, 13 and 21 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.
Claim 21 recites:
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Claim 21.
The rejection of claims 1 and 7 is incorporated herein by reference. As shown in the rejections of claim 1 and 7, Bloom teaches the combination of a vinblastine and a CTLA-4 antibody for the treatment of colon cancer (a form of colorectal cancer). While Bloom does not teach vinblastine N-oxide or ipilimumab specifically, one of ordinary skill in the art would have a reasonable expectation of success to treat a solid tumor such as colorectal cancer (which includes colon cancer) with a combination of a vinblastine and ipilimumab because Shah teaches that vinblastine N-oxide compositions can be administered intravenously and exhibit antitumor effects and Intensity therapeutics teaches that ipilimumab is a commercially available anti-CTLA-4 antibody with promising activity in combination with vinblastine.
Therefore, claim 21 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 – Previously Presented
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.
The rejection of claims 1-4, 7, 13 and 21 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) is maintained.
Claim 21 is newly added but contains subject matter which can be rejected over the patent and prior art of record.
Response to Arguments
The Applicant argues again that the claim requires the separation of active components (the administration of vinblastine N-oxide without cisplatin) (Remarks, p. 12). These arguments were fully considered but are not persuasive. The claim does not require the administration of vinblastine and an immune checkpoint inhibitor alone but rather is open ended and can include additional components or method steps. The response to arguments under 35 U.S.C. 103 is incorporated herein by reference.
Reiterated Rejection
Claims 1-4, 7, 13 and 21 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.
Claim 21 recites:
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Claim 21.
Claim 1 of the ‘775 patent claims the treatment of lung cancer, breast cancer, pancreatic cancer, cervical cancer, prostate cancer, soft tissue carcinoma, and colon cancer,
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
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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