DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, filed 04/03/2023, claims domestic benefit to US provisional application 63/327,584, filed on 04/05/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/07/23, 04/29/2024, 12/20/2024, 1/20/2026 were filed after the mailing date of the instant application filed on 04/03/2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of claims
The preliminary amendment of 08/07/2023 is acknowledged. Claims 2-45, 68-72, 92-114 are canceled. Claims 1, 46-67, and 73-91, filed on 08/07/2023, are currently pending and are examined on the merits herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 1, line 22, “https://seer.cancer.gov”.
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 46, 49, and 51 are objected to because of the following informalities:
Bevacizumab is misspelled (“bevancizumab”) in claims 46 and 49.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 46 and by dependency claims 47, 48, 50-67, and 73-90, are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling for a method of treating advanced inoperable metastatic colorectal cancer comprising administering the combination of magrolimab and bevacizumab, does not reasonably provide enablement for a method of preventing advanced inoperable metastatic colorectal cancer comprising administering the combination of magrolimab and bevacizumab. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 46 is drawn to the method of “preventing” colorectal cancer in a subject by administration of the magrolimab and bevacizumab. However, the art and the specification at the time the invention was made does not teach that the antibody treatments prevents colorectal cancer.
Cancer development is initiated by a genetic aberration of a cell in the body. For the genetic aberration of a malignant cell to further develop into cancer depends on the characteristically hallmarks of cancer, including sustained proliferative and deregulated signaling, avoidance of apoptosis, and immune evasion as taught by Hanahan 2022 (Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022 Jan;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059; listed in the PTO-892; page 32, Figure 1 left).
The nature of carcinogenesis lies in the genetic instability of the cell and, thus, a mode of cancer prevention should aim to reverse the genetic instability. Yet, the nature of this invention aims to treat colorectal cancer that has already been established through targeting angiogenesis with an anti-VEGF antibody as VEGF is highly overexpressed in colorectal cancer cells while simultaneously using the CD47 and SIRPα signaling pathway to increase phagocytosis by macrophages thereby curbing immune evasion. These treatment strategies merely address the enabling characteristics of cancer or hallmarks of cancer which is inducing or accessing vasculature and avoiding immune destruction as taught by Hanahan 2022 (page 32, Figure 1 left, “avoiding immune destruction, inducing or accessing vasculature) but does not address the initiation or development of cancer itself.
Further, the initiation, promotion, and progression of the genetic aberration of a malignant cell is multifactorial and influenced by a mixture of genetic and environmental factors, such as behavioral, lifestyle, and environmental exposures making it difficult to identify the single factor that can prevent cancer without undue experimentation and not all premalignant lesions progress to cancer (Loomans-Kropp HA, Umar A. Cancer prevention and screening: the next step in the era of precision medicine. NPJ Precis Oncol. 2019 Jan 28;3:3. doi: 10.1038/s41698-018-0075-9; listed in the PTO-892 ; page 1, column 2, paragraph 2). The recommended strategies for colorectal cancer prevention before the effective filing date of the present application is primarily to screen individuals via colonoscopy and diet and lifestyle changes which merely reduce the risk of developing cancer (Loomans-Kropp and Kumar 2019, page 4, Table 1, first row and page 3, Figure 2, “Primary prevention mechanisms, which include alterations in physical activity or diet, tobacco cessation, or use of sunscreen, may reduce the impact of exposures in cancer initiation.”).
The state of the prior art before the effective filing date of the instant application does not teach of methods of administering therapeutic agents like bevacizumab and magrolimab that can prevent metastatic colorectal cancer. While there exist several in vivo and in vitro study models for tumorigenesis by introducing genetic instability as taught by Balani et al., 2017 (Balani et al. Modeling the process of human tumorigenesis. Nat Commun 8, 15422 (2017). https://doi.org/10.1038/ncomms15422; listed in the PTO-892; page 5, Table 1), there are no current models to recapitulate the transition from the immune surveillance by the host to immune evasion of the malignant cell in humans therefore it is difficult to predict if the therapeutic agent will prevent colorectal cancer in a subject.
The applicant’s disclosed figures demonstrate the efficacy of reducing in vitro and in vivo mouse tumor burden with magrolimab and a chemotherapeutic agents oxaliplatin and irinotecan (See Figures 2-4). Applicant disclosed figure drawings do not show treatment efficacy of bevacizumab and magrolimab in vitro or in vivo. As a working example, Applicant discloses a clinical study design of magrolimab and bevacizumab without clinical results at the time of filing (Figure 1, and page 122, paragraph 0279).
Further, Applicant has not demonstrated the claimed combination of magrolimab and bevacizumab efficacy in preventing colorectal cancer. Applicant also has not disclosed parameters to measure prevention of cancer in the specification. Nor has Applicant provided any guidance regarding preventative treatment, including preventative dosing regimens, how to identify a subject who would benefit from preventative treatment, or when to initiate preventative treatment.
The amount of experimentation to require to formulate such guidance would be enormous. One would have to demonstrate the efficacy of the combination or composition in several models inducing genetic instability in colorectal cancer and determine the appropriate regimen (doses and frequency) for use of the combination or composition in a preventative setting. Further, one would have to conduct population analysis to identify definitive characteristics which indicate that a subject is at risk of developing any cancer to a degree that would outweigh potential adverse effects of treatment with the claimed combination or composition.
Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
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.
Claim 60, 66, 78, 79, and 84 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 60, 66, 78, 79, and 84, the phrase "e.g." pertains to exemplary language and renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 non-obviousness.
Claims 1, 46-67, and 73-91 are rejected under 35 U.S.C. 103 as being unpatentable over Aparicio et al., 2020 (Aparicio et al. Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease. J Clin Med. 2020 Nov 30;9(12):3889. doi: 10.3390/jcm9123889. PMID: 33265959; PMCID: PMC7761096) and further in view of Chen 2021 (WO 2021/170077 A1, published on 09/02/2021; original listed in the IDS 04/29/2024; machine-translated English copy provided and listed in the PTO-892) and NCT02953782, 2021 (NCT02953782 Website: https://clinicaltrials.gov/study/NCT02953782?tab=history&a=11#version-content-panel, published version V11 (2021-02-08)) and as evidenced by Fisher et al., 2020 (Fisher et al., A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients. J Clin Oncol 38, 114-114(2020), doi:10.1200/JCO.2020.38.4_suppl.114;listed in the IDS 08/07/2023) .
Regarding instant claims 1, 46, and 49, Aparicio et al., 2020 teaches a method of treating metastatic colorectal cancer in a subject comprising co-administering to the subject an effective amount of the anti-CD47 antibody that inhibits binding between VEGFA and one or more VEGFA cognate receptors, bevacizumab (page 5, paragraph 2, “bevacizumab, a monoclonal antibody directed against the circulating vascular endothelial growth factor A (VEGF-A), has been authorized since 2004 in combination with CT [chemotherapy] for the first-line treatment of patients with mCRC, independently of the RAS mutational status”). However, Aparicio et al., 2020 does not teach the method of treating comprises administering the anti-CD47 antibody that inhibits binding between CD47 and SIRPα, magrolimab.
NCT02953782, 2021 teaches a method of treating previously treated metastatic colorectal cancer with magrolimab (page 1, title ” Study of Magrolimab (Hu5F9-G4) in Combination With Cetuximab in Participants With Solid Tumors and Advanced Colorectal Cancer”). Further, Chen 2021 teaches the combination of an anti-CD47 antibody and an anti-VEGF antibody, bevacizumab (page 2, paragraph 7, “present invention provides a pharmaceutical combination comprising (i) an anti-CD47 antibody and/or an antigen-binding fragment thereof; and (ii) an anti-VEGF antibody and/or an antigen-binding fragment thereof” and page 3, paragraph 3, “Preferably, the anti-VEGF monoclonal antibody is bevacizumab”) to treat solid tumors (page 4, paragraph 6) and teaches that the that the combination of the two antibodies resulted in a better tumor inhibitory effect or synergistic effect (page 21, paragraph 1, “the anti-CD47 antibody and anti-VEGF antibody combination drug has a significantly better tumor inhibitory effect on A431 tumor-bearing mice than the anti-CD47 antibody single agent and the anti-VEGF antibody single agent”, page 20, paragraph 7, “anti-CD47 antibody and anti-VEGF antibody have a synergistic effect in anti-tumor”).
Therefore, it would have been obvious to the person of ordinary kill in the art to combine the bevacizumab as taught by Aparicio and magrolimab as taught by NCT02953782 to treat metastatic colorectal cancer by enhancing phagocytosis and improving anti-tumor activity as taught by Chen.
Regarding instant claims 1, 47, 48, 49, 54, 55, and 57, Aparicio et al., 2020 teaches the metastatic colorectal cancer (mCRC) is inoperable, unresectable and metastatic and discloses first line treatment options for this patient population as recited in claim 1, 47, 48, and 49 (page 1, title). Aparicio et al., 2020 also discloses that the bevacizumab can be administered to subject that do not have the BRAF V600E mutation as recited in claim 54 and does not comprise high microsatellite instability as recited in claim 55 (page 7, Table 2, current recommendations under molecular profiles “MSS [microsatellite stable]” “any” “native BRAF”). Indeed, Aparicio teaches that “there is no predictive biomarker of bevacizumab efficacy, and patients with either wild-type or mutant RAS may benefit from this therapy” (page 5, paragraph 2). Also, Aparicio teaches that the metastatic colorectal cancer is adenocarcinoma originating in the colon or rectum as recited in claim 57 (page 1, introduction, “most common histology by far is colorectal adenocarcinoma, and we will refer to this subtype in this review”).
Regarding instant claims 56, 58, and 59, NCT02953782 teaches that the method of treating metastatic colorectal cancer with the magrolimab wherein the cancer has one or more KRAS mutations and not responded to EFGR antibody as recited in claim 56, 58, and 59 (page 19, “KRAS Wild-Type CRC: Advanced KRAS wild type CRC who have progressed or are ineligible for fluoropyrimidine, irinotecan, and oxaliplatin based chemotherapy and who are relapsed or refractory to at least 1 prior systemic therapy that included an anti-epidermal growth factor receptor (EGFR) antibody, such as cetuximab, panitumumab or others.”).
Regarding instant claim 53, Chen teaches the cancer has a cell surface expression of CD47 (page 10, paragraph 8, “stronger affinity constants specifically bind to CD47 on the surface of tumor cells, thereby blocking or inhibiting the binding of CD47 to SIRPα on the surface of macrophages”).
Regarding instant claims 50, 51, and 52, Aparicio et al., 2020 teaches a method of treating further comprising co-administering a chemotherapy regimen with bevacizumab wherein chemotherapy regimen is FOLFIRI (page 2, paragraph 5, “The main doublet therapies used in first-line treatment are FOLFIRI (CI 5-FU plus irinotecan), FOLFOX (CI 5-FU plus oxaliplatin)[…]” and page 5, paragraph 2, “Bevacizumab induces a consistent improvement in PFS with any of the CT schemes (monotherapy or multiagent) employed in first-line treatment, so its use is standard for most patients with no formal contraindication”).
Regarding instant claims 60, 61, 73, 74, 75, 76, and 77, Aparicio et al., 2020 and NCT02953782 teach the bevacizumab and magrolimab as described in claim 46 and Chen further teaches that the combination treatment reduces the tumor burden or size by at least 15% as recited in instant claim 60, 61, and 77 (page 18, paragraph 6, “anti-CD47 antibody + anti-VEGF antibody - 1mg/kg+0.25mg/kg group combined tumor inhibition rate of 100.17%”).
Chen also teaches the method of treating wherein administration of the anti-CD47 antibody and anti-VEGF antibody provides a synergistic effect as recited in claim 73, 74, 75, and 76 (page 19, paragraph 2, “it can be seen that the anti-CD47 antibody has a certain anti-tumor efficacy, and its combination with anti-VEGF antibody significantly enhances its anti-tumor effect, indicating that the two drugs The combination has a synergistic effect. Moreover, compared with the same dose of each single agent, the anti-CD47 antibody and anti-VEGF antibody combination drug has a significantly better tumor inhibition effect on MDA-MB-231 tumor-bearing mice than the anti-CD47 antibody single agent and the anti-VEGF antibody single agent”).
Chen further teaches that the bevacizumab and magrolimab increased cancer cell death and/or decreased cancer cell growth when comparing the effect of the combination versus either the magrolimab or the bevacizumab alone in claim 75 (page 2, paragraph 4, “anti-VEGF […] inhibit the proliferation and metastasis of tumor cells, and induce tumor cell apoptosis, so as to achieve the anti-tumor therapeutic effect“ and page 20, paragraph 7 “effect of each administration group on the tumor volume of tumor-bearing mice over time is shown in Figure 6 […] indicating that anti-CD47 antibody and anti-VEGF antibody have a synergistic effect in anti-tumor”).
Chen further teaches that the anti-CD47 antibody or magrolimab increased phagocytosis of cancer cells by macrophages when comparing the effect of the combination versus either the magrolimab or the bevacizumab alone as recited in claim 76 (page 2, paragraph 1, “The results showed that the anti-CD47 antibody can improve the phagocytosis of macrophages and has significant effects. Its anti-tumor activity can significantly inhibit the growth of tumors and even make tumors disappear completely”).
Regarding instant claims 62, 63, 64, 65, 66, and 67, Aparicio et al., 2020 teaches co-administering additional therapeutics and/or one or more blockers or inhibitors of one or more T cell stimulatory immune checkpoint proteins or receptors as recited in instant claim 65 (page 7, table 2, current treatment recommendations for first-line treatment according to molecular profile, see “anti-EGFR” and “pembrolizumab”).
Aparicio et al., 2020 teaches a method comprising co-administering an antibody that binds to epidermal growth factor receptor (EGFR) as recited in claim 62 and 63 wherein the EGFR antibody is selected from cetuximab and panitumumab as recited in claim 64 (page 6, paragraph 1, “Recommendation: Chemotherapy doublets with anti-EGFR are recommended for fit patients with unresectable mCRC and RAS wild-type tumors”).
Aparicio et al., 2020 teaches a method comprising co-administering one or more blockers or inhibitors of one or more T-cell stimulatory immune checkpoint proteins wherein the inhibitors comprises PDL1 recited from claim 66 and 67 (page 7, paragraph 2, “Nowadays, only immunotherapy with pembrolizumab has been approved for first-line treatment in patients with mCRC and MSI-high tumors”).
Regarding instant claims 78, 79, 80, 81, 82, and 83, NCT02953782 teaches magrolimab doses (page 10, Arms and Interventions, Arms, “Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by intravenous (IV) infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22”, page 9, “maintenance dose of magrolimab 20 mg/kg of body weight by IV infusion” and page 10 “maintenance dose of magrolimab 45 mg/kg of body weight”). As an evidentiary reference, Fisher et al., 2020 discloses from the same clinical trial that magrolimab has not reached the maximum tolerated dose (MTD) (page 1, results, “No maximum tolerated dose was reached”) and therefore one of ordinary skill in the art is able to reasonably optimize the dose of 60 mg/kg as recited in instant claim 80 and 15 mg/kg as recited in instant claim 82 without inducing toxicity. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding instant claims 84, 85, and 86, Chen teaches one or more doses of bevacizumab (page 13, paragraph 3, “A dose of the anti-VEGF antibody and/or antigen-binding fragment thereof can be selected from 0.1-10 mg/kg of the subject's body weight (e.g.,0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg or 10mg/kg). Chen also teaches that the anti-VEGF antibody is an intravenous administration form (page 13, paragraph 7).
Regarding instant claims 87, 88, and 89, Chen and NCT02953782 teach the bevacizumab and magrolimab doses as described above. Further, NCT02953782 teaches dosing regimen consisting of 28-day cycles of magrolimab (page 8, “Each cycle will consist of 4 weeks (28 days)”). Magrolimab is administered a priming dose of 1 mg/kg on day 1, followed by weekly maintenance doses starting on day 8 (page 7, “Day 1 followed by a maintenance dose of magrolimab 10 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8”). Chen teaches bevacizumab is administered on days 1 and 15 (page 13, paragraph 3, “The next dose is administered at 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 10 weeks.”) The combined dosing regimen of the magrolimab and bevacizumab taught by NCT02953782 and Chen is a result of an effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding instant claim 90, Chen teaches that the subject is human (page 10, paragraph 6).
Regarding instant claim 91, Chen teaches a kit comprising one or more unitary doses of: (a) an agent that inhibits binding between CD47 and SIRPα; and (b) an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors (page 4, paragraph 2, “In the third aspect, the present invention provides a kit of medicines comprising an anti-CD47 antibody and an anti-VEGF antibody drug combination. Preferably, the kit is in the form of a drug dosage unit, so that the drug can be provided according to the dosage regimen”).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim Claims 1, 46-67, and 73-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 70, 71, 74, 76, 77, 78, 79, 80, 81, 83, 84, 85, 86, 87, 90 of copending Application No. 18/373,655 (herein Reference application) in view of Aparicio et al., 2020 (cited previously), Fisher et al., 2020 (cited previously), Chen 2020 (cited previously), NCT02953782, 2021 (cited previously) and as evidenced by Liu et al., 2015 (Liu et al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345. doi: 10.1371/journal.pone.0137345).
Regarding instant claims 1, 46, and 49, reference application claims 70, 74, and 76 recite a method of treating a human subject having an epithelial ovarian cancer or reducing the size of the epithelial ovarian cancer in the human subject comprising: a) administering a priming dose of an anti-CD47 antibody to the subject, wherein the priming dose is from about 0.5 to about 5 mg/kg of antibody; and b) administering a therapeutically effective dose of the anti-CD47 antibody to the subject and recite the additional agent is a VEGF inhibitor, optionally bevacizumab, regorafenib, or aflibercept. However, the reference claims do not recite a method of treating a human subject having previously treated advanced inoperable metastatic colorectal cancer as recited in instant claims 1, 46, 47, 48, and 49. NCT02953782, 2021 teaches a method of treating previously treated metastatic colorectal cancer with the anti-CD47 antibody magrolimab (page 1, title ” Study of Magrolimab (Hu5F9-G4) in Combination With Cetuximab in Participants With Solid Tumors and Advanced Colorectal Cancer”). Chen 2020 further teaches a treatment with an anti-CD47 antibody and anti-VEGF antibody that can be used to treat various blood cancers and solid tumors (page 4, paragraph 4) and that the treatment can induce enhanced anti-tumor effect (page 21, paragraph 1, “it can be seen that the anti-CD47 antibody has a certain anti-tumor efficacy, and its combination with anti-VEGF antibody significantly enhanced its anti-tumor effect, indicating that the combination of the two drugs has a synergistic effect.”).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the method of treating solid cancers using the anti-CD47 antibody and anti-VEGF antibody for colorectal cancer as recited in the instant claims and as taught by NCT02953782 to enhance anti-tumor effect taught by Chen.
Regarding instant claims 78, 79, 80, 81, 82, 83, 87, 88, and 89, reference application claim 71 recite the method comprises (a) administering the priming dose of anti-CD47 antibody to the subject at a dose of 1 mg/kg of antibody on day 1; and (b) administering the therapeutically effective dose of the anti-CD47 antibody to the subject at a dose of 20 mg/kg of antibody, 30 mg/kg of antibody, 45 mg/kg of antibody, 60 mg/kg of antibody, or 67.5 mg/kg of antibody on day 8 as recited in instant claims 78, 79, 80, 81, and 82. Reference application claim 90 recites the therapeutically effective dose is administered about every 7, 14, 21, or 28 days as recited in instant claims 87, 88, and 89. Reference application claim 86 recites the anti-CD47 antibody is administered intravenously or intra-tumorally as recited in instant claim 83.
Regarding instant claim 87, 88, and 89, reference application claim 80 recites the anti-CD47 antibody and the additional agent are administered concurrently or sequentially.
Regarding instant claim 50, 51, and 52, reference claim 74 recites administering at least one additional agent to the human subject, wherein the additional agent comprises at least one of a chemotherapeutic agent as recited in instant claim 50. However, the reference application does not teach the chemotherapeutic agent is FOLFIRI as recited in instant claims 51 and 52. Aparicio et al., 2020 teaches a method of treating further comprising co-administering a chemotherapy regimen with bevacizumab wherein chemotherapy regimen is FOLFIRI (page 2, paragraph 5, “The main doublet therapies used in first-line treatment are FOLFIRI (CI 5-FU plus irinotecan), FOLFOX (CI 5-FU plus oxaliplatin)[…]” and page 5, paragraph 2, “Bevacizumab induces a consistent improvement in PFS with any of the CT schemes (monotherapy or multiagent) employed in first-line treatment, so its use is standard for most patients with no formal contraindication”).
Therefore, it would have been obvious to the person of ordinary skill in the art to use commonly accepted chemotherapeutic agents like FOLFIRI to treat colorectal cancer recited in the instant claims as there are no contraindications when combining with bevacizumab as taught by Aparicio et al., 2020.
Regarding instant claim 62, 65, 66, and 67, reference application claims 74, 77, 79, and 78 recite comprising administering one or more therapeutic antibodies and comprising administering one or more blockers or inhibitors of one or more T cell stimulatory immune checkpoint proteins or receptors (reference application claim 77, “PARP inhibitor, optionally the PARP inhibitor is Rucaparib, Niraparib, Olaparib, Talazoparib, or Veliparib” and reference application claim 79 “additional agent is a folate inhibitor that inhibits folate metabolism or targets the folate receptor” and reference application claim 78, “additional agent is an immune checkpoint inhibitor, optionally wherein the additional agent inhibits at least one of CTLA4, PD 1, and PDL1”).
Regarding instant claim 90, reference claims 70 and 87 recite the subject is human.
Regarding instant claim 91, the reference application claim 85 recites the anti-CD47 is formulated in a pharmaceutical composition with a pharmaceutically acceptable excipient but does not recite a kit as recited in instant claim 91. Chen 2020 teaches that the anti-CD47 antibody and anti-VEGF antibody can be in “a pharmaceutical composition or kit of components containing the pharmaceutical combination” (page 1, abstract). It would be obvious to one of ordinary skill in the art formulate pharmaceutically acceptable excipients with the therapeutically effective doses to package in a kit for treatment use.
Reference application claims recite that the anti-CD47 antibody is Hu5F9-G4 (claim 84) and comprises an IgG4 Fc (claim 81), and that the anti-CD47 antibody binds to the same CD47 epitope as Hu5F9-G4 (claim 83). However, the reference claim does not teach that it is magrolimab in the instant claims 46, 49, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 87, 88, 89, and 91. NCT02953782, 2021 teaches that the antibody magrolimab is Hu5F9-G4 (page 1, Title). As evidentiary reference, Liu et al., 2015 teaches that the Hu5F9-G4 has a human IgG4 Fc format to minimize recruitment of antibody Fc-dependent effector functions (page 3, paragraph 2, “novel humanized anti-human CD47 antibody, designated Hu5F9-G4, generated by complementarity determining region (CDR) grafting onto a human IgG4 scaffold to minimize the recruitment of antibody Fc-dependent effector functions”).
Reference application claims do not teach the cancer is adenocarcinoma originating in the colon or rectum as recited in instant claim 57; does not comprise a BRAF V600E mutation as recited in instant claim 54; does not comprise high microsatellite instability in instant claim 55; has one or more KRAS mutation and the subject has not responded to anti-EGFR antibody therapy as recited in instant claim 56; and has progressed after one or more prior systemic therapies as recited in instant claims 58 and 59.
As described previously, NCT02953782 teaches that the method of treating metastatic colorectal cancer with the magrolimab wherein the cancer has one or more KRAS mutations and not responded to EFGR antibody as recited in instant claim 56, 58, and 59 (page 19, “KRAS Wild-Type CRC: Advanced KRAS wild type CRC who have progressed or are ineligible for fluoropyrimidine, irinotecan, and oxaliplatin based chemotherapy and who are relapsed or refractory to at least 1 prior systemic therapy that included an anti-epidermal growth factor receptor (EGFR) antibody, such as cetuximab, panitumumab or others.”). Further, as described previously, Aparicio et al., 2020 also discloses that the bevacizumab can be administered to subject that do not have the BRAF V600E mutation as recited in claim 54 and does not comprise high microsatellite instability as recited in claim 55 (page 7, Table 2, current recommendations under molecular profiles “MSS [microsatellite stable]” “any” “native BRAF”). Indeed, Aparicio teaches that “there is no predictive biomarker of bevacizumab efficacy, and patients with either wild-type or mutant RAS may benefit from this therapy” (page 5, paragraph 2). Also, Aparicio teaches that the metastatic colorectal cancer is adenocarcinoma originating in the colon or rectum as recited in claim 57 (page 1, introduction, “most common histology by far is colorectal adenocarcinoma, and we will refer to this subtype in this review”).
Reference application claims do not teach that the cancer has a cell surface expression of CD47 as recited in instant claim 53. Chen teaches the cancer has a cell surface expression of CD47 (page 10, paragraph 8, “stronger affinity constants specifically bind to CD47 on the surface of tumor cells, thereby blocking or inhibiting the binding of CD47 to SIRPα on the surface of macrophages”).
Reference claims do not recite doses and dosing regimen of the anti-VEGF antibody, bevacizumab as recited in instant claims 84, 85, 86, 87, 88, and 89. As described above, Chen 2020 teaches one or more doses of bevacizumab (page 13, paragraph 3, “A dose of the anti-VEGF antibody and/or antigen-binding fragment thereof can be selected from 0.1-10 mg/kg of the subject's body weight (e.g.,0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg or 10mg/kg)”)and Chen teaches bevacizumab is administered on days 1 and 15 (page 13, paragraph 3). Chen also teaches that the anti-VEGF antibody is an intravenous administration form (page 13, paragraph 7).
Reference claims do not teach a reduction of tumor burden or a synergistic effect of the anti-CD47 antibody and anti-VEGF antibody as recited in instant claims 60, 61, 73, 74, 75, 76, and 77. As described above, Chen 2020 teaches that the combination treatment reduces the tumor burden or size by at least 15% as recited in claim 60, 61, and claim 77 (page 18, paragraph 6, “anti-CD47 antibody + anti-VEGF antibody - 1mg/kg+0.25mg/kg group combined tumor inhibition rate of 100.17%”). Chen also teaches the method of treating wherein administration of the anti-CD47 antibody and anti-VEGF antibody provides a synergistic effect as recited in claim 74, 75, and 76 (page 19, paragraph 2).
Chen further teaches that the bevacizumab and magrolimab increased cancer cell death and/or decreased cancer cell growth when comparing the effect of the combination versus either the magrolimab or the bevacizumab alone in claim 75 (page 2, paragraph 4, “anti-VEGF […] inhibit the proliferation and metastasis of tumor cells, and induce tumor cell apoptosis, so as to achieve the anti-tumor therapeutic effect“ and page 20, paragraph 7 “effect of each administration group on the tumor volume of tumor-bearing mice over time is shown in Figure 6 […] indicating that anti-CD47 antibody and anti-VEGF antibody have a synergistic effect in anti-tumor”).
Chen further teaches that the anti-CD47 antibody or magrolimab increased phagocytosis of cancer cells by macrophages when comparing the effect of the combination versus either the magrolimab or the bevacizumab alone as recited in claim 76 (page 2, paragraph 1, “The results showed that the anti-CD47 antibody can improve the phagocytosis of macrophages and has significant effects. Its anti-tumor activity can significantly inhibit the growth of tumors and even make tumors disappear completely”).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647