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 .
DETAILED ACTION
The amendment filed May 1, 2026 in response to the Office Action of February 6, 2026 is acknowledged and has been entered.
Claims 29, 31, 32, and 35-37 have been amended.
Claims 21-28 have been cancelled.
Claims 29-40 are pending.
It is noted that Applicant elected without traverse the species: 1) a PD-1 inhibitor as the specific immune checkpoint inhibitor; 2) toripalimab as the specific PD-1 inhibitor; 3) colon cancer as the specific cancer, in the reply filed on December 29, 2025.
Accordingly, claims 34 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 29-33, 35, and 37-40 are currently under consideration as drawn to the elected invention.
In view of the amendments on claim 29, the 112(b) rejection set forth in the Office Action of February 6, 2026 is hereby withdrawn.
In view of In view of the amendments on claim 29, the 112(a) rejection set forth in the Office Action of February 6, 2026 is hereby withdrawn.
The amended claims introduced new limitations on specific tumor and dosage for each component, thus, the 102 rejections set forth in the Office Action of February 6, 2026 are hereby withdrawn.
MAINTAINED/MODIFIED REJECTION
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.
Claims 29-32, 35, and 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 9-18, 20-23, and 26 of copending Application No. 18/840,378 (hereinafter Appl. 378, US 2025/0188164 A1, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 1 of Appl. 378 teaches a therapeutic combination comprising chiauranib or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) or a crystalline form thereof (e.g., non-solvated crystalline form A, B or C) and at least one (e.g., 1, 2 or 3) anti-CTLA4-anti-PD-1 bispecific antibody. As evidenced by [0201] of specification of Appl. 378 (US 2025/0188164 A1), non-solvated crystalline form A, B, or C read on the instant claim 30. An anti-CTLA-anti-PD-1 bispecific antibody would read on “an immune checkpoint inhibitor” of instant claim 29, a PD-1 inhibitor and a CTLA-4 inhibitor of instant claim 32.
Claim 26 of Appl. 378 teaches s method for treating a tumor, comprising a step of administering to a subject in need an effective amount of the therapeutic combination according to claim 1; preferably, the tumor is selected from one or more of melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, leukemia, breast cancer, …, malignant melanoma and ovarian germ cell neoplasm.
Regarding the dosages, claim 4 of Appl. 378 teaches the chiauranib or the pharmaceutically acceptable salt thereof or the crystalline form thereof is in a unit dose of 0.1 mg-100 mg, 0.5 mg-50 mg, 1 mg-20 mg, 2 mg-15 mg, 3 mg-12 mg, 4 mg-8 mg, or 5 mg, which reads on the range of 5 to 80 mg (instant claim 29) or 10 to 50 mg (instant claim 31) as instantly claimed.
Claim 3 of the Appl. 378 teaches the anti-CTLA4-anti-PD-1 bispecific antibody is in a unit dose of 100 mg-1000 mg, 200 mg-800 mg, 200 mg-500 mg, 300 mg-600 mg, 400 mg-500 mg, or 450 mg, which reads on the range 1-1000 mg (instant claim 29) or 10-800 mg (instant claim 35) of instantly claimed.
In addition, regarding the claimed dosages, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Taken together, the claims of Appl. 378 teach the instant claims 29-32, 35, and 37.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 38-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 9-18, 20-23, and 26 of copending Application No. 18/840,378 (hereinafter Appl. 378, US 2025/0188164 A1), as applied to claims 29-32, 35, and 37, in view of Yang (Yang et al., WO 2019/096194 A1, Publication Date: 05/23/2019, cited in IDS of 03/08/2023, of record).
The claims of Appl. 378 teach the method of instant claim 29 as set forth above. However, the claims of Appl. 378 do not teach the administration method as recited by instant claims 38-40.
Regarding claim 38-39, Yang teaches In a preferred embodiment of the present invention, when administering, the dosage of the PD-1 antibody is 60 to 600 mg, intravenous infusion, once every three weeks; the dosage of the VEGFR inhibitor is 250 mg to 500 mg, orally, once every one to two days ([0040] of English translation on page 7); or in a preferred embodiment of the present invention, when administering, the dosage of the PD-1 antibody is 200 mg, intravenous infusion, once every two weeks; the dosage of the VEGFR inhibitor is 375 mg, orally, once a day ([0043] of English translation on page 7).
Regarding claim 40, as shown above, PD-1 antibody is administered once every two weeks; VEGFR inhibitor is administered once a day, thus, the first component and the second component are administered separately.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to apply the administration method of Yang for the combination taught by the claims of Appl. 378, because Yang and the claims of Appl. 378 are drawn to the method in the same field (treating cancers) with the same combination (a chiauranib and an immune checkpoint inhibitor). One of ordinary skill would have a reasonable expectation of success with the well-known administration methods for treating cancers, as evidenced by Yang.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
For the Double Patenting rejection, Applicant argues:
The present application is an application having an earlier patent term filing date of September 3, 2021, while the copending patent application 18/840,378 is an application having a later patent term filing date of February 24, 2024. Applicant submits that the claim rejections under 35 USC.§§ 102, 103, 112(a), and 112(b), that is, all of the rejections other than the outstanding provisional nonstatutory double patenting, have been overcome by the present amendment. Furthermore, while a provisional rejection on the ground of nonstatutory double patenting has not yet been made in the copending Application No. 18/840,378 (the '378 Application has not yet been examined), Applicant submits that the provisional nonstatutory double patenting for the present application should also be withdrawn without the requirement of filing a terminal disclaimer under 37 CFR l.32l(d).
Applicant’s arguments have been fully considered but they are not persuasive because the claims of the instant application are still obvious in view of the co-pending claims and a terminal disclaimer has not been filed. MPEP 804 I-B states: “The “provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in at least one of the applications.” Because new 103 rejections are made for the amended claims (see below), thus, the rejections above are maintained for the reasons of record.
NEW REJECTION
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 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.
Claims 29, 31, 32, 35, and 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., WO 2018/223923 A1, Publication Date: 12/13/2018, English translation, cited in IDS of 03/08/2023, of record) in view of Sun (Sun et al., Journal of Hematology & Oncology, (2019) 12:9, Publication Date: 01/14/2019), as evidenced by Chiauranib_PubChem (downloaded from: https://pubchem.ncbi.nlm.nih.gov/compound/Ibcasertib, on 02/03/2026, of record).
Chen teaches that blocking PD-1/PD-L1 has become a potent treatment for cancer immunotherapy ([0003] of English translation).
Chen teaches although the anti-PD-1 antibody has achieved remarkable effect on tumor suppression, it is not effective for some patients ([0004] of English translation).
Chen teaches an anti-PD-1 antibody comprising light chain of SEQ ID NO: 8 and heavy chain of SEQ ID NO: 7 ([0024] of English translation, and claim 6).
Chen teaches using the combination of the anti-PD-1 antibody and VEGF inhibitor (such as CS-2164) for treating cancer ([0033] of the English translation, claims 1 and 7). As evidenced by Chiauranib_PubChem (see page 1), CS-2164 is the same as chiauranib.
Chen teaches the PD-1 antibody or antigen-binding fragment and the VEGF inhibitor or VEGF ligand inhibitor have a synergistic pharmacological effect in treating tumor ([0034]). Thus, the VEGF inhibitor or VEGF ligand inhibitor would enhancing anti-tumor activity of anti-PD-1 antibody.
Chen teaches that the cancers can be colon cancer (the elected species) or liver cancer ([0037] and [0036] of English translation, claims 8 and 9).
Chen teaches that preferably, the dose of PD-1 antibody is 25mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg, 800 mg, 1000mg, which reads on the range of 1-1000 mg as instantly claimed.
Chen teaches a method for treating means administering a therapeutic agent internally or externally ([0066] of the English translation).
Chen teaches the administration mode of the combination, including simultaneously administration, independently preparation and co-administration or independently preparation and sequential administration ([0045] of the English translation).
Thus, Chen teaches the method for treating colon cancer or liver cancer in a subject by administering a combination of anti-PD-1 antibody and an VEGF inhibitor or VEGF ligand inhibitor (such as chiauranib). However, Chen does not teach a dosage of 5-80 mg of chiauranib.
Sun teaches that chiauranib shows broadly activity against human tumor xenograft models inoculated with human cancer cell lines derived from colon, liver or stomach cancers (page 2, col. 1, para. 1).
Sun teaches that based on the overall results from preclinical studies and the principle for human equivalent dose (HED) analysis, 25 mg/day would be suggested as the starting dose for chiauranib in human (§ Drug administration, on page 2).
Sun teaches that dosages from 10 mg to 65 mg show anti-tumor activity in patients with various cancers (page 6, col. 2, para. 3).
Sun teaches that chiauranib is generally well-tolerated with manageable side effects (§ Safety and adverse event profile, on page 4).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to treat colon cancer or liver cancer in a subject by administering a combination of anti-PD-1 antibody at a dose of 1-1000 mg and an VEGF inhibitor or VEGF ligand inhibitor (such as chiauranib), as taught by Chen, and to administer a dose of 5-80 mg (e.g. 25 mg) of chiauranib because Sun teaches that 25 mg chiauranib daily is the recommended dosage for human and is effective for treating various cancers including colorectal cancer. One of ordinary of skill in the art would have had a reasonable expectation that the claimed combination and dosage would be more effective for colon cancer because the combination bring two different anti-tumor mechanisms together and the dosages for both components are well-known in the art, as evidenced by Chen and Sun. The motivation would have been to develop a more effective method for treating colon cancer.
In addition, regarding the claimed dosages, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 35, Chen teaches that preferably, the dose of PD-1 antibody is 25mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg, 800 mg, 1000mg, which reads on the range of 10-800 mg as instantly claimed.
Regarding claims 38 and 39, Chen teaches that administration route of the PD-1 antibody or antigen-binding fragment thereof is preferably a parenteral administration route, more preferably intravenous injection, intramuscular injection, or subcutaneous injection. This reads on “parentally administering the second component” of claim 38 and “injecting the second component” of claim 39.
Regarding claim 40, Chen teaches the administration mode of the combination, including simultaneously administration, independently preparation and co-administration or independently preparation and sequential administration ([0045] of the English translation).
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., WO 2018/223923 A1, Publication Date: 12/13/2018, English translation, cited in IDS of 03/08/2023, of record) in view of Sun (Sun et al., Journal of Hematology & Oncology, (2019) 12:9, Publication Date: 01/14/2019), as evidenced by Chiauranib_PubChem (downloaded from: https://pubchem.ncbi.nlm.nih.gov/compound/Ibcasertib, on 02/03/2026), as applied to claims 29, 31, 32, 35, and 37-40 above, and further in view of Lu (Lu et al., CN 107868044 A, Publication Date: 04/03/2018, English translation, cited in IDS of 03/08/2023, of record).
Chen and Sun teach method of claim 29 as set forth above. However, Chen and Sun does not teach a non-solved crystal of chiauranib as recited by claim 30.
Lu teaches non-solvated crystals of N-(2-aminophenyl)-6- (7-methoxyquinoline-4-oxygen)-1-naphthylcarboxamide ([0002] and [0004] of English translation). Based on paragraphs [0002] and [0003] of the original publication (CN 107868044 A), the compound has a structure as shown below:
PNG
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176
300
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Greyscale
As evidenced by Chiauranib in PubChem (see page 4), the compound of formula (I) is the same as chiauranib.
Lu teaches that the crystal of the compound of formula (I) made by previous method contains N.N-dimethylformamide (DMF) ([0007] of English translation). Due to the potential toxicity of organic solvents to drug users, it is generally not suitable to prepare crystals containing organic solvents ([0008] of English translation).
Lu teaches three non-solvated crystals of the compound of formula (I) ([0012], claim 2).
Lu teaches that the non-solvated crystal A has characteristic peaks at 6.88°, 9.26°, 12.74°, 13.82°, 18.58°, 20.86° and 25.72° in its X-ray powder diffraction pattern at reflection angles 2θ (claim 2); the non-solvated crystal B has characteristic peaks at 4.88°, 9.68°, 12.74 °, 14.52°, 17.72°, 24.30°, and 25.26 ° in its X-ray powder diffraction pattern at reflection angles 2θ (claim 4); the non-solvated crystal C has characteristic peaks at 4.84°, 9.68°, 12.92 °, 14.60°, 16.46°, 17.44°, 22.00°, and 25.28° in its X-ray powder diffraction pattern at reflection angles 2θ (claim 6). Thus, the no-solvated crystal A, B or C reads on the non-solvated crystals of instant claim 30.
Lu teaches the method of making the non-solvated crystals, (see Examples 1-3, [0055] and [0056] of English translation).
Lu teaches that the crystals are stable and suitable for pharmaceutical production and long-term storage ([0060] of English translation) and for treating diseases (claims 12 and 13).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the anti-PD-1 antibody and chiauranib for treating colon cancer of a subject as taught by Chen and Sun, and to substitute chiauranib with the no-solvated crystal of chiauranib taught by Lu in the combination, because the no-solvated crystals do not contain organic solvent; stable and suitable for pharmaceutical use as taught by Lu. One of ordinary skill in the art would have had a reasonable expectation that the non-solvated crystal of chiauranib would be more suitable to be used in the claimed method due to its lower toxicity and have longer storage life, as taught by Lu. The motivation would have been to develop a better and safer combination for cancer treatment.
Claim 33, of is rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., WO 2018/223923 A1, Publication Date: 12/13/2018, English translation, cited in IDS of 03/08/2023, of record) in view of Sun (Sun et al., Journal of Hematology & Oncology, (2019) 12:9, Publication Date: 01/14/2019), as evidenced by Chiauranib_PubChem (downloaded from: https://pubchem.ncbi.nlm.nih.gov/compound/Ibcasertib, on 02/03/2026), as applied to claims 29, 31, 32, 35, and 37-40 above, and further in view of Yang (Yang et al., European Journal of Cancer, 130 (2020), 182-192, Publication Date: 03/27/2020, of record).
Chen and Sun teach method of claim 29 as set forth above. However, Chen and Sun does not teach the PD-1 antibody is toripalimab (the elected species).
Yang teaches that toripalimab, also known as JS001 or TAB001, is a recombinant humanized anti-PD-1 monclonal antibody (page 183, col. 2, para. 1).
Yang teaches that toripalimab has good binding to PD-1, promotes T-cell proliferation and induces a strong response in cytokine production (page 183, col. 2, para. 1).
Yang teaches administration regimens in human (page 184, col. 1, paras. 2-3).
Yang teaches that toripalimab demonstrated a well-tolerated safety profile and a promising antitumor activity in patients with various cancers (page 191, col. 1, para. 2).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the anti-PD-1 antibody and chiauranib for treating colon cancer of a subject as taught by Chen and Sun, and to use toripalimab as the anti-PD-1 antibody in the combination, because Yang teaches that toripalimab is a novel anti-PD-1 antibody with good anti-tumor activity for multiple cancers. One of ordinary skill in the art would have had a reasonable expectation that toripalimab would be suitable to be used in the claimed method due to its lower toxicity and have good anti-tumor activity and good binding to PD-1, as taught by Yang. The motivation would have been to expand the options for the combination for colon cancer treatment.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646
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