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 .
Response to Amendment
The rejection of claims 33, 37 and 39 are moot in view of the cancelation of the claims.
The rejection of claims 35 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment adding sequences for the heavy chain and light chain.
The rejection of claims 14-23, 32 and 34-41 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement, is withdrawn in view of the amendment limiting the antibody CDRs to those of a single antibody, 5G11, and removal of % homology language.
The rejection of claims 14-23 and 32-41 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn in view of the amendment limiting the antibody CDRs to those of a single antibody, 5G11, and removal of % homology language.
The rejection of claim(s) 14 -23, 32-37 and 38-41 under 35 U.S.C. 103 as being unpatentable over WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024), Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and ClinicalTrial.gov Study NCT03996408 (https://clinicaltrials.gov/study/NCT03996408?intr=pd-l1%20and%20(anlotinib%20OR%20AR3181%20OR%20AR-3181)%20&viewType=Table&limit=50&page=1&rank=7&tab=history&a=1#version-content-panel, 21 Jun. 2019) is withdrawn in favor of a new rejection set forth below.
The rejection of claim(s) 14-23 and 32-41 under 35 U.S.C. 103 as being unpatentable over WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in favor of a new rejection set forth below.
The provisional rejection A) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 20-25 and 28-34 of copending Application No. 17/438,804 (‘804) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) is replaced with a nonprovisional rejection because the copending application has issued as patent US 12,527,784 B2.
The provisional rejection B) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 15 and 19-31 of copending Application No. 17/595,519 (‘519) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn upon further consideration because the claims of the copending application do not recite the antibody of the instant claims but instead the anti-PD-1 antibody sintilimab and do not recite treatment of STS.
The provisional rejection C) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 17-24 and 31-34 of copending Application No. 17/613,332 (‘332) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in view of the abandonment of the copending application.
The provisional rejection D) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 22-24, 30-41 of copending Application No. 17/773,723 (‘723) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn upon further consideration because the claims of the copending application do not recite the antibody of the instant claims but instead the anti-PD-1 antibody sintilimab and do not recite treatment of STS.
The provisional rejection E) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 33, 35-39, 40, 44-52 of copending Application No. 17/997,444 (‘444) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in favor of a new rejection set forth below.
The provisional rejection F) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 18, 19, 22 and 24-40 of copending Application No. 18/003,718 (‘718) in view of Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in favor of a new rejection set forth below.
The provisional rejection G) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 49, 50, 53-61 and 65-68 of copending Application No. 18/292,655 (‘655) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in favor of a new rejection set forth below.
The rejection H) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. US 11,419,862 (‘862) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn upon further consideration because the claims of the copending application do not recite the antibody of the instant claims but instead the anti-PD-1 antibody sintilimab and do not recite treatment of STS.
The rejection I) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,390,458 (’458) in view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn upon further consideration because the claims of the copending application do not recite the antibody of the instant claims but instead the anti-PD-1 antibody sintilimab and do not recite treatment of STS.
The rejection J) of claims 14-23 and 32-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,421,313 (‘313) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in favor of a new rejection set forth below.
The rejection K) of claims 14-23 and 32-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,472,173 (‘173) view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action) and as evidenced by Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) is withdrawn in favor of a new rejection set forth below.
Priority
Filing of the certified translation of foreign priority application (CN202010814874.6), 4/20/2026, is acknowledged. With this, the effective filing date of the instant application is 08/13/2021.
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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 14 -23, 34-36, 38 and 40-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024), Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018, cited in the PTO-892 mailed 1/22/2026) in view of Hoang et al. (Cancer Management Ress,10:1089–1114, 2018) and ClinicalTrial.gov Study NCT03996408 (https://clinicaltrials.gov/study/NCT03996408?intr=pd-l1%20and%20(anlotinib%20OR%20AR3181%20OR%20AR-3181)%20&viewType=Table&limit=50&page=1&rank=7&tab=history&a=1#version-content-panel, 21 Jun. 2019, cited in the PTO-892 mailed 1/22/2026) and Coyne et al. (Paper #66, COTS Annual Meeting 2019 Program, Tokyo, Japan, Nov. 13-16, 2019, pp. iii, 124-125, https://www.ctos.org/Portals/0/PDF/2019%20CTOS%20Final%20Program.pdf).
WO 2016/022630 (Zha) teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leimyosarcoma, lymphangiosarcoma, lymphangioendothelio-
sarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]). Zha does not teach treatment with anlotinib or dosing amounts or frequencies.
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
NCT03996408 is a clinical trial designed to treat advanced cholangiocarcinoma by administration with humanized anti-PD-L1 antibody TQB2450 with anlotinib (Official Title). TQB2450 blocks binding of PD-L1 to PD-1 and restores T cell activity (Arms and Interventions: Assigned Interventions). The antibody is administered at a dose of 1200 mg intravenously on day 1 of each 21-day cycle plus anlotinib capsule given orally one a day for the first 14 days of the cycle followed by a 7 day break (Arms and Interventions:Arms).
Coyne et al. teaches a phase II clinical trial for treatment of alveolar soft part sarcoma with anti-PD-L1 antibody atezolizumab (Objective and start of Methods). Atezolizumab is administered at a fixed dose of 1200 mg in adults or 15 mg/kg (1200 mg max) in pediatric patients once every 21 days (Methods). Of 24 patients, one had a complete response (CR), 10 had a partial response (PR), 11 had stable disease (SD), and the overall response rate (ORR) was 37.5% at the time of paper submission. No patients with CR/PR progressed (Results on p. 124). Six patients had metastatic disease and six had undergone surgery (third and fifth sentences of Results). It is concluded (Conclusion, first sentence), “Atezolizumab is very well tolerated, with single-agent activity resulting in durable responses.”
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have treated a STS by the method of NCT03996408 wherein humanized anti-PD-L1 antibody hu5G11 was substituted for TQB2450 because both antibodies were shown to bind PD-L1, block its binding to PD-1 and increase T cell activity, e.g., IFN-γ secretion, for the treatment of a cancer, including a STS. Further, Coyne et al. supported the use of an anti-PD-L1 antibody for treatment of STS, in particular alveolar soft part sarcoma, including with a single intravenous dose of 1200 mg once every three weeks (see NCT03996408 and Coyne et al.). As implied in Coyne et al., by noting that six patients underwent surgery prior to starting the trial, these patients likely had advanced alveolar soft part sarcoma, while others had CNS metastases. Because both Zha and Shen teach the anti-PD-L1 antibody and anlotinib were useful for treatment of STSs, e.g., leiomyosarcoma, and had the same activities as the agents in NCT03996408, one of ordinary skill in the art would have had a reasonable expectation of success. This is also supported by Table 2 of Hoang et al. wherein it is shown that both PD-1/PD-L1 antibodies and anlotinib are in phase II or III clinical trials for treatment of a variety of STSs. It would have been obvious wherein the dosing regimen of the humanized anti-human PD-L1 antibody of Zha and anlotinib was as set forth in NCT03996408, Coyne et al. and Shen et al., i.e., antibody administered at a dose of 1200 mg intravenously on day 1 of each 21-day cycle plus 12 mg anlotinib capsule given orally once a day for the first 14 days of the cycle followed by a 7 day break. Further, determining the optimal dosage at a particular dosing frequency would have been obvious because “It is not inventive to discover the optimum or workable ranges by routine experimentation” In re Aller, 220, F.2d 4554, 456, (CCPA); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). “Discovery of an optimum value of a result effective variable in a known process is ordinary within the skill of the art.” In re Boesch, 617 F. 2d 272, 276 (CCPA1980). The sequence of anti-PD-L1 antibody hu5G11 of Zha is the same as that of the instant claims.
The Supreme court has acknowledged that (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 at 1390, U.S. 2007):
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, and would see the benefit of doing so, 103 likely bars its patentability. Moreover, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
“…The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” (ibid at 1395) (emphasis added).
Applicant’s arguments that pertain to the new rejection are addressed here:
Applicant argues (page 8, paragraphs 1-4, of REMARKS) clinical trial NCT03996408 is for treatment of cholangiocarcinoma, an epithelial-derived cancer, that is distinct from soft tissue sarcoma (STS), which originates from mesenchymal tissue. These two cancer types have different driving etiologies, e.g., chronic inflammation and infections compared to genetic abnormalities. As a result, they also have different standard regimens of treatment using distinct types of drugs. Therefore, one skilled in the art would understand that treatment of cholangiocarcinoma may not be suitable for STS. Two articles presented as Exhibits 2 and 3 (Jean-Yves Blay, 2017, and Hoang et al., 2018) are mentioned as teaching that STSs are aggressive with little improvement in 5-year survival over the past 5 years. Therefore, one skilled in the art would not have been motivated to look to NCT0399748 with respect to the instant invention. The argument has been fully considered but is not persuasive. It is noted that none of the references submitted as exhibits and discussed in Applicant’s Remarks were listed on an information disclosure statement. As a result, they have been addressed only in so far as Applicant addresses them in their response, with the exception of Hoang et al., which is cited on the attached PTO-892 and relied upon in the rejection above. The new rejection clearly shows that the artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Further Coyne et al. (relied upon above) presented results showing positive effects on alveolar small part sarcoma with the anti-PD-L1 antibody atezolizumab. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma, including alveolar soft part sarcoma, with an anti-PD-L1 antibody and anlotinib. Not only does NCT0399748 provide motivation to use an anti-PD-L1 antibody an anlotinib together, which even though that study is not directed to treated of STS it is directed to treatment of cancer, but all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the instant invention and the results would have been reasonably expected to have been superior to those of either agent alone due to their different but therapeutic mechanisms in their effect on STS.
Applicant argues (end of p. 8 through top of p. 9) that Zha does not disclose the pharmacological activities of antibody 5G11, only that it affects T cell activation/function of T regulatory cells (Examples 5-7). One skilled in the art would understand the examples of Zha do not reflect anticancer activities of the anti-PD-L1 antibody. There is no efficacy data or other information to provide a reasonable expectation of effective treatment of soft tissue sarcoma. The argument has been fully considered but is 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). Antibody 5G11 has excellent pharmacokinetic properties as shown in Tables 4, 7 and 10 of Zha, with the property of blocking binding of PD-L1 to PD-1 (Tables 10 and 16). Examples 5-8 showed it increased IFNγ and IL-2 secretion, reduced the inhibitory effect of Tregs on secretion of IFNγ by T effector cells and could enhance IFNγ secretion by memory T cells. These functions are consistent with those of atezolizumab and other anti-PD-L1 antibodies, which are overall superior to anti-PD-1 antibodies (De Souza et al., Nat. Scientific Rep. 9:11472, 9 pages, 2019, e.g., Abstract).
Applicant argues (pp. 9-10) that Shen et al. only discloses efficacy data for anlotinib in treating STS without combined use of the specific anti-PD-L1 antibody. However, the inventors showed that combined use led to unexpected results of ORR >50% and DCR >90%, which would not been have expected from Zha, Shen and NCT03996408. “Also, it is known in the art that the combination use of an antibody and a small molecule drug cannot easily be expected whether it will be successful in clinical trials. Otherwise, time-consuming and costly clinical trials would not be needed. In fact, the therapeutic efficacy of combination drug regimens is highly dependent on tumor type and is unpredictable.” In the CONTACT-03 phase III study of patients previously treated with an immune checkpoint inhibitor for treatment of advance renal cell carcinoma with atezolizumab plus cabozantinib or cabozantinib alone, the combination was not better than the monotherapy and caused a higher incidence of adverse events (citing Pal et al., The Lancet, 2023, Exhibit 4). On the other hand, pembrolizumab (an anti-PD-1 antibody) with Lenvatinib was therapeutic for treatment of advance renal cell carcinoma but not metastatic NSCLC (Exhibit 5, Yang et al., 2024). The arguments have been fully considered but are not persuasive. A rejection under 35 USC 103 does not require absolute certainty of success but only that there would more likely than not have been success. Shen shows the effectiveness of anlotinib in the treatment of STSs. Hoang et al. showed that in 2018 (two years before the effective filing date of the instant application) two anti-PD-L1 and an anti-PD-1 antibody were in phase II clinical trials for treatment of a variety of STS. Coyne et al. showed anti-PD-L1 atezolizumab was effective for treating alveolar soft part sarcoma. The skilled artisan would have been motivated to have combined two treatments which were both effective for the same disease but worked through different mechanisms and had a reasonable expectation of success based on the known performance of each alone. Further, Applicant has not shown that or provided a preponderance of evidence supporting that the unexpected results referred to in the REMARKS would extend to other STS beyond alveolar soft part sarcoma (see legend of Table 1 of specification). While it is shown that the antibody + anlotinib were effective to establish a disease control rate (DCR, which represents, PR, SD and/or CR) of 100% for 5 different STS, excluding alveolar soft part sarcoma the ORR was 11%. There was some benefit (PR or SD) for all patients; however, the numbers were small with 4, 1, 2 and 2 patients having respectively leiomyosarcoma, epithelioid sarcoma, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma, and fibrosarcoma (Table 2). It is noted that for the CONTACT-03 study referred to by applicant, the patient being treated had already failed treatment with an immune checkpoint inhibitor. Further, as discussed in MPEP 716.02(d) (see In re Clements, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”” In this instance, the evidence supports only treatment of alveolar soft tissue sarcoma where antibody hu5G11-IgG1 is administered intravenously once every 3 weeks and anlotinib capsule was administered daily for 2 weeks within 5 minutes before or after the start of anti-PD-L1 antibody infusion, followed by a 1 week break in anlotinib, such that one treatment cycle was 3 weeks long (p. 26, last paragraph). While individual claims recite one aspect or another of the above treatment, no claim comprises all the limitations of the treatment producing the results which Applicant states are unexpected.
It is maintained for the reasons set forth in the new rejection above and discussed here that the invention is obvious.
Claim(s) 14 -23, 34-36, 38 and 40-45 is/are rejected under 35 U.S.C. 103 as being obvious over WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018, cited in the PTO-892 mailed 1/22/2026), Hoang et al. (Cancer Management Ress,10:1089–1114, 2018) and Coyne et al. (Paper #66, COTS Annual Meeting 2019 Program, Tokyo, Japan, Nov. 13-16, 2019, pp. iii, 124-125).
The applied reference WO 2020/239085 A1 has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1, with the later having the sequences of HCDR1-3 of SEQ ID NO:1-3 and LCDR1-3 of SEQ ID NO:7-9 and variable heavy/light chain region sequences of SEQ ID NO:13/15 (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinib is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients with melanoma were given 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsule form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day of each cycle (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). Yang does not teach treatment of soft tissue sarcoma with the disclosed method.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, antiosarcoma, endothelial sarcoma, leiomyosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
Coyne et al. teaches a phase II clinical trial for treatment of alveolar soft part sarcoma with anti-PD-L1 antibody atezolizumab (Objective and start of Methods). Atezolizumab is administered at a fixed dose of 1200 mg in adults or 15 mg/kg (1200 mg max) in pediatric patients once every 21 days (Methods). Of 24 patients, one had a complete response (CR), 10 had a partial response (PR), 11 had stable disease (SD), and the overall response rate (ORR) was 37.5% at the time of paper submission. No patients with CR/PR progressed (Results on p. 124). Six patients had metastatic disease and six had undergone surgery (third and fifth sentences of Results). It is concluded (Conclusion, first sentence), “Atezolizumab is very well tolerated, with single-agent activity resulting in durable responses.”
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have treated an STS by the method of Yang because both Zha and Shen teach the anti-PD-L1 antibody and anlotinib were useful for treatment of STSs, e.g., leiomyosarcoma. Coyne et al. supported the use of an anti-PD-L1 antibody for treatment of STS, in particular alveolar soft part sarcoma, including with a single intravenous dose of 1200 mg once every three weeks. As implied in Coyne et al., by noting that six patients underwent surgery prior to starting the trial, these patients likely had advanced alveolar soft part sarcoma, while others had CNS metastases. Because both Zha and Shen teach the anti-PD-L1 antibody and anlotinib were useful for treatment of STSs, e.g., leiomyosarcoma, one of ordinary skill in the art would have had a reasonable expectation of success with their combined use. This is also supported by Table 2 of Hoang et al. wherein it is shown that both PD-1/PD-L1 antibodies and anlotinib are in phase II or III clinical trials for treatment of a variety of STSs. The antibodies of Zha have sequences identical to those of Yang and are the same as those of the instant claims.
The Supreme court has acknowledged that (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 at 1390, U.S. 2007):
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, and would see the benefit of doing so, 103 likely bars its patentability. Moreover, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
“…The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” (ibid at 1395) (emphasis added).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Applicant’s arguments that pertain to the new rejection are addressed here:
Applicant argues (p. 10, two last paragraphs, and top of p. 11) that Yang is directed to treatment of melanoma, which is different from soft tissue sarcoma (STS). As discussed above, Zha has no efficacy data or reasonable expectation of effective treatment of STS, while Shen only discloses efficacy data of anlotinib only for treating STS. The arguments have been fully considered but are not persuasive. The new rejection above clearly shows that the artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Further Coyne et al. (relied upon above) presents results showing positive effects on alveolar small part sarcoma with the anti-PD-L1 antibody atezolizumab provided at the same dose as the instantly claimed anti-PD-L1 antibody. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. In view of Yang and Shen, Hoang et al. and Coyne et al., the prior art supports the reasonable expectation of success in treating a soft tissue sarcoma, including alveolar soft part sarcoma, with an anti-PD-L1 antibody and anlotinib. All the claimed elements were known in the prior art and one of ordinary skill in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the instant invention and the results would have been reasonably expected to have been superior to those of either drug alone due to their different but therapeutic mechanisms in their effect on STS.
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.
A) Claims 14 -23, 34-36, 38 and 40-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,527,784 B2 in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024), Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and Hoang et al. (Cancer Management Ress,10:1089–1114, 2018).
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs and the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS) and claims of ‘804 are drawn to treatment of small cell lung cancer.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leiomyosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
It would have been obvious to treat STS with the method of ‘804 in view of the prior art teaching of the applicability of anti-PD-L1 antibodies and anlotinib in the treatment of STS, which prior art also supported a reasonable expectation of success.
Applicant argues (middle of p. 12) as discussed above (in reference to the rejection under 35 USC 103) “the clinical efficacy of antibody-small molecule combination therapy is difficult to predict, and even the same combination therapy can produce vastly different outcomes in different types of tumors.” Therefore, even in view of Zha and Shen, a person skilled in the art would not reasonably expect the successful treatment of STS with the claimed specific antibody and anlotinib. The argument has been fully considered but is not persuasive. The artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma with an anti-PD-L1 antibody and anlotinib.
E) Claims 14 -23, 34-36, 38 and 40-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 33, 35-39, 40, 44-52 of copending Application No. 17/997,444 (‘444) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024), Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and Hoang et al. (Cancer Management Ress,10:1089–1114, 2018).
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs or the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 1200 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. A pharmaceutical combination comprises the anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1 is recited in the claims of both.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS) and claims of ‘444 are drawn to treatment of kidney cancer.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leiomyosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have lead to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
It would have been obvious to treat STS with the method of ‘444 in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS, which prior art also supported a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Applicant argues (top of p. 14) as discussed above (in reference to the rejection under 35 USC 103) “the clinical efficacy of antibody-small molecule combination therapy is difficult to predict, and even the same combination therapy can produce vastly different outcomes in different types of tumors.” Therefore, even in view of Zha and Shen, a person skilled in the art would not reasonably expect the successful treatment of STS with the claimed specific antibody and anlotinib. The argument has been fully considered but is not persuasive. The artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma with an anti-PD-L1 antibody and anlotinib.
F) Claims 14 -23, 34-36, 38 and 40-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, 19, 24-30 and 41-47 of copending Application No. 18/003,718 (‘718) in view of Shen et al. (J. Hematol. Oncol. 11:120, 11 pages, 2018) and Hoang et al. (Cancer Management Ress,10:1089–1114, 2018).
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs or least the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS). Independent claim 18 of ‘718 is drawn to treatment of endometrial cancer. However, independent claim 31 of ‘718 is drawn to a method of treating a MSI-H and/or dMMM tumor with the same anti-PD-L1 antibody, including as specified in claim 32 wherein the tumor is a soft tissue sarcoma (STS), but administration of anlotinib is absent from the STS treatment claims.
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
Because the methods are identical in terms of agents used in the treatment and dosing amounts and regimen and all claims are drawn to a method of treating a cancer, and because ‘718 claims the antibody can be used to treat STS, it would have been obvious in view of Shen and Hoang et al. to have used the method of claim 1 of ‘718 and dependent claims to treat STS, which prior art also supported a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Applicant argues (middle of p. 14) as discussed above (in reference to the rejection under 35 USC 103) “the clinical efficacy of antibody-small molecule combination therapy is difficult to predict, and even the same combination therapy can produce vastly different outcomes in different types of tumors.” Therefore, even in view of Zha and Shen, a person skilled in the art would not reasonably expect the successful treatment of STS with the claimed specific antibody and anlotinib. The argument has been fully considered but is not persuasive. The artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma with an anti-PD-L1 antibody and anlotinib.
G) Claims 14 -23, 34-36, 38 and 40-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 49, 53-57, 59, 61, 65-68 and 70-74 of copending Application No. 18/292,655 (‘655) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024), Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and Hoang et al. (Cancer Management Ress,10:1089–1114, 2018).
The claims of the instant and copending application are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib. Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDRs or the VH/VL of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle.
The difference between the applications is that the instant claims are drawn to treatment of soft tissue sarcoma (STS) and claims of ‘655 are drawn to treatment of small cell lung cancer and include treatment with a platinum-based anti-tumor drug and topoisomerase inhibitor. Claim 56 of ‘655 specifies a second treatment phase may be administration of only the anti-PD-L1 antibody and anlotinib.
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leiomyosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
It would have been obvious to treat STS with the method of ‘655 with or without the additional therapeutics because ‘655 said a second treatment phase could be anti-PD-L1 antibody and anlotinib and in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS, which prior art also supported a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Applicant argues (section bridging pp. 14-15) as discussed above (in reference to the rejection under 35 USC 103) “the clinical efficacy of antibody-small molecule combination therapy is difficult to predict, and even the same combination therapy can produce vastly different outcomes in different types of tumors.” Also, treatment with three agents does not predict good clinical efficacy with only two of the agents. Therefore, even in view of Zha and Shen, a person skilled in the art would not reasonably expect the successful treatment of STS with the claimed specific antibody and anlotinib. The argument has been fully considered but is not persuasive. The artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma with an anti-PD-L1 antibody and anlotinib and without a further third anticancer agent.
J) Claims 14 -23, 34-36, 38 and 40-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,421,313 (‘313) in view of WO 2016/022630 A1 (Zha, cited in the IDs filed 11/07/2024) and Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and Hoang et al. (Cancer Management Ress,10:1089–1114, 2018).
The claims of the instant and patent are both drawn to a method of treating a cancer in a subject by administration of an antibody that binds PD-L1 and anlotinib (instant claim 1 and claim 8 of ‘313). Both applications recite in the claims the same anti-PD-L1 antibody, having the 6 CDR, VH/VL or heavy and light chain of hu13C5 or hu5G11. They recite the same doses and administration schedule, including 1200 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib. Administration is claimed as anlotinib administered on days 1-14 of each 3-week cycle (84-168 mg total) and antibody is administered on day 1 of the cycle. A pharmaceutical combination comprises the anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35—29):1 is recited in the claims of both.
The patent differs in that the treatment is of a tumor in the biliary system, liver cancer, triple negative breast cancer and/or lung cancer, with the instant claims drawn to treatment of soft tissue sarcoma (STS).
Zha teaches treatment of cancer by administration of an anti-human PD-L1 antibody (Example 1 and [0087]), including liposarcoma, angiosarcoma, endothelial sarcoma, leiomyosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, rhabdomyosarcoma, fibrosarcoma and myxosarcoma ([0089]). The antibody may be administered with an additional therapeutic agent and administration may be concurrent or sequential. They may be formulated separately or administered in the same formulation (([0095]). Anti-PD-L1 antibodies hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1are taught, including their sequences, heavy and light chain CDR1-3 of SEQ ID NO: 81-85 (5G11) and 93-98 (13C5) ([0109]), comprised by the humanized (hu) heavy and light chain variable regions (VH/VL) of SEQ ID NO:42/44 and 46/48, respectively (see also claim 5). Heavy chain of hu5G11-IgG1 and -IgG4 are SEQ ID NO:70 and 72, respectively, and light chain is SEQ ID NO:74. The heavy chain of hu13C5-IgG1 and -IgG4 are SEQ ID NO:76 and 78, respectively, and light chain is SEQ ID NO:80 ([0110]). The antibodies block binding of PD-L1 to PD-1 ([0116]). They also induced secretion of IFN-γ and IL-2 in mixed lymphocyte cultures and also reduced the inhibitory effect of T regulatory cells on secretion of IFN-γ by T effector cells ([0118]-[0119]). They enhanced IFN-γ secretion by T cells ([0120]).
Shen et al. discusses the clinical use of anlotinib, which is an oral receptor tyrosine kinase (RTK) inhibitor taken orally that targets multiple RTKs (Fig. 1 and p. 2/11, col. 1, third paragraph). Its antiangiogenic activity is stronger than 3 other such drugs, including sunitinib, sorafenib and ninetedanib (p. 2/11, start of col. 2). As discussed on p. 4/11, col. 1, second and third full paragraph, a phase I study showed that anlotinib caused tumor shrinkage in soft tissue sarcomas (STSs). This led to a single-arm phase II study in patients with advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, who failed previous conventional treatment. For the phase II study, “Overall, anlotinib demonstrated better clinical benefits in many pathological types of STS.” A related phase IIb study in patients with advance STS who were treatment-intolerant or progressed on anthracycline-based chemotherapy showed overall response rate (ORR) and disease control rate (DCR) that was significantly higher than in the control group. “This trial further confirmed the efficacy and safety of anlotinib in advanced STS [44].” Based on clinical findings, the recommended dosing has been 12 mg daily for 2 weeks, followed by a 1-week break (p. 3/11, end of col. 1 and first paragraph of col. 2). There are ongoing clinical trials evaluating anlotinib in several STS subtypes, including leiomyosarcoma and synovial sarcoma (p. 7/11, col. 2, second full paragraph, also Table 3). It is concluded (p. 7/11, last paragraph), “Anlotinib has exceptional efficacy and acceptable toxicity for the treatment of advanced NSCLC [non-small cell lung cancer] and STS.”
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
It would have been obvious to treat STS with the method of ‘313 in view of the prior art teaching of the applicability of the anti-PD-L1 antibody and anlotinib in the treatment of STS, which prior art also supported a reasonable expectation of success.
Applicant argues (section bridging pp. 15-16) as discussed above (in reference to the rejection under 35 USC 103) “the clinical efficacy of antibody-small molecule combination therapy is difficult to predict, and even the same combination therapy can produce vastly different outcomes in different types of tumors.” Therefore, even in view of Zha and Shen, a person skilled in the art would not reasonably expect the successful treatment of STS with the claimed specific antibody and anlotinib. The argument has been fully considered but is not persuasive. The artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma with an anti-PD-L1 antibody and anlotinib.
K) Claims 14-23, 34-36, 38 and 40-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,472,173 (‘173) view of WO 2020/239085 A1 (Yang; cited in the IDS filed 02/09/2023, translation attached as an appendix to this Office action), as evidenced by Shen et al., (J. Hematol. Oncol. 11:120, 11 pages, 2018) and in view of Hoang et al. (Cancer Management Ress,10:1089–1114, 2018).
The claims of the instant application are drawn to a method of treating a soft tissue sarcoma (STS) in a subject by administration of an antibody that binds PD-L1 and anlotinib. The anti-PD-L1 antibody has the 6 CDRs or least the VH/VL of hu13C5 or hu5G11. The doses and administration schedule include 600-2400 mg anti-PD-L1 and 6, 8, 10 and/or 12 mg anlotinib, as well as a pharmaceutical composition comprising 600-2400 mg anti-PD-L1 antibody and 84-168 mg anlotinib. Anlotinib is administered on days 1-14 of each 3-week cycle and antibody is administered on day 1 of the cycle. Further claimed is a pharmaceutical composition having a concentration of 10-60 mg/mL anti-PD-L1 antibody.
Patent ‘173 claims a method of treating a soft tissue sarcoma comprising administering the compound of formula 1, 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, and toripalimab (claim 1). Treatment according to claim 2 is after STS has progressed or recurred after chemotherapy treatment or has not previously been systemically treated with a tyrosine kinase inhibitor (TKI) or PD-1/PD-L1 inhibitor (claim 3). The compound of formula 1 is administered at a dose of 6, 8, 10 or 12 mg once daily and anti-PD-1 antibody toripalimab is administered once every week, every 2, 3 or 4 weeks in a single dose up to 600 mg (claims 5-6). Toripalimab is defined in the specification as an anti-PD-1 antibody (col. 8, lines 23-24). The compound of formula 1 is defined as anlotinib (col. 1, lines 63-67).
The claims of ‘173 differ from the instant claims in that they do not recite the same antibody or any dosages thereof.
WO 2020/239085 (Yang) teaches treatment of melanoma with the anti-PD-L1 antibody hu13V5-hIgG1 and -hIgG4 and 5G11-hIgG1 having the sequences of HCDR1-3 of SEQ ID NO:1-3 and 4-6 and LCDR1-3 of SEQ ID NO:7-9 and 10-12, respectively, and variable heavy and light chain regions of SEQ ID NO:13/15 and 14/16, respectively (p. 6, last full paragraph; [0010] of translation). The amount of antibody administered is 600-2400 mg and amount of anlotinib is 84-168 mg, with a treatment cycle that may be 21 days (claim 6). More specifically, a pharmaceutical composition comprising 6, 8, 10 or 12 mg anlotinib and 600-2400 mg anti-PD-L1 is taught in claim 4. The weight ratio of the anti-PD-L1 antibody and anlotinb is (0.35-29):1, (3.5-29):1, (3.5- 14.5):1 or (7-14.5):1 (claim 5). Administration of the antibody and anlotinib may be simultaneous or sequential (claim 9). In the example, patients were give 10 cycles, 21 days each, of 1200 mg anti-PD-L1 antibody hu5G11-hG1 by injection and 12 mg oral anlotinib (capsule form, section 1.2 of p. 11 through 1.5 of p. 12; [0160], [0171]-[0173] of translation). It is taught that anlotinib can be administered daily on days 1-14 of each 21-day cycle, while the antibody is administered only on the first day (p. 3, last third, [0043]-[0045] of translation). A pharmaceutical composition comprising the anti-PD-L1 antibody may have an antibody concentration of 10-60 mg/ml (p. 4, third paragraph; [0051] translation). A kit is claimed comprising a combination of anti-PD-L1 antibody and anlotinib (claims 5 and 12-18).
Shen et al. defines 1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine as anlotinib (p. 2/11, col. 1, start of third paragraph).
Hoang et al. reviews treatment of soft tissue sarcomas as of two years prior to the effective filing date of the instant application. Table 2 shows that two different anti-PD-L1 antibodies were being used in phase II clinical trials, one, avelumab, for the treatment of liposarcoma and leiomyosarcoma, and the other, atezolizumab, for treatment of several STS, in conjunction with a second therapeutic. Further, also shown in Table 2 is that anti-PD-1 antibody nivolumab in combination with AB1009 (an mTOR inhibitor) is in a phase II clinical trial for treatment of liposarcoma, Ewing’s sarcoma, angiosarcoma and undifferentiated pleomorphic sarcoma. A phase III trial with Anlotinib for treatment of leiomyosarcoma and synovial sarcoma are listed in Table 2. Hoang et al. notes (p. 1104, col. 2, third paragraph) that “Breakthroughs in immunobased treatments, notably with regard to PDL1/PD1-inhibiting antibodies, have led to successful treatments in several cancers. Recently, the FDA approved a fourth PDL1-specific antibody -- durvalumab.” There is evidence that tumors do not need to express PDL1 for an anti-PD-L1 antibody to cause a therapeutic response (p. 1105, col. 1, first paragraph).
It would have been obvious to treat STS with the method of ‘173, substituting anti-PD-L1 antibody hu5G11 of Yang and Zha for toripalimab because both inhibited the binding of PD-1 to PD-L1 and were used to treat cancers. Further, Hoang et al. support treatment of STS with PD-1 and PD-L1 antibodies, including treatment of STS with anlotinib. It would have been obvious to administer the anti-PD-L1 antibody in the dosage and in the regimen taught by Yang since that was for treatment of a cancer and the amounts of and timings of anlotinib were the same. The success of the prior art supports a reasonable expectation of success for the antibody + anlotinib combination in the treatment of STS.
Applicant argues (top of p. 14) as discussed above (in reference to the rejection under 35 USC 103) “the clinical efficacy of antibody-small molecule combination therapy is difficult to predict, and even the same combination therapy can produce vastly different outcomes in different types of tumors.” Therefore, even in view of Zha and Shen, a person skilled in the art would not reasonably expect the successful treatment of STS with the claimed specific antibody and anlotinib. The argument has been fully considered but is not persuasive. The artisan of ordinary skill would have looked to anti-PD-L1 antibodies and anlotinib (see, for example, Hoang) for treatment of STS. Shen et al. (relied upon above) showed anlotinib had positive therapeutic results for advanced STS, including fibrous histocytoma, liposarcoma, leiomyosarcoma, synovial sarcoma and others, for patients who failed previous conventional treatment. Shen et al. also reports there are ongoing clinical trials evaluating anlotinib in several STS subtypes. The prior art supports the reasonable expectation of success in treating a soft tissue sarcoma with an anti-PD-L1 antibody and anlotinib.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
July 16, 2026
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