DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage entry of PCT/CN2020/085552 filed on 04/20/2020.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in CHINA (201910315417) on 04/19/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 23, 2025 has been entered.
Response to Amendment
By Applicant’s amendment filed on December 3, 2025 claims 3 and 25-26 have been amended; and claims 1, 2, 6, 16-20 have been canceled. Claims 5, 7, 12-15, 22 and 23 were previously canceled.
Claims 3-4, 8-11, 21, and 24-26 are currently presented for examination.
Response to Arguments
Due to Applicant’s amendments to the claims the previous rejection of claims 1-4, 6, 9-11, 16, 18-21 and 24 under 35 U.S.C. 102(a)(1) over Clinical Trials NCT03416517 is hereby withdrawn since the prior art reference does not teach vindesine. Applicant’s arguments with respect to said rejection are moot in view of the withdrawal of the rejection. However, Applicant’s amendments to the claims necessitate a new rejection under 35 USC 103.
Due to Applicant’s amendments to the claims the previous rejection of claims 8, 17, 25 and 26 under 35 U.S.C. 103 over Clinical Trials NCT03416517 in view of Chen et al. is hereby withdrawn since the prior art reference does not teach vindesine. Applicant’s arguments with respect to said rejection are moot in view of the withdrawal of the rejection. However, Applicant’s amendments to the claims necessitate a new rejection under 35 USC 103.
Due to Applicant’s amendments to the claims the previous rejection of claims 1-4, 8-11, 16-21 and 24-26 under 35 U.S.C. 103 as being unpatentable over Zhang et al. in view of Shen et al. is hereby withdrawn since the prior art reference does not teach vindesine. Applicant’s arguments with respect to said rejection are moot in view of the withdrawal of the rejection. However, Applicant’s amendments to the claims necessitate a new rejection under 35 USC 103.
Due to Applicant’s amendments to the claims the previous rejection of claim 6 under 35 U.S.C. 103 over Zhang et al. in view of Shen et al. and Raciborska et al. is hereby withdrawn since the prior art reference does not teach vindesine. Applicant’s arguments with respect to said rejection are moot in view of the withdrawal of the rejection. However, Applicant’s amendments to the claims necessitate a new rejection under 35 USC 103.
Due to Applicant’s amendments to the claims the previous double patenting rejections are hereby withdrawn since the patents do not teach vindesine. However, Applicant’s amendments to the claims necessitate new double patenting rejections.
Although all previous rejections have been withdrawn, some of Applicant’s arguments with respect to the references which are being utilized again in the new rejections detailed below will be discussed below.
With respect to the publication of the clinical trial protocol on the ClinicalTrials.gov website, Applicant argues that said publication merely constitutes one part of the clinical trial filing procedure and it does not explicitly or implicitly disclose that the drug exhibits specific pharmacological activity, therapeutic use, or efficacy. Applicant argues that NCT '517 only discloses a clinical protocol for anlotinib combined with irinotecan in treating Ewing's sarcoma, while providing no efficacy data, specific pharmacological activity or therapeutic use. Applicant argues that this was only a planned clinical trial with an estimated study completion date of December 2020 and this completion date was later than the international application date of the present application (April 20, 2020), which claims priority back to Chinese Patent Application No. 201910315417.X filed on April 19, 2019. Applicant argues that prior to the effective filing date of the present invention, one skilled in the art could not have known the results of the clinical trial in NCT '517.
These arguments are found not persuasive because efficacy is not a requirement for prior art enablement. A prior art is enabling if a person of ordinary skill in the art could make or use the claimed invention without undue experimentation based on the disclosure of that particular document. A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005)). See also MPEP § 2122.
Furthermore, a reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the effective filing date of the claimed invention for applications or patents subject to the first inventor to file provisions of the AIA or at the time the invention was made for applications or patents subject to pre-AIA law. "Such possession is effected if one of ordinary skill in the art could have combined the publication’s description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
In the instant case, the NCI’517 clinical trial protocol made available prior to the effective filing date of the claimed invention, provides adequate, in depth detail to enable a person of ordinary skill in the art to carry out the claimed invention without undue experimentation. Applicant provides no specific evidence or persuasive reasoning as to why undue experimentation would have been required for an ordinary artisan to follow the disclosure of NCI’517 which is similar to the method as currently claimed.
With respect to the Zhang and Shen references, Applicant argues that as known in the art, Ewing’s sarcoma (ES) is recognized as an independent bone tumor, defined as a small round cell tumor of bone or soft tissue originating in neuroectoderm, while soft tissue sarcomas (STS) are a group of rare malignant tumors arising from mesenchymal cells, and thus, ES sarcoma cannot be considered as one type of STS. Applicant argues that Zhang relates to a method for treating STS with anlotinib, rather than treating Ewing’s sarcoma (ES) and Shen discloses that a randomized phase IIB trial demonstrated that anlotinib significantly prolonged the median progression-free survival (PFS) in patients with advanced STS. Shen also discloses that several ongoing trials are attempting to clarify the roles of anlotinib in STS, particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma. Thus Applicant argues that Shen clearly indicates that, although anlotinib can significantly prolong the median PFS in patients with advanced STS, the effect of anlotinib on treating Ewing sarcoma is still unknown for those skilled in the art.
Applicant further argues that in Example 7 of the present application, patients with advanced Ewing's sarcoma who failed a prior treatment were divided into groups A and B, in which Group A had 23 patients aged 16 years or over and Group B had 12 patients younger than 16 years. Each group was provided with the effective therapeutic doses of anlotinib + irinotecan + vindesine. The research results of groups A and B were evaluated at week 12: for the two groups, the objective response rates (ORRs) at week 12 was 62.5% and 83.3%, respectively, and a complete response (CR) is observed in one case of 23 patients aged 16 or over. The combination of anlotinib with vindesine and irinotecan has achieved an improved objective response rate for patients with Ewing's sarcoma, which cannot be expected based on the applied references. Thus Applicant argues that the combination of anlotinib + irinotecan + vindesine had unexpected effects in treating Ewing's sarcoma.
These arguments are found not persuasive since the rejection of record recognizes that Zhang does not teach the treatment of Ewing’s sarcoma but rather teaches the treatment of STS. However, this deficiency is cured by the teachings of Shen et al. which specifically teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. further states that it is noteworthy that most of these are phase III studies due to the rare incidence of STS (page 7). Thus Shen et al. teaches and suggests that a person of ordinary skill in the art would reasonably expect similar results for the treatment of Ewing sarcoma as STS and would be able to reasonably predict efficacy for STS based on results achieved for Ewing sarcoma treatment. Therefore Shen et al. teaches that Ewing sarcoma is a STS subtype and provides a rationale or reasoning to treat ES based on the teachings of Zhang which teaches treating STS. Furthermore Shen et al. specifically teaches that prior to the effective filing date of the claimed invention, a phase III trial for treating advanced Ewing sarcoma with anlotinib and irinotecan was already ongoing (Table 3 page 8). Thus prior to the effective filing date of the claimed invention, treating advanced Ewing sarcoma with anlotinib and irinotecan was known in the art as taught by Shen et al. Accordingly, based on the teachings of Shen et al., a person of ordinary skill in the art would have reasonably expected anlotinib to be suitable for the treatment of ES based on the teaching of Zhang et al. which teaches that anlotinib is useful for the treatment of STS.
Furthermore, at the very least, it would have been obvious to try anlotinib for the treatment of Ewing sarcoma based on the teachings of Zhang et al. which teaches the treatment of another type of sarcoma comprising the administration of anlotinib. An "obvious to try" rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. " [A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under 35 USC § 103." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 538, 421, 82 USPQ2d 1385, 1397 (2007).
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Applicant’s data as presented in Example 7 is found not persuasive since said data does not demonstrate unexpected results since the data is not compared with any other data. Applicant has not compared the data to data of the closest prior art or provided any explanation why said data would have been considered unexpected in view of the prior art cited. Thus Applicant’s data merely affirms that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716.
New and modified rejections necessitated by Applicant’s amendments to the claims are detailed below. This action is NON-final.
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 3-4, 8-11, 16, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-22 of U.S. Patent No. 10,100,034 in view of Shen et al. (Journal of Hematology & Oncology (2018) 11:120) (Provided on IDS 11/09/2021) and Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095).
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, and further administering a second therapeutic agent.
The patent claims salts of anlotinib including the bishydrochloride acid salt as well as a method of treating neoplastic disease including sarcoma comprising administering the salts of anlotinib and further administering a second therapeutic agent.
The patent does not specifically teach treating Ewing’s sarcoma as claimed in the instant claims. The patent does not teach administering a second therapeutic agent that is a combination of irinotecan and vindesine.
However, the patent claims the treatment of sarcoma.
Shen et al. teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. teaches a phase III trial treating advanced Ewing sarcoma with anlotinib and irinotecan (Table 3 page 8).
Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to treat Ewing’s sarcoma based on the claims of the patent which claims a method of treating sarcoma comprising the administration of salts of anlotinib and according to Shen et al. Ewing’s sarcoma is a type of sarcoma which is being investigated for treatment with anlotinib.
Thus in view of the combination of the patent claims and the teachings of Shen et al. a person of ordinary skill in the art would have been specifically motivated to treat Ewing’s sarcoma comprising the administration of anlotinib and the salts of anlotinib claimed in the patent.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine cited prior art teachings which render obvious the combination of anlotinib and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to combine vindesine to anlotinib and irinotecan with a reasonable expectation of improved treatment of Ewing’s sarcoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application and the cited claims of the patent are mutually obvious and thus not patentably distinct.
Claims 3-4, 8-11, 16, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,544,125 in view of Shen et al. (Journal of Hematology & Oncology (2018) 11:120) (Provided on IDS 11/09/2021) and Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095).
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, and further administering a second therapeutic agent.
The patent claims salts of anlotinib including the bishydrochloride acid salt as well as a method of treating neoplastic disease including sarcoma comprising administering the salts of anlotinib and further administering a second therapeutic agent.
The patent does not specifically teach treating Ewing’s sarcoma as claimed in the instant claims. The patent does not teach administering a second therapeutic agent that is a combination of irinotecan and vindesine
However, the patent teaches the treatment of sarcoma.
Shen et al. teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. teaches a phase III trial treating advanced Ewing sarcoma with anlotinib and irinotecan (Table 3 page 8).
Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to treat Ewing’s sarcoma based on the claims of the patent which claims a method of treating sarcoma comprising the administration of salts of anlotinib and according to Shen et al. Ewing’s sarcoma is a type of sarcoma which is being investigated for treatment with anlotinib.
Thus in view of the combination of the patent claims and the teachings of Shen et al. a person of ordinary skill in the art would have been specifically motivated to treat Ewing’s sarcoma comprising the administration of anlotinib and the salts of anlotinib claimed in the patent.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine cited prior art teachings which render obvious the combination of anlotinib and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to combine vindesine to anlotinib and irinotecan with a reasonable expectation of improved treatment of Ewing’s sarcoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application and the cited claims of the patent are mutually obvious and thus not patentably distinct.
Claims 3-4, 8-11, 16, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,251,876 (Provided on IDS 11/09/2021) in view of Shen et al. (Journal of Hematology & Oncology (2018) 11:120) (Provided on IDS 11/09/2021) and Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095).
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, and further administering a second therapeutic agent.
The patent claims method of treating tumors including soft tissue sarcoma comprising administering anlotinib or a pharmaceutically acceptable salt thereof such as dihydrochloride.
The patent does not specifically teach treating Ewing’s sarcoma as claimed in the instant claims. The patent does not teach administering a second therapeutic agent that is a combination of irinotecan and vindesine.
However, the patent teaches the treatment of soft tissue sarcoma.
Shen et al. teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. teaches a phase III trial treating advanced Ewing sarcoma with anlotinib and irinotecan (Table 3 page 8).
Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to treat Ewing’s sarcoma based on the claims of the patent which claims a method of treating soft tissue sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as dihydrochloride, and according to Shen et al. which teaches that Ewing’s sarcoma is a subtype of soft tissue sarcoma which is being investigated for treatment with anlotinib and a second therapeutic agent irinotecan.
Thus in view of the combination of the patent claims and the teachings of Shen et al. a person of ordinary skill in the art would have been specifically motivated to treat Ewing’s sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as the dihydrochloride salt and further administer a second therapeutic agent such as irinotecan as taught by Shen et al.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine cited prior art teachings which render obvious the combination of anlotinib and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to combine vindesine to anlotinib and irinotecan with a reasonable expectation of improved treatment of Ewing’s sarcoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application and the cited claims of the patent are mutually obvious and thus not patentably distinct.
Claims 3-4, 8-11, 16, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,968,597 (Provided on IDS 11/09/2021) in view of Shen et al. (Journal of Hematology & Oncology (2018) 11:120) (Provided on IDS 11/09/2021) and Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095).
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, and further administering a second therapeutic agent.
The patent claims a method of treating soft tissue sarcoma comprising administering anlotinib or a pharmaceutically acceptable salt thereof such as dihydrochloride.
The patent does not specifically teach treating Ewing’s sarcoma as claimed in the instant claims. The patent does not teach administering a second therapeutic agent that is a combination of irinotecan and vindesine.
However, the patent teaches the treatment of soft tissue sarcoma.
Shen et al. teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. teaches a phase III trial treating advanced Ewing sarcoma with anlotinib and irinotecan (Table 3 page 8).
Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to treat Ewing’s sarcoma based on the claims of the patent which claims a method of treating soft tissue sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as dihydrochloride, and according to Shen et al. which teaches that Ewing’s sarcoma is a subtype of soft tissue sarcoma which is being investigated for treatment with anlotinib and a second therapeutic agent irinotecan.
Thus in view of the combination of the patent claims and the teachings of Shen et al. a person of ordinary skill in the art would have been specifically motivated to treat Ewing’s sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as the dihydrochloride salt and further administer a second therapeutic agent such as irinotecan as taught by Shen et al.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine cited prior art teachings which render obvious the combination of anlotinib and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to combine vindesine to anlotinib and irinotecan with a reasonable expectation of improved treatment of Ewing’s sarcoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application and the cited claims of the patent are mutually obvious and thus not patentably distinct.
Claims 3-4, 8-11, 16, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,183,017 in view of Shen et al. (Journal of Hematology & Oncology (2018) 11:120) (Provided on IDS 11/09/2021) and Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095).
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, and further administering a second therapeutic agent.
The patent claims a method of treating soft tissue sarcoma comprising administering anlotinib or a pharmaceutically acceptable salt thereof such as dihydrochloride.
The patent does not specifically teach treating Ewing’s sarcoma as claimed in the instant claims. The patent does not teach administering a second therapeutic agent that is a combination of irinotecan and vindesine.
However, the patent teaches the treatment of soft tissue sarcoma.
Shen et al. teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. teaches a phase III trial treating advanced Ewing sarcoma with anlotinib and irinotecan (Table 3 page 8).
Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to treat Ewing’s sarcoma based on the claims of the patent which claims a method of treating soft tissue sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as dihydrochloride, and according to Shen et al. which teaches that Ewing’s sarcoma is a subtype of soft tissue sarcoma which is being investigated for treatment with anlotinib and a second therapeutic agent irinotecan.
Thus in view of the combination of the patent claims and the teachings of Shen et al. a person of ordinary skill in the art would have been specifically motivated to treat Ewing’s sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as the dihydrochloride salt and further administer a second therapeutic agent such as irinotecan as taught by Shen et al.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine cited prior art teachings which render obvious the combination of anlotinib and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to combine vindesine to anlotinib and irinotecan with a reasonable expectation of improved treatment of Ewing’s sarcoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application and the cited claims of the patent are mutually obvious and thus not patentably distinct.
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.
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 3-4, 9-11, 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials NCT03416517 First posted January 31, 2018-herein referred to as NCT’517 (Provided on IDS 03/01/2023) in view of Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095).
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I having the following structure:
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also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent which is a combination of irinotecan and vindesine.
NCT’517 clinical trial provides the following teachings:
The investigators explored the activity of anlotinib combined with irinotecan in patients with relapsed and metastatic Ewing Sarcoma (Brief Summary). After standard multimodal therapy, the prognosis of relapsed and metastatic Ewing Sarcoma is dismal and unchanged over the last decades. Thus, the investigators explored the activity of anlotinib combined with irinotecan in patients with relapsed and metastatic Ewing Sarcoma after the failure of first-line chemotherapy with doxorubicin, vincristine, cyclophosphamide, ifosphamide and etoposide (Detailed Description).
Treatment in phase 1b includes Anlotinib 12 or 8 mg/d PO on days 1-14 q3w; Irinotecan 20 or 15 mg/m2/d over 60 minutes on days 1-5 and 8-12 q3w; and Vincristine 1.4mg/m2/d IV on days 1,8 q3w (Arms and Intervention). Treatment repeats every 3 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Treatment in phase 2 includes Anlotinib 12 or 8 mg/d PO on days 1-14 q3w; Irinotecan 20 or 15 mg/m2/d IV over 60 minutes on days 1-5 and 8-12 q3w; the final dose of anlotinib and irinotecan depends on the result from previous phase Ib study; and Vincristine 1.4mg/m2/d IV on days 1,8 q3w. Treatment repeats every 3 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity (Arms and intervention).
Thus the clinical trial teaches a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I also known as anlotinib and AL3818 and further administering a second therapeutic agent such as a combination of irinotecan and vincristine wherein the patient treated is one that is after failure of a prior treatment.
NCT’517 does not teach administration of vindesine.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of NCT’517 which teaches the combination of anlotinib, vincristine and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to substitute vindesine for vincristine in the methos of NCT’517 with a reasonable expectation of improving the treatment of Ewing’s sarcoma since Pessetto et al. demonstrates that vindesine is a potent inhibitor of EWS. It is prima facie obvious to substitute one known compound having the same or similar function for another known compound to obtain predictable results. In the alternative, it would have been obvious to a person of ordinary skill in the art to combine vindesine to the treatment compounds of NCT’517 with a reasonable expectation of improved results. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings,
Claims 8, 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials NCT03416517 First posted January 31, 2018-herein referred to as NCT’517 (Provided on IDS 03/01/2023) in view of Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095) as applied to claims 3-4, 9-11, 21 and 24 above and further in view of Chen et al. U.S. Publication No. 2016/0326138 A1.
Claims 8, 25 and 26 of the instant application claim the use of a pharmaceutically acceptable salt of the compound of formula I such as a salt formed by hydrochloric acid to produce a dihydrochloride salt.
NCT’517 is as set forth above.
NCT’517 does not teach a salt form of anlotinib.
Chen et al. teaches salts of anlotinib (abstract). Chen et al. teaches the preparation of a pharmaceutical composition that comprises the salts or stable crystalline salt forms of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)-methyl)cyclopropanamine and a pharmaceutically acceptable carrier [0032]. Chen et al. teaches bishydrochloride acid, bishydrochloridehydrate acid, bismaleic acid and succinic acid salt, and their stable crystalline salt forms or stable crystalline free base form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-cyclopropanamine [0036]-[0038]. Chen et al. teaches AL3818 free base, its 2HCl salts (mono or bis), its bis-maleic acid salt and its succinic salt [0059] and [0069]. Chen et al. specifically teaches AL3818 bisHCl salt [0071]. Claim 11 of Chen et al. claims a salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)-methyl)-cyclopropanamine is selected from: bishydrochloride acid salt, bishydrochloridehydrate acid salt, bismaleic acid salt and succinic acid salt.
Thus prior to the effective filing date, pharmaceutically acceptable salts of anlotinib, including bishydrochloride acid salt, were known in the art.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to utilize anlotinib free base or any suitable pharmaceutically acceptable salt of anlotinib known in the art including the dihydrochloride (bishydrochloride) acid salt of anlotinib with a reasonable expectation of similar success. Therefore, in the absence of secondary considerations such as unexpected results the use of any suitable pharmaceutically acceptable salt of anlotinib known in the art including the dihydrochloride (bishydrochloride) acid salt of anlotinib is rendered obvious.
Thus claims 8, 25 and 26 of the instant application are rendered obvious in view of the cited prior art teachings.
Claims 3-4, 8-11, 21 and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. U.S. Publication No. 2017/0202828 A1 in view of Shen et al. (Journal of Hematology & Oncology (2018) 11:120) (Provided on IDS 11/09/2021) and Pessetto et al. (Oncotarget, 2017, Vol. 8, (No. 3), pp: 4079-4095.
The cited claims of the instant application claim a method of treating Ewing’s sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I having the following structure:
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also known as anlotinib and AL3818 or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent that is a combination of irinotecan and vindesine.
Zhang et al. teaches methods and uses of quinoline derivatives in the treatment of tumors and pharmaceutical compositions for treatment of tumors, specifically, a method and applications for the use of the quinoline derivative 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine in the treatment of soft tissue sarcomas and pharmaceutical compositions for treatment of soft tissue sarcomas (abstract). Said compound of Zhang et al. has the following structure:
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[0022].
Zhang et al. teaches soft tissue sarcomas (STS) are a group of rare malignant tumors arising from mesenchymal cells, which can occur at any age, and have no significant gender difference, and have a wide distribution and different histological appearance [0002]. Zhang et al. teaches common soft tissue sarcomas include malignant fibrous histiocytoma, fibrosarcoma, liposarcoma, leiomyosarcoma of soft tissue, rhabdomyosarcoma, and synovial sarcoma [0004]. Other soft tissue sarcomas also include dermatofibrosarcoma protuberans, malignant peripheral nerve sheath tumor, alveolar soft-part sarcoma, clear cell sarcoma, hemangiosarcoma, malignant mesenchymoma, epithelioid sarcoma, undifferentiated sarcoma and the like [0004].
Zhang et al. teaches a method for treating soft tissue sarcomas, which comprises administrating a therapeutically effective amount of Compound I or pharmaceutically acceptable salts thereof to patients in need of treatment ([0016] and [0020]) Zhang et al. teaches said soft tissue sarcomas include, but not limited to, malignant fibrous histiocytoma, fibrosarcoma, liposarcoma, leiomyosarcoma of soft tissue, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberans, malignant peripheral nerve sheath tumor, alveolar soft-part sarcoma, clear cell sarcoma, hemangiosarcoma, malignant mesenchymoma, epithelioid sarcoma and undifferentiated sarcoma [0020].
Zhang et al. teaches a method for treating advanced soft tissue sarcomas ([0021] [0036] and [0043]). Zhang et al. teaches a method for treating advanced soft tissue sarcomas which have been treated with chemotherapy ([0021], [0036] and [0043]).
Zhang et al. teaches that Compound I can be administrated in the free base form thereof, and also can be administrated in the form of salts, hydrates and prodrugs thereof (the prodrugs will be converted into the free base form of Compound I in vivo), for example, the pharmaceutically acceptable salts of Compound I are within the scope of the present invention, and the salts can be produced from different organic acids and inorganic acids according to well-known processes in the art [0023].
Zhang et al. teaches in some embodiments, Compound I is administrated in the form of hydrochloride thereof [0024]. In some embodiments, Compound I is administrated in the form of monohydrochloride thereof [0024]. In some embodiments, Compound I is administrated in the form of dihydrochloride thereof [0024]. Zhang et al. teaches in a certain embodiment, Compound I is administrated in the crystal form of dihydrochloride thereof [0024].
Zhang et al. teaches that Compound I or pharmaceutically acceptable salts thereof can be administrated via various administration routes, and the routes include, but not limited to, the one selected from the following routes: orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraoccularly, via local administration, subcutaneously, intraadiposally, intraarticularly, intraperitoneally or intrathecally [0025]. Zhang et al. teaches in a certain embodiment, the administration is performed orally [0025].
Zhang et al. teaches the daily administration dosage of Compound I or pharmaceutically acceptable salts thereof is 2 mg-20 mg, 5 mg-20 mg, 8 mg-20 mg, 10 mg-16 mg, 10 mg-14 mg, 10 mg, 12 mg, 14 mg or 16 mg [0026]. Zhang et al. teaches that Compound I or pharmaceutically acceptable salts thereof can be administrated one or more time daily such as once per day in the form of single dosage [0027].
Zhang et al. teaches interval administration includes administration periods and rest periods, and during the administration periods, Compound I or pharmaceutically acceptable salts thereof can be administrated one or more times daily [0029]. For example, Compound I or pharmaceutically acceptable salts thereof is administrated daily in an administration period, and then the administration is stopped for a period of time in a rest period, followed by an administration period and then a rest period, such an administration regimen can be repeated many times [0029]. Among them, the ratio of the administration periods to the rest periods in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and most preferably 2:0.5-1 [0029]. Zhang et al. teaches in some embodiments, the administration is continuously performed for 2 weeks and rest for 2 weeks and in some embodiments, the administration is continuously performed once daily for 14 days and rest for 14 days, followed by continuous administrating once daily for 14 days and resting for 14 days, such an administration regimen with two-week continuous administration periods and two-week rest periods can be repeated many times [0030]-[0032]. Zhang et al. teaches Compound I or pharmaceutically acceptable salts thereof can be separately administrated to patients as the sole active ingredient [0033].
Thus Zhang et al. teaches a method for treating soft tissue sarcoma, including advanced soft tissue sarcoma previously treated with chemotherapy comprising the administration of anlotinib or pharmaceutically salts thereof such as the dihydrochloride salt.
Zhang et al. does not specifically teach treating Ewing’s sarcoma as claimed in the instant claims. Zhang et al. does not teach administering a second therapeutic agent that is a combination of irinotecan and vindesine.
Shen et al. teaches that there are several ongoing trials that are attempting to clarify the roles of anlotinib in soft tissue sarcoma (STS), particularly the activity of anlotinib in several STS subtypes, such as Ewing sarcoma, ASPS, leiomyosarcoma, and synovial sarcoma (page 7). Shen et al. teaches a phase III trial treating advanced Ewing sarcoma with anlotinib and irinotecan (Table 3 page 8).
Accordingly, prior to the effective filing date of the instant claims it would have been obvious to a person of ordinary skill in the art to combine the teachings of Zhang et al. which teaches a method for treating soft tissue sarcoma, including advanced soft tissue sarcoma previously treated with chemotherapy comprising the administration of anlotinib or pharmaceutically salts thereof such as the dihydrochloride salt, with the teachings of Shen et al. which teaches that Ewing’s sarcoma is a subtype of soft tissue sarcoma and also that Ewing’s sarcoma is being investigated for treatment with anlotinib and a second therapeutic agent irinotecan. Thus a person of ordinary skill in the art would have been motivated to treat Ewing’s sarcoma according to the method of Zhang et al. which relates to treating soft tissue sarcoma comprising the administration of anlotinib since Shen et al. specifically teaches that Ewing’s sarcoma is a subtype of soft tissue sarcoma and furthermore teaches that Ewing’s sarcoma is being investigated for treatment with anlotinib and a second therapeutic agent irinotecan.
Thus in view of the combination of teachings a person of ordinary skill in the art would have been specifically motivated to treat Ewing’s sarcoma comprising the administration of anlotinib or a pharmaceutically acceptable salt thereof such as the dihydrochloride salt and further administer a second therapeutic agent such as irinotecan as taught by Shen et al.
Pessetto et al. teaches that the long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery (abstract). Pessetto et al. teaches a study to identify new therapeutic options, by employing a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs (abstract). Pessetto et al teaches that twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches (abstract). Pessetto et al. teaches that vindesine was one of the six most potent drugs against EWS (page 4087). Pessetto et al. further teaches that vindesine is an analog of vincristine which is a first-line chemotherapy for EWS treatment (pages 4087-4088).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine cited prior art teachings which render obvious the combination of anlotinib and irinotecan for the treatment of Ewing’s sarcoma with the teachings of Pessetto et al. which identifies the analog of vincristine which is vindesine as a potent inhibitor of EWS. Thus an ordinary skilled artisan would have been motivated to combine vindesine to anlotinib and irinotecan with a reasonable expectation of improved treatment of Ewing’s sarcoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 3-4, 8-11, 21, and 24-26 are rejected. Claims 1-2, 5-7, 12-20, 22 and 23 are canceled. No claims are allowed.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM