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 .
Please note the Examiner has changed.
The Non-Final mailed July 7, 2025 is herby withdrawn.
Claims 15-23 and 26-28 are pending and being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/048,351, filed July 6, 2020, 63/045,529 filed June 29, 2020 and 62/930,651, filed November 5, 2019, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Oct 31, 2025 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on June 10, 2025 are acceptable.
Specification
The substitute specification filed on September 20, 2022 has been entered.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objection
Claim 15 is objected to because of the following informalities: the claim uses the abbreviation TIGIT without first defining it. To clarify the claim, applicant should first spell out the full term before using an abbreviation. Given the subject matter of the specification, the examiner presumes that "TIGIT" stands for “T-cell immunoreceptor with Ig and ITIM domains”. Appropriate correction is required.
Rejection Withdrawn
The rejection of claims 13-15 and 26 under 35 U.S.C. 102(a)(1) as being anticipated by CARVALHO et al., (WO 2018234793 A2; published 12/27/2018) is withdrawn in view of the claim amendment.
The rejection of claims 13-20 under 35 U.S.C. 103 as being unpatentable over CARVALHO et al., (WO 2018234793 A2; published 12/27/2018) in view of DAVID et al., (Oncoimmunology. 2017 Jul 13;6(10):e1349589. PMID: 29123964) is withdrawn in view of the claim amendment.
The rejection of claim 21 under 35 U.S.C. 103 as being unpatentable over CARVALHO et al., (WO 2018234793 A2; published 12/27/2018) in view of DAVID et al., (Oncoimmunology. 2017 Jul 13;6(10):e1349589. PMID: 29123964) as applied to claims 13-20 above, and further in view of STRAUSS et al (Clin Cancer Res. 2018 Mar 15;24(6):1287-1295. PMID: 29298798) is withdrawn in view of the claim amendment. The addition of Strauss does not cure the deficiency of Carvalho and David.
Rejection Maintained
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 15-23, and 26-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 70-83 of copending Application No. 17/774,685 (US 20220403022 A1) (reference application) in view of Meng et al (WO2019165434, published August 29, 2019; PTO 892) and Lo et al (of record, US 20180118832 A1; published 05/03/2018).
The copending application 17/774,685 (reference application) discloses and claims anti-TIGIT antibody comprising a heavy chain sequence of SEQ ID NO: 18 and a light chain sequence which corresponds to SEQ ID NO: 19 (claim 83).
The reference SEQ ID NO: 18 is at least 99.8% identical to instant SEQ ID NO: 28, which corresponds to instant claim 23, see sequence alignment below, CDRs are in bold:
Query Match 99.8%; Score 2403; Length 451;
Best Local Similarity 99.3%;
Matches 448; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTSYPMNWVRQAPGQGLEWMGWINTNTGNPTY 60
::||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIQLVQSGSELKKPGASVKVSCKASGYTFTSYPMNWVRQAPGQGLEWMGWINTNTGNPTY 60
Qy 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARVGGYSVDEYAFDVWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||:|||
Db 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARVGGYSVDEYAFDVWGQGTMVTV 120
Qy 121 SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
Qy 181 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL 240
Qy 241 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 300
Qy 301 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 360
Qy 361 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 420
Qy 421 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 451
|||||||||||||||||||||||||||||||
Db 421 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 451
The reference SEQ ID NO: 19 is at least 99.1 % identical to instant SEQ ID NO: 27, which is identical to instant claim 23, see sequence alignment below, CDRs are in bold:
Query Match 98.8%; Score 1083; Length 213;
Best Local Similarity 99.1%;
Matches 210; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 2 IQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSR 61
|:||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 IRLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSR 61
Qy 62 FSGSGSGTEFTLTISSLQPEDFATYYCQQLSSYPTFGGGTKVEIKRTVAAPSVFIFPPSD 121
||||||||||||||||||||||||||||||:|||||||||||||||||||||||||||||
Db 62 FSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPTFGGGTKVEIKRTVAAPSVFIFPPSD 121
Qy 122 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 181
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 181
Qy 182 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 213
||||||||||||||||||||||||||||||||
Db 182 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 213
The reference also discloses a method of treating cancer, e.g., MC38 tumor, which is a colon cancer, by administering to a subject a combination of anti-TIGIT antibody, e.g., 3963H03-12-muIgG2c and M7824 (aka bintrafusp alfa or anti-PD-L1/TGFβ Trap) which comprises anti-PD-L1:TGFβRII fusion protein that inhibits PD-1 and TGFβ, which corresponds to instant claims 15, 17, 18, 20, 26, 27, 28, see example bridging p. 92 and 93.
The reference anti-TIGIT antibody heavy chain comprises SEQ ID NO: 16, which comprises the instant SEQ ID NO: 31 (CDRH1), SEQ ID NO: 32 (CDRH2) and SEQ ID NO: 33 (CDRH3), see sequence alignment below:
ALIGNMENT:
Query Match 85.0%; Score 144.5; Length 122;
Best Local Similarity 36.0%;
Matches 31; Conservative 0; Mismatches 0; Indels 55; Gaps 2;
Qy 1 GYTFTSYP-----------------INTNTGNP--------------------------- 16
|||||||| ||||||||
Db 26 GYTFTSYPMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISS 85
Qy 17 -----------ARVGGYSVDEYAFDV 31
|||||||||||||||
Db 86 LKAEDTAVYYCARVGGYSVDEYAFDV 111
The reference anti-TIGIT antibody comprises identical heavy and light chain variable regions and associated CDRs (Db) as those recited in instant claims 22 and 27 (Qy).
US 17/774,685
Claim 24, HVRs H1-H3
Query Match 100.0%; Score 170; DB 1; Length 31;
Best Local Similarity 100.0%;
Matches 31; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GYTFTSYP-INTNTGNP-ARVGGYSVDEYAFDV 31
|||||||| |||||||| |||||||||||||||
Db 1 GYTFTSYP-INTNTGNP-ARVGGYSVDEYAFDV 31
US 17/774,685
Claim 24, HVRs L1-L3
Query Match 100.0%; Score 83; DB 1; Length 17;
Best Local Similarity 100.0%;
Matches 17; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QGISSY-AAS-QQLSSYPT 17
|||||| ||| ||||||||
Db 1 QGISSY-AAS-QQLSSYPT 17
The reference claims differ from the instant claims by not reciting the anti-TIGIT antibody is administered once every two weeks with a dose of about 300 mg as per claims 15 and 27 and the genus of cancer types recited in instant claims 26 or 28.
However, Meng teaches and claims a method of treating cancer, e.g., (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC)) one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, e.g., tiragolumab or antigen binding fragment thereof, e.g., Fab, Fab’, scFv (see p. 3, line 9-12, p. 15, 22-24) and an effective amount of an anti-PD-L1 antagonist antibody, e.g., atezolizumab, or antigen binding fragment thereof, e.g., Fab, Fab’, Fab’-SH, scFv, (Fab’)2 (p. 4, line 1-5, p. 16, lines 11-15), thereby treating the subject, see p. 2, Summary of invention.
Meng teaches that the anti-TIGIT antagonist antibody is administered at a fixed dose of about 300 mg to about 1200 mg every three weeks, between about 100 mg to about 300 mg, or between about 300 mg to about 800 mg see p. 14, lines 5-11, p. 46, Dosing Regimens and administration, in particular.
Lo discloses a combination therapy for cancer (title), comprising a bifunctional molecule comprising TGFβRII domains fused to an antibody, or antigen binding fragment thereof, that binds to the immune checkpoint protein Programmed Death Ligand 1 (PD-L1) and (ii) at least one additional anti-cancer therapeutic agent (see abstract; see figure 1; see ¶s 0003 and 0007). The additional anti-cancer therapeutic agent disclosed by Lo may include chemotherapeutics OR biologics (e.g. ¶0007-0008). The combination therapy disclosed by Lo may be used to treat a litany of different cancer types (¶0030-0031); those recited by Lo comprise a largely overlapping, if not identical list of cancer types including small cell lung cancer, non-small cell lung cancer, myeloma, lymphoma, leukemia and/or glioblastoma (¶0030-0031).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by administering to a subject a combination of anti-TIGIT antibody at a fixed dose of about 300 mg to about 1200 mg every three weeks as taught by Meng, and M7824 (aka bintrafusp alfa or anti-PD-L1/TGFβ Trap) which comprises anti-PD-L1:TGFβRII fusion protein that inhibits PD-1 and TGFβ, to treat various cancers of Lo to arrive at the claimed invention with a reasonable expectation of success.
One of ordinary skill in the art would have been motivated to do so because Lo teach that combinational immunotherapies may be advantageous for an improved or even synergistic efficacy compared to the effect of administering individual agents separately (¶0006-0007).
This is a provisional nonstatutory double patenting rejection.
Applicant’s arguments, filed Oct 31, 2025, have been fully considered
Applicant’s position is that Claims 24 and 25 were acknowledged to be allowable. Independent claims 15 and 27 are amended herein to recite the limitations of claims 24 and 25 and are therefore allowable for at least that reason. Reconsideration and withdrawal of the double patenting rejection is respectfully requested.
In response, the amendment to claims 15 and 27 is acknowledged.
In response to the argument that claims now recite wherein the TIGIT antibody is administered once every three weeks with a dose of about 300 mg or 900 mg.
Meng teaches that the anti-TIGIT antagonist antibody is administered at a fixed dose of about 300 mg to about 1200 mg once every three weeks, between about 100 mg to about 300 mg, or between about 300 mg to about 800 mg see p. 14, lines 5-11, p. 46, Dosing Regimens and administration, in particular. The reference range of about 300 to 1200 mg encompasses the claimed range of about 300 mg or about 900 mg, once every three weeks.
The copending application 17/774,685 (reference application) discloses and claims anti-TIGIT antibody comprising a heavy chain sequence of SEQ ID NO: 18 and a light chain sequence which corresponds to SEQ ID NO: 19 (claim 83).
The reference SEQ ID NO: 18 is at least 99.8% identical to instant SEQ ID NO: 28, which corresponds to instant claim 23, see sequence alignment below, CDRs are in bold:
Query Match 99.8%; Score 2403; Length 451;
Best Local Similarity 99.3%;
Matches 448; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTSYPMNWVRQAPGQGLEWMGWINTNTGNPTY 60
::||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIQLVQSGSELKKPGASVKVSCKASGYTFTSYPMNWVRQAPGQGLEWMGWINTNTGNPTY 60
Qy 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARVGGYSVDEYAFDVWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||:|||
Db 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARVGGYSVDEYAFDVWGQGTMVTV 120
Qy 121 SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
Qy 181 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL 240
Qy 241 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 300
Qy 301 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 360
Qy 361 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 420
Qy 421 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 451
|||||||||||||||||||||||||||||||
Db 421 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 451
The reference SEQ ID NO: 19 is at least 99.1 % identical to instant SEQ ID NO: 27, which is identical to instant claim 23, see sequence alignment below, CDRs are in bold:
Query Match 98.8%; Score 1083; Length 213;
Best Local Similarity 99.1%;
Matches 210; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 2 IQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSR 61
|:||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 IRLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSR 61
Qy 62 FSGSGSGTEFTLTISSLQPEDFATYYCQQLSSYPTFGGGTKVEIKRTVAAPSVFIFPPSD 121
||||||||||||||||||||||||||||||:|||||||||||||||||||||||||||||
Db 62 FSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPTFGGGTKVEIKRTVAAPSVFIFPPSD 121
Qy 122 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 181
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS 181
Qy 182 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 213
||||||||||||||||||||||||||||||||
Db 182 KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 213
The reference also discloses a method of treating cancer, e.g., MC38 tumor, which is a colon cancer, by administering to a subject a combination of anti-TIGIT antibody, e.g., 3963H03-12-muIgG2c and M7824 (aka bintrafusp alfa or anti-PD-L1/TGFβ Trap) which comprises anti-PD-L1:TGFβRII fusion protein that inhibits PD-1 and TGFβ, which corresponds to instant claims 15, 17, 18, 20, 26, 27, 28, see example bridging p. 92 and 93.
The reference anti-TIGIT antibody heavy chain comprises SEQ ID NO: 16, which comprises the instant SEQ ID NO: 31 (CDRH1), SEQ ID NO: 32 (CDRH2) and SEQ ID NO: 33 (CDRH3), see sequence alignment below:
ALIGNMENT:
Query Match 85.0%; Score 144.5; Length 122;
Best Local Similarity 36.0%;
Matches 31; Conservative 0; Mismatches 0; Indels 55; Gaps 2;
Qy 1 GYTFTSYP-----------------INTNTGNP--------------------------- 16
|||||||| ||||||||
Db 26 GYTFTSYPMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISS 85
Qy 17 -----------ARVGGYSVDEYAFDV 31
|||||||||||||||
Db 86 LKAEDTAVYYCARVGGYSVDEYAFDV 111
The reference anti-TIGIT antibody comprises identical heavy and light chain variable regions and associated CDRs (Db) as those recited in instant claims 22 and 27 (Qy).
US 17/774,685
Claim 24, HVRs H1-H3
Query Match 100.0%; Score 170; DB 1; Length 31;
Best Local Similarity 100.0%;
Matches 31; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GYTFTSYP-INTNTGNP-ARVGGYSVDEYAFDV 31
|||||||| |||||||| |||||||||||||||
Db 1 GYTFTSYP-INTNTGNP-ARVGGYSVDEYAFDV 31
US 17/774,685
Claim 24, HVRs L1-L3
Query Match 100.0%; Score 83; DB 1; Length 17;
Best Local Similarity 100.0%;
Matches 17; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QGISSY-AAS-QQLSSYPT 17
|||||| ||| ||||||||
Db 1 QGISSY-AAS-QQLSSYPT 17
The reference claims differ from the instant claims by not reciting the anti-TIGIT antibody is administered once every two weeks with a dose of about 300 mg as per claims 15 and 27 and the genus of cancer types recited in instant claims 26 or 28.
However, it is within the purview of one of ordinary skilled in the pharmaceutical art to optimize or adjust the dosage and timing of administration based on various factors, such as the body weight of the subject, the sex, the condition of the subject and for patient compliance and convenience. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215,218-219 (C.C.P.A. 1980).
Further, there is no restriction on the record in either application. The subject matter claimed in the instant application is fully disclosed in the referenced copending application and would be covered by any patent granted on that copending application ‘685. A person of skill in the art, reading the claims of the copending application, would look to the copending application ‘685 and follow the ‘685’s express instruction on how to treat cancer within the reference, e.g., Examples thereby arriving at the binding molecule of the examined claims.
For these reasons, the rejection is maintained.
New ground of rejection
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-23, and 26-28 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
Claim 15 encompasses a method of treating any cancer in any subject, the method comprising administering any PD-1 inhibitor, any TGFP inhibitor and any TIGIT inhibitor to the subject; wherein the PD-1 inhibitor is any anti-PD-L1 antibody, or a fragment thereof capable of binding PD- L1, the TGFP inhibitor is any TGFβRII, or a fragment thereof capable of binding TGF-β, or any anti-TGFO antibody, or a fragment thereof capable of binding TGFO, and the TIGIT inhibitor is an anti-TIGIT antibody, or a fragment thereof capable of binding TIGIT wherein the TIGIT inhibitor is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg.
Claim 16 encompasses the method according to claim 15, wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 1, a CDRH2 having the sequence of SEQ ID NO: 2 and a CDRH3 having the sequence of SEQ ID NO: 3, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 4, a CDRL2 having the sequence of SEQ ID NO: 5 and a CDRL3 having the sequence of SEQ ID NO: 6; or
wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 19, a CDRH2 having the sequence of SEQ ID NO: 20 and a CDRH3 having the sequence of SEQ ID NO: 21, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 22, a CDRL2 having the sequence of SEQ ID NO: 23 and a CDRL3 having the sequence of SEQ ID NO: 24.
Claim 17 encompasses the method according to claim 15, wherein the TGFP inhibitor is an extracellular domain of any TGFβRII or a fragment thereof capable of binding TGFβ.
Claim 18 encompasses the method according to claim 17, wherein the PD-1 inhibitor and the TGFP inhibitor are fused as an anti-PD-L1:TGFβRII fusion protein.
Claim 19 encompasses the method according to claim 18, wherein the light chain sequences and the heavy chain sequences of the anti-PD-LI:TGFβRII fusion protein have at least 90% sequence identity to the light chain sequence and the heavy chain sequence selected from the group consisting of: (1) SEQ ID NO: 7 and SEQ ID NO: 8, (2) SEQ ID NO: 15 and SEQ ID NO: 17, and (3) SEQ ID NO: 15 and SEQ ID NO: 18.
Claim 20 encompasses the method according to claim 19, wherein the amino acid sequence of the anti-PD-L1:TGFORII fusion protein corresponds to the amino acid sequence of bintrafusp alfa.
Claim 21 encompasses the method according claim 20, wherein the anti-PD-L1:TGFβRII fusion protein is administered at a dose of 1200 mg once every two weeks or at a dose of 2400 mg once every three weeks.
Claim 22 encompasses the method according to claim 15, wherein the TIGIT inhibitor is an anti- TIGIT antibody which heavy chain comprises the amino acid sequences of SEQ ID NO: 31 (CDRH1), SEQ ID NO: 32 (CDRH2) and SEQ ID NO: 33 (CDRH3), and which light chain comprises the amino acid sequences of SEQ ID NO: 34 (CDRL1), SEQ ID NO: 35 (CDRL2) and SEQ ID NO: 36 (CDRL3).
Claim 23 encompasses the method according to claim 15, wherein the TIGIT inhibitor is an anti- TIGIT antibody which light chain sequences and heavy chain sequences have at least 90% sequence identity to the light chain sequence and the heavy chain sequence of SEQ ID NO: 27 and SEQ ID NO: 28, respectively.
Claim 26 encompasses the method according to claim 15, wherein the cancer is selected from the group consisting of squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, biliary tract cancer, and head and neck cancer.
Claim 27 encompasses a method of treating any cancer in any subject, the method comprising administering any PD-1 inhibitor, any TGFP inhibitor and any TIGIT inhibitor to the subject; and wherein the PD-1 inhibitor and TGFP inhibitor are fused in a molecule having the amino acid sequence of bintrafusp alfa and the TIGIT inhibitor is an anti-TIGIT antibody which light chain sequences and heavy chain sequences respectively correspond to SEQ ID NO: 27 and SEQ ID NO:28; and wherein the TIGIT inhibitor is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg.
Claim 28 encompasses the method of claim 27, wherein the cancer is selected from the group consisting of squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, biliary tract cancer, and head and neck cancer.
Regarding “PD-1 inhibitor”, the specification discloses:
[0056] “PD-1 inhibitor” as used herein refers to a molecule that inhibits the PD-1 pathway, e.g., by inhibiting the interaction of PD-1 axis binding partners, such as between the PD-1 receptor and the PD-L1 and/or PD-L2 ligand. Possible effects of such inhibition include the removal of immunosuppression resulting from signaling on the PD-1 signaling axis. Inhibition in this context need not be complete or 100%. Instead, inhibition means reducing, decreasing or abrogating binding between PD-1 and one or more of its ligands and/or reducing, decreasing or abrogating signaling through the PD-1 receptor. In some embodiments, the PD-1 inhibitor binds to PD-L1 or PD-1 to inhibit the interaction between these molecules, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the PD-1 inhibitor is a PD-L1 antibody and such antibody may be fused to the TGFβ inhibitor, e.g., as an anti-PD-L1:TGFβRII fusion protein.
Regarding anti-PD-L1 antibody, the specification discloses:
[0032] “Anti-PD-L1 antibody” or “anti-PD-1 antibody” means an antibody, or an antigen-binding fragment thereof, that specifically binds to PD-L1 or PD-1 respectively and blocks binding of PD-L1 to PD-1. In any of the treatment methods, medicaments and uses of the present invention in which a human subject is being treated, the anti-PD-L1 antibody specifically binds to human PD-L1 and blocks binding of human PD-L1 to human PD-1. In any of the treatment methods, medicaments and uses of the present invention in which a human subject is being treated, the anti-PD-1 antibody specifically binds to human PD-1 and blocks binding of human PD-L1 to human PD-1. The antibody may be a monoclonal antibody, human antibody, humanized antibody or chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments.
[0033] “Anti-PD(L)1 antibody” refers to an anti-PD-L1 antibody or an anti-PD-1 antibody.
Thus, the anti-PD-L1 antibody or antigen binding fragment thereof is not limited and can be any antibody that binds to PD-1 receptor or its ligand.
Regarding TGFβ inhibitor, the specification discloses:
[0066] “TGFβ inhibitor” as used herein refers to a molecule that inhibits the TGFβ pathway, e.g., by inhibiting the interaction between a TGFβ and a TGFβ receptor (TGFβR). Possible effects of such inhibition include the removal of immunosuppression resulting from signaling on the TGFβ signaling axis. Inhibition in this context need not be complete or 100%. Instead, inhibition means reducing, decreasing or abrogating binding between TGF-β and the TGFβR and/or reducing, decreasing or abrogating signaling through the TGFβR. In some embodiments, the TGFβ inhibitor binds to TGFβ or a TGFβR to inhibit the interaction between these molecules. In some embodiments, the TGFβ inhibitor comprises the extracellular domain of a TGFβRII, or a fragment of TGFβRII capable of binding TGFβ. In some embodiments, such TGFβ inhibitor is fused to the PD-1 inhibitor, e.g., as an anti-PD-L1:TGFβRII fusion protein.
Regarding anti-TIGIT antibody, the specification discloses:
[0034] “Anti-TIGIT antibody” means an antibody, or an antigen-binding fragment thereof, that specifically binds to TIGIT and blocks binding of TIGIT to its ligands, such as CD112 and/or CD155. In some embodiments, the anti-TIGIT antibody blocks binding of TIGIT to both CD112 and CD155. In any of the treatment methods, medicaments and uses of the present invention in which a human subject is being treated, the anti-TIGIT antibody specifically binds to human TIGIT and blocks binding of human TIGIT to human TIGIT ligands, such as human CD112 and/or human CD155. The antibody may be a monoclonal antibody, human antibody, humanized antibody or chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments.
Regarding “Bintrafusp alfa”, the specification discloses:
[0035] “Bintrafusp alfa”, also known as M7824, is well understood in the art. Bintrafusp alfa is an anti-PD-L1:TGFβRII fusion protein and described under the CAS Registry Number 1918149-01-5. It is also described in WO 2015/118175 and further elaborated in Lan et al (Lan et al, “Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β”, Sci. Transl. Med. 10, 2018, p.1-15). In particular, bintrafusp alfa is a fully human IgG1 monoclonal antibody against human PD-L1 fused to the extracellular domain of human TGF-β receptor II (TGFβRII). As such, bintrafusp alfa is a bifunctional fusion protein that simultaneously blocks PD-L1 and TGF-β pathways. In particular, WO 2015/118175 describes bintrafusp alfa on page 34 in Example 1 thereof as follows (bintrafusp alfa is referred to in this passage as “anti-PD-L1/TGFβ Trap”): “Anti-PD-L1/TGFβ Trap is an anti-PD-L1 antibody-TGFβ Receptor II fusion protein. The light chain of the molecule is identical to the light chain of the anti-PD-L1 antibody (SEQ ID NO: 1). The heavy chain of the molecule (SEQ ID NO:3) is a fusion protein comprising the heavy chain of the anti-PD-L1 antibody (SEQ ID NO: 2) genetically fused to via a flexible (Gly4Ser)4Gly linker (SEQ ID NO:11) to the N-terminus of the soluble TGFβ Receptor II (SEQ ID NO: 10). At the fusion junction, the C-terminal lysine residue of the antibody heavy chain was mutated to alanine to reduce proteolytic cleavage.”
Regarding cancer, the specification discloses:
[0037] By “cancer” is meant a collection of cells multiplying in an abnormal manner. As used herein, the term “cancer” refers to all types of cancer, neoplasm, malignant or benign tumors found in mammals, including leukemia, carcinomas, and sarcomas. Exemplary cancers include breast cancer, ovarian cancer, colon cancer, liver cancer, kidney cancer, lung cancer, pancreatic cancer, glioblastoma. Additional examples include cancer of the brain, lung cancer, non-small cell lung cancer, melanoma, sarcomas, prostate cancer, cervix cancer, stomach cancer, head and neck cancers, uterus cancer, mesothelioma, metastatic bone cancer, medulloblastoma, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macrobulinemia, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, and neoplasms of the endocrine and exocrine pancreas.
Regarding subject, the specification discloses:
[0055] “Patient” and “subject” are used interchangeably herein to refer to a mammal in need of treatment for a cancer. Generally, the patient is a human diagnosed or at risk for suffering from one or more symptoms of a cancer. In certain embodiments a “patient” or “subject” may refer to a non-human mammal, such as a non-human primate, a dog, cat, rabbit, pig, mouse, or rat, or animals used, e.g., in screening, characterizing, and evaluating drugs and therapies.
The specification exemplifies just treating colon cancer by administering to mice an anti-TIGIT antibody H03-12-muIgG2c in combination with bintrafusp alfa, which is an anti-PD-L1:TGFβRII fusion protein.
Example 1: Immune Cell Activation by the Combined Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa
[0217] The ability to activate immune cells of the anti-TIGIT antibody H03-12 in combination with bintrafusp alfa was evaluated in an allogenic two-way MLR assay by measuring IFN-γ in the supernatant of co-cultured PBMCs from two different human donors after 2 days treatment. H03-12 was shown to dose-dependently enhance IFN-γ production compared to the isotype control, with an EC.sub.50 of 158.9 ± 185.0 ng/mL (1.065 ± 1.240 nM) (see FIG. 3A). The addition of bintrafusp alfa further enhanced the effect of H03-12 on IFN-γ production (see FIG. 3B). These results suggest that H03-12 stimulates immune cell activation and combination with bintrafusp alfa further enhances this activation.
[0218] The ability of the combination of H03-12 and bintrafusp alfa to enhance T cell activation was further tested in a one-way MLR assay. H03-12 dose-dependently enhanced IFN-γ production in these cells compared with the isotype control, with an EC50 of 136.9 ± 114.6 ng/mL (0.917 ± 0.768 nM) (see FIG. 3C). The combination of H03-12 with bintrafusp alfa further enhanced T cell activation (see FIG. 3D).
Example 2: Flow Cytometric Analysis of Samples Treated With Bintrafusp Alfa
[0219] Cellular subsets in CT26-KSA tumor-bearing mice were analyzed by flow cytometry after bintrafusp alfa treatment. Bintrafusp alfa monotherapy (24.6 mg/kg) showed significant anti-tumor efficacy (P = 0.0029, day 22) relative to isotype control in CT26-KSA tumor-bearing mice (see FIG. 4A). Flow cytometry analysis of spleens and tumors from separate mice treated with bintrafusp alfa showed that bintrafusp alfa monotherapy led to an increased percentage of splenic CD4+ T cells (P < 0.0001), CD8+ T cells (P = 0.0001), and Tregs (P < 0.0001) expressing TIGIT, relative to isotype control. Bintrafusp alfa also tended towards increased percentages of TIGIT+ tumor infiltrating CD4+ T cells, CD8+ T cells, NK cells, and Tregs (see FIG. 4B). This data indicates that the increase of TIGIT expression on immune subsets elicited by bintrafusp alfa treatment may induce resistance to bintrafusp alfa treatment.
Example 3: Anti-Tumor Efficacy of the Combination Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa in the CT26-KSA Tumor Model in BALB/c Mice
[0220] The anti-tumor efficacy of the anti-mouse TIGIT antibody 18G10 having the light chain sequences of SEQ ID NO: 39 and the heavy chain sequences of SEQ ID NO: 40 and/or bintrafusp alfa was tested in the CT26-KSA tumor model in BALB/c mice.
[0221] Bintrafusp alfa (24.6 mg/kg) monotherapy led to moderate tumor growth inhibition (49.5%) relative to isotype control (P < 0.0001, day 21). 18G10 monotherapy led to even greater tumor growth inhibition (TGI = 85.3%) relative to isotype control (P < 0.0001, day 21). However, the combination of 18G10 with bintrafusp alfa (TGI = 110.1%) further enhanced anti-tumor efficacy relative to 18G10 monotherapy (P < 0.0001, day 33), or bintrafusp alfa monotherapy (P < 0.0001, day 21) (See FIG. 5A). Indeed, at day 33, complete tumor regression was observed in 70% of mice treated with 18G10 and bintrafusp alfa combination therapy (7/10 mice, See FIG. 5C).
[0222] Median survival was also significantly prolonged with combination therapy with 18G10 and bintrafusp alfa (undefined) relative to 18G10 monotherapy (50 days, P < 0.0001) or bintrafusp alfa monotherapy (35 days, P = 0.0002) (see FIG. 5B).
Example 4: Anti-Tumor Efficacy of the Combination Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa in the MC38 Tumor Model in C57BL/6 Mice
[0223] The anti-tumor efficacy of an anti-TIGIT antibody and/or bintrafusp alfa was tested in the MC38 tumor model in C57BL/6 mice.
[0224] Monotherapy of bintrafusp alfa (24.6 mg/kg) led to tumor growth inhibition (TGI = 40.2%) relative to isotype control (P < 0.0001, day 24). 18G10 monotherapy led to more moderate tumor growth inhibition (TGI = 18.2%) relative to isotype control (P = 0.0219, day 24). However, the combination of 18G10 with bintrafusp alfa further enhanced anti-tumor efficacy (TGI =58.8%) relative to 18G10 monotherapy (P < 0.0001, day 24), and bintrafusp alfa monotherapy (P = 0.0169, day 24) (see FIGS. 6A and 6C).
[0225] Median survival was also slightly prolonged with 18G10 and bintrafusp alfa (34 days) combination therapy relative to 18G10 monotherapy (29.5 days) or isotype control (26 days) (see FIG. 6B).
Example 5: Anti-Tumor Efficacy of the Combination Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa in the MC38 Tumor Model in B-huTIGIT Knock-in Mice
[0226] The anti-tumor efficacy of the anti-human TIGIT antibody H03-12-mulgG2c in combination with bintrafusp alfa was evaluated in MC38 tumor-bearing B-huTIGIT knock-in mice. An anti-PD-L1 antibody having the light and heavy chain sequences of SEQ ID NO: 7 and SEQ ID NO: 16, respectively, was used as a further control.
[0227] Since H03-12 lacks cross-reactivity with mouse TIGIT protein, the murine extracellular domain of TIGIT was replaced with a human extracellular domain of TIGIT in mice on the C57BL/6 genetic background. Specifically, the coding region of amino acid 22-131 of exon 2 of mouse TIGIT was replaced with human coding sequence using CRISPR/Cas9 technology. Furthermore, to avoid potential immunogenicity and achieve effector function in mice, an H03-12 mouse chimeric antibody (H03-12-mulgG2c, H03-12′s human IgG1 Fragment crystallizable (Fc) region was replaced with mouse IgG2c Fc) was developed. The light and heavy chain sequences of H03-12-mulgG2c are reflected by SEQ ID NO: 37 and SEQ ID NO: 38, respectively.
[0228] As reflected by FIG. 7 and Table 1, compared with the anti-HEL and inactive anti-PD-L1 isotype controls, the Trap control (a mutant of bintrafusp alfa, which is no longer able to bind to PD-L1 and which light and heavy chain sequences are reflected by SEQ ID NO: 47 and SEQ ID NO: 48, respectively) did not show any anti-tumor efficacy. H03-12-mulgG2c, anti-PD-L1 and bintrafusp alfa monotherapies all displayed tumor growth inhibition (TGI = 36.65%, 61.87% and 66.3%, relative to isotype control at day 32, P < 0.0001 for all three monotherapies), and prolonged median survival (47, 47, and 51 days, P=0.01, P=0.0008, P=0.0004, respectively) relative to isotype control (39 days).
[0229] Tumor growth inhibition was enhanced for the combination of H03-12-mulgG2c with Trap control (TGI = 64.26%) relative to H03-12-mulgG2c (P = 0.0055, day 32) and Trap control (P < 0.0001, day 32) monotherapies. The combination of H03-12-mulgG2c with anti-PD-L1 further enhanced anti-tumor efficacy (TGI = 80.07%) relative to H03-12-mulgG2c (P = 0.0001, day 32) and tended towards increased anti-tumor efficacy relative to anti-PD-L1 monotherapy (P < 0.2215, day 32), and the anti-tumor efficacy of the combination of H03-12-mulgG2c with bintrafusp alfa (TGI = 88.2%) was enhanced relative to H03-12-mulgG2c monotherapy (P < 0.0001, day 32) and tended towards increased anti-tumor efficacy relative to bintrafusp alfa monotherapy (P =0.0658, day 32).
[0230] Combination treatment of H03-12-mulgG2c with Trap control, anti-PD-L1 or bintrafusp alfa also prolonged median survival (51, 54.5 and 74 days, respectively). At day 39, the average tumor volume of the combination treatment of H03-12-mulgG2c with Trap control, anti-PD-L1 or bintrafusp alfa was 437.58 mm.sup.3, 285.35 mm.sup.3 and 193.19 mm.sup.3 respectively.
Regarding antibody that binds to TIGIT, the specification discloses just antibody comprises a light chain sequence of SEQ ID NO: 27 and a heavy chain sequence of SEQ ID NO: 28 wherein the heavy chain comprises a CDRH1 having the sequence of SEQ ID NO: 31, a CDRH2 having the sequence of SEQ ID NO: 32 and a CDRH3 having the sequence of SEQ ID NO: 33, and wherein light chain comprises a CDRL1 having the sequence of SEQ ID NO: 34, a CDRL2 having the sequence of SEQ ID NO: 35 and a CDRL3 having the sequence of SEQ ID NO: 36, is not representative of the entire genus. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
However, one species is not representative of the genus of antibodies that bind to any and all possible TIGIT. An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Notably, the specification, does not describe the structure, e.g., amino acid sequence of the heavy and light chain variable domains that correlated with binding to any PD-1, PD-L1, and/or TIGIT (claims 15, 26, 27, 28).
The specification does not describe i. Complete structure, e.g., heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of antibodies or antigen binding fragment thereof that correlated with binding to which PD-1, PD-L1, or TIGIT from all mammalian species. The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual antibody or antigen-binding fragment thereof that bind to PD-1, PD-L1, and/or TIGIT encompassed by the claimed method.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 334(1): 103-118, 2003; PTO 892, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Further, antibody that binds to human protein may not bind to the same protein from other species.
For example, Yu et al (Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 892) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular). Yu et al further teaches administering bevacizumab does not inhibit the growth of B16F1 melanoma tumor cells in nude mice (see page 525, Figure 5, in particular) or inhibits neovascularization in the laser-induced choroid injury in mouse model (see page 525, Figure 4, in particular).
As another example, Witte et al (Cancer and Metastasis Reviews 17: 155-161, 1998; PTO 892) teach monoclonal antibody such as DC101 that binds to mouse VEGFR2 and blocks the binding of VEGF to its receptor, and yet the same antibody does not bind to human VEGFR2 despite of high percentage (85%) of sequence homology between mouse and human VEGFR2 (also known as KDR), see abstract, in particular.
The specification does not teach the disclosed anti-TIGIT antibody can bind to TIGIT from other species, e.g., human, non-human mammal, such as a non-human primate, a dog, cat, rabbit, pig, or rat for treating such subject having any and all possible cancer.
Regarding “administering a PD-1 inhibitor, a TGFβ inhibitor and a TIGIT inhibitor to the subject, wherein the PD-1 inhibitor is an anti-PD-L1 antibody or a fragment thereof capable of binding PD-L1, the TGFβ inhibitor is a TGFβRII or a fragment thereof capable of binding TGF-β and the TIGIT inhibitor is an anti-TIGIT antibody or a fragment thereof capable of binding TIGIT” in claims 15 and 27, the specification discloses administering a combination of anti-TIGIT antibody and Bintrafusp alfa, which is a fusion protein comprising TGFβRII-Fc fused to anti-PDL-1 Fab domains.
However, the specification does not disclose administering to a subject a triple combination of agents, e.g., a PD-1 inhibitor, a TGFβ inhibitor and a TIGIT inhibitor to the subject. There is no objective evidence of administering a triple combination of any an anti-PD-L1 antibody or a fragment thereof capable of binding PD-L1, any TGFβRII or a fragment thereof capable of binding TGF-β and any anti-TIGIT antibody or a fragment thereof capable of binding TIGIT to a subject.
Regarding anti-TIGIT antibody which light chain sequences and heavy chain sequences having at least 90% sequence identity to SEQ ID NO: 27 and SEQ ID NO: 28, respectively (claim 23), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 27 or SEQ ID NO: 28 to be substituted, added, deleted or a combination thereof such that the modified heavy and light chains having at least 90% sequence identity to SEQ ID NO: 27 and SEQ ID NO: 28 still maintain binding to human TIGIT, in turn, effective for treating which cancer in which mammalian subject.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc Natl Acad Sci USA 79: 1979, 1982; PTO 892). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding.
Wu et al (J. Mol. Biol. 294: 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular.
Since the disclosure fails to describe common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the disclosure is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species of PD-1 inhibitor, TGFβ inhibitor and TIGIT inhibitor to describe the genus for the method as broadly claimed.
Regarding PD-1 inhibitor and TGFβ inhibitor are any fusion protein (claims 17-18), the specification discloses bintrafusp alfa having the structure shown in Fig 2 comprises a light chain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 8, see FIG. 1A-B, 2, in particular.
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However, the specification does not describe the structures, e.g., amino acid sequences of all possible anti-PD-L1:TGFβII fusion proteins encompassed by the claimed method.
Even assuming the anti-PD-L1:TGFβII fusion proteins are the ones set forth in claim 19, the specification does not teach where and what amino acids within the full-length sequence of SEQ ID NO: 7 and SEQ ID NO: 8 or SEQ ID NO: 15 and SEQ ID NO: 17 or SEQ ID NO: 15 and SEQ ID NO: 18 to be substituted, added, deleted or a combination thereof such that the modified anti-PD-L1:TGFβII fusion protein having at least 90% sequence identity to the light chain sequence and the heavy chain sequence of anti-PD-L1:TGFβII fusion protein still effective for treating cancer.
Regarding method of treating any cancer such as the ones recited in claim 26 and 28, the specification exemplifies just treating colon cancer by administering to mice an anti-TIGIT antibody H03-12-muIgG2c in combination with bintrafusp alfa, which is an anti-PD-L1:TGFβRII fusion protein.
However, the specification does not teach the disclosed anti-TIGIT antibody H03-12-muIgG2c binds to TIGIT from other species, e.g., human, non-human primate, a dog, cat, rabbit, pig, or rat.
Mullard (Nature reviews drug discovery 25: 157-161, 2026; PTO 892) teaches that TIGIT inhibitor, e.g., tiragolumab (Genentech) fails in lung cancer, promoting the company to wind down its TIGIT programe, which had spanned lung, liver, oesophageal cancer and beyond, see p. 157, left col. In mouse models of colorectal and breast cancer, single-agent treatment with anti-TIGIT or anti-PD-L1 antibody did little to decrease the tumor burden or to shift survival. The mismatch between the preclinical and clinical data, re-affirms that mice aren’t humans, see p. 160, left col. Thus, it is not clear the claimed method can treat any and all possible cancers in any mammalian subject.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a method of treating a T-cell immunoreceptor with Ig and ITIM domains (TIGIT) mediated cancer in a human subject, the method comprising administering to the subject in needed thereof an anti-TIGIT antibody or antigen binding fragment thereof in combination with bintrafusp alfa, wherein the anti-TIGIT antibody or antigen binding fragment thereof comprises a light chain and a chain wherein the light chain comprises the amino acid sequence of SEQ ID NO: 27 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 28, and wherein the anti-TIGIT antibody or antigen binding fragment thereof is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg, (2) Said method wherein anti-TIGIT antibody or antigen binding fragment thereof which comprises a CDRH1 having the sequence of SEQ ID NO: 31, a CDRH2 having the sequence of SEQ ID NO: 32 and a CDRH3 having the sequence of SEQ ID NO: 33, and a CDRL1 having the sequence of SEQ ID NO: 34, a CDRL2 having the sequence of SEQ ID NO: 35 and a CDRL3 having the sequence of SEQ ID NO: 36, (3) the method above wherein the bintrafusp alfa comprises a light chain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 8 or a light chain comprising the amino acid sequence of SEQ ID NO: 15 and the a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 17 or a light chain comprising the amino acid sequence of SEQ ID NO: 15 and the a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 18, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 15-23, and 26-28 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a method of treating a T-cell immunoreceptor with Ig and ITIM domains (TIGIT) mediated cancer in a human subject, the method comprising administering to the subject in needed thereof an anti-TIGIT antibody or antigen binding fragment thereof in combination with bintrafusp alfa, wherein the anti-TIGIT antibody or antigen binding fragment thereof comprises a light chain and a chain wherein the light chain comprises the amino acid sequence of SEQ ID NO: 27 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 28, and wherein the anti-TIGIT antibody or antigen binding fragment thereof is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg, (2) Said method wherein anti-TIGIT antibody or antigen binding fragment thereof which comprises a CDRH1 having the sequence of SEQ ID NO: 31, a CDRH2 having the sequence of SEQ ID NO: 32 and a CDRH3 having the sequence of SEQ ID NO: 33, and a CDRL1 having the sequence of SEQ ID NO: 34, a CDRL2 having the sequence of SEQ ID NO: 35 and a CDRL3 having the sequence of SEQ ID NO: 36, (3) the method above wherein the bintrafusp alfa comprises a light chain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 8 or a light chain comprising the amino acid sequence of SEQ ID NO: 15 and the a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 17 or a light chain comprising the amino acid sequence of SEQ ID NO: 15 and the a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 18, does not reasonably provide enablement for the method of treating any and all possible cancer in any subject as set forth in claims 15-24, and 26-28. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
There are many factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 15 encompasses a method of treating any cancer in any subject, the method comprising administering any PD-1 inhibitor, any TGFP inhibitor and any TIGIT inhibitor to the subject; wherein the PD-1 inhibitor is any anti-PD-L1 antibody, or a fragment thereof capable of binding PD- L1, the TGFP inhibitor is any TGFβRII, or a fragment thereof capable of binding TGF-β, or any anti-TGFO antibody, or a fragment thereof capable of binding TGFO, and the TIGIT inhibitor is an anti-TIGIT antibody, or a fragment thereof capable of binding TIGIT wherein the TIGIT inhibitor is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg.
Claim 16 encompasses the method according to claim 15, wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 1, a CDRH2 having the sequence of SEQ ID NO: 2 and a CDRH3 having the sequence of SEQ ID NO: 3, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 4, a CDRL2 having the sequence of SEQ ID NO: 5 and a CDRL3 having the sequence of SEQ ID NO: 6; or
wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 19, a CDRH2 having the sequence of SEQ ID NO: 20 and a CDRH3 having the sequence of SEQ ID NO: 21, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 22, a CDRL2 having the sequence of SEQ ID NO: 23 and a CDRL3 having the sequence of SEQ ID NO: 24.
Claim 17 encompasses the method according to claim 15, wherein the TGFP inhibitor is an extracellular domain of any TGFβRII or a fragment thereof capable of binding TGFβ.
Claim 18 encompasses the method according to claim 17, wherein the PD-1 inhibitor and the TGFP inhibitor are fused as an anti-PD-L1:TGFβRII fusion protein.
Claim 19 encompasses the method according to claim 18, wherein the light chain sequences and the heavy chain sequences of the anti-PD-LI:TGFβRII fusion protein have at least 90% sequence identity to the light chain sequence and the heavy chain sequence selected from the group consisting of: (1) SEQ ID NO: 7 and SEQ ID NO: 8, (2) SEQ ID NO: 15 and SEQ ID NO: 17, and (3) SEQ ID NO: 15 and SEQ ID NO: 18.
Claim 20 encompasses the method according to claim 19, wherein the amino acid sequence of the anti-PD-L1:TGFORII fusion protein corresponds to the amino acid sequence of bintrafusp alfa.
Claim 21 encompasses the method according claim 20, wherein the anti-PD-L1:TGFβRII fusion protein is administered at a dose of 1200 mg once every two weeks or at a dose of 2400 mg once every three weeks.
Claim 22 encompasses the method according to claim 15, wherein the TIGIT inhibitor is an anti- TIGIT antibody which heavy chain comprises the amino acid sequences of SEQ ID NO: 31 (CDRH1), SEQ ID NO: 32 (CDRH2) and SEQ ID NO: 33 (CDRH3), and which light chain comprises the amino acid sequences of SEQ ID NO: 34 (CDRL1), SEQ ID NO: 35 (CDRL2) and SEQ ID NO: 36 (CDRL3).
Claim 23 encompasses the method according to claim 15, wherein the TIGIT inhibitor is an anti- TIGIT antibody which light chain sequences and heavy chain sequences have at least 90% sequence identity to the light chain sequence and the heavy chain sequence of SEQ ID NO: 27 and SEQ ID NO: 28, respectively.
Claim 26 encompasses the method according to claim 15, wherein the cancer is selected from the group consisting of squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, biliary tract cancer, and head and neck cancer.
Claim 27 encompasses a method of treating any cancer in any subject, the method comprising administering any PD-1 inhibitor, any TGFP inhibitor and any TIGIT inhibitor to the subject; and wherein the PD-1 inhibitor and TGFP inhibitor are fused in a molecule having the amino acid sequence of bintrafusp alfa and the TIGIT inhibitor is an anti-TIGIT antibody which light chain sequences and heavy chain sequences respectively correspond to SEQ ID NO: 27 and SEQ ID NO:28; and wherein the TIGIT inhibitor is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg.
Claim 28 encompasses the method of claim 27, wherein the cancer is selected from the group consisting of squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, biliary tract cancer, and head and neck cancer.
Enablement is not commensurate in scope with claims as how to use any for treating any and all cancer in any mammalian subject by administering a combination of virtually any PD-1 inhibitor, any TGFβ inhibitor and any TIGIT inhibitor.
Regarding “PD-1 inhibitor”, the specification discloses:
[0056] “PD-1 inhibitor” as used herein refers to a molecule that inhibits the PD-1 pathway, e.g., by inhibiting the interaction of PD-1 axis binding partners, such as between the PD-1 receptor and the PD-L1 and/or PD-L2 ligand. Possible effects of such inhibition include the removal of immunosuppression resulting from signaling on the PD-1 signaling axis. Inhibition in this context need not be complete or 100%. Instead, inhibition means reducing, decreasing or abrogating binding between PD-1 and one or more of its ligands and/or reducing, decreasing or abrogating signaling through the PD-1 receptor. In some embodiments, the PD-1 inhibitor binds to PD-L1 or PD-1 to inhibit the interaction between these molecules, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the PD-1 inhibitor is a PD-L1 antibody and such antibody may be fused to the TGFβ inhibitor, e.g., as an anti-PD-L1:TGFβRII fusion protein.
Regarding anti-PD-L1 antibody, the specification discloses:
[0032] “Anti-PD-L1 antibody” or “anti-PD-1 antibody” means an antibody, or an antigen-binding fragment thereof, that specifically binds to PD-L1 or PD-1 respectively and blocks binding of PD-L1 to PD-1. In any of the treatment methods, medicaments and uses of the present invention in which a human subject is being treated, the anti-PD-L1 antibody specifically binds to human PD-L1 and blocks binding of human PD-L1 to human PD-1. In any of the treatment methods, medicaments and uses of the present invention in which a human subject is being treated, the anti-PD-1 antibody specifically binds to human PD-1 and blocks binding of human PD-L1 to human PD-1. The antibody may be a monoclonal antibody, human antibody, humanized antibody or chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments.
[0033] “Anti-PD(L)1 antibody” refers to an anti-PD-L1 antibody or an anti-PD-1 antibody.
Thus, the anti-PD-L1 antibody or antigen binding fragment thereof is not limited and can be any antibody that binds to PD-1 receptor or its ligand.
Regarding TGFβ inhibitor, the specification discloses:
[0066] “TGFβ inhibitor” as used herein refers to a molecule that inhibits the TGFβ pathway, e.g., by inhibiting the interaction between a TGFβ and a TGFβ receptor (TGFβR). Possible effects of such inhibition include the removal of immunosuppression resulting from signaling on the TGFβ signaling axis. Inhibition in this context need not be complete or 100%. Instead, inhibition means reducing, decreasing or abrogating binding between TGF-β and the TGFβR and/or reducing, decreasing or abrogating signaling through the TGFβR. In some embodiments, the TGFβ inhibitor binds to TGFβ or a TGFβR to inhibit the interaction between these molecules. In some embodiments, the TGFβ inhibitor comprises the extracellular domain of a TGFβRII, or a fragment of TGFβRII capable of binding TGFβ. In some embodiments, such TGFβ inhibitor is fused to the PD-1 inhibitor, e.g., as an anti-PD-L1:TGFβRII fusion protein.
Regarding anti-TIGIT antibody, the specification discloses:
[0034] “Anti-TIGIT antibody” means an antibody, or an antigen-binding fragment thereof, that specifically binds to TIGIT and blocks binding of TIGIT to its ligands, such as CD112 and/or CD155. In some embodiments, the anti-TIGIT antibody blocks binding of TIGIT to both CD112 and CD155. In any of the treatment methods, medicaments and uses of the present invention in which a human subject is being treated, the anti-TIGIT antibody specifically binds to human TIGIT and blocks binding of human TIGIT to human TIGIT ligands, such as human CD112 and/or human CD155. The antibody may be a monoclonal antibody, human antibody, humanized antibody or chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments.
Regarding “Bintrafusp alfa”, the specification discloses:
[0035] “Bintrafusp alfa”, also known as M7824, is well understood in the art. Bintrafusp alfa is an anti-PD-L1:TGFβRII fusion protein and described under the CAS Registry Number 1918149-01-5. It is also described in WO 2015/118175 and further elaborated in Lan et al (Lan et al, “Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β”, Sci. Transl. Med. 10, 2018, p.1-15). In particular, bintrafusp alfa is a fully human IgG1 monoclonal antibody against human PD-L1 fused to the extracellular domain of human TGF-β receptor II (TGFβRII). As such, bintrafusp alfa is a bifunctional fusion protein that simultaneously blocks PD-L1 and TGF-β pathways. In particular, WO 2015/118175 describes bintrafusp alfa on page 34 in Example 1 thereof as follows (bintrafusp alfa is referred to in this passage as “anti-PD-L1/TGFβ Trap”): “Anti-PD-L1/TGFβ Trap is an anti-PD-L1 antibody-TGFβ Receptor II fusion protein. The light chain of the molecule is identical to the light chain of the anti-PD-L1 antibody (SEQ ID NO: 1). The heavy chain of the molecule (SEQ ID NO:3) is a fusion protein comprising the heavy chain of the anti-PD-L1 antibody (SEQ ID NO: 2) genetically fused to via a flexible (Gly4Ser)4Gly linker (SEQ ID NO:11) to the N-terminus of the soluble TGFβ Receptor II (SEQ ID NO: 10). At the fusion junction, the C-terminal lysine residue of the antibody heavy chain was mutated to alanine to reduce proteolytic cleavage.”
Regarding cancer, the specification discloses:
[0037] By “cancer” is meant a collection of cells multiplying in an abnormal manner. As used herein, the term “cancer” refers to all types of cancer, neoplasm, malignant or benign tumors found in mammals, including leukemia, carcinomas, and sarcomas. Exemplary cancers include breast cancer, ovarian cancer, colon cancer, liver cancer, kidney cancer, lung cancer, pancreatic cancer, glioblastoma. Additional examples include cancer of the brain, lung cancer, non-small cell lung cancer, melanoma, sarcomas, prostate cancer, cervix cancer, stomach cancer, head and neck cancers, uterus cancer, mesothelioma, metastatic bone cancer, medulloblastoma, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macrobulinemia, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, and neoplasms of the endocrine and exocrine pancreas.
Regarding subject, the specification discloses:
[0055] “Patient” and “subject” are used interchangeably herein to refer to a mammal in need of treatment for a cancer. Generally, the patient is a human diagnosed or at risk for suffering from one or more symptoms of a cancer. In certain embodiments a “patient” or “subject” may refer to a non-human mammal, such as a non-human primate, a dog, cat, rabbit, pig, mouse, or rat, or animals used, e.g., in screening, characterizing, and evaluating drugs and therapies.
The specification exemplifies just treating colon cancer by administering to mice an anti-TIGIT antibody H03-12-muIgG2c in combination with bintrafusp alfa, which is an anti-PD-L1:TGFβRII fusion protein.
The specification exemplifies:
Example 1: Immune Cell Activation by the Combined Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa
[0217] The ability to activate immune cells of the anti-TIGIT antibody H03-12 in combination with bintrafusp alfa was evaluated in an allogenic two-way MLR assay by measuring IFN-γ in the supernatant of co-cultured PBMCs from two different human donors after 2 days treatment. H03-12 was shown to dose-dependently enhance IFN-γ production compared to the isotype control, with an EC.sub.50 of 158.9 ± 185.0 ng/mL (1.065 ± 1.240 nM) (see FIG. 3A). The addition of bintrafusp alfa further enhanced the effect of H03-12 on IFN-γ production (see FIG. 3B). These results suggest that H03-12 stimulates immune cell activation and combination with bintrafusp alfa further enhances this activation.
[0218] The ability of the combination of H03-12 and bintrafusp alfa to enhance T cell activation was further tested in a one-way MLR assay. H03-12 dose-dependently enhanced IFN-γ production in these cells compared with the isotype control, with an EC50 of 136.9 ± 114.6 ng/mL (0.917 ± 0.768 nM) (see FIG. 3C). The combination of H03-12 with bintrafusp alfa further enhanced T cell activation (see FIG. 3D).
Example 2: Flow Cytometric Analysis of Samples Treated With Bintrafusp Alfa
[0219] Cellular subsets in CT26-KSA tumor-bearing mice were analyzed by flow cytometry after bintrafusp alfa treatment. Bintrafusp alfa monotherapy (24.6 mg/kg) showed significant anti-tumor efficacy (P = 0.0029, day 22) relative to isotype control in CT26-KSA tumor-bearing mice (see FIG. 4A). Flow cytometry analysis of spleens and tumors from separate mice treated with bintrafusp alfa showed that bintrafusp alfa monotherapy led to an increased percentage of splenic CD4+ T cells (P < 0.0001), CD8+ T cells (P = 0.0001), and Tregs (P < 0.0001) expressing TIGIT, relative to isotype control. Bintrafusp alfa also tended towards increased percentages of TIGIT+ tumor infiltrating CD4+ T cells, CD8+ T cells, NK cells, and Tregs (see FIG. 4B). This data indicates that the increase of TIGIT expression on immune subsets elicited by bintrafusp alfa treatment may induce resistance to bintrafusp alfa treatment.
Example 3: Anti-Tumor Efficacy of the Combination Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa in the CT26-KSA Tumor Model in BALB/c Mice
[0220] The anti-tumor efficacy of the anti-mouse TIGIT antibody 18G10 having the light chain sequences of SEQ ID NO: 39 and the heavy chain sequences of SEQ ID NO: 40 and/or bintrafusp alfa was tested in the CT26-KSA tumor model in BALB/c mice.
[0221] Bintrafusp alfa (24.6 mg/kg) monotherapy led to moderate tumor growth inhibition (49.5%) relative to isotype control (P < 0.0001, day 21). 18G10 monotherapy led to even greater tumor growth inhibition (TGI = 85.3%) relative to isotype control (P < 0.0001, day 21). However, the combination of 18G10 with bintrafusp alfa (TGI = 110.1%) further enhanced anti-tumor efficacy relative to 18G10 monotherapy (P < 0.0001, day 33), or bintrafusp alfa monotherapy (P < 0.0001, day 21) (See FIG. 5A). Indeed, at day 33, complete tumor regression was observed in 70% of mice treated with 18G10 and bintrafusp alfa combination therapy (7/10 mice, See FIG. 5C).
[0222] Median survival was also significantly prolonged with combination therapy with 18G10 and bintrafusp alfa (undefined) relative to 18G10 monotherapy (50 days, P < 0.0001) or bintrafusp alfa monotherapy (35 days, P = 0.0002) (see FIG. 5B).
Example 4: Anti-Tumor Efficacy of the Combination Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa in the MC38 Tumor Model in C57BL/6 Mice
[0223] The anti-tumor efficacy of an anti-TIGIT antibody and/or bintrafusp alfa was tested in the MC38 tumor model in C57BL/6 mice.
[0224] Monotherapy of bintrafusp alfa (24.6 mg/kg) led to tumor growth inhibition (TGI = 40.2%) relative to isotype control (P < 0.0001, day 24). 18G10 monotherapy led to more moderate tumor growth inhibition (TGI = 18.2%) relative to isotype control (P = 0.0219, day 24). However, the combination of 18G10 with bintrafusp alfa further enhanced anti-tumor efficacy (TGI =58.8%) relative to 18G10 monotherapy (P < 0.0001, day 24), and bintrafusp alfa monotherapy (P = 0.0169, day 24) (see FIGS. 6A and 6C).
[0225] Median survival was also slightly prolonged with 18G10 and bintrafusp alfa (34 days) combination therapy relative to 18G10 monotherapy (29.5 days) or isotype control (26 days) (see FIG. 6B).
Example 5: Anti-Tumor Efficacy of the Combination Treatment With an Anti-TIGIT Antibody and Bintrafusp Alfa in the MC38 Tumor Model in B-huTIGIT Knock-in Mice
[0226] The anti-tumor efficacy of the anti-human TIGIT antibody H03-12-mulgG2c in combination with bintrafusp alfa was evaluated in MC38 tumor-bearing B-huTIGIT knock-in mice. An anti-PD-L1 antibody having the light and heavy chain sequences of SEQ ID NO: 7 and SEQ ID NO: 16, respectively, was used as a further control.
[0227] Since H03-12 lacks cross-reactivity with mouse TIGIT protein, the murine extracellular domain of TIGIT was replaced with a human extracellular domain of TIGIT in mice on the C57BL/6 genetic background. Specifically, the coding region of amino acid 22-131 of exon 2 of mouse TIGIT was replaced with human coding sequence using CRISPR/Cas9 technology. Furthermore, to avoid potential immunogenicity and achieve effector function in mice, an H03-12 mouse chimeric antibody (H03-12-mulgG2c, H03-12′s human IgG1 Fragment crystallizable (Fc) region was replaced with mouse IgG2c Fc) was developed. The light and heavy chain sequences of H03-12-mulgG2c are reflected by SEQ ID NO: 37 and SEQ ID NO: 38, respectively.
[0228] As reflected by FIG. 7 and Table 1, compared with the anti-HEL and inactive anti-PD-L1 isotype controls, the Trap control (a mutant of bintrafusp alfa, which is no longer able to bind to PD-L1 and which light and heavy chain sequences are reflected by SEQ ID NO: 47 and SEQ ID NO: 48, respectively) did not show any anti-tumor efficacy. H03-12-mulgG2c, anti-PD-L1 and bintrafusp alfa monotherapies all displayed tumor growth inhibition (TGI = 36.65%, 61.87% and 66.3%, relative to isotype control at day 32, P < 0.0001 for all three monotherapies), and prolonged median survival (47, 47, and 51 days, P=0.01, P=0.0008, P=0.0004, respectively) relative to isotype control (39 days).
[0229] Tumor growth inhibition was enhanced for the combination of H03-12-mulgG2c with Trap control (TGI = 64.26%) relative to H03-12-mulgG2c (P = 0.0055, day 32) and Trap control (P < 0.0001, day 32) monotherapies. The combination of H03-12-mulgG2c with anti-PD-L1 further enhanced anti-tumor efficacy (TGI = 80.07%) relative to H03-12-mulgG2c (P = 0.0001, day 32) and tended towards increased anti-tumor efficacy relative to anti-PD-L1 monotherapy (P < 0.2215, day 32), and the anti-tumor efficacy of the combination of H03-12-mulgG2c with bintrafusp alfa (TGI = 88.2%) was enhanced relative to H03-12-mulgG2c monotherapy (P < 0.0001, day 32) and tended towards increased anti-tumor efficacy relative to bintrafusp alfa monotherapy (P =0.0658, day 32).
[0230] Combination treatment of H03-12-mulgG2c with Trap control, anti-PD-L1 or bintrafusp alfa also prolonged median survival (51, 54.5 and 74 days, respectively). At day 39, the average tumor volume of the combination treatment of H03-12-mulgG2c with Trap control, anti-PD-L1 or bintrafusp alfa was 437.58 mm.sup.3, 285.35 mm.sup.3 and 193.19 mm.sup.3 respectively.
Regarding antibody that binds to TIGIT, the specification discloses just antibody comprises a light chain sequence of SEQ ID NO: 27 and a heavy chain sequence of SEQ ID NO: 28 wherein the heavy chain comprises a CDRH1 having the sequence of SEQ ID NO: 31, a CDRH2 having the sequence of SEQ ID NO: 32 and a CDRH3 having the sequence of SEQ ID NO: 33, and wherein light chain comprises a CDRL1 having the sequence of SEQ ID NO: 34, a CDRL2 having the sequence of SEQ ID NO: 35 and a CDRL3 having the sequence of SEQ ID NO: 36, is not representative of the entire genus. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
However, the specification, does not teach the structure, e.g., amino acid sequence of the heavy and light chain variable domains that correlated with binding to any PD-1, PD-L1, or TIGIT (claims 15, 26, 27, 28).
The specification does not teach i. Complete structure, e.g., heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of antibodies or antigen binding fragment thereof that correlated with binding to PD-1, PD-L1, or TIGIT from any and all mammalian species for treating any cancer.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 2003 Nov 14;334(1): 103-118, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Further, antibody that binds to human protein may not bind to the same protein from other species.
For example, Yu et al (Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 892) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular). Yu et al further teaches administering bevacizumab does not inhibit the growth of B16F1 melanoma tumor cells in nude mice (see page 525, Figure 5, in particular) or inhibits neovascularization in the laser-induced choroid injury in mouse model (see page 525, Figure 4, in particular).
As another example, Witte et al (Cancer and Metastasis Reviews 17: 155-161, 1998; PTO 892) teach monoclonal antibody such as DC101 that binds to mouse VEGFR2 and blocks the binding of VEGF to its receptor, and yet the same antibody does not bind to human VEGFR2 despite of high percentage (85%) of sequence homology between mouse and human VEGFR2 (also known as KDR), see abstract, in particular.
The specification does not teach the disclosed anti-TIGIT antibody H03-12 can bind to TIGIT from other species, e.g., human, non-human mammal, such as a non-human primate, a dog, cat, rabbit, pig, or rat for treating such subject having any and all possible cancer.
Regarding “administering a PD-1 inhibitor, a TGFβ inhibitor and a TIGIT inhibitor to the subject, wherein the PD-1 inhibitor is an anti-PD-L1 antibody or a fragment thereof capable of binding PD-L1, the TGFβ inhibitor is a TGFβRII or a fragment thereof capable of binding TGF-β and the TIGIT inhibitor is an anti-TIGIT antibody or a fragment thereof capable of binding TIGIT” in claims 15 and 27, the specification discloses administering a combination of anti-TIGIT antibody and Bintrafusp alfa, which is a fusion protein comprising TGFβRII-Fc fused to anti-PDL-1 Fab domains.
However, the specification does not teach administering to a subject a triple combination of agents, e.g., a PD-1 inhibitor, a TGFβ inhibitor and a TIGIT inhibitor to the subject. There is no objective evidence of administering a triple combination of any an anti-PD-L1 antibody or a fragment thereof capable of binding PD-L1, any TGFβRII or a fragment thereof capable of binding TGF-β and any anti-TIGIT antibody or a fragment thereof capable of binding TIGIT to a subject.
Regarding anti-TIGIT antibody which light chain sequences and heavy chain sequences having at least 90% sequence identity to SEQ ID NO: 27 and SEQ ID NO: 28, respectively (claim 23), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 27 or SEQ ID NO: 28 to be substituted, added, deleted or a combination thereof such that the modified heavy and light chains having at least 90% sequence identity to SEQ ID NO: 27 and SEQ ID NO: 28 still maintain binding to human TIGIT, in turn, effective for treating which cancer in any and all subject.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc Natl Acad Sci USA 79: 1979, 1982; PTO 892). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding.
Wu et al (J. Mol. Biol. 294: 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular.
Regarding PD-1 inhibitor and TGFβ inhibitor are any fusion protein (claims 17-18), the specification discloses bintrafusp alfa having the structure shown in Fig 2 comprises a light chain comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain fused to the extracellular domain of TGF-βRII comprising the amino acid sequence of SEQ ID NO: 8, see FIG. 1A-B, 2, in particular.
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However, the specification does not teach the structures, e.g., amino acid sequences of all possible anti-PD-L1:TGFβII fusion proteins encompassed by the claimed method.
Even assuming the anti-PD-L1:TGFβII fusion proteins are the ones set forth in claim 19, the specification does not teach where and what amino acids within the full-length sequence of SEQ ID NO: 7 and SEQ ID NO: 8 or SEQ ID NO: 15 and SEQ ID NO: 17 or SEQ ID NO: 15 and SEQ ID NO: 18 to be substituted, added, deleted or a combination thereof such that the modified anti-PD-L1:TGFβII fusion protein having at least 90% sequence identity to the light chain sequence and the heavy chain sequence of anti-PD-L1:TGFβII fusion protein still effective for treating cancer.
Regarding method of treating any cancer such as the ones recited in claim 26 and 28, the specification exemplifies just treating colon cancer by administering to mice an anti-TIGIT antibody H03-12-muIgG2c in combination with bintrafusp alfa, which is an anti-PD-L1:TGFβRII fusion protein.
However, the specification does not teach the disclosed anti-TIGIT antibody H03-12-muIgG2c binds to TIGIT from other species, e.g., human, non-human primate, a dog, cat, rabbit, pig, or rat.
Mullard (Nature reviews drug discovery 25: 157-161, 2026; PTO 892) teaches that TIGIT inhibitor, e.g., tiragolumab (Genentech) fails in lung cancer, promoting the company to wind down its TIGIT programe, which had spanned lung, liver, oesophageal cancer and beyond, see p. 157, left col. In mouse models of colorectal and breast cancer, single-agent treatment with anti-TIGIT or anti-PD-L1 antibody did little to decrease the tumor burden or to shift survival. The mismatch between the preclinical and clinical data, re-affirms that mice aren’t humans, see p. 160, left col. Thus, the prior art teaches the therapeutic effectiveness of an antibody that targets cancer cells is not a certainty, and is necessarily determined empirically.
There are insufficient in vivo working examples. It is unpredictable which undisclosed PD-1 inhibitor, TGFβ inhibitor and TIGIT inhibitor is effective for treating any and all possible cancers in any subject. The claims are broad in that they encompass treating any and all cancers in any mammalian subject. The specification is narrow in that only a single colon cancer in mice treated with anti-TIGIT antibody H03-12-muIgG2c in combination with bintrafusp alfa commensurate in scope with the claims is described. The art is unpredictable and complex as described above. Given these factors, and the lack of specific guidance in the specification as to how to perform the full scope of the claimed methods, one skilled in the art would need to resort to undue experimentation in a complex and unpredictable field in order to determine how to perform the invention as claimed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 15-20 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Carvalho (of record, WO2018234793, published December 27, 2018; PTO 1449) in view of Meng et al (WO2019165434, published August 29, 2019; PTO 892) and US Patent No. 9,676,863 (issued June 13, 2017; PTO 892).
Claim 15 encompasses a method of treating any cancer in any subject, the method comprising administering any PD-1 inhibitor, any TGFP inhibitor and any TIGIT inhibitor to the subject; wherein the PD-1 inhibitor is any anti-PD-L1 antibody, or a fragment thereof capable of binding PD- L1, the TGFP inhibitor is any TGFβRII, or a fragment thereof capable of binding TGF-β, or any anti-TGFO antibody, or a fragment thereof capable of binding TGFO, and the TIGIT inhibitor is an anti-TIGIT antibody, or a fragment thereof capable of binding TIGIT wherein the TIGIT inhibitor is administered once every two weeks with a dose of about 300 mg, once every two weeks with a dose of about 900 mg, once every two weeks with a dose of about 1600 mg, once every three weeks with a dose of about 300 mg, once every three weeks with a dose of about 900 mg, or once every three weeks with a dose of about 1600 mg.
Regarding claims 15, 20, 26, Carvalho teaches a method of treating cancer (p. 12, lines 20-30, p. 109) by administering (p. 19) to a subject a combination of anti-TIGT antibody (p. 108), anti-PD-L1 antibody (see p. 114, p. 131) or a bispecific fusion protein M7824 (aka bintrafusp alfa, as evidenced in instant specification at p. 10, para. 2), which is an anti-PD-L1/TGFβ Trap fusion protein, see p. 110, last paragraph, in particular.
Carvalho does not teach the method wherein the anti-TIGT antibody is administered once every three weeks with a dose of about 900 mg as per claim 15.
However, Meng teaches and claims a method of treating cancer, e.g., (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC)) one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, e.g., tiragolumab or antigen binding fragment thereof, e.g., Fab, Fab’, scFv (see p. 3, line 9-12, p. 15, 22-24) and an effective amount of an anti-PD-L1 antagonist antibody, e.g., atezolizumab, or antigen binding fragment thereof, e.g., Fab, Fab’, Fab’-SH, scFv, (Fab’)2 (p. 4, line 1-5, p. 16, lines 11-15), thereby treating the subject, see p. 2, Summary of invention.
Meng teaches that the anti-TIGIT antagonist antibody is administered at a fixed dose of about 300 mg to about 1200 mg every three weeks, between about 100 mg to about 300 mg, or between about 300 mg to about 800 mg see p. 14, lines 5-11, p. 46, Dosing Regimens and administration, in particular.
The anti-PD-L1 is administered at a dose between about 1200 mg, every three weeks, see p. 47, line 8, in particular.
Carvalho and Meng do not teach that the method wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 1, a CDRH2 having the sequence of SEQ ID NO: 2 and a CDRH3 having the sequence of SEQ ID NO: 3, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 4, a CDRL2 having the sequence of SEQ ID NO: 5 and a CDRL3 having the sequence of SEQ ID NO: 6 as per claim 16, wherein the TGFP inhibitor is an extracellular domain of any TGFβRII or a fragment thereof capable of binding TGFβ as per claim 17, wherein the PD-1 inhibitor and the TGFP inhibitor are fused as an anti-PD-L1:TGFβRII fusion protein, wherein the light chain sequences and the heavy chain sequences of the anti-PD-LI:TGFβRII fusion protein have at least 90% sequence identity to the light chain sequence and the heavy chain sequence selected from the group consisting of: (1) SEQ ID NO: 7 and SEQ ID NO: 8 as per claim 19.
However, regarding claim 17-18, 20, the ‘863 patent teaches that anti-PD-L1/TGFβ Trap fusion protein comprising TGFβRII fused to the C-terminus of Fc (TGFβRII-Fc) tethered to an anti-PD-L1 antibody moiety, see entire document, Fig 1A, in particular.
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The ‘863 patent teaches a method of treating various cancers by administering the reference anti-PD-L1/TGFβ Trap fusion protein (aka bintrafusp alfa or M7824) and has superior anti-tumor effect that is synergistic of anti-PD-L1 and TGFβ trap activities, see Examples 12, 13, 14, in particular. The anti-PD-L1/TGFβ Trap elicits a synergistic anti-tumor effect due to the simultaneous blockade of the interaction between PD-L1 on tumor cells and PD-1 on immune cells, and the neutralization of TGFβ in the tumor microenvironment.
Regarding claim 16, the ‘863 patent teaches that the anti-PD-1 antibody or antigen binding fragment thereof of the heavy chain sequence comprises the amino acids sequence of SEQ ID NO: 2, which comprises the claimed SEQ ID NO: 1, 2 and 3, see sequence alignment below:
Query Match 85.5%; Score 145.4; Length 450;
Best Local Similarity 41.8%;
Matches 33; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 SYIMM--------------SIYPSGGITFYADTVKG------------------------ 22
||||| |||||||||||||||||
Db 31 SYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAED 90
Qy 23 --------IKLGTVTTVDY 33
|||||||||||
Db 91 TAVYYCARIKLGTVTTVDY 109
And the anti-PD-1 antibody or antigen binding fragment thereof of the light chain sequence comprises the amino acids sequence of SEQ ID NO: 45, which comprises the claimed SEQ ID NO: 4, 5 and 6, see sequence alignment below:
ALIGNMENT:
Query Match 84.2%; Score 131.3; Length 110;
Best Local Similarity 39.7%;
Matches 31; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 TGTSSDVGGYNYVS---------------DVSNRPS------------------------ 21
|||||||||||||| |||||||
Db 23 TGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQA 82
Qy 22 --------SSYTSSSTRV 31
||||||||||
Db 83 EDEADYYCSSYTSSSTRV 100
Regarding claim 19, the ‘863 patent teaches that the light chain sequence of the anti-PD-L1:TGFβII fusion protein comprising the amino acid sequence of SEQ ID NO: 6, which is at least 99.1% identical to the claimed SEQ ID NO: 7, see sequence alignment below:
Query Match 99.0%; Score 1116; Length 216;
Best Local Similarity 99.1%;
Matches 214; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGV 60
|||||||||||||||||||||||||||||||||||||||||||||||||||:||||||||
Db 1 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGV 60
Qy 61 SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVT 120
|||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||
Db 61 SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTYVFGTGTKVTVLGQPKANPTVT 120
Qy 121 LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS 180
Qy 181 YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 216
||||||||||||||||||||||||||||||||||||
Db 181 YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 216
And the heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 3, which is at least 100% identical to the claimed SEQ ID NO: 7, see sequence alignment below:
Query Match 100.0%; Score 3267; Length 607;
Best Local Similarity 100.0%;
Matches 607; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFY 60
Qy 61 ADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS 120
Qy 121 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
Qy 181 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG 240
Qy 241 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 300
Qy 301 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 360
Qy 361 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 420
Qy 421 QQGNVFSCSVMHEALHNHYTQKSLSLSPGAGGGGSGGGGSGGGGSGGGGSGIPPHVQKSV 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 QQGNVFSCSVMHEALHNHYTQKSLSLSPGAGGGGSGGGGSGGGGSGGGGSGIPPHVQKSV 480
Qy 481 NNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKND 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 NNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKND 540
Qy 541 ENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEE 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 ENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEE 600
Qy 601 YNTSNPD 607
|||||||
Db 601 YNTSNPD 607
Regarding claim 26, the ‘863 patent teaches that the anti-PD-L1/TGFβ Trap proteins can be used to treat cancer or reduce tumor growth in a patient. Exemplary cancers include colorectal, breast, ovarian, pancreatic, gastric, prostate, renal, cervical, myeloma, lymphoma, leukemia, thyroid, endometrial, uterine, bladder, neuroendocrine, head and neck, liver, nasopharyngeal, testicular, small cell lung cancer, non-small cell lung cancer, melanoma, basal cell skin cancer, squamous cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, glioblastoma, glioma, sarcoma, mesothelioma, and myelodisplastic syndromes, see col. 25, in particular. The ‘863 patent teaches that the dose can be determined by routine experimentation, see col. 26, line 19-22, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to treat cancer by administering to a subject Carvalho’s anti-TIGIT antibody and bispecific fusion protein M7824 (bintrafusp afa) that binds to PD-L1 and TGFβ or ‘863 patent anti-PD-L1:TGFβRII fusion protein wherein the dose of anti-TIGIT antibody is administered once every three weeks at a dose of about 900 mg as taught by Meng to arrive at the claimed invention with a reasonable expectation of success since the dose can be determined by routine experimentation as taught by the ‘863 patent.
One of ordinary skill in the art would be motivated to combine the teachings of Carvalho, Meng, and the ‘863 patent because the ‘863 patent teaches that it is advantageous to combine anti-TIGIT antibody with the anti-PD-L1/TGFβ Trap fusion protein (aka bintrafusp alfa or M7824) since the combination has superior anti-tumor effect and synergistic of anti-PD-L1 and TGFβ trap activities, see Examples 12, 13, 14, in particular. The anti-PD-L1/TGFβ Trap elicits a synergistic anti-tumor effect due to the simultaneous blockade of the interaction between PD-L1 on tumor cells and PD-1 on immune cells, and the neutralization of TGFβ in the tumor microenvironment.
One of ordinary skill in the art would have been motivated to do so in order to simultaneous neutralization of TGFβ, a molecule known to inhibitor tumor immune activation, might stimulate response in patients who failed to respond to single agent.
One of ordinary skill in the art would have been motivated to do so because Meng teaches that the dose of anti-TIGIT antagonist antibody is administered at a fixed dose of about 300 mg to about 1200 mg every three weeks, between about 100 mg to about 300 mg, or between about 300 mg to about 800 mg see p. 14, lines 5-11, p. 46, Dosing Regimens and administration, in particular and the ‘863 patent teaches that the dose can be determined by routine experimentation (see col. 26, line 19-22).
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215,218-219 (C.C.P.A. 1980).
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Carvalho (of record, WO2018234793, published December 27, 2018; PTO 1449) in view of Meng et al (WO2019165434, published August 29, 2019; PTO 892) and US Patent No. 9,676,863 (issued June 13, 2017; PTO 892) as applied to claims 15-20 and 26 mentioned above and further in view of Strauss et al (of Record, Clin Cancer Res 24(6): 1287-1295, 2018; PTO 892) or El Bawab (US20190330375, published Oct 31, 2019, claimed earliest priority to 62/581,978, filed November 6, 2017; PTO 892).
The combine teachings of Carvalho, Meng and the ‘863 patent have been discussed supra.
The references above do not teach that the anti-PD-L1/TGFβ Trap fusion protein (aka bintrafusp alfa or M7824) is administered at a dose of 1200 mg once every two weeks.
However, Strauss teaches that the dose of M7824 is administered at 3 mg/kg, 10 mg/kg, 500 mg, and 1,200 mg every two weeks (W2Q), see p. 1294, left col., end of the first para, in particular. Carvalho, Meng, the ‘863 patent and Strauss are all directed to cancer treatments comprising anti-PD-L1 and/or anti-TGFβ binding agents.
Likewise, El Bawab teaches a method of treating cancer, e.g., non-small cell lung cancer (para. [0017]) by administering to a human subject a bifunctional protein targeting human protein Programmed Death Ligand 1 (PD-L1) and Transforming Growth Factor β (TGFβ) at a dose of about 1200 mg once every two weeks is required to maintain a C.sub.trough of about 100 μg/mL. Typically, about 1200 mg to about 3000 mg (e.g., about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, etc.) of anti-PD-L1/TGFβ Trap) is administered to a subject once every two weeks, see para. [0053], [0054]. The localized reduction in TGFβ in a tumor microenvironment by capturing the TGFβ using a soluble cytokine receptor (TGFβRII) tethered to an antibody moiety targeting a cellular immune checkpoint receptor found on the exterior surface of certain tumor cells or immune cells. An example of an antibody moiety of the disclosure to an immune checkpoint protein is anti-PD-L1. This bifunctional molecule, sometimes referred to in this document as an “antibody-cytokine Trap,” is effective precisely because the anti-receptor antibody and cytokine Trap are physically linked. The resulting advantage (over, for example, administration of the antibody and the receptor as separate molecules) is partly because cytokines function predominantly in the local environment through autocrine and paracrine functions. The antibody moiety directs the cytokine Trap to the tumor microenvironment where it can be most effective, by neutralizing the local immunosuppressive autocrine or paracrine effects. Furthermore, in cases where the target of the antibody is internalized upon antibody binding, an effective mechanism for clearance of the cytokine/cytokine receptor complex is provided.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was filed, to modify the method of Carvalho, Meng and the ‘863 patent with the dosage taught by Strauss or El Bawab to achieve the predictable result of obtaining a composition suitable for treating neoplastic disease.
One of ordinary skill in the art would have been motivated to do so because Strauss discloses that the doses greater than or equal to 3mg/kg, resulted in complete PD-L1 target occupancy and TGFβ trapping in blood throughout the dosing interval in humans, and were associated with preliminary clinical efficacy and a manageable safety profile, thereby informing the dosage regimens including 1200mg Q2W for expansion cohorts (pg 1294, left column, end of the first ¶).
One of ordinary skill in the art would have been motivated to do so because El Bawab teaches that the anti-PD-L1/TGFβ Trap fusion protein is typically administered to a cancer patient at a dose of about 1200 mg once every two weeks to maintain a C.sub.trough of about 100 μg/mL and about 1200 mg to about 3000 mg (e.g., about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, etc.) of anti-PD-L1/TGFβ Trap) is administered to a subject once every two weeks, see para. [0053], [0054].
Allowable Subject Matter
The anti-TIGIT antibody comprising heavy chain complimentary determining region sequences (CDRH1-3) of SEQ ID NOs: 31-33 and light chain CDR sequences (CDRL1-3) of SEQ ID NOs: 34-36 with corresponding heavy/light chain sequences according to SEQ ID NOs: 28 and 27, respectively, appears to be free of prior art.
Claims 22-23, 27 are free of prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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