DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-8, 13-16, 19, 21-23, 44, 47, and 49 are pending and under examination in the instant office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-8, 13-16, 19, 21-23, 44, 47, and 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCT04931654 "A Study to Assess the Safety and Efficacy of AZD7789 in Participants With Advanced or Metastatic Solid Cancer" Version 9 published 27 April 2022 (hereinafter ‘NCT’654’) as evidenced by U.S. 20220332818 to Pollizzi et. al. published 20 October 2022 (IDS dated 9/4/2024) and Pourmir, Ivan, et al. "Longitudinal study of advanced non-small cell lung cancer with initial durable clinical benefit to immunotherapy: Strategies for anti-PD-1/PD-L1 continuation beyond progression." Cancers 15.23 (2023): 5587 in view of WO2017193032 to Kasturirangan et. al. published 9 November 2017 and U.S. 20170121409 to Verona et. al.; U.S. 20220259314 A1 to Codarri-Deak et. al. published 18 August 2022; and NCT04785820 “A Study of Lomvastomig (RO7121662) and Tobemstomig (RO7247669) Compared With Nivolumab in Participants With Advanced Metastatic Squamous Cell Carcinoma of the Esophagus” Version 30 published 3 May 2023 (hereinafter ‘NCT’820).
Regarding claim 1, NCT’654 teaches a method of treating non-small cell lung cancer (See “Conditions” section, “Arms and Interventions” section) comprising administering the bispecific anti-PD-1 and anti-TIM3 antibody AZD7789 to the NSCLC patients (“Arms and Interventions” section). As evidenced by Pollizzi et. al., AZD7789 comprises anti-TIM3 CDRs of SEQ ID NOs: 1-3 and 7-9 (100% identical to instant SEQ ID NOs: 1-3 and 7-9) and anti-PD-1 CDRs of SEQ ID NOs: 4-6 and 10-12 (100% identical to instant SEQ ID NOs: 4-6 and 10-12).
Regarding claim 14, NCT’654 teaches a Part B Cohort B2 wherein the patients must not have received prior systemic therapy (p. 19, “Inclusion criteria” section).
Regarding claim 15, NCT’654 teaches a Part B Cohort B1 wherein the patients must have received at least one but no more than two prior lines of systemic therapy, of which only one prior line of therapy contained approved anti-PD-1/PD-L1 (p. 19, “Inclusion criteria” section).
Regarding claim 16, NCT’654 teaches a Part A Cohort wherein the patients must have received at least one prior line of systemic therapy, or which at least one prior line of therapy contained an approved anti-PD-1/PD-L1 (reads on an IO therapy; p. 19, “Inclusion criteria” section).
Regarding claim 19, NCT’654 teaches a Part A Cohort wherein the patients must have received at least one prior line of systemic therapy, or which at least one prior line of therapy contained an approved anti-PD-1/PD-L1 wherein the subject must have immune-oncology acquired or primary resistance (p. 19, “Inclusion criteria” section).
Regarding claim 22, NCT’654 teaches several cohort wherein the tumor expresses PD-L1 (e.g. Part B Cohort B1 “PD-L1 >1% documented”; p. 19 “Inclusion criteria” section).
Regarding claim 44, the cancer is NSCLC (See “Conditions” section, “Arms and Interventions” section).
Regarding claim 47, NCT’654 teaches several cohorts where the PD-L1 tumor proportion score is greater than or equal to 1% (e.g. Part B Cohort B1 “PD-L1 >1% documented”; p. 19 “Inclusion criteria” section).
Regarding claim 49, NCT’654 teaches a cohort where the PD-L1 tumor proportion score is greater than or equal to 1% (e.g. Part B Cohort B2 “PD-L1 >50% documented”; p. 19 “Inclusion criteria” section) and the patients must not have received prior systemic therapy including IO therapy (reads on checkpoint inhibitor naïve).
Kasturirangan et. al. teaches an anti-PD-1 anti-TIM3 antibodies (see e.g. Table 8), including an anti-TIM3/anti-PD-1 antibody comprising anti-PD1 VH SEQ ID NO: 51 (100% identical to instant SEQ ID NO: 19):
Query Match 100.0%; Score 648; Length 122;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMHWVRQAPGKGLEWVAYISSGSYTIYS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMHWVRQAPGKGLEWVAYISSGSYTIYS 60
Qy 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRAPNSFYEYYFDYWGQGTTVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRAPNSFYEYYFDYWGQGTTVTV 120
Qy 121 SS 122
||
Db 121 SS 122
Anti-PD1 VL SEQ ID NO: 49 (100% identical to instant SEQ ID NO: 21):
Query Match 100.0%; Score 595; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QIVLTQSPATLSLSPGERATLSCSASSKHTNLYWSRHMYWYQQKPGQAPRLLIYLTSNRA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QIVLTQSPATLSLSPGERATLSCSASSKHTNLYWSRHMYWYQQKPGQAPRLLIYLTSNRA 60
Qy 61 TGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSSNPFTFGQGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSSNPFTFGQGTKLEIK 112
Anti-TIM3 VH of SEQ ID NO: 68 (100% identical to instant SEQ ID NO: 14)
Query Match 100.0%; Score 643; Length 122;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSYGTYYGNYFEYWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSYGTYYGNYFEYWGQGTLVTV 120
Qy 121 SS 122
||
Db 121 SS 122
and anti-TIM3 VL of SEQ ID NO: 28 (100% identical to instant SEQ ID NO: 17)
Query Match 100.0%; Score 574; Length 214;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SYVLTQPPSVSVAPGKTARITCGGDNIGGKSVHWYQQKPGQAPVLVIYYDSDRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SYVLTQPPSVSVAPGKTARITCGGDNIGGKSVHWYQQKPGQAPVLVIYYDSDRPSGIPER 60
Qy 61 FSGSNSGNTATLTISRVEAGDEADYYCQVLDRRSDHFLFGGGTKLTVL 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISRVEAGDEADYYCQVLDRRSDHFLFGGGTKLTVL 108
Kasturirangan et. al. teaches that this bispecific anti-TIM3/anti-PD-1 antibody enhanced CD8+ T cell proliferation ([00323], Fig. 32A-C) and enhanced IFNɣ secretion in an MLR assay more strongly than monotherapy ([00325-00326], Fig. 33A-D). Kasturirangan et. al. teaches “All bispecific formats show in vitro functionality equivalent to or better than anti-PD-1, suggesting that these molecules may provide superior advantage to current immuno-oncology strategies” [00326].
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the anti-TIM3/anti-PD-1 antibody of Kasturirangan et. al. in the method of treating NSCLC using an anti-TIM3/anti-PD-1 antibody as taught by NCT’654 in order to benefit from the activity that is better than PD-1 monotherapy in a target population for anti-TIM-3 anti-PD-1 antibody therapy. This would have a reasonable expectation of success because a person of ordinary skill in the art would believe that effective anti-TIM3/anti-PD-1 antibodies as taught by Kasturirangan et. al. would be suitable in the patient population as taught by NCT’654. Regarding claim 23, the sequences of NCT’654 in view of Kasturirangan as described above are identical to SEQ ID NO: 19 and 21 and 14 and 17 as described above.
NCT’654 in view of Kasturirangan et. al. does not teach the method wherein the dose of the bispecific antibody is from about 750 mg to about 1500 mg. This deficiency is resolved by Verona et. al.
Verona et. al. teaches bispecific antibodies specifically binding to PD-1 and TIM-3 (e.g. see claim 69 p. 266). Verona et. al. teaches that the antibodies of the invention may be given in a therapeutically effective amount and discloses specific fixed unit doses of 50, 100, 200, 500, or 1000 mg [1373]. Verona et. al. teaches that the doses may be repeated (reads on cycles) in intervals including two weeks and three weeks [1374].
Codarri-Deak et. al. teaches bispecific antibody for PD1 and TIM3 (Abstract) and demonstrates that an effective dose for treating a tumor in a mouse in vivo was 10mg/kg resulting in tumor control (See Fig. 14; Example 18 [0909]).
NCT’820 teaches an anti-PD-1 anti-TIM3 bispecific antibody lomvastomig (See “Official Title” section) wherein the antibody is administered in a dose of 2100 mg by IV infusion once every 2 weeks on Day 1 of each 14-day cycle (“Arms and Interventions” section).
In regard to the specific dosage and interval amounts recited in the instant claims 1 and 2, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Therefore, it would have been obvious, at the time of filing, for a person of ordinary skill in the art to optimize the dose interval and timing of the anti-PD-1/TIM-3 bispecific in the method of treating NSCLC as taught by NCT’654 in view of Kasturirangan et. al. in order to benefit from the particular dosing and timing that results in the most effective treatment for cancer in the patient population. This would have a reasonable expectation of success because Verona et. al., Codarri-Deak et. al., and NCT’820, teach the general ranges and conditions that could be appropriate for an anti-TIM3/PD-1 bispecific antibody and clinical benchmarks for bispecific antibody binding to the same target proteins (of 2100 mg). The Examiner further notes that a dose of 10mg/kg in a human rather than a mouse is a fixed dose of approximately 600-800 mg; and therefore a person of ordinary skill in the art would be able to derive the optimal doses and ranges for this particular bispecific antibody in the NSCLC patients as suggested by NCT’654.
Regarding claims 3 and 4, the optimization of ranges by a person of ordinary skill in the art would arrive a doses of about 750 mg (which is 10mg/kg for an average 75 kg human) and is within the range disclosed by Verona and 1500 mg (which is below the 2100 mg range of the clinical benchmark as taught by NCT’820 and above the fixed dose of 1000 mg disclosed by Verona). This would have a reasonable expectation of success because, as described above, dosing is a results effective variable and the level of skill in the art is high; therefore, a person of ordinary skill in the art would be able to arrive at the optimal fixed doses.
Regarding claims 5 and 6, NCT’820 teaches a method of administering an anti-PD-1/TIM-3 binding protein on a cycle, wherein the binding protein is administered once every two weeks on Day 1 (Arms and Interventions section; reads on administered once per cycle and once about every 14 days).
Regarding claims 7 and 13, Verona et. al. teaches optimization of the intervals including repeating in groups every two or three weeks [1374]. It would have been obvious, at the time of filing, for a person of ordinary skill in the art to optimize the dosage timing as described above for NCT’654 in view of Kasturirangan, Verona, Codarri-Deak, and NCT’820 to benefit from the most appropriate interval for an effective cancer treatment at an effective dosage. As described above, this would have a reasonable expectation of success because a person of ordinary skill in the art would know that dose timing was a results-effective variable to optimize along with dose amount and would adjust for the particular patient, disease history, or population as appropriate. As described above, NCT’654 teaches wherein the patient has not received a prior line of systemic therapy.
Regarding claim 8, Verona recites that e.g. 9 or more, or 20 or more doses may be given (reads on repeated for more than 20 cycles). It would have been obvious, at the time of filing, for a person of ordinary skill in the art to repeat the treatment cycle for up to 35 cycles to benefit from continuing from as many cycles as may benefit the patient. This would have a reasonable expectation of success because a person of ordinary skill in the art would have been able to determine the number of useful cycles and when to cap or discontinue treatment.
Regarding claim 21, the claim states that the subject must have radiologically documented tumor progression or clinical deterioration following initial treatment with an anti-PD-1/PD-L1 therapy for a minimum of 3-6 months. The examiner notes that “clinical deterioration” is not defined by the instant specification. As described above, NCT’654 teaches arms of the study wherein the patient has acquired resistance and but have at least one prior line of PD-1/PD-L1 therapy (Part A and Part B Cohort B1, Inclusion Criteria section). As evidenced by Pourmir et. al., acquired resistance is understood as durable clinical benefit >6 months followed by tumor progression (reads on clinical deterioration following initial treatment with an anti-PD-1/PD-L1 therapy for a minimum of 3-6 months (Introduction ¶1.3-1.4).
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 1-8, 13-16, 19, 21-23, 44, 47, and 49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim1-19 of U.S. Patent No. US 11279759 B2 in view of NCT04931654 "A Study to Assess the Safety and Efficacy of AZD7789 in Participants With Advanced or Metastatic Solid Cancer" Version 9 published 27 April 2022 (hereinafter ‘NCT’654’) as evidenced by Pourmir, Ivan, et al. "Longitudinal study of advanced non-small cell lung cancer with initial durable clinical benefit to immunotherapy: Strategies for anti-PD-1/PD-L1 continuation beyond progression." Cancers 15.23 (2023): 5587 and U.S. 20170121409 to Verona et. al.; U.S. 20220259314 A1 to Codarri-Deak et. al. published 18 August 2022; and NCT04785820 “A Study of Lomvastomig (RO7121662) and Tobemstomig (RO7247669) Compared With Nivolumab in Participants With Advanced Metastatic Squamous Cell Carcinoma of the Esophagus” Version 30 published 3 May 2023 (hereinafter ‘NCT’820’).
Claims 1-14 of the ‘759 patent teaches a bispecific binding protein that binds to PD-1 and TIM3 comprising a first heavy chain, a first light chain, a second heavy chain, and a second light chain, comprising CDRs identified by SEQ ID NO and residue position (claim 1) and comprising a first heavy chain SEQ ID NO: 9 (which is 100% identical to instant SEQ ID NO: 19 and comprises instant CDRs SEQ ID NO: 4, 5, and 6), a first light chain SEQ ID NO: 7 (which is 100% identical to instant SEQ ID NO: 21), a second heavy chain comprising SEQ ID NO: 30 (100% identical to instant SEQ ID NO: 14), and a second light chain comprising SEQ ID NO: 28 (100% identical to instant SEQ ID NO: 17).
See alignments below:
Instant SEQ ID NO: 19 to ‘759 SEQ ID NO: 9:
Query Match 100.0%; Score 648; Length 452;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMHWVRQAPGKGLEWVAYISSGSYTIYS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMHWVRQAPGKGLEWVAYISSGSYTIYS 60
Qy 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRAPNSFYEYYFDYWGQGTTVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRAPNSFYEYYFDYWGQGTTVTV 120
Qy 121 SS 122
||
Db 121 SS 122
Instant SEQ ID NO: 21 to ‘759 SEQ ID NO: 7:
Query Match 100.0%; Score 595; Length 219;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QIVLTQSPATLSLSPGERATLSCSASSKHTNLYWSRHMYWYQQKPGQAPRLLIYLTSNRA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QIVLTQSPATLSLSPGERATLSCSASSKHTNLYWSRHMYWYQQKPGQAPRLLIYLTSNRA 60
Qy 61 TGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSSNPFTFGQGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSSNPFTFGQGTKLEIK 112
Instant SEQ ID NO: 14 to ‘759 SEQ ID NO: 30:
Query Match 100.0%; Score 643; Length 452;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSYGTYYGNYFEYWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSYGTYYGNYFEYWGQGTLVTV 120
Qy 121 SS 122
||
Db 121 SS 122
Instant SEQ ID NO: 17 to ‘759 SEQ ID NO: 28:
Query Match 100.0%; Score 574; Length 214;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SYVLTQPPSVSVAPGKTARITCGGDNIGGKSVHWYQQKPGQAPVLVIYYDSDRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SYVLTQPPSVSVAPGKTARITCGGDNIGGKSVHWYQQKPGQAPVLVIYYDSDRPSGIPER 60
Qy 61 FSGSNSGNTATLTISRVEAGDEADYYCQVLDRRSDHFLFGGGTKLTVL 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISRVEAGDEADYYCQVLDRRSDHFLFGGGTKLTVL 108
The claims of ‘759 further teach a method of treating cancer in a subject comprising administering the bispecific binding protein of claim 1 (claim 17); wherein the cancer is selected from a group including lung cancer (claim 18).
The claims of ‘759 do not teach wherein the cancer is non-small cell lung cancer and wherein the antibody is administered at a dose from about 70 mg to about 1500 mg. These deficiencies are resolved by NCT’654 as evidenced by Pourmir, Verona, Codarri-Deak, and NCT’820.
Regarding claim 1, NCT’654 teaches a method of treating non-small cell lung cancer (See “Conditions” section, “Arms and Interventions” section) comprising administering the bispecific anti-PD-1 and anti-TIM3 antibody AZD7789 to the NSCLC patients (“Arms and Interventions” section). As evidenced by Pollizzi et. al., AZD7789 comprises anti-TIM3 CDRs of SEQ ID NOs: 1-3 and 7-9 (100% identical to instant SEQ ID NOs: 1-3 and 7-9) and anti-PD-1 CDRs of SEQ ID NOs: 4-6 and 10-12 (100% identical to instant SEQ ID NOs: 4-6 and 10-12).
Regarding claim 14, NCT’654 teaches a Part B Cohort B2 wherein the patients must not have received prior systemic therapy (p. 19, “Inclusion criteria” section).
Regarding claim 15, NCT’654 teaches a Part B Cohort B1 wherein the patients must have received at least one but no more than two prior lines of systemic therapy, of which only one prior line of therapy contained approved anti-PD-1/PD-L1 (p. 19, “Inclusion criteria” section).
Regarding claim 16, NCT’654 teaches a Part A Cohort wherein the patients must have received at least one prior line of systemic therapy, or which at least one prior line of therapy contained an approved anti-PD-1/PD-L1 (reads on an IO therapy; p. 19, “Inclusion criteria” section).
Regarding claim 19, NCT’654 teaches a Part A Cohort wherein the patients must have received at least one prior line of systemic therapy, or which at least one prior line of therapy contained an approved anti-PD-1/PD-L1 wherein the subject must have immune-oncology acquired or primary resistance (p. 19, “Inclusion criteria” section).
Regarding claim 22, NCT’654 teaches several cohort wherein the tumor expresses PD-L1 (e.g. Part B Cohort B1 “PD-L1 >1% documented”; p. 19 “Inclusion criteria” section).
Regarding claim 44, the cancer is NSCLC (See “Conditions” section, “Arms and Interventions” section).
Regarding claim 47, NCT’654 teaches several cohorts where the PD-L1 tumor proportion score is greater than or equal to 1% (e.g. Part B Cohort B1 “PD-L1 >1% documented”; p. 19 “Inclusion criteria” section).
Regarding claim 49, NCT’654 teaches a cohort where the PD-L1 tumor proportion score is greater than or equal to 1% (e.g. Part B Cohort B2 “PD-L1 >50% documented”; p. 19 “Inclusion criteria” section) and the patients must not have received prior systemic therapy including IO therapy (reads on checkpoint inhibitor naïve).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the anti-TIM3/anti-PD-1 antibody of the ’759 claims in the method of treating NSCLC using an anti-TIM3/anti-PD-1 antibody as taught by NCT’654 in order to benefit from the activity that is better than PD-1 monotherapy in a target population for anti-TIM-3 anti-PD-1 antibody therapy. This would have a reasonable expectation of success because a person of ordinary skill in the art would believe that effective anti-TIM3/anti-PD-1 antibodies as taught by ‘759 claims would be suitable in the patient population as taught by NCT’654 and ‘759 explicitly recites lung cancer, of which NSCLC is a species. Regarding claim 23, the sequences of ‘759 as described above are identical to SEQ ID NO: 19 and 21 and 14 and 17.
‘759 in view of NCT’654 does not teach the method wherein the dose of the bispecific antibody is from about 750 mg to about 1500 mg. This deficiency is resolved by Verona et. al., Codarri-Deak et. al., and NCT’820.
Verona et. al. teaches bispecific antibodies specifically binding to PD-1 and TIM-3 (e.g. see claim 69 p. 266). Verona et. al. teaches that the antibodies of the invention may be given in a therapeutically effective amount and discloses specific fixed unit doses of 50, 100, 200, 500, or 1000 mg [1373]. Verona et. al. teaches that the doses may be repeated (reads on cycles) in intervals including two weeks and three weeks [1374].
Codarri-Deak et. al. teaches bispecific antibody for PD1 and TIM3 (Abstract) and demonstrates that an effective dose for treating a tumor in a mouse in vivo was 10mg/kg resulting in tumor control (See Fig. 14; Example 18 [0909]).
NCT’820 teaches an anti-PD-1 anti-TIM3 bispecific antibody lomvastomig (See “Official Title” section) wherein the antibody is administered in a dose of 2100 mg by IV infusion once every 2 weeks on Day 1 of each 14-day cycle (“Arms and Interventions” section).
In regards to the specific dosage and interval amounts recited in the instant claims 1 and 2, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses of the bispecific antibody of ‘759. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Therefore, it would have been obvious, at the time of filing, for a person of ordinary skill in the art to optimize the dose interval and timing of the antibody of the ‘759 claims using the anti-PD-1/TIM-3 bispecific in the method of treating NSCLC as taught by NCT’654 in order to benefit from the particular dosing and timing that results in the most effective treatment for cancer in the patient population. This would have a reasonable expectation of success because Verona et. al., Codarri-Deak et. al., and NCT’820, teach the general ranges and conditions that could be appropriate for an anti-TIM3/PD-1 bispecific antibody and clinical benchmarks for bispecific antibody binding to the same target proteins (of 2100 mg). The Examiner further notes that a dose of 10mg/kg in a human rather than a mouse is a fixed dose of approximately 600-800 mg; and therefore a person of ordinary skill in the art would be able to derive the optimal doses and ranges for this particular bispecific antibody in the NSCLC patients as suggested by NCT’654.
Regarding claims 3 and 4, the optimization of ranges by a person of ordinary skill in the art would arrive a doses of about 750 mg (which is 10mg/kg for an average 75 kg human) and is within the range disclosed by Verona and 1500 mg (which is below the 2100 mg range of the clinical benchmark as taught by NCT’820 and above the fixed dose of 1000 mg disclosed by Verona). This would have a reasonable expectation of success because, as described above, dosing is a results effective variable and the level of skill in the art is high; therefore a person of ordinary skill in the art would be able to arrive at the optimal fixed doses.
Regarding claims 5 and 6, NCT’820 teaches a method of administering an anti-PD-1/TIM-3 binding protein on a cycle, wherein the binding protein is administered once every two weeks on Day 1 (Arms and Interventions section; reads on administered once per cycle and once about every 14 days).
Regarding claims 7 and 13, Verona et. al. teaches optimization of the intervals including repeating in groups every two or three weeks [1374]. It would have been obvious, at the time of filing, for a person of ordinary skill in the art to optimize the dosage timing as described above for ‘759 in view of NCT’654, Verona, Codarri-Deak, and NCT’820 to benefit from the most appropriate interval for an effective cancer treatment at an effective dosage. As described above, this would have a reasonable expectation of success because a person of ordinary skill in the art would know that dose timing was a results-effective variable to optimize along with dose amount and would adjust for the particular patient, disease history, or population as appropriate. As described above, NCT’654 teaches wherein the patient has not received a prior line of systemic therapy.
Regarding claim 8, Verona recites that e.g. 9 or more, or 20 or more doses may be given (reads on repeated for more than 20 cycles). It would have been obvious, at the time of filing, for a person of ordinary skill in the art to repeat the treatment cycle for up to 35 cycles in order to benefit from continuing from as many cycles as may benefit the patient. This would have a reasonable expectation of success because a person of ordinary skill in the art would have been able to determine the number of cycles and when to cap or discontinue treatment.
Regarding claim 21, the claim states that the subject must have radiologically documented tumor progression or clinical deterioration following initial treatment with an anti-PD-1/PD-L1 therapy for a minimum of 3-6 months. The examiner notes that “clinical deterioration” is not defined by the instant specification. As described above, NCT’654 teaches arms of the study wherein the patient has acquired resistance and but have at least one prior line of PD-1/PD-L1 therapy (Part A and Part B Cohort B1, Inclusion Criteria section). As evidenced by Pourmir et. al., acquired resistance is understood as durable clinical benefit >6 months followed by tumor progression (reads on clinical deterioration following initial treatment with an anti-PD-1/PD-L1 therapy for a minimum of 3-6 months (Introduction ¶1.3-1.4).
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
