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 1-5 and 9-10 are under examination in the instant office action.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4-5, and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 4, the claim recites “having at least 80% identity to the corresponding CDR amino acid sequence of the light chain and the heavy chain of the antibody specifically binding to the tumor antigen or the immune checkpoint”. However, there is no previous antecedent basis for “the antibody” in either claim 1 or claim 4. Claim 1 recites a heavy chain and a light chain combined to “form a targeting moiety that exhibits binding specificity to a tumor antigen or an immune checkpoint”. Because the CDRs of “the antibody” are defined later in the claim, the claim will be interpreted to refer to “an antibody specifically binding to the tumor antigen or the immune checkpoint”, wherein the CDRs are SEQ ID NOs: 14-19, respectively as recited in claim 4 and the heterodimer comprises both a light chain and a first heavy chain each with at least one CDR (equivalent to “a complementary region containing amino acid sequences”) having at least 80% identity to the corresponding CDR amino acid sequences of the light chain and the heavy chain of the antibody.
The metes and bounds of claim 10 are indefinite. MPEP 2173.05(q) states attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness. Recitation of a use without any active, positive steps delimiting how this use is actually practiced is indefinite. Therefore, the recitation of “Use of the heterodimeric protein of claim 1 comprising:” followed by the noun form of active steps “preparation” make it unclear whether the claims are directed towards a method and what active steps would be required of the method.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 10 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claim is directed to the “use” of the heterodimeric protein. The claims are not directed toward a: 1) composition of matter; 2) machine; 3) manufacture; or 4) process, but rather a “use” of a heterodimeric protein comprising a targeting moiety with binding specificity to a tumor antigen or an immune checkpoint and an immunomodulator, wherein no active method steps are present to suggest a process is being claimed. "Use" claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101 MPEP 2173.05(q).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 1-5 and 9-10 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 1 and 4, the claims allow for changes to the CDR within the VH and VL of the antibody which is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the recited function of binding specificity to a tumor antigen or an immune checkpoint.
Scope of the claimed genus
Claim 1 recites a genus of heterodimeric proteins comprising an antibody binding fragment which exhibits binding specificity to any tumor antigen or immune checkpoint.
Claim 4 recites the heterodimeric protein of claim 1, wherein both the light chain and the first heavy chain contain a complementary determination region containing amino acid sequence having at least 80% identity to the corresponding CDR amino acid sequences of the light chain and the heavy chain of the antibody specifically binding to the tumor antigen or the immune checkpoint. The Examiner notes as described in the 112(b) above that there is no antecedent basis for “the antibody”. The claim further recites that the antibody contains LCDR1 of the amino acid sequence shown by SEQ ID NO:17, LCDR2 of the amino acid sequence shown by SEQ ID NO:18, and LCDR3 of the amino acid sequence shown by SEQ ID NO:19; and, the first heavy chain of the antibody specifically binding to the tumor antigen or the immune checkpoint contains HCDR1 of the amino acid sequence shown by SEQ ID NO:14, HCDR2 of the amino acid sequence shown by SEQ ID NO:15, and HCDR3 of the amino acid sequence shown by SEQ ID NO:16. Therefore, the claim is interpreted that the light chain and the first heavy chain making up the targeting moiety each comprise at least one CDR (“contain a complementary determination region”) with at least 80% identity to the corresponding CDR of one of SEQ ID NO: 17, 18, or 19 and SEQ ID NO: 14, 15, or 16.
Dependent claims 2-3, 5, and 9-10 depend from claims 1 or 4 without narrowing the scope of the targeting moiety.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 80% identity to only one CDR would allow for complete exchange of 2 of the heavy chain CDRs and 2 of the light chain CDRs.
In regards to anti-tumor antigen or immune checkpoint antibodies, this is a vast genus with no structural or functional similarity between the proteins themselves or even within the antibodies that binding the same antigen between them. For example, US20200354478 to Xu et. al. published 12 November 2020 teaches a proteinaceous heterodimer comprising an immunoregulator on one heavy chain and a light and a heavy chain comprising a targeting moiety (See e.g. Fig. 1). Xu et. al. teaches that in some embodiments the targeting moiety binds to the tumor antigen selected from the group consisting of EGFR, an EGFR mutant, HER2/neu, GPC3, FAP, Muc1, MUC5AC and Mesothelin [0014]. Xu et. al. teaches that the heavy chain variable region comprises SEQ ID NO: 108 and SEQ ID NO: 112 for the anti-EGFR targeting moiety and SEQ ID NO: 120 or 128 and SEQ ID NO: 124 or 132 for the anti-HER2 targeting domain. These VH sequences comprise CDRs that are different from each other and from instant SEQ ID NO: 1 and 2 as shown:
RESULT 1
US-16-621-925-108
Query Match 12.6%; Score 316.5; DB 1; Length 119;
Best Local Similarity 50.0%;
Matches 60; Conservative 23; Mismatches 34; Indels 3; Gaps 2;
Qy 20 QVQLQQSGAELVKPGASVKLSCKASGYTFTNYDINWVRQRPEQGLEWIGWIFPGDGSTQY 79
||||:||| ||:| |: ::| ||:: ||| ::|||| | :||||:| |: | |:| |
Db 1 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSG-GNTDY 59
Qy 80 NEKFKGKATLTTDTSSSTAYMQLSRLTSEDSAVYFCARQTT--ATWFAYWGQGTLVTVSA 137
| | : :: | | | : ::: | | |:|:|:||| | ||||||||||||||
Db 60 NTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 119
Regarding B7H3 targeting domain, others of these are known in the art. For example WO2021190586 to Ying et. al. teaches an anti-B7H3 antibody comprising a heavy chain and a light chain wherein the heavy chain an the light chain have completely different CDRs to the instantly described anti-B7H3 antibody:
RESULT 1
AASEQ2_08272026_141745
Query Match 81.9%; Score 2048.5; DB 1; Length 449;
Best Local Similarity 85.6%;
Matches 385; Conservative 28; Mismatches 34; Indels 3; Gaps 3;
Qy 20 QVQLQQSGAELVKPGASVKLSCKASGYTFTNYDINWVRQRPEQGLEWIGWIFPGDGSTQY 79
|||| ||| :|:|| |::||| |||: |:: ::|||| | :||||: : ||| :|
Db 1 QVQLVQSGGGVVQPGTSLRLSCAASGFIFSSSAMHWVRQAPGKGLEWVA-VISYDGSNKY 59
Qy 80 N-EKFKGKATLTTDTSSSTAYMQLSRLTSEDSAVYFCARQTTA-TWFAYWGQGTLVTVSA 137
: ||: |:: | | :| |:|:: | :||:|||:||| | ||||| |||||:
Db 60 YVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSARLYASFDYWGQGALVTVSS 119
Qy 138 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 197
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 120 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 179
Qy 198 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG 257
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 180 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG 239
Qy 258 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHENPEVKFNWYVDGVEVHNAKTKPREEQYN 317
||||||||||||||||||||||||||||||||:|||||||||||||||||||||||||||
Db 240 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 299
Qy 318 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 377
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||:|
Db 300 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE 359
Qy 378 MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 437
:||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||
Db 360 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 419
Qy 438 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 467
||||||||||||||||||||||||||||||
Db 420 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 449
Thus, a person of ordinary skill in the art would not have been able to envision a priori the entire genus of targeting moieties comprising a heavy and a light chain wherein the targeting moiety binds to a tumor antigen or an immune checkpoint, and variants comprising only one CDR at least 80% identical to both the light and heavy chain CDRs.
Summary of Species disclosed in the original specification
The instant specification discloses a single species of heterodimer comprising a first heavy chain SEQ ID NO: 1, a light chain SEQ ID NO: 2, and a second heavy chain SEQ ID NO: 3 (Example 1). There are no other heterodimers recited. The specification prophetically recites that the tumor antigen or immune checkpoint is selected from one or more of a group of antigens [0015] but does not provide any additional examples of targeting moieties.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding any tumor antigen or immune checkpoint molecule. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. The is a lack of appropriate examples of targeting moieties binding to other tumor antigens or checkpoint molecules. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the heterodimer claims 1 and 4 at the time of filing. Regarding claims 2-3, 5, and 9-10 the claims are ultimately dependent on the rejected claims 1 and 4 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3 and 9-10 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Qiao, Jian, et al. "Targeting tumors with IL-10 prevents dendritic cell-mediated CD8+ T cell apoptosis." Cancer cell 35.6 (2019): 901-915.
Regarding claim 1, Qiao et. al. teaches a heterodimeric protein to allow targeted delivery of IL-10 into tumor microenvironment comprising one arm comprising a Cetuximab (anti-EGFR; reads on targeting moiety that exhibits specificity to a tumor antigen) Fab comprising the Cetuximab heavy and light chain (see e.g. Fig. 1A-B) and a second arm comprising an IL-10 dimer fused to an Fc domain (reads on immunomodulator) (e.g. Fig. 1A, reproduced below, also see e.g. “Generation, Characterization, and Toxicity Assessment of an Anti-EGFR IL-10 Fusion Protein” section):
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402
376
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Regarding claim 2, Qiao et. al. teaches that the tumor antigen is EGFR (instant claim 2, line 16): “For proof-of-concept studies, we chose the FDA-approved anti-epidermal growth factor receptor (anti-EGFR) antibody Cetuximab (Erbitux) for targeted delivery of IL-10 to EGFR+ tumors” (p. 902 left column ¶3).
Regarding claim 3, Qiao et. al. teaches the immunomodulator is the cytokine IL-10 (e.g. “However, paradoxically, increasing evidence demonstrates that IL-10 can induce antitumor effects in an immune-dependent manner” (Introduction ¶2)).
Regarding claim 9, Qiao et. al. teaches administration of a composition comprising the heterodimer “TC-1 (left flank) and TC-1-cEGFR (right flank) tumor-bearing NSG mice were injected intravenously by IRDye® 800CW-labeled CmAb-(IL10)2 (4 mg/kg) on day 8 after tumor cell inoculation” (Method Details, “In Vivo Imaging”, p. e3; also see “Tumor Growth and Treatment” section) which must comprise an excipient or carrier to be injected intravenously.
Regarding claim 10, as described above the claim is directed towards “use of the heterodimeric protein”. As described in the 112(b) and 101 rejections above, it is unclear what statutory subject matter the claim is directed to. The claim is also directed at the use comprising “preparation of a drug for the treatment of an oncological disease comprising one or more of colorectal cancer, membrane adenocarcinoma, lung cancer, […]”. For the purposes of expedited prosecution, the claim will be interpreted as a directed towards a drug (interpreted as a pharmaceutical composition) comprising the heterodimeric protein. The phrase “for the treatment of an oncological disease” recites an intended use of the composition and does not further limit the structure of the composition. As described for claim 9 above, teaches administration of a composition comprising the heterodimer “TC-1 (left flank) and TC-1-cEGFR (right flank) tumor-bearing NSG mice were injected intravenously by IRDye® 800CW-labeled CmAb-(IL10)2 (4 mg/kg) on day 8 after tumor cell inoculation” (Method Details, “In Vivo Imaging”, p. e3; also see “Tumor Growth and Treatment” section) which must comprise an excipient or carrier to be injected intravenously and therefore is a pharmaceutically suitable composition.
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) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qiao, Jian, et al. "Targeting tumors with IL-10 prevents dendritic cell-mediated CD8+ T cell apoptosis." Cancer cell 35.6 (2019): 901-915 as applied to claim 1 above, and further in view of WO2016033225 A2 to Cheung et. al. published 3 March 2016 and Heubach, Florian, et al. "Abstract A131: Targeting B7-H3 (CD276) in neuroblastoma: In vitro evaluation of Fc-optimized antibodies and immunocytokines." Cancer Immunology Research 7.2_Supplement (2019): A131-A131.
The teachings of Qiao et. al. are in the 102 rejection above and are incorporated by reference herein.
Qiao et. al. does not teach the heterodimer wherein both the light chain and the first heavy chain contain a complementary determination region containing amino acid sequences having at least 80% identity to the corresponding CDR amino acid sequences of the light chain and the heavy chain as described in the 112(b) rejection and claim interpretation of claim 4 above.
The deficiency is resolved by Cheung et. al. and Heubach et. al.
Cheung et. al. teaches humanized anti-B7H3 antibodies, wherein antibody variant comprising the light chain as set forth in SEQ ID NO: 1 (e.g. [0006]) which is 90.9% identical to instant SEQ ID NO: 1 and comprising the CDRs identical to instant SEQ ID NOs: 17, 18, and 19 as shown below:
RESULT 1
AASEQ2_08262026_200746
Query Match 90.9%; Score 1099; DB 1; Length 214;
Best Local Similarity 99.1%;
Matches 212; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 20 DIVMTQSPATLSVTPGDRVTLSCRASQSISDYLYWYQQKSHESPRLLIKYASQSISGIPS 79
|||||||||||||||||||:|||||||||||||:||||||||||||||||||||||||||
Db 1 DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPS 60
Qy 80 RFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPLTFGAGTKLELKRTVAAPSVFIFPP 139
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPLTFGAGTKLELKRTVAAPSVFIFPP 120
Qy 140 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 199
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 200 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 233
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
And comprising the heavy chain as set forth in SEQ ID NO: 9 (e.g. [0006]) which is 94.9% identical to instant SEQ ID NO: 1 and comprises CDRs identical to instant SEQ ID NOs: 14, 15, and 16 as shown below:
Query Match 94.9%; Score 2374; Length 448;
Best Local Similarity 98.9%;
Matches 443; Conservative 4; Mismatches 1; Indels 0; Gaps 0;
Qy 20 QVQLQQSGAELVKPGASVKLSCKASGYTFTNYDINWVRQRPEQGLEWIGWIFPGDGSTQY 79
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQSGAELVKPGASVKLSCKASGYTFTNYDINWVRQRPEQGLEWIGWIFPGDGSTQY 60
Qy 80 NEKFKGKATLTTDTSSSTAYMQLSRLTSEDSAVYFCARQTTATWFAYWGQGTLVTVSAAS 139
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFKGKATLTTDTSSSTAYMQLSRLTSEDSAVYFCARQTTATWFAYWGQGTLVTVSAAS 120
Qy 140 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 199
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 180
Qy 200 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS 259
||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||||
Db 181 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPS 240
Qy 260 VFLFPPKPKDTLMISRTPEVTCVVVDVSHENPEVKFNWYVDGVEVHNAKTKPREEQYNST 319
||||||||||||||||||||||||||||||:|||||||||||||||||||||||||||||
Db 241 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 300
Qy 320 YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT 379
||||||||||||||||||||||||||||||||||||||||||||||||||||||||:|:|
Db 301 YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT 360
Qy 380 KNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 439
|||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 420
Qy 440 GNVFSCSVMHEALHNHYTQKSLSLSPGK 467
||||||||||||||||||||||||||||
Db 421 GNVFSCSVMHEALHNHYTQKSLSLSPGK 448
Cheung et. al. teaches that this antibody “hu8H9” bound with high affinity to B7H3 ([00377], Table 13). Cheung et. al. teaches that the antibody was effective for targeting tumor cells and had a cytotoxic anti-tumor effect in vitro through (e.g. Figs. 13 and 14).
Heubach et. al. teaches anti-B7H3 immunocytokines to target neuroblastoma. Heubach et. al. teaches that B7-H3 is highly overexpressed on many solid tumors and is thought to function as an immune checkpoint by regulating T and NK cell response. Heubach teaches that B7H3 is a potential alternative to targeting GD2. Heubach et. al. teaches that the B7H3-IL2 immunocytokine mediated permanent target cell lysis. Heubach et. al. states “B7-H3 has been demonstrated to be a suitable alternative target antigen in case GD2 expression is low or absent. Fc-optimized mAbs and mAb-cytokine fusions targeting B7-H3 might increase the efficacy of immunotherapy in GD2-negative tumors and in combinatory approaches”.
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to substitute the anti-B7H3 hu8H9 antibody of Cheung et. al. in the immunocytokine of Qiao in order to benefit from targeting an alternate antigen useful for targeting an immunocytokine to neuroblastoma as suggested by Heubach et. al. This would have a reasonable expectation of success because Qiao et. al. teaches that they use an known immunocytokine format and that targeting IL-10 to tumors using an antibody has an anti-tumor effect, and therefore a person of ordinary skill in the art would reasonably be able to adapt other antibodies for other tumor targets (e.g. the anti-tumor B7H3 antibody of Cheung) into the IL-10 fusion format as taught by Qiao et. al.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qiao, Jian, et al. "Targeting tumors with IL-10 prevents dendritic cell-mediated CD8+ T cell apoptosis." Cancer cell 35.6 (2019): 901-915 WO2016033225 A2 to Cheung et. al. published 3 March 2016 and Heubach, Florian, et al. "Abstract A131: Targeting B7-H3 (CD276) in neuroblastoma: In vitro evaluation of Fc-optimized antibodies and immunocytokines." Cancer Immunology Research 7.2_Supplement (2019): A131-A131 as applied to claim 4 above, and further in view of Wei H, et. al. Structural basis of a novel heterodimeric Fc for bispecific antibody production. Oncotarget. 2017 May 2;8(31):51037-51049. doi: 10.18632/oncotarget.17558; Uniprot P22301 “IL10_HUMAN” Sequence, last updated 1 August 1991; and Zhang, Z. and Henzel, W.J. (2004), Signal peptide prediction based on analysis of experimentally verified cleavage sites. Protein Science, 13: 2819-2824 as evidenced by Uniprot P0DOX5 “IGG1_Human”.
The teachings of Qiao et. al. in view of Cheung and Heubach in regard to claim 1 are in the 102 rejection above and are incorporated by reference herein.
Qiao et. al. further teaches that the CmAb-(IL10)2 was designed based on the heterodimeric Fc variant KiHss-AkKh platform and that the IL-10 chain was designed by fusing the IL-10 dimer to the hold variant Fc (“Production of Bispecific Fusion Proteins” section ¶1). Qiao et. al. also suggests that the IL-10 is human IL-10, stating “Next, we tested whether systemic delivery of CmAb-(IL10)2 induces toxicity since a prolonged half-life could cause severe side effects. Given that IL-2 has been well documented in terms both its therapeutic effects and toxicity in clinical studies (Atkins et al., 1999; Siegel and Puri, 1991), and that, like human IL-10, human IL-2 can bind to murine IL-2 receptor and transduce IL-2 signal, we, therefore, chose IL-2 as a model to compare the toxicity with IL-10 in immune competent mice” (“Generation, Characterization, and Toxicity Assessment of an Anti-EGFR-IL-10 Fusion Protein” ¶4).
Qiao et. al. does not explicitly teach the sequence of the second heavy chain comprising IL-10 and the Fc domain is at least 80% identical to instant SEQ ID NO: 3.
This deficiency is resolved by Wei et. al., Uniprot P22301, and Zhang et. al. as evidenced by Uniprot P0DOX5.
Wei et. al. teaches methods of making heterodimers using a novel KiHss-AkKh format which produced a heterodimer yield of 94%, which was the highest of all the heterodimer pairs tested (Fig. 1C). Wei et. al. teaches that traditional knob-in-hole is less good at preventing homodimerization of the hole chain, so they improved it by adding electrostatic steering (Discussion ¶1). Wei et. al. teaches that the Fc domains of their antibodies contained residues 238-444 of human IgG1. As evidenced by Uniprot P0DOX5, the sequence of human IgG1 residues 248-444 is: PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Wei et. al. teaches that the mutations made in the hole chain of KiHss-AkKh IgG1 chain are: Y349C/T366S/L368A/Y407V/F405K.
Uniprot P22301 “IL10_Human” teaches the sequence of human IL10 is: MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN.
Zhang et. al. teaches that the signal sequence of human IL10 is: MHSSALLCCLVLLTGVRA.
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to reconstruct the sequence of the IL-10 heavy chain of modified Qiao et. al. by making a dimer of IL-10 and fusing it to the modified hole chain as taught by Wei et. al. for making improved heterodimers. It additionally would have been obvious to a person of ordinary skill in the art to only use the signal sequence of IL-10 as taught by Zhang at the beginning of the protein. This results in a sequence that is 90.5% identical to instant SEQ ID NO: 3 as shown below:
RESULT 1
AASEQ2_08272026_121404
Query Match 90.5%; Score 2808.5; DB 1; Length 548;
Best Local Similarity 92.3%;
Matches 540; Conservative 4; Mismatches 4; Indels 37; Gaps 2;
Qy 1 MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQ 60
Qy 61 LDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLR 120
Qy 121 LRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNGG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN-- 178
Qy 181 GGSGGGGSGGGGSSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLL 240
|||||||||||||||||||||||||||||||||||||||||||||||
Db 179 -------------SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLL 225
Qy 241 LKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 226 LKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRR 285
Qy 301 CHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNGGGGSDK 360
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 286 CHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN------- 338
Qy 361 THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHENPEVKFNWYVDGV 420
||||||||||||||||||||||||||||||||:||||||||||||
Db 339 ---------------PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV 383
Qy 421 EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 384 EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ 443
Qy 481 PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 540
|||||| ||||||:|:|||||||:| ||||||||||||||||||||||||||||||||||
Db 444 PREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 503
Qy 541 SFFLASKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 585
|| | ||||||||||||||||||||||||||||||||||||||||
Db 504 SFKLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 548
This would have a reasonable expectation of success because a person of ordinary skill in the art would use the guidance of Qiao et. al. and art-known sequences taught by Wei et. al. as evidenced by Uniprot P0DOX5, Uniprot P22301, and Zhang et. al. in order to build the construct as taught by modified Qiao et. al above.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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