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 .
Claims Status
The Amendment filed on 07Jan2026 is acknowledged in which claim(s) 3-10, 14, 23, 27, 29, 31, 33, and 35 is/are canceled and claim(s) 36-37 is/are new.
Applicant’s election with traverse of Group 1 (claims 1-2, 11-13, and 15-21) and of species (1) a first part comprising a VH of SEQ ID NO: 30, and a VL of SEQ ID NO: 31; and (2) a second part comprising a VH of SEQ ID NO: 21 and a VL of SEQ ID NO: 22, in the reply filed on 03Sep2025 is acknowledged. New claim 37 and Claims 22, 24-26, 28, 30, 32, and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 03Sep2025.
Claim(s) 1-2, 11-13, 15-21, and 36 are presented for examination on the merits.
Response to Amendment
The objection(s) to claim(s) 16, and/or the specification have been withdrawn in view of the Amendment filed on 07Jan2026.
The previously set forth rejection(s) of claim(s) 2, 12-13, 17-19 under 35 U.S.C. § 112(a), of claim(s) 2, 11-13 under 35 U.S.C. § 112(b), of claim(s) 1-2, 15-21 under 35 U.S.C. § 102, and of claim(s) 11; 12-13 under 35 U.S.C. § 103 have been withdrawn in view of the recent claim amendment filed on 07Jan2026, which added new limitations to the claims, that were not considered in the previous rejections.
As all previously presented rejection(s) and/or objection(s) were withdrawn in view of the Amendment filed on 07Jan2026, only the arguments that read on the new rejection/objections are addressed below.
Rejections/Objections Maintained/New Rejections Necessitated by Claim Amendments
Claim Interpretation
Regarding claim 1, the specific limitations of claim 1(a-b, d) are functional limitations of the PD1 binding arm (e.g., “first part”) of the instant claimed multispecific molecule. Applicant elected anti-PD1 binding domain of SEQ ID NOs: 30 and 31 for the PD1 binding domain, and the Specification teaches SEQ ID NO: 24 the anti-PD-1 clone “29F.1A12” scFv, which comprises elected SEQ ID NOs: 30-31 (see alignment below) [e.g., pg. 215, lines 41-45]. Therefore, any prior art that teaches the elected PD1 arm sequences and/or 29F.1A12 clone will be considered to teach the specific functional limitations of claim 1(a-b, d).
CLUSTAL O(1.2.4) multiple sequence alignment
SeqID31 DVALTQTPVAQPVTLGDQASISCRSSQSLVHSNGRTYLEWYLQKPGQSPQLLIYKVSNRF 60
29F.1A12_SeqID24 DVALTQTPVAQPVTLGDQASISCRSSQSLVHSNGRTYLEWYLQKPGQSPQLLIYKVSNRF 60
SeqID30 ------------------------------------------------------------ 0
SeqID31 SGVPDRFIGSGSGSDFTLTISRVEPEDLGVYYCFQATHDPNTFGAGTKLELK-------- 112
29F.1A12_SeqID24 SGVPDRFIGSGSGSDFTLTISRVEPEDLGVYYCFQATHDPNTFGAGTKLELKGGGGSGGG 120
SeqID30 ------------------------------------------------------------ 0
SeqID31 ------------------------------------------------------------ 112
29F.1A12_SeqID24 GSGGGGSQVQLQQSGAELVKPGSSVKISCKASGYTFTSHFIHWIKQQPGNGLEWIGGIYP 180
SeqID30 -------QVQLQQSGAELVKPGSSVKISCKASGYTFTSHFIHWIKQQPGNGLEWIGGIYP 53
SeqID31 ------------------------------------------------------------ 112
29F.1A12_SeqID24 GDGDTEYNQQFNGKATLTADKSSSTAYMRLSSLTSEDSAVYFCATRVPSYWFFDFWGPGT 240
SeqID30 GDGDTEYNQQFNGKATLTADKSSSTAYMRLSSLTSEDSAVYFCATRVPSYWFFDFWGPGT 113
SeqID31 ------ 112
29F.1A12_SeqID24 MVTVSS 246
SeqID30 MVTVSS 119
Regarding claim 2, the specific limitations of claim 2(a-g) are functions associated with the specific PD1 binding arm (e.g., “first part”) of the instant claimed multispecific molecule. As discussed above, Applicant elected a first arm anti-PD1 comprising SEQ ID NOs: 30 and 31, which corresponds to clone 29F.1A12. Therefore, any prior art that teaches the elected PD1 arm sequences and/or 29F.1A12 clone will be considered to teach the specific functional limitations of claim 2(a-g).
Claim Rejections - 35 USC § 112(b)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 2, 12 is/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.
Claim(s) 2 recites the phrase "the first part comprises an amino acid sequence having at least 95% sequence identity with any of one of SEQ ID NOs: 24, 30, 31, 326-329, and amino acid residues 1-221 of SEQ ID NO: 2" in claim 2(g), rending the claim indefinite. Specifically, it is unclear if the phrase means that the first part comprises (1) one of the recited SEQ ID NOs 24, 30, 31, 326-329 and also requires SEQ ID NO: 2(residues 1-221); (2) one of SEQ ID NOs: 24, 30, 31, 326-329, residues 1-221 of 2; or (3) something else. For the purposes of compact prosecution, the phrase is considered to mean that any of SEQ ID NOs: 24, 30, 31, 326-329, residues 1-221 of 2 would meet the limitations. Applicant can overcome this rejection by amending claim 2 to clearly recited the intended limitations.
Claim(s) 12 recites the phrase "any one of SEO ID NOs: 21, 22, residues 231-352 of SEO
ID NO: 2, residues 1-107 of SEO ID NO: 3, and 316-325" in lines 3-4, rending the claim indefinite. Specifically, it is unclear if the phrase means that the first part comprises (1) one of SEQ ID NOs: 21, 22, residues 231-352 of SEQ ID NO: 2, residues 1-107 of SEO ID NO: 3 and also requires each of SEQ ID NOs: 316-325; (2) one of SEQ ID NOs: 21, 22, residues 231-352 of SEQ ID NO: 2, residues 1-107 of SEQ ID NO: 3, and residues 1-107 of SEQ ID NOs: 316-325; (3) one of SEQ ID NOs: 21, 22, residues 231-352 of SEQ ID NO: 2, residues 1-107 of SEO ID NO: 3 or one of SEQ ID NOs: 316-325; or (4) something else. For the purposes of compact prosecution, the phrase is considered to mean that any of the recited SEQ ID NOs would meet the limitations. Applicant can overcome this rejection by amending claim 12 to clearly recited the intended limitations.
Claim Rejections - 35 USC § 112(a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-2, 11-13, 15-21, and 36 is/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.
Claimed Invention
Claim(s) 1 (and dependent claims 2, 11-13, 15-21, 36), are drawn to an anti-PD1 bispecific molecule comprising an Fc domain comprising one of more mutations that inhibit FcyR binding.
Breadth of Claims
Further the invention as disclosed in claim(s) 1 (and dependent claims 2, 11-13, 15-21, 36) recite(s) “…the bispecific molecule comprises an Fc domain, wherein the Fc domain comprises one or more mutations that inhibit Fc gamma receptor binding …” and claim(s) 36 recite(s) “…the bispecific molecule does not bind a professional antigen-presenting cell via binding to the Fc-gamma receptor expressed on its surface…”. The specification discloses that the Fc regions of the instant invention include native-sequence Fcs, variant Fc, hIgG1, hIgG2, hIgG3, and hIgG4 [e.g., pg. 26, lines 21-27], and that L235E, E318A, K320A, and 5332A Fc variants decrease Fcy receptor binding [e.g., pg. 214, lines 24-26]. One of ordinary skill in the art would understand that the amino acid sequence of the portion(s) of the Fc domain of the antibody that interact with FcyRs are responsible for binding characteristics, including binding affinity. The claim does not disclose the structure of the Fc domain associated with the claimed function(s). The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision all of the possible Fc domain variants, particularly in the FcyR binding regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
The anti-PD1 bispecific molecules comprising native hIgG1, hIgG2, hIgG3, or hIgG4 Fc domains or L235E, E318A, K320A, and 5332A Fc variants in the Applicant disclosure with 100% sequence identity in the Fc sequence represents the anti-PD1 bispecific molecule-Fc variants that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, Fc domain variant interaction(s) with FcyRs were known to depend on the entire structure. It is understood by one of ordinary skill in the art that that mutation to the Fc domain in region(s) that bind to FcyRs may result in unpredictable changes in FcyR binding characteristics and that each new Fc variant requires function testing.
Mimoto et al. (Protein Engineering, Design & Selection vol. 26 no. 10 pp. 589–598, 2013; hereinafter “Mimoto”) taught human IgG1 Fc variants were recognized in the art, as were the therapeutic potentials thereof [e.g., title, abstract]. Mimoto taught various separate species of Fc domain variants with different relative binding characteristics to FcyRs [e.g., figs. 1-2, 4, tbl. 1]. Therefore, the prior art demonstrates that various human IgG1 Fc variants result in altered FcyR (e.g., FcyR2b vs. FcyR2a) binding characteristics. The prior art does not teach a known structure activity relationship human IgG1 Fc domain variants that would allow prediction of each and every Fc variant that would result in the instant claimed function(s).
US 2014/294812 A1 (hereinafter “US812”) taught human IgG1 Fc variants were recognized in the art, as were the therapeutic potentials thereof include treating autoimmune disease [e.g., title, abstract; fig. 82U, ¶ 0342, 0351]. Mimoto taught various separate species of Fc domain variants with different relative binding characteristics to FcyRs [e.g., figs. 78, 80]. Therefore, the prior art demonstrates that various human IgG1 Fc variants result in altered FcyR (e.g., FcyR2b vs. FcyR2a) binding characteristics. The prior art does not teach a known structure activity relationship human IgG1 Fc domain variants that would allow prediction of each and every Fc variant that would result in the instant claimed function(s).
Thus, making changes to the IgG Fc domain sequence of an antibody is an unpredictable process and one skilled in the art could not envisage the breadth of structurally unrelated IgG Fc domain variants that would still possess the required function(s).
Conclusion
As indicated by the art, IgG Fc domain variants may alter FcyR binding characteristics and one cannot predict which specific variants will result in the instant claimed binding affinity function(s). Written description can be met if the claims recite the specific Fc variant(s) that are known to perform the function(s) recited in the claims. Specifically, Applicant claim(s) 1 and 36 would need to recite the specific Fc variant(s) of the antibody that possess the instant claimed function(s). Dependent claims 2, 11-13, and 15-21 can overcome this rejection by amending claim 1 as recited above.
Claim(s) 1-2, 11-13, 15-21, and 36 is/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.
Claimed Invention
Claim(s) 1-2, 11-13, 15-16, 20-21, and 36, is/are drawn to a bispecific molecule wherein the first part specifically binds PD-1.
Claim(s) 12-13, is/are drawn to a bispecific molecule wherein the second part specifically binds H2Kb.
Claim(s) 17-19, is/are drawn to an isolated nucleic acid that encodes a bispecific molecule that binds PD-1 or H2Kb antigen.
Breadth of Claims
Further the invention as disclosed in claim(s) 1 (and dependent claims 2, 11-13, 15-16, 20-21, 36) recite(s) “…the difference in the equilibrium dissociation constant (Kd) of binding to PD-1 and the Kd of binding to the surface antigen is at least 50-fold”; and claim(s) 2 recite(s) “…a) i)the difference in the Kd of binding to PD-1 and the Kd of binding to the surface antigen is at least 100-fold, 500-fold, 1,000-fold, 5,000-fold, or 10,000-fold, optionally further wherein the Kd of binding to PD-1 is less than the Kd of binding to the tissue-specific surface antigen and/or ii) the difference in the off-rate when binding to PD-1 and the off-rate when binding to the surface antigen is at least 10-fold, 50-fold, 100-fold, 500-fold, 1,000 fold, 5,000-fold, or 10,000-fold, optionally further wherein the off-rate of binding to PD-1 is slower than the off-rate of binding to the tissue-specific surface antigen… ”. The specification defines Kd “the dissociation equilibrium constant of a particular antibody-antigen interaction…” [e.g., pg. 31, lines 28-32]. One of ordinary skill in the art would understand that the 6 CDRs of an antibody are responsible for antigen binding characteristics, including antigen specificity and Kd. The claim does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision all of the possible light and heavy chain sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
The invention as disclosed in claim(s) 2 recite(s) “…g) the first part comprises an amino acid sequence having at least 95% sequence identity with any of one of SEQ ID NOs: 24, 30, 31, 326-329, and amino acid residues 1-221 of SEQ ID NO: 2…”, “…h) … at least 95% sequence identity with SEQ ID NO: 30 and/or SEQ ID NO: 31…”, “…i) ...at least 95% sequence identity…of SEQ ID NO: 24…”, and “…j) … at least 95% sequence identity…of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.”; claim(s) 12 recite(s) “…at least 95% sequence identity with any one of SEQ ID NOs: 21, 22, residues 231-352 or SEQ ID NO: 2, residues 1-107 of SEQ ID NO: 3, and 316-325.”; and claim 13 recites “…at least 95% sequence identity with SEQ ID NO: 21 and/or SEQ ID NO: 22.”. The claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability (e.g., at least 95% identical) in the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to PD-1 (claim 2) or H2Kb (claims 12-13). This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining PD-1 (claim 2) or H2Kb (claims 12-13) antigen binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Further, the invention as disclosed in claim(s) 2 are readable to 3CDRs, which is effectively half of an antibody binding site, as being sufficient for a functional antibody binding region. Specifically, the claim limitations as written require only one VH sequence (e.g., SEQ ID NO: 21 or 30) comprising 3 CDRs (e.g., HCDR1-3) or one VL sequence (e.g., SEQ ID NO: 22 or 31) comprising 3 CDRs (e.g., LCDR1-3), which is effectively half an antibody binding site missing the either the VL complement (with 3 LCDRs) or the VH complement (with 3 HCDRs) to create a full antibody binding site (e.g., 6 CDRs). One of ordinary skill in the art would understand that one cannot use half of an antibody binding domain (e.g., VH only) and reasonably expect to maintain PD-1 or H2Kb antigen binding function.
The invention as disclosed in claim(s) 12-13 is/are readable to 3CDRs, which is effectively half of an antibody binding site, as being sufficient for a functional antibody binding region. Specifically, the claim limitations as written require only one VH sequence (e.g., SEQ ID NO: 21) comprising 3 CDRs (e.g., HCDR1-3), which is effectively half an antibody binding site missing the VL complement (with 3 LCDRs) to create a full antibody binding site (e.g., 6 CDRs). One of ordinary skill in the art would understand that one cannot use half of an antibody binding domain (e.g., VH only) and reasonably expect to maintain H2Kb antigen binding function.
The invention as disclosed in claim(s) 12-13 are readable to 3CDRs, which is effectively half of an antibody binding site, as being sufficient for a functional antibody binding region. Specifically, the claim limitations as written require only one light chain variable VL sequence (e.g., SEQ ID NO: 22) comprising 3 CDRs (e.g., LCDR1-3), which is effectively half an antibody binding site missing the VH complement (with 3 HCDRs) that would create the full antibody binding site (e.g., 6 CDRs). One of ordinary skill in the art would understand that one cannot use half of an antibody binding domain (e.g., VL only) and reasonably expect to maintain H2Kb antigen binding function.
The invention as disclosed in claim(s) 17 (and dependent claims 18-19) recite(s) “…at least about 95% homology to a nucleic acid encoding a polypeptide selected from … SEQ ID NOs: 1-14, 21-26, 28, and 30-31…”. The claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability (e.g., about 95% identical) in both the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to either PD-1 or H2Kb antigen. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining PD-1 or H2Kb antigen binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
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The anti-PD-1 and anti-H2Kb antibodies in the Applicant disclosure (see summary table above for details) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the antibodies that the applicant was in possession of at the time of filing.
State of the Prior Art
Antibody Binding
At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3].
Anti-PD-1 Antibodies
At the time of filing, US 20180185668 A1 (hereinafter “US668”) taught anti-PD-1 antibodies were recognized in the art as autoimmune disease therapy [e.g., title, abstract, brief summary of the invention]. US668 taught that different anti-PD-1 antibody species result in different EC50’s (e.g., different responses) [e.g., Tables 20-21]. US668 further taught various separate species of anti-PD-1 antibodies for autoimmune disease therapy [e.g., table 21]. Therefore, the prior art demonstrates that the binding of PD-1 is possible by various anti-PD-1 antibodies with different outcomes. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-PD-1 antibody that would allow prediction of CDR residues that specifically bind to PD-1.
Anti-H2Kb Antibodies
At the time of filing, WO 2020018715 A1 (hereinafter “WO715”) taught anti-H2Kb antibodies were recognized in the art as an autoimmune disease therapy [e.g., title, abstract, summary of the disclosure; figs. 5-6]. WO715 taught the single anti-H2Kb antibody species clone 26-D.16 [e.g., pg. 21, para 10; fig. 5]. Additional anti-H2Kb antibody clones AF6-88.5.3 and Y3 were known in the art at the time of filing (see US 20030082195 A1; paras 0045, 0220, 0271]. Therefore, the prior art at the time of filing demonstrates that the binding of H2Kb is possible by multiple anti-H2Kb antibodies with different outcomes. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-H2Kb antibody that would allow prediction of CDR residues that specifically bind to H2Kb.
Summary
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds PD-1 or H2Kb. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 1 would need to minimally recite the 6 CDRs (e.g., HCDR1-3 and LCDR1-3) that bind to PD1 with the recited function(s), without variability in the CDR sequences thereof; claim(s) 12-13 would need to minimally recite the 6 CDRs that bind to H2Kb, without variability in the CDR sequences thereof; and claim(s) 17 would need to minimally recite the 6 CDRs that bind to PD1 and/or the 6 CDRs H2Kb with the recited function(s), without variability in the CDR sequences thereof . Dependent claims 2, 11, 15-16, 18-21, and 36 can overcome this rejection by amending claims 1, 12-13, and 17 as recited above.
Response to Arguments
Applicant argues:
Even with sequence variability, the claim1 (and all dependent claims) require specific binding of the bispecific molecule to its antigens.
In response, as discussed in the rejections above, merely claiming specific antigen binding does not automatically meet written description requirements. For instance, (as applicant specifically argues claim 1) amended instant claim 1 requires specific Kd characteristics of the anti-PD1 arm of the bispecific antibody of the invention, and it would be unclear to a skilled artisan all of the possible CDR sequence combinations that would meet the limitation of binding PD1 with the claimed function(s) (e.g., Kd characteristics), and therefore instant claim 1 is considered to lack written description. For additional details regarding claim 1 and other written description rejections please see above. Applicant arguments have been fully considered and are not found to be persuasive for the reasons provided above.
It is well known in the art that VH domain alone can support binding, as demonstrated by naturally occurring VHH antibodies or dAb or other single domain antibodies. Further, claim 1, from which the remaining rejected claims depend, stipulated specific binding of the bispecific molecule to its antigens.
In response, (1) the stipulation of a binding domain does not automatically meet written description requirements (see above) and (2) the elected species of anti-PD1 and anti-H2Kb arms comprise scFvs of classical antibodies and are not VHH single domain antibodies, and therefore the argument of a VHH domain is drawn to a non-elected invention. However, in the interest of compact prosecution, a skilled artisan would understand that while single domain antibodies exist in the prior art, the VL or VH of an existing scFv is not necessarily readily functional as a VHH single domain antibody. Single domain VHH antibodies are separate from individual VH or VL domains in an antibody. Specifically, Wagner et al. (Int J Mol Sci. 2018 19(11): 3444; hereinafter “Wagner”) taught in the context of nanobodies®, universal scaffolds have been identified, enabling the generation of robust or humanized VHH variants but, this strategy has only been applied to graft CDRs to acceptor frames obtained from animals of the same taxonomic family [e.g., pg. 2, final ¶ ]. Wagner taught the design of nanobody grafts with CDRs derived from conventional antibodies requires careful consideration, because both the heavy and light chain variable domain (VH and VL) form the antigen binding site and are involved in the recognition of the antigenic epitope [e.g., pg. 2, final ¶ ]. Furthermore, the framework plays an important role in CDR conformation and orientation and distinct framework residues often contribute directly to antigen binding [e.g., pg. 2, final ¶ ]. Additionally, the prior art has taught single variable domains from species with VH and VL antibody pairing is distinct from other species with single domain only antibodies. Holliger et al. (Nature Biotechnology 2005 23 1126–1136); hereinafter “Holliger”). taught despite early excitement concerning the functional activity of single variable heavy domain antibodies, these antibody fragments rarely retained the affinity of the parent antibody and were also poorly soluble and often prone to aggregation [e.g., pg. 1127, bridging ¶ between left and right columns ]. Holliger taught while high affinity single variable like domain antibodies are present in camelid, as VhH, and shark, as V-NAR, domains, these single domain antibodies are structurally different, wherein each display long surface loops, often larger than for conventional murine and human antibodies, and are able to penetrate cavities in target antigens, such as enzyme active sites (for example, lysozyme) and canyons in viral and infectious disease biomarkers [e.g., pg. 1127, bridging ¶ between left and right columns ]. Holliger taught the structural changes are shown in Fig. 2, wherein superimposition of a human VH domain (Fig. 2b) and a single domain V-NAR(Fig. 2c) has a vastly different CDR3 that does not overlap structurally (Fig. 2d). Holliger taught unlike mouse VH domains, camelid VhH and shark V-NAR domains are in general soluble and can be produced as stable in vitro targeting reagents [e.g., pg. 1127, col. 2, ¶ 2]. Holliger did not describe single domain VL antibodies as successful. Thus, single-domain antibodies are not generally only a VH or VL and antibodies and require both the VH and VL, which are distinct from VHH. Applicant arguments have been fully considered and are not found to be persuasive.
In summary, Applicant arguments have been thoroughly reviewed but are not persuasive for the reasons provided above. The new rejection(s), necessitated by claim amendment, of claim(s) ) 1-2, 11-13, 15-21, and 36 are maintained.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2 and 15-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0185668 A1 (hereinafter “US668”), in view of Polesso et al. (bioRxiv 2020.04.14.041608; doi: https://doi.org/10.1101/2020.04.14.041608; hereinafter “Polesso”).
Regarding instant claims 1-2, 16, US668 teaches a bispecific molecule that specifically binds to PD-1 and a second part that specifically binds to a surface antigen of a target cell other than a T cell [e.g., abstract; brief summary of the invention; para 0033]. US668 teaches that simultaneous binding of the bispecific molecule to the surface antigen and to PD-1 facilitates clustering of PD-1 in proximity to an immunological synapse [e.g., paras 0154, 225-226, ]. US668 teaches that the bispecific may be used to inhibit T cell activation [e.g., para 0007]. US668 teaches the PD1 arm is an anti-mouse PD-1 clone “RPMI-14” [e.g., ¶ 0057-0058], and that methods exist to identify new clones [e.g., ¶ 0140]. US668 further teaches that the bispecific antibody comprises an Fc domain comprising one or more mutations which diminish FcRn binding [e.g., ¶ 0122-0124].
Regarding instant claims 15-16, US668 further teaches the first part or the second part of the bispecific antibody may be chimeric, fully human monoclonal, an antigen-binding fragment of the bispecific antibody, Fv fragments, scFv, or F(ab’)2 [e.g., paras 0105, 0133-0134].
Regarding instant claims 17-19, US668 further teaches a host cell comprising a vector comprising a polynucleotide that encodes the bispecific antibody [e.g., para 0047].
Regarding instant claim 20, US668 further teaches a device comprising the bispecific antibody [e.g., para 0164-0165]. US668 further teaches the anti-PD-1 arm of the bispecific antibody may be labeled with a detectable label or reporter molecule [e.g., para 0192].
Regarding instant claim 21, US668 further teaches methods for producing the bispecific antibody comprising culturing host cells containing a recombinant expression vector encoding the bispecific antibody, and recovering the antibodies and antibody fragments produced [e.g., para 0047].
US668 does not expressly teach (1) the PD1 arm of the bispecific molecule comprises 29F.1A12, (2) the 29F.1A12 bispecific molecule wherein the first part or the second part of the bispecific antibody may be chimeric, fully human monoclonal, an antigen-binding fragment of the bispecific antibody, Fv fragments, scFv, or F(ab’)2; (3) a host cell comprising a vector comprising a polynucleotide encoding the 29F.1A12 bispecific molecule; (4) a device comprising the 29F.1A12 bispecific molecule wherein the PD1 arm may be detectably labeled; or (5) producing the anti-29F.1A12 bispecific comprising culturing host cells containing a recombinant expression vector encoding the bispecific antibody, and recovering the antibodies and antibody fragments produced.
Regarding instant claim(s) 1-2, Polesso teaches 29F.1A12 had the brightest PD1 staining (e.g. most binding) and RMP1-14 had the weakest staining (e.g., least binding) of all the clones tested, that 29F.1A12 prevents PD1 interaction with PD-L1, and completely prevents PD1 detection with nearly all other clones [e.g., pg. 4, ¶ 3; fig. 4].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the PD1 binding domain of the anti-PD1 bispecific molecule taught by US668, with the anti-PD1 29F.1A12 clone taught by Polesso, in the context of designing and developing an anti-PD1 bispecific therapeutic. A PHOSITA would have been motivated to substitute the PD1 binding domain of the anti-PD1 bispecific molecule taught by US668, with the anti-PD1 29F.1A12 clone taught by Polesso, because Polesso teaches that of all the widely available clones tested, that 29F.1A12 demonstrated the highest staining, prevents PD1 interaction with PD-L1, and completely prevents PD1 detection with nearly all other clones, which a skilled artisan would understand may result in better PD1 target engagement as a therapeutic. There would have been a reasonable expectation of success for a PHOSITA to substitute the PD1 binding domain of the anti-PD1 bispecific molecule taught by US668, with the anti-PD1 29F.1A12 clone taught by Polesso, because US668 teaches the base bispecific molecule structure, and Polesso teaches the anti-PD1 29F.1A12 clone and superior antigen binding characteristics thereof relative to other clones tested. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified anti-PD1 29F.1A12 bispecific molecule of US668 and Polesso (see above) to include (1) the 29F.1A12 bispecific molecule wherein the first part or the second part of the bispecific antibody may be chimeric, fully human monoclonal, an antigen-binding fragment of the bispecific antibody, Fv fragments, scFv, or F(ab’)2; (2) a host cell comprising a vector comprising a polynucleotide encoding the 29F.1A12 bispecific molecule; (3) a device comprising the 29F.1A12 bispecific molecule wherein the PD1 arm may be detectably labeled; or (4) producing the anti-29F.1A12 bispecific comprising culturing host cells containing a recombinant expression vector encoding the bispecific antibody, and recovering the antibodies and antibody fragments produced.as taught by US668, because US668 and Polesso teach the base bispecific molecule structure, and US668 teaches additional modifications thereto and/or associated compositions (e.g., expression vectors for bispecific production) that a skilled artisan would understand to be common practice in the art. There is an expectation of success for a PHOPSITA to modify the modified anti-PD1 29F.1A12 bispecific molecule of US668 and Polesso to include the above recited additional bispecific modifications and/or associated compositions, because US668 and Polesso teach the base bispecific molecule structure, and US668 further teaches the modifications and/or associated compositions thereof, which are common in the art. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over by US 2018/0185668 A1 (hereinafter “US668”) and (bioRxiv 2020.04.14.041608; doi: https://doi.org/10.1101/2020.04.14.041608; hereinafter “Polesso”) as applied to claim(s) 1 above, and further in view of WO 2020018715 A1 (hereinafter “WO715”).
The teachings of US668 and Polesso as recited above apply for claim 1.
US668 and Polesso do not expressly teach the second arm of the bispecific binds H2Kb antigen.
Regarding instant claim 11, WO715 teaches multimeric antibodies (e.g., bispecific) and therapeutic uses thereof such as treating autoimmune diseases [e.g., title, abstract; pg. 19, para 5]. WO715 further teaches an anti-H2Kb antibody arm [e.g., pg. 21, para 9; figs. 5-6, 13C-D, 20B, 21B; table 5].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the second arm (e.g., “second part”) of the anti-PD1 29F.1A12 bispecific molecule of US668 and Polesso (see above), with the anti-H2Kb antibody arm taught by WO715, in the context of designing and developing a bispecific antibody therapy for autoimmune diseases. A PHOSITA would have been motivated to substitute the second arm of the anti-PD-1 bispecific antibody taught by US668 and Polesso with the anti-H2Kb arm taught by WO715, because US668 and Polesso teach an anti-PD-1 29F.1A12 bispecific antibody, US668 further teaches the treatment of autoimmune disease [e.g., abstract], and WO715 teaches the anti-H2Kb arm of a multispecific antibody for the treatment of autoimmune disease. There would have been a reasonable expectation of success for a PHOSITA to substitute the second arm of the modified anti-PD1 29F.1A12 bispecific molecule of US668 and Polesso (see above) with the anti-H2Kb arm taught by WO715, because US668 and Polesso teach the base bispecific structure, and both US668 and WO715 teach bispecific antibodies for the treatment of autoimmune diseases (e.g., overlapping subject matter). This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over 2018/0185668 A1 (hereinafter “US668”), and (bioRxiv 2020.04.14.041608; doi: https://doi.org/10.1101/2020.04.14.041608; hereinafter “Polesso”) and WO 2020018715 A1 (hereinafter “WO715”) as applied to claims 1 and 11 above, and further in view of US 20030082195 A1 (hereinafter “US195”).
The teachings of US668, Polesso, and/or WO715 as recited above apply for claims 1 and 11.
US668, Polesso and WO715 do not expressly teach the H2Kb binding arm comprises the VH and/or VL sequence of the AF6-88.5.3 clone.
Applicant disclosure provides that instant claimed anti-H2Kb VH and VL sequences (SEQ ID NOs: 21-22, respectively) are the AF6-88.5.3 clone [pg. 215, lines 25-31]]. Therefore, prior art that discloses the AF6-88.5.3 clone is necessarily considered to teach the instant claimed VH and VL sequence(s).
Regarding instant claims 12-13, US915 teaches the AF6-88.5.3 anti-H2Kb antibody is available from ATCC [e.g., para 0271].
Further, it would have been obvious to a PHOSITA to modify the modified anti-PD1 29F.1A112/anti-H2Kb bispecific molecule taught by US668, Polesso, and WO715 (see above) to include that the H2Kb binding arm comprises the VH and/or VL sequence of the AF6-88.5.3 clone as taught by US195, because US668, Polesso, and WO715 teach the bispecific anti-PD1 29F.1A112/anti-H2Kb bispecific structure, and US195 teaches an anti-H2Kb clone (AF6-88.5.3) that is readily available to one of ordinary skill in the art (e.g., from ATCC). There is an expectation of success for a PHOPSITA to substitute the anti-H2Kb arm taught by US668, Polesso, and WO715 with the H2Kb binding arm comprising the VH and/or VL sequence of the AF6-88.5.3 clone as taught by US195, because US668, Polesso, and WO715 teach the bispecific anti-PD1 29F.1A112/anti-H2Kb antibody structure, and US195 teaches an anti-H2Kb clone (AF6-88.5.3) that is readily available to one of ordinary skill in the art (e.g., from ATCC). This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
The combination of US668 and WO715 constitutes impressible hindsight because US668 doesn’t teach a H2Kb binding arm and WO715 doesn’t teach a PD1 binding arm.
In response, the combination of the references relied upon the common target indication of autoimmune diseases (see above for details). Briefly, the base structure of the bispecific molecule was taught by US668 and Polesso, US668 taught that the second arm binds a cell other than T cells, US668 and WO715 teach antibody arms that interact with surface antigens on non-T cells to treat autoimmune conditions, and WO715 teaches anti-H2Kb antigen binding domains as an effective autoimmune therapy (see rejections above). Applicant arguments have been fully considered and are not found persuasive.
US668 and WO715 do not teach the bispecific of amended claim 1.
In response, as amended claim 1 included new limitations not previously searched, Polesso was incorporated into the new rejections to meet the new limitations (see above for details). Briefly, Polesso taught the 29F.1A12 clone, which meets the newly added anti-PD1 functional limitations of amended claim 1 based on Applicant disclosure (see claim interpretations and rejections above). Applicant arguments have been fully considered and are not found persuasive.
US668 as a whole discloses anti-PD1 antibodies only, and mentions bispecific molecules on a few times in general terms, and does not identify any specific second antigen, let alone provide working examples. The only bispecific disclosed by US668 is the CD3xCD20 used to prepare cells for luciferase based PD1 bioassay. US668 does not provide sufficient guidance to design a bispecific molecule according to the pending claims.
In response, as discussed in the rejections above, US668 teaches a bispecific molecule comprising an anti-PD1 arm and a second arm that binds an antigen on a cell other than T cells (see above for details). US668 abstract, brief summary of the invention, ¶ 0033, 0048, 0056, 0073, 0099, 0149-0157 teach the invention includes anti-PD1 bispecific and/or multispecific molecules. A skilled artisan would understand that a structure of bispecific molecule known in the art (e.g., US668) can be modified to target different antigen(s) to treat specific diseases of interest (e.g., substitution of antigen binding domains to target a known autoimmune disease target). Applicant arguments have been fully considered and are not found to be persuasive.
Surprising therapeutic benefits. First (1), the bispecific molecules according to the pending claims have at least a 50-fold difference in the Kd of binding to PD-1 and the Kd of binding to the surface antigen (see claim l(b)). As described in the specification (e.g., page 15, lines 5-7), a bispecific molecule with a large difference in measured Kd between its binding partners would mediate T-cell inhibition over a wider range of concentrations than the bispecific molecules where the Kd for each of the binding partners is more similar. Thus, in contrast to the bispecific molecules disclosed in US668 and/or WO715, which would be effective only at a high concentration, the bispecific molecules according to the amended claims have an unexpected advantage of effectively inhibiting T cells both at a low concentration and at a high concentration of the bispecific molecules (e.g., in the blood of a patient). Second (2), the instantly claimed bispecific molecules comprise an Fc domain, wherein the Fc domain comprises one or more mutations that inhibit Fc gamma receptor binding. The bispecific molecules with a wild-type Fc domain would result in unintended binding to cells expressing an Fc gamma receptor, but without the surface antigen. This has two undesirable consequences: (i) the bispecific molecules would activate PD-1 on non-target cells expressing an Fc gamma receptor, but without the surface antigen (e.g., on professional antigen-presenting cells) thereby inducing unintended immune response; and (ii) by sequestering the bispecific molecules at the non-target cells, the effective concentration of the bispecific molecules to bind the true target cells would be lower, thereby limiting the therapeutic effects of the bispecific molecules. By contrast, the instantly claimed bispecific molecules would avoid these undesirable consequences and have a tighter tissue specificity, thereby making a safer and more efficacious drug for patients.
In response, (1) as discussed in claim interpretation above, the recited functions of the PD1 domain are a result of the specific anti-PD1 antigen binding domain, which Applicant discloses corresponds to the 29F.1A12 clone, which Polesso teaches prior to the effective filing date of the instant invention (see above). Briefly, US668 teaches the base anti-PD1 bispecific molecule structure, and Polesso teaches that 29F.1A12 demonstrates superior binding characteristics compared to other anti-PD1 clones commonly known and used in the art, thereby motivating a skilled artisan to substitute the 29F.1A12 clone in place of the anti-PD1 binding domain of US668 (see rejection above for details). Further, the instant elected claims are drawn to a composition of matter, not a method of treating and/or therapeutic benefits thereof. (2) US668 teaches a modified Fc domain with reduced FcyR binding (see rejection above), rendering Applicant arguments moot. In summary, the recited points are not considered to constitute unexpected results. Applicant arguments have been fully considered, but are not considered to be persuasive.
Applicant arguments have been thoroughly reviewed but are not persuasive. The new rejection(s), necessitated by amendment, of claim(s) 1-2, 11-13, 15-21, and 36 are maintained.
Conclusion
No claims are currently allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643