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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 20Feb2026 has been entered.
Claims Status
The Amendment filed on 20Feb2026 is acknowledged in which claim(s) 3, 14, 16-26, and 28-29 were canceled by Applicant.
Claim(s)1-2, 4-13, 15, 27, and 30-32 is/are currently pending and presented for examination on the merits.
Response to Amendment
All previous rejections and/or objections of claim(s) 3 and 29 are moot in view of claim cancelation.
The objection(s) to claim(s) 1-2, 4-13, 15, 30-32; 5; 27, have been withdrawn in view of the Amendment filed on 20Feb2026.
The previously set forth rejection(s) of claim(s) ) 1-2, 4-13, 15, 27, 30-32 under 35 U.S.C. § 112(a) have been withdrawn in view of the recent claim amendment filed on 20Feb2026, which added new limitations to the claims, that were not considered in the previous rejections.
All previously presented rejection(s) and/or objection(s) have been withdrawn. Therefore, only arguments applicable to new rejection(s) and/or objection(s) are addressed below.
Rejections/Objections Maintained/New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(b)
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 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.
Claim(s) 1-2, 4-13, 15, 27, and 30-32 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.
Regarding claim(s) 1 (and dependent claims 2, 4, 6-13, 15, 30-32), 5 and 27, the phrase “…antigen binding portion / fragment thereof…” in lines 6-7 (claim 1), lines 1-2 (claim 5), or lines 7-8 (claim 27) renders the claim(s) indefinite. Specifically, it is unclear if the phrase (1) is using “portion / fragment” within the phrase as synonyms; (2) how a “portion” and a “fragment” differ; (3) if the “/” separates only “portion” and “fragment”; (4) if the “/” separates the entire phrase “antigen binding portion” from “fragment thereof”, wherein the “fragment thereof” is not modified by “antigen-binding” and wouldn’t require that function; or (5) something else. For the purposes of compact prosecution, the phrase will be considered to read “antigen-binding fragment thereof”. This rejection may be overcome by amending claims 1 and 27 (1) as described above, and/or (2) to otherwise clearly recite the limitation(s) of the invention. Dependent claims 2, 4-13, 15, 30-32 can overcome this rejection by amending claim 1 as described above.
Regarding claim(s) 15, the phrase “(non-antibody)” is not defined in the terms preceding it. Thus, the phrase “(non-antibody)” renders the claim indefinite because it is unclear whether the limitation(s) in the parentheses are a part of the claimed invention. See MPEP 2173.05(d). It is unclear if “(non-antibody)” is a limitation or merely provided as an example. To promote compact prosecution, the phrase “(non-antibody)” is not considered a limitation of the claim(s). This rejection may be overcome by amending claims 15 to (1) delete the parenthesis around “non-antibody”, or (2) delete the phrase “(non-antibody)”. Dependent claim 32 can overcome this rejection by amending claim 15 as described above.
Claim Rejections - 35 USC § 112(a)
Claim(s) 1-2, 4-13, 15, 27, and 30-32 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, 4-13, 15, 27, 30-32, are drawn to an antibody that competes with any one of four (C1-C4) 6 CDR pairs (e.g., HCDR1-3 and LCDR1-3) for IGSF8 antigen binding.
Claim(s) 5, are drawn to an antibody comprising a IgNAR or vNAR antigen binding domain that competes with any one of four (C1-C4) 6 CDR pairs for IGSF8 antigen binding.
Breadth of Claims
The invention as disclosed in claim(s) 1 (and dependent claims 2, 4-13, 15, 30-32), and 27 recite(s) “…wherein the IGSF8 antagonist inhibits binding of IGSF8 to a cancer cell..”, and “…wherein the IGSF8 antagonist is an anti-IGSF8 antibody or an antigen-binding portion/fragment thereof that competes with the monoclonal antibody of any one of C 1-C4 for binding to IGSF8…”. One of ordinary skill in the art would understand that the six CDRs of an antibody or antigen binding fragment thereof (e.g., HCDR1-3 and LCDR1-3) are responsible for antigen recognition and binding characteristics (e.g., competing for binding). The claim(s) do/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 VH and VL sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed function(s).
The invention as disclosed in claim(s) 5 recite(s) “…V-NAR domain, IgNar…”. One of ordinary skill in the art would understand that V-NAR and IgNAR antibody domains are shark-derived antibody domains, wherein the antigen binding domain comprises CDR1, HV1, HV4, and CDR3. The claim(s) do/does not disclose the structure 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 vNAR and/or IgNAR sequences, particularly in the CDR1, HV1, HV4, and CDR3 regions, such that the obtained structure would result in the claimed function(s).
Scope of Disclosed Species
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The anti-IGSF8 antibodies designated C1-C29 in the Applicant disclosure pgs. 47-71 (see summary table above for details) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the anti-IGSF8 antibodies that the applicant was in possession of at the time of filing. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region that would have been predictable.
There are no vNAR and/or IgNAR antibody sequences or clones in the instant disclosure, and therefore the Applicant is considered to not have possession of any vNAR or IgNAR antibodies with the claimed function(s) at the time of filing.
State of the Prior Art
Conventional Antibodies
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 de novo CDR sequences and/or mutation to known CDRs is unpredictable and that each construct requires function testing to determine antigen recognition and the ability to compete with any given antibody for specific epitope(s).
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].
Given the above, a skilled artisan would understand that CDRs are responsible for specific epitope binding, and/or the ability to compete with another antibody or antigen binding molecule for specific epitope binding. Further in support of this summation, Kwak and Yoon (J Immuno Methods, 191 (1996) 49-54; hereinafter “Kwak”) teaches methods of epitope competition analysis [e.g., title, abstract]. Kwak teaches that epitope mapping is not a simple task to perform in general and that careful ELISA competition design is required to perform epitope mapping and determine if antibodies compete for antigen epitope binding [e.g., introduction; fig. 1].
Further, at the time of filing, US 2022/0144942 A1 (hereinafter “WO942”) taught anti-IGSF8 antibodies for cancer therapy [e.g., title; abstract; paras 0014-0018, 0024-0031; fig. 7A]. Therefore, the prior art demonstrates that the binding of IGSF8 is possible by various antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-IGSF8 antibody that would allow prediction of CDR residues that specifically bind to IGSF8, nor those that specifically bind to IGSF8 with the recited function(s).
Shark-Derived Antibodies
At the time of filing, vNAR and IgNAR functionality were known to depend on the entire structure, particularly a full complement of CDR1, HV4, and CDR3. It is understood by one of ordinary skill in the art that the binding of vNAR and/or IgNAR domain antibodies to a given antigen, a specific epitope, and/or the ability to compete for binding with another antigen binding molecule is unpredictable and that each construct requires function testing.
Zielonka et al (mAbs 7:1, 15--25; January/February 2015; hereinafter “Zielonka”) teaches IgNAR antibodies are shark-derived antibodies comprising a vNAR antigen binding domain and constant domains C1-C5, wherein domain C5 is unresolved an hypothetical in the art [e.g., “The New Antigen Receptor”; fig. 1C]. Zielonka further teaches that shark antibodies lack a light chain and that the IgNAR variable domain (vNAR) comprises only 2 CDRs known as CDR1 and CDR3, that there are four known types of vNARs (e.g., type I-type IV), and that the diversity vNARs is predominantly found in CDR3 [e.g., “The Variable Domain of IgNAR- Structural Features”; figs. 2-3, 5]. Zielonka further teaches that the vNARs comprise mutation prone hypervariable regions, termed HV2 and HV4, that have structural implications, and that somatic mutations in HV4 in particular have been shown to contribute to antigen binding e.g., “The Variable Domain of IgNAR- Structural Features”]. Zielonka further teaches antigen-specific vNAR domains are generally selected from immunized sharks, but that they can be selected from non-immunized origins, vNAR antibodies require function testing, and that selected vNARs may be optimized using in vitro affinity maturation through yeast surface display [e.g., “selection of antigen-specific vNAR domains from Shark Immune Repertoires”; tbl. 1]. Zielonka further teaches that vNARs have the ability to bind epitopes that are bound by conventional antibodies, as well as recessed cryptic epitopes not accessible by conventional antibodies [e.g., “introduction”; “The New Antigen Receptor”; pg. 21-22; “Conclusion”]. Given the teachings of Zielonka above, a skilled artisan would understand that vNAR structure is complex and that function testing is required to determine antigen binding characteristics, including competition with other antibodies.
No prior art was found that discloses vNAR or IgNAR that recognize IGSF8 antigen. With the lack of anti-IGSF8 vNAR and/or IgNAR disclosures in the prior art, and the teachings of Zielonka, the prior art is not considered to teach a known structure activity relationship for CDR1, HV4, and CDR3 in an anti-IGSF8 vNAR or IgNAR antibody that would allow prediction of which CDR1, HV4, and CDR3 combinations would specifically bind to IGSF8 with the recited function(s).
Summary
Thus, predicting the six CDR sequences of a conventional antibody or the CDR1, HV4, and CDR3 sequences of vNAR or IgNAR antibodies is a highly unpredictable process and one skilled in the art could not a priori make any predictions, nor envisage the breadth of all of the possible structurally unrelated six CDR combinations for conventional antibodies and/or CDR1, HV4 and CDR3 combinations for shark-derived antibodies (e.g., an entire genus) that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for conventional antigen binding and one cannot predict which CDR residues would result in an antibody that competes with recited C1-C4 antibodies for IGSF8 antigen binding. Further, the art indicates a full complement of CDR1, HV4, and CDR3 are required for vNAR antigen binding and one cannot predict which residues thereof may be changed and still result in an antibody that competes with the recited C1-C4 antibodies for IGSF8 antigen binding. 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 a conventional antibody antigen-binding domain, or the CDR1, HV4, and CDR3 in a vNAR antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 1 and 27 would each need to recite the 6 CDRs (e.g., HCDR1-3 and LCDR1-3) in the antibody that bind IGSF8 with the claimed function(s), without variability in the sequences thereof; and claim(s) 5 would need to (1) recite the CDR1, HV4, and CDR3 in the vNAR antibody that bind IGSF8 with the claimed function(s), without variability in the sequences thereof, or (2) delete references to “IgNar” and “V-NAR”. Dependent claims 2-4, 6-13, 15, 29, and 30-32 can overcome this rejection by amending claims 1 and 27 as recited above.
Free of the Prior Art
During the course of examination, the anti-IGSF8 antibodies designated C1-C29 by Applicant were found to be free from the prior art.
Specifically, C1-C29 antibody constructs are drawn to monoclonal anti-IGSF8 antibodies. The Applicant disclosure provides SEQ ID NOs for six CDRs (HCDR1-3 and LCDR1-3), a VH, and a VL for each individual antibody. A sequence search of each instant claimed antibody’s HCDRs (e.g., SEQ ID NOs: 1-3; C1) returned no 100% sequence identity matches which qualify as prior art. As the instant claimed HCDRs are required by the six CDR set and/or the VH/VL pair of each antibody, antibodies C1-29 are considered free of the prior art (summary table provided below for ease of reference).
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Conclusion
No claims are currently allowed.
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