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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1, 3-16, 20, and 23) and species listed below in the reply filed on 10/14/2025 is acknowledged.
Elected Species:
Anti-B7H3 antibody including the amino acid sequences of SEQ ID NOs: 4-6 as the CDRs and SEQ ID NO: 2 as the variable region; and
Multispecific compound of SEQ ID NO: 23 which comprises, from N- to C-terminus, SEQ ID NO: 19 (CD16 immune cell engaging domain), SEQ ID NO: 14 (linker), residues 143-258 of SEQ ID NO: 23 (immune cell activating domain), SEQ ID NO: 15 (second linker), and SEQ ID NO: 2 (targeting domain that is an anti-B7H3 single domain antibody).
Claim Status
Claims 2, 19, 21-22, 26-29, 32-33 and 36-43 have been cancelled and claims 12, 25, and 31 have been amended, as requested in the amendment filed on 10/14/2025. Following the amendment, claims 1, 3-18, 20, 23-25, 30-31, and 34-35 are pending in the instant application.
Claims 17-18, 24-25, 30-31, and 34-35 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions in the Response filed 10/14/2025, there being no allowable generic or linking claim.
Claims 1, 3-16, 20, and 23 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1, 3-16, 20, and 23 have an effective filing date of June 03, 2020 corresponding to PRO 63/033,989.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/02/2023, 06/13/2024, 06/04/2025, and 11/25/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The use of, for example, the transfection agents at Page 21 (e.g., LIPOFECTAMINE, HILYMAX, etc.), chemotherapeutic agents at Pages 30-31 (e.g., Erbitux, Avastin, etc.), and the terms Akta Pure, GOLGISTOP, GOLGIPLUG, INCUCYTE, and PRISM (GraphPad), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Art-Free Subject Matter
It is noted that the instantly elected species of anti-B7H3 polypeptide, and compound/protein thereof, has been thoroughly searched. Specifically, it is noted that the CDR set comprising full-length CDRs SEQ ID NOs: 4-6, full-length SEQ ID NO: 2, amino acids 19-284 of SEQ ID NO: 21, and full-length SEQ ID NO: 23 (or a sequence having 90% or greater identity to full-length SEQ ID NO: 23) have been thoroughly searched and are free of the prior art.
Claim Objections
Claims 7-9 and 13-14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 15 is objected to because of the following informalities: the claim currently reads "the compound is as set forth as in" in line 1, but should read "the compound is as set forth in". Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 3-6, 10-12, 16, 20, and 23 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. This is a WRITTEN DESCRIPTION rejection.
The claims are generally drawn to an anti-B7H3 polypeptide, wherein the anti-B7H3 polypeptide may comprise at least one of (i) SEQ ID NOs: 4-6 (i.e., individual CDRs) or a functional variant thereof or a CDR region of one of SEQ ID NOs 1-3 (i.e., variable domains) or a functional variant thereof.
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Thus, the claims identify the polypeptide by the function of binding B7H3 (i.e., anti-B7H3), and a partial sequence structure that comprises at least one CDR or a functional variant thereof or a variable domain or a functional variant thereof. It is noted that a protein is a "functional variant" to a reference protein if the amino acid sequence of the protein possesses a specified amount of identity compared to the reference protein and retains the activity of the reference protein (see Page 12 of the instant specification). As such, the claims are drawn to truncations and/or mutations with respect to the CDRs and variable domains. Thus, the claims encompass a vast genus of polypeptide variants comprising variable CDR and/or variable domain sequences and are required to bind B7H3.
The instant specification only discloses three B7H3 polypeptides that bind B7H3, as shown in Figure 1B (reproduced below).
Thus, the instant specification discloses making three structurally distinct B7H3 polypeptides, which require all three, complete CDR sequences of SEQ ID NOs: 4-6. The specification fails to disclose any other polypeptide sequence variants (i) having fewer than all three CDRs or (ii) variants (i.e., truncations/mutations) thereof that possess the function of binding B7H3.
To provide adequate written description and evidence of possession of the claimed polypeptide genus, the instant specification can structurally describe representative polypeptide variants that function to bind B7H3, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the polypeptide function, “anti-B7H3”, and partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the polypeptides disclosed in Figure 1B, the specification fails to provide the CDR structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of polypeptide sequence variants for the genus of polypeptides that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antibodies.
The claims broadly encompass any sequence variant that comprises at least one CDR (or a functional variant thereof) or a variable domain (or a functional variant thereof) that functions to bind B7H3. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain B7H3 binding, nor a sequence that confers upon fewer than all three CDRs the ability to bind B7H3. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single polypeptide comprising at least one CDR (or a functional variant thereof) or a variable domain (or a functional variant thereof) to the structure of any variants required to bind B7H3 as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for polypeptides that bind B7H3 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future polypeptides yet to be discovered that may function as claimed. The B7H3 antigen provides no information about the structure of a polypeptide that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant polypeptides, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the CDRs that provide B7H3-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of polypeptide variants that bind B7H3 and comprise as few as one CDR that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending independent claim 1 to recite: An anti-B7H3 polypeptide comprising SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.
The language above indicates that all three full-length CDR sequences (SEQ ID NOs: 4-6) must be present in the polypeptide, and as such any variants are directed to framework (i.e., non-binding) residue mutations only.
The Examiner further suggests similarly amending independent claim 3 to recite: A compound comprising:
(i) a targeting domain comprising an anti-B7H3 polypeptide, the anti-B7H3 polypeptide comprising:
SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6; and
(ii) an immune cell engaging domain operably linked to the targeting domain.
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 4-6, 11-12, and 16 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.
Claims 4-5 and 11 all recite the limitation "the immune cell" in lines 1, 2, and 2, respectively. There is insufficient antecedent basis for this limitation in the claim. It is noted that claim 3, from which all of claims 4-5 and 11 ultimately depend, recites “an immune cell engaging domain”; it is recommended that Applicant amend the claim language to clear recite that “the immune cell” is being targeted by the immune cell engaging domain or are amended to only recite the immune cell engaging domain. The limitation “the immune cell” lacks antecedent basis as claim 3 does not refer to immune cells themselves, only an “immune cell engaging domain”. Claims 6, 12, and 16 are included in this rejection as they encompass the rejected limitation(s) of claims 4, 5, and/or 11.
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.
Claims 1, 3-6, and 23 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2019/0127471 A1 (herein after referred to as "Loo").
With regard to claim 1, Loo discloses novel B7H3-binding molecules capable of binding to human and non-human B7H3, and in particular to such molecules that are cross-reactive with B7H3 of a non-human primate (e.g., a cynomolgus monkey) (Abstract). Specifically, Loo discloses a murine anti-human B7H3 antibody designated as “mAb-B”, which comprises VL SEQ ID NO: 97 and VH SEQ ID NO: 98 (Page 19). It is noted that Loo SEQ ID NO: 48 residues 31-34 correspond to residues 1-4 of instant SEQ ID NO: 4; thus, Loo SEQ ID NO: 98 comprises a sequence that is an 80% match to instant SEQ ID NO: 4 wherein said sequence is comprised within a sequence/antibody capable of binding B7H3 (i.e., Loo SEQ ID NO: 98 comprises a functional variant of instant SEQ ID NO: 4). Thus, Loo discloses an anti-B7H3 polypeptide (i.e., antibody) comprising a functional variant of instant SEQ ID NO: 4 and anticipates instant claim 1.
With regard to claim 3, Loo further discloses an embodiment of the invention wherein a B7H3-binding molecule is capable of simultaneously binding to B7H3 and to a second epitope, and particularly concerns the embodiment wherein the second epitope is an epitope of a second molecule present on the surface of an effector cell; exemplary second epitopes include epitopes of CD2, CD3, CDS, CD16, TCR, NKG2D, or CD3 (i.e., a second epitope is an immune-cell engaging epitope) (Paragraph 0035). Loo further teaches that in order to provide molecules having greater capability than natural antibodies, a wide variety of recombinant bispecific antibody formats have been developed, most of which use linker peptides either to fuse a further epitope-binding fragment (e.g., an scFv, VL, VH, etc.) to, or within the antibody core (IgA, IgD, IgE, IgG or IgM), or to fuse multiple epitope-binding fragments (e.g., two Fab fragments or scFvs) (Paragraph 0196; emphasis added). In one embodiment, the first polypeptide chain of a bispecific diabody comprises, in the N-terminal to C-terminal direction: an N-terminus, the VL Domain of a monoclonal antibody capable of binding to either the first or second epitope (i.e., either VLanti-B7H3-VL or VLEpitope2), a first intervening spacer peptide (Linker 1), a VH Domain of a monoclonal antibody capable of binding to either the second epitope (if such first polypeptide chain contains VLanti-B7H3-VL) or B7H3 (if such first polypeptide chain contains VLEpitope2), a second intervening spacer peptide (Linker 2) optionally containing a cysteine residue, a Heterodimer-Promoting Domain and a C-terminus (Paragraph 0265; FIG. 1). Thus, Loo discloses bispecific molecule wherein a B7H3 polypeptide (e.g., comprising a functional variant of instant SEQ ID NO: 4) may be operably linked to an immune cell engaging domain (e.g., binding domain specific to CD2, CD3, CDS, CD16, TCR, NKG2D, or CD3) and thus anticipates instant claim 3.
With regard to claims 4-6, Loo discloses an embodiment of the invention wherein a B7H3-binding molecule is capable of simultaneously binding to B7H3 and to a second epitope, and particularly concerns the embodiment wherein the second epitope is an epitope of a second molecule present on the surface of an effector cell; exemplary second epitopes include epitopes of CD2, CD3, CDS, CD16, TCR, NKG2D, or CD3 wherein the effector cell is a cytotoxic T-cell or a Natural Killer (NK) cell (Paragraph 0035). It is also specifically noted that the terms "antibody" and "antibodies" refer to monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, polyclonal antibodies, camelized antibodies, single-chain Fvs (scFv), single-chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked bispecific Fvs (sdFv), intrabodies, and epitope-binding fragments of any of the above (Paragraph 0155); epitope-binding sites may comprise either a complete variable domain fused onto constant domain or only the complementarity determining regions of such a variable domain grafted onto appropriate framework regions (Paragraph 0163). CD16 is a generic name for the activating Fc receptors, FcyRIIIA (CD16A) and FcyRIIIB (CD16B). CD16 is expressed by neutrophils, eosinophils, natural killer (NK) cells, and tissue macrophages that bind aggregated but not monomeric human IgG (Paragraph 0191). Thus. Loo discloses a bispecific molecule wherein a B7H3 polypeptide (e.g., comprising a functional variant of instant SEQ ID NO: 4) may be operably linked (e.g., via peptide linker to an immune cell engaging domain wherein the immune cell engaging domain may be an antibody/fragment thereof (e.g., scFv, Fab, etc.) that binds CD16 expressed on NK cells, and thus anticipates instant claims 4-6.
With regard to claim 23, Loo further discloses compositions of the invention which include bulk drug compositions useful in the manufacture of pharmaceutical compositions (e.g., impure or non-sterile compositions) and pharmaceutical compositions (i.e., compositions that are
suitable for administration to a subject or patient) that can be used in the preparation of unit dosage forms; such compositions comprise a therapeutically effective amount of the B7-H3-binding molecules of the invention, or a combination of such agents, and a pharmaceutically
acceptable carrier (Paragraph 0515). As such, Loo teaches pharmaceutical compositions which can include the compound of instant claim 3 and a pharmaceutically acceptable carrier, and thus anticipates instant claim 23.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-15, 20, 23, 67, and 69 of copending Application No. 18/250,735 (first reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of the first reference application is drawn to a cell or population thereof wherein the cell comprises a polynucleotide encoding a CAR targeting a B7H3 tumor antigen wherein the CAR comprises a binding domain that comprises, for example, and amino acid sequence represented by SEQ ID NO: 36. It is specifically noted that first reference application SEQ ID NO: 36 is an exact match to instant SEQ ID NO: 2 and comprises 100% matches to instant SEQ ID NOs: 4-6. First reference application claims 14-15 further disclose composition comprising the cell of claim 1. Claims 20 and 23 of the first reference application are drawn to a composition comprising a cell or population thereof wherein the cell comprises one or more polynucleotides encoding a chimeric antigen receptor (CAR), an engager, and optionally a CFR (chimeric fusion receptor) wherein the CAR may comprise an antigen recognition domain specific to B7H3 comprising an amino acid sequence represented by SEQ ID NO: 36. First reference application claims 67 and 69 are drawn to a CAR comprising a binding domain that may comprise an amino acid sequence represented by SEQ ID NO: 36 wherein the CAR may have at least one of the following characteristics: (i) being T cell specific; (ii) being NK cell specific; (iii) binding to tumor cell surface B7H3; (iv) reducing tumor cell surface shedding of B7H3 antigen; or (v) increasing tumor cell surface B7H3 density. Thus, the first reference application reads on (i) anti-B7H3 polypeptides, wherein said anti-B7H3 polypeptide comprises instant SEQ ID NO: 2.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 3-18, 20, 23-25, 30-31, and 34-35 are pending. Claims 17-18, 24-25, 30-31, and 34-35 are withdrawn. Claims 1, 3-6, 10-12, 16, 20, and 23 are rejected. Claims 7-9 and 13-15 are objected to. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642