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 .
Restriction Response
Applicant’s election without traverse of a species of a multispecific antibody wherein:
A first antigen-binding fragment that specifically binds CD3, wherein the first antigen- binding fragment is fused to a first masking moiety (MM1) comprising the amino acid sequence SEQ ID NO:417 via a first cleavable moiety (CM1) comprising the amino acid sequence SEQ ID NO:77, wherein the first antigen-binding fragment comprises an immunoglobulin heavy chain variable domain, VH1, comprising CDR H1-H3 comprising amino acid sequences SEQ ID NOs:390, 394, and 395, respectively, and an immunoglobulin light chain variable domain, VL1, comprising CDR L1-L3 comprising amino acid sequences SEQ ID NOs:397, 380, and 381, respectively; and
A second antigen-binding fragment that specifically binds HER2, wherein the second antigen-binding fragment is fused to a second masking moiety (MM2) comprising the amino acid sequence SEQ ID NO:419 via a second cleavable moiety (CM2) comprising the amino acid sequence SEQ ID NO:77, wherein the second antigen-binding fragment comprises an immunoglobulin heavy chain variable domain, VH2, comprising CDR H1- H3 comprising amino acid sequences SEQ ID NOs:423, 424, and 71, respectively, and an immunoglobulin light chain variable domain, VL2, comprising CDR L1-L3 comprising amino acid sequences SEQ ID NOs:72-74, respectively.
in the reply filed on June 12, 2026 is acknowledged.
Claims 1, 8-9, 14-19, 25-27, 30-32, 36-38, 41-53, and 135-150 are pending in the instant application.
Claims 25, 31, 38, 50-53, 141-145, and 149-150 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 12, 2026.
Claims 1, 8-9, 14-19, 26-27, 30, 32, 36-37, 41-49, 135-140, and 146-148 are under review for the Applicant elected species.
The Applicant elected species of the multispecific antibody as disclosed above is free of prior art.
The Examiner has elected the next species of a multispecific antibody wherein:
A first antigen-binding fragment that specifically binds CD3, wherein the first antigen- binding fragment is fused to a first masking moiety (MM1) comprising the amino acid sequence SEQ ID NO:35 via a first cleavable moiety (CM1) comprising the amino acid sequence SEQ ID NO:129, wherein the first antigen-binding fragment comprises an immunoglobulin heavy chain variable domain, VH1, comprising CDR H1-H3 comprising amino acid sequences SEQ ID NOs:376, 391, and 378, respectively, and an immunoglobulin light chain variable domain, VL1, comprising CDR L1-L3 comprising amino acid sequences SEQ ID NOs:396, 380, and 381, respectively; and
A second antigen-binding fragment that specifically binds HER2, wherein the second antigen-binding fragment is fused to a second masking moiety (MM2) comprising the amino acid sequence SEQ ID NO:419 via a second cleavable moiety (CM2) comprising the amino acid sequence SEQ ID NO:129, wherein the second antigen-binding fragment comprises an immunoglobulin heavy chain variable domain, VH2, comprising CDR H1- H3 comprising amino acid sequences SEQ ID NOs:423, 424, and 71, respectively, and an immunoglobulin light chain variable domain, VL2, comprising CDR L1-L3 comprising amino acid sequences SEQ ID NOs:72-74, respectively.
Information Disclosure Statement
The information disclosure statement filed 3/7/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. The objection specifically refers to the following non-patent literature document listed below:
Cite No. 35 Li et al., (2006).
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Amino acid sequences of 4 or more amino acids require a sequence identifier. See page 256, ¶ [0719].
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The use of the term BiTE®, SAFEbody®, GraphPadTM, Histopaque®, CytoFlex®, and FlowJoTM which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Examples of trademarks referenced herein which should be identified as such with the appropriate notation are shown below:
BiTE® (page 1, ¶ [0004]; page 85, ¶ [0232] and ¶ [0235]; page 86, ¶ [0235]-[0236]; page 103, ¶ [0281]; pages 104-105, ¶ [0282]-[0294]; etc.);
SAFEbody® (page 70, ¶ [0179]; page 235, Table 3A; page 300, ¶ [0803], etc.);
GraphPadTM (page 244, ¶ [0711]; page 299, ¶ [0798]);
Histopaque® (pages 298-299, ¶ [0798]-[0799]);
CytoFlex® (page 299, ¶ [0799]); and
FlowJoTM (page 299, ¶ [0799]).
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.
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, 8-9, 14-19, and 41-47 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Du (Du et al, WO2021148006A1, Priority to January 23, 2020; hereinafter Du).
The applied reference has a common assignee and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding instant claims 1 and 8, Du teaches a multispecific antibody comprising:
a scFv that specifically binds CD3, wherein the scFv is fused to a masking moiety (MM1) via a cleavable moiety (CM1) wherein (i) the MM1 comprises SEQ ID NO:35 (identical to instant SEQ ID NO:35) that is fused to the N-terminus of the scFv via the CM1 wherein MM1 inhibits binding of the multispecific antibody to CD3 when the CM1 is not cleaved; (ii) the scFv specifically binds to CD3 comprising (1) a VH comprising the amino acid sequence SEQ ID NO:67, wherein SEQ ID NO:67 comprises CDRH1-H3 comprising the amino acid sequences instant SEQ ID NOs:376, 391, and 378, and (2) a VL comprising the amino acid sequence SEQ ID NO:68, wherein SEQ ID NO:68 comprises CDRL1-L3 comprising the amino acid sequences instant SEQ ID NOs:396, 380, and 381, wherein the scFv comprises from the N-terminus to the C-terminus VL-L1-VH wherein L1 is a peptide linker (page 51, ¶ [00151]; pages 82-84, ¶ [00209]-[00212]); and
a second antigen binding fragment that specifically binds a target antigen (pages 82-84, ¶ [00209]-[00212]).
Regarding instant claims 9, 14-15, and 17, Du teaches an activatable antibody comprising a first polypeptide comprising a first CH3 domain, a second polypeptide comprising a second CH3 domain, and a third polypeptide, wherein:
the first polypeptide comprises a structure represented by the formula:
MM1-CM1-VH-CH1-hinge-CH2-first CH3;
the second polypeptide comprises a structure represented by the formula:
MM2-CM2-scFv-hinge-CH2-second CH3; and
the third polypeptide comprises a structure represented by the formula:
VL-CL;
wherein:
VL is an immunoglobulin light chain variable domain;
VH is an immunoglobulin heavy chain variable domain;
scFv is a single-chain variable fragment;
CL is an immunoglobulin light chain constant domain;
CH1 is an immunoglobulin heavy chain constant domain 1;
CH2 is an immunoglobulin heavy chain constant domain 2;
hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domain;
MM1 is a first masking peptide;
MM2 is a second masking peptide;
CM1 is a first cleavable peptide; and
CM2 is a second cleavable peptide;
wherein VL and VH associate to form a first Fv that specifically binds to a target antigen, and the scFv specifically binds to CD3 (pages 70-71, ¶ [00185]).
Regarding instant claims 16, 18, and 41, Du teaches a multispecific antibody, comprising:
a first polypeptide comprising a structure represented by the formula:
VH-CH1-hinge-CH2-first CH3;
a second polypeptide comprising a structure represented by the formula:
MM1-CM1-scFv-hinge-CH2-second CH3; and
a third polypeptide comprising a structure represented by the formula:
MM2-CM2-VL-CL;
wherein:
VL is an immunoglobulin light chain variable domain;
VH is an immunoglobulin heavy chain variable domain;
scFv is a single-chain variable fragment;
CL is an immunoglobulin light chain constant domain;
CH1 is an immunoglobulin heavy chain constant domain 1;
CH2 is an immunoglobulin heavy chain constant domain 2;
hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains;
MM1 is a first masking peptide;
MM2 is a second masking peptide;
CM1 is a first cleavable peptide; and
CM2 is a second cleavable peptide;
wherein the scFv specifically binds to CD3, and the VL and VH associate to form an Fv that specifically binds to a tumor antigen (e.g. HER2) (pages 84-85, ¶ [00210]-[00212]).
Regarding instant claim 19, Du discloses that the target binding moieties target human target antigens, e.g. CD3 (page 59, ¶ [00169]).
Regarding instant claims 42-43, Du teaches that the multispecific antibody of claim 41 comprises a VL comprising the amino acid sequence SEQ ID NO:76, wherein SEQ ID NO:76 is identical to instant SEQ ID NO:76 comprising CDRL1-L3 comprising the amino acid sequences instant SEQ ID NOs:72-74, respectively, and a VH comprising the amino acid sequence SEQ ID NO:75, wherein SEQ ID NO:75 is identical to instant SEQ ID NO:75 comprising CDRH1-H3 comprising the amino acid sequences instant SEQ ID NOs:423, 424, and 71, respectively (pages 83-84, ¶ [00210]-[00212]).
Regarding instant claims 44-46, Du teaches that the multispecific antibody of claim 42 comprises an MM2 comprising the amino acid sequence SEQ ID NO:36, which comprises instant SEQ ID NO:419, wherein MM2 inhibits the binding of the Fv to the tumor antigen (e.g. HER2) when CM2 is not cleaved (pages 83-84, ¶ [00210]-[00212]).
Regarding instant claim 47, Du discloses that the multispecific antibody comprises a protease cleavage moiety comprising the amino acid sequence ENLYFQG (SEQ ID NO:129), which is identical to instant SEQ ID NO:129.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-9, 14-19, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36-40 and 42-47 of copending Application No. 17/759,282 (Luo et al, US20230124669A1; hereinafter ‘282). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 36 of ‘282 teach an activatable antibody comprising a first polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM), a cleavable moiety (CM), and a target binding moiety (TBM), wherein the MM comprises the amino acid sequence of SEQ ID NO:35 (which is identical to instant SEQ ID NO:35); wherein the MM inhibits binding of the activatable antibody to human CD3 when the CM is not cleaved; wherein the CM comprises at least a first cleavage site; and wherein the TBM comprises from the N-terminus to the C-terminus, a VL and a VH, and wherein the activatable antibody binds to human CD3 via the VH and VL when the CM is cleaved (see instant claims 1, 8, and 19). Claim 39 of ‘282 teaches that the activatable antibody that binds to the TBM, e.g. CD3, comprises a VH comprising CDRH1-H3 comprising amino acid sequences SEQ ID NOs:61-63, respectively, and a VL comprising CDRL1-L3 comprising amino acid sequences SEQ ID NOs:64-66, respectively (see instant claim 1). Claim 37 of ‘282 teaches an activatable antibody comprising: a first polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM), a cleavable moiety (CM), and a target binding moiety (TBM), wherein the MM comprises the amino acid sequence of SEQ ID NO:36 wherein SEQ ID NO:36 comprises instant SEQ ID NO:419 and a linker peptide sequence, wherein (i) the MM inhibits binding of the activatable antibody to human HER2 when the CM is not cleaved (see instant claims 41); (ii) the CM comprises at least a first cleavage site (instant claim 16); (iii) the TBM comprises a VH and the activatable antibody further comprises a second polypeptide comprising a VL (see instant claims 9, 14, and 18); and (iv) the activatable antibody binds to human HER2 via the VH and VL when the CM is cleaved (see instant claims 14 and 16). Claim 40 of ‘282 teaches that the activatable antibody that binds to the TBM, e.g. HER2, comprises a VH comprising CDRH1-H3 comprising amino acid sequences SEQ ID NOs:69-71, respectively, and a VL comprising CDRL1-L3 comprising amino acid sequences SEQ ID NOs:72-74, respectively (see instant claim 42). Claim 38 of ‘282 teaches an activatable antibody of claims 36 or 37 comprising a first polypeptide, a second polypeptide and a third polypeptide, wherein:
the first polypeptide comprises a structure represented by the formula:
VH-CH1-hinge-CH2-first CH3 (Va);
the second polypeptide comprises a structure represented by the formula:
MM1-CM1-scFv-hinge-CH2-second CH3 (VIa); and
the third polypeptide comprises a structure represented by the formula:
MM2-CM2-VL-CL (IVb);
wherein:
VL is an immunoglobulin light chain variable domain;
VH is an immunoglobulin heavy chain variable domain;
scFv is a single-chain variable fragment;
CL is an immunoglobulin light chain constant domain;
CH1 is an immunoglobulin heavy chain constant domain 1;
CH2 is an immunoglobulin heavy chain constant domain 2;
hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains;
MM1 is a first masking peptide;
MM2 is a second masking peptide;
CM1 is a first cleavable peptide; and
CM2 is a second cleavable peptide;
wherein VL and VH associate to form a first Fv that specifically binds to a first target (see instant claim 15); wherein the scFv specifically binds to a second target (see instant claim 8-9 and 18); and wherein MM is MM1 or MM2 (see instant claims 1, 16-18 and 41).
Claims 42-44 of ‘282 teach a polynucleotide encoding the multispecific antibody, a vector comprising the polynucleotide encoding the multispecific antibody, and a host cell comprising the vector that comprises the polynucleotide encoding the multispecific antibody. Claim 45 of ‘282 teach a method of producing the multispecific protein from the host cell culture. The polynucleotide encoding the multispecific antibody is anticipated over the instantly claimed multispecific antibody, because the copending claims and specification discloses that the polynucleotide is to be used to generate the heterodimeric protein, e.g. multispecific antibody (page 29, ¶ [0050]).
Claims 46-47 of ‘282 teach a method for treating a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises the activatable antibody and a pharmaceutically acceptable carrier. The method of treating as claimed in claim 47 of ‘282 is comprised of administering an activatable antibody as discussed in claim 38 above, which is the same as the instant claimed multispecific antibody recited in instant claim 1. A claimed product is obvious over a patented method comprising the product. Therefore, although the claims at issue are not identical, the instant claims are not patentably distinct from the issue claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
Claims 26-27, 30, 32, 36-37, 48-49, 135-140, and 146-148 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Friday 7-2.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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