Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s amendments and remarks, filed 07/22/2026, are acknowledged.
Claims 4-6 and 15 are canceled.
Claims 1-3, 8-9, 11-14, 17-21 are amended.
Claims 22-25 are new.
Claims 1-3, 7-14, and 16-25 are pending.
Claims 7-10, 16-17, and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/29/2025.
As such, claims 1-3, 11-14, 18-22, and 24-25 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 07/22/2026.
Withdrawn Rejections
Applicant’s arguments, see pages 30-33, filed 06/23/2026, with respect to claims 1-6, 11-14, and 18-21 rejected under 35 USC 112(a) as allegedly lacking written description have been fully considered and are persuasive. The issue regarding the specification failing to disclose Applicant’s possession of the large genus of binding proteins that targets any antigen on any target cell and any antigen on any immune effector cell has been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claims 4-6 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(a) is withdrawn.
Applicant’s arguments, see pages 33-37, filed 06/23/2026, with respect to claims 2-6, 11-14, and 18-21 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive in part. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claims 4-6 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(b) is withdrawn.
Applicant’s remarks, see pages 37-39, filed 06/23/2026, with respect to claims 1-4 and 11-14 rejected under 35 USC 103 as allegedly being unpatentable over Moore (US 2014/0288275 A1, published 09/25/2014; previously submitted with the Restriction Requirement mailed on 11/05/2025), Timmer (US 2017/0015753, published 01/19/2017), Weidanz (US 2019/0071502, published 03/07/2019), and Eckelman (US 2023/0124851, with priority to 10/11/2018) have been fully considered and are persuasive. Examiner acknowledges that claim 4 is canceled, thus rendering the rejection moot. Further, Examiner acknowledges that claim 1 was amended to recite several VH and VL CDR sequences which are not disclosed by the art. As such, the rejection under 35 USC 103 is withdrawn.
Applicant’s arguments, see page 40, filed 06/23/2026, with respect to claims 1-6, 11-14, and 18-21 provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1, 25, 27-36, and 38-44 have been fully considered and are persuasive. Further, Examiner acknowledges that claims 4-6 are canceled thus rendering the rejection moot. As such, the provisional double patenting rejection is withdrawn.
Maintained Objections and Rejections
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The disclosure is objected to because of the following informalities:
[0189]: remove “kitscombination of”.
[0204]: “FIG.4shows” should read “FIG.4 shows”.
[0215]: “Bshows” should read “shows”.
[0324]: “BD FACS CANTOII” should read “BD FACSCanto II”.
[0428]: “Meltenyi” should read “Miltenyi”.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see [0242]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Bristol-Myers Squibb, Pfizer, Bio-Rad, GE Healthcare, NanoDrop, TSKgel, Tosoh Bioscience, Agilent Technologies, GenScript, Corning, CrownBio, Alexa Fluor, BD FACSCanto II, FlowJo, GraphPad Prism, Invitrogen, AffiniPure, ATCC, PeproTech, Sigma, Miltenyi, WinNonlin, GemPharmatech, and Bio X Cell, 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.
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.
Applicant’s Arguments
Applicant indicates that the abstract and specification were amended to overcome the objections; therefore, the objections are moot (see pages 28 and 29 of the Remarks filed 06/23/2026).
Response to Arguments
Applicant's amendments filed 06/23/2026 have not been entered as being non-responsive . As such, the abstract and specification objections are maintained as no amendment has been filed 07/22/2026.
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.
18/013,530
Claims 1-3, 11-14, 18-22, and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-9, 14-17, 19, and 21-25 of copending Application No. 18/013,530 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘530 application is drawn to a binding protein comprising at least two protein functional regions, wherein the binding protein comprises a protein functional region A and a protein functional region B; the protein functional region A and the protein functional region B target different antigens or different epitopes on the same antigen; wherein the protein functional region A is of a Fab structure; the protein functional region B is of a VH structure, and the binding protein further comprises an Fc homodimer; the number of the protein functional region A is two, and the number of the protein functional region B is two; the binding protein is of a left-right symmetric structure; the binding protein comprises a protein functional region A, a protein functional region B and an Fc homodimer sequentially from the N-terminus to the C-terminus, wherein the protein functional region A is linked to the protein functional region B via a first linker peptide (L1), and the protein functional region B is linked to the Fc via a second linker peptide (L2) (see claim 1).
Specifically, the ‘530 application is drawn to the binding protein according to claim 1, wherein the binding protein has four polypeptide chains, including two identical short chains and two identical long chains, wherein (1) the short chain comprises VH_A-CH1 sequentially from the N-terminus to the C-terminus, and the long chain comprises VL_A-CL-Li-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; or (2) the short chain comprises VL_A-CL sequentially from the N-terminus to the C-terminus, and the long chain comprises VH_A- CH1-Li-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; wherein the VL_A and the VH_A are VL and VH of the protein functional region A, respectively, and the VHB is VH of the protein functional region B; the CL is a domain of a light chain constant region; the CH1, CH2 and CH3 are a first domain, a second domain and a third domain of a heavy chain constant region, respectively; and the L1 or L2 is a linker peptide; preferably, the L1 and L2 are independently, e.g., "-" or GS or have amino acid sequences as shown in SEQ ID NOs: 161-182, respectively (see claim 2).
The ‘530 application is drawn to the binding protein according to claim 1, wherein the antigen is selected from one or more of PD-L1, HER2, B7H4, CTLA4, OX40, 4-1 BB and BCMA; preferably, the protein functional region A is Fab derived from a PD-L1 antibody or an antigen-binding fragment thereof, an HER2 antibody or an antigen-binding fragment thereof, a B7H4 antibody or an antigen-binding fragment thereof, or a BCMA antibody or an antigen- binding fragment thereof, and, the protein functional region B is VH derived from a CTLA4 antibody or an antigen-binding fragment thereof, a 4-1 BB antibody or an antigen-binding fragment thereof, an OX40 antibody or an antigen-binding fragment thereof, or a BCMA antibody or an antigen-binding fragment thereof (see claims 3-8 and 22). For example, instant CDR sequences SEQ ID Nos: 20, 53, and 86 are within SEQ ID NO: 113 of the ‘530 application; instant CDR sequences SEQ ID Nos: 110, 118, and 140 are within SEQ ID NO: 121 of the ‘530 application; and, instant CDR sequences SEQ ID Nos: 18, 50, and 54 are within SEQ ID NO: 111.
The ’530 application is drawn to a pharmaceutical composition comprising the binding protein according to claim 1, and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises an additional anti-tumor antibody as an active ingredient (see claim 14).
The ‘530 application is drawn a kit, combination of kits, and an administration device comprising the binding protein according to claim 1 (see claims 15-17).
The difference between the instant application and the ‘530 application is that the ‘530 application is drawn to a method of using. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘530 application anticipates the present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18/002,499
Claims 1-3, 11-14, 18-22, and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-32, 34-38, 40, and 42-49 of copending Application No. 18/002,499 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘499 application is drawn to a bispecific antibody comprising a B7-H4-targeting antigen- binding domain and a 4-1BB-targeting antigen-binding domain, wherein the B7-H4-targeting antigen-binding domain comprises a heavy chain variable region (VH) comprising a HCDR1, a HCDR2, and a HCDR3 and a light chain variable region (VL) comprising a LCDR1, a LCDR2, and a LCDR3, wherein the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3 are selected from the group consisting of the following (1)-(3): (1) the HCDR1 comprising the sequence of SEQ ID NO: 16, the HCDR2 comprising the sequence of SEQ ID NO: 60, the HCDR3 comprising the sequence of SEQ ID NO: 84, the LCDR1 comprising the sequence of SEQ ID NO: 112, the LCDR2 comprising the sequence of SEQ ID NO: 118 and the LCDR3 comprising the sequence of SEQ ID NO: 133; (2) the HCDR1 comprising the sequence of SEQ ID NO: 16, the HCDR2 comprising the sequence of SEQ ID NO: 46, the HCDR3 comprising the sequence of SEQ ID NO: 84, the LCDR1 comprising the sequence of SEQ ID NO: 112, the LCDR2 comprising the sequence of SEQ ID NO: 118 and the LCDR3 comprising the a sequence of SEQ ID NO: 131; and (3) the HCDR1 comprising the sequence of SEQ ID NO: 23, the HCDR2 comprising the sequence of SEQ ID NO: 59, the HCDR3 comprising the sequence of SEQ ID NO: 98, the LCDR1 comprising the sequence of SEQ ID NO: 113, the LCDR2 comprising the sequence of SEQ ID NO: 118 and the LCDR3 comprising the sequence of SEQ ID NO: 132 (see claims 26-28).
The ’499 application is drawn to the bispecific antibody according to claim 26, wherein: the 4-1BB-targeting antigen-binding domain comprises a heavy chain variable region (VH) comprising a HCDR1, a HCDR2, and a HCDR3 selected from the group consisting of the following (1)-(16): (1) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18, 61, and 95, respectively; (2) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 17,47, and 85, respectively; (3) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18,48, and 86, respectively; (4) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18, 49, and 86, respectively; (5) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 19, 49, and 94, respectively; (6) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18, 49, and 87, respectively; (7) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 19, 50, and 88, respectively; (8) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 20, 51, and 89, respectively; (9) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18, 52, and 90, respectively; (10) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18, 49, and 90, respectively; (11) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 21, 53, and 91, respectively; (12) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 21, 54, and 92, respectively; (13) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 19, 55, and 93, respectively; (14) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 22, 56, and 86, respectively; (15) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 18, 57, and 95, respectively; and (16) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID Nos: 19, 58 and 96, respectively; or wherein the 4-1BB-targeting antigen-binding domain comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2 and HCDR3, which comprise the sequences of SEQ ID Nos: 14, 43 and 81, respectively, and a light chain variable region (VL) comprising LCDR1, LCDR2 and LCDR3, which comprise the sequences of SEQ ID Nos: 109, 118, and 128, respectively (see claims 30-32).
Specifically, instant CDR sequences SEQ ID Nos: 20, 53, and 86 are within SEQ ID NO: 160 of the ‘499 application; instant CDR sequences SEQ ID Nos: 110, 118, and 140 are within SEQ ID NO: 168 of the ‘499 application; and, instant CDR sequences SEQ ID Nos: 18, 50, and 54 are within SEQ ID NO: 144.
The ‘499 application is drawn to the bispecific antibody according to claim 35, wherein: (1) the B7-H4-targeting antigen domain is in the form of IgG and the 4-1BB-targeting antigen-binding domain is in the form of single VH; (2) the B7-H4-targeting antigen domain is in the form of IgG and the 4-1BB-targeting antigen-binding domain is in the form of ScFv; (3) the B7-H4-targeting antigen domain is in the form of IgG and the 4-1BB-targeting antigen-binding domain is in the form of a tandem of 2 or 3 VHs; (4) the B7-H4-targeting antigen domain is in the form of Fab and the 4-1BB-targeting antigen-binding domain is in the form of HCAb or in the form of HCAb-VH; or (5) the B7-H4-targeting antigen domain is in the form of Fab and the 4-1BB-targeting antigen-binding domain is in the form of single VH, or a tandem of 2 or 3 VHs (see claim 36).
The ‘499 application is drawn to the bispecific antibody according to claim 35, wherein: (1) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1-hinge-CH2-CH3-linker-(VH4-1BB)n, wherein n is 1, 2, or 3; (2) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1-hinge-CH2-CH3-linker-VH4-1BB-linker-VL4-1BB; (3) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL-linker-VH4-1BB-linker-CH2-CH3; (4) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL-linker-VH4-1BB-linker-CH2-CH3-VH4-1BB; or (5) the bispecific antibody comprises a polypeptide chain 1, which Is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL, a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1-hinge-CH2-CH3, and a polypeptide chain 3, which is represented by the formula, from N-terminus to C-terminus, VH4-1BB-linker-CH2-CH3 or (VH4-1BB)n-linker-CH2-CH3, wherein n is 2 or 3 (see claim 37).
The ’499 application Is drawn to a pharmaceutical composition comprising the bispecific antibody according to claim 26 and a pharmaceutically acceptable excipient (see claim 42).
The difference between the instant application and the ‘499 application is that the ‘499 application is drawn to a method of using. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘499 application anticipates the present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant respectfully traverses the double patenting rejections (see pages 39 and 40 of the Remarks filed 06/23/2026).
On a structural basis, claim 1 of ‘530 claims a binding protein comprising at least two protein functional regions, which explicitly limits protein functional region A to a Fab structure and protein functional region B to a VH structure. In contrast, under the limitations recited in the present claims, the first protein functional region (corresponding to protein functional region A of ‘530) of the binding protein is a Fab structure, while the second protein functional region (corresponding to protein functional region B of ‘530) may be either a Fab structure or a VH structure. Accordingly, the claimed subject matter is patentably distinct from the ‘530 application. This disparity in structural limitations demonstrates that the claimed subject matter recited in the respective claims of the two applications are not structurally equivalent. Their scopes of coverage contain material distinguishing features, such that no situation of statutory double patenting arises.
Applicant submits that ‘499 has not yet issued, and the scope of its claims remains subject to final revision and unresolved. With respect to any potential double patenting conflict between the present application and the ‘499, Applicant respectfully requests the Examiner to defer evaluation of this issue until the claims of the ‘499 Application are finalized… Collectively, none of the three co-pending applications referenced above have issued to date, and none have finalized, fixed claim scopes. As such, there is no stable, complete basis for a definitive comparison to determine whether any statutory double patenting exists. For these reasons, Applicant respectfully requests the Examiner to withhold any ruling on the alleged double patenting issue raised against the present application. Once the full claim sets of all co-pending applications are fully finalized, Applicant will submit a comprehensive unified response addressing all double patenting-related issues at that time.
Response to Arguments
Applicant's arguments filed 06/23/2026 have been fully considered but they are not persuasive.
As stated in Applicant’s response, the present claims recite the first protein functional region (corresponding to protein functional region A of ‘530) of the binding protein is a Fab structure, while the second protein functional region (corresponding to protein functional region B of ‘530) may be either a Fab structure or a VH structure. As such, the ‘530 application claims a species of the present invention. Thus, the present claims and ‘530 claims are not structurally different.
Applicant is reminded that a request for a rejection to be held in abeyance does not “distinctly and specifically points out the supposed errors in the examiner’s action” as required under 37 CFR 1.111. See MPEP 714.02.
Further, Applicant is advised that a rejection under double patenting precludes the identification of allowable subject matter. Simply because the co-pending applications do not have finalized, fixed claim scopes does not negate the double patenting rejections. Applicant has not filed a terminal disclaimer, and the claims remain rejected for reasons set forth above.
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As such, the double patenting rejections are maintained.
New Objections and Rejections Necessitated by Amendment
Claim Objections
Claims 1, 2, 3, 21, and 24 are objected to because of the following informalities:
Claim 1: “B7H4”, “CLDN18.2”, “HER2”, “EPCAM”, “PSMA”, and “PD-L1” are acronyms and/or abbreviations which should be spelled out on first occurrence.
Claim 2 was amended to end with a semi-colon (;) followed by a period (.).
Claim 3: “being 0 in length” should be amended to recite “wherein there is no linker” or similar language.
Claim 21: add a comma (,) after “claim 20”.
Claim 24: add a conjunction (e.g., “and”, “or”, etc.) between characteristic (2) and (3).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 24 and 25 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 24 recites the “number of the second protein functional region is 1 or more than one” and claim 25 recites “the number of the second protein functional region is 1, 2 or 3”, however claim 2 indicates that the monomeric structure comprises two second protein functional regions. As such, claims 24 and 25 broaden the scope of claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 24 and 25 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 24 recites “the binding protein further comprises a third protein functional region”. It is unclear if the third protein functional region targets the antigens or comprises the sequences recited in claim 1, or if the third protein functional region is structurally different. As such, claim 24 and dependent claim 25 are rejected.
Claim Rejections - 35 USC § 112(a) Written Description
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 22 and 24-25 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 22 is drawn to the pharmaceutical composition according to claim 11, wherein the pharmaceutical composition further comprises an additional anti-tumor antibody as an active ingredient.
Claim 24 is drawn to the binding protein according to claim 2, wherein the binding protein possesses any one or more of the following characteristics (1) to (3): (1) the Fc is positioned between the first protein functional region and the second protein functional region; or, the Fc is positioned at the C-terminus of the second protein functional region; or, the Fc is positioned between the two second protein functional regions; (2) in each monomer, the number of the first protein functional region is 1, the number of the Fc is 1, and the number of the second protein functional region is 1 or more than one; (3) the binding protein further comprises a third protein functional region, wherein the third protein functional region is positioned at the C- or N-terminus of the binding protein, or at the C- or N-terminus of the Fc structure of the binding protein.
Claim 25 is drawn to the binding protein according to claim 24, wherein in the characteristic (2), the number of the second protein functional region is 1, 2 or 3.
The specification discloses multispecific immune cell engager binding proteins based on heavy-chain antibody (see Example 1). Specifically, Table 1 lists the molecular structures of the multispecific binding proteins and Examples 1.1-1.2 explain these structures in detail (see pages 49-54). Example 3 discloses the construction of bispecific immune cell engager binding proteins targeting costimulatory molecules. Several bispecific immune cell engager binding protein molecules were listed wherein one end can bind to a costimulatory molecule on the surface of an immune cell (e.g., 4-1BB, OX40, etc.), and the other end of which can bind to a specific antigen molecule on the surface of a tumor cell (e.g., HER2, PSMA, EPCAM, CLDN18.2, B7H4, etc.) or a co-inhibitory molecule on the surface of an immune cell (e.g., PD-L1, etc.) (see [0316]). Specifically, the specification discloses of bispecific binding protein molecules targeting both 4-1BB and tumor antigens (or co-inhibitory molecules) that were constructed using an antigen-binding fragment VH of an HCAb antibody binding to 4-1BB (PR001758, PR001760, PR001836 or PR004469), and an antigen-binding fragment Fab of an IgG antibody binding to a tumor antigen HER2 (trastuzumab), or an antigen-binding fragment Fab of an IgG antibody binding to B7H4 (PR002408 or PR002410), or an antigen-binding fragment Fab of an IgG antibody binding to EPCAM (PR001081), or an antigen-binding fragment Fab of an IgG antibody binding to PSMA (PR001331), or an antigen-binding fragment Fab or an IgG antibody binding to CLDN18.2 (PR002726) or an antigen-binding fragment Fab of an IgG antibody binding to PD-L1 (PR000265) (see [0317] and Tables 3-11). Additionally, the specification discloses of bispecific binding protein molecules targeting both OX40 and a tumor antigen (or a co-inhibitory molecule) that were constructed using an antigen-binding fragment VH of an HCAb antibody binding to OX40 (PR002067), and an antigen-binding fragment Fab of an IgG antibody binding to tumor antigen EPCAM (PR001081), or an antigen-binding fragment Fab of an IgG antibody binding to PSMA (PR001331), or an antigen-binding fragment Fab of an IgG antibody binding to CLDN18.2 (PR002726), or an antigen-binding fragment Fab of an IgG antibody binding to B7H4 (PR002408) or an antigen-binding fragment Fab of an IgG antibody binding to PD-L1 (PR000265) (see [0318]; Tables 3-4 and 6).
Example 4 discloses the binding activity of the antibodies targeting 4-1BB and the bispecific immune cell engager binding proteins to 4-1BB (see [0322]-[0349]). Example 5 discloses the binding activity of the antibodies targeting OX40 and the bispecific immune cell engager binding proteins to OX40 (see [0350]-[0359]). Example 6 discloses the binding activity of the bispecific immune cell engager binding proteins to tumor antigens (see [0360]-[0394]). Example 7 discloses the T cell activation activity of the bispecific immune cell engager binding protein targeting a costimulatory molecule on the surface of a T cell by binding to the costimulatory molecule in the presence of the target cell (see [0395]-[0424]). Example 8 discloses the T cell activation effects of the PD-L1x4-1BB bispecific antibody molecules by the mixed lymphocyte reaction (MLR) (see [0425]-[0430]). Example 9 discloses the pharmacokinetic properties of the bispecific immune cell engager binding protein molecules with different structures in mice (see [0431]-[0435] and Table 13). Example 10 discloses the anti-tumor effect of B7H4x4-1BB bispecific antibody molecule PR003334 in a BALB/c-hCD137/CT26-hB7H4 mouse tumor model (see [0436]-[0440]). Example 11 discloses the physicochemical properties such as molecular stability of the B7H4x4-1BB bispecific antibody molecules (PR003334, PR003335, and PR003338) (see [0441]-[0442] and Table 14).
However, the specification fails to disclose that Applicant was in possession of the large genus of binding proteins as claimed. Specifically, the specification fails to disclose that Applicant was in possession of the large genus of pharmaceutical compositions the claimed binding protein and any other anti-tumor antibody. Lastly, the claims fail to fully describe the claimed third protein functional region.
Although the specification discloses of different species of bispecific antibody molecules (see Tables 3-12), the claims are not limited to these molecules, and are inclusive of any additional anti-tumor antibody and third protein functional regions. This indicates that there are hundreds, if not thousands, of possible binding proteins encompassed by the claims. Thus, the claims encompass a vast genus of binding proteins that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of binding proteins because, inter alia, the specification does not disclose a correlation between the necessary structure of the proteins and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the terms antibody, Fab, and VH do impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/binding proteins and variants thereof claimed only by a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of binding proteins. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the first and second protein functional regions to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of binding proteins, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous binding proteins had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of binding proteins claimed only by a partial structure and functional characteristic(s). Thus the binding proteins described by the instant claims encompasses an overly broad genus, the structure of the first and second protein functional regions, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of binding proteins by the functions of the first and second protein functional regions. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed binding proteins, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed additional anti-tumor antibody and third protein functional regions that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416; previously submitted with the Office Action mailed 03/24/2026) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted with the Office Action mailed 03/24/2026), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible binding proteins and anti-tumor antibodies that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of binding proteins or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted with the Office Action mailed 03/24/2026), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted with the Office Action mailed 03/24/2026) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted with the Office Action mailed 03/24/2026) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted with the Office Action mailed 03/24/2026) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted with the Office Action mailed 03/24/2026) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted with the Office Action mailed 03/24/2026), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges, it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted with the Office Action mailed 03/24/2026). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed binding proteins and anti-tumor antibodies could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all binding proteins.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed binding proteins and anti-tumor antibodies. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of binding proteins anti-tumor antibodies as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Conclusion
No claims are 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 DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
