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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10 October 2025 has been entered.
Status of the Claims
Claims 1-10 were originally filed 5 December 2024. Claims 1, 2, and 4-11 and are currently under consideration.
Withdrawn Claim Objections
In view of Applicant’s amendment to claim 1 to remove the duplication of “is” the claim objection over claim 1 is hereby withdrawn.
Maintained Claim Rejections
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, and 4-11 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 8,461,308 B2 (referred to herein as Cardarelli) published 11 June 2013, US Patent Publication 2023/0099149 (referred to herein as Kraiem) published 30 March 2023, and WO2023/131219 A1 (referred to herein as Jackson) published 13 July 2023.
Cardarelli discloses a PSMA antigen binding domain (i.e., 2A10) set forth in Seq ID Nos: 6 (VH) and 15 (VL) which are 100% identical to instant Seq ID Nos: 1 and 2, respectively (see Cardarelli col. 3 lines 18-21, figures 8 and 11). In addition, Cardarelli discloses the PSMA antigen binding domains is conjugated to a therapeutic moiety such as a cytotoxin, a drug, or radiotoxin (see Cardarelli col. 38 lines 20-27, claim 2 and 3). The cytotoxin or drug can be conjugated to the PSMA antibody or fragment thereof by a cathepsins-cleavable moiety (see col. 38 lines 56-61). The PSMA antigen binding domain is administered in methods of inhibiting PSMA+ cell growth, such as tumors, and preferably administered as a treatment for prostate carcinoma tumor cells (see Cardarelli abstract, col. 6 lines 1-9). Cardarelli teaches an identical antigen binding domain conjugated to a cytotoxin or drug via a cathepsin linker.
Kraiem teaches a Nectin-4 antigen binding domains conjugated to a camptothecin analogue or derivative, such as exatecan or SN-38 for use in the treatment of cancers (see Kraiem abstract, pg. 2 para [0010], [0020]).The highly potent linkers can be conjugated to an antibody that binds a tumor antigen (see Kraiem pg. 2 para [0011]). The antibody drug conjugate has the formula Ab-X—Z, wherein Ab is an antigen binding protein (e.g., antibody), Z is a camptothecin analogue such as exatecan or SN-38, X is a linker molecule connecting Ab and Z (see Kraiem pg. 4 para [0039, 0041, 0043, and 0042]). In particular, X comprises a cleavable moiety under intracellular conditions, a self-eliminating or non-self-eliminating spacer system (Yʹ) between the cleavable moiety and Z, and a spacer (Y) positioned between the Ab and the cleavable moiety (see Kraiem pg. 4 para [0042]). The resulting formula is:
Ab-Y-cleavable moiety-Yʹ—Z.
Kraiem also specifies in one embodiment, the antibody drug conjugate has the following components in the following order:
Nectin-4 antigen binding domain,
a protected reactive group capable of reacting with a complementary reactive group on an antigen binding protein,
a spacer moiety (Y),
a di-peptide-cleavable moiety (e.g., valine-citrulline, valine alanine, or phenylalanine-lysine),
a self-eliminating spacer system (Yʹ), and lastly
a camptothecin analogue such as exatecan or SN-38 (see Kraiem pgs. 4-5 para [0044]).
Kraiem teaches a linker can function as a spacer or stretcher to distance an antibody from Z in order to avoid interference with the antigen binding function. In addition, Y can be a molecule that forms a bond with an amino acid of the antibody (e.g., sulfur atom) and which spacer or stretcher (Y) links the antibody to a cleavable amino acid unit (see Kraiem pg. 21 para [0228]). Kraiem also teaches the spacer chain Y can generally be any single molecular weight homopolymer with 1-6 units of the monomer (see Kraiem pg. 22 para [0232]). Kraiem also teaches wherein Y can comprise a reactive group such as maleimide (see Kraiem). Specifically, exemplary linkers comprising maleimide as the reactive group are represented in compounds 9a-9d wherein compound 9b is Mal-Glu-(Val-Ala-PAB-exatecan)-PEG8 wherein Y is the Mal-Glu (see Kraiem pgs. 31-32 para [0274], pg. 30, compound 9b).
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362
940
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(see Kraiem pg. 32, top)
The maleimide group is conjugated to the antigen binding domain via cysteine residues (see Kraiem pg. 30 para [0300]). In addition, the Yʹ group is p-aminobenzylcarbamate in particular embodiments (see Kraiem para [0240] spanning pgs. 22-23). The antibody drug ratio is an integer from 4-8 (see Kraiem para [0062]). Kraiem also teaches each of the exatecan linkers when conjugated to the Nectin-4 antibody permitted efficient killing of the Nectin-4 low expressing SUM190 cells (see Kraiem pg. 48 para [0412], figure 7, see structures on pgs. 47 and 48).
Likewise Jackson discloses an antibody drug conjugate with the following formula (see Jackson pg. 2 para [0006]):
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158
546
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,
wherein the following:
Ab is the antigen binding domain,
X1 is –(CH2)n- wherein n is 1-5,
L is a di- or tri- peptide linking moiety,
SP is either absent,
a di- or tri-peptide linking moiety having, or a linking moiety capable of self-immolation, and
T is a compound capable of inhibiting topoisomerase (see Jackson pg. 2 para [0006]).
In particular embodiments maleimide connects the antibody to the linker-drug and exatecan is the topoisomerase inhibitor (see Jackson pg. 3 para [0008], pg. 18 para [0078] last 4 lines). Jackson discloses an exemplary compound comprising the following structure (see Jackson pg. 36 Table 1, structure 92):
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149
881
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(see Jackson pg.36, structure 92).
This differs from the structure taught by Kraiem in the conjugation moiety and the number of PEG (i.e., 2 versus 8) residues. Jackson also discloses an exemplary compound comprising the following structure (see Jackson pg. 36 Table 1, structure 95): comprising a maleimide group-5 glycines-DxD (i.e., exatecan derivative) (see below).
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167
755
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(see Jackson pg. 36, structure 95).
The ordinary artisan would recognize the 5 glycine residues function as a “spacer” between the antibody and the drug.
Therefore, a person of ordinary skill in the art would conjugate the cytotoxin or drug to the PSMA antigen binding domain taught by Cardarelli using the formula, Ab-Y-cleavable moiety-Yʹ—Z, wherein Y is maleimide and PEG, the cleavable moiety is valine-alanine, the Yʹ is PAB, and Z is exatecan (i.e., compound 7), with a DAR of 4-8 (i.e., 4, 5, 6, 7, or 8) as taught by Kraiem (e.g., compound 9b) given Kraiem teaches these are potent linker drug conjugates and exemplary linkers were efficient at killing tumor cells with low expressing target tumor antigen. A person of ordinary skill in the art would also substitute the polyPEG spacer as taught by both Kraiem and Jackson with the polyglycine spacer taught by Jackson given Kraiem discloses the spacer given i. Kraiem teaches the Y spacer comprises a homopolymer with 1-6 units and the Y spacer functions to optimize the distance of the antibody from the drug moiety and ii. Jackson points to an exemplified structure wherein 5 glycines function as a spacer between the antibody and drug. Doing so would involve choosing among a finite number of predictable options (i.e., 1-6 glycines) which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385). In further support Jackson also discloses success using antibody drug conjugates with either ICAM-1 and Eph2A antigen binding domains and maleimide, a 5 glycine repeat, and an exatecan derivative. This is pertinent to instant claims 1-3 and 8.
Applicant's arguments filed 10 October 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues the following:
The Examiner has not provided a proper reason to combine the cited references and thus has not established a prima facie case of obviousness (see Remarks para spanning pgs. 7-8),
The ordinary artisan would not recognize DxD and exatecan as interchangeable and points to Nakada (see Remarks pg. 8, 1st full para),
The Examiner has used improper hindsight to identify the glycine spacer in Kraiem (see Remarks pg. 8 last para), and
Unexpected results (see Remarks pg. 1, starting in the middle).
Applicant’s arguments the Examiner has not established a prima facie case of obviousness is not found convincing because it amounts to nothing more than attorney argument, unsupported by objective evidence as to its veracity. As stated at MPEP 2145, "The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).”
Regarding Applicant’s arguments the ordinary artisan would not consider DxD and exatecan as interchangeable are not persuasive. As set forth previously, both structures have the same function and DxD was derived from exatecan (i.e., topoisomerase inhibitors) (see Shitara as cited on the PTO-892 mailed 07/10/2025, in particular pg. 781, 1st col. last para, 2nd col. last para). Nakada is directed to aggregation and how it relates to intervening moieties between the antibody and the cleavable linker. There is nothing in Nakada to suggest exatecan derivatives no longer functioned as topoisomerase inhibitors or have dramatically different structures.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Briefly, Cardarelli was relied upon for teaching a PSMA with the instantly claimed antigen binding domain conjugated to a drug or toxin. Kraiem was relied up for teaching an effective linker drug combination comprising maleimide-PEG8-Val-Ala-PABC-extecan wherein the PEG8 residues function as a spacer to distance the linker drug from the antigen binding domain to prevent interference in the antigen binding function. Furthermore, Kraiem also discloses the spacer is a homopolymer with 1-6 units. Applicant suggests it would not have been obvious to substitute the PEG8 residues taught by Kraiem with glycine. While Kraiem exemplifies PEG repeats as a spacer the disclosure does not limit the spacer to PEG more broadly teaching homopolymers. Jackson teaches a polyglycine repeat functions as a spacer as well. First, Jackson discloses similar linker drug combination differing in only the maleimide and number of PEG residues as taught by Kraiem. However, Jackson teaches a similar exemplified structure wherein an antigen binding domain is linked to an exatecan derivative (i.e., equivalent) via a 5 glycine spacer. Therefore, the ordinary artisan would recognize that both polyPEG and polyglycine are interchangeable as spacers. It is also noted that Jackson and Kraiem use the disclosed exatecan linker combinations with different antigen binding domains providing a reasonable expectation of success that the claimed linker drug combinations would work with a PSMA antigen binding domain.
Regarding Applicant’s allegedly unexpected results. In arguing unexpected results evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) (see MPEP § 716.02(b)(III)). It is noted the specification does not use the words unexpected or surprising to describe the results. In so far as Applicant is arguing unexpected results arguing the efficacy of the PSMA ADC was unexpected, Applicant has not set forth how the results are unexpected. The control antibody, B12, binds to HIV gp120, therefore would not be expected to show anti-tumor activity any greater than the DL-A (claimed). Cardarelli discloses the 2A10 anti-PSMA antibody is cytotoxic against the same cell line (LnCaP) in vitro (see Cardarelli col. 58 Table 3, figure 16A and B). Collectively, Applicant has demonstrated a species of the claimed structure works not that it works to an unexpected or greater extent. Furthermore, Applicant has demonstrated administering more ADC is more effective than administering less ADC. It is unclear how this would be surprising. It is also noted the functional results are drawn to an ADC comprising a full length heavy chain and light chain, a particular conjugation residue, number of glycines in the spacer, dipeptide linker, PAB and exatecan which is not commensurate in scope with the instant claim. In so far, as Applicant is arguing the number of glycines has unexpected properties relating to aggregation of the ADC this in not persuasive. It is known in the art that polyglycine chains longer than 5 residues are normally insoluble in water (see Bykov and Asher (2010) Raman studies of solution polyglycine conformations. J. Phys. Chem. B. Vol 114, Iss. 19, pgs. 6636-6641, in particular pg. 6636, 1st col. 3rd para). Applicant’s allegedly unexpected results regarding the polyglycine chain and aggregation with 5 glycines is not representative over the breadth of 5-8 glycines and therefore is not commensurate in scope with the instant claims.
Therefore, for the reasons stated above the 35 USC 103 rejection of claims 1, 2 and 4-11 is hereby maintained.
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, 2, and 5-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 8-13 of copending Application No. 18/971848 (referred to herein ‘848 application) in view of Cardarelli.
Applicant's arguments filed 10 October 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues in view of the reasons set forth in the 35 USC 103 rejection the ‘848 patent discloses an anti-Claudin 6 ADC the non-statutory double patenting rejection should be withdrawn (see Remarks pg. 12, section III).
The non-statutory double patenting rejection was made as an obviousness type double patenting rejection relying on Cardarelli for teaching an anti-PSMA ADC with the claimed PSMA bind domain and the ‘848 application with the linker drug combination (see Non-Final mailed 13 March 2025 starting on pg. 15).
Therefore, for the reasons set forth above in the 35 USC 103 rejection and the reasons made of record the non-statutory double patenting rejection is hereby maintained.
Conclusion
No claim allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HILARY ANN PETRASH whose telephone number is (703)756-4630. The examiner can normally be reached Monday-Friday 8:30-4:30 EST.
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/H.A.P./ Examiner, Art Unit 1644
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
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