DETAILED ACTION
This office action is in response to applicant’s filing dated June 29, 2026.
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 .
Status of claims
Claims 1, 2, 9, 11, 13, 15, 17, 28, 29, 31, 70, 71 and 73 - 84 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed June 29, 2026. Acknowledgment is made of Applicant’s cancelation of claims 32-34, 36, 41, 44, 46, 48, 50, 60-64, and 69 and addition of a new claims 75 - 84.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 2, 9, 11, 13, 15, 17, 28, 29, 31, 70, 71, 73, and 74, identified by the Office Action as being drawn to an antibody-drug conjugate (ADC), having the formula A-L and a pharmaceutical composition thereof in the reply filed on June 29, 2026 is acknowledged.
Claims, drawn to nonelected inventions were cancelled by Applicant in the reply filed on June 29, 2026.
Applicant’s election without traverse of the antibody-drug conjugate (ADC), where antibody is Trastuzumab and the linker has a structure:
PNG
media_image1.png
158
518
media_image1.png
Greyscale
, where payloads are exatecan (
PNG
media_image2.png
63
111
media_image2.png
Greyscale
) and glycinated exatecan (
PNG
media_image3.png
79
120
media_image3.png
Greyscale
), as a single elected species in the reply filed on June 29, 2026 is acknowledged. Claims 73, 75, 76, 77 and 83 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 29, 2026. Upon performing the search of prior art Examiner detected non-elected species: antibody Polatuzumab and antibody Enfortumab. Hence, the examination will expand to include claims 76 and 77, drawn to nonelected species: antibody Polatuzumab and antibody Enfortumab.
Claims 1, 2, 9, 11, 13, 15, 17, 28, 29, 31, 70, 71, 74, 76- 82 and 84 are presently under examination as related to the elected species: antibody Trastuzumab and linker of the structure shown above, as well as the expanded species, antibody Polatuzumab and antibody Enfortumab.
Priority
This application is a CON of PCT/EP2024/079076, filed October 15, 2024, which claims the benefits of priority to European Patent Application Nos. 24189861.8,filed July 19, 2024; 24187879.2, filed July 10, 2024; and 23203677.2, filed October 15, 2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/29/2025, 03/24/2026 and 06/30/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on July 15, 2025. These drawings are accepted.
Claim Rejections - 35 USC § 112
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.
Claim 84 is 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 84 recites the limitation "the method according to claim 1" in line 1. There is insufficient antecedent basis for this limitation in the claim. Since claim 1 is drawn to a product, an antibody-drug conjugate of formula A-L, it is unclear what method Applicant is referring to. Therefore, the abovementioned claim 84 will not be further treated on the merits. It is suggested to amend or cancel claim 84 in order to obviate this rejection.
Claim Rejections - 35 USC § 103
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, 9, 11, 13, 15, 17, 28, 29, 31, 70, 71, 74 and 76- 82 are rejected under 35 U.S.C. 103 as being unpatentable over Spycher et al (WO 2022/084560 A1, cited in IDS, filed 10/29/2025, hereinafter Spycher) in view of Hoogenboom et al (WO 2022/058395 A1, cited in IDS, filed 10/29/2025, hereinafter Hoogenboom).
Instant claims are drawn to an antibody-drug conjugate having the formula A-L, wherein A is an antibody or an antibody fragment and wherein L is a linker. Said linker comprising: as a first payload a topoisomerase I inhibitor which is cell-permeable, such as exatecan (
PNG
media_image4.png
107
180
media_image4.png
Greyscale
) ; and as a second payload a topoisomerase I inhibitor which is not cell-permeable such as glycinated exatecan (
PNG
media_image5.png
101
132
media_image5.png
Greyscale
).
The linker comprises the following structure:
[payload 1 ]-X-Z1-(Aa)m-Z2-(Aa)n-(Lys)-(Aa)o-Z3-X-[payload 2] or
[payload 2]-X-Z1-(Aa)m-Z2-(Aa)n-(Lys)-(Aa)o-Z3-X-[payload 1]; wherein:
[payload 1] is said first payload (exatecan);
[payload 2] is said second payload (glycinated exatecan);
(Aa) is any amino acid residue; m, n and o may be integers ranging from 0 to 10;
(Lys) is a lysine residue, a lysine mimetic or a lysine derivative;
Z1-3 is either absent or a spacer comprising an alkyl or a heteroalkyl group; or Z2 is a dicarboxylic acid linking the N-terminal end of (Aa)m to the N-terminal end of (Aa)n or (Lys);
X is either absent or a self-immolative group (such as p-aminobenzyl carbamoyl (PABC)).
Said linker may be a peptide linker, wherein (Aa)n-(Lys)-(Aa)o comprises the sequence motif Arg-Lys (RK), RKAA or His-Lys (in N -> C direction), where the first payload is linked to the N-terminus of the peptide linker and the second payload is linked to the C-terminus of the peptide linker, or the first payload is linked to the C-terminus of the peptide linker and the second payload is linked to the N-terminus of the peptide linker.
The exemplary linker has a structure:
PNG
media_image1.png
158
518
media_image1.png
Greyscale
Instant claims are further drawn to an ADC of structure A-L, wherein antibody (A) is an IgG antibody, such as an IgG1 antibody (Trastuzumab, Polatuzumab or Enfortumab), and the linker is conjugated to the antibody via an isopeptide bond formed between the glutamine residue Q295 (EU numbering) of the CH2 domain of the IgG antibody, wherein IgG antibody is glycosylated at residue N297 (EU numbering). Said ADC may consist of two first payloads and two second payloads (drug-to-antibody ratio of 4 "DAR4"). Instant claims are also drawn to a pharmaceutical composition comprising the ADC, described above and at least one pharmaceutically acceptable ingredient.
Spycher teaches antibody-drug-conjugates (ADC), where the antibody is conjugated to a linker, wherein the linker comprises one or more toxins. Spycher teaches an ADC where antibody is an IgG antibody, such as an IgG1 antibody (Trastuzumab, Polatuzumab or Enfortumab), and the linker is conjugated to the antibody via an isopeptide bond formed between the glutamine residue Q295 (EU numbering) of the CH2 domain of the IgG antibody and the primary amine comprised in the side chain of the lysine residue comprised in the linker, wherein IgG antibody is glycosylated at residue N297 (EU numbering) (pages 85 – 86, and page 12, embodiment 62). Spycher further teaches an antibody-payload conjugate, which may be generated with an antibody to payload ratio of 2 or 4 (DAR2-4), for example where each linker comprises two payloads (two identical or different toxins) and two linkers are conjugated to residue Q295 of the two heavy chains of an IgG antibody (page 130, 4th paragraph).
Spycher teaches antibody-drug-conjugates (ADC), where the linker comprises two or more payloads and has a structure:
(Sp4)-B2-(Sp1)-RK-(Sp2)-B1-(Sp3) or (Sp1)-B1-(Sp2)-RK-(Sp3)-B2-(Sp4), where
B1 and B2 are payloads, the payloads B1 and B2 may be identical or different payloads, where the payload comprises a toxin, such as a camptothecin (e.g. exatecans) (page 80 – 83);
(Sp1), (Sp2), (Sp3) and (Sp4) independently may be absent, or may be any straight, branched and/or cyclic C2-30 alkyl or C2-30 heteroalkyl; or (Sp1), (Sp2), (Sp3) and the RK motif consist exclusively of amino acids (page 30, 2nd paragraph), where (Sp1), (Sp2) and/or (Sp3) comprise at least one positively-charged amino acid, e.g. at least one histidine residue (page 29, 6th paragraph). Payload B may be coupled to the peptide or peptidomimetic via a self-immolative moiety, i.e. having a structure: RKAA-(self-immolative moiety)-B, wherein self-immolative moiety is p-aminobenzyl carbamoyl (PABC) moiety, such as RKAA-PABC-B (e.g. RKAA-PABC-Exa) (page 164, Table 12), where C-terminal alanine residue (A) in RKAA peptide is coupled to the amino group comprised in PABC via an amide bond. The toxin B may be attached to PABC through the formation of a carbamate (page 88, 3rd paragraph). The payload may be coupled to the C-terminal carboxyl group or the N-terminal amino group of an amino acid residue (page 40, 2nd paragraph).
The structure RKAA-PABC-Exa taught by Spycher is equivalent to the fragment of the instant linker (see the circled fragment below):
PNG
media_image6.png
171
526
media_image6.png
Greyscale
, where glycinated exatecan is coupled to the C-terminal alanine residue (A) in RKAA peptide through PABC.
Furthermore, Spycher teaches that the self-immolative moiety PABC is located between the payload and an alanine residue, where the alanine-alanine motif is known to be cleavable by a cathepsin (page 53, 1st and 2nd paragraph). Thus, Spycher teaches the linker fragment where payload is bonded to alanine-alanine motif through PABC moiety, which structural element is equivalent to the fragment of the instant linker (see the circled fragment below):
PNG
media_image7.png
164
521
media_image7.png
Greyscale
, where exatecan is coupled to C-terminal alanine residue (A) of alanine-alanine motif through PABC moiety. Instantly claimed linker further features a succinyl residue (see the circled fragment below), which links N-terminal alanine residue to the N-terminal arginine residue:
PNG
media_image8.png
158
518
media_image8.png
Greyscale
. Spycher also teaches dicarboxylic acid residue (succinyl), incorporated into the linker to connect two N-terminal ends of peptide chains, by formation of amide bonds e.g. (see the circled fragment):
PNG
media_image9.png
384
394
media_image9.png
Greyscale
(page 209, Fig. 30). Incorporating dicarboxylic acid such as succinic acid to connect two N-terminal amines via amide linkage represents a routine modification within the capabilities of a skilled artisan.
Spycher teaches a pharmaceutical composition comprising the antibody drug-conjugate and at least one pharmaceutically acceptable ingredient (page 19, embodiment 102).
Spycher does not teach ADC where the second payload is a topoisomerase I inhibitor which is not cell-permeable such as glycinated exatecan (
PNG
media_image5.png
101
132
media_image5.png
Greyscale
).
However, Hoogenboom teaches ADCs with exatecan payloads, e.g. conjugate of structure (1h):
PNG
media_image10.png
346
832
media_image10.png
Greyscale
, where ADC linker has two exatecan payloads. Although the exemplary structure of ADC does not have modified exatecan, such as not cell-permeable glycinated exatecan, Hoogenboom teaches that cytotoxic payloads that are neutral, such as DX-8951 (
PNG
media_image11.png
194
217
media_image11.png
Greyscale
), will show bystander killing whereas ionic (charged) payloads, such as G-DX-8951
PNG
media_image12.png
227
254
media_image12.png
Greyscale
do not, due to poor cell membrane permeability of aminoacylated exatecan (page 7, lines 6 – 8). Hoogenboom further teaches that ADCs having different degrees of bystander killing were benchmarked against deruxtecan-based ADCs (having bystander effect) and found to have at least the same potency against target-positive cells and enhanced potency against target-negative cells in coculture (bystander killing) (page 8, lines 8 – 12).
Thus, since Spycher teaches ADCs, where all the structural elements (antibody, linker and connection sites) are equivalent or similar to those of instantly claimed ADCs, and since Hoogenboom teaches that exatecan is cell-permeable and demonstrates bystander killing effect, whereas glycinated exatecan is not cell-permeable, and ADCs of different degrees of bystander killing were found to be potent against target-positive cells and target-negative cells (bystander killing), it would have been prima facies obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to combine known structural elements to arrive at ADCs of claimed structure. The one of ordinary skills would be motivated to do so in search of an ADCs with similar or improved desired properties, with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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, 9, 11, 13, 17, 28, 29, 31 and 78 – 82 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 9, 10, 22, 23, 29, 30, 32, 33, 38, 39 and 70 of copending Application No. 18/803,344 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims are directed to an antibody-drug conjugate having the formula A-L, wherein A is an antibody or an antibody fragment and wherein L is a linker. The linker comprises the following structure:
[payload 1 ]-X-Z1-(Aa)m-Z2-(Aa)n-(Lys)-(Aa)o-Z3-X-[payload 2] or [payload 2]-X-Z1-(Aa)m-Z2-(Aa)n-(Lys)-(Aa)o-Z3-X-[payload 1]; wherein:
[payload 1] is said first payload;
[payload 2] is said second payload;
(Aa) is any amino acid residue; m, n and o may be integers ranging from 0 to 10;
(Lys) is a lysine residue, a lysine mimetic or a lysine derivative;
Z1-3 is either absent or a spacer comprising an alkyl or a heteroalkyl group; or Z2 is a dicarboxylic acid linking the N-terminal end of (Aa)m to the N-terminal end of (Aa)n or (Lys);
X is either absent or a self-immolative group.
Said linker can be a peptide linker, wherein (Aa)n-(Lys)-(Aa)o comprises the sequence motif Arg-Lys (RK), RKAA or His-Lys (in N -> C direction), where the first payload is linked to the N-terminus of the peptide linker and the second payload is linked to the C-terminus of the peptide linker, or the first payload is linked to the C-terminus of the peptide linker and the second payload is linked to the N-terminus of the peptide linker.
Instant claims are further drawn to an ADC of structure A-L, wherein antibody (A) is an IgG antibody, and the linker is conjugated to the antibody via an isopeptide bond formed between the glutamine residue Q295 (EU numbering) of the CH2 domain of the IgG antibody, wherein IgG antibody is glycosylated at residue N297 (EU numbering). Said ADC may consist of two first payloads and two second payloads (drug-to-antibody ratio of 4 "DAR4"). Instant claims are also drawn to a pharmaceutical composition comprising the ADC, described above and at least one pharmaceutically acceptable ingredient.
Claims of copending application are directed to an antibody-payload conjugate comprising an antibody conjugated to a peptide linker comprising
a) an amino acid residue comprising a primary amine; and
b) two or more payloads; wherein each of the two or more payloads can be independently attached to: i) an N-terminal end of the peptide linker, ii) a C-terminal end of the peptide linker, or iii) a side chain of an amino acid residue comprised in the peptide linker, wherein the peptide linker is conjugated to the antibody via an isopeptide bond formed between a y-carboxamide group of a glutamine residue Q295 (EU numbering) of the CH2 domain of an IgG antibody and the primary amine comprised in an amino acid residue of the peptide linker, wherein the IgG-antibody is glycosylated at residue N297 (EU numbering) of the CH2 domain.
Said peptide linker comprises the following structure (in N -> C direction): [payload1]-[(Aa)ₙ-(Lys)-(Aa)n-(Arg/His)-(Aa)o]-[payload2]; wherein
[payload 1] and [payload 2] are payloads,
(Aa) may be any amino acid residue; m, n and o may be integers ranging from 0 to 10;
(Arg) may be an arginine residue, an arginine mimetic or an arginine derivative; (His) may be a histidine residue, a histidine mimetic or a histidine derivative,
(Lys) is a lysine residue, a lysine mimetic or a lysine derivative, wherein [payload1] is directly or indirectly attached to an N-terminal end of an (Aa) or (Lys) residue, and wherein
[payload 2] is directly or indirectly attached to a C-terminal end of an (Aa) or (Arg/His) residue.
The peptide linker comprises the structure:
[payload 1]-[peptide 1]-[dicarboxylic acid]-[peptide 2]-[payload 2]; wherein [payload 1] and [payload 2] are payloads,
[peptide 1] is a first peptide moiety,
[peptide 2] is a second peptide moiety, and
[dicarboxylic acid] is a dicarboxylic acid; wherein at least one of [peptide 1] and/or [peptide 2] comprises a free amine. Claims of copending application are further directed to a pharmaceutical composition comprising the antibody-payload conjugate and at least one pharmaceutically acceptable ingredient.
The conflicting claims are not patentably distinct from each other because, as set forth above, instant claims are directed to an ADC of identical or similar structure as ADC of copending claims.
Thus, the compound of the copending clams would anticipate the instantly claimed compounds.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 2, 9, 11, 13, 15, 17, 28, 29, 31, 70, 71, 74, 76- 82 and 84 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RENEE CLAYTOR can be reached at (571)272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/E.V.V./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
Prosecution Insights