DETAILED ACTION
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 the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 02/02/2026, in which claims 43, 47, 52, and 57 are amended.
Claims 43-62 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/NL2021/050392, filed on 06/22/2021, which claims foreign priority to Netherlands 2025904 filed on 06/24/2020 and Netherlands 2027439 filed on 01/26/2021.
Information Disclosure Statement
The information disclosure statement (IDS) dated 02/24/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statement has been considered by the examiner.
Objections and Rejections Withdrawn
Applicant’s amendment and remarks, filed 02/02/2026, with respect that claim 43 is objected to because of informalities has been fully considered and is persuasive, as claim 43 has been amended to fix the typographical error.
This objection has been withdrawn.
Applicant’s amendment and remarks, filed 02/02/2026, with respect that claims 43-51 and 53-62 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention has been fully considered and is persuasive, as claim 43 has been amended to remove recitation of LINKER A, claim 47 has been amended to remove the phrase preferably, and claim 57 has been amended to remove the parenthetical.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 02/02/2026, with respect that claims 43-51, 53-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 33, 34, 36, 41, and 43 of copending Application No. 17/629,796 has been fully considered and is persuasive, as claim 43 has been amended to limit that if R3 is an azide, the saponin derivative is not an SO1861 derivative.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 02/02/2026, with respect that claims 52 and 56-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 33, 34, 36, 41, and 43 of copending Application No. 17/629,796 (reference application), as applied to claim 43, in view of Gilabert-Oriol et al. (Hereafter Gilabert-Oriol-1; Biochemical Pharmacology, 2015; IDS 11/27/2023), Gilabert-Oriol et al. (Hereafter Gilabert-Oriol-2; Bioorganic & Medicinal Chemistry, 2013; PTO-892), Kensil et al. (US 5,583,112, 1996; PTO-892), Pickens et al. (Bioconjugate Chemistry, 2018; PTO-892). has been fully considered and is persuasive, as claim 43 has been amended to limit that if R3 is an azide, the saponin derivative is not an SO1861 derivative.
This rejection has been withdrawn.
The following are maintained or modified grounds of rejection necessitated by Applicant’s amendment, in which claim 43 has been amended to limit that if R3 is an azide, the saponin derivative is not an SO1861 derivative.
Claim Rejections - 35 USC § 112(a)
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 43-51 and 53-62 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. Claim 43 has been amended to recite a saponin derivative of formula (I) wherein if R3 is an azide, the saponin derivative is not an SO1861 derivative. Thus the scope of claims 43-51 and 53-62 now excludes the sub-genus of all compounds of formula (I) in which R3 is an azide and the saponin derivative is an SO1861 derivative.
The instant specification page 10 lines 11-12 describes a saponin derivative wherein the aldehyde functional group is transformed to a hydrazone functional group according to formula (I)
PNG
media_image1.png
109
193
media_image1.png
Greyscale
in which R3 is azide or R3 is OH, or R3 is a cyclooctyne moiety, with the proviso that if the saponin derivative is an SO1861 derivative, n is not 3 if R3 is azide, and R3 is not azide if n is 3. Thus the instant specification discloses exclusion of the sub-genus where the saponin derivative is an SO1861 derivative, R3 is an azide, and n is 3. However, the instant specification does not disclose the larger sub-genus recited in instant claim 43 in which n is 0-15. This sub-genus has not been previously disclosed and thus there is no support for a claim excluding the recited sub-genus. MPEP 2163(I)(B) states that newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. MPEP 2173.05(I) states that any negative limitations or exclusionary proviso must have basis in the original disclosure and that the mere absence of a positive recitation is not basis for an exclusion.
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.
Claims 43-62 are rejected under 35 U.S.C. 103 as being unpatentable over Gilabert-Oriol et al. (Hereafter Gilabert-Oriol-1; Biochemical Pharmacology, 2015; IDS 11/27/2023) in view of Gilabert-Oriol et al. (Hereafter Gilabert-Oriol-2; Bioorganic & Medicinal Chemistry, 2013; PTO-892), Kensil et al. (US 5,583,112, 1996; PTO-892), Pickens et al. (Bioconjugate Chemistry, 2018; PTO-892), and BroadPharm (Safety Data Sheet for Azido-PEG4-hydrazide HCl Salt, 2018; PTO-892).
Gilabert-Oriol-1 discloses an approach to increase efficacy of the antibodies Cetuximab, Panitumumab and Trastuzumab in cancer therapy by dianthin conjugation and co-application of SO1861. In cancer therapies, the conjugated antibodies not only direct the binding of immunotoxins to cancer-specific receptors and mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity (abstract). Specifically, Gilabert-Oriol-1 teaches that one of the main limitations of immunotoxins in cancer therapy is that the toxin moiety has to be released from endo/lysosomes (page 254, paragraph 3). Gilabert-Oriol-1 discloses three immunotoxins in which each of the antibodies Cetuximab (anti-EGFR), Panitumumab (anti-EGFR) and Trastuzumab (anti-HER2) are conjugated to dianthin (page 254, paragraph 6). The immunotoxins of Gilabert-Oriol-1 are interpreted as the antibody-drug conjugates of the instant claims. The application of SO1861 in combination with these immunotoxins enhances the efficacy of the immunotoxins against cancer cells. This is because dianthin is internalized into cancer cells and accumulates in acidic vesicles i.e., late endosomes and lysosomes. Only after addition of SO1861 is dianthin able to escape from the acidic vesicles and reach the ribosomes in the cytosol, resulting in apoptosis of the cancer cell (page 254, paragraphs 3-5). SO1861 is a plant saponin with a triterpenoidal skeleton of oleanane type and two sugar side chains (bisdesmosidic) attached to it at positions C-3 and C-28. SO1861 is rapidly distributed in vivo and may interact with the immunotoxin once both compounds are internalized by target tumor cells (page 248, paragraph 4).
The teachings of Gilabert-Oriol-1 differ from that of the instantly claimed invention in that Gilabert-Oriol-1 does not teach a saponin derivative comprising a hydrazone functional group.
Gilabert-Oriol-2 provides an analysis of the membrane permeabilizing effects of oleanane saponins on lysosomal membranes and hemolysis (abstract). Saponins have been applied together with other anti-tumor drugs to enhance their cytotoxicity in tumor therapy (page 2387, paragraph 2). Gilabert-Oriol-2 teaches that the saponin SO1861 has a high hemolytic profile comparable to that of digitonin. SO1861 presented 61% hemolysis at 6 µM and complete membrane permeabilizing effects at 12 µM (page 2392, paragraph 4). Gilabert-Oriol-2 discloses the structure of SO1861, which is shown below (Table 1).
PNG
media_image2.png
241
376
media_image2.png
Greyscale
Thus Gilabert-Oriol-2 discloses that SO1861 is a bidesmosidic 12,13-dehydrooleanane type saponin with a triterpene aglycone core bearing an aldehyde group in position C-23 and the sugar chains are Gal-(1 →2)-[Xyl-(1 →3)]-GlcA and Glc-(1 → 3)-Xyl-(1 →4)-Rha-(1 →2)-[Xyl-(1 → 3)-4-O-Ac-Qui-(1 →4)]-Fuc.
Kensil discloses saponin-antigen conjugates useful for enhancing immune responses (abstract). Kensil teaches that the formation of saponin antigen conjugates may serve to reduce the toxicity of the composition, such that the conjugates may be administered to an animal without causing any untoward effects (col. 8, lines 34-37). Kensil teaches that the saponins of the saponin-antigen conjugates may be directly linked to the antigen or may be linked via a linking group. The linker group one or more bifunctional molecules which can be used to covalently couple the saponin or saponin mixture to the antigen and which do not interfere with the production of antigen-specific antibodies in vivo (col. 9, lines 6-9). Kensil teaches that the saponin may be coupled to a linker group by reaction of the aldehyde group of the quillaic acid residue (col. 10, lines 12-16).
Pickens reviews the state of the art in bioconjugation via azide−alkyne cycloaddition. Pickens teaches that the emergence of “click chemistry” has revolutionized bioconjugate chemistry by providing facile reaction conditions amenable to both biologic molecules and small molecule probes such as fluorophores, toxins, or therapeutics (abstract). Of all the bioorthogonal click reactions that have been developed, the most widely applied is the copper-catalyzed azide−alkyne cycloaddition reaction (CuAAC). In order to improve upon the CuAAC reaction, the strain promoted azide−alkyne cycloaddition reaction (SPAAC) was introduced, which mitigated several disadvantages of the CuAAC (page 686, paragraph 2). Pickens provides the following general formula for the outcomes of SPAAC reactions (Table 1).
PNG
media_image3.png
58
357
media_image3.png
Greyscale
In the biopharmaceutical field, click chemistry is an attractive option for antibody-drug conjugates in which click chemistry is being explored for the conjugation of payloads to antibodies, and heterobifunctional linkers have been used to functionalize the payload molecule (page 693, paragraph 1). A large variety of heterobifunctional linkers are commercially available with different of solubilizing moieties like PEG and sulfate groups. PEGylated forms of the heterobifunctional linkers are available in various lengths, which permits precise spacing of the reactive handle. Pickens teaches that including PEG in the linker can improve water solubility and alleviate steric effects between the two molecules (page 692, paragraph 4). Pickens further teaches that NHS esters are among the most popular compounds used to functionalize biomolecules due to their aqueous compatibility, commercial availability, and ability to selectively target primary amines present on lysine residues or the N-terminus (page 688, paragraph 2). As shown below, a primary amine on the biomolecule reacts with the NHS ester to form an amide bond (Figure 2A).
PNG
media_image4.png
198
338
media_image4.png
Greyscale
Pickens further teaches that linkers employed for installation of a reactive handle include DBCO-COOH, shown below (Figure 3D).
PNG
media_image5.png
85
123
media_image5.png
Greyscale
BroadPharm discloses the compound azido-PEG4-hydrazide (section I).
It would have been prima facie obvious to combine the teachings of Gilabert-Oriol-1 with that of Gilabert-Oriol-2, Kensil, Pickens, and BroadPharm before the effective filing date of the claimed invention by derivatizing the SO1861 saponin of Gilabert-Oriol-1 using a linker composed of the azido-PEG4-hydrazide of BroadPharm and an NHS functionalized DBCO moiety joined by SPAAC as taught by Pickens in order to provide a linker which can conjugate to the immunotoxin of Gilabert-Oriol-1. One of ordinary skill in the art would have been motivated to derivatize SO1861 using the commercially available azido-PEG4-hydrazide heterobifunctional linker of BroadPharm because Pickens teaches that a large variety of heterobifunctional linkers are commercially available and that including PEG in the heterobifunctional linker can improve water solubility and alleviate steric effects between the two molecules. It would have further been prima facie obvious to append the azido functionalized linker to the cyclooctyne moiety of an NHS ester substituted DBCO-COOH moiety by SPAAC because Pickens teaches that DBCO-COOH is employed in the installation of a reactive handle and that NHS esters react with a primary amine on a biomolecule to form an amide bond. This results in a compound comprising the linker of instant formula (IV)g. It would have been prima facie obvious to react the azido-PEG4-hydrazide heterobifunctional linker of BroadPharm with SO1861 saponin of Gilabert-Oriol-1 at the aldehyde group, thereby forming a saponin derivative of instant formula (VIII) comprising a hydrazone function group according to instant formula (I), thereby synthesizing a compound of instant claim 43, because Kensil teaches that similar saponins may be coupled to a linker group by reaction of the aldehyde group of the quillaic acid residue. One of ordinary skill in the art would have been motivated to conjugate the co-administered immunotoxin and SO1861 saponin of Gilabert-Oriol-1 because Gilabert-Oriol-2 teaches that the saponin SO1861 has a high hemolytic profile, Gilabert-Oriol-1 teaches that SO1861 is rapidly distributed in vivo which suggests that SO1861 may have off target effects, and Kensil teaches that the formation of saponin antigen conjugates may serve to reduce the toxicity of the composition. One of ordinary skill in the art would have had a reasonable expectation of success because Kensil teaches that saponin-antigen conjugates in which the saponin is linked to the antigen via a linking group are useful for enhancing immune responses, and Gilabert-Oriol-1 teaches antibody conjugates which mediate the elimination of tumor cells though the innate immune system.
Regarding instant claims 51-52, it would have been prima facie obvious to optimize the length of the NHS functionalized DBCO moiety by altering the number of CH2 groups because Pickens teaches that the length of the heterobifunctional linker affected the reaction efficiency and binding profiles of DBCO linkers.
Regarding instant claims 58-61, it would have been prima facie obvious to treat cancer with a combination of the SO1861 conjugated immunotoxin suggested by the combined teachings of Gilabert-Oriol-1, Gilabert-Oriol-2, Kensil, Pickens, and BroadPharm, with the same immunotoxin conjugated to other saponins because Kensil teaches that saponin-antigen conjugates for enhancing an immune response may comprise a mixture of saponins and teaches additional saponins useful for enhancing an immune response (abstract and col. 8, lines 28-31), and Gilabert-Oriol-1 teaches antibody conjugates which mediate the elimination of tumor cells though an immune response.
Response to Arguments
Applicant's arguments filed 02/02/2026 have been fully considered but they are not persuasive.
Applicant argues that the grounds of rejection characterize claim 43 as an antibody-drug conjugate (Remarks, page 18, paragraph 1). Because Applicant does not explain or point to any portion of the grounds of rejection in the office action of 11/06/2025 it is not clear that a misinterpretation has taken place and the argument is not persuasive. Rather, the instant grounds of rejection state that it would be prima facie obvious to form a saponin derivative of instant formula (VIII) comprising a hydrazone function group according to instant formula (I), which is not a compound that is conjugated to an antibody.
Applicant argues that the rejection is silent with regard to identifying a particular species, such as a lead compound, to be modified in a particular manner (Remarks, page 19, paragraphs 2-3). This is not persuasive.
The instant rejection states that it would be obvious to derivatize the SO1861 saponin of Gilabert-Oriol-1and thus identifies a particular species. The instant rejection further identifies a particular modification of this particular species including derivatization using a linker composed of the azido-PEG4-hydrazide of BroadPharm and an NHS functionalized DBCO moiety joined by SPAAC as taught by Pickens.
Applicant further argues one of ordinary skill in the art would not have been motivated to functionalize the SO1861 of Gilabert-Oriol-1 to arrive at the instantly claimed invention because one of skill in the art would first need to be motivated to use SO1861 as a single compound, rather than in combination with an antibody drug conjugate as taught by Gilabert-Oriol-1 and then need further motivation to derivatize the saponin in the manner claimed (page 20, paragraph 4). Applicant then further argues that one of ordinary skill in the art would not have been motivated to modify the SO1861 of Gilabert-Oriol-1 with the specific combination of structural features to arrive at the presently claimed saponin derivatives because Kensil describes a reductive amination of the aldehyde to afford the primary amine rather than functionalizing the aldehyde of the saponin to the hydrazone using the claimed linkers (page 20, paragraph 5). This is not persuasive.
The limitations of the instant claims do not require that one of ordinary skill in the art would have been motivated to administer SO1861 as a single compound in order to arrive at the instantly claimed invention as recited in instant claim 43 because instant claim 43 is directed a compound rather than a method of using the compound and does not require administration. As described in above grounds of rejection, one of ordinary skill in the art would have been motivated to synthesize a compound of instant claim 43 in order to arrive at a derivative of SO1861 that is capable of subsequent conjugation because Gilabert-Oriol-2 teaches that the saponin SO1861 has a high hemolytic profile, Gilabert-Oriol-1 teaches that SO1861 is rapidly distributed in vivo which suggests that SO1861 may have off target effects, and Kensil teaches that the formation of saponin antigen conjugates may serve to reduce the toxicity of the composition. Although the teachings of the prior art suggest the conjugation of SO1861, they nevertheless render obvious a compound of instant claim 43 as an intermediate for that subsequent conjugation. As such, the prior art suggests both a compound of instant claim 43 as well as conjugates of than compound.
Furthermore, the teachings of Kensil are not limited to teaching reductive amination of an aldehyde on a saponin. Rather, Kensil broadly teaches that similar saponins may be coupled to a linker group by reaction of the aldehyde group of the quillaic acid residue, and that the formation of saponin antigen conjugates may serve to reduce the toxicity of the composition. It is the teachings of Pickens and BroadPharm that are relied upon to suggest the instantly claimed linkers, and the combined teachings of Gilabert-Oriol-1, Gilabert-Oriol-2, Kensil, Pickens, and BroadPharm are relied up to teach functionalization of the aldehyde of the saponin to the hydrazone.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 02/02/2026.
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.
Claims 43-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 33, 34, 36, 41, and 43 of copending Application No. 17/629,796 (reference application), in view of Gilabert-Oriol et al. (Hereafter Gilabert-Oriol-1; Biochemical Pharmacology, 2015; IDS 11/27/2023), Gilabert-Oriol et al. (Hereafter Gilabert-Oriol-2; Bioorganic & Medicinal Chemistry, 2013; PTO-892), Kensil et al. (US 5,583,112, 1996; PTO-892), Pickens et al. (Bioconjugate Chemistry, 2018; PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of ‘796 are directed to a saponin derivative of SO1861 (claim 31) wherein the aldehyde group at C23 has been derivatized by transformation into a hydrazone bond (claim 33). Claim 36 of ‘796 is directed to the compound of the below formula.
PNG
media_image6.png
403
524
media_image6.png
Greyscale
Claim 34 further limits that the saponin derivative has a molecular weight of less than 2,500 g/mol. Claim 42 further limits a pharmaceutical composition comprising the saponin derivative according to claim 41 and one or more of an antibody-oligonucleotide conjugate and a pharmaceutically acceptable excipient and/or diluent.
The claims of ‘796 differ from that of the instant claims in that they do not expressly claim a saponin derivative of claim 43 where R3 is not azide, the saponin derivative of instant claims 52, a method for transferring a molecule from outside a cell to inside a cell, or a conjugate of instant claim 57.
Gilabert-Oriol-1 discloses an approach to increase efficacy of the antibodies Cetuximab, Panitumumab and Trastuzumab in cancer therapy by dianthin conjugation and co-application of SO1861. In cancer therapies, the conjugated antibodies not only direct the binding of immunotoxins to cancer-specific receptors and mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity (abstract). Specifically, Gilabert-Oriol-1 teaches that one of the main limitations of immunotoxins in cancer therapy is that the toxin moiety has to be released from endo/lysosomes (page 254, paragraph 3). Gilabert-Oriol-1 discloses three immunotoxins in which each of the antibodies Cetuximab (anti-EGFR), Panitumumab (anti-EGFR) and Trastuzumab (anti-HER2) are conjugated to dianthin (page 254, paragraph 6). The immunotoxins of Gilabert-Oriol-1 are interpreted as the antibody-drug conjugates of the instant claims. The application of SO1861 in combination with these immunotoxins enhances the efficacy of the immunotoxins against cancer cells. This is because dianthin is internalized into cancer cells and accumulates in acidic vesicles i.e., late endosomes and lysosomes. Only after addition of SO1861 is dianthin able to escape from the acidic vesicles and reach the ribosomes in the cytosol, resulting in apoptosis of the cancer cell (page 254, paragraphs 3-5).
Gilabert-Oriol-2 provides an analysis of the membrane permeabilizing effects of oleanane saponins on lysosomal membranes and hemolysis (abstract). Saponins have been applied together with other anti-tumor drugs to enhance their cytotoxicity in tumor therapy (page 2387, paragraph 2). Gilabert-Oriol-2 teaches that the saponin SO1861 has a high hemolytic profile comparable to that of digitonin. SO1861 presented 61% hemolysis at 6 µM and complete membrane permeabilizing effects at 12 µM (page 2392, paragraph 4). Gilabert-Oriol-2 discloses the structure of SO1861, which is shown below (Table 1).
PNG
media_image2.png
241
376
media_image2.png
Greyscale
Kensil discloses saponin-antigen conjugates useful for enhancing immune responses (abstract). Kensil teaches that the formation of saponin antigen conjugates may serve to reduce the toxicity of the composition, such that the conjugates may be administered to an animal without causing any untoward effects (col. 8, lines 34-37). Kensil teaches that the saponins of the saponin-antigen conjugates may be directly linked to the antigen or may be linked via a linking group. The linker group is linker group is one or more bifunctional molecules which can be used to covalently couple the saponin or saponin mixture to the antigen and which do not interfere with the production of antigen-specific antibodies in vivo (col. 9, lines 6-9). Kensil teaches that the saponin may be coupled to a linker group by reaction of the aldehyde group of the quillaic acid residue (col. 10, lines 12-16).
Pickens reviews the state of the art in bioconjugation via azide−alkyne cycloaddition. Pickens teaches that the emergence of “click chemistry” has revolutionized bioconjugate chemistry by providing facile reaction conditions amenable to both biologic molecules and small molecule probes such as fluorophores, toxins, or therapeutics (abstract). Of all the bioorthogonal click reactions that have been developed, the most widely applied is the copper-catalyzed azide−alkyne cycloaddition reaction (CuAAC). In order to improve upon the CuAAC reaction, the strain promoted azide−alkyne cycloaddition reaction (SPAAC) was introduced, which mitigated several disadvantages of the CuAAC (page 686, paragraph 2). Pickens provides the following general formula for the outcomes of SPAAC reactions (Table 1).
PNG
media_image3.png
58
357
media_image3.png
Greyscale
In the biopharmaceutical field, click chemistry is an attractive option for antibody-drug conjugates in which click chemistry is being explored for the conjugation of payloads to antibodies, and heterobifunctional linkers have been used to functionalize the payload molecule (page 693, paragraph 1). A large variety of heterobifunctional linkers are commercially available with different of solubilizing moieties like PEG and sulfate groups. PEGylated forms of the heterobifunctional linkers are available in various lengths, which permits precise spacing of the reactive handle. Pickens teaches that including PEG in the linker can improve water solubility and alleviate steric effects between the two molecules (page 692, paragraph 4). Pickens further teaches that NHS esters are among the most popular compounds used to functionalize biomolecules due to their aqueous compatibility, commercial availability, and ability to selectively target primary amines present on lysine residues or the N-terminus (page 688, paragraph 2). As shown below, a primary amine on the biomolecule reacts with the NHS ester to form an amide bond (Figure 2A).
PNG
media_image4.png
198
338
media_image4.png
Greyscale
Pickens further teaches that linkers employed for installation of a reactive handle include DBCO-COOH, shown below (Figure 3D).
PNG
media_image5.png
85
123
media_image5.png
Greyscale
It would have been prima facie obvious to combine the claims of ‘796 with the teachings of Gilabert-Oriol-1, Gilabert-Oriol-2, Kensil, and Pickens before the effective filing date of the claimed invention by joining molecule 23 of ‘796 by SPAAC to an NHS functionalized DBCO moiety as taught by Pickens in order to provide a linker which can conjugate to the immunotoxin of Gilabert-Oriol-1 because Pickens teaches that DBCO-COOH is employed in the installation of a reactive handle and that NHS esters react with a primary amine on a biomolecule to form an amide bond. This results in a compound comprising the linker of instant formula (IV)g and is a derivative of instant claim 43. One of ordinary skill in the art would further have been motivated to conjugate molecule 23 of ‘796 with the immunotoxin of Gilaber-Oriol-1 because Gilabert-Oriol-1 teaches the co-administration of an immunotoxin and SO1861 saponin, and Gilabert-Oriol-2 teaches that the saponin SO1861 has a high hemolytic profile, Gilabert-Oriol-1 teaches that SO1861 is rapidly distributed in vivo which suggests that SO1861 may have off target effects, and Kensil teaches that the formation of saponin antigen conjugates may serve to reduce the toxicity of the composition. One of ordinary skill in the art would have had a reasonable expectation of success because Kensil teaches that saponin-antigen conjugates in which the saponin is linked to the antigen via a linking group are useful for enhancing immune responses, and Gilabert-Oriol-1 teaches antibody conjugates which mediate the elimination of tumor cells though the innate immune system.
Regarding instant claims 51-52, it would have been prima facie obvious to optimize the length of the NHS functionalized DBCO moiety by altering the number of CH2 groups because Pickens teaches that the length of the heterobifunctional linker affected the reaction efficiency and binding profiles of DBCO linkers.
Regarding instant claims 58-61, it would have been prima facie obvious to treat cancer with a combination of the SO1861 conjugated immunotoxin suggested by the combined claims of ‘796 and teachings of Gilabert-Oriol-1, Gilabert-Oriol-2, Kensil, and Pickens, with the same immunotoxin conjugated to other saponins because Kensil teaches that saponin-antigen conjugates for enhancing an immune response may comprise a mixture of saponins and teaches additional saponins useful for enhancing an immune response (abstract and col. 8, lines 28-31), and Gilabert-Oriol-1 teaches antibody conjugates which mediate the elimination of tumor cells though an immune response.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 02/02/2026 have been fully considered but they are not persuasive. Applicant argues that the subject matter of '796 no longer overlaps with that of the amended claims (Remarks, page 22, paragraphs 3 and 7). This is not persuasive.
The new grounds of rejection necessitated by Applicant’s amendment demonstrate that the instantly claimed invention is patentably indistinct from the claims of ‘796 in view of the prior art and suggest a saponin derivative comprising the linker of instant formula (IV)g. Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 02/02/2026.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah Grace Hibshman whose telephone number is (703)756-5341. The examiner can normally be reached Monday-Thursday 7:30am-5:30pm (EST). 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, Scarlett Goon can be reached on (571) 270-5241. 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.
/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
Prosecution Insights