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 . 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.
Priority
The instant application is a 371 of PCT/NL2021/050394 filed on 06/23/2021 and claims foreign priority to PCT/NL2021/050384 filed on 06/18/2021 and Netherlands application no. NL2025902 filed on 06/24/2020. The certified copies of the foreign priority applications filed on 12/23/2022 in the instant application are acknowledged.
Status of the Claims
The claim amendments and remarks filed on 03/12/2026 is acknowledged. Claims 1-4, 10, 12-14, 16, 19, 21, 23-25, and 30 are amended. Claims 7-9, 11, 15, 17-18, 22, 27-29, and 31-35 are cancelled. Claims 36-39 are newly added.
Accordingly, claims 1-6, 10, 12-14, 16, 19-21, 23-26, 30, and 36-39 are pending and being examined on the merits herein.
Withdrawn Objections/Rejections
The objection to the drawings is withdrawn because the newly filed drawings on 03/12/2026 have sufficient resolution for the chemical structures shown in FIG. 1-7 and 21-22.
The 35 USC 112(b) rejection over claim 10 is withdrawn because claim 10 has been amended to remove the recited “including” term and the following limitation which was interpreted as an exemplary embodiment and therefore it is clear what the scope of the claim.
The 35 USC 112(a) rejection over claims 25-26 is withdrawn because claim 25 has been amended to remove the “prophylaxis” term, rendering the scope of enablement issue over this term moot.
All of the 35 USC 103 rejections are withdrawn because these rejections previously relied on meeting the recited saponin structure with either a digitonin or substituting the digitonin with the SO1861 saponin. However, Applicant has amended the claims such that the digitonin no longer meets the structure of the recited saponin. Here, Applicant has removed digitonin as a saponin species that can be selected as well as now requiring the saponin to have new limitations of being “a quillaic acid derivative or gypsogenin derivative comprising an aglycone core, and wherein a functional group of the saponin derivative is covalently conjugated via a linker to a reactive functional group capable of further conjugation”, which has changed the scope of the claims and requires new search and consideration.
All of the nonstatutory double patenting rejections are withdrawn because Applicant has amended the claims such that the digitonin no longer meets the structure of the recited saponin. Here, Applicant has removed digitonin as a saponin species that can be selected as well as now requiring the saponin to have new limitations of being “a quillaic acid derivative or gypsogenin derivative comprising an aglycone core, and wherein a functional group of the saponin derivative is covalently conjugated via a linker to a reactive functional group capable of further conjugation”, which has changed the scope of the claims and requires new search and consideration.
The following grounds of rejection are new as necessitated by Applicant’s amendments.
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.
Claim 16 is 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 16 recites that the saponin derivative of claim 1 is represented by Molecule 1, wherein A1 and A2 can represent hydrogen.
Claim 16 depends from claim 1. Claim 1 now requires that the saponin derivative is a bidesmosidic triterpene glycoside, which means the A1 and A2 in Molecule 1 must contain a saccharide and cannot be hydrogen. Therefore, claim 16 fails to include all the limitations of the claim upon which it depends.
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 § 103
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.
Claim(s) 1, 3-6, 12-14, 16, 20, 25-26, 30, and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (Nucleic Acids Research, 2014 in PTO-892 dated 11/14/2025) in view of Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), and as evidenced by BOC Sciences (BOC Sciences website, structure of SO1861 in PTO-892 dated 11/14/2025).
Prakash teaches targeted delivery of antisense oligonucleotides (ASOs) to hepatocytes using triantennary N-acetyl galactosamine (GalNAc, GN3) (see Abstract). Prakash teaches that GalNac (GN3) is a high-affinity ligand for the hepatocyte-specific asialogylcoprotein receptor (ASGPR) (see Abstract). Prakash teaches the structure the of their GN3-ASO conjugate in Figure 1 and shown below:
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Here, the GN3-ASO conjugate of Prakash meets the limitation of a conjugate of an effector molecule and a ligand for ASGPR, wherein the ligand for ASGPR comprises at least one GalNAc moiety as well as wherein the ligand for ASGPR and the effector molecule are conjugated via a covalent bond. Prakash teaches that GN3-ASO conjugates showed high affinity for mouse ASGPR, which resulted in enhanced ASO delivery to hepatocytes versus non-parenchymal cells (see Abstract). Prakash teaches that the potency of the ASO was increased by 6-10-fold in mouse liver (see Abstract). Prakash teaches and demonstrates in Figure 4 that GN3-ASO conjugates were internalized into cells and metabolized to liberate the parent ASO in the liver (see Abstract). Prakash teaches that no metabolism of the GN3-ASO conjugate was detected in the plasma suggesting that GN3 acts as a hepatocyte targeting prodrug that is detached from ASO by metabolism after internalization in the liver (see Abstract). Prakash further teaches and demonstrates in Figures 5 and 6 that GalNac conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice (see Abstract). Prakash concludes that the ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs (see Abstract).
Prakash, however, does not disclose including the recited saponin derivative.
Weng teaches improved intracellular delivery of peptide and lipid-nanoplexes by natural glycosides (see Abstract).
Weng teaches that nanocarriers for DNA or siRNA delivery are transport vehicles in the nanoscale range, which protect the genetic material against degradation and increase their bioavailability (first paragraph left column page 75). Weng teaches that these nanocarriers consist of two motifs: a positively charged carrier component to facilitate complex formation with siRNA/DNA and a targeting ligand to facilitate cell-specific binding of the nanocarrier (first paragraph left column page 75). Weng teaches that an ideal sequence for this delivery involves a) binding of the nanocarrier to the cell surface, b) endocytosis of the carrier and delivery of the cargo into intracellular compartments such as early endosomes and c) release of the genetic cargo (siRNA/DNA) out of the intracellular compartments into the cytosol and in the case of DNA transport into the nucleus (first column right column page 75). Furthermore, Weng discloses that endosomal escape is a critical step for successful DNA delivery (first column right column page 75). However, Weng teaches that insufficient endosomal escape is one of the main obstacles for efficient delivery of DNA/siRNA containing nanocarriers (see first paragraph left column page 76) and discloses several strategies to augment the endo-/lysosomal escape of siRNA/DNA to overcome this limitation (see page 76).
Weng teaches that a natural, plant derived glycoside called SO1861 from Saponaria officinalis L. greatly improves the efficacy of lipid based as well as non-lipid based targeted nanoplexes consisting of a targeted K16 peptide with a nucleic acid binding domain and plasmid-DNA, minicircle-DNA or small interfering RNA (siRNA) (see Abstract). Here, the SO1861 meets the limitation of a saponin derivative that is a quillaic acid derivative and that comprises a saccharide chain with a carboxy group of a glucuronic acid moiety as seen in Fig. 1 of Weng and shown below:
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Here, SO1861 consists of a hydrophobic triterpene backbone and branched carbohydrate chains that is labeled “R”. As evidenced by BOC Sciences, the saccharide chains on the SO1861 shown below meet the limitation of the saccharide chains recited in instant claims 12 and 20:
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Weng discloses that they have previously demonstrated that SO1861 triggers the endo-/lysosomal escape of a 30 kDa protein plant toxin (saporin) into the cytosol of cells that have endocytosed saporin (coined as synergistic principle) (second paragraph right column page 76).
Weng demonstrates in Fig. 2 that SO1861 significantly increased the transfection efficiency of a non-lipid based peptide-DNA nanoplex with either plasmid DNA (pEGFP-N3) or minicircle-DNA (MC EGFP) (see left column page 81). Weng teaches that SO1861 enhances the endosomal escape of peptide-DNA-nanoplexes out of late endosomes/lysosomes into the cytosol (see second paragraph left column page 88) based on confocal live cell imaging in combination with single cell analysis seen in Fig. 5 and 6 on pages 82-84. Weng hypothesizes that SO1861 first associates with the positively charged nanoplexes and mediates in a second step the endosomal escape of nanoplexes via its membrane active properties (see right column page first paragraph page 88). Weng concludes that SO1861 holds tremendous potential as a new transfection multiplier for non-viral transfection systems (see section “Conclusions” first paragraph on page 89).
Here, Weng discloses the saponin structure (SO1861) recited in the instant claims but does not disclose the recited derivatized locations to conjugate a linker such as the C23 position of quillaic acid or the carboxylic acid of a glucuronic acid moiety of the saccharide chain.
US’502 discloses novel saponin derivatives to deliver a polynucleotide molecule to cells of an animal, to stimulate or generate an immune response in an animal, and to generate a detectable immune response in an animal (Abstract).
US’502 discloses that their saponin compounds can i) facilitate the targeting and delivery of DNA or RNA to the cytosol of antigen presenting cells (APC), i.e. act as carriers, and/or ii) co-stimulate the immune system to produce an effective response, preferentially that of a Th1 type, i.e. to act as immune stimulants (paragraph 0012).
US’502 discloses that their novel saponin compounds are covalently linked to one or more oligosaccharide chains; (b) a positively charged cationic chain, and optionally (c) a naturally occurring or synthetic lipophilic chain (Abstract). US’502 further discloses that these modified groups on the saponin are capable of forming a complex with DNA or RNA (claim 8 and 14). Furthermore, US’502 discloses a method of delivering a polynucleotide to cells of an animal in need therefore comprising forming a saponin derivative/nucleic acid complex, wherein said complex is formed by association of a compound of claim 1 and a polynucleotide sequence encoding an immunogen; and (b) administering said complex in vitro to the cells of the animal in an amount sufficient that uptake of said polynucleotide sequence into the cells of the animal occurs (claim 30)
US’502 provides a general Formula 1 structure of their novel saponins (paragraph 0066) shown below:
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Here, the Formula 1 structures contain the same aglycone core as the SO1861. Furthermore, US’502 discloses that the R3 and R5 positions are where the oligosaccharide chains, positively charged cationic chain, or lipophilic chain is located at (paragraphs 0072-0080). Here, the R3 position corresponds to the carboxyl group of a glucuronic acid moiety on the saccharide chain of the saponin and is the same derivatized location as recited in the instant claims. Furthermore, the R5 position corresponds to the aldehyde group of the quillaic acid and is the same aldehyde derivatized location as recited in the instant claims
US’502 also discloses that their invention include pharmaceutical compositions comprising one or more of the saponin derivatives and one or more pharmaceutically acceptable diluents, carriers or excipients (paragraph 0029). US’502 discloses their pharmaceutical compositions comprise their saponin derivative compound, a polynucleotide, and a pharmaceutically acceptable carrier or diluent (claims 20-21).
Marciani et al. discloses novel triterpene saponin analogs (see Abstract).
Marciani et al. discloses that their novel compounds contain a lipophilic moiety covalently attached to a carboxyl group present on the 3-O-glucoronic acid of the triterpene saponin (see Abstract). Marciani et al. provides a Formula II structure which represents their conjugated saponin-lipophilic compounds shown below:
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Here, the circled portion highlights the conjugation of the lipophilic moiety to a saponin compound. X is S, O, NH or a linking group and R3 is a residue of a lipophilic molecule. This conjugated location, which is the carboxyl group of a glucuronic acid moiety on the saccharide chain of the saponin, is the same derivatized location as recited in claims 14 and 16.
Marciani et al. discloses that the lipophilic moiety can be attached to the saponins via a linking group (see column 8 lines 50-53). Marciani et al. discloses that the linking group can be one or more bifunctional linkers that covalently attach the carboxylic acid group of the 3-O glucuronic acid moiety of the triterpene core to a suitable functional group present on the lipophilic molecule (see column 8, lines 50-59). Marciani et al. discloses other suitable heterobifunctional cross-linkers such as sulfosuccinimidyl 4-(N-maleimidocyclohexane)-1-carboxylate (see column 14, lines 44-57) and also discloses using suitable reagents to form an amide or ester linkage to a lipophilic moiety (see column 11 lines 22-30).
It would have been prima facie obvious before the effective filing date of the claimed invention to have further included, alongside the GN3-ASO conjugate of Prakash, the SO1861 of Weng and further modify the SO1861 by conjugating a positively charged cationic/lipophilic chain at either the carboxyl group of a glucuronic acid moiety on the saccharide chain or the aldehyde group of the quillaic acid as disclosed in US’502 using the linking chemistries such as the bi-functional linkers of Marciani to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to include the SO1861 because Weng discloses that the endo-/lysosomal escape of siRNA/DNA into the cytosol of the targeted cell is one the major obstacles for efficient siRNA/DNA delivery, and Weng further discloses and demonstrates that SO1861 augments and enhances the escape of the genetic cargo out of the intracellular compartments into the cytosol, which is critical for the successful delivery of nucleic acids.
One of ordinary skill in the art would have a reasonable expectation of success because both Prakash and Weng disclose similar delivery methods of nucleic acids by using targeting ligands to bind to a target cell and release the genetic cargo into the cell. Furthermore, Weng provides guidance that escape of the genetic cargo out of the intracellular compartments into the cytosol is critical for the successful delivery of nucleic acids, which suggests an ordinary skilled artisan would have reasonably expected that other targeted nucleic acid delivery methods would benefit from the addition of the disclosed SO1861.
One of ordinary skill in the art would have combined prior art elements according to known methods of further modifying the SO1861 with side chains to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of using these types of saponin derivatives to form complexes with nucleic acids and perform the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell.
One of ordinary skill in the art would have combined prior art elements according to known methods of using the linking chemistries in Marciani for linking the side chains onto the SO1861 to yield predictable results and would have a reasonable expectation of success in doing so because Marciani provides guidance of using several linking chemistries such as bi-functional linkers to conjugate similar lipophilic moieties onto the same positions of a saponin compound.
In regards to instant claim 30, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used the SO1861 derivative and GN3-ASO conjugate composition as disclosed in the combined teachings of Prakash, Weng, US’502, and Marciani described above for an in vitro method for transferring the conjugate outside a cell to inside a cell as disclosed in Weng to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated because Weng provides guidance that SO1861 can enhance the escape of the genetic cargo out of the intracellular compartments into the cytosol.
One of ordinary skill in the art would have a reasonable expectation of success because Weng provides guidance that escape of the genetic cargo out of the intracellular compartments into the cytosol is critical for the successful delivery of nucleic acids, which suggests an ordinary skilled artisan would have reasonably expected that other targeted nucleic acid delivery methods would benefit from the addition of the disclosed SO1861 for transferring a nucleic acid conjugate from outside to inside a cell.
Claim(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (Nucleic Acids Research, 2014 in PTO-892 dated 11/14/2025) in view of Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), and Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), as applied to claim 1 above, and further in view of US20080064762 (in PTO-892 dated 11/14/2025 dated 11/14/2025).
The combined teachings of Prakash, Weng, US’502, and Marciani are as described above and teach the pharmaceutical combination of claim 1 as discussed above.
The combined references, however, do not teach at least two pharmaceutical compositions wherein the first composition comprises the conjugate and the second composition comprising the saponin.
US’762 teaches a composition comprising a pharmacologically active agent coupled to a target cell specific component, and a saponin, to uses of said composition and to a kit comprising said composition (see Abstract). US’762 teaches the pharmacologically active agent coupled to said target cell specific component is a chimeric toxin or toxin conjugate, wherein, preferably, said pharmacologically active agent is a peptidic or protein cytotoxin and said target cell specific component is an antibody, growth factor, cytokine or transferrin or a fragment, combination or derivative thereof (see 0017). US’762 teaches that the saponin is used for enhancing the function and/or the target cell specificity of a pharmacologically active agent (see paragraph 0040). US’762 teaches that the saponin is administered separately from said pharmacologically active agent coupled to said target cell specific component as well as further teaching a kit containing the active agent coupled to a target cell specific component and the saponin in separate containers, meeting the limitation of two separate compositions.
It would have been prima facie obvious before the effective filing date of the claimed invention to have prepared the SO1861 derivative and GN3-ASO conjugate composition as disclosed in the combined teachings of Prakash, Weng, US’502, and Marciani described above in two separate pharmaceutical compositions as disclosed in US’762 to arrive at the claimed invention.to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because US’762 provides guidance of separately preparing a similar effector conjugate and a saponin with a similar function of enhancing the function of the conjugate.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (Nucleic Acids Research, 2014 in PTO-892 dated 11/14/2025) in view of Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), and Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), as applied to claim 1 above, and further in view of Cawley et al. (PNAS, 1981 in PTO-892 dated 11/14/2025).
The combined teachings of Prakash, Weng, US’502, and Marciani are as described above and teach the pharmaceutical combination of claim 1 as discussed above. Furthermore, Weng discloses that they have previously demonstrated that SO1861 triggers the endo-/lysosomal escape of a 30 kDa protein plant toxin (saporin) into the cytosol of cells that have endocytosed saporin (coined as synergistic principle) (second paragraph right column page 76).
The combined references, however, do not teach the effector molecule being a recited toxin in instant claim 10.
Cawley teaches a toxic hybrid protein that is recognized by asialoglycoprotein (ASGP) receptors of cultured rat hepatocytes. The conjugate consists of fragment A of diphtheria toxin (DTA) linked by a disulfide bond to asialofetuin (ASF) (see Abstract). Cawley teaches that ASF is a well-characterized ASGPR and was chosen as a model system for the construction of a cell-type and receptor-specific toxic conjugate (see second paragraph right column page 3383). Cawley teaches that the ASF-DTA conjugate was 600 and 1800 times as toxic as diphtheria toxin and DTA, respectively, on primary rat hepatocytes (see Abstract). Cawley teaches that the highly toxic ASF-DTA conjugate is cell-type specific, and its action is mediated by a well-characterized receptor, whose mechanism of receptor-ligand internalization has been extensively investigated (see Abstract).
It would have also been prima facie obvious before the effective filing date of the claimed invention to have substituted the GN3-ASO in the SO1861 derivative and GN3-ASO conjugate composition as disclosed in the combined teachings of Prakash, Weng, US’502, and Marciani described above with the ASF-DTA conjugate disclosed in Cawley to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (GN3-ASO) for another (ASF-DTA) to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined teachings of Prakash, Weng, US’502, and Marciani described above and Cawley teach effector molecules that are conjugated to a ASGPR ligand for enhanced delivery into hepatocyte cells, and Weng further discloses SO1861 triggers the endo-/lysosomal escape of a similar toxin into the cytosol of cells.
Claim(s) 19, 21, and 23 rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (Nucleic Acids Research, 2014 in PTO-892 dated 11/14/2025) in view of Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), and Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), as applied to claims 1, 14, and 16 above, and further in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025).
The combined teachings of Prakash, Weng, US’502, and Marciani are as described above and teach the pharmaceutical combination of claim 1 as discussed above.
The combined references, however, do not teach a combination wherein the saponin comprises a saccharide chain that has been derivatized on the carboxyl group of a glucuronic acid moiety through reaction with AEM as recited in instant claims 19, 21, and 23.
Qi et al. discloses conjugation of beta-glucan with hydrazone and disulfide linkers to improve the immunogenicity of Zika Virus E protein (see Abstract). Qi et al. discloses that E proteins are an ideal antigen for vaccine development, but have poor immunogenicity, which necessitates a formulation with adjuvants (see Abstract). Qu et al. discloses that the antigenic epitopes of the antigen may be shielded by the macromolecular adjuvant, which in turn, the immunomodulatory sites of the adjuvant may be shielded by the bulky antigen. Moreover, Qi et al. discloses that the conjugate may elicit the undesired immune response to the adjuvant, which is harmful for vaccine development. Thus, Qu et al. proposes conjugation with beta-glucan to overcome these disadvantages and improve the immunogenicity via acidic-labile hydrazone linkers between the E protein and beta-glucan to sufficiently detach the two components into the immune cells (see Abstract). Qi et al. discloses that acid-labile hydrazone bonds have been utilized for nanoparticle-targeted anticancer drugs, in which low pH values of endosomes (pH 5.5–6.0) and lysosomes (pH 4.5–5.0) rendered rapid cargo release after hydrolysis of pH-sensitive hydrazone bonds in the micelle (see left column page 1934). Qi et al. discloses the structures of four conjugates that were prepared in Figure 11 and shown below:
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Here, the conjugate “E-PS-2” (top right conjugate) is a EMCH linker and meets the limitations of the hydrazide linker recited in the instant claims, and the conjugate “E-PS-1” (top left conjugate) is an AEM linker and meets the limitations of transformation into an amide bond through reaction with AEM recited in the instant claims.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the conjugation of the positively charged cationic/lipophilic chain on the SO1861 in the SO1861 derivative and GN3-ASO conjugate composition as disclosed by combined teachings of Prakash, Weng, US’502, and Marciani described above by using the AEM linker as disclosed in Qi to arrive at the claimed invention
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Marciani provides guidance of forming lipophile - saponin conjugates using heterobifunctional linkers as described above, and Qi demonstrates the use of an heterobifunctional AEM linker for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
Claim(s) 24 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (Nucleic Acids Research, 2014 in PTO-892 dated 11/14/2025) in view of Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), and Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), as applied to claim 1 above, and further in view of Wada et al. (Nucleic Acid Therapeutics, 2018 in PTO-892 dated 11/14/2025) and Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025).
The combined teachings of Prakash, Weng, US’502, and Marciani are as described above and teach the pharmaceutical combination of claim 1 as discussed above.
The combined references, however, do not teach wherein the saponin a saponin derivative represented by Molecule 2 or 3 as well as the saponin being conjugated to a ligand for ASGPR such as (GalNAc)3Tris.
Wada teaches a cholesterol-GalNAc dual conjugation strategy for reducing renal distribution of antisense oligonucleotides (ASOs) (see Abstract). Wada shows the structure of this dual conjugation in FIG. 1 and shown below:
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Wada teaches that the cholesterol conjugation serves the purpose of reducing renal distribution and GalNAc serves the purpose of liver targeting (see Abstract). Wada teaches that nephrotoxicity is a problem for ASOs targeting liver-associated diseases and in order to reduce the possibility of nephrotoxic effects of ASOs, Wada investigated ligands that would be capable of conjugating to the ASO in order to reduce their renal distribution, while maintaining the gene-silencing activity in the liver, the target organ (see first paragraph right column page 50).
Wada teaches that cholesterol conjugation is a widely utilized strategy for delivery of oligonucleotides to the liver and found that cholesterol conjugation helps oligonucleotides interact with serum proteins and lipoproteins to trespass into hepatocytes through receptor mediated or nonmediated pathways (see second paragraph right column page 50). Wada teaches that GalNAc had gained attention as a liver target ligand and GalNAc conjugation permits hepatocyte-specific delivery of ASOs due to multivalent GalNAc specificity to the ASGPR receptor expressed in hepatocytes. Therefore, taken together, Wada suggests that dual cholesterol-GalNAc conjugation would enable reduction of ASO amounts in the kidney by altering the pharmacokinetics and pharmacodynamics of ASOs (see left column second paragraph page 51).
The teachings of Qi are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the SO1861 derivative and GN3-ASO conjugate composition as disclosed by the combined teachings of Prakash, Weng, US’502, and Marciani described by further conjugating the SO1861 derivative to the (GalNAc)3Tris on the GN3-ASO conjugate as suggested by Wada and US’502 at the aldehyde group of the quillaic acid as disclosed in US’502 using the EMCH linker as disclosed in Qi to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating the SO1861 to the GN3-ASO conjugate to yield predictable results and would have a reasonable expectation of success in doing so because Wada provides guidance of multifunctionalized ASOs with the same GalNAc targeting moiety as well as cholesterol moiety that serves a similar purpose as the saponin compounds of improving delivery of oligonucleotides, and further discloses that these multifunctionalized ASOs reduce the nephrotoxic potential of ASOs. Furthermore, US’502 also provides guidance of complexing saponin derivatives with nucleic acids to help facilitate the delivery into the cytosol of a target cell.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating at the aldehyde group of the quillaic acid to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of forming saponin conjugates as this position and perform the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell.
One of ordinary skill in the art would have combined prior art elements according to known methods of using the EMCH linker to yield predictable results and would have a reasonable expectation of success in doing so because Marciani provides guidance of forming lipophile - saponin conjugates using heterobifunctional linkers as described above, and Qi demonstrates the use of an heterobifunctional EMCH linker for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
Lastly, while the recited Molecule 2 and 3 structures do not show an effector conjugate being attached to the EMCH linker, the modified saponin conjugate as described above from the combination of references would result in the formation of either the Molecule 2 or 3 structure because the combined references teach the same EMCH linker being attached at the same position of the recited saponin (SO1861 derivative) before the conjugation of the effector conjugate (GN3-ASO conjugate).
Response to Arguments
Applicant’s arguments filed on 03/12/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant states that there is no motivation and no reasonable expectation of success in substituting digitonin with quillaic acid or gypsogenin.
However, the new rejections above do not rely on a substitution of digitonin with quillaic acid or gypsogenin, rendering Applicant’s arguments here moot.
Applicant states that there is no motivation to derivatize the saponin. Applicant states that Marciani teaches therapeutic effects related to adjuvanticity and immunostimulation and does not disclose improving intracellular delivery of ASGPR-effector conjugates. Applicant states that there is no explanation as to why a modification of the saponin for vaccine adjuvant properties would beneficially impact ASGPR-effector mediated delivery.
Applicant’s argument described above was not found persuasive because it is first noted that an explicit teaching of a motivation to combine in the prior art is not required to establish obviousness. See MPEP 2143. Furthermore, the new rejection above does not rely on Marciani for providing guidance of derivatizing the saponin molecule. Rather, US’502 is relied upon to derivatize the saponin, and Marciani is only relied upon to establish the use of linking chemistries such as bi-functional linkers to conjugate the moieties disclosed in US’502 onto the saponin molecule.
Furthermore, the new rejection relies upon KSR (A) to establish obviousness as stated in MPEP 2141 III. Here, an ordinary skilled artisan would have combined known prior art elements according to known methods of derivatizing the saponin at the recited locations to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of using derivatized saponin at the recited locations on the saponin to form complexes with nucleic acids and perform the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell.
Applicant states that Examples 2 through 6 demonstrate unexpected effects of using a saponin conjugate in combination with the recited effector molecule conjugate. Applicant states that Example 2 demonstrates that SO1861-EMCH can enhance endosomal escape and target gene silencing of trivalent-GalNAc-L-BNA or trivalent-GalNAc-S-BNA for two independent gene targets (see, e.g., specification at 42). Applicant states that Example 3 demonstrate that very low concentrations of trivalent-GalNAc-L-HSP27BNA or trivalent-GalNAc-S-HSP27BNA effectively induce gene silencing in ASGPR1 expressing cells when the conjugate is in combination with trivalent-GalNAc-L-SO1861 (see, e.g., specification at 42-43). Applicant states that Examples 4 and 5 demonstrate that SO1861-EMCH can strongly enhance (GalNAc)3-targeted delivery of an oligonucleotide payload in human primary hepatocytes (see, e.g. specification at 43-44). Applicant states that Example 6 demonstrates that either (GalNAc)3-SO1861 or S01861-EMCH can enhance the gene silencing activity of (GalNAc)3-ApoB#02 BNA by effectively inducing ApoB RNA downmodulation (see, e.g., specification at 44).
In response to Applicant’s showing of unexpected results, the evidence of an unexpected result must compare the claimed invention with the closest prior art as stated in MPEP 816.02(e).
The closest prior art to compare against for the alleged unexpected result is Weng. Here, Weng discloses the use of an unmodified SO1861 saponin as an endosomal escape enhancer for improving intracellular delivery of nucleic acids as described above.
As described above, Applicant has only provided examples demonstrating that their recited saponin structure can improve delivery of the recited effector molecule conjugates. However, Applicant has not provided sufficient evidence of an unexpected result over the closest prior art because Applicant has not presented evidence comparing to the unmodified SO1861 as disclosed in Weng, making it difficult to ascertain if Applicant has demonstrated an unexpected improvement in delivery of the effector molecule compared to the closest prior art. It is noted that Weng also discloses the use of SO1861 to improve the intracellular delivery of nucleic acids into the cytosol of the cell. Therefore, a proper comparison to the unmodified SO1861 structure is required in order to determine if Applicant has demonstrated a sufficient showing of unexpected results.
Lastly, as stated in MPEP 716.02(d), the showing of unexpected results must be commensurate in scope with the claims and further states that “nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof.”
Here, Applicant has only demonstrated in the examples of improved delivery of trivalent-GalNAc-L/S-BNA using a derivatized SO1861 saponin such as SO1861-EMCH or trivalent-GalNAc-L-5O1861 and only discloses that the EMCH linker is conjugated at the aldehyde position of the SO1861 (page 41 lines 17-19). However, the current claims encompass a large selection of saponin species with different chemical structures such as recited in instant claim 12 and several derivatization options on the saponin such as the glucuronic acid moiety on the saccharide chain or the aldehyde group of the quillaic acid as well as several different linkers such as EMCH, BMPH, LMUH, AMPD, and AEM as recited instant claim 19. Furthermore, claim 1 recites any effector molecule that is conjugated to a GalNAc target moiety.
Therefore, based on the current evidence disclosed by Applicant in the specification, it cannot be reasonably determined that the showing of improved delivery of one type of GalNac-effector molecule conjugate for one type of saponin (SO1861) and one type of derivatization (EMCH at the aldehyde position) will extend to the scope of the currently recited claims, which as discussed above, encompass any GalNAc conjugated effector molecule and several different saponin species as well as different derivatization location and linkers. Therefore, Applicant’s showing of unexpected results is not commensurate in scope with the claims.
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 1-6, 10, 12-14, 16, 19-21, 23-26, 30, and 36-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,769 (‘769) in view of Wada et al. (Nucleic Acid Therapeutics, 2018 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), and Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025).
The claims of ‘769 recite a saponin conjugate comprising at least one saponin covalently linked to a ligand for ASGPR, wherein the ligand for AGPR comprises at least one GalNAc moiety (claim 58). The claims of ‘769 recites the saponin is SO1861 and among others (claim 61). The claims of ‘769 recite a pharmaceutical composition comprising first composition comprising the saponin conjugate of claim 58 and second composition comprising an conjugate of an effector molecule and a ligand for ASGPR (claim 64). The claims of ‘769 recite the effector molecule can be a plant toxin, antisense oligonucleotide, and among others (claims 67 and 69-71). The claims of ‘769 recite a method of treating a cancer, an infectious disease, and among others as well an in vitro or ex vivo method for transferring the conjugate from outside to inside a cell (claims 75-77).
The claims of ‘769, however, do not recite a composition further comprising a saponin derivative that comprises a saccharide chain that has been derivatized on the carboxyl group of a glucuronic acid moiety using an AEM linker and an aglycone core structure comprising an aldehyde group which has been derivatized by transformation into a hydrazone bond through reaction with EMCH as well as the recited molecules in claim 24.
The independent teachings of Wada, US’502, Marciani, and Qi are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have conjugated the SO1861 of ‘769 to an effector molecule of ‘769 as suggested by Wada and US’502 at either the carboxyl group of a glucuronic acid moiety on the saccharide chain or the aldehyde group of the quillaic acid as disclosed in US’502 using the EMCH linker as suggested by Marciani and Qi, and/or further conjugating a positively charged cationic/lipophilic chain at the carboxyl group of a glucuronic acid moiety as disclosed in US’502 using an AEM linker as suggested by Marciani and Qi to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating the SO1861 to the effector molecule to yield predictable results and would have a reasonable expectation of success in doing so because Wada provides guidance of multifunctionalized ASOs with the same GalNAc targeting moiety as well as cholesterol moiety that serves a similar purpose as the saponin compounds of improving delivery of oligonucleotides, and further discloses that these multifunctionalized ASOs reduce the nephrotoxic potential of ASOs. Furthermore, US’502 also provides guidance of complexing saponin derivatives with nucleic acids to help facilitate the delivery into the cytosol of a target cell.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating the effector molecule or side chain moiety at either the carboxyl group of a glucuronic acid moiety on the saccharide chain or the aldehyde group of the quillaic acid to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of forming saponin conjugates as these positions and performing the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell.
One of ordinary skill in the art would have combined prior art elements according to known methods of using the EMCH or AEM linker to yield predictable results and would have a reasonable expectation of success in doing so because Marciani provides guidance of forming lipophile - saponin conjugates using heterobifunctional linkers as described above, and Qi demonstrates the use of an heterobifunctional EMCH or AEM linker for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
Lastly, while the recited Molecule 2 and 3 structures do not show an effector conjugate being attached to the EMCH linker, the modified saponin conjugate as described above from the combination of the claims and references would result in the formation of either the Molecule 2 or 3 structure because the combined claims and references recite the same EMCH linker being attached at the same position of the recited saponin (SO1861) before the conjugation of the effector conjugate.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6, 12-14, 16, 19-21, 23-26, and 36-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/571,599 (‘599) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), and Marciani et al. (US5977081A in PTO-892 dated 11/14/2025).
The claims of ‘599 recite an oligonucleotide conjugate comprising at least one saponin covalently linked to a ligand for ASGPR according to the recited DD1 structure, which is further covalently linked to an oligonucleotide (claim 20). The claims of ‘599 recite the saponin is SO1861 with the conjugation shown according to molecule (VII)a. The claims of ‘599 recite a method for the treatment of a cancer, an infectious disease, and among others by administering the recited conjugate.
The claims of ‘599, however, do not recite an EMCH linker and do not recite a saccharide chain that has been derivatized on the carboxyl group of a glucuronic acid moiety using an AEM linker
The independent teachings of US’502, Marciani and Qi are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the linker recited in the claims of ‘599 with the EMCH linker recited in Qi and/or to further conjugate a positively charged cationic/lipophilic chain at the carboxyl group of a glucuronic acid moiety as disclosed in US’502 using an AEM linker as suggested by Marciani and Qi to arrive at the claimed invention to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (linker in ‘599) for another (EMCH linker) to obtain predictable results and would have a reasonable expectation of success in doing so because both ‘599 and Qi disclose the use of bifunctional linkers for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating the effector molecule or side chain moiety at either the carboxyl group of a glucuronic acid moiety on the saccharide chain or the aldehyde group of the quillaic acid using an EMCH or AEM linker to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of forming saponin conjugates as these positions and performing the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell. Furthermore, Marciani provides guidance of forming lipophile - saponin conjugates using heterobifunctional linkers as described above, and Qi demonstrates the use of an heterobifunctional EMCH or AEM linker for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
Lastly, while the recited Molecule 2 and 3 structures do not show an effector conjugate being attached to the EMCH linker, the modified saponin conjugate as described above from the combination of the claims and references would result in the formation of either the Molecule 2 or 3 structure because the combined claims and references recite the same EMCH linker being attached at the same position of the recited saponin (SO1861) before the conjugation of the effector conjugate.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 10, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/571,599 (‘599) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), Cawley et al. (PNAS, 1981 in PTO-892 dated 11/14/2025), and Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025 dated 11/14/2025)
The combined references of ‘599 in view of Qi, US’502, and Marciani are as described above and teach the pharmaceutical combination of instant claim 1 as discussed above.
The combined references, however, do not recite wherein the effector molecule is a toxin which comprises or consists of at least one proteinaceous molecule.
The independent teachings of Cawley and Weng are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to substitute the oligonucleotide recited in the combined references described above with the fragment A of diphtheria toxin (DTA) of Cawley and as suggested by Weng to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (oligonucleotide) for another (DTA) to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined references described above and Cawley teach effector molecules that are conjugated to a ASGPR ligand for enhanced delivery into cells, and Weng further discloses SO 1861 triggers the endo-/lysosomal escape of a similar toxin into the cytosol of cells.
In regards to instant claim 30, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used the conjugate composition as disclosed by the combined references described above for an in vitro method for transferring the conjugate outside a cell to inside a cell as disclosed in Weng to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Weng provides guidance that SO1861 can enhance the escape of the genetic cargo out of the intracellular compartments into the cytosol, which is critical for the successful delivery of nucleic acids.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6, 12-14, 16, 19-21, 23-26, and 36-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/044,945 (‘945) in view of US20040242502A1 (in PTO-892), Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), and Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025).
The claims of ‘945 recite an oligonucleotide conjugate comprising at least one saponin covalently linked to a ligand for ASGPR, wherein the ASGPR ligand comprises at least one GalNAc moiety, and further covalently linked to an oligonucleotide (claim 1). The claims of ‘945 recite the conjugate is represented by the recited Molecule 2 structure (claim 17). The claims of ‘945 recite the oligonucleotide is an ASO (claim 30), and recites a method of treating cancer, an infectious disease, and among others using the recited conjugate.
The claims of ‘945, however, do not recite a saccharide chain that has been derivatized on the carboxyl group of a glucuronic acid moiety using an AEM linker.
The independent teachings of US’502, Marciani and Qi are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the conjugate recited in the claims of ‘845 by further conjugating a positively charged cationic/lipophilic chain at the carboxyl group of a glucuronic acid moiety as disclosed in US’502 using an AEM linker as suggested by Marciani and Qi to arrive at the claimed invention to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating the side chain moiety at the carboxyl group of a glucuronic acid moiety on the saccharide chain using an AEM linker to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of forming saponin conjugates as this position and performing the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell. Furthermore, Marciani provides guidance of forming lipophile - saponin conjugates using heterobifunctional linkers as described above, and Qi demonstrates the use of an heterobifunctional EMCH or AEM linker for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 10, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/044,945 (‘945) in view of US20040242502A1 (in PTO-892), Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025), Cawley et al. (PNAS, 1981 in PTO-892 dated 11/14/2025), and Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025)
The combination of the claims of ‘945 and the teachings of US,502, Marciani, and Qi are as described above and teach the pharmaceutical combination of instant claim 1 as discussed above.
The combined references, however, do not teach wherein the effector molecule is a toxin which comprises or consists of at least one proteinaceous molecule.
The independent teachings of Cawley and Weng are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to substitute the oligonucleotide recited in the combined references described above with the fragment A of diphtheria toxin (DTA) of Cawley and as suggested by Weng to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (oligonucleotide) for another (DTA) to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined references described above and Cawley teach effector molecules that are conjugated to a ASGPR ligand for enhanced delivery into cells, and Weng further discloses SO 1861 triggers the endo-/lysosomal escape of a similar toxin into the cytosol of cells.
In regards to instant claim 30, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used the conjugate composition as disclosed by the combined references described above for an in vitro method for transferring the conjugate outside a cell to inside a cell as disclosed in Weng to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Weng provides guidance that SO1861 can enhance the escape of the genetic cargo out of the intracellular compartments into the cytosol, which is critical for the successful delivery of nucleic acids.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6, 12-14, 16, 19-21, 23-26, and 36-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/986,821 (‘821) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), and Marciani et al. (US5977081A in PTO-892 dated 11/14/2025).
The claims of ‘821 recite a therapeutic method of treating a subject suffering from a disease or condition related to a defect in the expression of a gene and/or a disease or condition that is treatable by modulating the expression and/or expression level of a gene; said therapeutic method comprising: i) the administration, to said subject, preferably the repeated administration, of a nucleic acid or oligonucleotide therapeutic that is capable of modulating the expression of said gene and/or modulating the expression level of said gene; and ii) the administration, to said subject, of the saponin component; wherein the saponin component is administered after the nucleic acid or oligonucleotide therapeutic has been administered, resulting in an extension of the duration of effect of the nucleic acid or oligonucleotide therapeutic and/or in an extension of the dosing interval of the nucleic acid or oligonucleotide therapeutic and/or in a reduction of the dosing frequency of the nucleic acid or oligonucleotide therapeutic and/or in a (delayed) boost in the effect of the nucleic acid or oligonucleotide therapeutic (claim 37). The claims of ‘821 recite the saponin is a SO1861 and among others (claim 39). The claims of ‘821 recite wherein saponin component comprises a saponin moiety with covalently bound thereto a linker, or wherein said saponin component comprises a saponin moiety with covalently bound thereto a linker with a further molecule covalently bound to the linker, wherein said further molecule is a ligand for binding to an endocytic cell-receptor (claim 40). The claims of ‘821 recite ligand is a protein ligand capable of binding to an endocytic cell-surface receptor, such as a cytokine or EGF; an antibody; a non-proteinaceous ligand capable of binding to an endocytic cell-surface receptor, such as a ligand for asialoglycoprotein receptor (ASGPR) (see claim 42). The claims of ‘821 recite the oligonucleotide is an ASO and among others (claim 43). The claims of ‘821 recite the disease or condition is Homozygous familial hypercholesterolemia and/or (other) apoB-100-related diseases, and among others (claim 45).
The claims of ‘821, however, do not recite a composition further comprising a saponin derivative that comprises a saccharide chain that has been derivatized on the carboxyl group of a glucuronic acid moiety using an AEM linker and an aglycone core structure comprising an aldehyde group which has been derivatized by transformation into a hydrazone bond through reaction with EMCH as well as the recited molecules in claim 24.
The independent teachings of Qi, US’502, and Marciani are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the linker in the conjugate recited in the claims of ‘831 with the EMCH linker disclosed in Qi to attach the saponin at the aglycone core structure comprising an aldehyde group as disclosed in US’502, and/or to further conjugate a positively charged cationic/lipophilic chain at the carboxyl group of a glucuronic acid moiety as disclosed in US’502 using an AEM linker as suggested by Marciani and Qi to arrive at the claimed invention to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (linker in ‘831) for another (EMCH linker) to obtain predictable results and would have a reasonable expectation of success in doing so because both ‘831 and Qi recite the use of bifunctional linkers for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
One of ordinary skill in the art would have combined prior art elements according to known methods of conjugating the effector molecule or side chain moiety at either the carboxyl group of a glucuronic acid moiety on the saccharide chain or the aldehyde group of the quillaic acid using an EMCH or AEM linker to yield predictable results and would have a reasonable expectation of success in doing so because US’502 provides guidance of forming saponin conjugates as these positions and performing the same function of facilitating the delivery of nucleic acids into the cytosol of a target cell. Furthermore, Marciani provides guidance of forming lipophile - saponin conjugates using heterobifunctional linkers as described above, and Qi demonstrates the use of an heterobifunctional EMCH or AEM linker for a similar carbohydrate-based conjugate to improve the delivery of similar effector molecules into cells.
Lastly, while the recited Molecule 2 and 3 structures do not show an effector conjugate being attached to the EMCH linker, the modified saponin conjugate as described above from the combination of the claims and references would result in the formation of either the Molecule 2 or 3 structure because the combined claims and references recite the same EMCH linker being attached at the same position of the recited saponin (SO1861) before the conjugation of the effector conjugate.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 10, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/986,821 (‘821) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892 dated 11/14/2025), US20040242502A1 (in PTO-892), Marciani et al. (US5977081A in PTO-892 dated 11/14/2025), Cawley et al. (PNAS, 1981 in PTO-892 dated 11/14/2025), and Weng et al. (Journal of Controlled Release, 2015 in PTO-892 dated 11/14/2025)
The combined references of ‘821 in view of Qi, US’502, and Marciani are as described above and teach the pharmaceutical combination of instant claim 1 as discussed above.
The combined references, however, do not teach wherein the effector molecule is a toxin which comprises or consists of at least one proteinaceous molecule.
The independent teachings of Cawley and Weng are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to substitute the oligonucleotide recited in the combined references described above with the fragment A of diphtheria toxin (DTA) of Cawley and as suggested by Weng to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (oligonucleotide) for another (DTA) to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined references described above and Cawley teach effector molecules that are conjugated to a ASGPR ligand for enhanced delivery into cells, and Weng further discloses SO 1861 triggers the endo-/lysosomal escape of a similar toxin into the cytosol of cells.
In regards to instant claim 30, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used the conjugate composition as disclosed by the combined references described above for an in vitro method for transferring the conjugate outside a cell to inside a cell as disclosed in Weng to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Weng provides guidance that SO1861 can enhance the escape of the genetic cargo out of the intracellular compartments into the cytosol, which is critical for the successful delivery of nucleic acids.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments filed on 03/12/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant requests the non-statutory double patenting rejections to be held in abeyance until allowable subject matter has been identified in the instant application.
Since allowable subject matter has not yet been identified, the non-statutory double patenting rejections over the reference applications are maintained.
Conclusion
No claim is found allowable.
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 DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-5PM.
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 at 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.
/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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