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 .
This Office action is in response to the communications filed 12-22-25.
Claims 58-77 are pending in the instant application.
Election/Restrictions
Claims 69, 71, 75-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12-22-25.
Applicant’s election without traverse of Group I, gypsogenin as the aglycone structure, Gal-(1--2)-[Xyl-(1--3)]-GlcA as the saccharide chain, S01861 as the saponin, antisense oligonucleotides, apolipoprotein B (apoB) as the effector molecule, claims 58-68, 70, 72-74, in the reply filed on 12-22-25 is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 58-68, 70, 72-74 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims:
The claims are drawn to compositions comprising at least one saponin conjugate covalently linked either directly or indirectly via a linker to a ligand for asialoglycoprotein receptor (ASGPR) comprising at least one N-acetylgalactosamine (GalNAc) moiety optionally comprising (GalNAc)3, which saponin is optionally any monodesmosidic, triterpenoid, or bidesmosidic triterpenoid saponin, and which saponin optionally further comprises any aglycone core structure, and which saponin conjugate optionally further comprises a saccharide chain bound to the aglycone core structure and optionally comprising the saccharides listed in claim 60, which conjugate optionally comprises between 1-128 saponin moieties, which compositions optionally further comprise an oligonucleotide capable of silencing apolipoprotein B (apo B), or which composition optionally further comprises another conjugate comprising an effector molecule and a binding site for a cell surface molecule, or optionally further comprising a third conjugate comprising a receptor ligand drug conjugate.
Teachings in the art:
The teachings in the art address concerns about the structure function relationship of saponins, the unpredictable effects of mixing and matching sugars and saccharide chains with aglycone core structures. According to Cao et al (Molecular Pharmaceutics, Vol. 17, pages 683-694 (Jan. 8, 2020)), structure function relationships are based on the studies of a limited number of saponins with similar structures. The diversity of the sidechain structures and biological acidity of oleanane type saponins illustrate the highly complex relationship between saponin structure and activity. (pages 683-684)
In addition, on page 514, right column, Sama et al (Planta Med., Vol. 85, pages 513-518 (2019)) characterize the findings in their instant study as
…a valuable first impression of the structure activity relationship of triterpenoid saponins. Nevertheless, a number of open questions remain unanswered and need to be taken under consideration: Does the hydroxyl group at C-16 in quillaic acid (aglycon) play a positive role? Which and how many modifications of the sugar chains are necessary? Can specific sugars in one of the sugar chains be determined? And finally, which structural features play a more and which a less important role?
[Emphasis added].
Teachings in the specification:
The specification teaches the general toxicity (MTS) of GalNAc-SO1861 and trivalent-GalNAc-SO1861 on HepG2 cells in vitro. The specification teaches trivalent GalNAc conjugated with SO1861 ((GN)₃-SPT), the combination of 10 pM monoclonal antibody anti-CD71 conjugated with saporin (CD71-SPRN) and a concentration series of SO1861 with EMCH bound to the aglycone aldehyde group (SPT-EMCH), the combination of 10 pM CD71-SPRN and a concentration series of (GN)₃-SPT, and the combination of 10 pM CD71-SPRN and a concentration series of (GN)₃ conjugated with a dendron with four SO1861 moieties covalently bound thereto (DAR = 4 for the bound SO1861) ((GN)₃-dSPT4), and trivalent GalNAc conjugated with SO1861 (Trivalent GalNAc-SPT001), the combination of 10 pM monoclonal antibody anti-CD71 conjugated with saporin (CD71-saporin) and a concentration series of covalent conjugate Trivalent GalNAc-SPT001.
These teachings are not representative or correlative of the myriad of the combinations of saccharides, saponins, and conjugated entities instantly claimed. The specification, prior art and claims do not adequately describe the genus of compositions of conjugate and modulatory agents claimed, and/or fail to provide a representative number of species, and do not indicate what distinguishing attributes are concisely shared by the members of this genus.
For the reasons stated above, the instant rejection for lacking adequate written description is proper.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 58-68, 70, 72-74 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sama et al (Planta Med., Vol. 85, pages 513-518 (2019)), Cao et al (Molecular Pharmaceutics, Vol. 17, pages 683-694 (Jan. 8, 2020)), Weng et al (J. Controlled Release, Vol. 164, pages 74-86 (2012)), Wang et al (Molecular Therapy Nucleic Acids, Vol. 11, pages 192-202 (2018)), Sucheck et al (WO 2013/123282), and JP 2004/534088, the combination in view of Boons et al (WO 2011/156751) and Wada et al (Nucleic Acid Therapeutics, Vol. 28, No. 1, pages 50-57 (2018)), the combination further in view of Heyes et al (US 2013/0123339).
The claims are drawn to compositions comprising at least one saponin conjugate covalently linked either directly or indirectly via a linker to a ligand for asialoglycoprotein receptor (ASGPR) comprising at least one N-acetylgalactosamine (GalNAc) moiety optionally comprising (GalNAc)3, which saponin is optionally a monodesmosidic, triterpenoid, or bidesmosidic triterpenoid saponin, and which saponin optionally further comprises an aglycone core structure comprising gypsogenin, and which saponin conjugate optionally further comprises a saccharide chain bound to the aglycone core structure and optionally comprising Gal-(1--2)-[Xyl-(1--3)]-GlcA, which conjugate optionally comprises between 1-128 saponin moieties, which compositions optionally further comprise an oligonucleotide capable of silencing apoliprprotein B (apo B), or which composition optionally further comprises another conjugate comprising an effector molecule and a binding site for a cell surface molecule, or optionally further comprising a third conjugate comprising a receptor ligand drug conjugate.
Sama et al (Planta Med., Vol. 85, pages 513-518 (2019)) teach the ability of certain triterpenoid saponins to modulate endosomal release in target cells. Sama studies the structure activity relationship of several diverse saponins for their transfection improving ability. Sama teaches the saponin SO1861 for ensuring enhanced gene delivery. Sama teaches the structure of SO1861, including the carbohydrate chains on the aglycone core (see esp. page 513 and the text and illustration on page 514, Figure 1 on page 515.
On page 514, right column, Sama characterizes the findings in this study as
…a valuable first impression of the structure activity relationship of triterpenoid saponins. Nevertheless, a number of open questions remain unanswered and need to be taken under consideration: Does the hydroxyl group at C-16 in quillaic acid (aglycon) play a positive role? Which and how many modifications of the sugar chains are necessary? Can specific sugars in one of the sugar chains be determined? And finally, which structural features play a more and which a less important role?
Sama describes an overview of tested saponins in terms of structure and transfection efficiency (Figure 3 on page 516) and provides a hypothetical ideal saponin for reaching high efficiency levels (see Figure 4 on page 517).
Cao et al (Molecular Pharmaceutics, Vol. 17, pages 683-694 (Jan. 8, 2020)) (See IDS filed 12-22-25) teach that plant based saponins are amphipathic glycosides composed of a hydrophobic aglycone backbone covalently bound to one or more hydrophilic sugar moieties. Triterpenoid saponins are being investigated for their endosomal escape activity and improved cytosolic penetration of co-administered protein drugs internalized by endocytic uptake. There is a paucity in understanding the structure-activity relationship of saponins. Cao screened 12 triterpenoid saponins with diverse structural side chains for their use as endosomolytic agents and their synergistic effects on toxins. Cao teaches that glycosylated triterpenoids are a class of saponins comprising a triterpene aglycone to which one or more sugar moieties are attached, giving rise to a diversity of structural variations. According to Cao, these metabolites are thought to play a role in defense against herbivores and pathogens.
Cao teaches that the most common glycosylated triterpenoids are tetracyclic triterpenes, cucurbitane, dammarane and Ianostane, and pentacyclic triterpenoids, oleanane and lupine. The striking efficacy of oleanane-type triterpenoids saponins in enhancing endosomal escape of protein drugs makes it extremely attractive for therapeutic development. Saponinum album obtained from Gypsophila paniculata L. enhances cytotoxicity of saponin derived target toxins by more than 10,000 times. Analysis of the saponin SO1861 revealed the contribution of C-4, C-28 and C-16 sidechains to its endosomal escape activity. The role of charge in saponin mediated endosomal escape showed that saponins with different relative electrophoretic mobilities exerted distinct endosomal escape. Saponins greater than 1600 g/mol with branched trisaccharide at C-3 containing a glucuronic acid and branched sugar chains attached at C-28 are necessary for activity. According to Cao, structure function relationships are based on the studies of a limited number of saponins with similar structures. The diversity of the sidechain structures and biological acidity of oleanane type saponins illustrate the highly complex relationship between saponin structure and activity. (pages 683-684) Cao discloses the structures of the 12 oleanane type triterpenoid saponins and compares their enhancement of toxin activity and endosomal escape (Table 1 and Figure 1 on page 686; see also Figure 6 on page 690, text on pages 690-691).
Weng et al (J. Controlled Release, Vol. 164, pages 74-86 (2012)) (See IDS filed 12-22-25) teach saporin to be a group of N-glycosidases that are categorized as type 1 ribosome inactivating proteins, but do not contain a natural cell binding domain. Saporin is isolated from the seeds of Saponariia officinalis L and synthesizes huge amounts of a complex mixture of triterpenoid saponins. Triterpenoids are saponins that consist of a hydrophobic backbone, aglycone, and one or two branched hydrophilic carbohydrate moieties attached to the aglycone. (see text on pag74). Weng teaches the structures of the saponins SA1641 and SA1657 (Figure 1 on page 76). Weng discloses that triterpenoid saponins (SA1641) trigger the release of internalized saporin out of late endosomes/lysosomes into the cytosol, leading to cytotoxicity. The toxicity of triterpenoid saponin containing plants such as Saponaria officinalis L. or Agrostemma githago L. is generally attributed to the content of saponins. Weng teaches therapeutic efficacy of the synergistic principle of saponin plus type 1 ribosome inactivating proteins using highly purified triterpene saponin SA1641 in combination with saporin – EGF as anti-tumor agents, showing triterpene saponins as valuable tolls to augment the cytosolic delivery of anti-tumor toxins (text on pages 84-85).
Wang et al (Molecular Therapy Nucleic Acids, Vol. 11, pages 192-202 (2018)) (See IDS filed 12-22-25) teach a comparison of a few saponins for their potential to improve delivery performance of antisense oligomers. The saponins, especially digitonin and tomatine improved delivery efficiency of the oligonucleotides. Wang demonstrates optimization of saponins in molecular size and composition as key factors for providing higher efficiency and lower toxicity for antisense therapy (text on page 192, Conclusions on page 198). Wang teaches the structures of the saponins digitoxin, tomatine and glycyrrhizin (Figure 1 on page 193).
Sucheck et al (WO 2013/123282) teach vaccines comprising lipid peptide conjugates, mucin 1 peptides conjugated to tumor associated carbohydrate antigens (TACA), and various linkers for covalent conjugation, including TACAs comprising GalNAc termini. (See pages 13, 14, 16). Sucheck teaches sugar epitopes comprising beta linked alpha galactose disaccharide epitopes and alpha and beta linked Forssmann disaccharide epitopes. Sucheck teaches compositions comprising multiple conjugates comprising sugar, lipid and antigen moieties covalently linked. Antigens are also conjugated to lipids, including cholesterol, using linkers such as tretraethylene glycol (TEG). (see pages 3-6, 18, 19, 24-25, 27, 35, 42). Sucheck teaches compositions comprising antigens, sugars and the immunologic adjuvant, saponin (e.g., QS21) (see page 19).
JP 2004/534088 (hereinafter “JP”) teaches compositions comprising tumor specific antigen conjugates in heptavalent vaccines and in vaccines comprising at least two conjugated antigens optionally comprising glycolipid, polysaccharide, mucin and glycosylated mucin antigens in combination with the saponin based adjuvants, QS21 and GPI-0100 (see paragraphs 0004-0013, 0028, 0035). Covalent linkages are described in paragraph 0139. The saponins are compared for their effective adjuvant activity (para 0148).
Boons et al (WO 2011/156751) teach conjugates for vaccines comprising carbohydrate components, lipids and mucin 1 (MUC1) peptides. Boons teaches glycosylated MUC1 glycopeptide components comprising GalNAc, GlcNAc, Gal, fucose, mannose, glucose, NANA or NGNA (abstract, page 6, Figures 26, 28, pages 16-25, 77-78, 95, 103, 49-54).
Wada et al (Nucleic Acid Therapeutics, Vol. 28, No. 1, pages 50-57 (2018)) (See IDS filed 12-22-25) teach dual conjugation strategies for reducing renal distribution of antisense oligonucleotides by conjugating GalNAc to cholesterol (see esp. the Abstract on page 50, Figure 1 on page 51).
Heyes et al (US 2013/0123339) teach antisense oligonucleotides for inhibiting ApoB (See entire document, esp. claim 1).
It would have been obvious to produce the conjugate compositions instantly claimed because saponins have been recognized as endosomal escape agents for improving the efficiency of cell targeting and cytosolic uptake of effector proteins, cell surface binding agents, toxins for target therapy. One of ordinary skill in the art would have been motivated to include GalNAc modifications to the conjugates to reduce kidney toxicity, and optimize the saponins regarding their enhancement of cell toxicity.
For these and aforementioned reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
4-4-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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