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 7-21-26.
Claims 58-77 are pending in the instant application.
Claims 69, 71, 75-77 are withdrawn from further consideration as being drawn to a nonelected invention or species.
Claims 58-68, 70, 72-74 have been examined on their merits as set forth below.
Response to Arguments and Amendments
Withdrawn Objections/Rejections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
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 for the reasons of record set forth in the Office action mailed 4-21-26 and as set forth below.
Applicant’s Arguments
Applicant argues the following:
Applicant submits that the specification as filed amply demonstrates possession of the claimed genus of saponin conjugates comprising at least one saponin covalently linked to a GalNAc-containing ASGPR ligand. The specification introduces the saponin conjugate concept at the outset, disclosing as the first aspect of the invention "a saponin conjugate comprising at least one saponin covalently linked to a ligand for asialoglycoprotein receptor (ASGPR), wherein the ligand for ASGPR comprises at least one N-acetylgalactosamine (GalNAc) moiety, preferably three or four GalNAc moieties, more preferably the ligand for ASGPR comprises or consists of (GalNAc)3Tris, wherein the at least one saponin is selected from monodesmosidic triterpenoid saponins and bidesmosidic triterpenoid saponins." See, the as-filed Specification, at page 4 (Summary) and page 19 (Detailed Description).
The specification further identifies the structural features that define the genus: GalNAc as the ASGPR ligand moiety, covalent linkage via specified linker chemistries (including click chemistry such as azide-alkyne cycloaddition yielding a 1,2,3-triazole, and hydrazone formation), and triterpenoid saponins that are monodesmosidic or bidesmosidic. Detailed structural formulas are provided, including formulas (I), (II)S, (III)S, and (IV)S, which illustrate the GalNAc linkage to saponin moieties via linkers and bridging moieties.
Beyond the general disclosure, the specification provides extensive synthesis schemes and working examples demonstrating actual preparation and characterisation of multiple GalNAc-saponin conjugates. Figure 3 depicts the synthesis of monovalent-GalNAc-SO1861, Figure 4 depicts the synthesis of trivalent-GalNAc-SO1861, Figures 25-26 depict the synthesis of (GalNAc)3-Ls-SO1861, and Figures 33A-C depict the synthesis of dendron(SO1861)4- trivalent GalNAc. These synthesis schemes are accompanied by detailed experimental procedures including reagents, reaction conditions, purification methods, and analytical characterisation data (LC-MS). The specification thus discloses conjugates with varying GalNAc valency (monovalent and trivalent) and varying saponin loading (DAR=1, DAR=4, and DAR=8), demonstrating that the inventors had possession of a range of species within the claimed genus.
The specification further provides in vitro experimental results demonstrating the biological activity of the GalNAc-saponin conjugates on ASGPR-expressing cells, including HepG2 cells, Huh7 cells, and primary human hepatocytes (Figures 9, 29A, 30A-B, 31A-B).
Importantly, the specification also provides in vivo results in C57BL/6J mice demonstrating ApoB knockdown when (GalNAc)3-SO1861 conjugates are co-administered with GalNAc- ApoB antisense oligonucleotides (Figures 19-22), confirming functional activity of the saponin conjugates in a living system. These data collectively demonstrate that the inventors had actual possession of the claimed saponin conjugates and understood their structural and functional properties.
Applicant submits that the specification discloses far more than the limited teachings acknowledged by the Examiner. The Examiner's characterisation of the disclosure omits the detailed structural formulas, the multiple synthesis schemes, the range of conjugate architectures (monovalent, trivalent, dendron-based), and the breadth of experimental validation across multiple cell types and in vivo models. The specification identifies the common structural attributes shared by members of the genus - namely, a triterpenoid saponin (monodesmosidic or bidesmosidic) covalently linked via a linker to a GalNAc-containing ASGPR ligand - and provides a representative number of species that adequately describe the genus
Response to Applicant’s Arguments
Applicant's arguments filed 7-22-26 have been fully considered but they are not persuasive.
The breadth of the claims:
The claims are broadly 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 comprises the saccharides listed in claim 60, which conjugate optionally comprises between 1-128 saponin moieties, which composition optionally further comprises 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:
As stated previously, 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 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?
What’s more, Walkowicz et al (Chemical Science, Vol. 7, pages 2371-2380 (2016)) investigate the design, synthesis, immunologic evaluation and molecular dynamics analyses of a series of novel QS-21 variants with different linker lengths, flexibility and stereochemistry to investigate the role of linkages in saponin adjuvant activity and conformation. Conservative structural modifications were found to exhibit striking differences in adjuvant activity. Walkowicz highlights a critical role of the junction of triterpenes and linear oligosaccharide domains in immunoadjuvant activity of the Quillaja saponins. (Abstract) Linkage variants provided a remarkable range of adjuvant activities and toxicities. (Fig. 1 on page 2372; Fig. 2 on page 2376; Fig. 3 on page 2377).
[Emphases added].
Teachings in the specification:
As stated previously, 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.
Contrary to Applicant’s assertions, 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 properly maintained.
New Rejections
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 58-68, 70, 72-74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 9-11, 13, 18, 19, 21-23, 26, 27, 29, 30, 35, 38 of copending Application No. 18/044,945 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of 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 any aglycone core structure, and which saponin conjugate optionally further comprises a saccharide chain bound to the aglycone core structure and optionally comprises the saccharides listed in claim 60, which conjugate optionally comprises between 1-128 saponin moieties, which composition optionally further comprises 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
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 58-68, 70, 72-74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 27-33, 37 of copending Application No. 18/571,599 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of 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 any aglycone core structure, and which saponin conjugate optionally further comprises a saccharide chain bound to the aglycone core structure and optionally comprises the saccharides listed in claim 60, which conjugate optionally comprises between 1-128 saponin moieties, which composition optionally further comprises an oligonucleotide capable of silencing a target gene.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
9-17-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
Prosecution Insights