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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 06/22/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 02/19/2026 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 06/22/2026, claims 1, 4-6, 9-11, 13, 17-19, 21-23, 26, 27, 29, 30, 35, 38 and 43 are pending. Claims 1, 4-6, 9-11, 13, 18, 19, 21-23, 26, 27, 29, 30, 35 and 38 are currently under examination. Claims 17 and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Any rejection not reiterated in this Office Action is hereby withdrawn.
Maintained Rejections
Claim Objections
Claim 9 remains objected to because of the following informalities: The claim recites monosaccharides that are recited by their symbol and not the full name. These monosaccharides should be spelled out the first time they are used in a claim followed by their symbol. For example Galactose represents Gal, Xylose represents Xyl and D-Glucuronic acid represents GlcA. Appropriate correction is required.
Claim Rejections – Improper Markush
Claims 5 and 9 remain rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to an oligonucleotide conjugate comprising at least one saponin linked to a GalNAc moiety wherein the saponin comprising a saccharide chain bound to the aglycone core structure selected from a vast number of different saccharide chains in claims 5 and 9.
Applicant’s arguments are not persuasive. Applicant argues “the claimed alternatives are linked by a common technical contribution and a shared structure-function relationship. In particular, the saponins recited in claims 5 and 9 share the same essential structural feature, namely the aglycone core as defined in claim 1, a monodesmosidic or bidesmosidic pentacyclic triterpene saponin of the 12,13-dehydrooleanane type bearing an aldehyde function at position C-23. The remaining saccharide chains represent alternative structures that nonetheless provide the same EEE effect and therefore satisfy the requirements for a proper and allowable grouping”.
Applicant has not provided any evidence for the statement the “remaining saccharide chains represent alternative structures that nonetheless provide the same EEE effect”. As stated previously, activity of any specific saccharide chain is dependent upon the specific combination of individual monosaccharides. Table A1 in the instant specification describes the endosomal and lysosomal escape enhancing activity of different saccharide chains with groups having different aglycone cores. There is no expectation that any one of the nucleotide sequences as claimed can be substituted for any of the other with a completely different sequence with the expectation of the same activity.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
Claims Rejections – 35 USC § 103
The rejection of claims 1, 4-6, 9-11, 13, 18, 19, 21-23, 26, 27, 29 and 30 under 35 U.S.C. 103 as being unpatentable over Lu, Yuping, et al. ("Antiproliferative quillaic acid and gypsogenin saponins from Saponaria officinalis L. roots." Phytochemistry 113 (2015): 108-120), Marciani et al. (US20040242502) and Sewing et al. (March 2019 cited on IDS filed 10/21/2024) is maintained for the reasons of record.
Applicant argues Lu et al. does not specifically disclose SO1831 or SO1832 or any derivative thereof. Applicant argues Lu et al. distinguishes QS21 as superior to SO1831 or SO1832 whereas the instant application these saponins are treated as equivalent because they share a common endosomal escape enhancing effect. In response, claim 1 broadly recites any saponin and claim 6 recites the saponins in the alternative. Thus a prior art reference that teaches any of the saponins would anticipate the claims. Lu et al. teach QS21 and this is acknowledged by Applicant on page 15 of the response filed 06/22/2026.
Applicant next argues Marciani et al. explicitly teach aldehyde-contain saponins are not suitable stimulators when used with DNA and RNA vaccines and a person of ordinary skill in the art would not be motivated to omitting the positively charged chain to directly conjugate to an oligonucleotide. In response Marciani et al. teach the aldehyde group at position C-23 can be derivatized and teach the use of saponin adjuvants along with nucleic acids and further teach the saponin derivative can comprise a nucleic acid such as an antisense. Thus it would have been obvious to incorporate the teachings of Marciani et al. with Lu et al.
Applicant then argues Sewing et al. does not teach a three component systems or recognize the synergist interaction between a GalNAc-oligonucleotide conjugate and a saponin to enhance endosomal escape. Applicant is arguing limitations that are not in the claim. Sewing et al. teach tri-GalNAc conjugates for delivering oligonucleotides, such as antisense oligonucleotides (Figure 1A). Sewing et al. teach tri-GalNAc structure can comprise cleavable linkers (page 71). Sewing et al. teach use of the GalNAc conjugate had favorable properties for delivery of the antisense oligonucleotide to cells. It would have therefore been obvious to conjugate the GalNAc moiety to the antisense oligonucleotide for delivery to cells to induce immune responses given Marciani et al. Lu and Marciani et al. together provide motivation to use a saponin derivative along with an oligonucleotide for induction of an immune response in a subject.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
The rejection of claim 35 under 35 U.S.C. 103 as being unpatentable over Lu, Yuping, et al. ("Antiproliferative quillaic acid and gypsogenin saponins from Saponaria officinalis L. roots." Phytochemistry 113 (2015): 108-120), Marciani et al. (US20040242502) and Grijalvo, Santiago, et al. ("Covalent strategies for targeting messenger and non-coding RNAs: an updated review on siRNA, miRNA and antimiR conjugates." Genes 9.2 (2018)) is maintained for the reasons of record.
Applicant argues Marciani et al. and Grijalvo, Santiago, et al do not recognize or suggest the central contribution of the invention, namely, the use of a saponin to enhance endosomal escape. Applicant is arguing limitation that are not in the claim.
It would have been obvious to use the antisense linked to a GalNAc moiety to restore the function of a miRNA in a subject and further linked to a saponin derivative given Marciani et al. Lu and Marciani et al. together provide motivation to use a saponin derivative along with an oligonucleotide for treatments in a subject.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Written Description
The rejection of claims 1, 4-6, 9-11, 13, 18, 19, 21-23, 26, 27, 29, 30, 35 and 38 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 is maintained for the reasons of record.
Applicant argues written description rejection does not reflect the disclosure as a whole, particularly Examples lA-1D, 2, and 3, which provide multiple working embodiments demonstrating:
" Different effector cargos (protein toxin, antisense oligonucleotides),
" Different gene targets (apoB, HSP27; scrambled controls),
" Different conjugation architectures (non-covalent combinations vs. covalent three- component conjugates),
" Different linker chemistries (labile vs. non-cleavable),
" Different valencies and stoichiometries, and
" A consistent functional outcome (endosomal escape enhancement) attributable to the saponin component.
This argument is not persuasive because describing a protein toxin cargo or an antisense oligonucleotide does not represent the genus which encompasses a vast number of oligonucleotide which can include RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing using a CRISPR/Cas system, LNA, BNA, xeno nucleic acids, aptamers, decoy oligonucleotides, lncRNA and antisense molecules, for example. While the genus encompasses a large number of different nucleic acids, the specification and claims do not indicate what distinguishing characteristics are concisely shared by the members of the broad genus that would convey to one of skill in the art that these oligonucleotides represent the entire genus. Specifically, the specification does not indicate what distinguishing characteristics are shared between a protein toxin cargo or antisense and any oligonucleotide, particularly an oligonucleotide conjugate linked to a GalNAc moiety.
Further, describing a protein toxin cargo or an antisense oligonucleotide targeting two target genes, apoB and HSP27, does not represent the genus which encompasses a vast number of gene targets wherein the function is gene silencing and inducing endosomal escape.
With respect to the genus of saponins, describing SO1861 in the oligonucleotide conjugate does not represent the genus which encompasses a vast number of saponin structures, particularly as in claims 5, 9 and claims 6 reciting SO1861 derivatives and SO1862 derivatives. The genus of saponins is vast, particularly as recited in claim 1 and as described in the specification (0274 published application): the saponin is selected from the group consisting of: Quillaja bark saponin, dipsacoside B, saikosaponin A, saikosaponin D, macranthoidin A, esculentoside A, phytolaccagenin, aescinate, AS6.2, NP-005236, AMA-1, AMR, alpha-Hederin, NP-012672, NP-017777, NP-017778, NP-017774, NP-018110, NP-017772, NP-018109, NP-017888, NP-017889, NP-018108, SA1641, AE X55, NP-017674, NP-017810, AG1, NP-003881, NP-017676, NP-017677, NP-017706, NP-017705, NP-017773, NP-017775, SA1657, AG2, SO1861, GE1741, SO1542, SO1584, SO1658, SO1674, SO1832, SO1862, SO1904, QS-7, QS1861, QS-7 api, QS1862, QS-17, QS-18, QS-21 A-apio, QS-21 A-xylo, QS-21 B-apio, QS-21 B-xylo, beta-Aescin, Aescin Ia, Teaseed saponin I, Teaseedsaponin J, Assamsaponin F, Digitonin, Primula acid 1 and AS64R, stereoisomers thereof, derivatives thereof, and combinations thereof, preferably the saponin is selected from the group consisting of QS-21, a QS-21 derivative, SO1861, a SO1861 derivative, S01832, a S01832 derivative, SA1641, a SA1641 derivative, GE1741, a GE1741 derivative and combinations thereof, more preferably the saponin is selected from the group consisting of a QS-21 derivative, a SO1861 derivative and combinations thereof, most preferably the saponin is a SO1861 derivative. More preferred, the saponin is selected from the group consisting of QS-21, a QS-21 derivative, SO1861, a SO1861 derivative, SA1641, a SA1641 derivative, GE1741, a GE1741 derivative and combinations thereof, more preferably the saponin is selected from the group consisting of a QS-21 derivative, a SO1861 derivative, SO1861 and combinations thereof, most preferably the saponin is a SO1861 derivative or SO1861, or a SO1832 derivative or SO1832.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every type of oligonucleotide capable of reducing expression of ApoB. The genus of oligonucleotides can include RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing using a CRISPR/Cas system, LNA, BNA, xeno nucleic acids, aptamers, decoy oligonucleotides, lncRNA and antisense molecules.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
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. See 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);and, 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
The rejection of claims 1, 4-6, 18, 19, 21-23, 26, 29, 30, 35 and 38 are provisionally rejected under the judicially created doctrine of double patenting over claims 64-71 and 75-77 of co-pending Application No. 18,012,769 (App769).
Applicant’s argument regarding claims 58-63 are persuasive however claims 64-71 and 75-77 and the instant claims are not patentably distinct from each other because the instant claims and the claims of the patent are drawn to patently indistinguishable subject matter.
This is a provisional obviousness-type double patenting rejection.
The rejection of claims 1, 4-6, 9-11, 13, 18, 19, 22-23, 26, 27, 29, 30, 35 and 38 are provisionally rejected under the judicially created doctrine of double patenting over claims 1-37 co-pending Application No. 18,571,599 (App599).
Applicant’s argument regarding instant claim 21 are persuasive however claims 1-37 of App599 and the instant claims are not patentably distinct from each other because the instant claims and the claims of the patent are drawn to patently indistinguishable subject matter. The instant claims are drawn to a GalNAc moiety which encompasses the GalNAc moiety of App599.
This is a provisional obviousness-type double patenting rejection.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at (571)272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636
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