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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 07, 2026 has been entered.
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed on 01/07/2026 and 01/16/2026 have been considered by the Examiner inasmuch as foreign documents have been submitted into the file wrapper in English.
Claim Status
Claims 1-30, 32, 35, 37-40, 42 and 44 are canceled. Claim 36 is new. Thus, claims 31, 33-34, 36, 41 and 43 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the final office action on October 20, 2025:
The objection to claim 36 is withdrawn in view of Applicant’s amendments to claim 36.
Response to Arguments
The rejection of claims 31, 33-34, 41 and 43 under 35 U.S.C. 103 is maintained:
Applicant argues:
(A) Claim 31 has been amended to recite a saponin derivative based on an endosomal escape enhancer SO1861 as recited in amended claim 1, see Applicant’s arguments, pg. 6, 35 U.S.C. §103, paragraph 1.
(B) Claim 31 further requires specific derivatizations of the aldehyde group at position C23, the carboxyl group of a glucuronic acid in A1, and/or the acetyoxy group in A2, see Applicant’s arguments, pg. 6, 35 U.S.C. §103, paragraph 1.
(C) Zhang teaches gypsogenin which is an aglycone without any sugar chains – structurally far removed from the claimed SO1861 derivative, see Applicant’s arguments, pg. 6, 35 U.S.C. §103, paragraph 4.
(D) Gypsogenin lacks the complex bidesmosidic structure of SO1861 which comprises two specific polysaccharide chains (A1 and A2) as now recited in amended claim 31, see Applicant’s arguments, pg. 6, 35 U.S.C. §103, paragraph 4 – pg. 7, paragraph 1.
(E) The present application addresses improving the therapeutic window of saponin derivatives by reducing toxicity and hemolytic activity while preserving endosomal escape enhancing activity, see Applicant’s arguments, pg. 7, paragraph 2.
(F) In contrast, Zhang’s objective is to enhance cytotoxicity and anti-cancer activity, Applicant’s arguments, pg. 7, paragraph 3.
(G) A person of ordinary skill in the art starting from Gilabert-Oriol’s teaching of SO1861 for enhancing immunotoxin efficacy would have no motivation to apply Zhang’s cytotoxicity-enhancing modifications as it would be counterproductive to achieving an improved therapeutic window with reduced toxicity, see Applicant’s arguments, pg. 7, second paragraph from the bottom of the page.
(H) There would be no reasonable expectation of success that modifications shown to enhance cytotoxicity in simple gypsogenin algycones would preserve endosomal escape enhancing activity while reducing toxicity in complex bidesmosidic saponins like SO1861, Applicant’s arguments, pg. 7, last paragraph of the page.
(I) Zhang’s structure-activity studies are specific to gypsogenin derivatives and provide no teaching or suggestion regarding the effect of such modifications on the endosomal escape enhancing activity or therapeutic window of SO1861 derivatives, see Applicant’s arguments, pg. 8, paragraph 1.
(J) Baumer cannot remedy the deficiencies noted above in view of Gilabert-Oriol and Zhang. Baumer does not render obvious the pharmaceutical composition comprising an antibody-oligonucleotide conjugate of claim 43. The surprising effect noted in the application as filed is from the composition comprising the saponin derivative of claim 31 with an antibody-oligonucleotide conjugate, see Applicant’s arguments, pg. 8, paragraph 3.
With respect to Applicant’s arguments (A)-(J), the Examiner respectfully notes the maintained 103 rejections below teach SO1861 within the Gilabert-Oriol-1 reference and wherein the Gilabert-Oriol-2 reference teaches the triterpene aglycone core and first and second saccharide chains as recited within molecule 1 of instant claim 31.
However, the Examiner respectfully notes neither Gliabert-Oriol-1 or Gliabert-Oriol-2 teach wherein the saponin is a saponin derivative where the aldehyde group at position C23 of the guillaic acid is derivatized with a hydrazone bond, wherein the Examiner respectfully notes said limitation of a hydrazone bond corresponds to the elected species as modified by the Examiner on pg. 2 within the Election/Restrictions section, paragraph 2, of the non-final rejection mailed April 21, 2025.
Accordingly, the Examiner then introduced the Zhang reference in order to teach and respectfully notes is only relied upon to modify the aldehyde at position C23 of the guillaic acid of SO1861 which is taught by Gilabert-Oriol-2 in the maintained 103 rejections below.
The Examiner respectfully notes Zhang teaches the 2,4-dinitrophenylhydrazone at the C-23 position of compound 4, which Zhang exemplifies as a gypsogenin alygcone core, and wherein said modification enhances its anti-cancer activity. The Examiner also respectfully notes before modification with 2,4-dinitrophenylhydrazone at the C-23 position of compound 4; the previous structure of compound 4 contained an aldehyde at the C-23 position directly connected at the C-4 of the aglycone’s pentacyclic triterpenoid structure of the exemplified gypsogenin.
Additionally, the Examiner respectfully notes Gilabert-Oriol-2 teaches SO1861 having a quillaic acid core structure which is structurally similar to the gysogenin core taught by Zhang.
The Examiner further respectfully notes the only structural difference between the quillaic acid core of SO1861 taught by Gilabert-Oriol-2 and the gypsogenin aglycone core taught by Zhang is a 16α-hydroxyl group on the guillaic acid which is not present on gypsogenin.
Moreover, the Examiner respectfully reiterates Zhang teaches the chemical transformation of the C-23 aldehyde of gypsogenin into a hydrazone bond using 2,4-dinitrophenylhydrazone as a known consideration within the prior art and thereby improves gyposgenin’s anti-cancer activity.
The Examiner respectfully notes said modification as taught by Zhang is useful for the combinational approach taught by Gilabert-Oriol-1 above to further enhance the cytotoxicity of SO1861 which contains an aldehyde at position C23 of the guillaic acid core structure as taught by Gilabert-Oriol-2 above.
Therefore, the modification taught by Zhang is directly applicable to increasing the efficacy of therapeutic antibodies as taught by Gilabert-Oriol-1 above, and may help in overcoming their resistances and limitations in targeted tumor therapies also taught by Gilabert-Oriol-1 above.
With particular respect to Applicant’s arguments (E), (G), (H) and (I), specifically improving the therapeutic window of saponin derivatives by reducing toxicity and hemolytic activity while preserving endosomal escape enhancing activity in Argument (E), Argument (G) and/or Argument (H); or with respect to the inclusion of the modification of Zhang into SO1861 as taught by Gilabert-Oriol-1 on preserving endosomal escape enhancing activity while reducing toxicity in complex bidesmosidic saponins like SO1861 in Argument (H) and/or Argument (I) as discussed above; the Examiner respectfully notes improving the therapeutic window of saponin derivatives by reducing toxicity and hemolytic activity while preserving endosomal escape enhancing activity is not a required limitation within claim 31 or in any of its dependent claims or claims that rely on claim 31.
The Examiner respectfully notes to Applicants that claim 31 is drawn to a compound which the Examiner respectfully notes is taught by the combination of Gilabert-Oriol-1, Zhang and Gilabert-Oriol-2 as discussed above.
Furthermore, the Examiner particularly notes that claim 31 is a compound claim which only requires a saponin comprising a triterpene aglycone core and two saccharide chains linked to the aglycone core which is represented by Molecule 1 of instant claim 31, line 6, which the Examiner respectfully notes Gilabert-Oriol-2 teaches, and with the additional limitation that the saponin be a saponin derivative based on an endosomal escape enhancer SO1861 that is derivatized, wherein the derivatized group is the aldehyde at position C23 of the guillaic acid core structure as discussed above.
Consequently, the Examiner also respectfully notes the modification of the C-23 aldehyde within the gypsogenin aglycone core of Zhang for a 2,4-dinitrophenylhydrazone also taught by Zhang increases gypsogenin’s cytotoxic activity as taught by Zhang, and wherein the Examiner respectfully reiterates the modification taught by Zhang above is directly applicable to increasing the cytotoxicity of SO1861 by modifying SO1861’s aldehyde at the C23 position of its quillaic acid core structure as taught by Gilabert-Oriol-2 as discussed above.
Therefore, the combination of Gilabert-Oriol-1, Zhang and Gilabert-Oriol-2 teach all structural requirements required within claim 31 which is drawn to the recited compound of instant claim 31.
Finally, the Examiner also respectfully notes claims 31, 34, 41 and 43 do not require the derivatized aldehyde at position C23 of the quillaic acid of Molecule 1 be a hydrazone bond at all.
The Examiner further respectfully notes instant claim 31 only requires the aldehyde group at position C23 of the quillaic acid of Molecule 1 be derivatized, which the Examiner reasonably interprets can include any chemical structure that modifies the existing aldehyde group; additionally claim 33 only requires the aldehyde group be transformed into a hydrazone bond, which the Examiner reasonably interprets can include any chemical structure that contains a hydrazone bond, for example the hydrazone bond contained within 2,4-dinitrophenylhydrazone as taught by Zhang above in order to modify the existing C-23 aldehyde within the quillaic acid core structure of SO1861 as taught by Gilabert-Oriol-2 above for the purpose of increasing the cytotoxicity of SO1861 within the antitumor combination as taught by Gilabert-Oriol-1 above.
Therefore, in view of the foregoing reasons above, the Examiner reasonably interprets the saponin derivative as recited in claims 31, 33-34, 41 and 43 do not require the functional limitations as recited in Applicant’s arguments (E) and (G)-(I) above.
Thus, Applicant’s arguments have been fully considered but are not found persuasive.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 31, 33-34, 41 and 43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 31, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 31, pg. 3, line 6 recites the phrase “preferably any combinations of two derivatisations i., ii., and iii.”.
Thus, in the interest of compact prosecution, the Examiner will interpret the limitation “preferably” when referring to the possible derivatizations of the saponin of claim 31 as discussed above as an optional limitation that is not required by the claim.
Claims 33-34, 41 and 43 are included in this rejection as they depend from or rely on the saponin derivative of claim 31.
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.
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.
(I) Claims 31, 33-34 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Gilabert-Oriol et al. (hereafter known as "Gilabert-Oriol-1", Published 01 October 2015, Biochemical Pharmacology, Vol. 97, Issue 3, pp. 247-255, IDS filed 07/13/2022) in view of Zhang et al. (Published 24 January 2018, Royal Society Open Science, Vol. 5, Issue 1, pp. 1-19, PTO-892 mailed 04/21/2025) as evidenced by Gilabert-Oriol et al. (hereafter known as "Gilabert-Oriol-2", Published 15 April 2013, Bioorganic & Medicinal Chemistry, Vol. 21, Issue 8, pp. 2387-2395, PTO-892).
Regarding claims 31, 33-34 and 41, Gilabert-Oriol-1 teaches SO1861 is a plant saponin with a triterpenoidal skeleton of oleanane type and two sugar side chains (bisdesmosidic) attached to it at positions C-3 and C-28, see pg. 248, left column, paragraph 5. The Examiner makes the reasonable interpretation that SO1861 comprises an aldehyde group at position C-23 of the quillaic acid as evidenced by the structure of Formula (II) disclosed in the Specification (see pg. 3, Formula II); and wherein the Specification discloses Formula (II) as SO1861 (see pg. 2, line 18).
Gilabert-Oriol-1 teaches co-application of SO1861 as a novel strategy to enhance the efficacy of therapeutic antibodies, see pg. 255, left column, paragraph 2.
Although, Gilabert-Oriol-1 does not teach (a) SO1861 having its aldehyde group at position C-23 transformed into a hydrazone bond, required in claims 31, 33-34 and 41; and (b) the pharmaceutical composition required in claim 41.
However, in the same filed of endeavor of derivatizing aldehydes, Zhang teaches gypsogenin a natural pentacyclic triterpenoid having four active sites, such as a C-23 aldehyde group, is amenable to a wide range of chemical transformations. Zhang teaches the C-23 aldehyde group of gypsogenin has been used to prepare hydrazone, see pg. 2, 1. Introduction, paragraph 2. Zhang teaches the structure of gypsogenin is very similar to the structure of oleanolic acid, see pg. 2, 1. Introduction, paragraph 3.
Zhang teaches gypsogenin (compound 1) was treated with 2,4-dinitrophenylhydrazine in acetic acid at room temperature to obtain compound 4,
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; wherein scheme 1a illustrates the C-23 aldehyde group of gypsogenin is derivatized and transformed into a hydrazone bond comprising a 2,4-dinitrophenyl group, see pg. 3, paragraph 1 and scheme 1a.
Zhang teaches 2,4-dinitrophenylhydrazone in the C-23 position of compound 4 enhanced its anti-cancer activity, see pg. 8, 3. Conclusion, paragraph 1.
With particular respect to the limitation of molecule 23 of claim 31, as evidenced by Gilabert-Oriol-2, Gilabert-Oriol-2 discloses the structure of SO1861 which is depicted as
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, see pg. 2389, table 1, SO1861.
The Examiner respectfully notes the teachings of both Gilabert-Oriol-1 and Gilabert-Oriol-2, teach SO1861 and said structure of SO1861 respectively. The Examiner respectfully notes the structure of SO1861 taught by Gilabert-Oriol-2 depicted above shows that SO1861 comprises a quillaic acid aglycone core structure, as recited within Molecule 1 in claim 31, line 6.
The Examiner also respectfully notes the structure of SO1861 taught by Gilabert-Oriol-2 corresponds to the structure of Molecule 1 of claim 31, line 1 when:
R is defined as hydroxyl, in claim 31, line 8;
the first saccharide chain A1 is Gal-(1→2)-[Xyl-(1→3)]-GlcA-, in claim 31, line 9; and
the second saccharide chain A2 is Glc-(1→3)-Xyl-(1→4)-Rha-(1→2)-[Xyl-(1→3)-4-OAc-Qui-(1→4)]-Fuc-, in claim 31, lines 10-11.
It would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have modified the C-23 aldehyde group of SO1861 taught by Gilabert-Oriol-1 for a hydrazone bond as taught by Zhang above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to improve the anti-cancer activity of SO1861 using the modification of a hydrazone bond at the C-23 aldehyde group as taught by Zhang above. One of ordinary skill in the art would have has a reasonable expectation of success to have included this modification as Zhang teaches compound 4 which contains the C-23 hydrazone bond that improves anti-cancer activity as discussed above.
With respect to the limitation of “A saponin derivative based on an endosomal escape enhancer SO1861”, as required in claim 31, line 1; the Examiner reasonably interprets this limitation to be a functional limitation of the saponin derivative having a quillaic acid aglycone core structure represented by Molecule 1. Since the teachings of Gilabert-Oriol-1 as evidenced byGilabert-Oriol-2 above teach a saponin derivative based on an endosomal escape enhancer SO1861 saponin comprising a quillaic acid core structure represented by Molecule 1; and wherein said saponin derivative comprises an aldehyde group at position C23 of the quilliac acid which has been derivatized as taught by Zhang, the functional limitation as discussed above will be met by the combined teachings of Gilabert-Oriol-1 and Zhang as evidenced by Gilabert-Oriol-2 as discussed above.
With respect to the claim limitation “wherein the saponin derivative has a molecular weight of less than 2,500 g/mol”, required in claim 34; the Examiner reasonably interprets this limitation as a physical limitation that is met as the combination of Gilabert-Oriol-1, Zhang and Gilabert-Oriol-2 teach an SO1861 derivative that comprises an aldehyde group which has been derivatized as required within instant claim 31.
With respect to the claimed limitation of “a first pharmaceutical composition”, required in claim 41, Gilabert-Oriol-1, Zhang and Gilabert-Oriol-2 are each silent regarding a pharmaceutical composition.
However, it would have been within the scope of the artisan to formulate the saponin derivative as taught by Gilabert-Oriol-1 and Zhang into a pharmaceutical composition as recited in claim 41, as claim 41 only requires that a saponin derivative be included in the first pharmaceutical composition. One of ordinary skill in the art would have been motivated to formulate said saponin of Gilabert-Oriol-1 and Zhang into a pharmaceutical composition as Zhang teaches the substitution of the C-23 aldehyde for the C-23 hydrazone within the gypsogenin structure improved its anti-cancer activity as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success to have made the formulation as discussed above because instant claim 41 only requires the SO1861 derivative within the pharmaceutical composition and Gilabert-Oriol-1 teaches co-application of SO1861 as discussed above.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have derivatized the C-23 aldehyde of SO1861 with a C-23 hydrazone bond exemplified by compound 4 as taught by Zhang above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to substitute the C-23 aldehyde within the quillaic acid core of SO1861 as taught by Gilabert-Oriol-1 for the C-23 hydrazone exemplified on the gypsogenin core as taught by Zhang above, because Zhang teaches improved anti-cancer activity when the C-23 aldehyde is substituted with a C-23 hydrazone as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to have modified the SO1861 of Gilabert-Oriol-1 with the modification of Zhang as discussed above, as Zhang teaches the transformation of a C-23 aldehyde into a C-23 hydrazone on gypsogenin as exemplified in compound 4 as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(II) Claim 43 are rejected under 35 U.S.C. 103 as being unpatentable over Gilabert-Oriol-1 (Published 01 October 2015, Biochemical Pharmacology, Vol. 97, Issue 3, pp. 247-255, IDS filed 07/13/2022), Zhang et al. (Published 24 January 2018, Royal Society Open Science, Vol. 5, Issue 1, pp. 1-19, PTO-892 mailed 04/21/2025) and Gilabert-Oriol et al. (hereafter known as "Gilabert-Oriol-2", Published 15 April 2013, Bioorganic & Medicinal Chemistry, Vol. 21, Issue 8, pp. 2387-2395, PTO-892) as applied to claims 31, 33-34 and 41 above, and further in view of Baumer et al. (Published 12 March 2015, Clinical Cancer Research, Vol. 21, Issue 6, pp. 1383-1394, PTO-892 mailed 04/21/2025).
Gilabert-Oriol-1, Zhang and Gilabert-Oriol-2 address claims 31, 33-34 and 41 as written above. Although, Gilabert-Oriol-1, Zhang and Gilabert-Oriol-2 do not teach a second pharmaceutical composition comprising an antibody-oligonucleotide conjugate, required in claim 43.
However, in the same field of endeavor of compounds with anti-cancer activity, Baumer teaches the in vivo antibody-mediated deliver of anti-KRAS-siRNA overcomes therapy resistance in colon cancer, see pg. 1383, title. Baumer exemplifies an αEGFR-mAB–esiRNA (antibody-siRNA conjugate) (e.g. the antibody-oligonucleotide conjugate, required in claim 43), see pg. 1387, right column, Efficacy of KRAS-siRNA–anti-EGFR complexes in mouse tumor xenografts, paragraph 1.
Baumer teaches anti-EGFR mAB–protamine–KRAS-esiRNA complexes significantly inhibited tumor growth, see pg. 1387, right column, Efficacy of KRAS-siRNA–anti-EGFR complexes in mouse tumor xenografts, paragraph 1 and pg. 1391, Figure 5D.
With respect to the claimed limitation of “a second pharmaceutical composition”, required in claim 43, Baumer is silent regarding a pharmaceutical composition.
However, it would have been within the scope of the artisan to formulate the antibody-oligonucleotide conjugate as taught by Baumer above into a pharmaceutical composition as recited in claim 43, as claim 43 only requires an antibody-oligonucleotide conjugate be included in the second pharmaceutical composition; and (b) Baumer teaches the anti-EGFR mAB–protamine–KRAS-esiRNA complexes significantly inhibited tumor growth as discussed above.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the antibody-oligonucleotide conjugate taught by Baumer above with the pharmaceutical composition taught by Gilabert-Oriol-1 and Zhang above as within the scope of the artisan as a simple addition according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to make the addition as discussed above to enhance the anti-cancer activity of the SO1861 derivative taught by the combination of Gilabert-Oriol-1 and Zhang above. One of ordinary skill in the art would have had a reasonable expectation of success to make the modification above, as both the combination of Gilabert-Oriol-1 and Zhang; and Baumer are drawn to compositions with anti-cancer activity as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
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.
(I) Claims 31 and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 14 and 19 of copending Application No. 17/312,104 (amended claim set 09/15/2025; Applicant: Sapreme Technologies B.V.; filed 12/09/2019) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to an SO1861 derivative comprising an aldehyde group which has been derivatized.
Reference claim 1 recites a conjugate of an oligonucleotide and a saponin, wherein the saponin is a bidesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23, and is covalently bound involving a hydrazone bond to the oligonucleotide via at least one linker, or is covalently bound directly to said oligonucleotide.
Reference claim 7 recites wherein the bisdesmosidic triterpene saponin is selected from any one or more of and including SO1861.
Reference claim 14 recites the at least one linker comprises a polymeric or oligomeric structure and a chemical group, wherein the chemical group is a cleavable bond; wherein the cleavable bond is a hydrazone bond subject to cleavage under acidic conditions.
Reference claim 19 recites wherein the covalent bond involves the aldehyde function in position C-23 of the saponin, and when present the covalent bond being a hydrazone bond.
With respect to the claim limitation, “wherein the saponin derivative has a molecular weight of less than 2,000 g/mol”, required in instant claim 34; the Examiner is interpreting this limitation as a physical limitation that is met as the combined recitations of ‘104 recite an SO1861 derivative that comprises an aldehyde group which has been derivatized.
Thus, the combined recitations of ‘104 anticipate instant claims 31 and 33-34.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(II) Claims 31, 33-34 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7, 14 and 33 of copending Application No. 17/312,193 (amended claim set 07/25/2025; Applicant: Sapreme Technologies B.V.; filed 12/09/2019) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to an SO1861 derivative comprising an aldehyde group which has been derivatized.
Reference claim 1 recites a first proteinaceous molecule comprising a first binding site for binding to a first epitope of a first cell-surface molecule with at least one saponin covalently bound via at least one linker, wherein the first binding site comprises an antibody; and wherein the saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23.
Reference claim 4 recites wherein the at least one saponin is one or more of the saponins including SO1861.
Reference claim 7 recites wherein the saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23, wherein the at least one saponin is covalently coupled to the amino acid residue of the first proteinaceous molecule via an aldehyde group in the saponin.
Reference claim 33 recites wherein the cleavable linker is subject to cleavage under acidic conditions. The Examiner reasonably interprets a hydrazone bond is encompassed within the cleavable linker under acidic conditions as evidenced by the specification which discloses in Figure 64 the hydrolysis of the hydrazone bond of SO1861-EMCH under acidic conditions (see pg. 31, lines 30-35, Figure 64).
Reference claim 14 recites a therapeutic combination comprising a first pharmaceutical composition comprising the first proteinaceous molecule of claim 1 and optionally a pharmaceutically acceptable excipient.
With respect to the claim limitation, “wherein the saponin derivative has a molecular weight of less than 2,000 g/mol”, required in instant claim 34; the examiner is interpreting this limitation as a physical limitation that is met as the combined recitations of ‘193 recite an SO1861 derivative that comprises an aldehyde group which has been derivatized.
Thus, the combined recitations of ‘193 anticipate instant claims 31, 33-34 and 41.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(III) Claims 31 and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 8 and 11 of copending Application No. 17/312,476 (amended claim set 05/22/2025; Applicant: Sapreme Technologies B.V.; filed 12/09/2019) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to an SO1861 derivative comprising an aldehyde group which has been derivatized.
Reference claim 1 recites a scaffold comprising a polymeric or oligomeric structure and at least one biologically active molecule covalently bound to said polymeric or oligomeric structure.
Reference claim 5 recites wherein the at least one biologically active molecule is more preferably a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 or one or more saponins including SO1861.
Reference claim 8 recites wherein the at least one biologically active molecule is covalently bound to the polymeric or oligomeric structure via a cleavable bond, and more preferably the cleavable bond is a hydrazone bond.
Reference claim 11 recites the aldehyde function in position C-23 of the at least one saponin is involved in the covalent bonding to the polymeric or oligomeric structure.
With respect to the claim limitation, “wherein the saponin derivative has a molecular weight of less than 2,000 g/mol”, required in instant claim 34; the examiner is interpreting this limitation as a physical limitation that is met as the combined recitations of ‘476 recite an SO1861 derivative that comprises an aldehyde group which has been derivatized.
Thus, the combined recitations of ‘476 anticipate instant claims 31 and 33-34.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(IV) Claims 31, 33-34 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13, 22 and 35 of copending Application No. 17/415,759 (amended claim set 12/12/2025; Applicant: Sapreme Technologies B.V.; filed 12/09/2019) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to an SO1861 derivative comprising an aldehyde group which has been derivatized.
Reference claim 1 recites a therapeutic molecule known as compound 1, where C is a saponin which is a bidesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23.
Reference claim 13 recites wherein the saponin C is a single specific saponin such as one or more of the saponins including SO1861.
Reference claim 22 recites wherein the saponin C is covalently coupled to an amino-acid residue and/or an effector molecule via the aldehyde function in the saponin C, preferably said aldehyde function in position C-23, via a cleavable linker, and preferably the cleavable linker comprises a hydrazone bond.
Reference claim 35 recites a pharmaceutical composition comprising the therapeutic molecule of compound 1 according to reference claim 1 and optionally further comprising a pharmaceutically acceptable excipient.
With respect to the claim limitation, “wherein the saponin derivative has a molecular weight of less than 2,000 g/mol”, required in instant claim 34; the examiner is interpreting this limitation as a physical limitation that is met as the combined recitations of ‘759 recite an SO1861 derivative that comprises an aldehyde group which has been derivatized.
Thus, the combined recitations of ‘759 anticipate instant claims 31, 33-34 and 41.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(V) Claims 31, 33-34 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39, 48, 53, 55-57 and 60 of copending Application No. 18/012,710 (amended claim set 12/29/2025; Applicant: Sapreme Technologies B.V.; filed 07/09/2020) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to an SO1861 derivative comprising an aldehyde group which has been derivatized.
Reference claim 39 recites a conjugate for transferring a saponin wherein the conjugate comprises a saponin, wherein the saponin is a bidesmosidic triterpene glycoside and comprises an aglycone structure is guillaic acid.
Reference claim 48 recites wherein the saponin is selected from and including SO1861.
Reference claim 53 recites an oligomeric or polymeric molecule is covalently bond to the saponin.
Reference claim 55 recites wherein at least one of the molecules of the saponin is covalently bound to the oligomeric or polymeric molecule via the linker.
Reference claim 56 recites wherein the at least one of the molecules of the saponin comprises an aglycone core structure selected from and including quillaic acid, wherein the aldehyde function in position C-23 of the aglycone core structure is involved in the covalent binding of the linker.
Reference claim 57 recites wherein the linker covalently bound through the aldehyde function in position C-23 of the aglycone core comprises a cleavable bond selected from a hydrazone bond.
Reference claim 60 recites a pharmaceutical composition comprising the conjugate of instant claim 39 and a pharmaceutically acceptable excipient and/or diluent.
With respect to the claim limitation, “wherein the saponin derivative has a molecular weight of less than 2,000 g/mol”, required in instant claim 34; the examiner is interpreting this limitation as a physical limitation that is met as the combined recitations of ‘710 recite an SO1861 derivative that comprises an aldehyde group which has been derivatized.
Thus, the recitations of ‘710 anticipate instant claims 31, 33-34 and 41.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
Claim 36 is allowed.
The following is a statement of reasons for the indication of allowable subject matter: Gilabert-Oriol-1 and Zhang teach as set forth above. The Examiner also respectfully notes BroadPharm (Published 05 March 2018, Safety Data Sheet: Azido-PEG4-hydrazide HCl Salt, pg. 1, PTO-892) exemplifies an azido PEG derivative known as azido-PEG4-hydrazide (e.g. the azido-PEG4-hydrazide as recited within molecule 23 of claim 36), see section I. identification of the substance, product name.
However, neither Gilabert-Oriol-1 nor BroadPharm teach or even suggest why one of ordinary skill in the art would derivatize the aldehyde group at position C-23 of the quillaic acid of SO1861 as taught by Gilabert-Oriol-1 above for the particular azido PEG derivative known as azido-PEG4-hydrazide as taught by BroadPharm above; wherein the Examiner respectfully notes is exemplified within molecule 23 of instant claim 36.
Conclusion
Claim 36 is allowed in this action.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691