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 .
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed on 08/26/2026 and 09/23/2026 have been considered by the Examiner inasmuch as foreign documents have been submitted into the file wrapper in English.
Claim Status
The claim set and Applicant’s remarks filed August 04, 2026, have been entered.
Claims 1-30, 32, 35, 37-40, 42 and 44 are canceled.
Claim 45 is new.
Thus, claims 31, 33-34, 36, 41, 43 and 45 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the non-final office action on March 04, 2026:
(I) The rejection of claims 31, 33-34, 41 and 43 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of Applicant’s amendment to claim 31.
(II) The provisional rejection of claim 34 on the ground of nonstatutory double patenting of copending Application Nos. 17/312,104; 17/312,476; 17/415,759; and 18/012,710 are each withdrawn as Applicant’s argument of the molecular weight limitation of less than 2,000 g/mol for the SO1861-containing conjugates is found persuasive in view of the copending applications above as discussed in Applicant’s remarks on the applicable pages that refer to each of the copending applications discussed above.
(III) The provisional rejection of claims 31, 33-34 and 41 on the ground of nonstatutory double patenting of copending Application No. 17/312,193 is withdrawn in view of the most recent claim set of this application filed July 16, 2026 which does not recite SO1861 as the saponin used to create the proteinaceous conjugates; nor would it have been obvious why one of ordinary skill in the art would have selected SO1861 as the particular saponin for said proteinaceous conjugates recited in the ‘193 application above.
Response to Arguments
(I) The rejection of claims 31, 33-34, 41 and 43 under 35 U.S.C. 103 is maintained:
Applicant argues:
(A) Applicant respectfully disagrees that the suggested modification of Gilabert-Oriol 1 in view of Zhang would lead to a predictable result as shown in the examples of the specification, see Applicant’s remarks, pg. 6, last paragraph.
(B) The derivatization of the C-23 aldehyde group of SO1861 by transformation into a hydrazone bond, as recited in claim 33, does not increase the cytotoxicity or the lytic activity of SO1861, it reduces them as exemplified in SO1861-Ald-EMCH, see Applicant’s remarks, pg. 6, last paragraph – pg. 7, first paragraph.
(C) The transformation of the C-23 aldehyde of SO1861 into a hydrazone bond, as recited in claim 33, produces the opposite of the property the Examiner relies upon to supply both the motivation and the expectation of success, Applicant’s remarks, pg. 7, second paragraph.
With respect to Applicant’s arguments (A)-(C), the Examiner respectfully notes to Applicant that independent claim 31 nor its dependents therefrom recite or require the consideration of cytotoxicity from the resulting derivatized SO1861, wherein as recited in instant claim 33, said derivative comprises a hydrazone bond at the C-23 position of the quillaic acid aglycone core structure.
Therefore, Applicant’s arguments (A)-(C) regarding the derivatized SO1861 as discussed above are not particularly persuasive as the Examiner notes the combination of Gilabert-Oriol-1 and Zhang meet all structural limitations as recited and required in claims 31 and 33.
Thus, consideration of the resulting derivatized SO1861 having no cytotoxicity, a lower cytotoxicity, or in not having increased the cytotoxicity of the derivatized SO1861 when compared to the unmodified C-23 position in the quillaic acid aglycone core of the original SO1861 is not recited nor required within the pending claims as the Examiner notes above and in view the combination taught by Gilabert-Oriol-1 and Zhang meeting all structural limitations recited and required in claims 31 and 33.
Finally, Applicant argues the combination of Gilabert-Oriol-1 and Zhang is not predictable based on the one cited SO1861 derivative, wherein the C-23 aldehyde is derivatized into a hydrazone bond, specifically the hydrazone bond created by reacting the hydrazide comprised within the EMCH moiety with the aldehyde at the C-23 position of SO1861 to produce the SO1861-Ald-EMCH compound argued by Applicant as having not increasing the cytotoxicity of SO1861.
The Examiner further notes this exemplification is not particularly persuasive in view of claim 33 reciting and requiring a hydrazone bond per se which the Examiner reasonably interprets includes any additional unrecited structures connected to the hydrazone bond as discussed above; nor is it particularly persuasive in view of claim 31 which recites and requires the aldehyde group at position C-23 of the quillaic acid be derivatized; accordingly, claim 31 does not require the hydrazone bond as the derivatization and thus the Examiner reasonably interprets any structure can be incorporated as long as the aldehyde group at the C-23 position is derivatized.
(D) Zhang accordingly provides no reasonable expectation that transformation of the C-23 aldehyde into a hydrazone bond, as recited in claim 33, would produce the effect the Examiner attributes to it in the bidesmodic SO1861 scaffold recited by claim 31, see Applicant’s remarks, pg. 7, last paragraph – pg. 8, first paragraph.
(E) The Examiner’s stated purpose for the modification is incompatible with the operation of Gilabert-Oriol-1’s combination, see Applicant’s remarks, pg. 8, second full paragraph.
(F) Read as a whole, the reference relied upon identify the lytic and haemolytic activity of SO1861 as the property to be reduced not increased, and demonstrate that increasing it destroys the endo/lysosomal escape mechanism on which Gilabert-Oriol-1’s combination depends, therefore a modification made for the express purpose of increasing the cytotoxicity of SO1861 would render Gilabert-Oriol-1 unsatisfactory for its intended purpose, see Applicant’s remarks, pg. 8, last paragraph.
With respect to Applicant’s arguments (D)-(F), the Examiner reiterates their positions above, and further notes Zhang teaches the exemplified hydrazone-substituted gypsogenin (compound 4), which the Examiner notes compound 4 comprises a hydrazone bond where the aldehyde group at the C-23 position of gypsogenin has been derivatized and shows improved IC50 data when compared to the unmodified gypsogenin (compound 1) in LOVO cells, see pg. 5 Table 1; where LOVO cells are a colon cancer cell line, see pg. 4, paragraph 1.
The Examiner notes the SO1861 of Gilabert-Oriol-1 is not derivatized until the modification taught by Zhang.
Gilabert-Oriol-1 teaches SO1861 promotes enhanced cytotoxicity via its unmodified glucuronic acid by way of its molecular interactions with ribosome-inactivating proteins, see pg. 248, left column, second paragraph from the bottom of the column.
Gilabert-Oriol-1 examines the combination comprising SO1861 against HCT-116 cells, which are a type of colorectal carcinoma, see pg. 249, right column, 2.6. cell culture.
Additionally, in view of the cytotoxicity assay of Gilabert-Oriol-1 it showed a concentration dependent effect on cancer cells after addition of dianthin plus SO1861 which takes place within several hours after addition and is an indication that cells are undergoing cell cycle arrest, see pg. 254, right column, paragraph 1.
Moreover, the Examiner notes Zhang teaches via cell cycle analysis in section 2.2.3, the differential growth inhibition mechanism mediated by 2,4-dinitrophenylhydrazone compounds in cell cycle dynamics, where the effect of compound 4 on cell cycle progression was determined, see pg. 7, section 2.2.3, paragraph 1.
Zhang teaches LOVO cells treated with compound 4 for 48 hours resulted in a marked accumulation of cells in S-phase; and these experiments showed a dose-dependent S-phase arrest in cells treated with compound 4, see pg. 7 paragraph 1.
Zhang indicates the results of compound 4 inhibited the growth of the cancer cell by inhibiting the cell cycle, see pg. 7, paragraph 1 - pg. 8, paragraph 1.
Zhang teaches the structure-activity relationship studies revealed the introduction of a 2,4-dinitrophenylhydrazone in the 23 position, exemplified on compound 4, enhanced anti-cancer activity and is considered a possible anti-cancer agent as it was shown to affect the cell cycle causing cell cycle arrest, see pg. 8, conclusion.
Therefore, the Examiner notes in view of the teachings of Zhang above the cytotoxic effect of the 2,4-dinitrophenylhydrazone-substituted gypsogenin as exemplified in compound 4 of Zhang above demonstrated cytotoxicity in cancer cells by inhibiting the cell cycle and not by cell lysis which the Examiner reasonably interprets as Applicant's argument.
Additionally, Gilabert-Oriol-1 teaches a final concentration of SO1861 added to cells in the cytotoxicity assay was 2 micrograms/mL see pg. 249, right column, section 2.7, paragraph 2.
Moreover, Gilabert-Oriol-1 teaches there was an initial decrease in normalized cell index (NCI) due to compound addition, but thereafter past the incubation time NCI recovered to 1, see pg. 2390, left column, section 3.1, paragraph 2; and further evidenced by Figure 1e, where at a concentration of 3 micromolar the NCI reduced to 0.8 at approximately 20 h and returned to a value of 1 at approximately 22 h, see pg. 2391, Figure 1e.
Furthermore, as evidenced by Figure 4 of Gilabert-Oriol-2 when SO1861 is administered between 1.5 and 3 micromolar demonstrated hemolysis at 0%, see pg. 2392, Figure 4; and where the Examiner particularly points out to Applicant the concentration of compound 4 of Zhang used to demonstrate increased cytotoxicity related to increased S-phase cycle arrest was tested at 2.5 micromolar, see pg. 7, paragraph 1.
With that said, it appears to the Examiner that Applicant is arguing SO1861’s cytotoxicity increases at increased concentrations, and at said concentrations cause cell lysis and hemolysis which destroys SO1861's endo/lysosomal escape mechanism.
However, in view of the foregoing reasons above, the Examiner notes when the SO1861 of Gilabert-Oriol-1 is derivatized with the 2,4-dinitrophenylhydrazone at the 23 position to provide the enhanced cytotoxic effect via cell cycle arrest (e.g. S-phase accumulation) as taught by Zhang; the concentration required to provide said effect does not render the SO1861 of Gilabert-Oriol-1 unsatisfactory for its intended purpose as Zhang demonstrates the increased cytotoxic effect can be demonstrated at 2.5 micromolar; and as evidenced by Gilabert-Oriol-2, said concentration of Zhang does not increase the lytic or hemolytic activity of SO1861 of Gilabert-Oriol-1 as evidenced by Figure 1e and Figure 4 of Gilabert-Oriol-2 as discussed above and as such the Examiner reasonably interprets said modification taught by the combination of Gilabert-Oriol-1 and Zhang does not destroy the endo/lysosomal escape mechanism of SO1861 of Gilabert-Oriol-1 as argued by Applicant.
(G) Nothing in Gilabert-Oriol-1 directs the skilled person to the C-23 aldehyde group of SO1861 at all, see Applicant’s remarks, pg. 9, first paragraph.
With respect to Applicant’s argument (G), the Examiner reiterates their positions above, and further notes Zhang teaches increased cell cycle arrest via increased S-phase accumulation was demonstrated for the exemplified hydrazone-C23-substituted-gypsogenin (compound 4) and where the unmodified C23-gypsogenin (compound 1) consists of an aldehyde group as discussed above.
(H) The surprising effect noted in the application as filed does not come from how the pharmaceutical compositions are formulated but the fact that they comprise the saponin derivative of claim 31, see pg. 9, last paragraph.
With respect to Applicant’s argument (H), the Examiner reiterates their positions above, and further notes Applicant's argument of a surprising effective "e.g. having a lower haemolytic activity and a lower cytotoxicity than SO1861", is not a required limitation of molecule 1 of claim 31; nor a limitation where the derivatization is a hydrazone bond as required in claim 33. Rather this limitation is only required in claim 45.
Thus, Applicant’s arguments (A)-(H) have been fully considered but are not found persuasive.
(II) The provisional rejections of claims 31, 33 and 41 where applicable in copending applications 17/312,104; 17/312,476; 17/415,759; and 18/012,710 are maintained.
Applicant argues:
(I) The Examiner’s nonstatuatory double patenting analysis isolates only the derivatized SO1861 portion of the claimed subject matter, whereas the recited reference claims, however, require additional structural elements which materially limit the claim scope. Applicant further argues the pending claims do not require those additional structural elements and therefore are not coextensive with the recited instant claims, see Applicant’s remarks, pg. 10, first paragraph.
The Examiner has considered Applicant’s arguments regarding the additional structural elements as discussed above for each provisional rejection against each copending application which are provided on pp. 10-15 of Applicant’s remarks.
However, after considering Applicant’s argument (I), the Examiner notes in response that instant claims 31 and 33 recite Molecule 1 as a derivative of SO1861 wherein the aldehyde function at the C23-position of said SO1861 has been derivatized; and where instant claim 33 further limits said derivatization to include the structural limitation of a hydrazone bond.
Additionally, the Examiner respectfully reminds the Applicant of their reasonable interpretation of the pending claims, specifically where claim 33 recites and requires a hydrazone bond per se and where the Examiner had reasonably interpreted said hydrazone bond includes any additional unrecited structures connected to the hydrazone bond as discussed above; as well as the additional interpretation of instant claim 31 which recites and requires the aldehyde group at position C-23 of the quillaic acid be derivatized; accordingly, the Examiner reasonably interpreted instant claim 31 encompasses any structure that can be incorporated into Molecule 1 as long as the aldehyde group at the C-23 position is derivatized.
Consequently, in view of these interpretations, the Examiner particularly notes to Applicant neither instant claim 31 nor instant claim 33 limit in any way what is connected to the hydrazone bond and thus the Examiner reasonably interprets any structure is encompassed.
Therefore, the Examiner notes the additional recited structures as argued by Applicant above which are recited in each copending application are in fact connected to SO1861 at the C-23 position via a linker, specifically a hydrazone bond, and thus said structures recited in the reference claims of each of the copending applications as written above are encompassed by the derivatized SO1861 per se as presently claimed by Applicant.
Thus, Applicant’s argument (I) has been fully considered but is not found persuasive.
(III) The Examiner respectfully notes after considering new claim 45 as discussed above, in response, the Examiner has written a new 112(a)-written description rejection which is discussed in greater detail below.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 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.
Claim 45 is 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 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Accordingly, MPEP 2163(I)(B) states “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, the inventor was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
The MPEP states that for a generic claim drawn to a genus, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163(II)(3)((a)(ii). If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163(II)(3)((a)(ii).
The MPEP further states satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP § 2163(II)(3)((a)(ii).
Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Accordingly, the instant claims have been analyzed in accordance with the methodology for determining adequacy of written description, see MPEP 2163(II):
1. For each claim, determine what the claim as a whole covers, e.g. the first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim.
The Examiner notes instant claim 45 is drawn to a SO1861 derivative represented by the generic compound of Molecule 1 having a hydrazone bond at the C23 of the quillaic acid, and wherein said derivative has a lower haemolytic activity and a lower cytotoxicity than SO1861.
The Examiner notes the recitation of a hydrazone bond in claim 45 is reasonably interpreted to mean a hydrazone bond per se and where the Examiner further reasonably interprets said hydrazone bond includes any additional unrecited structures connected to the hydrazone bond as discussed above.
2. Review the entire application to understand how Applicant provides support for the claimed invention including each element and/or step, e.g. the second step is to fully review the application to understand how Applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim(s) with the scope of the description.
The genus of compounds as collectively recited in claim 45 is extremely broad as reasonably interpreted by the Examiner above.
The Examiner also notes Applicant’s specification provides exemplified lists of SO1861 having a hydrazone bond incorporated at the aldehyde group at the C-23 position of the quillaic acid (see pg. 21, lines 1-10; pg. 23, lines 1-30; and pg. 48, Table A2).
However, a “laundry list” disclosure of many or even every possible species does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species. MPEP 2163.I.A. and Fujikawa v. Wattanasin, 93 F. 3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996). Therefore, there is no disclosure of species (e.g. by disclosure of structural/chemical formulae) in addition to the considerations discussed below, which was reduced to practice.
3. Determine whether there is sufficient written description to inform a skilled artisan the Inventor was in possession of the claimed Invention as a whole at the time the application was filed, e.g. the third step is to determine whether the Applicant was in possession of the claimed invention as a whole at the time of filing.
This should include the following considerations: (1) actual reduction to practice, (2) disclosure of drawings or structural chemical formulas, (3) sufficient relevant identifying characteristics such as complete structure, partial structure, physical and/or chemical properties and functional characteristics when coupled with a known or disclosed correlation between function and structure, (4) method of making the claimed invention, (5) level of skill and knowledge in the art and (6) predictability of the art.
The preceding six considerations have been considered, with the most relevant factors discussed below.
Actual Reduction to Practice:
For claim 45, the specification provides support for only one species within the broadly claimed genus of SO1861 derivatives having a hydrazone bond at the C-23 position of the quillaic acid as discussed above which is demonstrated to have a lower haemolytic activity and a lower cytotoxicity than SO1861. The structure is exemplified as SO1861-Ald-EMCH, see pg. 68, Table A5, conjugate sample, SO1861-Ald-EMCH.
The Examiner notes SO1861-Ald-EMCH is represented by Molecule 2, see pg. 52, lines 25-27; and visually depicted on pg. 53 of the specification.
Sufficient Relevant Identifying Characteristics:
The Examiner notes the example of actual reduction to practice as discussed above.
Accordingly, in view of the claimed scope of claim 45 and the level of disclosure in the specification as discussed above; the specification does not disclose a sufficient number of representative species to adequately describe the broadly claimed genus associated with the compounds recited in claim 45.
Furthermore, Applicant’s disclosure does not describe in sufficient detail (a) how the compounds encompassed by claim 45 have lower haemolytic activity and lower cytotoxicity than SO1861 in view of the generic structure claimed; and (b) what if any considerations are required in relating the physical, chemical, or functional aspects of a compound to its structure per se.
Thus, one skilled in the art would reasonably be lead to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Henceforth, the 103 rejection as written below captures what Applicant has claimed within instant claim 45 above and further demonstrates to Applicant that any hydrazone bond incorporated at the C-23 position of the quillaic acid core structure of SO1861 does not necessarily have both a lower haemolytic activity and a lower cytotoxicity than SO1861 as recited in instant claim 45 as discussed above.
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 remain 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 mailed 03/04/2026).
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 quillaic 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 remains 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 mailed 03/04/2026) 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 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7 and 14 of copending Application No. 17/312,104 (amended claim set 03/04/2026; 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 at least one 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 that is covalently bound involving a hydrazone bond to the oligonucleotide via at least one linker.
Reference claim 7 recites wherein the bisdesmosidic triterpene saponin is selected from the group consisting 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.
Thus, the combined recitations of ‘104 anticipate instant claims 31 and 33.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(II) Claims 31 and 33 remain 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 08/24/2026; 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 the saponin 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, 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.
Thus, the combined recitations of ‘476 anticipate instant claims 31 and 33.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(III) Claims 31, 33 and 41 remain 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 06/29/2026; 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 an endosomal escape enhancer 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 of the first ligand B1 and/or an effector molecule moiety A1 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.
Thus, the combined recitations of ‘759 anticipate instant claims 31, 33 and 41.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(IV) Claims 31, 33 and 41 remain 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 09/10/2026; 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 which is quillaic 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 and the sdAb.
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.
Thus, the recitations of ‘710 anticipate instant claims 31, 33 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 respectfully reiterates the reasons for the allowability of subject matter recited for claim 36 as discussed in the non-final rejection mailed March 04, 2026.
Conclusion
Claim 36 is allowed in this action.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
