SAPONIN CONJUGATED TO EPITOPE-BINDING PROTEINS

Application No. 17/312,193

• Filed: Jun 09, 2021
• Examiner: HUYNH, PHUONG N
• Art Unit: 1641
• Tech Center: 1600 — Biotechnology & Organic Chemistry
• Assignee: Sapreme Technologies B V
• OA Round: 3 (Non-Final)

Office 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 .

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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 15, 2025 has been entered.

Claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, 49 and 50 are pending.

Claim 4 is withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.

Claims 1, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, 49 and 50, drawn to a first proteinaceous molecule that read on a. SO1861 as the species of saponin, b. CD71 as the particular first epitope of the first cell-surface molecule to which the first binding site of the first proteinaceous molecule binds, c. An antibody drug conjugate wherein the antibody can bind to CD71 (claim 11), d. antibody cetuximab as the second binding site of the second proteinaceous molecule cetuximab as the species of antibody (claim 26), e. antibody cetuximab as the third binding site of a third proteinaceous molecule (claim 27), f. the second or third cell-surface molecule in the combination is same" is elected (claim 16), g. oligonucleotide as the particular effector moiety is elected (claim 29) and dianthin is elected as the particular effector moiety (claim 30), h. a cleavable linker is elected (claims 33 and 34), i. An antibody-drug conjugate wherein the antibody can bind to CD71 is elected (claim 43), are being acted upon in this Office Action.

Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.

Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 16, 2025 and December 18, 2025 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.

Specification
The amendment to the specification filed on December 15, 2025 has been entered.

Objection and Rejection Withdrawn
The objection to claims 11, 27 is withdrawn in view of the claim amendment.
The rejection of claims 1, 4, 11, 26 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.

The rejection of claims 1 and 11 under 35 U.S.C. 102 (a)(1) as being anticipated by WO03/088907 publication (of record, published Oct 30, 2003; PTO 892) is withdrawn in view of the claim amendment.

The rejection of claim 49 under 35 U.S.C. 102 (a)(1) as being anticipated by Rosazza et al (newly cited, US20030203856, published Oct 30, 2003; PTO 892) is withdrawn in view of the claim amendment.

The rejection of claims 1, 4, 9, 11, 13, 14, 26-30 and 32-33 under 35 U.S.C. 103 as being unpatentable over Gao et al (newly cited, WO2015157595 publication, published Oct 15, 2015; PTO 892) in view of Rosazza et al (newly cited, US20030203856, published Oct 30, 2003; PTO 892), Weng (of record, J of Controlled release 164: 74-86, 2012; PTO 892) or Fuchs et al (of record, US20080064762. Published March 13, 2008; PTO 892) is withdrawn in view of the claim amendment.

The rejection of claim 1 under 35 U.S.C. 103 as being unpatentable over Gao et al (newly cited, WO2015157595 publication, published Oct 15, 2015; PTO 892) in view of Rosazza et al (newly cited, US20030203856, published Oct 30, 2003; PTO 892), Weng (of record, J of Controlled release 164: 74-86, 2012; PTO 892) or Fuchs et al (of record, US20080064762. Published March 13, 2008; PTO 892) as applied to claims 4, 9, 11, 13, 14, 26-30 and 32-33 mentioned above and further in view of Menjoge et al. (newly cited, Drug Discovery Today, Vol. 15, Issues 5-6, page 171-185, 2010; PTO-892) is withdrawn in view of the claim amendment.

Drawings
The drawings are objected to because the figure labels for Figures 1, 2A-B, 4, 5B-D, 6-17, 21-22, 24, 34, 37-40, 41-42, 43B/D, 44B, 45, 47-56, 58, 60-61, 63-64, 66-87, and 89-90 do match the orientation of the Figures. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.

Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it exceeds 150 words and includes both legal phraseology and implied phrases. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The use of the terms, for example, Alexa Fluor, Thermo Scientific, Multiskan, DMEM, CellTiter 96, Eppendorf, etc., which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.

Claim Objection
Claim 1 is objected to because of the following informalities:
“immunoglobulin” and “antibody” are defined the same on page 18 of the specification. As such, “immunoglobulin” and “antibody” are duplicate embodiments.
“binding domain” and “binding fragment” are defined the same on page 18 of the specification. As such, “binding domain” and “binding fragment” are duplicate embodiments.
Claim 8 is objected to because of the following informality: the punctuation marks “,.” should have been “.”.
Claim 27 is objected to because of the following informality: the verb agreement in “the first proteinaceous molecule and the third proteinaceous molecule comprises” should have been “comprise”.
Claim 32 is objected to because of the following informality: “any combination” should have been “a combination”.
Claim 33 is objected to because of the following informality: multiple plural “conditions” should have been singular “condition”.
Appropriate correction is required.

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 1, 19, 26, 28, 29, 30, 32 and 50 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 applicant regards as the invention.
The recitation of “binding domain” and “binding fragment” in claim 1 is indefinite because it is not clear if “binding domain” and “binding fragment” are referring to the antigen-binding fragment or the Fc binding domain or Fc fragment. Further, the inconsistency between the recitation of singular proteinaceous molecule comprising a first binding site for binding to a first epitope” at line 1 and the plural “first proteinaceous molecules to their respective first epitope” raises the issue of indefinite and confusion. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
The recitation of “xeno nucleic acid” in claim 29 is indefinite because it is not clear the nucleic acid is different/foreign from which species. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Claims 19, 28, 29, 30 and 50 recite the limitation "the third proteinaceous molecule" in claim 14. There is insufficient antecedent basis for this limitation in the claim.
The recitation of the multiple “and/or”, “is/are or “comprise(s)” in claim 26 is indefinite and ambiguous. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Regarding claim 29, the claim is indefinite because the claim ends with a “,”. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Regarding claim 32, the phrase “or any number of saponins therein between” at line 2 renders the claim indefinite because it is unclear what is the number between more than one saponin. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.

Claim rejections under - 35 U.S.C. 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.

Claims 1, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, 49 and 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses a first proteinaceous molecule comprising any first binding site for binding to any first epitope of any first target cell-surface molecule on a target cell, the first proteinaceous molecule provided with at least one endosomal escape enhancer saponin covalently bound via at least one linker or via any oligomeric or polymeric scaffold to an amino-acid residue of said first proteinaceous molecule or covalently bound directly to an amino-acid residue of said first proteinaceous molecule, wherein the first binding site comprises any immunoglobulin or antibody or at least one binding domain or at least one binding fragment thereof, wherein binding of the first proteinaceous molecules to their respective first proteinaceous molecules to their respective first epitope on the target cell is followed by endocytosis of the complexes of the first proteinaceous molecule and the first target cell-surface molecule, wherein the at least one saponin is any triterpenoid saponin or any bisdesmosidic triterpene saponin belonging to the type of a 12, 13-dehydrooleanane with al aldehyde function in position C-23.
Claim 7 encompasses the first proteinaceous molecule of claim1, wherein the at least one 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 function in the saponin.
Claim 8 encompasses the first proteinaceous molecule of claim1, wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, wherein the at least one saponin is covalently coupled to the amino-acid residue of the first proteinaceous molecule via the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the saponin.
Claim 9 encompasses the first proteinaceous molecule of claim 4, wherein the aldehyde function in position C-23 of the at least one saponin is covalently coupled to linker N-s-maleimidocaproic acid hydrazide, which linker is covalently coupled via a thio-ether bond to a sulfhydryl group in the first proteinaceous molecule, or a sulfhydryl group of a cysteine.
Claim 10 encompasses the first proteinaceous molecule of claim4, wherein the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the at least one saponin is covalently coupled to linker 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, which linker is covalently coupled via an amide bond to an amine group in the first proteinaceous molecule, or an amine group of a lysine or an N-terminus of the first proteinaceous molecule.
Claim 11 encompasses the first proteinaceous molecule of claim1, wherein the first epitope of the first cell-surface molecule to which the first binding site of the first proteinaceous molecule binds is any epitope of any CD71.
Claim 13 encompasses the first proteinaceous molecule of claim 11, wherein the first binding site of the first proteinaceous molecule comprises or consists of any one of cetuximab (elected species).
Claim 14 encompasses a therapeutic combination, wherein the therapeutic combination comprises: (a) a first pharmaceutical composition comprising the first proteinaceous molecule of claim1 and optionally a pharmaceutically acceptable excipient; and (b) a second pharmaceutical composition comprising a second proteinaceous molecule different from the first proteinaceous molecule, the second proteinaceous molecule comprising a second binding site for binding to a second epitope of a second cell-surface molecule different from the first cell-surface molecule, and comprising an effector moiety, the second pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the second epitope is different from the first epitope.
Claim 16 encompasses a therapeutic combination, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of claim 14 and comprising the first binding site for binding to the first epitope on the first cell-surface molecule, the first pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient; and (b) a third pharmaceutical composition comprising a third proteinaceous molecule, the third proteinaceous molecule comprising the first binding site for binding to the first epitope on the cell-surface molecule of (a) and an effector moiety, the third pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the first binding site of the first proteinaceous molecule and the first binding site of the third proteinaceous molecule are the same, and wherein the first cell-surface molecule and the first epitope on the first cell-surface molecule, to which the first proteinaceous molecule can bind, and the first cell-surface molecule and the first epitope on the first cell-surface molecule, to which the third proteinaceous molecule can bind, are the same.
Claim 19 encompasses the therapeutic combination of claim14, wherein the second binding site of the second proteinaceous molecule and/or the first binding site of the third proteinaceous molecule comprises any immunoglobulin, at least one binding domain of an immunoglobulin and/or at least one binding fragment of an immunoglobulin, or any antibody.
Claim 26 encompasses the first proteinaceous molecule of claim 1, wherein the first binding site and/or a second binding site is/are or comprise(s) a monoclonal antibody or at least one cell-surface molecule binding fragment and/or domain thereof, and optionally comprise cetuximab (elected species).
Claim 27 encompasses the therapeutic combination of claim16, wherein the first binding site of the first proteinaceous molecule and the third proteinaceous molecule comprises a monoclonal antibody or at least one of a cell-surface molecule binding domain and/or fragment thereof, and optionally comprise cetuximab, with the proviso that the first binding site of the first proteinaceous molecule is the same as the first binding site of the third proteinaceous molecule.
Claim 28 encompasses the therapeutic combination of claim 14, wherein the second binding site of the second proteinaceous molecule and/or the first binding site of the third proteinaceous molecule comprises a monoclonal antibody.
Claim 29 encompasses the therapeutic combination of claim14, wherein the effector moiety that is comprised by the second proteinaceous molecule and/or by the third proteinaceous molecule comprises any one or more of an oligonucleotide, a nucleic acid, a Xeno nucleic acid.
Claim 30 encompasses the therapeutic combination of claim 14, wherein the effector moiety that is comprised by the second proteinaceous molecule and/or by the third proteinaceous molecule comprises at least one proteinaceous molecule.
Claim 32 encompasses the first proteinaceous molecule of claim 1, wherein the first proteinaceous molecule comprises more than one saponin, or any number of saponins therein between, or 7, 9, 12 saponins, covalently bound directly to an amino-acid residue of the first proteinaceous molecule, or
covalently bound via at least one linker,
or via at least one cleavable linker,
or via at least one polymeric or oligomeric scaffold, or any combination of I, ii, and iii, wherein the at least one scaffold is optionally based on a dendron, wherein 1-32 saponins or 2, 3, 4, 5, 6, 8, 10, 16, 32 saponins, or 7, 9, 12 saponins, are covalently bound to the at least one scaffold.
Claim 33 encompasses the first proteinaceous molecule of claim 7, wherein the at least one linker is a non-cleavable linker or a cleavable linker, wherein the cleavable linker is subject to cleavage under acidic conditions, reductive conditions, enzymatic conditions or light-induced conditions.
Claim 34 encompasses the first proteinaceous molecule of claim 7, wherein the cleavable linker is subject to cleavage in vivo under acidic conditions as present in endosomes and/or lysosomes of mammalian cells.
Claim 43 encompasses any antibody-drug conjugate or any ligand-drug conjugate comprising the first proteinaceous molecule of claim1 and any effector moiety, wherein the antibody can bind to any CD71.
Claim 49 encompasses the first proteinaceous molecule of claim 1, wherein the first binding site comprises at least one ligand for binding to any cell-surface molecule or any EGF or any cytokine.
Claim 50 encompasses the therapeutic combination of claim 14, wherein the second binding site of the second proteinaceous molecule and/or the first binding site of the third proteinaceous molecule comprises at least any one ligand for binding to a cell-surface molecule or any EGF or any cytokine.
Regarding “binding site”, the specification defines as follow:
[0166] The term “binding site” has its regular scientific meaning, and here refers to a region or an epitope on a molecule, e.g. a protein, DNA or RNA, to which another molecule can bind.

Regarding “scaffold”, the specification defines as follow:
[0167] The term “scaffold” has its regular scientific meaning, and here refers to an oligomeric or polymeric template or a carrier or a base (base molecule or base structure), to which one or more molecules, e.g. ligand molecule, effector molecule, can be covalently bound, either directly, or via a linker, such as a cleavable linker. A scaffold may have a structurally ordered formation such as a polymer, oligomer, dendrimer, dendronized polymer, or dendronized oligomer or have an assembled polymeric structure such as a hydrogel, microgel, nanogel, stabilized polymeric micelle or liposome, but excludes structures that are composed of non-covalent assemblies of monomers such as cholesterol/phospholipid mixtures. A scaffold may comprise a polymeric or oligomeric structure, such as poly- or oligo(amines), e.g., polyethylenimine and poly(amidoamine); or structures such as polyethylene glycol, poly- or oligo(esters), such as poly(lactides), poly(lactams), polylactide-co-glycolide copolymers; or poly(dextrin), poly- or oligosaccharides, such as cyclodextrin or polydextrose; or structures such as natural and/or artificial poly- or oligoamino acids such as poly-lysine or a peptide or a protein, DNA oligo- or polymers, stabilized RNA polymers or PNA (peptide nucleic acid) polymers. Preferably, the polymeric or oligomeric structures are biocompatible, wherein biocompatible means that the polymeric or oligomeric structure does not show substantial acute or chronic toxicity in organisms and can be either excreted as it is or fully degraded to excretable and/or physiological compounds by the body's metabolism.

Regarding “ligand”, the specification defines as follow:
[0168] The term “ligand” has its regular scientific meaning, and here refers to any molecule or molecules which may selectively bind to a target cell-surface molecule or target cell-surface receptor expressed at target cells, e.g. target cancer cells or target auto-immune cells. The ligand may bind to an epitope comprised by receptors or other antigens on the target cells. Preferably, the cell-binding ligands are antibodies.

Regarding “antibody”, the specification defines as follow:
[0169] The term “antibody” as used herein is used in the broadest sense, which may refer to an immunoglobulin (Ig) defined as a protein belonging to the class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), or a functional binding fragment or binding domain of an immunoglobulin. In the context of the present invention, a “binding fragment” or a “binding domain” of an immunoglobulin is defined as antigen-binding fragment or -domain or other derivative of a parental immunoglobulin that essentially maintains the antigen binding activity of such parental immunoglobulin. Functional fragments and functional domains are antibodies in the sense of the present invention even if their affinity to the antigen is lower than that of the parental immunoglobulin. “Functional fragments and -domains” in accordance with the invention include, but are not limited to, F(ab′)2 fragments, Fab′ fragments, Fab fragments, scFv, dsFv, single-domain antibody (sdAb), monovalent IgG, scFv-Fc, reduced IgG (rIgG), minibody, diabodies, triabodies, tetrabodies, Fc fusion proteins, nanobodies, variable V domains such as VHH, Vh, and other types of antigen recognizing immunoglobulin fragments and domains. The fragments and domains may be engineered to minimize or completely remove the intermolecular disulphide interactions that occur between the CH1 and CL domains. Functional fragment and -domains offer the advantage of greater tumor penetration because of their smaller size. In addition, the functional fragment or -domain can be more evenly distributed throughout the tumor mass as compared to whole immunoglobulin.

[0170] The antibodies (immunoglobulins) of the present invention may be bi- or multifunctional. For example, a bifunctional antibody has one arm having a specificity for one receptor or antigen, while the other arm recognizes a different receptor or antigen. Alternatively, each arm of the bifunctional antibody may have specificity for a different epitope of the same receptor or antigen of the target cell.

[0171] The antibodies (immunoglobulins) of the present invention may be, but are not limited to, polyclonal antibodies, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, resurfaced antibodies, anti-idiotypic antibodies, mouse antibodies, rat antibodies, rat/mouse hybrid antibodies, llama antibodies, llama heavy-chain only antibodies, heavy-chain only antibodies, and veterinary antibodies. Preferably, the antibody (immunoglobulin) of the present invention is a monoclonal antibody. The resurfaced, chimeric, humanized and fully human antibodies are also more preferred because they are less likely to cause immunogenicity in humans. The antibodies of the ADC of the present invention preferably specifically binds to an antigen expressed on the surface of a cancer cell, an autoimmune cell, a diseased cell, an aberrant cell, while leaving any healthy cell essentially unaltered (e.g. by not binding to such normal cell, or by binding to a lesser extent in number and/or affinity to such healthy cell).

Regarding “proteinaceous molecule”, the specification defines as follow:
[0180] The term “proteinaceous”, used in e.g. “proteinaceous molecule” and “proteinaceous toxin”, are molecules and toxins comprising at least a string of amino acid residues that can be obtained as an expression product from a single mRNA. Such a molecule or toxin may further comprise any post-translational modifications, a carbohydrate such as an N- or O-linked carbohydrate, disulphide bonds, phosphorylations, sulphatations, etc., as a result of any post-translational modification, and/or may further comprise any other modification such as those resulting from chemical modifications (e.g., linking of effector moieties, saponin, scaffolds, ligands, etc., either directly to e.g. an amino-acid side chain, or via at least one linker (covalently) bound to the molecule for chemically modifying the proteinaceous molecule, and chemically bound (covalently) to the proteinaceous molecule). The term “proteinaceous” also encompasses and includes assemblies of such molecules, e.g. homodimers, heterotrimers, heterohexamers or complex assemblies such as ribosomes.

The specification exemplifies:

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Other than cetuximab, trastuzumab or anti-CD71 conjugated to SO1861-EMCH (N-ε-maleimidocaproic acid hydrazide) or SO1861-HATU linker or dendron-L-SO1861 or saporin or HSPBNA, the specification does not describe i. the structure, e.g., amino acid sequence of heavy and light chain variable domains, or ii. Partial structure, i.e., the six CDRs, iii. Physical and/or chemical properties and iv Functional characteristics, i.e., binding affinity or epitope specificity share by members of the genus of immunoglobulins, antibodies, IgG, VHH, VH domain, Fab, scFv, Fv dAb, F(ab)2, Fcab that correlated with binding to any first epitope of any and all cell-surface molecule (claims 1, 19) conjugated to any and all endosomal escape enhancer saponin (claim 1), such as any combination of saponins (claim 4) via any linker or oligomer or polymeric scaffold (claim 1) or effector moiety that is the same or different (claims 14, 16) such as any oligonucleotide, any nucleic acid, any xeno nucleic acid (claim 29) or any proteinaceous molecule (claim 30). There is no limitation on the structure or function of the antibody, or the epitope to which it binds (claims 1 and dependent claims thereof). Thus a representative number of species falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus are not adequately described.
Even assuming the antibody binds to CD71 (claims 11, 43), one species of antibody mAb OKT-9 that binds to just CD71 is not representative of the claimed genus.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling within the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Cochran et al. (J. Immunol. Meth. 287: 147-158, 2004; PTO 892) describes two anti-EGFR antibodies that bind to spatially overlapping epitopes of EGFR; yet only one of the two competes with EGF for binding to the receptor; see entire document (e.g., page 156, column 1). Thus, an antibody that binds to the same region of EGFR, or perhaps even an antibody that binds to an isoform of EGFR that is expressed in certain cancer cells, but not normal cells, may not have therapeutic value in and of itself.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen or epitope of such antigen (as held in AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As in Amgen, the pending claims of the instant case attempt to describe a genus of antibodies by describing something that is not an antibody, i.e. the antigen to which the antibody binds. Also analogous to Amgen, the fact that antigenic structures are known in detail would enable one of skill in the art to make antibodies meeting the binding limitations of the claims. As noted in Amgen, however, this is not enough to meet the written description requirement.
In AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014), a claim drawn to a genus of antibodies having a recited binding affinity and binding specificity to a fully characterized antigen was found to be invalid for lack of written description such that it was not infringed by a subsequently disclosed antibody having all of the recited functional characteristics but a completely different structure (amino acid sequence). The Court held:
“It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date... The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara®, whereas the patents do not describe representative examples to support the full scope of the claims. (AbbVie, 759 F.3d at 1298; 111 USPQ2d at 1791) (emphasis added).
Thus, the Amgen and the AbbVie decisions each support the finding that the detailed knowledge of one antibody structure does not reliably predict the structure of other antibodies that bind to the same epitope of an antigen and have the same effects. No structure-function relationship is established.
Regarding antibody drug conjugate, the state of the prior art is such that the location or site of conjugation on the drug and the antibody affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.

Regarding any oligomeric or polymeric scaffold, the specification discloses:
[0866] The Cy3-PAMAM-NC-SO1861-DBCO and Cy3-PAMAM-SO1861-DBCO conjugates were reacted with Alexa Fluor™ 488 labeled azido-toxins to perform a strain-promoted alkyne-azide cycloaddition. The conjugation between the reacting agents was indicated via gel electrophoresis and the co-localization of the fluorescent signals of Cy3 that is only attached on the PAMAM polymer and Alexa Fluor™ 488 that is only attached on the toxins on a polyacrylamide gel after gel electrophoresis (FIG. 77).
[0867] As an alternative polymeric structure to the PAMAM dendrimer, a G4-dendron (PFd-G4-Azide-NH-BOC, Polymer Factory) with 16 functional amino end groups and an azido group at the focal point was utilized for the conjugation to SO1861 (FIG. 84). The advantage of using a dendron over a dendrimer is the focal point that the dendron structure is exhibiting. This focal point allows the direct conjugation to a targeted toxin without the need of its post-modification with orthogonal click functions (FIG. 85). As shown in FIG. 85, the dendron underwent the same methodology as described for the PAMAM dendrimer. Briefly, after partial dye labeling and deprotection (FIG. 86), the amino groups of the dendron were converted into thiols using the thiolating reagent 2-iminothiolane followed by conjugation to SO1861-EMCH. For the conjugation to SO1861-EMCH three different feed equivalents of SO1861-EMCH were used. The dendron-SO1861 conjugates were analyzed via MALDI-TOF-MS. As expected, the conjugate species of 1 and 2 SO1861 molecules per dendron molecule were obtained when low SO1861-EMCH feed equivalents of 3 and 10 were used (FIGS. 87B, C). Higher dendron-SO1861 conjugate species of up to 9 SO1861 molecules per dendron were obtained (FIG. 87A) when using a feed equivalent of 22 SO1861-EMCH molecules per dendron molecule. In further experiments, the saponin functionalized dendron will be conjugated to targeted toxins over its focal point to yield a functionalized scaffold and will be evaluated biologically.
However, two species of PAMAM dendrimer and G4-dendron with 16 functional amino end groups and an azido group at the focal point was utilized for the conjugation to SO1861 are not representative the of genus of polymer or scaffold having any number in between of saponins bound to the scaffold (claim 32). Further, the large PAMAM can block endosomal acidification and prevent endosomal escape activity of saponin SO1861, which is required for killing cancer cells, see para. [0879].
Regarding saponins, the state of the prior art teaches that saponin represents a heterogenous phytochemicals with different structures and properties.
Fuchs et al. (newly cited, Biomedicines, 5 (14): 1-25, published 29 March 2017; PTO 892) teaches that saponins represent a wide spectrum in the field of secondary plant compounds and are subdivided into two groups, the steroid saponins and triterpenoid saponins, even including steroid alkaloid saponins, see page 2, section 2.1, 1st paragraph. The wide range of structural variation options, both in the aglycone and sugar moieties explains the variety of different saponins with diverse effects, see page 2, section 2.1, 3rd paragraph. For example, only saponins of a certain electrophoretic mobility are able to enhance the endosomal escape, see page 8, last paragraph. In addition, the enhancing effect of saponin (SA1641) on a targeted toxin is clathrin- and actin-dependent. Six inhibitory agents that are known to inhibit either clathrin-mediated endocytosis, GTPase activity of dynamin-2, actin-polymerization, endosomal acidification, or caveolae-dependent endocytosis were tested. Inhibition of clathrin-mediated endocytosis, actin-polymerization, and endosomal acidification blocked the enhancer effect of Saponinum album, see page 12.
Likewise, Barr et al. (newly cited, Advanced Drug Delivery Reviews 32 (3): 247-271, 6 July 1998; PTO 1449) teaches that saponins have different molecular weight, different adjuvant activity, different toxicity, and different structures, see page 249, 1st full paragraph; page 250, Table 1 and section 3. Structural and functional analysis of purified Quillaia saponins.
Given the broadness of the claims, one of ordinary skilled would not be able to readily visualize or recognize a first proteinaceous molecule comprising a first binding site for binding to which first epitope of which first cell-surface molecule covalently linked to which one or more saponin via at least one linker or an oligomeric or polymeric scaffold (claims 1, 4, 7-10, 26, 32-34, 49) wherein the first epitope of the first cell-surface molecule to which the first binding site of the first proteinaceous molecule binds is any CD71 (claims 11, 43) or therapeutic combination comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein each composition comprises proteinaceous molecule comprising binding sites for binding different epitopes of different cell-surface molecules and effector moieties, e.g., oligonucleotide, nucleic acid, xeno nucleic acid encompassed by the claims 14, 16, 19, 27-30, 50).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a proteinaceous molecule comprising a first antibody, and a second antibody or an antigen binding fragment thereof that binds to a cell surface receptor covalently linked to at least one endosomal escaper enhancer saponin SO1861 via a linker N-ε-maleimidocaproic acid hydrazide (EMCH), or a polymeric scaffold comprising saponin SO1861, or saporin wherein the first or second antibody is selected from the group consisting of cetuximab that binds to human EGFR, trastuzumab that binds to human HER2 and an anti-CD71 antibody, and wherein the scaffold is PAMAM dendrimer or a G4-dendron with 16 functional amino end groups, (2) a therapeutic combination, wherein the therapeutic combination comprises: (a) a first antibody cetuximab or antigen binding fragment thereof that binds to a human EGF receptor, wherein the first antibody or antigen binding fragment thereof is covalently linked to at least one endosomal escaper enhancer saponin SO1861 via a linker N-ε-maleimidocaproic acid hydrazide (EMCH), or a polymeric scaffold comprising saponin SO1861 and a second anti-CD71 antibody or antigen binding fragment thereof wherein the anti-CD71 antibody is conjugated to a toxin saporin or dianthin, and optionally a pharmaceutically acceptable excipient; (3) The proteinaceous protein above wherein the at least one saponin is a bisdesmosidic triterpene belonging to the type of 12,13-dehydrooleanane with an aldehyde at position C-23, and a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group and wherein the linker is covalently linked to a cysteine or a lysine residue, (7) the first proteinaceous molecule wherein the linker is N-ε-maleimidocaproic acid hydrazide, or 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).

Applicants’ arguments filed December 15, 2025 have been fully considered but are not found persuasive.
Given the lack of any additional rebuttal, the rejection is maintained for reasons of record.

Claims 1, 7-11, 13-14, 16, 19, 26-30, 32-34, 45, 49 and 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a proteinaceous molecule comprising a first antibody, and a second antibody or an antigen binding fragment thereof that binds to a cell surface receptor covalently linked to at least one endosomal escaper enhancer saponin SO1861 via a linker N-ε-maleimidocaproic acid hydrazide (EMCH), or a polymeric scaffold comprising saponin SO1861, or saporin wherein the first or second antibody is selected from the group consisting of cetuximab that binds to human EGFR, trastuzumab that binds to human HER2 and an anti-CD71 antibody, and wherein the scaffold is PAMAM dendrimer or a G4-dendron with 16 functional amino end groups, (2) a therapeutic combination, wherein the therapeutic combination comprises: (a) a first antibody cetuximab or antigen binding fragment thereof that binds to a human EGF receptor, wherein the first antibody or antigen binding fragment thereof is covalently linked to at least one endosomal escaper enhancer saponin SO1861 via a linker N-ε-maleimidocaproic acid hydrazide (EMCH), or a polymeric scaffold comprising saponin SO1861 and a second anti-CD71 antibody or antigen binding fragment thereof wherein the anti-CD71 antibody is conjugated to a toxin saporin or dianthin, and optionally a pharmaceutically acceptable excipient; (3) The proteinaceous protein above wherein the at least one saponin is a bisdesmosidic triterpene belonging to the type of 12,13-dehydrooleanane with an aldehyde at position C-23, and a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group and wherein the linker is covalently linked to a cysteine or a lysine residue, (7) the first proteinaceous molecule wherein the linker is N-ε-maleimidocaproic acid hydrazide, or 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, does not reasonably provide enablement for any proteinaceous molecules as set forth in claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, 45, 49 and 50. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses a first proteinaceous molecule comprising any first binding site for binding to any first epitope of any first target cell-surface molecule on a target cell, the first proteinaceous molecule provided with at least one endosomal escape enhancer saponin covalently bound via at least one linker or via any oligomeric or polymeric scaffold to an amino-acid residue of said first proteinaceous molecule or covalently bound directly to an amino-acid residue of said first proteinaceous molecule, wherein the first binding site comprises any immunoglobulin or antibody or at least one binding domain or at least one binding fragment thereof, wherein binding of the first proteinaceous molecules to their respective first proteinaceous molecules to their respective first epitope on the target cell is followed by endocytosis of the complexes of the first proteinaceous molecule and the first target cell-surface molecule, wherein the at least one saponin is any triterpenoid saponin or any bisdesmosidic triterpene saponin belonging to the type of a 12, 13-dehydrooleanane with al aldehyde function in position C-23.
Claim 7 encompasses the first proteinaceous molecule of claim1, wherein the at least one 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 function in the saponin.
Claim 8 encompasses the first proteinaceous molecule of claim1, wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, wherein the at least one saponin is covalently coupled to the amino-acid residue of the first proteinaceous molecule via the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the saponin.
Claim 9 encompasses the first proteinaceous molecule of claim 4, wherein the aldehyde function in position C-23 of the at least one saponin is covalently coupled to linker N-s-maleimidocaproic acid hydrazide, which linker is covalently coupled via a thio-ether bond to a sulfhydryl group in the first proteinaceous molecule, or a sulfhydryl group of a cysteine.
Claim 10 encompasses the first proteinaceous molecule of claim4, wherein the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the at least one saponin is covalently coupled to linker 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, which linker is covalently coupled via an amide bond to an amine group in the first proteinaceous molecule, or an amine group of a lysine or an N-terminus of the first proteinaceous molecule.
Claim 11 encompasses the first proteinaceous molecule of claim1, wherein the first epitope of the first cell-surface molecule to which the first binding site of the first proteinaceous molecule binds is any epitope of any CD71.
Claim 13 encompasses the first proteinaceous molecule of claim 11, wherein the first binding site of the first proteinaceous molecule comprises or consists of any one of cetuximab (elected species).
Claim 14 encompasses a therapeutic combination, wherein the therapeutic combination comprises: (a) a first pharmaceutical composition comprising the first proteinaceous molecule of claim1 and optionally a pharmaceutically acceptable excipient; and (b) a second pharmaceutical composition comprising a second proteinaceous molecule different from the first proteinaceous molecule, the second proteinaceous molecule comprising a second binding site for binding to a second epitope of a second cell-surface molecule different from the first cell-surface molecule, and comprising an effector moiety, the second pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the second epitope is different from the first epitope.
Claim 16 encompasses a therapeutic combination, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of claim 14 and comprising the first binding site for binding to the first epitope on the first cell-surface molecule, the first pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient; and (b) a third pharmaceutical composition comprising a third proteinaceous molecule, the third proteinaceous molecule comprising the first binding site for binding to the first epitope on the cell-surface molecule of (a) and an effector moiety, the third pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the first binding site of the first proteinaceous molecule and the first binding site of the third proteinaceous molecule are the same, and wherein the first cell-surface molecule and the first epitope on the first cell-surface molecule, to which the first proteinaceous molecule can bind, and the first cell-surface molecule and the first epitope on the first cell-surface molecule, to which the third proteinaceous molecule can bind, are the same.
Claim 19 encompasses the therapeutic combination of claim14, wherein the second binding site of the second proteinaceous molecule and/or the first binding site of the third proteinaceous molecule comprises any immunoglobulin, at least one binding domain of an immunoglobulin and/or at least one binding fragment of an immunoglobulin, or any antibody.
Claim 26 encompasses the first proteinaceous molecule of claim 1, wherein the first binding site and/or a second binding site is/are or comprise(s) a monoclonal antibody or at least one cell-surface molecule binding fragment and/or domain thereof, and optionally comprise cetuximab (elected species).
Claim 27 encompasses the therapeutic combination of claim16, wherein the first binding site of the first proteinaceous molecule and the third proteinaceous molecule comprises a monoclonal antibody or at least one of a cell-surface molecule binding domain and/or fragment thereof, and optionally comprise cetuximab, with the proviso that the first binding site of the first proteinaceous molecule is the same as the first binding site of the third proteinaceous molecule.
Claim 28 encompasses the therapeutic combination of claim 14, wherein the second binding site of the second proteinaceous molecule and/or the first binding site of the third proteinaceous molecule comprises a monoclonal antibody.
Claim 29 encompasses the therapeutic combination of claim14, wherein the effector moiety that is comprised by the second proteinaceous molecule and/or by the third proteinaceous molecule comprises any one or more of an oligonucleotide, a nucleic acid, a xeno nucleic acid.
Claim 30 encompasses the therapeutic combination of claim 14, wherein the effector moiety that is comprised by the second proteinaceous molecule and/or by the third proteinaceous molecule comprises at least one proteinaceous molecule.
Claim 32 encompasses the first proteinaceous molecule of claim 1, wherein the first proteinaceous molecule comprises more than one saponin, or any number of saponins therein between, or 7, 9, 12 saponins, covalently bound directly to an amino-acid residue of the first proteinaceous molecule, or
covalently bound via at least one linker,
or via at least one cleavable linker,
or via at least one polymeric or oligomeric scaffold, or any combination of I, ii, and iii, wherein the at least one scaffold is optionally based on a dendron, wherein 1-32 saponins or 2, 3, 4, 5, 6, 8, 10, 16, 32 saponins, or 7, 9, 12 saponins, are covalently bound to the at least one scaffold.
Claim 33 encompasses the first proteinaceous molecule of claim 7, wherein the at least one linker is a non-cleavable linker or a cleavable linker, wherein the cleavable linker is subject to cleavage under acidic conditions, reductive conditions, enzymatic conditions or light-induced conditions.
Claim 34 encompasses the first proteinaceous molecule of claim 7, wherein the cleavable linker is subject to cleavage in vivo under acidic conditions as present in endosomes and/or lysosomes of mammalian cells.
Claim 43 encompasses any antibody-drug conjugate or any ligand-drug conjugate comprising the first proteinaceous molecule of claim1 and any effector moiety, wherein the antibody can bind to any CD71.
Claim 49 encompasses the first proteinaceous molecule of claim 1, wherein the first binding site comprises at least one ligand for binding to any cell-surface molecule or any EGF or any cytokine.
Claim 50 encompasses the therapeutic combination of claim 14, wherein the second binding site of the second proteinaceous molecule and/or the first binding site of the third proteinaceous molecule comprises at least any one ligand for binding to a cell-surface molecule or any EGF or any cytokine.
The teachings of the specification has been discussed above in the written description and incorporated here by reference.
Other than cetuximab, trastuzumab or anti-CD71 conjugated to SO1861-EMCH (ε-maleimidocaproic acid hydrazide) or SO1861-HATU linker or dendron-L-SO1861 or saporin or HSPBNA, the specification does not teach i. the structure, e.g., amino acid sequence of heavy and light chain variable domains, or ii. Partial structure, i.e., the six CDRs, iii. Physical and/or chemical properties and iv Functional characteristics, i.e., binding affinity or epitope specificity share by members of the genus of immunoglobulins, antibodies, IgG, VHH, VH domain, Fab, scFv, Fv dAb, F(ab)2, Fcab that correlated with binding to which first epitope of which cell-surface molecule (claims 1, 19) conjugated to any and all endosomal escape enhancer saponin (claim 1), such as any combination of saponins (claim 4, 7-10) via any linker or oligomer or polymeric scaffold (claim 1) or effector moiety (claims 14, 16) such as any oligonucleotide, any nucleic acid, any xeno nucleic acid (claim 29) or any proteinaceous molecule (claim 30) wherein the first and second proteinaceous molecules are different (claims 14, 16) so that one of skill in the art can make and use the genus of the actual claimed first and second proteinaceous molecules themselves without undue experimentation.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Regarding antibody drug conjugate, the state of the prior art is such that the location or site of conjugation on the drug and the antibody affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.

Regarding any oligomeric or polymeric scaffold, the specification discloses:
[0866] The Cy3-PAMAM-NC-SO1861-DBCO and Cy3-PAMAM-SO1861-DBCO conjugates were reacted with Alexa Fluor™ 488 labeled azido-toxins to perform a strain-promoted alkyne-azide cycloaddition. The conjugation between the reacting agents was indicated via gel electrophoresis and the co-localization of the fluorescent signals of Cy3 that is only attached on the PAMAM polymer and Alexa Fluor™ 488 that is only attached on the toxins on a polyacrylamide gel after gel electrophoresis (FIG. 77).
[0867] As an alternative polymeric structure to the PAMAM dendrimer, a G4-dendron (PFd-G4-Azide-NH-BOC, Polymer Factory) with 16 functional amino end groups and an azido group at the focal point was utilized for the conjugation to SO1861 (FIG. 84). The advantage of using a dendron over a dendrimer is the focal point that the dendron structure is exhibiting. This focal point allows the direct conjugation to a targeted toxin without the need of its post-modification with orthogonal click functions (FIG. 85). As shown in FIG. 85, the dendron underwent the same methodology as described for the PAMAM dendrimer. Briefly, after partial dye labeling and deprotection (FIG. 86), the amino groups of the dendron were converted into thiols using the thiolating reagent 2-iminothiolane followed by conjugation to SO1861-EMCH. For the conjugation to SO1861-EMCH three different feed equivalents of SO1861-EMCH were used. The dendron-SO1861 conjugates were analyzed via MALDI-TOF-MS. As expected, the conjugate species of 1 and 2 SO1861 molecules per dendron molecule were obtained when low SO1861-EMCH feed equivalents of 3 and 10 were used (FIGS. 87B, C). Higher dendron-SO1861 conjugate species of up to 9 SO1861 molecules per dendron were obtained (FIG. 87A) when using a feed equivalent of 22 SO1861-EMCH molecules per dendron molecule. In further experiments, the saponin functionalized dendron will be conjugated to targeted toxins over its focal point to yield a functionalized scaffold and will be evaluated biologically.
However, two species of PAMAM dendrimer and G4-dendron with 16 functional amino end groups and an azido group at the focal point was utilized for the conjugation to SO1861 are not representative the of genus of polymer or scaffold having 32, 64 up to 100 saponins bound to the scaffold (claim 32). Further, the large PAMAM can block endosomal acidification and prevent endosomal escape activity of saponin SO1861, which is required for killing cancer cells, see para. [0879].
The state of the prior art teaches that saponin represents a heterogenous phytochemicals with different structures and properties.
Fuchs et al. (newly cited, Biomedicines, 5 (14): 1-25, published 29 March 2017; PTO 1449) teaches that saponins represent a wide spectrum in the field of secondary plant compounds and are subdivided into two groups, the steroid saponins and triterpenoid saponins, even including steroid alkaloid saponins, see page 2, section 2.1, 1st paragraph. The wide range of structural variation options, both in the aglycone and sugar moieties explains the variety of different saponins with diverse effects, see page 2, section 2.1, 3rd paragraph. For example, only saponins of a certain electrophoretic mobility are able to enhance the endosomal escape, see page 8, last paragraph. In addition, the enhancing effect of saponin (SA1641) on a targeted toxin is clathrin- and actin-dependent. Six inhibitory agents that are known to inhibit either clathrin-mediated endocytosis, GTPase activity of dynamin-2, actin-polymerization, endosomal acidification, or caveolae-dependent endocytosis were tested. Inhibition of clathrin-mediated endocytosis, actin-polymerization, and endosomal acidification blocked the enhancer effect of Saponinum album, see page 12.
Likewise, Barr et al. (newly cited, Advanced Drug Delivery Reviews 32 (3): 247-271, 6 July 1998; PTO 892) teaches that saponins have different molecular weight, different adjuvant activity, different toxicity, and different structures, see page 249, 1st full paragraph; page 250, Table 1 and section 3. Structural and functional analysis of purified Quillaia saponins.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
Given the different combinations of antibody, saponin, effector moiety, linker chemistry and conjugation site, the lack of sufficient guidance and in vivo working examples, it is unpredictable which undisclosed proteinaceous molecule(s) or antibody-drug conjugate or ligand-drug conjugate is/are effective for treating which cancer in a human subject.
As such, it would require undue experimentation of one skilled in the art to practice the claimed invention commensurate in scope with the claims at the time of filing. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).

Applicants’ arguments filed December 15, 2025 have been fully considered but are not found persuasive.
Given the lack of any additional rebuttal, the rejection is maintained for reasons of record.

Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.

The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).

Claims 1, 9, 13, 26-30 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al (of record, WO2015157595 publication, published Oct 15, 2015; PTO 892) as evidenced by Freeman et al (Abstract 14536, 26 (15 Suppl), published 2008 ASCO Annual meeting; PTO 892) in view of Fuchs I (US20080064762, published March 13, 2008; PTO 892), Rosazza et al (of record, US20030203856, published Oct 30, 2003; PTO 892), Weng (of record, J of Controlled release 164: 74-86, 2012; PTO 892) and/or Fuchs II (Toxins 8: 200, 2016; PTO 892).

Claim 1 recites a first proteinaceous molecule comprising any first binding site for binding to any first epitope of any first target cell-surface molecule on a target cell, the first proteinaceous molecule provided with at least one endosomal escape enhancer saponin covalently bound via at least one linker or via any oligomeric or polymeric scaffold to an amino-acid residue of said first proteinaceous molecule or covalently bound directly to an amino-acid residue of said first proteinaceous molecule, wherein the first binding site comprises any immunoglobulin or antibody or at least one binding domain or at least one binding fragment thereof, wherein binding of the first proteinaceous molecules to their respective first proteinaceous molecules to their respective first epitope on the target cell is followed by endocytosis of the complexes of the first proteinaceous molecule and the first target cell-surface molecule, wherein the at least one saponin is any triterpenoid saponin or any bisdesmosidic triterpene saponin belonging to the type of a 12, 13-dehydrooleanane with al aldehyde function in position C-23.

Regarding claims 1, 9, 13, 26, 27, 28, Gao teaches a first proteinaceous molecule, e.g., conjugate comprising a cysteine engineered antibody conjugated to any heterologous moiety which can be covalently attached to the cysteine-engineered antibody, see para. [0130]. The conjugate comprises at least one heterologous moieties, e.g., saponin, see para. [0140]. Examples of heterologous moieties attached to a thiol group of an engineered cysteine antibody include toxin, drug, cytokine, enzyme, oligonucleotide, DNA, peptide, lipid, carbohydrate, scaffolding molecule, see page 39, para. [0131] in particular. Examples of cysteine-engineered antibody comprising an epitope binding domain or ligand domain that competes with ligand for binding EGFR (ErbB1), HER2 (ErbB0 or p185neu), see para. [0170], cetuximab as per claims 13 and 26 (which is an anti-EGFR antibody, also known as ERBITUX®, p. 57, line 5), pantitumumab (also known as ABX-EGF), see para. [0171] or anti-HER2 antibody or antigen-binding fragment thereof such as trastuzumab (also known as HERCEPTIN® (see para. [0171], [0188]). The cetuximab and pantitumumab are monoclonal antibodies (mAbs, para. [0002],[0037], [0039], [0040]) that bind to a cell-surface molecule, e.g., human EGFR.
Claims 13 and 26 are included because Gao teaches such antibodies and evidentiary reference Freeman teaches that pantitumumab (a fully human monoclonal against epidermal growth factor receptor) and cetuximab bind to comparable surface exposed amino acids in domain III of EGFR, resulting in inhibition of receptor activation, see abstract, in particular.
Regarding claims 29-30, Gao teaches that the at least one heterologous moiety is a cytokine (aka proteinaceous molecule, see para. [0203]) or oligonucleotide or nucleic acid, e.g., DNA, see para. [0203].
Claim 32 is included as Gao teaches at least one (one or more) heterologous moiety, e.g., saponin (para. [0140]). Cysteine thiol groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker reagents or compound-linker intermediates or drugs including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides, such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups; and (iv) disulfides, including pyridyl disulfides, via sulfide exchange. Nucleophilic groups on a heterologous moiety or linker include, but are not limited to amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents, see para. [0197].
Regarding claim 33, Gao teaches that the linker is non-cleavable or a cleavable linker, see para. [0158] to [0159].
Gao does not teach that saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12, 13-dehydrooleanane with an aldehyde functional in position C-23 as per claim 1.
However, Fuchs I (US20080064762) teaches a composition comprising at least one pharmacologically active agent, e.g., toxin (see para. [0045]) coupled to a target cell specific component, e.g., antibody or antigen binding fragment or natural EGF ligand that binds to a cell surface receptor, e.g., EGFR or HER2 (see para. [0002], [0010], [0014]), and saponins, see entire document, claims 1 and 11. Typical target antigens are the epidermal growth factor (EGF) receptor, the proto-oncogene receptor ErbB2 (also known as HER-2 in humans), the interleukin-2 receptor or cancer-associated carbohydrates, see paragraph[0002], in particular. Examples of conjugate include EGF directly coupled to Sap-3 (SE), see para. [0077]. Examples of saponins are triterpenoic saponins, preferably having an aldehyde function at the aglycone and two sugar residues glycosidically bound to the aglycone. The triterpenoic saponins with basic structures belonging to the type of 12,13-dehydrooleanane with an aldehyde function in position 23, e.g. Saponinum album from Gypsophila paniculata, see para. [0020]. The saponins and triterpenoic saponins, preferably having an aldehyde function at the aglycone and two sugar residues glycosidically bound to the aglycone, wherein said saponin is selected from the group comprising triterpenoic saponins with basic structures belonging to the type of 12,13-dehydrooleanane with an aldehyde function in position 23, see reference claim 11.

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Rosazza teaches triterpene saponin (see entire document, para. [0005], [0006], [0029], [0037]) may be linked to one or more targeting agents that are capable of delivery the active molecules to the tumor region, see para. [0081], [0082]. Exemplary methods for linking compounds to a secondary molecule are disclosed on pages 35-39. Typical linkers include Sulfhydryls SPDP Primary amines Thiolation 6.8 A Sulfhydryls Cleavable cross-linking LC-SPDP Primary amines Extended spacer arm 15.6 A Sulfhydryls Sulfo-LC-SPDP Primary amines Extended spacer arm 15.6 A Sulhydryls Water-soluble SMCC Primary amines Stable maleimide reactive 11.6 A Sulfhydryls group Enzyme-antibody conjugation Hapten-carrier protein conjugation Sulfo-SMCC Primary amines Stable maleimide reactive 11.6 A Sulfhydryls group Water-soluble Enzyme-antibody conjugation MBS Primary amines Enzyme-antibody 9.9 A Sulhydryls conjugation Hapten-carrier protein conjugation Sulfo-MBS Primary amines Water-soluble 9.9 A Sulfhydryls SIAB Primary amines Enzyme-antibody 10.6 A Sulfhydryls conjugation Sulfo-SIAB Primary amines Water-soluble 10.6 A Sulhydryls SMPB Primary amines Extended spacer arm 14.5 A Sulfhydryls Enzyme-antibody conjugation Sulfo-SMPB Primary amines Extended spacer arm 14.5 A Sulhydryls Water-soluble EDC/Sulfo-NHS Primary amines, see Table 1, in particular.

Weng (J of Controlled release 164: 74-86, 2012; PTO 892) teaches various triterpenoid saponins SA1641 and SA1657 isolated from Saponinum album, which are bisdemosidic (two sugar chains), see Fig. 1 below. The triterpenoid saponin SO1861 was isolated from the roots of Saponaria officinalis L, which are bisdesmosidic (two sugar chains) triterpenoidal saponin SO1861 isolated from the roots of Saponaria offianlis L. 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.
The triterpenoid saponins SA1641 and SA1657 isolated from Saponinum album have the following structures:

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and belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and a glucuronic acid function in a carbohydrate substitute at the C-3beta-OH group, see p. 75, left col., Fig. 1 (reproduced below), in particular.

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Thus, Weng teaches that saponins SA1641 and SA1657 isolated from Saponinum album are bisdesmosidic triterpene and belonging to the type of 12,13-dehydrooleane with an aldehyde function at C-23 (the CHO group) and a glucuronic acid function at the C-3beta-OH group (the negatively charge group).
Weng further teaches that the combination of saponin SA1641 with EGF ligand conjugated saporin toxin (saporin-EGF) enhances the release of internalized saporin toxin out of the late endosomes/lysosomes into the cytosol (aka endosomal escape enhancer, Fig. 5), follows by formation of apoptotic, morphological changes induced by the toxic activity of saporin. Weng teaches that triterpene saponins are valuable tools to augment the cytosolic delivery of anti-tumor toxins, see p. 85, in particular.
Claim 49 is included because it is an obvious variation of Weng’s teaching by conjugating Weng’s EGF ligand to saponin as opposed to saporin since both EGF and anti-EGFR antibody bind to human EGFR.
Likewise, Fuchs II (Toxins 8: 200, 2016; PTO 892) teaches that glycosylated triterpenoids (saponins) of the oleanane type isolated from Gypsophila paniculata L.(baby’s breath) and Saponaria officinalis L. (common soapwort) have the ability to specifically augment the cytotoxicity of several ribosome-inactivating proteins by Mediation of an enhanced endosomal escape (EEE), see p. 14-15. SO1861 from Saponaria officinalis L. and SA1641 from Saponinum album (a saponin composite from Gypsophila spec.) are two of the few saponins that were found to display such tremendous synergism with several type I RIPs, such as saporin, dianthin, or agrostin, see p. 15, in particular.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the saponin in the antibody conjugated saponin of Gao for any one of the bisdemosidic triterpenoid saponin from Rosazza or Weng or Fuchs I and Fuchs II isolated from Saponinum album, e.g., SA1641 and/or SA1657 belonging to the type of 12,13-dehydrooleanane with an aldehyde function in position 23 from Gypsophila paniculata and/or the bisdesmosidic, triterpenoid saponin SO1861 (elected species) from the roots of Saponaria offianlis L, then covalently linked to Gao’s cetuximab or pantitumumab using any one of Rosazza’s linker
to arrive at the claimed invention with a reasonable expectation of success, e.g. covalently linked saponins to anti-EGFR antibody that binds to different epitope on human EGFR for delivery of bisdesmosidic triterpene saponin and toxin to cells expressing the same receptor of interest in order to enhance the endosome escape of the targeted toxins as taught by Fuchs II.
One of ordinary skill in the art would have been motivated to do so because Weng teaches that triterpene saponins are valuable tools to augment the cytosolic delivery of anti-tumor toxins and enhance the release of internalized saporin toxin out of the late endosomes/lysosomes into the cytosol (aka endosomal escape enhancer, see Fig. 5, see p. 85, in particular.
One of ordinary skill in the art would have been motivated to do so because Fuchs II teaches saponins facilitate the endosomal/lysosomal escape of the internalized toxin conjugate and coupling of saponins and a pharmacologically active agent to a target cell specific component is a promising tool for delivering of both the pharmacologically active agent and saponin to target cells at the same time, see para. [0080].
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify the conjugate of Gao by “The simple substitution of a known element, e.g., saponin for another, SA1641 or SA1657 Saponinum album from Gypsophila paniculata is likely to be obvious when it does no more than yield predictable results.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
One of ordinary skill in the art would have been motivated to do so because Fuchs II teaches that saponins are important tools to improve the endosomal escape rate of targeted toxins and accordingly decrease the dosage, see p. 17.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.

Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Gao et al (of record, WO2015157595 publication, published Oct 15, 2015; PTO 892) as evidenced by Freeman et al (Abstract 14536, 26 (15 Suppl), published 2008 ASCO Annual meeting; PTO 892) in view of Fuchs I (US20080064762, published March 13, 2008; PTO 892), Rosazza et al (of record, US20030203856, published Oct 30, 2003; PTO 892), Weng (of record, J of Controlled release 164: 74-86, 2012; PTO 892), and/or Fuchs II (Toxins 8: 200, 2016; PTO 892) as applied to claims 9, 11, 13, 26-30 and 32-33 mentioned above and further in view of Menjoge et al. (of record, Drug Discovery Today, Vol. 15, Issues 5-6, page 171-185, 2010; PTO-892).

The teachings of Gao, Freeman, Fuchs I, Rosazza, Weng, and Fuchs II have been discussed supra.
The references do not teach that the linker is a polymeric scaffold as per claim 1.
However, Menjoge et al. teach that polymeric scaffold such as dendrimers are members of a versatile, fourth new class of polymer architecture. Typically, dendrimers are used as well-defined scaffolding to conjugate, complex or encapsulate therapeutic drugs:

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As a delivery vector, dendrimer conjugate linker or spacer chemistry plays a crucial part in determining optimum drug delivery to disease sites by conserving active drug efficacy while influencing appropriate release patterns (Abstract). Menjoge et al. disclose the Tomalia-type poly(amidoamine), such as PAMAM (page 172, Left Col., para. 2), wherein PAMAM has been used to conjugate with antibody (page 174, Table 3). Dendrimers confers several structural benefits over linear polymer. Such advantages include rapid cellular entry, reduced macrophage uptake, targetability and more facile passage across biological barriers by transcytosis (page 174, Left Col., para. 1). The dendrimer-drug conjugates are attached directly via linkers or spaces to dendrimer terminal groups and, in some instances, in combination with targeting moieties. A key feature for achieving improved drug delivery and efficacy is the ability to tailor the drug release from the dendrimer conjugate in an active form, at or in very close proximity to the target site and with minimum exposure to healthy collateral tissue (page 175, Left Col., para. 2; Right Col., para. 1). Menjoge et al. also disclose a strategy involved N-acetyl cysteine (NAC), which was linked to PAMAM dendrimers possessing carboxylic acid and amine terminal groups via cleavable disulfide linkages, wherein the NAC-PAMAM conjugates are 16 times more efficacious than the drug alone for the treatment of maternal fetal infections (page 175, Right Col., para. 2; page 176, Left Col., para. 1). Furthermore, Menjoge et al. disclose that Adriamycin (ADR) is conjugated to PEG-grafted G = 4; PAMAM dendrimers by amide and hydrazone linkage revealed that remarkable amounts of ADR (at endosomal pH 5.5) are released from the conjugates possessing hydrazone linkage compared with the amide linkage. The conjugates bearing hydrazone linkages exhibit seven times more efficacy than those with amide linkages (page 176, Left Col., para. 2).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the linker or scaffold in the conjugate of Gao, Freeman, Rosazza, Weng and Fuchs for the dendrimer or PEG-grafted PAMAM in view of Menjoge et al. because Menjoge et al. teach that it is known in the art to use dendrimer as a conjugate linker to link more than one molecules in the conjugate.
One would have been motivated to substitute the linker as taught by Gao with PEG-grafted PAMAM in view of Menjoge et al. because Menjoge et al. teach the benefits of using dendrimer as a conjugate linker, such as rapid cellular entry, reduced macrophage uptake, targetability and more facile passage across biological barriers by transcytosis and improved the amount of drug released and efficacy via hydrazone linkage. Menjoge et al. indicate that a remarkable amounts of ADR has been released at an acidic environment with pH = 5.5, which shows that the bonds are cleaved.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
In this case, applying a known technique of conjugating a known antibody, e.g., cetuximab or trastuzumab to at least one known saponin SA1641, SA1657, SO1861 via a linker, e.g., PEG-grafted PAMAM would yield predictable results, more than one saponins and payload covalently linked to a cysteine residue on the cetuximab or trastuzumab antibody for site-specific delivery.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.

Claims 7, 9, 11, 33 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al (of record, WO2015157595 publication, published Oct 15, 2015; PTO 892) as evidenced by Freeman et al (Abstract 14536, 26 (15 Suppl), published 2008 ASCO Annual meeting; PTO 892) in view of Fuchs I (of record, US20080064762. Published March 13, 2008), Rosazza et al (of record, US20030203856, published Oct 30, 2003; PTO 892), Weng (of record, J of Controlled release 164: 74-86, 2012; PTO 892) and/or Fuchs II (Toxins 8: 200, 2016; PTO 892) as applied to claims 1, 11, 13, 26-30 and 32-33 mentioned above and further in view of Doronina et al (US20040157782, published August 12, 2004; PTO 892).
The teachings of Gao, Freeman, Fuchs I, Rosazza, Weng, and Fuchs II have been discussed supra.
The references do not teach that wherein the aldehyde function in position C-23 of the least one saponin is covalently coupled to linker N-ε-maleimidocaproic acid hydrazide (EMCH), which linker is covalently bound via a thio-ether bond to a sulfhydryl group in the antibody as per claim 9, wherein the cleavable linker is cleaved under acidic condition as per claim 33, wherein the antibody binds to CD71 as per claim 11 and 43.
However, Doronina teaches antibody conjugates to a effector or drug of interest, e.g., doxorubicin via a linker, see para. [0326]. Suitable heterobifunctional linkers include commercially available various linkers such as maleimido hydrazides (e.g., .beta.-maleimido propionic acid hydrazide, .epsilon.-maleimidocaproic acid hydrazide (EMCH), and SMCC hydrazide, available from Molecular Biosciences, Inc. Boulder Colo.), see para. [0298], thio-ether modified linker via the sulfhydryl group (aka cysteines) on the mAb, see Examples 22-23, in particular. Doronina teaches that the targeting ligand is an antibody, e.g., chimeric or humanized or a fragment thereof, see para. [0327]. Examples of antibody for treatment of cancer include, but not limited to, Herceptin™ (trastuzumab), see para. [0343], anti-transferrin receptor (also known as CD71 as per claims 11 and 43) for carcinomas, see para. [0344], in particular). Doronina teaches that the mAb-pentapeptide conjugates can be used to deliver the cytotoxic drug to tumor cells. Without being bound by theory, once the antibody has bound to tumor associated antigens, it is taken up inside cells through receptor-mediated endocytosis into endosomes and lysosomes. These intracellular vesicles are acidic and can induce the hydrolysis of an acid-sensitive linker bond, e.g., a hydrazone bond as per claim 33, between the drugs and the mAbs. In addition, ester bonds can be cleaved by proteases and esterases, which are in abundance within lysosomes wherein the pH is < 6.5. The released drug is then free to migrate in the cytosol and induce cytotoxic activities. In an alternative embodiment, the drug is cleaved from the conjugate outside the cell and subsequently penetrates the cell.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Gao, Freeman, Rosazza, Weng, Fuchs and Fuchs II in view of Doronina by covalently linking Gao’s saponins to any one of the cetuximab (anti-EGFR) or panitumumab (anti-EGFR) or trastuzumab (anti-HER2) or Doronina’s anti-CD71 antibody using Doronina’s heterobifunctional linker epsilon.-maleimidocaproic acid hydrazide (EMCH), that covalently link an aldehyde function group at position C-23 of the aglycone core of saponin SO1861 via a thio-ether bond to a sulfhydryl group of the cysteine residues on the antibody to arrive at the claimed invention with a reasonable expectation of success.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to conjugate saponins SO1816 to the same or different antibody of Gao or Doronina in order to deliver the saponins to the same cancer cells that express the same or different cell surface receptor for enhancing saponin-mediated the endo/lysosomal escape of dianthin (see p. 251) and avoid off-targeted effects of saponins, see abstract, in particular.
One of ordinary skill in the art would have been motivated to use any one of the commercially available heterobifunctional linker such as N-epsilon maleimidocaproic acid hydrazide (EMCH) because Doronina teaches that such acid-sensitive hydrazone bond can be hydrolyze in acidic environment such as the endosome and lysosome of the cell to release the toxins or effector moiety, thereby enhance endosome escape of the targeted toxin. Conjugating saponins to antibody that binds to cell-surface receptor is expected to reduce off-targeted effects of saponins and reduced side effects.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.

Claims 14, 16, 19, 27, 28, 29, 30 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al (of record, WO2015157595 publication, published Oct 15, 2015; PTO 892) as evidenced by Freeman et al (Abstract 14536, 26 (15 Suppl), published 2008 ASCO Annual meeting; PTO 892) in view of Weng (of record, J of Controlled release 164: 74-86, 2012; PTO 892), Fuchs et al (of record, US20080064762. Published March 13, 2008; PTO 892) and Gilabert-Oriol et al (Biochemical Pharmacology 97: 247-255, 2015; PTO 892).
Claim 14 is drawn to a therapeutic combination comprising:
(a) a first pharmaceutical composition comprising a conjugate comprising any first binding molecule comprising a first binding region for binding to any first binding site of any cell-surface molecule and the conjugate comprising at least one of any saponin covalently bound to said first binding molecule, wherein the saponin is a triterpene glycoside or a bidesmosidic triterpene glycoside; and
(b) a second pharmaceutical composition comprising a second proteinaceous molecule different from the first proteinaceous molecule, the second proteinaceous molecule comprising a second binding region different from the first cell-surface molecule, and comprising an effector molecule, the second pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient and optionally further comprising a pharmaceutically acceptable diluent.
Claim 16 encompasses a therapeutic combination, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of claim 14 and comprising the first binding site for binding to the first epitope on the first cell-surface molecule, the first pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient; and (b) a third pharmaceutical composition comprising a third proteinaceous molecule, the third proteinaceous molecule comprising the first binding site for binding to the first epitope on the cell- surface molecule of (a) and an effector moiety, the third pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the first binding site of the first proteinaceous molecule and the first binding site of the third proteinaceous molecule are the same, and wherein the first cell-surface molecule and the first epitope on the first cell-surface molecule, to which the first proteinaceous molecule can bind, and the first cell-surface molecule and the first epitope on the first cell-surface molecule, to which the third proteinaceous molecule can bind, are the same.
Gao teaches a first proteinaceous molecule, e.g., conjugate comprising a cysteine engineered antibody conjugated to any heterologous moiety which can be covalently attached to the cysteine-engineered antibody, see para. [0130]. Gao further teaches conjugate comprises at least one heterologous moieties, e.g., saponin, see para. [0140]. Examples of heterologous moieties attached to a thiol group of an engineered cysteine antibody include toxin, drug, cytokine, enzyme, oligonucleotide, DNA, peptide, lipid, carbohydrate, or scaffolding molecule, see page 39, para. [0131] in particular.
Examples of cysteine-engineered antibody comprising an epitope binding domain or ligand domain that competes with ligand for binding EGFR (ErbB1), HER2 (ErbB0 or p185neu), see para. [0170], cetuximab (which is an anti-EGFR antibody, also known as ERBITUX®, p. 57, line 5), pantitumumab (also known as ABX-EGF), see para. [0171] or anti-HER2 antibody or antigen-binding fragment thereof such as trastuzumab (also known as HERCEPTIN® (see para. [0171], [0188]). The cetuximab and pantitumumab are monoclonal antibodies (mAbs, para. [0002],[0037], [0039], [0040]) that bind to a cell-surface molecule, e.g., human EGFR.
Evidentiary reference Freeman teaches that pantitumumab (a fully human monoclonal against epidermal growth factor receptor) and cetuximab bind to comparable surface exposed amino acids in domain III of EGFR, resulting in inhibition of receptor activation, see abstract, in particular.
Gao does not teach that saponin is a triterpenoid saponin or a bisdesmosidic triterpene saponin belonging to the type of a 12, 13-dehydrooleanane with an aldehyde functional in position C-23 as per claim 14.
However, Weng (J of Controlled release 164: 74-86, 2012; PTO 892) teaches various triterpenoid saponins SA1641 and SA1657 isolated from Saponinum album and triterpenoid saponin SO1861 (elected species) is a bisdesmosidic (two sugar chains) triterpenoidal saponin isolated from the roots of Saponaria offianlis L, see p. 75, left col., Fig. 1, in particular. Weng further teaches that the combination of saponin SA1641 with EGF ligand conjugated saporin toxin (saporin-EGF) enhances the release of internalized saporin toxin out of the late endosomes/lysosomes into the cytosol (Fig. 5), follows by formation of apoptotic, morphological changes induced by the toxic activity of saporin. Weng teaches that triterpene saponins are valuable tools to augment the cytosolic delivery of anti-tumor toxins, see p. 85, in particular.
Claim 50 is included because it is an obvious variation of Weng’s teaching by conjugating Weng’s EGF ligand to saponin as opposed to saporin since both EGF and anti-EGFR antibody bind to human EGFR.
Fuchs teaches bisdesmosidic triterpene saponin belonging to the type of 12,13-dehydrooleanane with an aldehyde function in position 23, e.g. Saponinum album from Gypsophila paniculata as per claims 1, 7, See para. [0020]. Fuchs further teaches non-toxic concentrations of saponins, e.g. gypsophila saponin, are able to enhance the specific cytotoxicity of chimeric toxin or toxin conjugate or immunotoxins, e.g. Sap-3 containing ITs (Sap-3=saporin-3=type I RIP (ribosome inactivating protein)) dependent on the cell line, 3560 to 385000-fold (Tab. 1). Fusion protein of Sap-3 (saporin-3) and EGF, and of SA2E, a protein where EGF is linked to Sap-3 via a cleavable molecular adapter that reduces side effects on non-target cells in vitro, see para. [0051]. When saponins are combined with immuno adapter toxins instead of conventional immunotoxins further reduction of side effects are likely in vivo due to intracellular removal of the ligand and the PTD from the toxin, see para. [0054].
Gilabert-Oriol teaches a pharmaceutical composition comprising a first immunotoxin conjugate, e.g., dianthin-cetuximab or dianthin-panitumumab comprising a first binding molecule, e.g., cetuximab (anti-EGFR monoclonal, aka proteinaceous) or panitumumab (anti-EGFR monoclonal, and proteinaceous) that bind a cell-surface molecule or receptor, e.g., EGFR wherein the binding region is different from each other, and wherein each of the antibody is covalently linked (conjugated) to an effector molecule, e.g., dianthin (see p. 248, right col) in combination with a bidesmosidic triterpenoid saponin, e.g., SO1861 from Saponaria officinalis, and a pharmaceutical acceptable carrier, PBS, see entire document, abstract, p. 248, right col., p. 249, right col. Gilabert-Oriol teaches that saponin-mediated the endo/lysosomal escape of dianthin (see p. 251) without disrupting the plasma membrane, enhance the efficacy of the therapeutic antibodies, see abstract, in particular.
Claims 16, 19, 27, 28, 29 and 30 are included because Gao teaches cetuximab (which is an anti-EGFR antibody, also known as ERBITUX®, p. 57, line 5) or pantitumumab (also known as ABX-EGF) conjugated to saponin, see para. [0140] or oligonucleotide or DNA, see page 39, para. [0131] in particular. The term “first, second or third proteinaceous molecule” is arbitrary. The term “or” does not require the third antibody (proteinaceous molecule).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the saponin in the cetuximab antibody conjugated saponin of Gao for any one of the triterpenoid saponin from Weng’s triterpenoid saponins SA1641 and SA1657 isolated from Saponinum album or the bisdesmosidic, triterpenoid saponin SO1861 (elected species) isolated from the roots of Saponaria offianlis L or Fuchs’ bisdesmosidic triterpene saponin belonging to the type of 12,13-dehydrooleanane with an aldehyde function in position 23 from Gypsophila paniculata and then combine with Gilabert-Oriol’s dianthin-panitumumab for binding to different on the same human EGFR but to arrive at the claimed invention with a reasonable expectation of success, e.g. site-specific delivery of saponin and toxin to cells to different region of the human EGFR for enhance cell killing.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to combine the conjugate comprising cetuximab conjugated to saponins SO1816 and the conjugate comprising dianthin-panitumumab or panitumumab conjugated to saponins SO1816 and cetuximab conjugated to dianthin toxin in order to deliver the saponins to the same cancer cells that express human EGFR for enhancing saponin-mediated the endo/lysosomal escape of dianthin (see p. 251) and avoid off-targeted effects of saponins, see abstract, in particular.
One of ordinary skill in the art would have been motivated to do so because Weng teaches that triterpene saponins are valuable tools to augment the cytosolic delivery of anti-tumor toxins, see p. 85, in particular.
One of ordinary skill in the art would have been motivated to do so because Fuchs teaches saponins facilitate the endosomal/lysosomal escape of the internalized toxin conjugate and coupling of saponins and a pharmacologically active agent to a target cell specific component is a promising tool for delivering of both the pharmacologically active agent and saponin to target cells at the same time, see para. [0080].
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify the conjugate of Gao by “The simple substitution of one known element, e.g., saponin for another, SA1641 or SA1657 or SO1861 or saponin from Gypsophila paniculata is likely to be obvious when it does no more than yield predictable results.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.

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 claims at issue 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); 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. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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.

Claims 1, 7-11, 13, 19, 26, 32-34, 45 and 49 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 5, 8, 10-11, 16-19, 23-26 and 32 of copending Application No. 17/312,476. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope.
Copending claims as follow:

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Copending claim 11 recites the Scaffold according to claim 5, wherein 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 of the scaffold, and/or, if present, the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the at least one saponin, is involved in the covalent bonding to the polymeric or oligomeric structure of the scaffold, either via direct binding or via at least one linker, which corresponds to instant claim 8.

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, which corresponds to instant claim 29.

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Thus, both set of claims read on the claimed proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Applicants’ arguments filed December 15, 2025 have been fully considered but are not found persuasive.
Applicant’s request that the rejection be held in abeyance until allowable subject matter identified is acknowledged. So the rejection stands.

Claims 1, 7-11, 13, 19, 26, 32-34, 45 and 49 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 38-50 of copending Application No. 18/981,715. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope.
Copending claim 38 recites a conjugate comprising a first proteinaceous molecule comprising a binding site for binding to an epitope on a cell-surface molecule and at least one saponin covalently bound to said first proteinaceous molecule and comprising at least one effector moiety of Structure C:
A(- S)b (- E)c Structure C, wherein A is the binding site; S is the saponin; E is the effector moiety; b = 1 - 64, or any whole number or fraction therein between; c = 1 - 8, or any whole number or fraction therein between, wherein S is coupled to A and/or E,E is coupled to A and/or S (genus) whereas instant claim limits the binding site to antibody, IgG, VHH domain, VH domain, Fab, scFv, Fv, dAb, F(ab)2, Fcab fragment or EGF or cytokine (instant claims 1, 14, 19).
Copending claim 39 recites the conjugate of claim 38, wherein S (saponin) is coupled to A (binding site) and E (effector moiety) is coupled to A, which corresponds to instant claims 1, 4, 14, 16.
Copending claim 40 recites the conjugate of claim 38, wherein A is an anti-EGFR antibody, an anti-HER2 antibody, an anti-CD71 antibody, which corresponds to instant claim 11.
Copending claim 41 recites the conjugate of claim 38, wherein A is an anti-CD71 antibody (subgenus), which corresponds to instant claim 11, wherein the antibody that binds to CD71 is OKT-9 anti-CD71 monoclonal antibody (species) of instant claims 13, 26, 27.
Copending claim 42 recites the conjugate of claim 38, wherein S is any one or more of a saponin, a triterpenoid saponin and/or a bisdesmosidic triterpene saponin belonging to the type of a 12,13- -2- dehydrooleanane with an aldehyde function in position C-23, S01861, GE1741, SA1641, Quil-A, QS-21, and saponins in water soluble saponin fraction of Quillaja Saponaria, which corresponds to instant claims 4, 7.
Copending claim 43 recites the conjugate of claim 38, wherein S is any one or more of a saponin, a triterpenoid saponin and/or a bisdesmosidic triterpene saponin belonging to the type of a 12,13- dehydrooleanane with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, which corresponds to instant claim 8.
Copending claim 44 recites the conjugate of claim 38, wherein the saponin is covalently coupled to an amino- acid residue of the first proteinaceous molecule via the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the saponin, which corresponds to instant claim 10.
Copending claim 45 recites the conjugate of claim 38, wherein E is any one or more of an oligonucleotide, an antisense oligonucleotide, an siRNA, an antisense BNA, which corresponds to instant claim 29.
Copending claim 46 recites the conjugate of claim 38, wherein E is oligonucleotide and selected from: deoxyribonucleic acid (DNA), ribonucleic acid (RNA), anti-sense oligonucleotide (ASO, AON), short interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, mini-circle DNA, peptide nucleic acid (PNA), phosphoramidate morpholino oligomer (PMO), locked nucleic acid (LNA), bridged nucleic acid (BNA), 2'-deoxy-2'-fluoroarabino nucleic acid (FANA), 2'-O-methoxyethyl-RNA (MOE), 2'-O,4'-aminoethylene bridged nucleic acid, 3'-fluoro hexitol nucleic acid (FHNA), a plasmid, glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof, which corresponds to instant claim 29.
Copending claim 47 recites the conjugate of claim 38, wherein the saponin, and/or the effector moiety is covalently coupled via at least one linker, and/or via at least one oligomeric or polymeric scaffold, or a tri-functional linker, and/or wherein at least a lysine side chain and/or a cysteine side chain of the binding site, is involved in the covalent bond with the saponin and/or the effector moiety and/or the linker and/or the cleavable linker and/or the scaffold, which corresponds to instant claim 1.
Copending claim 48 recites the conjugate of claim 38, wherein the saponin, and/or the effector moiety is covalently coupled via at least one linker based on N-ε-maleimidocaproic acid hydrazide (EMCH) succinimidyl 3-(2-pyridyldithio)propionate or 3-(2-Pyridyldithio)propionic acid N- hydroxysuccinimide ester (SPDP) or 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), which corresponds to instant claim 9.
Copending claim 49 recites the conjugate of claim 38, wherein the saponin and/or the effector moiety is covalently linked to the binding site wherein the covalent link comprises or consists of an amide bond, a hydrazone bond, a disulphide bond, which corresponds to instant claims 10, 33.
Copending claim 50 recites the conjugate of claim 38, wherein A is an anti-CD71 antibody and E is any one or more of an oligonucleotide, an antisense oligonucleotide, an siRNA, an antisense BNA, which corresponds to instant claims 11, 13, 26, 27, 29.

This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Applicants’ arguments filed December 15, 2025 have been fully considered but are not found persuasive.
Applicant’s request that the rejection be held in abeyance until allowable subject matter identified is acknowledged. So the rejection stands.

Claims 14, 16, 19, 27-30 and 50 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 28-29 of copending Application No. 17/312,104 (reference). Although the conflicting claims are not identical, they are not patentably distinct from each other because the copending claims recite:
28. A therapeutic combination comprising:
(a) a conjugate of oligonucleotide and a saponin wherein the oligonucleotide is conjugated to at least one saponin, wherein the at least one saponin is a bisdesmosidic 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 and optionally a pharmaceutically acceptable excipient; and
(b) an antibody-drug (effector molecule) conjugate or a ligand-drug conjugate, and optionally a pharmaceutically acceptable excipient.
29. The therapeutic combination of claim 28, wherein the antibody-drug conjugate can bind to any one of tumor-cell receptors CD71, CA125, EpCAM(17- 1A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular integrin alpha-V beta-3, HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Cripto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, and/or wherein the antibody of the antibody- drug conjugate is or comprises any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, OKT-9 anti-CD71 monoclonal antibody of the IgG type, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, OKT-10 anti-CD38 monoclonal antibody, an antibody of Table A2 or Table A3 or Table A4, or at least one tumor- cell specific receptor binding-fragment thereof and/or at least one tumor-cell specific receptor binding-domain thereof, and/or wherein the antibody-drug conjugate comprises any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and an antibody-drug conjugate of Table A2 and Table A3, and/or wherein the ligand-drug conjugate comprises or consists of at least one non-proteinaceous ligand and/or at least one proteinaceous ligand for binding to a cell- surface molecule.
Thus, both set of claims read on the claimed combination of first proteinaceous molecules and second proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Claims 14, 16, 19, 27-30 and 50 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 57-65, 67-76 of copending Application No. 18/012,741 (reference). Although the conflicting claims are not identical, they are not patentably distinct from each other because the reference claims recite:
57. (Currently Amended) A pharmaceutical combination comprising:
- a first conjugate comprising an effector molecule and a single-domain antibody (sdAb) for binding to a first cell-surface molecule, wherein the effector molecule and the sdAb are covalently linked to each other, wherein the effector molecule comprises or consists of an oligonucleotide;
- a second conjugate comprising a saponin and a binding molecule for binding to a second cell-surface molecule, wherein
o the saponin and the binding molecule are covalently linked to each other,
o the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside comprising
an aglycone core structure which is quillaic acid or gypsogenin and
(ii) an aldehyde at position C23 of the aglycone core structure or an acid-sensitive bond at position C23 of the aglycone core structure, wherein the acid-sensitive bond breaks under acidic conditions such that it forms the aldehyde at position C23 of the aglycone core structure, ando the second cell-surface molecule and the first cell-surface molecule are present on the surface of the same target cell; and optionally
- a pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

58. The pharmaceutical combination of claim 57 comprising two pharmaceutical compositions wherein:- the first pharmaceutical composition comprises the first conjugate; and- the second pharmaceutical composition comprises the second conjugate.
59. The pharmaceutical combination of claim 57, wherein the first conjugate and the second conjugate are provided in a single pharmaceutical composition.
60. The pharmaceutical combination of claim 57, wherein the sdAb is a VHH domain.
61. (Previously Presented) The pharmaceutical combination of claim 57, wherein the first conjugate comprises at least two sdAbs that are the same sdAbs or are capable of binding to the same binding site on the first cell-surface molecule.
62. (Currently Amended) The pharmaceutical combination of claim 57, wherein the first cell- surface molecule is a tumor-cell surface receptor and/or a tumor-cell specific receptor and/or a receptor selected from: CD71, CA125, EpCAM(17-1A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin receptor, syndecan-1, vascular integrin alpha-V beta-3, HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD27L receptor, integrin-alphaV, CD33, mesothelin, Cripto, CD3, CD30, CD239, CD70, CD123, CD352, CD25, ephrinA4, MUC-1, Trop2, CEACAMS, CEACAM6, HER3, CD74, PTK7, Notch3, C4.4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA-4, CD52, PDGFRA, VEGFR1, VEGFR2, c-Met (HGFR), RANKL, CD16, CXCR7 (ACKR3), and glucocorticoid-induced TNFR-related protein (GITR).
63. (Previously Presented) The pharmaceutical combination of claim 57, wherein the first conjugate comprises an sdAb that can bind to HER2 or CD71.
64. (Previously Presented) The pharmaceutical combination of claim 57, wherein the oligonucleotide is a natural, synthetic, or modified oligonucleotide that is selected from any one or more of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), anti-sense oligonucleotide (ASO, AON), short interfering RNA (siRNA), anti-microRNA (anti-miRNA), DNA aptamer, RNA aptamer, peptide nucleic acid (PNA), phosphoramidate morpholino oligomer (PMO), locked nucleic acid (LNA), bridged nucleic acid (BNA), 2'-deoxy-2'-fluoroarabino nucleic acid (FANA), 2'-O-methoxyethyl-RNA (MOE), 3'-fluoro hexitol nucleic acid (FHNA), glycol nucleic acid (GNA), and threose nucleic acid (TNA).Attorney Docket No.: 40306-54337/US 65. (Previously Presented) The pharmaceutical combination of claim 57, wherein the saponin comprises an aglycone core structure selected from:2alpha-hydroxy oleanolic acid; 16alpha-hydroxy oleanolic acid; hederagenin (23-hydroxy oleanolic acid); 16alpha,23-dihydroxy oleanolic acid; gypsogenin; quillaic acid; protoaescigenin-21(2-methylbut-2-enoate)-22-acetate; 23-oxo-barringtogenol C-21,22-bis(2-methylbut-2-enoate); 23-oxo-barringtogenol C-21(2-methylbut-2-enoate)-16,22-diacetate; 3,16,28-trihydroxy oleanan-12-en; and gypsogenic acid.

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Thus, both set of claims read on the claimed combination of first proteinaceous molecules and second proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Claims 14, 16, 19, 27-30 and 50 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3, 7-8, 11, 13-14, 16, 19, 26-30, 32, 39-40 of copending Application No. 17/413,965 (reference). Although the conflicting claims are not identical, they are not patentably distinct from each other because the reference claims are drawn to the same pharmaceutical combination as disclosed in the present claims.

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Thus, both set of claims read on the claimed combination of first proteinaceous molecules and second proteinaceous molecules and/or third proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Claims 14, 16, 19, 27-30 and 50 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 77 and 78 of copending Application No. 18/012,754 (reference). Although the conflicting claims are not identical, they are not patentably distinct from each other because the reference claims recite:
77. A pharmaceutical combination comprising:
- a first conjugate comprising an effector molecule and a single-domain antibody for binding to a first cell-surface molecule, wherein the single-domain antibody is a VHH domain that can bind to CD71, wherein the first cell-surface molecule is CD71, wherein the effector molecule and the sdAb are covalently linked to each other and wherein the effector molecule comprises or consists of a nucleic acid, a modified saponin, wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside, wherein the modified saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside comprising a modified aglycone core structure being a modified quillaic acid or a modified gypsogenin wherein the aldehyde group in position C-23 of quillaic acid or of gypsogenin, respectively, is chemically modified by transformation into a hydrazone bond;
wherein the modified saponin is comprised within a second conjugate, which comprises a binding molecule for binding to a second cell-surface molecule and the modified saponin, which binding molecule and the modified saponin are covalently linked to each other, either directly or via a linker, the combination optionally further comprising a pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.
78. (New) The pharmaceutical combination of claim 77, wherein the modified saponin is covalently bound to the binding molecule via the hydrazone bond at C-23 of said quillaic acid or of said gypsogenin aglycone core structure.
Thus, both set of claims read on the claimed combination of first proteinaceous molecules and second proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Claims 14, 16, 19, 27-30 and 50 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 58-59 of copending Application No. 18/012,791 (reference). Although the conflicting claims are not identical, they are not patentably distinct from each other because the reference claims are drawn to the same pharmaceutical combination as disclosed in the present claims.

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Thus, both set of claims read on the claimed combination of first proteinaceous molecules and second proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Claims 14, 16, 19, 27-30 and 50 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 41-57 of copending Application No. 18/012,791 (reference). Although the conflicting claims are not identical, they are not patentably distinct from each other because the reference claims recite:

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PNG
media_image57.png
367
705
media_image57.png
Greyscale

PNG
media_image58.png
637
685
media_image58.png
Greyscale

PNG
media_image59.png
287
680
media_image59.png
Greyscale

PNG
media_image60.png
442
707
media_image60.png
Greyscale

PNG
media_image61.png
427
700
media_image61.png
Greyscale

PNG
media_image62.png
662
705
media_image62.png
Greyscale

PNG
media_image63.png
253
695
media_image63.png
Greyscale

PNG
media_image64.png
460
715
media_image64.png
Greyscale

PNG
media_image65.png
460
698
media_image65.png
Greyscale

PNG
media_image66.png
558
723
media_image66.png
Greyscale

Thus, both set of claims read on the claimed combination of first proteinaceous molecules and second proteinaceous molecules.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.

Conclusion

No claim is allowed.

Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is [phone]. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/Primary Examiner, Art Unit 1641

Prosecution Timeline

• Jun 09, 2021: Application Filed
• May 04, 2025: Non-Final Rejection — §103, §112, §DP
• Jul 25, 2025: Response Filed
• Oct 03, 2025: Final Rejection — §103, §112, §DP
• Dec 15, 2025: Request for Continued Examination
• Dec 16, 2025: Response after Non-Final Action
• Mar 17, 2026: Non-Final Rejection — §103, §112, §DP (current)