DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application is a 371 of PCT/EP2021/067030 filed on 06/22/2021 and claims foreign priority to PCT/EP2020/069340 filed on 07/09/2020 and Netherlands application no. NL2025900 filed on 06/24/2020. The certified copies of the foreign priority applications filed in the instant application are acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/12/2026 and 02/18/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Claims
The claim amendments and remarks filed on 02/26/2026 is acknowledged. Claims 57 and 64-65 are amended. Claims 1-56 are cancelled.
Accordingly, claims 57-80 are pending and being examined on the merits herein.
Withdrawn Rejections
The 35 USC 112(b) rejection for claims 64-65 are withdrawn because there is now proper antecedence for “the nucleic acid” recited in claim 64, and the phrase “such as” has been amended to “or” in claim 65, making it clear the BNA-based siRNA is an alternative.
The following grounds of rejection are maintained with amendments as necessitated by Applicant’s amendments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 57, 60-61, 63-76, and 79-80 are rejected under 35 U.S.C. 103 as being unpatentable over US’042 (US20150337042A1 in PTO-892 dated 10/28/2025) in view of Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025), Kreutz (Plos One, 2012 in PTO-892 dated 10/28/2025), and Marciani (US5977081A in PTO-892 dated 10/28/2025).
US’042 teaches anti-epidermal growth factor (EGFR) antibodies and antibody drug conjugates (ADCs) including compositions and methods of using said antibodies and ADCs (abstract). US’042 teaches that the disclosed anti-EGFR antibodies may be conjugated to a drug moiety to form an anti-EGFR antibody drug conjugate which increases the antibodies therapeutic efficacy in the treatment of cancer due to the ability of the ADC to selectively deliver one or more drug moieties to target tissues, such as a tumor associated antigen, e.g., EGFR expressing tumors (page 22, [0198]). US’042 teaches that anti-EGFR ADCs of the invention comprise an anti-EGFR antibody, i.e., an antibody that specifically binds to EGFR, and delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]), which indicate that the ADCs transport conjugated drugs from the outside to inside of cells. US’042 further teaches that known ligands of EGFR include EGF (page 1, [0004]). US’042 teaches methods of using their antibodies and ADCs to inhibit human EGFR activity in vitro or in vivo (paragraph 0078). US’042 further teaches that the antibody or antigen binding portions thereof include a Fab, a Fab’, a F(ab’)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody (sdAb), or a diabody (page 20, [042]).
US’042 discloses several active compounds that can be conjugated to the antibody and lists dianthin proteins and among others (see paragraph 0299). US’042 also teaches antisense oligonucleotides can be conjugated to the anti-EGFR antibodies (see paragraph 0288). US’042 teaches that the antisense oligonucleotide inhibits expression of the target gene by non-catalytic mechanisms, such as modulation of splicing or translation arrest, which can also be potent and selective modulators of gene function (see paragraph 0288). US’042 teaches that the antisense mechanism can also involve an RNAi (RNA interreference) effect, in which a shorter double-stranded RNA, eg small interfering RNA (siRNA) and/or microRNA (miRNA) are introduced to the cell and interferes with the gene expression of a particular sequence within the cells (see paragraph 0289). Here, this RNAi effect using a miRNA meets the limitation of antagonizing a miRNA function when present in a cell comprising such miRNA as recited in claim 66. US’042 teaches that their ADCs comprise an antisense oligonucleotide which interferes with target cell expression of EGFR at the mRNA level (see paragraph 0289).
US’042 teaches the anti-EGFR ADCs can be conjugated via linkers (see paragraph 0200). US’042 teaches the linker may be bifunctional or multifunctional and may include one conjugating component or may include multiple components (see paragraph 0303). US’042 teaches that the linker may include a spacer, which is a moiety that extends the drug linkage to avoid, for example, shielding the active site of the antibody or improving the solubility of the ADC (page 33, [0303]). US’042 further teaches that linkers are preferably stable extracellularly in a sufficient manner to be therapeutically effective. US’042 teaches that before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e., the antibody remains conjugated to the drug moiety. US’042 teaches that linkers that are stable outside the target cell may be cleaved at some efficacious rate once inside the cell. Thus, an effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular deliver of the drug moiety; and (iii) maintain the therapeutic effect of the drug moiety (page 34, [0311]). US’042 teaches that suitable linkers include, for example, cleavable and non-cleavable linkers. A linker may be a “cleavable linker,” facilitating the release of a drug. Nonlimiting exemplary cleavable linkers include acid-liable linkers, e.g., comprising hydrazone (page 33, [0310]). The linker is cleavable under intracellular conditions, such that the cleavage of the linker sufficiently releases the drug from the antibody in the intracellular environment to be therapeutically effective. In some embodiments, the cleavable linker is pH sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the PH sensitive linker is hydrolysable under acidic conditions. For example, an acid-liable linker that is hydrolysable in the lysosome, such as a hydrazone, can be used. Such linkers are relatively stable under neutral pH conditions, such as those of the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In certain embodiments, the hydrolysable linker is a thioether linker, such as a thioether attached to the therapeutic agent via an acylhydrazone bond (page 34, [0312]). US’042 also teaches additional linkers for use in their invention can include non-peptide polymers such as polyethylene glycol (see paragraph 0366).
US’042 teaches that conjugation of the drug to the antibody via a linker can be accomplished by any technique known in the art. A number of different reactions are available for covalent attachment of drugs to linkers and linkers to antibodies. This may be accomplished by reaction of the amino acid residues of the antibody, including the amine groups of lysine, the free carboxylic acid groups of glutamic and aspartic acid, the sulfhydryl groups of cysteine and the various moieties of the aromatic amino acid (page 41, [0368]). US’042 further teaches that the compositions comprising the antibodies and antibody portions may further comprise an agent useful as an adjuvant, such as those used to increase the absorption or dispersion of a therapeutic protein (page 53, [0433]).
While US’042 teaches an antibody drug conjugate comprising an anti-EGFR sdAb and effector molecules such as protein toxins and/or oligonucleotides, US’042 does not disclose the conjugation of a saponin.
Lacaille-Dubois teaches examples of triterpene glycosides from natural sources which exhibit adjuvant activity when they are co-administered with anticancer drugs, targeted toxins, antimicrobial, anti-inflammatory drugs and with antigens in vaccines (see Abstract). Lacaille-Dubois teaches that triterpene glycosides possess great structural diversity and display a broad spectrum of biological and pharmacological properties among them immunoadjuvant, antitumor, anti-inflammatory, antimicrobial properties, which have been extensively studied and reviewed (see page 50 left column). Lacaille-Dubois teaches that these compounds possess foaming and pore forming abilities which result in increasing membrane permeability and represents an attractive mechanism for drug delivery into cells (see page 50 left column). Lacaille-Dubois provides the structure of several triterpene glycosides in Fig. 3 on page 52, the QS-21 and SO 1861 structure are shown below:
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Here, the SO1861 and QS-21 meet the limitations of the recited saponin in claims 57 and 69-73. Lacaille-Dubois discloses that three immunotoxins constructed with Cetuximab (anti-EGFR), Panitumumab (anti-EGFR), and Trastuzumab (anti-HER2) and chemically conjugated to dianthin showed increased cytotoxicity on colon and breast cancer cells in the presence of SO-1861 (2.5 ug/mL) with the corresponding GI50 values of 5.3 pM (HCT 116 cells), 1.5 pM (HCT 116 cells), 23 pM (BT-474 cells), respectively, whereas they didn't show any cytotoxic effect when they were administered alone at dose up to 10 nM (see page 53 last paragraph left column).
Kreutz teaches antibody-antigen-adjuvant conjugates to co-deliver antigen and adjuvant to dendritic cells in cis (see Abstract). Kreutz discloses that co-administration of unlinked adjuvant cannot ensure that all cells targeted by antibody conjugates are appropriately activated (see Abstract). Kreutz teaches that this could also potentially lead to counterproductive side effects such as the induction of autoimmune responses (see right column page 1). Kreutz teaches that while antibody-mediated delivery of antigens to particular APC ensures efficient antigen presentation, the presence of suitable adjuvants is required to guarantee the appropriate activation and, consequently, T cell stimulatory properties of the APC (see left column page 1). Kreutz demonstrates in Fig. 1 on page 3 that their antibody-antigen-adjuvant conjugates were more potent at inducing cytotoxic T lymphocyte (CTL) responses than control conjugates mixed with soluble CpG oligodeoxynucleotides (ODN). Kreutz concludes that their antibody-antigen-adjuvant conjugates are superior to antibody-free antigen-adjuvant conjugates in priming CTL responses and efficiently induce anti-tumour immunity in the murine B16 pseudo-metastasis model (see Abstract).
Marciani et al. discloses novel triterpene saponin analogs having adjuvant and immunostimulatory activity (see Abstract). Marciani et al. discloses that their novel compounds contain a lipophilic moiety covalently attached to a carboxyl group present on the 3-O-glucoronic acid of the triterpene saponin (see Abstract). Marciani et al. discloses that the attachment of the lipophile moiety yields a saponin derivative that is easier to purify, potentially less toxic, chemically more stable, and with equal or better adjuvant properties than the original saponins (see Abstract). Marciani et al. provides a Formula II structure which represents their conjugated saponin-lipophilic compounds shown below:
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Here, the circled portion highlights the conjugation of the lipophilic moiety to a saponin compound. X is S, O, NH or a linking group and R3 is a residue of a lipophilic molecule. This conjugated location, which is the carboxyl group of a glucuronic acid moiety on the saccharide chain of the saponin, is the same derivatized location as recited in claim 76. Marciani et al. discloses that the lipophilic moiety can be attached to the saponins via a linking group (see column 8 lines 50-53). Marciani et al. discloses that the linking group can be one or more bifunctional linkers that covalently attach the carboxylic acid group of the 3-O glucuronic acid moiety of the triterpene core to a suitable functional group present on the lipophilic molecule (see column 8, lines 50-59). Marciani et al. discloses other suitable heterobifunctional cross-linkers such as sulfosuccinimidyl 4-(N-maleimidocyclohexane)-1-carboxylate (see column 14, lines 44-57) and also discloses using suitable reagents to form an amide or ester linkage to a lipophilic moiety (see column 11 lines 22-30). Marciani et al. discloses pharmaceutical compositions comprising their saponin-lipophile conjugate and one or more pharmaceutically acceptable diluents, carriers, or excipients (see column 6, lines 7-12). Marciani et al. discloses that their saponin conjugates can be administered to enhance the immune response against antigens produced by the use of DNA vaccines (see column 23, lines 40-45). Marciani et al. discloses that typical vaccines used in this approach include viral vaccines (influenzas, herpes, and others), cancer vaccines, and parasitic vaccines (see column 23, lines 40-52).
It would have been prima facie obvious to combine US’042 with Lacaille-Dubois, Kreutz, and Marciani before the effective filing date of the claimed invention by selecting an anti-EGFR sdAb dianthin conjugate from the teachings of US’042 and attaching this conjugate to the saponin SO1861 disclosed in Lacaille-Dubois using the acid-labile linker chemistry disclosed in US’042 with further guidance from Kreutz and Marciani to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include a saponin to an ADC with a reasonable expectation of success because Lacaille Dubois demonstrates significant increases in cytotoxicity when antibody effector molecule conjugates are delivered in combination with a saponin. Furthermore, one of ordinary skill in the art would have selected anti-EGFR sdAn and dianthin as well as further conjugating the saponin onto the ADC with a reasonable expectation of success because US’042 provides guidance of selecting a sdAb and dianthin toxin for their anti-EGFR ADCs, and Lacaille-Dubois provides guidance that saponin compounds have adjuvant activity for several agents including similar anti-EGFR dianthin conjugates. Furthermore, Kruetz provides motivation to conjugate an adjuvant compound to an antibody conjugate in order to ensure that all cells targeted by the antibody conjugate is appropriately activated by the adjuvant as well as to reduce unwanted side effects such as induction of autoimmune responses, and Marciani demonstrates the formation of saponin conjugates. Therefore, an ordinary skilled artisan would have been motivated to conjugate a saponin compound as an adjuvant to an active agent such as an EGFR-drug conjugate in order to gain the advantages disclosed in Kruetz described above.
Furthermore, the sdAb (anti-EGFR sdAb) in the combined teachings described above would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above, and furthermore, US’042 teaches that the anti-EGFR ADCs, comprising an anti-EGFR antibody, delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]). See MPEP 2111.02 II
Lastly, as evidenced by Lacaille-Dubois on page 52 left column, triterpene glycosides increase endo/lysosomal escape of ribosome inactivating proteins into the cytosol. Therefore, this function would be necessarily present in the combined teachings described above because the combined teachings disclose the same triterpene glycosides (SO1861) that is conjugated to sdAb-toxin conjugate (anti-EGFR sdAb dianthin conjugate). Furthermore, as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
In regards to claims 63-66, it would have also been prima facie obvious to use a miRNA that interferes with EGFR expression at the RNA level as disclosed in US‘042 for the active agent in the modified anti-EGFR conjugate as disclosed by the combined teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani described above to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because US’042 provide guidance that their EGFR ADCs can include short double-stranded RNA that provide an RNAi effect by interfering with gene expression within target cells at the RNA level.
In regards to claim 76, it would have also been prima facie obvious to attach the anti-EGFR conjugate as disclosed by the combined teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani described above to the saponin at the glucuronic acid moiety on the saccharide chain as disclosed in Marciani to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Marciani demonstrates the formation of saponin conjugates at the glucuronic acid moiety on the saccharide chain. Therefore, an ordinary skilled artisan could have predictably conjugated a saponin compound at this position with a reasonable expectation of success.
In regards to claim 78-80, it would have also been prima facie obvious to administer the modified anti-EGFR conjugate as disclosed by the combined teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani described above to a patient with a cancer characterized by overexpressing EGFR and/or to tumor cells with overexpressing EGFR in vitro to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because US’042 provide guidance of several anti-EGFR conjugates for inhibiting overexpressing EGFR tumors by targeting the EGFR using anti-EGFR antibodies in vivo and in vitro, and Lacaille-Dubois provides further guidance that saponins enhance the cytotoxicity of similar anti-EGFR dianthin conjugates in cancer cells.
Claim(s) 77 is rejected under 35 U.S.C. 103 as being unpatentable over US’042 (US20150337042A1 in PTO-892 dated 10/28/2025) in view of Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025), Kreutz (Plos One, 2012 in PTO-892 dated 10/28/2025), and Marciani (US5977081A in PTO-892 dated 10/28/2025), as applied to claim 57 above, and further in view of Mlynarczyk et al. (Nanostructured Materials-Fabrication to Applications, 2017 in PTO-892 dated 10/28/2025).
The combination of US’042, Lacaille-Dubois, Kreutz, and Marciani teach the conjugate of claim 57 as discussed above.
The discussed combination of references, however, do not disclose wherein the conjugate comprises an oligomeric or polymeric molecule to which more than one saponin is bound.
Mlynarczyk teaches dendrimers as a distinct class of polymers —highly branched and uniform, with a relatively small size when compared to their mass. They are composed of the core, from
which branched polymeric dendrons diverge and they are end‐capped with selected terminal groups. Recently, dendrimers have attracted considerable attention from medicinal chemists, mostly due to their well‐defined and easy‐to‐modify structure (see Abstract). Mlynarczyk teaches therapeutic efficiency of dendrimers as nanocarriers has been proved so far for, for example, potent anticancer, nonsteroidal and anti‐inflammatory, antimicrobial and antiviral drugs (see first paragraph page 117). Mlynarczyk illustrates in Figure 4 on page 117 that dendrimer carriers can covalently bond to multiple molecules including antibodies, targeting molecules, drug molecules, and others. Mlynarczyk teaches dendrimer end-groups can be easily modified as well as substituted with active substances, targeting molecules, and others, that are relevant and needed for modern applications (see last two paragraphs on page 114). Mlynarczyk teaches that the outstanding feature that makes dendrimers so special is the enormous number of terminal groups in such a small molecule. The number of end‐groups increases in exponential manner while the round molecule size increases linearly (see first paragraph on page 114).
It would have been prima facie obvious to combine US’042, Lacaille-Dubois, Kreutz, and Marciani with Mlynarczyk before the effective filing date of the claimed invention by substituting the linking chemistry for the modified anti-EGFR saponin conjugate as disclosed by the combined teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani described above with the dendrimer molecule disclosed in Mlynarczyk such that multiple saponins, dianthins, and anti-EGFR antibodies are covalently bound at the terminal ends of the dendrimer. One of ordinary skill in the would have made this substitution with a reasonable expectation of success because Mlynarczyk provides guidance that dendrimers can be used effectively for anticancer treatments as well as to covalently link multiple antibodies, targeting molecules, drug molecules, and other molecules of interest which can include a saponin molecule. Furthermore, Mlynarczyk provides motivation to use dendrimers as a linking molecule due to its advantage of linking a large number of molecules to the terminal ends. Therefore, an ordinary skilled artisan could have predictably considered using dendrimers as the linking molecule to attach multiple saponins, dianthins, and anti-EGFR antibodies.
Claim(s) 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over US’042 (US20150337042A1 in PTO-892 dated 10/28/2025) in view of Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025), Kreutz (Plos One, 2012 PTO-892 dated 10/28/2025), and Marciani (US5977081A in PTO-892 dated 10/28/2025), as applied to claim 57 above, and further in view of Nessler (Cancer Res, published 01/15/2020 in PTO-892 dated 10/28/2025).
The combination of US’042, Lacaille-Dubois, Kreutz, and Marciani teach the conjugate of claim 57 as discussed above.
The discussed combination of references, however, do not disclose that the single domain antibody is a VH domain derived from a heavy chain of an antibody, a VL domain derived from the light chain of an antibody, or a VHH domain, or that the conjugate comprises at least two sdAbs.
Nessler teaches that antibody-drug conjugates have opened a new field of targeted therapeutics based on “hybrid” drugs combining desirable targeting properties of biologics with the potency of small molecule cytotoxic payloads (page 2 paragraph 1). Nessler teaches that for ADCs, the protein carrier is typically a monoclonal antibody that specifically binds to a target antigen expressed on cancer cells, increasing the delivery of the small molecule payload to the site of action in vivo. However, a drawback of antibodies is slow tumor penetration. The tumor uptake of antibodies is limited by their extravasation rate and they tend to penetrate only a few cell layers outside of blood vessels due to their rapid antigen binding rate relative to intratumoral diffusion. In the clinic, unconjugated antibodies are often well tolerated, such that they can be delivered at very high doses that saturate receptors on cell layers closer to the blood vessel, enabling the antibody to diffuse farther through the tumor. However, the payload toxicity of ADCs limits the dose and frequency of administration, restricting tumor penetration depths and allowing regrowth between doses (page 2 paragraph 1).
Nessler teaches that some smaller scaffolds are already being tested in the clinic including bivalent single-domain antibodies (page 3, paragraph 1). In the work presented by Nessler, the tumor tissue pharmacokinetics and efficacy of 3 different PSMA-binding single domain antibody (Humabody) drug conjugates and an IgG drug conjugate was tested. Humabodies are fully human, single heavy chain variable (VH) domains, which are generated using a proprietary transgenic mouse platform. The mice lack murine heavy chain, and light chain expression, but contain human heavy chain genes. After in vitro maturation and development, multiple VH domain Humabodies can be constructed with a range of functionality to optimize target engagement and improve therapeutic benefit. Nessler used this platform to test the impact of two main design parameters with the ADCs: the cellular internalization rate and the plasma clearance rate. The first construct, VH2-VH1-HLE is a fusion between three VH domains: two PSMA binding domains to two different epitopes conjugated to an albumin binding half-life extender VH domain. Targeting multiple epitopes results in antigen cross-linking and rapid internalization, while binding albumin can slow plasma clearance. The second construct consisted of a monovalent binding domain, VH2, connected via a linker to the albumin-binding domain, and the third consisted of VH2-VH1, without the addition of the half-life extender (page 3, paragraph 2).
Nessler concludes that single-domain antibodies provide a promising platform for controlling the internalization kinetics, binding affinity, size, and plasma clearance of ADC constructs. While the use of a variable heavy chain binding domain provides improved transport characteristics, e.g., blood vessel permeability and diffusion (page 13, paragraph 2).
It would have been prima facie obvious to combine US’042, Lacaille-Dubois, Kreutz, and Marciani with Nessler before the effective filing date of the claimed invention by modifying the conjugate taught by the combination of combination of US’042, Lacaille-Dubois, Kreutz, and Marciani described above to use a variable heavy chain derived from the anti-EGFR antibody heavy chain based on the teachings of Nessler. It would have further been obvious to include at least two sdAbs linked to the saponin in the conjugate based on the teachings of Nessler. One of ordinary skill in the art would have been motivated to make these modifications because Nessler teaches that such sdAbs improve the transportation characteristics of ADCs including permeability and diffusion. Therefore, an ordinary skilled artisan would be motivated to try these sdAbs such as in the modified conjugate as disclosed by the combination of US’042, Lacaille-Dubois, Kreutz, and Marciani described above for the treatment of cancer with a reasonable expectation of success. Furthermore, Nessler teaches delivery of antibody drug conjugates, and the modified conjugate as disclosed by the combination of US’042, Lacaille-Dubois, Kreutz, and Marciani described above also pertains to antibody drug conjugates include those that comprise sdAbs. Additionally, Nessler studied prostate cancer, which is a cancer disclosed by US’042 that can be treated with the anti-EGFR conjugates (US’042, page 44, [0386]).
Claim(s) 62 is rejected under 35 U.S.C. 103 as being unpatentable over US’042 (US20150337042A1 in PTO-892 dated 10/28/2025) in view of Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025), Kreutz (Plos One, 2012 PTO-892 dated 10/28/2025), and Marciani (US5977081A in PTO-892 dated 10/28/2025), as applied to claim 57 above, and further in view of Flavell (Cancer Research, 2011 in PTO-892 dated 10/28/2025) and Sagert (US20160355599A1 in PTO-892 dated 10/28/2025).
The combination of US’042, Lacaille-Dubois, Kreutz, and Marciani teach the conjugate of claim 57 as discussed above.
The discussed combination of references, however, do not disclose the sdAb binds to CD71.
Flavell teaches that Gypsophila saponins dramatically and significantly augment the cytotoxicity of saporin-based immunotoxins (ITs) directed against CD19, CD22, CD38, and CD71 expressed on the membrane surface of five different human leukaemia and lymphoma cell lines (see Abstract). Flavell teaches that the mechanism through which saponins exert this effect is not clearly understood but suggests it is likely mediated through membrane disruption of endosomes that contain internalized IT thus allowing more efficient escape of IT to the cytosol and thence direct access of the RIP to target ribosomes (see Abstract). Flavell teaches that there was variability in the augmentative effect exerted by the saponin compound on different target molecules as well as different cell lines, and speculates that the differences likely represent individual variations in lipid/cholesterol membrane composition, particularly within lipid microdomains (lipid rafts) to which target molecules such as CD19 and CD38 migrate prior to receptor-mediated endocytosis following cross linking by the antibody component of IT (see Abstract). Flavell teaches that these variations make understanding the mechanism behind this phenomenon very important if saponins are to be successfully developed as a treatment modality to be used in conjunction with saporin-based ITs or cytotoxins for individual patients with haematological and other types of malignancy (see Abstract).
Sagert teaches antibodies that bind CD71, activatable antibodies that specifically bind to CD71 and methods of making and using these anti-CD71 antibodies and anti-CD71 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications (see Abstract). Sagert teaches that the antibody that binds to CD71 can be monoclonal antibody, domain antibody, single chain, Fab fragment, a F(ab′)2 fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody (see paragraph 0007). Sagert teaches that their CD71 antibodies can be conjugated to a cytotoxic agent (see paragraph 0387). Sagert teaches the agent can be linked to the antibody using a maleimide linker and shows several linker structures in paragraph 0388.
It would have been prima facie obvious to combine US’042, Lacaille-Dubois, Kreutz, and Marciani with Flavell and Sagert before the effective filing date of the claimed invention by substituting the anti-EGFR antibody in the modified conjugate taught by the combination of US’042, Lacaille-Dubois, Kreutz, and Marciani described above with an anti-CD71 sdAb as disclosed in Sagert with further guidance from the teachings of Flavell to arrive at the claimed invention. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Flavell provide guidance of using a similar saponin compound as an adjuvant for similar immunotoxin conjugates that target CD71 in cancer cells, and Sagert provide guidance of conjugating an anti-CD71 sdAb to similar cytotoxic agents. Therefore, an ordinary skill artisan would have found it obvious to try anti-CD71 sdAb as the targeting moiety such as in the saponin-ADC conjugate disclosed in the combination of US’042, Lacaille-Dubois, Kreutz, and Marciani described above with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments filed on 02/26/2026 have been fully considered but were not persuasive.
Applicant states in response to the 103 rejection over US’042 in view of Lacaille-Dubois, Kreutz, and Marciani that none of these references disclose an endosomal escape enhancer saponin. Applicant states that the adjuvant and immunostimulatory activity taught by these references are fundamentally different from and undesirable in the context of the claimed conjugate. Applicant states that the technical effect achieved by the saponins in the claimed conjugate is the successful intracellular delivery of the effector molecule and overcoming the endosomal entrapment problem and not immune stimulation. Applicant further states that the saponin as claimed is preferably not toxic and does not invoke an immune response and states that this directly contrary to the adjuvant/immunostimulatory function taught by the prior art references. Therefore, Applicant states that without any recognition that the prior art that saponins possess an endosomal escape enhancing function, an ordinary skilled artisan would have no motivation to combine these references to arrive at the claimed conjugate comprising an endosomal escape enhancer saponin.
Applicant’s arguments described above were not found persuasive because MPEP 2144 IV states that “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”.
Here, an ordinary skilled artisan would have still been motivated to include the saponin with an antibody-effector molecule conjugate to arrive at the claimed invention because Lacaille Dubois demonstrates significant increases in cytotoxicity when antibody effector molecule conjugates are delivered in combination with a saponin, and further discloses that saponin compounds have adjuvant activity for several agents including similar anti-EGFR dianthin conjugates.
Furthermore, as evidenced by Lacaille-Dubois on page 52 left column, triterpene glycosides increase endo/lysosomal escape of ribosome inactivating proteins into the cytosol. Therefore, this function would be necessarily present in the combined teachings described above because the combined teachings disclose the same triterpene glycosides (SO1861) that is conjugated to sdAb-toxin conjugate (anti-EGFR sdAb dianthin conjugate). Furthermore, as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Lastly, in response to the saponin as claimed being preferably non-toxic and not invoking an immune response, these limitations are not recited in the instant claims.
Applicant states in response to the 103 rejection over US’042 in view of Lacaille-Dubois, Kreutz, and Marciani, and further in view of Mlynarczyk for claim 77 that Mlynarczyk acknowledges the use of dendrimers as carriers for therapeutic agents but equally highlight several drawbacks associated with dendrimers such as time-consuming preparation, high cost of synthesis, and difficulty of purifying higher-generation dendrimers. Applicant further states that Mlynarczyk does not disclose or suggest conjugate of three functionally and structurally distinct molecules, nor does it teach that such three different components would retain their respective functionalities upon release. Applicant states that the specific architecture and coordinated functional interplay required by the claimed conjugate are entirely absent from Mlynarczyk.
Applicant’s arguments described above were not found persuasive because claim 77 only requires that the conjugate comprises an oligomeric or polymeric molecule to which more than one saponin is bound. Here, Mlynarczyk illustrates in Figure 4 on page 117 that dendrimer carriers can covalently bond to multiple molecule types including antibodies, targeting molecules, drug molecules, and others. Furthermore, Mlynarczyk teaches dendrimer end-groups can be easily modified as well as substituted with active substances, targeting molecules, and others, that are relevant and needed for modern applications (see last two paragraphs on page 114). Therefore, an ordinary skilled artisan would have substituted the linking chemistry for the anti-EGFR saponin conjugate as disclosed by the combined teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani described above with the dendrimer molecule disclosed in Mlynarczyk such that multiple saponins, dianthins, and anti-EGFR antibodies are covalently bound at the terminal ends of the dendrimer. An ordinary skilled artisan would have a reasonable expectation of success because both the combined teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani described above and Mlynarczyk disclose linking chemistries to conjugate antibodies, targeting molecules, and drug molecules.
Furthermore, even though Mlynarczyk discloses disadvantages of using dendrimers, Mlynarczyk still demonstrates and provides examples of the dendrimers being used as a carrier for multiple molecules and therefore, Mlynarczyk does not necessarily teach away or discredit the use of dendrimers as a carrier and conjugating multiple molecules on the terminal ends of the dendrimer.
Applicant states in response to the 103 rejection over US’042 in view of Lacaille-Dubois, Kreutz, and Marciani, and further in view of Nessler for claims 58-59 that Nessler discloses disadvantages of using variable chain binding domain such as rapid clearance from the blood through the kidneys resulting in short plasma half-lives which limits therapeutic potential. Therefore, an ordinary skilled artisan would not be readily motivated to try sdAbs in the conjugate as disclosed in the other four references.
Applicant’s arguments described above were not found persuasive because the Nessler reference was not used as a motivation to try sdAbs in the conjugate. Rather, Nessler was brought in as a secondary reference to use a variable heavy chain derived from the anti-EGFR antibody heavy chain as well as include at least two sdAbs linked to the saponin in the conjugate as described above. Furthermore, even though Nessler discloses a disadvantage of using variable chain binding domain as noted by Applicant, Nessler does not necessarily teach away because Nessler still demonstrates the effectiveness of variable heavy chain binding domain in providing improved transport characteristics such as blood vessel permeability and diffusion.
Applicant states in response to the 103 rejection over US’042 in view of Lacaille-Dubois, Kreutz, and Marciani, and further in view of Flavell and Sagert for claim 62 that Flavell discloses that the mechanism through which saponins exert their effect is not well understood. Applicant further states that neither Flavell nor Sagert suggest that saponin will preserve their effect when conjugated to a targeted toxin or drug. Applicant states that none of the references propose or provide motivation for conjugating a saponin to a targeted toxin or drug.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, it is the combined teachings of US’042, Lacaille-Dubois, Kreutz, Marciani, Flavell, and Sagert that establishes a prima facie obviousness case to arrive at the claimed invention of conjugating a saponin to a targeted toxin as described above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 57-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/723,191 (‘191).
Claim 1 of ‘191 A conjugate for delivery of an effector molecule from outside a first cell into the cytosol of said first cell, the conjugate comprising at least one saponin, at least one effector molecule, and at least one single domain antibody (sdAb),wherein the saponin, the effector molecule, and the at least one sdAb are covalently bound together … wherein the at least one effector molecule is selected from: a pharmaceutically active substance, a toxin, an oligonucleotide, a peptide, and a protein; and wherein the at least one sdAb targets a first cell surface molecule that is present on the first cell. Claim 4 of ‘191 recites the conjugate of claim 1 … wherein the sdAb(s) is/are selected from: a VH domain derived from a heavy chain of an antibody, preferably of immunoglobulin G origin, and/or preferably of human origin, a VL domain derived from a light chain of an antibody, preferably of immunoglobulin G origin, and/or preferably of human origin, and a VHH domain derived from a heavy-chain only antibody (HCAb … and/or wherein the conjugate comprises 1-20 sdAbs … and/or wherein the cell surface molecule is a cell surface receptor, preferably an endocytic cell-surface receptor, preferably a tumor-cell specific receptor, more preferably the cell-surface molecule is selected from any one or more of: CD71, EGFR, and among others. Claim 32 of ‘191 recites the conjugate of claim 1, wherein the oligonucleotide is selected from deoxyribonucleic acid (DNA) oligomer, ribonucleic acid (RNA) oligomer, anti-sense oligonucleotide (ASO, AON), short interfering RNA (siRNA), anti-microRNA (anti-miRNA) … wherein the oligonucleotide is an oligonucleotide that is capable of silencing a gene, when present in a cell comprising such gene, wherein the gene is selected from apolipoprotein B (apoB) and among others. Claim 25 of ‘191 recites the conjugate of claim 1 wherein the at least one saponin comprises a first saccharide chain and a second saccharide chain … a carboxyl group of a glucuronic acid moiety in a first saccharide chain of the at least one saponin has been derivatised when present in the at least one saponin … an aglycone core structure comprising an aldehyde group which has been derivatised by:
reduction to an alcohol; transformation into a hydrazone bond through reaction with N-g-maleimidocaproic acid hydrazide (EMCH), wherein the maleimide group of the EMCH is optionally derivatised by formation of a thioether bond with mercaptoethanol … wherein the at least one saponin is any one or more of: QS-21, SO1861, and among others. Claim 51 of ‘191 recites the conjugate of claim 45, wherein the at least one saponin is covalently bound directly to an amino-acid residue of the first linker, preferably to a cysteine and/or to a lysine, and/or is covalently bound via the first additional linker, wherein preferably said first additional linker is a cleavable linker; and/or wherein the first additional linker to which the one or more saponins are covalently bound comprises a polymeric molecule or an oligomeric molecule to which the one or more saponins are covalently bound. Claim 63 of ‘191 recites a method for the treatment or the prophylaxis of any one or more of: a cancer and among others … wherein the method comprises administering the pharmaceutical composition of claim 61 or the conjugate of claim 1 to a subject.
Even though the claims of ‘191 recite several combinations of the conjugate, it would have been prima facie obvious before the effective filing date of the claimed invention to have selected the various components recited in the instant claims from the within the claims of ‘191 to arrive at the claimed invention with a reasonable expectation of success because the claims of ‘191 recite all of the same saponin, antibodies, therapeutic agents, and linking chemistries of the conjugate recited in the instant claims.
Furthermore, the sdAb in the claims of ‘191 would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above. See MPEP 2111.02 II
Lastly, even though the claims of ‘191 do not explicitly recite that the saponin is an endosomal escape enhancer, this property would be necessarily present in the claims of ‘191 because the claims of ‘191 recite the same SO1861 that is conjugated to sdAb-toxin conjugate, and as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 57-66 and 69-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,723 (‘723).
Claim 57 of ‘723 recites a conjugate for transferring an effector molecule from outside a cell into said cell, the conjugate comprising: an effector molecule comprising or consisting of an oligonucleotide; at least one single-domain antibody capable of binding to a binding site on a cell- surface molecule of said cell (sdAb), and at least one saponin, wherein: the effector molecule, the sdAb, and the saponin are covalently bound to each other, wherein the covalent binding of the saponin is made via a linker, and
the saponin is a mono-desmosidic triterpene glycoside or is a bi-desmosidic triterpene glycoside. Claim 58 of ‘723 recites the conjugate of claim 57, wherein the sdAb is selected from a Vu domain derived from a heavy chain of an antibody, a VL domain derived from a light chain of an antibody, and a Van domain. Claim 59 of ‘723 recites the conjugate of claim 57, wherein the conjugate comprises at least two sdAbs, wherein two sdAbs are the same or are capable of binding to the same binding site on the cell- surface molecule. Claims 60-61 of ‘723 recite the conjugate of claim 57, wherein the cell-surface molecule is a cell-surface receptor and/or a tumor-cell specific receptor and wherein the sdAb is selected from an anti-CD71 sdAb, an anti-HER2 sdAb, and among others. Claim 63 of ‘723 recites the conjugate of claim 57, wherein the oligonucleotide is selected from deoxyribonucleic acid (DNA), ribonucleic acid (RNA), single-stranded RNA, double-stranded RNA (dsRNA), anti-sense oligonucleotide (ASO, AON), short interfering RNA (siRNA), anti- microRNA (anti-miRNA, anti-miR), anti-hairpin-shaped microRNA (miRNA), and among others. Claim 64 of ‘723 recites the conjugate of claim 57, wherein the oligonucleotide is capable of one or more of the following: - silencing a gene when present in a cell comprising such gene, wherein the gene is any one of genes: apolipoprotein B (apoB) and among others
Claim 66 of ‘723 recites the conjugate of claim 57, wherein the saponin comprises an aglycone core structure selected from quillaic acid and gypsogenin, wherein C23 of the aglycone core structure is an aldehyde or an acid-sensitive bond that breaks under acidic conditions such that it forms an aldehyde at C23 of the aglycone core structure. Claim 69 and 72 of ‘723 recite wherein the saponin is selected from QS-21, SO1861, SA1641 and GE1741, and wherein the acid-sensitive linker is covalently bound to the saponin at position C23 of the aglycone core structure via an acid-sensitive bond. Claims 73-74 of ‘723 recites wherein the saponin comprises the first saccharide chain at the C3beta-OH group of the aglycone core structure, and the first saccharide chain comprises a glucuronic acid moiety, and wherein the conjugate further comprises an oligomeric or polymeric molecule to which more than one saponin is bound. Claim 76 of ‘723 recites a method for treating a disease in a patient in need thereof comprising administering to the patient an effective amount of the conjugate of claim 57, wherein the disease is selected from a cancer and among others. Claim 77 of ‘723 recites an in vitro method for transferring an oligonucleotide from outside a cell to inside said cell comprising: a) providing the conjugate of claim 57; b) providing a cell which expresses on its surface the binding site for the sdAb of the conjugate; and contacting the cell with the conjugate.
The claims of ‘723 teach all of the same limitations as the instant claims for the recited conjugate such as that an ordinary skilled artisan could readily envision the claimed conjugate.
Furthermore, the sdAb in the claims of ‘723 would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above. See MPEP 2111.02 II
Lastly, even though the claims of ‘723 do not explicitly recite that the saponin is an endosomal escape enhancer, this property would be necessarily present in the claims of ‘723 because the claims of ‘723 recite the same SO1861 that is conjugated to sdAb-toxin conjugate, and as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 67-68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,723 (‘723) in view of Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025).
The claims of ‘723 recite the conjugate of instant claim 57.
The difference between the claims of ‘723 and the claimed invention is that the claims of ‘723 do not recite an effector molecule that is a proteinaceous molecule such as a protein toxin.
The teachings of Lacaille-Dubois are as described above.
It would have been prima facie obvious to combine the claims of ‘723 with Lacaille-Dubois before the effective filing date of the claimed invention by substituting the oligonucleotide recited in the claims of ‘723 with the targeted toxins such as a dianthin as disclosed in Lacaille-Dubois to arrive the claimed invention. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because both the claims of ‘723 and Lacaille-Dubois recite similar conjugates useful for the same purpose of treating cancer, and Lacaille-Dubois provides further guidance that saponin compounds have adjuvant activity for several agents including a similar anti-EGFR dianthin conjugates for treating cancer. Therefore, an ordinary skilled artisan could have predictably considered alternative agents to use to treat cancer such as targeted toxins disclosed in Lacaille-Dubois with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 57-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,710 (‘710) in view of US’042 (US20150337042A1 in PTO-892 dated 10/28/2025) and Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025).
Claim 39 of ‘710 recites a conjugate for transferring a saponin from outside a cell into said cell, the conjugate comprising: the saponin; and a single-domain antibody (sdAb) capable of binding to said cell, wherein the sdAb and the saponin are covalently bound via a linker, and wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside. Claims 40-43 of ‘710 recites wherein the sdAb is selected from a Vu domain derived from a heavy chain of an antibody, a Vi domain derived from a light chain of an antibody, and a Van domain, wherein the conjugate comprises at least two sdAbs, wherein at least one sdAb is covalently linked to the saponin, wherein the conjugate comprises from one to eight sdAbs capable of binding to the same binding site on a cell-surface molecule of the cell, and wherein the conjugate comprises from 1 to 100 molecules of the saponin. Claims 46-47 of ‘710 recites wherein the saponin comprises an aglycone core structure selected from quillaic acid and gypsogenin, wherein an aldehyde function present at position C23 of the aglycone core structure is either chemically unmodified or is involved in the covalent binding of the linker, and wherein the saponin comprises a first saccharide chain bound to the Cs atom of the aglycone core structure of the saponin, wherein the first saccharide chain comprises a glucuronic acid moiety or is selected from the recited list. Claims 49-51 of ‘710 recite wherein the saponin is selected from: QS-21, GE1741, SA1641, and SO1861, wherein the first saccharide chain comprises a glucuronic acid moiety comprising a carboxyl group that is either chemically unmodified or is involved in the covalent binding of the linker, and wherein the linker is a cleavable linker that is subject to cleavage under acidic conditions, reductive conditions, enzymatic conditions, and/or light- induced conditions, or wherein the cleavable linker comprises a cleavable bond that is subject to cleavage under acidic conditions, and/or is susceptible to proteolysis. Claims 53 and 59 of ‘710 recite further comprising an oligomeric or polymeric molecule, wherein the oligomeric molecule or polymeric molecule is covalently bound to the saponin and the sdAb, and wherein the sdAb binds to a tumor cell surface receptor. Claim 62 of ‘710 recites a method of treating a patient suffering from a disease selected from: a cancer, an auto-immune disease, an infection, a disorder or disease relating to an enzyme deficiency, a disorder or disease relating to a gene defect, the method comprising administering the pharmaceutical composition of claim 61 to the patient. Claim 63 of ‘710 recites an in vitro method for transferring an active pharmaceutical ingredient from outside a cell to inside said cell, the in vitro method comprising: (a) providing a cell which expresses on the cell surface a binding site for the sdAb as comprised in the conjugate of claim 39; (b) providing an active pharmaceutical ingredient; (c) providing the conjugate of claim 39; (d) contacting the cell of step a) in vitro with the active pharmaceutical ingredient of step b) and the conjugate of step c), therewith establishing the transfer of the active pharmaceutical ingredient from outside the cell into said cell.
The difference between the claims of ‘710 and the claimed invention is that the claims of ‘710 do not recite an effector molecule that is linked to the conjugate.
The independent teachings of US’042 and Lacaille-Dubois are as described above.
It would have been prima facie obvious to combine the claims of ‘710 with US’042 and Lacaille-Dubois before the effective filing date by substituting the sdAb recited in the claims of ‘710 with either an anti-EGFR sdAb dianthin conjugate from the teachings of US’042 or an anti-EGFR miRNA conjugate that interferes with EGFR expression at the RNA level as disclosed in US‘042 with further guidance from Lacaille-Dubois. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because both the claims of ‘710 and US‘042 recite similar sdAb conjugates useful for the same purpose of treating cancer, and Lacaille-Dubois provides further guidance that saponin compounds have adjuvant activity for several agents including a similar anti-EGFR dianthin conjugates for treating cancer. Therefore, an ordinary skilled artisan could have predictably considered alternative sdAb to use with the saponin to treat cancer such as the anti-EGFR conjugates disclosed in US’042 with a reasonable expectation of success.
Furthermore, the sdAb in the combined references described above would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above, and furthermore, US’042 teaches that the anti-EGFR ADCs, comprising an anti-EGFR antibody, delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]). See MPEP 2111.02 II
Lastly, as evidenced by Lacaille-Dubois on page 52 left column, triterpene glycosides increase endo/lysosomal escape of ribosome inactivating proteins into the cytosol. Therefore, this function would be necessarily present in the combined references described above because the combined references disclose the same triterpene glycosides (SO1861) that is conjugated to sdAb-toxin conjugate (anti-EGFR sdAb dianthin conjugate). Furthermore, as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 57-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,715 (‘715) in view of US’042 (US20150337042A1 in PTO-892 dated 10/28/2025) and Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025).
Claim 22 of ‘714 recites a conjugate for transferring a saponin from outside a cell into said cell, comprising a single-domain antibody (sdAb) capable of binding to said cell and covalently bound to at least one saponin via a cleavable linker, wherein the at least one saponin is a monodesmosidic or a bidesmosidic triterpene glycoside comprising an aglycone core structure selected from quillaic acid or gypsogenin, wherein an aldehyde function present at position C23 of the aglycone core structure is either chemically unmodified or is involved in covalent binding of the cleavable linker, and wherein the cleavable linker comprises an acidic-conditions-cleavable bond subject to cleavage under acidic conditions present in endosomes and/or lysosomes of mammalian cells and adapted to release the at least one saponin in a free form from the conjugate under said conditions. Claims 24-25 of ‘715 recite wherein the sdAb is a Vu domain derived from a heavy chain of an antibody, a Vi domain derived from a light chain of an antibody, or a Van domain, and wherein the conjugate comprises at least two sdAbs with a single first sdAb covalently linked to the at least one saponin, or with two or more sdAbs linked to the at least one saponin, or with all of the at least two sdAbs linked to the at least one saponin. Claim 26 of 715 recites wherein the conjugate comprises from one to eight sdAbs capable of binding to the same binding site on a cell-surface molecule of the cell, wherein the at least one saponin 1s linked to a single first sdAb of the one to eight sdAbs or wherein the at least one saponin is linked to two or more of the sdAbs, if present. Claim 30 of ‘715 recites wherein the at least one saponin is selected from:QS1861, QS-21, and among others. Claim 32 of ‘715 recites wherein the conjugate further comprises an oligomeric molecule or a polymeric molecule to which the at least one saponin is covalently bound via the cleavable linker, and wherein the sdAb is also covalently bound to the same oligomeric molecule or polymeric molecule as to which the at least one saponin is covalently bound via the cleavable linker. Claim 34 of ‘715 recites wherein the at least one saponin is covalently bound to the oligomeric molecule or to the polymeric molecule of the covalent saponin conjugate via a hydrazone bond, and/or wherein a glucuronic acid function in a first saccharide chain at the Csbeta-OH group of the aglycone core structure is involved in the covalent binding of the at least one saponin to the oligomeric molecule or to the polymeric molecule, and/or further wherein the polymeric molecule or the oligomeric molecule is bound to the sdAb. Claim 37 of ‘715 recites wherein the conjugate comprises an sdAb that can bind to HER2, CD71 or to EGFR. Claim 39 of ‘715 recites wherein the active pharmaceutical ingredient of the second pharmaceutical composition is an ADC or an AOC, and/or wherein the conjugate comprises an sdAb that can bind to HER2, CD71 or EGFR, and/or wherein one or more active pharmaceutical ingredients comprise(s) an sdAb that can bind to HER2, CD71 or EGFR, and/or wherein the ADC comprises dianthin or saporin.
The difference between the claims of ‘715 and the claimed invention is that the claims of ‘715 do not recite an effector molecule that is linked to the conjugate.
The independent teachings of US’042 and Lacaille-Dubois are as described above.
It would have been prima facie obvious to combine the claims of ‘715 with US’042 and Lacaille-Dubois before the effective filing date by substituting the sdAb recited in the claims of ‘715 with either an anti-EGFR sdAb dianthin conjugate from the teachings of US’042 or an anti-EGFR miRNA conjugate that interferes with EGFR expression at the RNA level as disclosed in US‘042 with further guidance from Lacaille-Dubois. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because both the claims of ‘715 and US‘042 recite similar sdAb conjugates that target EGFR or CD71, and Lacaille-Dubois provides further guidance that saponin compounds have adjuvant activity for several agents including a similar anti-EGFR dianthin conjugates for treating cancer. Therefore, an ordinary skilled artisan could have predictably considered alternative sdAb conjugate to use with the saponin to treat cancer such as the anti-EGFR conjugates disclosed in US’042 with a reasonable expectation of success.
Furthermore, the sdAb in the combined references described above would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above, and furthermore, US’042 teaches that the anti-EGFR ADCs, comprising an anti-EGFR antibody, delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]). See MPEP 2111.02 II
Lastly, as evidenced by Lacaille-Dubois on page 52 left column, triterpene glycosides increase endo/lysosomal escape of ribosome inactivating proteins into the cytosol. Therefore, this function would be necessarily present in the combined references described above because the combined references disclose the same triterpene glycosides (SO1861) that is conjugated to sdAb-toxin conjugate (anti-EGFR sdAb dianthin conjugate). Furthermore, as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”.In regards to instant claims 78-80, it would have also been prima facie obvious before the effective filing date of the claimed invention to have administered the modified conjugate as recited by the combination of the claims of ‘715, US’042, and Lacaille-Dubois discussed above to treat a patient with cancer and/or to transfer the modified conjugate from outside a cell to inside said cell to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Lacaille-Dubois provides guidance of co-administering saponin with anti-EGFR drug conjugates to treat cancers as well as to enhance the uptake of the conjugate into the cells for killing.
Claims 57-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,754 (‘754) in view of US’042 (US20150337042A1 in PTO-892 dated 10/28/2025), Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025), Kreutz (Plos One, 2012 in PTO-892 dated 10/28/2025), and Marciani (US5977081A in PTO-892 dated 10/28/2025).
Claim 57 of ‘754 recites a pharmaceutical combination comprising: a first conjugate comprising an effector molecule and a single-domain antibody for binding to a first cell-surface molecule (sdAb), 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 or a xeno nucleic acid; a saponin and/or 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; the combination optionally further comprising a pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.Claim 60 of ‘754 recites wherein the first conjugate comprises an sdAb which is selected from: a Vu domain derived from a heavy chain of an antibody; a VL domain derived from a light chain of an antibody; and a Van domain. Claim 61 of ‘754 recites wherein the first conjugate comprises at least two sdAbs, wherein two sdAbs are the same or are capable of binding to the same binding site on the first cell-surface molecule. Claim 62 of ‘754 recites wherein the first cell-surface molecule is a tumor-cell surface receptor and/or a tumor-cell specific receptor and/or is a receptor selected from: CD71, EGFR, and among others. Claim 64 of ‘754 recites wherein the effector molecule is selected from any one or more of a oligonucleotide (ASO, AON), short interfering RNA (siRNA), anti-microRNA (anti-miRNA), and among others Claim 67 of ‘754 recites wherein the saponin and/or the modified saponin is selected from any one or more of: the saponin comprising an aglycone core structure selected from quillaic acid and gypsogenin, and/or the modified saponin comprising the aglycone core structure selected from: a modified quillaic acid wherein the aldehyde group in position C-23 of quillaic acid is chemically modified by transformation into a hydrazone bond, and a modified gypsogenin wherein the aldehyde group in position C-23 of gypsogenin is chemically modified by transformation into a hydrazone bond. Claim 69 of ‘754 recites wherein the hyrazone bond comprised by the modified saponin was obtained by chemically modifying the aldehyde group in position C-23 of quillaic acid or of gypsogenin: through reaction with N-g-maleimidocaproic acid hydrazide (EMCH), wherein the maleimide group of the EMCH is further optionally derivatised by formation of a thioether bond with mercaptoethanol; Claim 70 of ‘754 recites wherein the first saccharide chain comprising the glucuronic acid unit either comprises a carboxyl group on the glucuronic acid unit or comprises an amide bond obtained by transformation of the carboxyl group, optionally through reaction with 2-amino-2-methyl-1,3-propanediol (AMPD) or N-(2- aminoethyl)maleimide (AEM). Claim 72 of ‘754 recites wherein the saponin or the modified saponin is selected from any one or more of: QS-21 , SO1861, SA1641, and GE1741, or the modified version of any one thereof as specified in claim 57. Claim 75 of ‘754 recites a method of treating a disease in a patient in need thereof comprising administering to the patient an effective amount of the pharmaceutical combination of claim 57, wherein the disease is selected from: a cancer, and among others. Claim 75 of ‘754 recites an in vitro method for transferring an effector molecule comprising or consisting of a nucleic acid or a xeno nucleic acid from outside a cell to inside said cell comprising: a) providing the first conjugate of the pharmaceutical combination of claim 57; b) providing the saponin or the modified saponin of the pharmaceutical combination of claim 57; c) providing a cell which expresses the first cell-surface molecule as recognized by the sdAb of the first conjugate; and d) contacting the cell in vitro with the first conjugate and the saponin or the modified saponin, therewith establishing the transfer of the effector molecule from outside the cell into said cell.
The difference between the claims of ‘754 and the claimed invention is that the claims of ‘754 do not recite that the antibody and effector molecule conjugate is covalent linked to the saponin.
The independent teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani are as described above.
It would have been prima facie obvious to combine the claims of ‘754 with US’042, Lacaille-Dubois, Kreutz, and Marciani before the effective filing date of the claimed invention by conjugating the antibody, effector molecule, and saponin together using the linking chemistries recited in US’042 with further guidance from the teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because US’042 provides guidance of conjugating sdAb to various active agents for their anti-EGFR ADCs using similar linking chemistries to treat cancer, and Lacaille-Dubois provides guidance that saponin compounds have adjuvant activity for several agents including similar antibody conjugates. Furthermore, Kruetz provides motivation to conjugate an adjuvant compound to an antibody conjugate in order to ensure that all cells targeted by the antibody conjugate is appropriately activated by the adjuvant as well as to reduce unwanted side effects such as induction of autoimmune responses, and Marciani demonstrates the formation of saponin conjugates. Therefore, an ordinary skilled artisan would have been motivated to conjugate a saponin compound as an adjuvant to an active agent such as an EGFR-drug conjugate in order to gain the advantages disclosed in Kruetz described above.
Furthermore, the sdAb in the combined references described above would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above, and furthermore, US’042 teaches that the anti-EGFR ADCs, comprising an anti-EGFR antibody, delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]). See MPEP 2111.02 II
Lastly, as evidenced by Lacaille-Dubois on page 52 left column, triterpene glycosides increase endo/lysosomal escape of ribosome inactivating proteins into the cytosol. Therefore, this function would be necessarily present in the combined references described above because the combined references disclose the same triterpene glycosides (SO1861) that is conjugated to sdAb-toxin conjugate (anti-EGFR sdAb dianthin conjugate). Furthermore, as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
In regards to instant claims 67-68, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used a targeted protein toxin such as the anti-EGFR dianthin disclosed in Lacaille-Dubois in place of the nucleic acid recited in the combination of the claims of ‘754 and US’042, Lacaille-Dubois, Kreutz, and Marciani described above to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Lacaille-Dubois provides guidance that saponin compounds have adjuvant activity for several agents including a similar anti-EGFR dianthin conjugates for treating cancer. Therefore, an ordinary skilled artisan could have predictably considered alternative agents to use with the saponin to treat cancer such as dianthin disclosed in Lacaille-Dubois with a reasonable expectation of success.
Claims 57-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/012,741 (‘741) in view of US’042 (US20150337042A1 in PTO-892 dated 10/28/2025), Lacaille-Dubois (Phytomedicine, 2017 in PTO-892 dated 10/28/2025), Kreutz (Plos One, 2012 in PTO-892 dated 10/28/2025), and Marciani (US5977081A in PTO-892 dated 10/28/2025).
Claim 57 of ‘741 recites a pharmaceutical combination comprising: a first conjugate comprising an effector molecule and a single-domain antibody for binding to a first cell-surface molecule(sdAb), 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 the saponin and the binding molecule are covalently linked to each other, the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside, and the second cell-surface molecule and the first cell-surface molecule are present on the surface of the same target cell. Claim 60 of ‘741 recites wherein the sdAb is selected from any one or more of: a Va domain derived from a heavy chain of an antibody, a VL domain derived from a light chain of an antibody, and a Van domain. Claim 61 of ‘741 recites 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. Claim 62 of ‘754 recites 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, EGFR, and among others. Claim 64 of ‘741 recites 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 (MOB), 3’-fluoro hexitol nucleic acid (FHNA), glycol nucleic acid (GNA), and threose nucleic acid (TNA). Claim 66 of’741 recites wherein the saponin comprises (i) an aglycone core structure selected from quillaic acid and gypsogenin and (11) an aldehyde function in position C23 of the aglycone core structure or an acid-sensitive bond in position C23 of the aglycone core structure, wherein the acid-sensitive bond breaks under acidic conditions such that it forms the aldehyde function in position C23 of the aglycone core structure. Claim 67 of ‘741 recites wherein the saponin comprises a first saccharide chain bound to the C3 atom of the aglycone core structure of the saponin, wherein the first saccharide chain comprises a glucuronic acid moiety and/or is selected from the recited list Claim 69 of ‘741 recites wherein the saponin is selected from any one or more of QS-21, SO1861, SA1641, and GE1741. Claim 74 of ‘741 recites wherein the acid-sensitive linker is covalently bound to the saponin at position C23 of the aglycone core structure via an acid- sensitive bond. Claim 75 of ‘741 recites wherein the saponin comprises the first saccharide chain at the C3beta-OH group of the aglycone core structure, the first saccharide chain comprising a glucuronic acid unit that is covalently bound to the linker. Claim 77 of ‘741 recites a method of treating a patient in need thereof comprising administering to the patient an effective amount of the pharmaceutical combination of claim 57, wherein the disease is selected from: a cancer, an auto-immune disease, and a disease relating to a gene defect. Claim 78 of ‘741 recites an in vitro method for transferring an oligonucleotide effector molecule being an from outside a cell to inside said cell comprising: a) providing the first conjugate of the pharmaceutical combination of claim 57; b) providing the second conjugate of the pharmaceutical combination of claim 57; c) providing a cell which expresses (1) the first cell-surface molecule as recognised by the sdAb of the first conjugate and (i1) the second cell-surface molecule as recognised by the binding molecule of the second conjugate; d) contacting the cell of step c) in vitro with the first conjugate of step a) and the second conjugate of step b), therewith establishing the transfer of the effector molecule from outside the cell into said cell.
The difference between the claims of ‘741 and the claimed invention is that the claims of ‘741 do not recite that the antibody and effector molecule conjugate is covalent linked to the saponin.
The independent teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani are as described above.
It would have been prima facie obvious to combine the claims of ‘741 with US’042, Lacaille-Dubois, Kreutz, and Marciani before the effective filing date of the claimed invention by conjugating the antibody, effector molecule, and saponin together using the linking chemistries recited in US’042 with further guidance from the teachings of US’042, Lacaille-Dubois, Kreutz, and Marciani to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because US’042 provides guidance of conjugating sdAb to various active agents for their anti-EGFR ADCs using similar linking chemistries to treat cancer, and Lacaille-Dubois provides guidance that saponin compounds have adjuvant activity for several agents including similar antibody conjugates. Furthermore, Kruetz provides motivation to conjugate an adjuvant compound to an antibody conjugate in order to ensure that all cells targeted by the antibody conjugate is appropriately activated by the adjuvant as well as to reduce unwanted side effects such as induction of autoimmune responses, and Marciani demonstrates the formation of saponin conjugates. Therefore, an ordinary skilled artisan would have been motivated to conjugate a saponin compound as an adjuvant to an active agent such as an EGFR-drug conjugate in order to gain the advantages disclosed in Kruetz described above.
Furthermore, the sdAb in the combined references described above would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above, and furthermore, US’042 teaches that the anti-EGFR ADCs, comprising an anti-EGFR antibody, delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]). See MPEP 2111.02 II
Lastly, as evidenced by Lacaille-Dubois on page 52 left column, triterpene glycosides increase endo/lysosomal escape of ribosome inactivating proteins into the cytosol. Therefore, this function would be necessarily present in the combined references described above because the combined references disclose the same triterpene glycosides (SO1861) that is conjugated to sdAb-toxin conjugate (anti-EGFR sdAb dianthin conjugate). Furthermore, as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates.
MPEP 2112 section I states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II states that “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
In regards to instant claims 67-68, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used a targeted protein toxin such as the anti-EGFR dianthin disclosed in Lacaille-Dubois in place of the nucleic acid recited in the combination of the claims of ‘741 and US’042, Lacaille-Dubois, Kreutz, and Marciani described above to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Lacaille-Dubois provides guidance that saponin compounds have adjuvant activity for several agents including a similar anti-EGFR dianthin conjugates for treating cancer. Therefore, an ordinary skilled artisan could have predictably considered alternative agents to use with the saponin to treat cancer such as dianthin disclosed in Lacaille-Dubois with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments filed on 02/26/2026 have been fully considered but were not persuasive.
Applicant states in response to the nonstatutory double patenting rejection over ‘723 that amended claim 57 now has additional functional limitations of an endosomal escape enhancer saponin and the sdAb being capable of inducing endocytosis, and ‘723 does not recite these additional limitations. Applicant further states that Lacaille-Dubois discloses saponins as adjuvants and not conjugates having at least one endosomal escape enhancer.
Applicant’s arguments described above were not found persuasive because the sdAb in the claims of ‘723 would be capable of inducing endocytosis of the conjugate because all of the structural limitations of the recited sdAb is met as described above. See MPEP 2111.02 II
Furthermore, even though the claims of ‘723 do not explicitly recite that the saponin is an endosomal escape enhancer, this property would be necessarily present in the claims of ‘723 because the claims of ‘723 recite the same SO1861 that is conjugated to sdAb-toxin conjugate, and as demonstrated in FIG. 1C-E of the drawings, the conjugated SO1861 is an endosomal escape enhancer for several sdAb-toxin conjugates. See MPEP 2112.
Lastly, it is noted that MPEP 2144 IV states that “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”.
Therefore, an ordinary skilled artisan would have still been motivated to include the saponin with an antibody-effector molecule conjugate and arrive at the claimed invention because Lacaille Dubois demonstrates significant increases in cytotoxicity when antibody effector molecule conjugates are delivered in combination with a saponin, and further discloses that saponin compounds have adjuvant activity for several agents including similar anti-EGFR dianthin conjugates. Applicant states in response to the nonstatutory double patenting rejection over ‘710 and over ‘715 that the difference between these reference applications and the instant conjugate is not simply an effector molecule linked to the conjugate, and that the teachings of US’042 and Lacaille-Dubois are not relevant to the instant claims. Applicant states that none of the prior art references suggest a conjugate with 3 different molecules that could preserve their individual function and the cited prior art does not teach the endosomal escape enhancer effect of saponins and rather as an adjuvant initiating an immune response which is undesirable according to the instant specification.
Applicant’s arguments described above were not found persuasive because an ordinary skilled artisan would have substituted one known element (the sdAb in the claims of ‘710 and ‘715) for another (anti-EGFR sdAb-dianthin conjugate or anti-EGFR miRNA conjugate of US’042) to obtain predictable results and would have a reasonable expectation of success in doing so because the claims of ‘710 and US‘042 recite sdAb-saponin conjugates and sdAb-dianthin/miRNA conjugates, respectively, that are useful for similar purposes, and Lacaille-Dubois provides further guidance that saponin compounds have adjuvant activity for several agents including a similar anti-EGFR dianthin conjugates for treating cancer. Lastly, the endosomal escape enhancer property of the recited saponin would be necessarily present as described above, and an ordinary skilled artisan can arrive at the claimed invention for a different purpose or to solve a different problem as described above.
Applicant states in response to the nonstatutory double patenting rejection over ‘754 and ‘741 that the amended claims of ‘754 and ‘741 recite additional structural and functional limitations compared to instant claim 57. Furthermore, Applicant states that none of the references disclose the endosomal escape enhancer property of saponin and also disclose adjuvant activity of saponin.
Applicant’s arguments described above were not found persuasive because even though additional structural and functional limitations are recited for the saponin and sdAb in the claims of ‘754 and ‘741, these components are still within scope of the instant claims, and the only difference between ‘754 and ‘741 compared to the instant claims is still the conjugation of the antibody-effector molecule conjugate to the saponin, which was rendered obvious as described above. Furthermore, the endosomal escape enhancer property of the recited saponin would be necessarily present as described above, and an ordinary skilled artisan can arrive at the claimed invention for a different purpose or to solve a different problem as described above.
Conclusion
No claim is found allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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