Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 57-65 and 67-78 are pending in the instant application.
Claim 66 is canceled.
Claim Rejections Withdrawn
The rejections to claim 66 are moot in view of claim cancelation.
The rejections to claims 57-61, 63-65 and 67-78 under 35 USC §112(b) are withdrawn in view of claim amendment.
The rejection to claim 60 under 35 USC §112(a) is withdrawn in view of claim amendment.
The rejections to claims 57-65 and 67-78 under 35 USC §103 are withdrawn in view of claim amendment.
The rejections to claims 57-65 and 67-78 under Nonstatutory Double Patenting are withdrawn in view of claim amendment.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
The rejection to claim 62 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is maintained.
Regarding claim 62:
the claim recites EGFR and it is further unclear if applicant intends EGFR to encompass a family of EGF receptors, or the first member of the family, EGFR1. Thus, the claim is indefinite and the metes and bounds are unclear;
Response to Arguments
Applicant argues claim 62 has been amended to delete the rejected species.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. The receptor EGFR still remains in claim 62 and it is further unclear if applicant intends EGFR to encompass a family of EGF receptors, or the first member of the family, EGFR1.
Claim Rejections – 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claims 57-60, 62, and 64-65, and 67-78 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and US 2004/0242502 (Marciani D et al. reference of record).
Regarding instant claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising:
a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second conjugate comprising an EGFR targeted antibody covalently linked to melittin (page 148, [0689]),
wherein melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]), wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to an EGFR targeted antibody covalently linked to the siRNA alone (Fig. 33). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the endosomolytic moiety as an endosomolytic small molecule and an endosomolytic polymer (page 73, [0389]). Geall taught targeting CD71 with an antibody siRNA conjugate (Fig. 54), wherein the CD71 targeting antibody siRNA conjugate effectively silenced HPRT expression (Fig. 86).
Geall did not teach: A) a pharmaceutical composition of a first conjugate comprising a sdAb-siRNA effector and a second conjugate covalently linked to a saponin; and B) conjugation of the endosomal escape moiety at a C23 of an aglycone core or C3beta-OH glucuronic acid group of a saponin, but this is obvious in view of Marciani., but this is obvious in view of Heukers, Weng, King, and Marciani.
Heukers taught EGFR-targeted nanobody® VHH single domain conjugates are specific and potently kill cancer cells (abstract and Fig. 2). Heukers taught a biparatopic EGFR-targeted single domain antibody 7D12-9G8 that is known to be internalized (page 1442, left column, first paragraph). Heukers taught 7D12-9G8-PS induces the lysosomal trafficking (page, 1448, right column first paragraph). Heukers taught EGFR-targeted single domain antibodies showed a faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody (page 1442, left column, first paragraph).
Weng taught the glycoside saponin SO1861 greatly improves the efficacy of lipid based as well as non-lipid based targeted nanoplexes consisting of a targeted K16 peptide with a nucleic acid binding domain and plasmid-DNA, minicircle-DNA or small interfering RNA (siRNA) (abstract). Weng taught SO1861 augments the escape of the genetic cargo out of the intracellular compartments into the cytosol (abstract). Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes (abstract), wherein the lumen of the endosomes and lysosomes are acidified (page 75, right column, last paragraph). Weng taught that SO1861 integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties (page 85, right column, last paragraph and Fig. 10). Weng taught that SO1861 in combination with siRNA increased siRNA silencing in cancer cells (page 85, left to right column, bridging paragraph and Fig. 9).
Weng taught an effective in vitro method for transferring an oligonucleotide effector molecule from outside a Neuro-2A cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a conjugate comprising SO1861 sensitized receptor-targeted nanoplexes and an oligonucleotide effector of EGFP;
providing a Neuro-2A cells wherein the surface of the cell is targeted by the receptor-targeted nanoplexes;
contacting the cell of step b) with the pharmaceutical composition of step a),
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell, wherein the integration of SO1861 into the nanoplex caused a tremendous shift of the median fluorescence value, and wherein the high transfection efficiency
of the SO1861 sensitized LPDS-nanoplexes is corroborated by the fluorescence
image (page 85, right column, last paragraph, Fig. 10 legend, and Fig. 10).
Weng taught the RISC (RNA-Induced-Silencing Complex) is located in the cytosol (page 75-76 bridging paragraph). Weng taught to exert a silencing effect, siRNA has to escape from the endosomes/lysosomes into the cytosol because in lysosomes siRNA/DNA are degraded by nucleases (page 75-76 bridging paragraph). Weng taught: 1) If the endo-/lysosomal escape of the genetic cargo does not occur the siRNA/DNA is degraded within the lysosome thus leading to a therapeutic failure; 2) limited release of siRNA/DNA into the cytosol is one of the major obstacles for efficient siRNA/DNA delivery; and 3) development of innovative strategies to augment the endo-/lysosomal escape of siRNA/DNA and the delivery of a minimal amount of siRNA/DNA are desired for an efficient therapeutic response (page 75-76 bridging paragraph).
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody (page 279, left column, first paragraph).
King taught hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating free doxorubicin payload (page 279, left column, first paragraph).
King taught BR96-DOX conjugates produced antigen-specific antitumor activity and were more potent, were more active, and produced less systemic toxicity than unconjugated DOX in vivo(page 279, left column, first paragraph).
King taught the branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a doxorubicin and antibody basis (abstract).
King taught the linear and branched hydrazone antibody payload conjugates were effective in cancer cells (Table 3).
Regarding instant claims 57 and 74-75, Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid (pages 13-16, Schemes 1a-c). Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core (pages 23-25, Schemes 5a-b).
Regarding instant claims 57-60, 62, 64-65, 67-77, it would have been obvious for a person having ordinary skill in the art to take the effective method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a pharmaceutical combination comprising a single pharmaceutical composition:
a first pharmaceutical composition comprising a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition comprising a second conjugate comprising an EGFR targeted antibody covalently linked to melittin which is an endosomolytic moiety that causes endosomal escape agent
of Geall – and:
Exchange the EGFR targeting moieties with a bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 of Heukers;
Exchange the endosomal escape molecule melittin for the endosomal escape molecule glycoside saponin SO1861 of Weng;
Exchange the attachment linker of the endosomal escape moiety for an acid sensitive hydrazone linker of King that was a single or branched polymer for linking the payload; and
covalently conjugate the linear or branched polymer acid sensitive hydrazone linker that releases the SO1861 payload(s) to cause endosomal escape at: i) the C23 aldehyde of SO1861; or ii) the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, as taught by Marciani.
This is obvious because:
Geall taught the antibody as a sdAb and Heukers taught the bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells;
Weng taught the saponin SO1861: i) augments the escape of the genetic cargo out of the intracellular compartments into the cytosol; ii) integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties; and iii) in combination with siRNA increased siRNA silencing in cancer cells;
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload with a single or branched polymer payload were effective in cancer cells and employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the hydrazone linker would release the SO1861 payload in the endosomes/lysosomes, where SO1861 has its effects; and
i) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid; and 4ii) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core.
There is a reasonable expectation of success because:
The bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells;
The saponin SO1861 would: i) augment the escape of the siRNA genetic cargo out of the intracellular compartments into the cytosol; ii) improve DNA transfection and provide improved effector properties; and iii) increase siRNA silencing in cancer cells to promote;
Single or branched hydrazone linkers are known to be effective, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the single or branched polymer hydrazone linker would release the SO1861 payload(s) in the endosomes/lysosomes, where SO1861 has its effects; and
i) and ii) the linear or branched polymer acid sensitive hydrazone linker connected at either the C23 aldehyde of SO1861 or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861 would connect to either of the carbonyls and release the payload under acidic conditions to allow the SO1861 to perform the endosomal escape of the siRNA.
This would produce a method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination (instant claim 59) comprising two pharmaceutical compositions (instant claim 58) comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR targeted (instant claim 62 ) VHH 7D12-9G8 antibody (instant claims 60 ) covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claim 64 ); and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody immunoglobin binding fragment (instant claim 70) covalently linked to a linker and SO1861 (instant claims 68-69 ) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claim 65) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 67) wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape (instant claim 73 ), wherein the linker is covalently connected to linear or branched polymer acid sensitive hydrazone linker at either the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure (instant claim 74) or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861 (instant claim 75) wherein EGFR is a second cell-surface receptor (instant claim 71 ), wherein the covalently branched polymer linker would comprise more than one saponin molecule (instant claim 76 ), wherein the EGFR molecules are present on the surface of the same cell (instant claims 57 and 77)
Regarding instant claim 78, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of Geall, Heukers, Weng, King, and Marciani above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein the linker is covalently connected to linear or branched polymer acid sensitive hydrazone linker at either the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, wherein EGFR is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR molecules are present on the surface of the same cell,
– and: include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR expressing cell to inside of said cell of Weng;
This is obvious because: 1) the method of Weng taught SO1861 was effective at transferring oligonucleotides into cells when targeted to the cell, Thus, the two compositions comprising SO1861 or an siRNA effector could be used for transferring nucleotides into the cell.
There is a reasonable expectation of success because: 1) SO1861 is a known endosomal escape agent that can effectively increase the effectiveness of oligonucleotide effector into the cell and the VHH would target the agents to the cells for internalization to the endosome..
This would produce an in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR expressing cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a first pharmaceutical composition a first conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
providing a pharmaceutical composition comprising a second pharmaceutical composition a second conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein the linker is covalently connected to linear or branched polymer acid sensitive hydrazone linker at either the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, wherein EGFR is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR molecules are present on the surface of the same cell,
providing a cell that expresses EGFR on the surface wherein the surface of the cell is targeted by the pharmaceutical compositions in a) and b);
contacting the cell of step c) in vitro with the pharmaceutical composition of step a) and the pharmaceutical composition of step b).
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell.
Response to Arguments
Applicant argues the pending claims are directed to a pharmaceutical composition comprising two conjugates featuring:
(1) a first conjugate comprising effector molecule covalently linked to a single-domain
antibody, wherein the effector molecule comprises an oligonucleotide; and
(2) a second conjugate comprising a saponin covalently linked to binding molecule for
binding to a second cell-surface molecule.
In contrast, the Office asserts that Geall teaches a method of treating cancer by silencing a protein in a cancer cell comprising: (1) a first conjugate comprising an siRNA oligonucleotide covalently linked to an EGFR targeted antibody; and (2) a second conjugate comprising an EGFR targeted antibody linked to melittin. The Office concedes that Geall does not teach the claimed composition and characterizes Geall as teaching a single composition comprising a combination of conjugates, where one of conjugates comprises an oligonucleotide as a payload (e.g., siRNA), and the other conjugate comprises a melittin, which functions as an endosomolytic peptide payload.
Applicant disagrees with the Office's characterization. One of skill in the art could not arrive at the claimed composition based on the disclosures of Geall, Heukers, Weng, and King alone or in any fair combination. Geall merely teaches a single conjugate comprising a binding moiety conjugated to a polynucleic acid molecule and a polymer, see, e.g., Geall at [0004]. In particular, Geall teaches an antibody-siRNA-PEG conjugate, where a variety of antibodies can be conjugated to siRNAs with various PEG sizes or polymer linkers. The preferred antibodies of Geall are full-length antibodies such as zalutumumab, panitumumab, and herceptin, as well as other full-sized antibodies for PSMA, ASGR, and anti-B cell. Example 8 teaches that cholsiRNA conjugates cleared much faster from plasma than the mAb-siRNA conjugates. Thus, the preferred antibody is one that is large enough, e.g., - 150 kDa, that avoids rapid renal clearance. One of skill in the art would have no motivation to merely "exchange" the full-length antibody with a single-domain antibody based on the disclosure of Geall even in view of the teachings of Heukers.
Heukers teaches photosensitizer-EGFR-targeting nanobody conjugates. In a binding assay, once the cells reached approximate values of saturation, the cells were exposed to a light dose to induce photodynamic therapy (PDT) and then cell viability was measured. The authors state "[i]mportantly, free PS, R2-PS, and the non-illuminated EGFR-targeted NB-PS conjugates did not affect cell viability ... which highlights the specificity of the PDT approach." See Heukers at 1443. One of skill in the art would have no motivation nor any reasonable expectation of success to substitute the antibody fragments of Heukers for the full-length antibodies of Geall.
Geall teaches that a PEG linker is required as part of the conjugate. In Example 10, PSMA-Ab(Cys)-EGFR (no PEG) was directly compared to PSMA-Ab(Cys)-EGFR-PEG5k; the PEG-containing construct delivered more siRNA to tumors and produced greater EGFR mRNA knockdown than the PEG-free counterpart. One of skill in the art would have no motivation to substitute the PEG linker with any linker group let alone an acid labile linker, as purportedly taught by King. The proposed substitution cannot change the principle of operation of Geall for its intended purpose. See MPEP § 2143.0l(VI). In other words, not only does Geall provide results that demonstrate that having the siRNA in between the EGFR-Ab and the PEGSK resulted in significantly higher plasma concentrations than the alternative format, e.g., EGFR antibody-KRAS-PEG5k, but the PEG5k moiety serves an entirely different function than the hydrazone. Geall in combination with King renders the conjugate inoperative.
The failure of an asserted combination to teach or suggest each and every feature of a claim remains fatal to a rejection under§ 103.
Turning to the saponin limitation of the second conjugate, the Office contends that Geall teaches that melittin is an endosomolytic moiety that causes endosomal escape agent [0689]. Example 8, to which the Office is referring to, evaluates whether the addition of melittin increased delivery of the siRNA to the target tissue:
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(Id. at [0689], emphases added.)
Applicant argues the results showed that adding melittin slightly reduced tumor uptake. The results of Example 8 teach away from at least administering a second conjugate to increase tumor uptake of the first conjugate through the addition of an endosomal escape peptide, such as melittin. The Office must consider the prior art in its entirety. MPEP § 2141.02. One of skill in the art evaluating the cited reference as a whole would not be motivated to (a) add a second conjugate and (b) add a second conjugate with an endosomal escape enhancer.
Even if the results of Geall did not dissuade one of skill in the art from trying another endosomal escape enhancer -- which Applicant asserts that Geall does -- there must be some basis for arriving at a saponin. The Office's reliance on functional similarity is misplaced. Geall teaches melittin, a linear peptide of 26 amino acids, which has a structure as follows:
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374
527
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In contrast, the pending claims saponin having a gypsogenin core or quillaic acid core with the following general structure:
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As referenced above Geall dissuades a person of skill in the art from using melittin because the melittin did not increase tumor uptake, rather there was an increase in plasma clearance of the conjugate. One of skill in the art would not look to Weng to cure the deficiencies of Geall. Weng teaches nanoplex formulations for the delivery of nucleic acids. The SO 1861 is added to the DNA solution before or during nanoparticle assembly. There is no covalent bond to saponin (see, e.g., Weng at 77, left column, 11. 41-45).
The cited references fail to teach each and every element of the pending claims. There is no motivation to modify the teachings of Geall, and substituting elements is improper for establishing a suggestion to modify, and there is no reasonable expectation of success. For at least these reasons, the pending claims are nonobvious over Geall, Heukers, Weng, and King. Reconsideration and withdrawal of the rejection is respectfully requested.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above.
Regarding 1) Geall; 2) motivation to "exchange" the full-length antibody with a single-domain antibody based on the disclosure of Geall even in view of the teachings of Heukers; 3) motivation nor any reasonable expectation of success to substitute the antibody fragments of Heukers for the full-length antibodies of Geall –
As described above, Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising:
a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second conjugate comprising an EGFR targeted antibody covalently linked to melittin (page 148, [0689]),
wherein melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]), wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to an EGFR targeted antibody covalently linked to the siRNA alone (Fig. 33). Geall further taught: a) the antibody as a single-domain antibody (sdAb) (page 1, [0019]); b) the endosomolytic moiety as an endosomolytic small molecule and an endosomolytic polymer (page 73, [0389]). Thus, targeting an siRNA oligonucleotide conjugated to a sdAb in combination with an endosomolytic moiety that causes endosomal escape agent conjugated to a sdAb would be obvious with a reasonable expectation of success.
Additionally, Heukers taught the bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells.
Thus, targeting an siRNA oligonucleotide conjugated to an effective tumor targeting sdAb with desirable properties in combination with an endosomolytic moiety that causes endosomal escape agent conjugated to an effective tumor targeting sdAb with desirable properties would be obvious with a reasonable expectation of success.
Regarding Geall and a PEG linker, combination treatment with EGFR antibody-KRAS-PEG5k and EGFR targeted antibody-melittin was shown to be effective in a tumor in vivo (Fig. 33). The EGFR antibody-KRAS-PEG5k contains a PEG linker connected at the end of the siRNA, not between the antibody and the siRNA. Thus, the antibody to siRNA linker does not involve PEG and does not change the principle of operation of Geall. Further, the claim does not exclude siRNA modifications attached to the end of the siRNA and antibody siRNA conjugates without PEG attachments are functional. Exchange of the linker between the antibody and siRNA with the hydrazone linker of King is thus still obvious with a reasonable expectation of success.
Regarding the saponin, Fig. 33 shows combination treatment with EGFR antibody-KRAS-PEG5k and EGFR targeted antibody-melittin was shown to be effective in a tumor in vivo. Including EGFR targeted antibody-melittin in the composition caused tumor KRAS mRNA to be lower at all time points tested in Fig. 33.. Thus, including EGFR targeted antibody-melittin in the composition was more effective at lowering target mRNA levels, not less effective, in vivo. These results do not teach away from including an endosomolytic moiety that causes endosomal escape agent conjugated to an antibody or sdAb.
Regarding the argument of the Office's reliance on functional similarity is misplaced – Geall taught melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]) and Weng taught to exert a silencing effect, siRNA has to escape from the endosomes/lysosomes into the cytosol because in lysosomes siRNA/DNA are degraded by nucleases (page 75-76 bridging paragraph). Weng taught: 1) If the endo-/lysosomal escape of the genetic cargo does not occur the siRNA/DNA is degraded within the lysosome thus leading to a therapeutic failure; 2) limited release of siRNA/DNA into the cytosol is one of the major obstacles for efficient siRNA/DNA delivery; and 3) development of innovative strategies to augment the endo-/lysosomal escape of siRNA/DNA and the delivery of a minimal amount of siRNA/DNA are desired for an efficient therapeutic response (page 75-76 bridging paragraph). Weng taught the saponin SO1861: i) augments the escape of the genetic cargo out of the intracellular compartments into the cytosol; ii) integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties; and iii) in combination with siRNA increased siRNA silencing in cancer cells. Thus, exchanging one effective endosomal escape agent for another is obvious with a reasonable expectation of success. The covalent bond to SO1861 would be a hydrazone linker as described above. Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the hydrazone linker of King would release the SO1861 payload in the endosomes/lysosomes, where SO1861 has its effects.
Claims 57-62, and 64-65, and 67-78 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and US 2004/0242502 (Marciani D et al. reference of record) as applied to claims 57-60, 62, and 64-65, and 67-78 above, and further in view of Tang J et al. (Oncotarget. 2016 7(23):34070–34083 reference of record).
Geall, Heukers, Weng, King, and Marciani are described above.
Geall did not teach the first conjugate comprises at least two sdAbs that were the same, but this is obvious in view of Tang.
Tang taught an effective method of administering a subject with cancer a monospecific bivalent CD7 single domain antibody conjugated immunotoxin PG002 that increased survival of the subject (abstract and Fig. 6), wherein the monospecific bivalent CD7 single domain antibody comprised the same single domain antibody (Fig. 4A). Tang taught a key property of CD7 for therapeutic applications in cancer cases is its rapid internalization after binding to an antibody or antibody derivative which makes it well suited for drug delivery (page 34071, left column, last paragraph). Tang taught to improve the cell-binding affinity and in vivo half-life of the monovalent single domain antibody-based immunotoxin PG001, as well as to potently induce leukemia cell apoptosis, construction of a bivalent nanobody-based immunotoxin with a longer half-life and greater cell-binding affinity was necessary, wherein the bivalent monospecific single domain conjugate PG002 was produced.
Regarding instant claim 61, it would have been obvious for a person having ordinary skill in the art to take the method of Geall, Heukers, Weng, King, and Marciani above and in the pharmaceutical composition: – 1) exchange the EGFR targeting sdAb of the first and second conjugate with the monospecific bivalent CD7 single domain antibody of Tang.
This is obvious because: 1) Tang taught administering a subject with cancer a monospecific bivalent CD7 single domain antibody conjugated immunotoxin PG002 was effective at increasing survival of the subject, wherein the monospecific bivalent CD7 single domain antibody comprised the same single domain antibody.
There is a reasonable expectation of success because: 1) Tang taught a key property of CD7 for therapeutic applications in cancer cases is its rapid internalization after binding to an antibody or antibody derivative which makes it well suited for drug delivery and the monospecific bivalent CD7 was to improve the cell-binding affinity and in vivo half-life of the monovalent single domain.
This would produce a method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a monospecific bivalent CD7 single domain VHH (instant claims 61 ) covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition a second conjugate comprising a monospecific bivalent CD7 single domain VHH covalently linked to a linker and SO1861, wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein the linker is covalently connected to linear or branched polymer acid sensitive hydrazone linker at either the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, wherein CD7 is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the CD7 molecules are present on the surface of the same cell.
Response to Arguments
Applicant argues none of Geall, Huekers, Weng, and King render claims 57-60, 62, 64-65, 67-73 and 76-78 obvious, thus Tang cannot cure the deficiencies. For at least these reasons, the pending claims are nonobvious over Geall, Heukers, Weng, and King, in view of Tang.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. Discussion of Geall, Huekers, Weng, and King and claims 57-60, 62, 64-65, 67-73 and 76-78 is above.
Claims 57-60, 62-65, and 67-78 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and US 2004/0242502 (Marciani D et al. reference of record) as applied to claims 57-60, 62, and 64-65, and 67-78 above, and further in view of Deken MM et al. (J Control Release. 2020 Apr 21;323:269–281 reference of record).
Geall, Heukers, Weng, King, and Marciani are described above.
Geall taught the targeting antibody as trastuzumab or binding fragment thereof as trastuzumab which targets HER2 (page 66, [0343])
Geall did not teach the first conjugate as a single embodiment of a HER2 targeting sdAb, but this is obvious in view of Deken.
Deken taught HER2-targeted nanobodies® VHHs 1D5 and 1D5-18A12 were conjugated to a photosensitizer and administered to subjects with cancer, wherein both VHH-PS conjugates potently and selectively induced cell death of HER2 overexpressing cells in vitro and in vivo (abstract). Deken taught the 18A12 VHH showed a slightly higher internalization rate as compared to 1D5, while the biparatopic VHH 1D5-18A12 showed a ten-fold increase in internalization, compared to 1D5 (page 274, right column, fourth paragraph). Deken taught internalization of the payload was achieved by employing a biparatopic VHH, which is known to promote receptor-mediated internalization (page 278, left column, last paragraph). The bivalent nanobody-PS in this study led to a higher internalization rate constant of the HER2, in comparison to a monovalent counterpart (page 278, left column, last paragraph).
Regarding instant claim 63, it would have been obvious for a person having ordinary skill in the art to take the method of Geall, Heukers, Weng, King, and Marciani above and in the pharmaceutical composition: – 1) exchange the EGFR targeting sdAb of the first and second conjugate with the single domain HER2 biparatopic VHH 1D5-18A12 antibody of Deken.
This is obvious because Geall taught the antibody could be an antibody that targets HER2 and: 1a) Deken taught the HER2-targeted VHH 1D5-18A12 conjugated to a toxic payload was effective when administered to subjects with cancer, wherein both the conjugate potently and selectively induced cell death of HER2 overexpressing cells in vitro and in vivo; and 1b) Deken taught the biparatopic VHH 1D5-18A12 was effectively internalized.
There is a reasonable expectation of success because: 1a) Deken taught the HER2-targeted VHH 1D5-18A12 conjugated to a toxic payload was effective when administered to subjects with cancer, wherein both the conjugate potently and selectively induced cell death of HER2 overexpressing cells in vitro and in vivo; and 1b) Deken taught the biparatopic VHH 1D5-18A12 was effectively internalized. Thus, the sdAb targeting HER2 internalize the siRNA and SO1861 for release.
This would produce a method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a HER2 targeted biparatopic VHH (instant claim 63) covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition a second conjugate comprising a HER2 targeted biparatopic VHH covalently linked to a linker and SO1861, wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein the linker is covalently connected to linear or branched polymer acid sensitive hydrazone linker at either the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, wherein HER2 is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the HER2 molecules are present on the surface of the same cell.
Response to Arguments
Applicant argues none of Geall, Huekers, Weng, and King render claims 57-60, 62-65, 67-73 and 76-78 obvious, thus Deken cannot cure the deficiencies. For at least these reasons, the pending claims are nonobvious over Geall, Heukers, Weng, and King, in view of Deken.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. Discussion of Geall, Huekers, Weng, and King and claims 57-60, 62, 64-65, 67-73 and 76-78 is 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 57-60, 64-65, 67-69, 72-74, 76-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-57 of copending Application No.19/044,661. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 57-60, 64-65, 67-69, 72-74, and 76-77, the copending claims taught a method for treating a disease condition associated with the presence of an aberrant cell, comprising administering to a human subject a therapeutic combination, wherein the therapeutic combination comprises:
(a) a first pharmaceutical composition comprising a first proteinaceous molecule comprising a first binding site for binding to a first cell-surface molecule of the sdAb VHH and at least one saponin covalently bound to said first proteinaceous molecule preferably covalently bound to an amino- acid residue of said first proteinaceous molecule, the first pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient; and
(b) a second pharmaceutical composition comprising a second proteinaceous molecule preferably different from the first proteinaceous molecule, the second proteinaceous molecule comprising a second binding site for binding to a second cell-surface molecule different from the first cell-surface molecule as a sdAb VHH and an oligonucleotide effector moiety, the second pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient (instant claim 57-58, 60, and 77),
wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23, wherein the saponin is covalently coupled the first proteinaceous molecule, preferably covalently coupled to an amino- acid residue of the first proteinaceous molecule, via an aldehyde function in the saponin, preferably said aldehyde function in position C-23, preferably via at least one linker, and/or via at least one cleavable linker,
wherein the amino-acid residue preferably is selected from cysteine and lysine in copending claim 41,
wherein the saponin is SO1861 in copending claim 43 (instant claim 65, 67-69 ),
wherein the aldehyde function in position C-23 of the at least one saponin is covalently coupled to linker N-e-maleimidocaproic acid hydrazide, which is an acid sensitive linker in copending claim 44 (instant claim 72-74 ),
wherein the effector moiety is an siRNA in copending claim 46 (instant claim 64),
wherein the first proteinaceous molecule comprises more than one covalently bound saponin via at least one oligomeric or polymeric scaffold (instant claim 76)
wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 , wherein the saponin is covalently coupled the first proteinaceous molecule via an aldehyde function in the saponin in position C-23 via at least one cleavable linker, wherein the cleavable linker is subject to cleavage in vivo under acidic conditions as present in endosomes and/or lysosomes of mammalian cells, preferably human cells, preferably at pH 4.0 - 6.5, and more preferably at pH s; 5.5 in copending claim 53,
wherein the first pharmaceutical composition and the second pharmaceutical composition are administered to the patient in need thereof in copending claim 55,
A method for treating a disease condition associated with the presence of an aberrant cell, in a patient in need thereof comprising administering to the patient the first pharmaceutical composition, wherein the first pharmaceutical composition further comprises the second proteinaceous molecule in copending claim 56 (instant claim 59).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-65, 67-74, 76-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-57 of copending Application No.19/044,661.
The claims of copending ‘661 teach the limitations of claims 57-60, 64-65, 67-69, 72-74, and 76-77 for the reasons set forth above.
‘661 is described above.
‘661 further claimed the first proteinaceous molecule as an antibody that targeted CD71 in copending claim 45.
‘661 did not teach the first and second molecules as sdAb that targeted CD71, but this is obvious in view of the copending claim 45 claiming a CD71 targeting antibody.
Regarding instant claims 61-63 and 70-71, it would have been obvious for a person having ordinary skill in the art to: 1) use a first conjugate that comprised a VHH to target CD71 because copending claim 45 taught CD71 antibodies as the targeting molecule and the VHH of CD71; 2) use a second conjugate that comprised a VHH to target CD71 because the effector would target the same cells that express CD71.
This is obvious with a reasonable expectation of success because: 1) copending claim 45 taught CD71 antibodies as the targeting molecule and the VHH of CD71 would still target CD71 and be expected to perform the same function; and 2) the siRNA effector would be targeted to the same cells if the second conjugate was the same as the first.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-65, 67-74, 76-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-57 of copending Application No.19/044,661 in view of US 2004/0242502 (Marciani D et al. reference of record).
The claims of copending ‘661 teach the limitations of claims 57-60, 64-65, 67-69, 72-74, and 76-77 for the reasons set forth above.
‘661 is described above.
‘661 did not teach the saponin conjugated to the C3beta-OH group of the aglycone core structure on the first saccharide chain comprising a glucuronic acid unit that is covalently bound to the linker, but this is obvious in view of Marciani.
Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid (pages 13-16, Schemes 1a-c). Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core (pages 23-25, Schemes 5a-b).
Regarding instant claims 75, it would have been obvious for a person having ordinary skill in the art to take the method of ‘661 above and in the pharmaceutical composition: – 1) covalently conjugate the acid sensitive linker bound to the SO1861 payload(s): 1) the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861 as taught by Marciani.
This is obvious because: 1) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid.
There is a reasonable expectation of success because: 1) the acid sensitive hydrazone linker connected at the C3beta-OH of SO1861 would connect to the carbonyl and release the payload under acidic conditions to allow the SO1861 to perform the endosomal escape of the siRNA.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-60, 62-65, 67-74, and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-2, 5, 7, 11, 13-14, 17-19, 23-26, and 28-29 of copending Application No. 17/312,104;
claims 1-2, 5, 8, 10-11, 16-19, 23-26, 29, and 32-33 of copending Application No. 17/312,476;
claims 1, 5-6, 9, 12-13, 20-24, 29-31, 35, 38, and 43 of copending Application No. 17/415,759;
claims 1-2, 5, 9, 11, 17, 19, 23-24, 26, 28-29, and 39-43 of copending Application No. 17/312,019
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), and King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record).
‘104 copending claims 1-2, 5, 7, 11, 13-14, 17-19, 23-26, and 28-29 claim an oligonucleotide covalently conjugated to at least one saponin with a hydrazone linker, wherein the saponin is a bisdesomsidic triterpene with an aldehyde in position C-23:
‘104 taught an oligonucleotide covalently conjugated to at least one saponin with a hydrazone linker, wherein the saponin is a bisdesomsidic triterpene with an aldehyde in position C-23 in copending claim 1, wherein the oligonucleotide is an siRNA oligonucleotide in copending claim 2, wherein the saponin is SO1861 in copending claim 7, wherein the bond is a hydrazone or hydrazine bond subject to cleavage under acidic conditions in copending claim 14, wherein the cleavage under acidic conditions occurs in vivo in the endosomes and/or lysosomes in copending claim 17, wherein one or more saponins are conjugated in copending claim 24, wherein the conjugate further comprises an antibody that binds EGFR or CD71 in claims 26 and 28.
‘476 copending claims 1-2, 5, 8, 10-11, 16-19, 23-26, 29, 32-33 claim a scaffold covalently bound to a biologically active molecule covalently coupled to a carrier molecule, wherein the scaffold is covalently attached to an immunoglobin, an effector molecule of siRNA, and wherein the biologically active molecule is a saponin.
‘476 taught a scaffold for covalently binding at least one biologically active molecule to a carrier molecule in copending claim 1, wherein the biologicallly active molecule is SO1861 in copending claim 5, wherein the covalent bond is a hydrazone or hydrazide cleavable bond subject to cleavage in vivo under acidic conditions in copending claim 8, wherein the aldehyde bond in position C-23 of the saponin is involved in the covalent bond to the scaffold or the C3beta-OH group of the saponin is involved in the covalent bond to the scaffold in copending claim 11, wherein the at least one biologically active molecule has 1-128 glycoside molecules in copending claim 17, wherein the carrier molecule is a VHH domain and an anti-CD71 antibody or anti-EGFR antibody in copending claim 19, wherein the carrier molecule is covalently bound to the scaffold via a cysteine in copending claim 23, wherein the carrier molecule comprises an effector molecule of at least one oligonucleotide in copending claim 24, wherein the oligonucleotide comprises siRNA in copending claim 26,
‘759 copending claims 1, 5-6, 9, 12-13, 20-24, 29-31, 35, 38, and 43 claimed a therapeutic molecule comprising a covalent linked saponin and a covalent linked effector moiety.
‘759 taught a therapeutic molecule comprising a saponin linked to an effector moiety, wherein the saponin is a 12,13-dehydrooleanane bisdesmosidic triterpene saponin with an aldehyde function in position C-23 and optionally comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, wherein the effector A1 comprises an oligonucleotide and the ligand B1 comprises a VHH in copending claim 1, wherein the ligand binds EGFR or CD71 in copending claim 5, wherein the ligand comprises cetuximab in copending claim 6, wherein the effector molecule is an siRNA in copending claim 9, wherein the saponin is an SO1861 in copending claim 13, wherein more than one saponin is covalently bound in copending claim 20, wherein the saponin C is a bisdesmosidic triterpene saponin with an aldehyde function in position C-23, wherein the saponin C is covalently coupled to an amino-acid residue of the first ligand at said aldehyde function in position C-23, via a cleavable linker comprising a hydrazone bond or a hydrazide bond subject to cleavage under acidic conditions when bound to saponin in copending claims 22-23, in a pharmaceutical composition in copending claim 35;
‘019 copending claims 1-2, 5, 9, 11, 17, 19, 23-24, 26, 28-29, 39-43 claims a conjugate comprising a cell-surface molecule targeting molecule and at least one effector moiety and further comprising at least one covalently bound saponin, wherein the at least one 12,13-dehydrooleanane bisdesmosidic triterpene saponin with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, and wherein the cell-surface molecule targeting molecule comprises a VHH domain, and wherein the at least one effector moiety comprises an siRNA.
‘019 taught a conjugate comprising a cell-surface molecule targeting molecule and at least one effector moiety and further comprising at least one covalently bound saponin, wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, and wherein the cell-surface molecule targeting molecule comprises a VHH domain, and wherein the at least one effector moiety comprises an siRNA in copending claim 1, Wherein the at least one saponin is SO1861 in copending claim 5, wherein the cell-surface molecule targeting molecule can bind to CD71 in copending claim 9, wherein the cell-surface molecule targeting molecule comprises an anti-CD71 antibody in copending claim 11, wherein the at least one saponin is covalently bound to the cell-surface molecule targeting molecule, via an aldehyde function in the saponin, and/or to the at least one effector moiety, via an aldehyde function in the saponin in copending claim 17, wherein the saponin is covalently bound to an amino-acid residue of the cell-surface molecule targeting molecule and/or to the at least one effector moiety via said glucuronic acid function in copending claim 19, and wherein the linker to the saponin comprises at least one cleavable linker, wherein said cleavable linker is subject to cleavage under acidic conditions in copending claim 24, and wherein the conjugate is in a pharmaceutical composition in copending claim 43.
While the claims of ‘104, ‘476, ‘759, and ‘019 taught embodiments of a CD71 targeted antibody covalently conjugated to one or more of saponin SO1861 and an siRNA, wherein the bond is a hydrazone or hydrazine bond subject to cleavage under acidic conditions, they did not teach the conjugates as separate saponin and siRNA conjugates on different molecules, but this is obvious in view of Geall, Heukers, Weng, and King.
Regarding instant claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising:
a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second conjugate comprising an EGFR targeted antibody covalently linked to melittin (page 148, [0689]),
wherein melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]), wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to an EGFR targeted antibody covalently linked to the siRNA alone (Fig. 33). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the endosomolytic moiety as an endosomolytic small molecule and an endosomolytic polymer (page 73, [0389]). Geall taught targeting CD71 with an antibody siRNA conjugate (Fig. 54), wherein the CD71 targeting antibody siRNA conjugate effectively silenced HPRT expression (Fig. 86).
Heukers taught EGFR-targeted nanobody® VHH single domain conjugates are specific and potently kill cancer cells (abstract and Fig. 2). Heukers taught a biparatopic EGFR-targeted single domain antibody 7D12-9G8 that is known to be internalized (page 1442, left column, first paragraph). Heukers taught 7D12-9G8-PS induces the lysosomal trafficking (page, 1448, right column first paragraph). Heukers taught EGFR-targeted single domain antibodies showed a faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody (page 1442, left column, first paragraph).
Weng taught the glycoside saponin SO1861 greatly improves the efficacy of lipid based as well as non-lipid based targeted nanoplexes consisting of a targeted K16 peptide with a nucleic acid binding domain and plasmid-DNA, minicircle-DNA or small interfering RNA (siRNA) (abstract). Weng taught SO1861 augments the escape of the genetic cargo out of the intracellular compartments into the cytosol (abstract). Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes (abstract), wherein the lumen of the endosomes and lysosomes are acidified (page 75, right column, last paragraph). Weng taught that SO1861 integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties (page 85, right column, last paragraph and Fig. 10). Weng taught that SO1861 in combination with siRNA increased siRNA silencing in cancer cells (page 85, left to right column, bridging paragraph and Fig. 9).
Weng taught an effective in vitro method for transferring an oligonucleotide effector molecule from outside a Neuro-2A cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a conjugate comprising SO1861 sensitized receptor-targeted nanoplexes and an oligonucleotide effector of EGFP;
providing a Neuro-2A cells wherein the surface of the cell is targeted by the receptor-targeted nanoplexes;
contacting the cell of step b) with the pharmaceutical composition of step a),
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell, wherein the integration of SO1861 into the nanoplex caused a tremendous shift of the median fluorescence value, and wherein the high transfection efficiency
of the SO1861 sensitized LPDS-nanoplexes is corroborated by the fluorescence
image (page 85, right column, last paragraph, Fig. 10 legend, and Fig. 10). Weng taught the RISC (RNA-Induced-Silencing Complex) is located in the cytosol (page 75-76 bridging paragraph). Weng taught to exert a silencing effect, siRNA has to escape from the endosomes/lysosomes into the cytosol because in lysosomes siRNA/DNA are degraded by nucleases (page 75-76 bridging paragraph). Weng taught: 1) If the endo-/lysosomal escape of the genetic cargo does not occur the siRNA/DNA is degraded within the lysosome thus leading to a therapeutic failure; 2) limited release of siRNA/DNA into the cytosol is one of the major obstacles for efficient siRNA/DNA delivery; and 3) development of innovative strategies to augment the endo-/lysosomal escape of siRNA/DNA and the delivery of a minimal amount of siRNA/DNA are desired for an efficient therapeutic response (page 75-76 bridging paragraph).
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody (page 279, left column, first paragraph). King taught hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating free doxorubicin payload (page 279, left column, first paragraph). King taught BR96-DOX conjugates produced antigen-specific antitumor activity and were more potent, were more active, and produced less systemic toxicity than unconjugated DOX in vivo(page 279, left column, first paragraph). King taught the branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a doxorubicin and antibody basis (abstract). King taught the linear and branched hydrazone antibody payload conjugates were effective in cancer cells (Table 3).
Regarding instant claims 57-60, 62-65, 67-74, and 76-77, it would have been obvious for a person having ordinary skill in the art to take copending claims:
1, 2, 7, 14, 17, 28 of ‘104;
1, 5, 8, 11, 19, 23, 24, 26 of ‘476;
1, 5, 9, 13, 20, 22-23, and 35 of ‘759; and
1, 4, 5, 9, 13, 20, 22-23, 33, and 43 of ‘019,
of an EGFR or CD71 targeted antibody covalently conjugated to one or more of saponin SO1861 and an siRNA, wherein the bond is a hydrazone or hydrazine bond subject to cleavage under acidic conditions, wherein the aldehyde bond in position C-23 of the saponin is involved in the covalent bond – and:
Prepare a pharmaceutical composition comprising a) an antibody covalently linked to an endosomal escape moiety; and separately b) an antibody covalently linked to an siRNA, and administer it for treatment of cancer as taught by Geall;
Use a VHH CD71 or EFGR targeting moiety as taught by Geall and Heukers; and
Attach the endosomal escape saponin moiety at the C-23 aldehyde to an acid sensitive hydrazone linker of King that was a single or branched polymer for linking the payload
This is obvious because:
Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising: a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and a second conjugate comprising an EGFR targeted antibody covalently linked to melittin, wherein melittin is an endosomolytic moiety that causes endosomal escape agent, Geall taught targeting CD71, and Weng taught SO1861 is an endosomal escape agent;
Heukers taught the bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells. Thus, a VHH conjugate would be obvious for an effective targeting agent for endosomal uptake; and
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload with a single or branched polymer payload were effective in cancer cells and employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the hydrazone linker would release the SO1861 payload in the endosomes/lysosomes, where SO1861 has its effects.
There is a reasonable expectation of success because:
A pharmaceutical composition comprising an endosomal escape moiety and an siRNA on a targeting agent separately was effective wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to a targeted antibody covalently linked to the siRNA alone, and EGFR and CD71 targeted antibodies were both effective;
The bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells. Thus, a VHH receptor targeting moieties are effective; and
Single or branched hydrazone linkers are known to be effective, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the single or branched polymer hydrazone linker would release the SO1861 payload(s) in the endosomes/lysosomes, where SO1861 has its effects.
This would produce a method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination (instant claim 59) comprising two pharmaceutical compositions (instant claim 58) comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR or CD71 (instant claim 62-63 ) targeted VHH (instant claims 60) covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claim 64); and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR or CD71 targeted VHH immunoglobin binding fragment (instant claim 70) covalently linked to a linker and SO1861 (instant claims 68-69) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claim 65) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 67) wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape (instant claim 73 ), wherein EGFR or CD71 is a second cell-surface receptor (instant claim 71 ), wherein the covalently branched polymer linker would comprise more than one saponin molecule (instant claim 76 ), wherein the conjugation site is an aldehyde at position C23 of the aglycone core which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure (instant claim and 74), wherein the EGFR or CD71 molecules are present on the surface of the same cell (instant claims 57 and 77)
Regarding instant claim 78, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of ‘104, ‘476, ‘759, or ‘019 and Geall, Heukers, Weng, and King above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR or CD71 targeted VHH covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR or CD71 targeted VHH immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein EGFR is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR molecules are present on the surface of the same cell,
– and: include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR or CD71 expressing cell to inside of said cell of Weng;
This is obvious because: 1) the method of Weng taught SO1861 was effective at transferring oligonucleotides into cells when targeted to the cell, Thus, the two compositions comprising SO1861 or an siRNA effector could be used for transferring nucleotides into the cell.
There is a reasonable expectation of success because: 1) SO1861 is a known endosomal escape agent that can effectively increase the effectiveness of oligonucleotide effector into the cell and the VHH would target the agents to the cells for internalization to the endosome..
This would produce an in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR expressing cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a first pharmaceutical composition a first conjugate comprising a single domain EGFR or CD71 targeted VHH covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
providing a pharmaceutical composition comprising a second pharmaceutical composition a second conjugate comprising a single domain EGFR or CD71 targeted VHH immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein EGFR or CD71 is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR or CD71 molecules are present on the surface of the same cell,
providing a cell that expresses EGFR or CD71 on the surface wherein the surface of the cell is targeted by the pharmaceutical compositions in a) and b);
contacting the cell of step c) in vitro with the pharmaceutical composition of step a) and the pharmaceutical composition of step b).
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-65, 67-74, and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-2, 5, 7, 11, 13-14, 17-19, 23-26, and 28-29 of copending Application No. 17/312,104;
claims 1-2, 5, 8, 10-11, 16-19, 23-26, 29, and 32-33 of copending Application No. 17/312,476;
claims 1, 5-6, 9, 12-13, 20-24, 29-31, 35, 38, and 43 of copending Application No. 17/415,759; or
claims 1-2, 5, 9, 11, 17, 19, 23-24, 26, 28-29, and 39-43 of copending Application No. 17/312,019,
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and Tang J et al. (Oncotarget. 2016 7(23):34070–34083 reference of record).
The claims of copending ‘104, ‘476, ‘759, or ‘019 in view of Geall, Heukers, Weng, and King teach the limitations of claims 57-60, 62-74, and 76-78 for the reasons set forth above.
‘104, ‘476, ‘759, ‘019, Geall, Heukers, Weng, and King are discussed above.
The claims of ‘104, ‘476, ‘759, and ‘019 did not teach the first conjugate comprises at least two sdAbs that were the same, but this is obvious in view of Tang.
Tang taught an effective method of administering a subject with cancer a monospecific bivalent CD7 single domain antibody conjugated immunotoxin PG002 that increased survival of the subject (abstract and Fig. 6), wherein the monospecific bivalent CD7 single domain antibody comprised the same single domain antibody (Fig. 4A). Tang taught a key property of CD7 for therapeutic applications in cancer cases is its rapid internalization after binding to an antibody or antibody derivative which makes it well suited for drug delivery (page 34071, left column, last paragraph). Tang taught to improve the cell-binding affinity and in vivo half-life of the monovalent single domain antibody-based immunotoxin PG001, as well as to potently induce leukemia cell apoptosis, construction of a bivalent nanobody-based immunotoxin with a longer half-life and greater cell-binding affinity was necessary, wherein the bivalent monospecific single domain conjugate PG002 was produced.
Regarding instant claim 61, it would have been obvious for a person having ordinary skill in the art to take the method of ‘104, ‘476, ‘759, or ‘019, and Geall, Heukers, Weng, and King above and in the pharmaceutical composition: – 1) exchange the EGFR or CD71 targeting sdAb of the first and second conjugate with the monospecific bivalent CD7 single domain antibody of Tang.
This is obvious because: 1) Tang taught administering a subject with cancer a monospecific bivalent CD7 single domain antibody conjugated immunotoxin PG002 was effective at increasing survival of the subject, wherein the monospecific bivalent CD7 single domain antibody comprised the same single domain antibody.
There is a reasonable expectation of success because: 1) Tang taught a key property of CD7 for therapeutic applications in cancer cases is its rapid internalization after binding to an antibody or antibody derivative which makes it well suited for drug delivery and the monospecific bivalent CD7 was to improve the cell-binding affinity and in vivo half-life of the monovalent single domain.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-65 and 67-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-2, 5, 7, 11, 13-14, 17-19, 23-26, and 28-29 of copending Application No. 17/312,104;
claims 1-2, 5, 8, 10-11, 16-19, 23-26, 29, and 32-33 of copending Application No. 17/312,476;
claims 1, 5-6, 9, 12-13, 20-24, 29-31, 35, 38, and 43 of copending Application No. 17/415,759; or
claims 1-2, 5, 9, 11, 17, 19, 23-24, 26, 28-29, and 39-43 of copending Application No. 17/312,019,
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and US 2004/0242502 (Marciani D et al. reference of record).
The claims of copending ‘104, ‘476, ‘759, or ‘019 in view of Geall, Heukers, Weng, and King teach the limitations of claims 57-60, 62-74, and 76-78 for the reasons set forth above.
‘104, ‘476, ‘759, ‘019, Geall, Heukers, Weng, and King are discussed above.
The claims of ‘104, ‘476, ‘759, and ‘019 did not teach conjugation of the endosomal escape moiety at a C23 of an aglycone core or C3beta-OH glucuronic acid group of a saponin, but this is obvious in view of Marciani.
Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid (pages 13-16, Schemes 1a-c). Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core (pages 23-25, Schemes 5a-b).
Regarding instant claims 75, it would have been obvious for a person having ordinary skill in the art to take the method of ‘104, ‘476, ‘759, or ‘019, and Geall, Heukers, Weng, and King above and in the pharmaceutical composition: – 1) covalently conjugate the linear or branched polymer acid sensitive hydrazone linker that releases the SO1861 payload(s) to cause endosomal escape at: 1) the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, as taught by Marciani.
This is obvious because: 1) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid.
There is a reasonable expectation of success because: 1) the linear or branched polymer acid sensitive hydrazone linker connected at the C3beta-OH of SO1861 would connect to the carbonyl and release the payload under acidic conditions to allow the SO1861 to perform the endosomal escape of the siRNA.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-65, 67-74 and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 57-59, 61, 64-65, 67-78 of copending Application No. 18/012,754;
claims 57-77 of copending Application No. 18/012,723; or
claims 57-80 of copending Application No. 18/012,729.
in view of US 2017/0281795 (Geall AJ et al. reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), and King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record).
‘754 copending claims 57-59, 61, 64-65, 67-78 claim a pharmaceutical combination comprising: - a first conjugate comprising an effector molecule and a single-domain antibody VHH that binds CD71 for binding to a first cell-surface molecule CD71, wherein the effector molecule and the sdAb are covalently linked to each other and wherein the effector molecule comprises or consists of a nucleic acid 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;
‘754 taught a pharmaceutical combination comprising: -a first conjugate comprising an effector molecule and a single-domain antibody VHH that binds CD71 for binding to a first cell-surface molecule CD71, wherein the effector molecule and the sdAb are covalently linked to each other and wherein the effector molecule comprises or consists of a nucleic acid 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; in copending claim 57, wherein the pharmaceutical combination comprises two pharmaceutical compositions, wherein the first pharmaceutical composition comprises the first conjugate; and the second pharmaceutical composition comprises the saponin and/or the modified saponin in copending claim 58, wherein the first conjugate and the modified saponin are provided in a single pharmaceutical composition in copending claim 59, wherein two sdAbs are the same or are capable of binding to the same binding site on the first cell-surface molecule in copending claim 61, wherein the effector molecule is an siRNA in copending claims 64-65, wherein the modified saponin is a modified quillaic acid wherein the aldehyde group in position C-23 of quillaic acid is chemically modified by transformation into a hydrazone bond in copending claim 67, 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-s-maleimidocaproic acid hydrazide (EMCH) in copending claim 69, 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 in copending claim 70 wherein the saponin is SO1861 in copending claims 71-74. ‘754 taught a method of treating a disease of cancer in a patient in need thereof comprising administering to the patient an effective amount of the pharmaceutical combination of claim 57 in copending claim 75.
‘754 taught 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 above; 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 in copending claim 76.
‘723 copending claims 57-76 claim 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 bidesmosidic triterpene glycoside.
‘723 taught 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 in copending claim 5, wherein the sdAb is a VHH domain in copending claim 58, wherein the conjugate comprises at least two sdAbs, wherein two sdAbs are the same in copending claim 59, wherein the cell-surface molecule is a cell-surface receptor and/or a tumor-cell specific receptor in copending claim 60, wherein the sdAb anti-EGFR sdAb in copending claim 61, wherein the sdAb is an anti-CD71 sdAb in copending claim 62, wherein the oligonucleotide is an siRNA in copending claim 63, wherein gene silencing targets are further claimed in copending claim 64, wherein the saponin comprises a quillaic acid aglycone core structure 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 in copending claim 66, wherein the saponin is SO1861 in copending claims 68-69, wherein the effector molecule is covalently bound to the sdAb and/or to the saponin in copending claim 70, wherein the linker covalently binding the saponin is an acid-sensitive linker in copending claim 71, wherein the acid-sensitive linker is covalently bound to the saponin at position C23 of the aglycone core structure via an acid-sensitive bond in copending claim 71, wherein the conjugate further comprises an oligomeric or polymeric molecule to which more than one saponin is bound in copending claim 74.
‘723 taught a method for treating a disease of cancer in a patient in need thereof comprising administering to the patient an effective amount of 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 in copending claim 76.
‘723 taught an in vitro method for transferring an oligonucleotide from outside a cell to inside said cell comprising:
providing the conjugate of
- 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;
- providing a cell which expresses on its surface the binding site for the sdAb of the conjugate; and contacting the cell with the conjugate in copending claim 77
‘729 copending claims 57-80 claimed a conjugate for transferring an effector molecule from outside a cell into said cell, the conjugate comprising: a) an effector molecule that is a pharmaceutically active substance; b) at least one single-domain antibody capable of binding to a binding site on a cell-surface molecule of said cell; and c) 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.
‘729 taught a conjugate for transferring an effector molecule from outside a cell into said cell, the conjugate comprising: a) an effector molecule that is a pharmaceutically active substance; b) at least one single-domain antibody capable of binding to a binding site on a cell-surface molecule of said cell; and c) 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 in copending claim 57, wherein the sdAb is a VHH domain in copending claim 58, wherein the conjugate comprises at least two sdAb that are the same in copending claim 59, wherein the cell surface molecule is a cell surface receptor in copending claim 60, wherein the sdAb is an antiCD71 antibody or an ant-EGFR antibody in copending claim 61, wherein the oligonucleotide is a nucleic acid in copending claim 63, wherein the oligonucleotide is a siRNA in copending claim 65, wherein the saponin is SO1861 in copending claims 72-73, wherein the effector molecule is covalently bound to the sdAb and to the saponin in copending claim 74, wherein the linker covalently bound to the saponin is an acid sensitive linker in copending claim 75, wherein the saponin comprises the first saccharide chain bound at the C3beta-OH group of the aglycone core structure and the first saccharide chain comprises a glucuronic acid moiety, wherein the saponin is covalently bound to the sdAb and/or the effector molecule via carboxyl group of the glucuronic acid moiety in the first saccharide chain, optionally via a linker covalently bound to the saponin that is an acid sensitive linker in copending claim 76,
‘729 taught a method of treating the disease of cancer by administering a conjugate for transferring an effector molecule from outside a cell into said cell, the conjugate comprising: a) an effector molecule that is a pharmaceutically active substance; b) at least one single-domain antibody capable of binding to a binding site on a cell-surface molecule of said cell; and c) 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 in copending claim 76.
‘729 taught an in vitro method for transferring an oligonucleotide from outside a cell to inside said cell comprising: a) providing the conjugate above; 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 in copending claim 80.
While the claims of ‘754, ‘723, and ‘729 taught embodiments of a CD71 targeted antibody covalently conjugated to one or more of saponin SO1861 and an siRNA, wherein the bond can undergo cleavage under acidic conditions, they did not teach the conjugates as separate saponin and siRNA conjugates on different molecules, but this is obvious in view of Geall, Weng, and King.
Regarding instant claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising:
a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second conjugate comprising an EGFR targeted antibody covalently linked to melittin (page 148, [0689]),
wherein melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]), wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to an EGFR targeted antibody covalently linked to the siRNA alone (Fig. 33). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the endosomolytic moiety as an endosomolytic small molecule and an endosomolytic polymer (page 73, [0389]). Geall taught targeting CD71 with an antibody siRNA conjugate (Fig. 54), wherein the CD71 targeting antibody siRNA conjugate effectively silenced HPRT expression (Fig. 86).
Weng taught the glycoside saponin SO1861 greatly improves the efficacy of lipid based as well as non-lipid based targeted nanoplexes consisting of a targeted K16 peptide with a nucleic acid binding domain and plasmid-DNA, minicircle-DNA or small interfering RNA (siRNA) (abstract). Weng taught SO1861 augments the escape of the genetic cargo out of the intracellular compartments into the cytosol (abstract). Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes (abstract), wherein the lumen of the endosomes and lysosomes are acidified (page 75, right column, last paragraph). Weng taught that SO1861 integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties (page 85, right column, last paragraph and Fig. 10). Weng taught that SO1861 in combination with siRNA increased siRNA silencing in cancer cells (page 85, left to right column, bridging paragraph and Fig. 9).
Weng taught an effective in vitro method for transferring an oligonucleotide effector molecule from outside a Neuro-2A cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a conjugate comprising SO1861 sensitized receptor-targeted nanoplexes and an oligonucleotide effector of EGFP;
providing a Neuro-2A cells wherein the surface of the cell is targeted by the receptor-targeted nanoplexes;
contacting the cell of step b) with the pharmaceutical composition of step a),
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell, wherein the integration of SO1861 into the nanoplex caused a tremendous shift of the median fluorescence value, and wherein the high transfection efficiency
of the SO1861 sensitized LPDS-nanoplexes is corroborated by the fluorescence
image (page 85, right column, last paragraph, Fig. 10 legend, and Fig. 10). Weng taught the RISC (RNA-Induced-Silencing Complex) is located in the cytosol (page 75-76 bridging paragraph). Weng taught to exert a silencing effect, siRNA has to escape from the endosomes/lysosomes into the cytosol because in lysosomes siRNA/DNA are degraded by nucleases (page 75-76 bridging paragraph). Weng taught: 1) If the endo-/lysosomal escape of the genetic cargo does not occur the siRNA/DNA is degraded within the lysosome thus leading to a therapeutic failure; 2) limited release of siRNA/DNA into the cytosol is one of the major obstacles for efficient siRNA/DNA delivery; and 3) development of innovative strategies to augment the endo-/lysosomal escape of siRNA/DNA and the delivery of a minimal amount of siRNA/DNA are desired for an efficient therapeutic response (page 75-76 bridging paragraph).
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody (page 279, left column, first paragraph). King taught hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating free doxorubicin payload (page 279, left column, first paragraph). King taught BR96-DOX conjugates produced antigen-specific antitumor activity and were more potent, were more active, and produced less systemic toxicity than unconjugated DOX in vivo(page 279, left column, first paragraph). King taught the branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a doxorubicin and antibody basis (abstract). King taught the linear and branched hydrazone antibody payload conjugates were effective in cancer cells (Table 3).
Regarding instant claims 57-65, 67-74, and 76-77, it would have been obvious for a person having ordinary skill in the art to take copending claims:
57, 59, 61, 64-65, 69, 71-74, and 75 of ‘754;
57-63, 66, 68-71, 74 of ‘723; and
57-63, 65, 72-76 of ‘729,
of a method of treating a disease of cancer in a patient in need thereof comprising administering to the patient an effective amount of the pharmaceutical combination comprising:
- a VHH conjugate comprising two sdAbs that are the same that target EGFR or CD71 comprising an effector molecule and a saponin, wherein the effector molecule and the sdAb are covalently linked to each other and wherein the effector molecule comprises an siRNA, wherein the saponin is SO1861 conjugated via an acid sensitive linker, – and:
Prepare a pharmaceutical composition comprising a) an antibody covalently linked to an endosomal escape moiety; and separately b) an antibody covalently linked to an siRNA, wherein the antibody may be an EGFR targeted VHH if not a CD71 VHH, and administer it for treatment of cancer as taught by Geall;
Attach the endosomal escape saponin moiety at the C-23 aldehyde to an acid sensitive hydrazone linker of King that was a single or branched polymer for linking the payload
This is obvious because:
Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising: a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and a second conjugate comprising an EGFR targeted antibody covalently linked to melittin, wherein melittin is an endosomolytic moiety that causes endosomal escape agent, Geall taught targeting CD71, and Weng taught SO1861 is an endosomal escape agent;
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload with a single or branched polymer payload were effective in cancer cells and employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the hydrazone linker would release the SO1861 payload in the endosomes/lysosomes, where SO1861 has its effects.
There is a reasonable expectation of success because:
A pharmaceutical composition comprising an endosomal escape moiety and an siRNA on a targeting agent separately was effective wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to a targeted antibody covalently linked to the siRNA alone, and EGFR and CD71 targeted antibodies were both effective;
Single or branched hydrazone linkers are known to be effective, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the single or branched polymer hydrazone linker would release the SO1861 payload(s) in the endosomes/lysosomes, where SO1861 has its effects.
This would produce a method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination (instant claim 59) comprising two pharmaceutical compositions (instant claim 58) comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR or CD71 (instant claim 62-63 ) targeted VHH (instant claims 60) covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claim 64); and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR or CD71 targeted VHH immunoglobin binding fragment (instant claim 70) comprising two sdAb that are the same (instant claim 61) covalently linked to a linker and SO1861 (instant claims 68-69) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claim 65) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 67) wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape (instant claim 73 ), wherein EGFR or CD71 is a second cell-surface receptor (instant claim 71 ), wherein the covalently branched polymer linker would comprise more than one saponin molecule (instant claim 76 ), wherein the conjugation site is an aldehyde at position C23 of the aglycone core which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure (instant claim and 74), wherein the EGFR or CD71 molecules are present on the surface of the same cell (instant claims 57 and 77).
Regarding instant claim 78, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of ‘754, ‘723, or ‘729 and Geall, Weng, and King above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR or CD71 targeted VHH covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR or CD71 targeted VHH immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein EGFR is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR molecules are present on the surface of the same cell,
– and: 1) use it in the in vitro method taught by: A) ‘754 copending claim 76; B) ‘723 copending claim 76; or C) ‘729 copending claim 80, comprising:
an in vitro method for transferring an oligonucleotide from outside a cell to inside said cell comprising:
a) providing the conjugate above;
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; and
2) include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR or CD71 expressing cell to inside of said cell of Weng;
This is obvious because the copending applications taught an in vitro method and: 1) the method of Weng taught SO1861 was effective at transferring oligonucleotides into cells when targeted to the cell, Thus, the two compositions comprising SO1861 or an siRNA effector could be used for transferring nucleotides into the cell.
There is a reasonable expectation of success because: 1) SO1861 is a known endosomal escape agent that can effectively increase the effectiveness of oligonucleotide effector into the cell and the VHH would target the agents to the cells for internalization to the endosome.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-65 and 67-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 57-59, 61, 64-65, 67-78 of copending Application No. 18/012,754;
claims 57-77 of copending Application No. 18/012,723; or
claims 57-80 of copending Application No. 18/012,729.
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and US 2004/0242502 (Marciani D et al. reference of record).
The claims of copending ‘754, ‘723, or ‘729 in view of Geall, Weng, and King teach the limitations of claims 57-74 and 76-78 for the reasons set forth above.
‘754, ‘723, or ‘729, Geall, Weng, and King are discussed above.
The claims of ‘754, ‘723, or ‘729 did not teach conjugation of the endosomal escape moiety at a C23 of an aglycone core or C3beta-OH glucuronic acid group of a saponin, but this is obvious in view of Marciani.
Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid (pages 13-16, Schemes 1a-c). Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core (pages 23-25, Schemes 5a-b).
Regarding instant claim 75, it would have been obvious for a person having ordinary skill in the art to take the method of ‘754, ‘723, or ‘729, and Geall, Weng, and King above and in the pharmaceutical composition: – 1) covalently conjugate the linear or branched polymer acid sensitive hydrazone linker that releases the SO1861 payload(s) to cause endosomal escape at: 1) the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, as taught by Marciani.
This is obvious because: 1) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid.
There is a reasonable expectation of success because: 1) the linear or branched polymer acid sensitive hydrazone linker connected at the C3beta-OH of SO1861 would connect to the carbonyl and release the payload under acidic conditions to allow the SO1861 to perform the endosomal escape of the siRNA.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-60, 62, 64-65, and 67-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-6, 8-9, 11-14, 17, 21-26, and 54 of copending Application No. 18/012,760;
claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, 49-50 of copending Application No. 17/312,193; or
claims 29-31, 37, 39, 41, 45-50, 52, and 58-64 of copending Application No. 18/723,163;
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), and US 2004/0242502 (Marciani D et al. reference of record).
Copending ‘760 claims 1-6, 8-9, 11-14, 17, 21-26, and 54 claimed a therapeutic or pharmaceutical combination comprising: (a) a first pharmaceutical composition comprising a conjugate comprising a first binding molecule comprising a first binding region for binding to a first binding site of a cell- surface molecule and the conjugate comprising at least one saponin covalently bound to said first binding molecule, wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside; and (b) a second pharmaceutical composition comprising a conjugate comprising a second binding molecule different from the first binding molecule, the second binding molecule comprising a second binding region different from the first binding region, the second binding region for binding to a second binding site of said cell-surface molecule different from the first binding site of said cell-surface molecule, and the conjugate comprising an effector molecule covalently bound to said second binding molecule,
‘760 taught a therapeutic or pharmaceutical combination comprising: (a) a first pharmaceutical composition comprising a conjugate comprising a first binding molecule comprising a first binding region for binding to a first binding site of a cell- surface molecule and the conjugate comprising at least one saponin covalently bound to said first binding molecule, wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside; and (b) a second pharmaceutical composition comprising a conjugate comprising a second binding molecule different from the first binding molecule, the second binding molecule comprising a second binding region different from the first binding region, the second binding region for binding to a second binding site of said cell-surface molecule different from the first binding site of said cell-surface molecule, and the conjugate comprising an effector molecule covalently bound to said second binding molecule in copending claims 1-2, wherein the first and second binding molecules are proteinaceous binding molecules in copending claim 3, wherein the saponin of the first binding molecule is covalently bound in copending claim 4, wherein the first binding site is a first epitope of said cell surface molecule and the second binding site is a second epitope of the same cell surface molecule that is a different epitope from the first epitope in copending claim 5, wherein the saponin is a bisdesomsidic triterpene saponin in copending claim 6, wherein the first and second binding sites are a VHH in copending claim 9, wherein the first and second binding sites simultaneously bind the same cell surface molecule at the first and second binding site in copending claim 11, wherein the saponin is SO1861 in copending claim 17, wherein the saponin is a bisdesomsidic triterpene saponin with an aldehyde at C23 of the aglycone core that is covalently bound to the first binding molecule in copending claim 21, wherein the aldehyde is covalently bound to the linker EMCH via a thioether sulfhydryl in copending claim 22, wherein the saponin is a bisdesomsidic triterpene saponin with an aldehyde at C23 of the aglycone core with a C3beta OH saccharide glucuronic acid that is covalently bound to the first binding molecule in copending claim 23,
Copending ‘193 claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, and 49-50 claimed a first proteinaceous molecule comprising a first binding site for binding to a first epitope of a first cell-surface molecule, the first proteinaceous molecule provided with at least one saponin covalently bound via at least one linker or via an oligomeric or polymeric scaffold to an amino-acid residue of said first proteinaceous molecule, wherein the first binding site comprises a binding fragment of an immunoglobin.
‘193 taught a first proteinaceous molecule comprising a first binding site for binding to a first epitope of a first cell-surface molecule, the first proteinaceous molecule provided with at least one saponin covalently bound via at least one linker or via an oligomeric or polymeric scaffold to an amino-acid residue of said first proteinaceous molecule, wherein the first binding site comprises a binding fragment of an immunoglobin in copending claim 1, wherein the saponin is SO1861 in copending claim 4, wherein the saponin is a bidesmosidic triterpene glycoside with an aldehyde function in position C-23 covalently coupling the saponin to the proteinaceous molecule in copending claim 7, wherein the saponin is a bidesmosidic triterpene glycoside with an aldehyde function in position C-23 and a C3beta-OH glucuronic acids that covalently couples the saponin to the proteinaceous molecule in copending claim 8, wherein the C-23 linker is N-e-maleimidocaproic acid hydrazide, which is acid labile and covalently coupled to a sulfhydryl group to the fist proteinaceous molecule in copending claim 9, wherein the C3beta-OH carbohydrate is covalently coupled to a linker to which is further coupled to an amine group of a lysine to the first proteinaceous molecule in copending claim 10, wherein the first epitope of the first cell surface molecule which binds the first proteinaceous molecule is CD71 in copending claim 11, wherein the first proteinaceous molecule is cetuximab in copending claims 13 and 26, wherein the saponin comprises more than one saponin covalently bound to a linker in copending claim 32, wherein the linker is a linker that is subject to cleavage under acidic conditions in copending claims 33-34, and wherein the proteinaceous molecule binds CD71 in copending 43.
‘163 claims 29-31, 37, 39, 41, 45-50, 52, 58-64 claimed a therapeutic combination comprising: a) a nucleic acid; and b) a saponin, wherein the saponin is a triterpenoid 12,13 -dehydrooleanane-type saponin comprising an aldehyde group at position C-23 of the saponin' s aglycone core structure under acidic conditions present in endosomes and/or lysosomes of human cells.
‘163 taught a therapeutic combination comprising: a) a nucleic acid; and b) a saponin, wherein the saponin is a triterpenoid 12,13 -dehydrooleanane-type saponin comprising an aldehyde group at position C-23 of the saponin' s aglycone core structure under acidic conditions present in endosomes and/or lysosomes of human cells in copending claim 29, wherein the aldehyde group at position C-23 of the saponin' s aglycone core structure is either a free aldehyde group, or is an aldehyde group substituted by a maleimide-comprising moiety attached at said position C-23 with a cleavable covalent bond that cleaves off under acidic conditions present in endosomes and/or lysosomes of human cells; and, wherein said aldehyde group at position C-23 of the saponin's aglycone core structure is restored upon said cleavage under acidic conditions present in endosomes and/or lysosomes of human cells in copending claim 30, wherein the maleimide-comprising moiety is a part of a molecule comprising 4- (6-(2,5-dioxo-2,5-dihydro- 1H-pyrrol- 1-yl)hexanoyl)piperazine- 1-carbohydrazide that is attached at position C-23 of the saponin's aglycone core structure upon forming a semicarbazone bond (SC-Maleimide); or wherein the maleimide-comprising moiety is a part of a molecule comprising N-e-maleimidocaproic acid (EMCH) hydrazide that is attached at position C-23 of the saponin's aglycone core structure upon forming a hydrazone bond in copending claim 31, wherein the saponin is SO1861 in copending claim 37, wherein the nucleic acid is siRNA in copending claim 41, wherein the endocytic receptor to which the ligand binds is CD71 in copending claim 45, wherein the ligand is an antibody or a binding fragment thereof specific for binding to the endocytic receptor, wherein the endocytic receptor is CD71 in copending claim 60, and wherein the ligand is a single domain antibody specific for binding to a transferrin receptor in copending claim 62.
‘760, ‘193, or ‘163 did not teach: a) a pharmaceutical composition of a first conjugate comprising a sdAb-siRNA effector and a second conjugate covalently linked to a saponin; or b) a single embodiment of VHH conjugation of the endosomal escape moiety at a C23 of an aglycone core or C3beta-OH glucuronic acid group of a saponin, but this is obvious in view of Geall, Heukers, Weng, King, and Marciani.
Regarding instant claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught an effective method of cancer treatment by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination comprising:
a first conjugate comprising an EGFR targeted antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second conjugate comprising an EGFR targeted antibody covalently linked to melittin (page 148, [0689]),
wherein melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]), wherein the expression of KRAS in the tumor was effectively silenced from 24 to 168 hours and wherein KRAS was decreased more in tumors that were administered the combination compared to an EGFR targeted antibody covalently linked to the siRNA alone (Fig. 33). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-60, 62, 64-65, 67-73, and 76-78, Geall taught the endosomolytic moiety as an endosomolytic small molecule and an endosomolytic polymer (page 73, [0389]). Geall taught targeting CD71 with an antibody siRNA conjugate (Fig. 54), wherein the CD71 targeting antibody siRNA conjugate effectively silenced HPRT expression (Fig. 86).
Heukers taught EGFR-targeted nanobody® VHH single domain conjugates are specific and potently kill cancer cells (abstract and Fig. 2). Heukers taught a biparatopic EGFR-targeted single domain antibody 7D12-9G8 that is known to be internalized (page 1442, left column, first paragraph). Heukers taught 7D12-9G8-PS induces the lysosomal trafficking (page, 1448, right column first paragraph). Heukers taught EGFR-targeted single domain antibodies showed a faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody (page 1442, left column, first paragraph).
Weng taught the glycoside saponin SO1861 greatly improves the efficacy of lipid based as well as non-lipid based targeted nanoplexes consisting of a targeted K16 peptide with a nucleic acid binding domain and plasmid-DNA, minicircle-DNA or small interfering RNA (siRNA) (abstract). Weng taught SO1861 augments the escape of the genetic cargo out of the intracellular compartments into the cytosol (abstract). Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes (abstract), wherein the lumen of the endosomes and lysosomes are acidified (page 75, right column, last paragraph). Weng taught that SO1861 integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties (page 85, right column, last paragraph and Fig. 10). Weng taught that SO1861 in combination with siRNA increased siRNA silencing in cancer cells (page 85, left to right column, bridging paragraph and Fig. 9).
Weng taught an effective in vitro method for transferring an oligonucleotide effector molecule from outside a Neuro-2A cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a conjugate comprising SO1861 sensitized receptor-targeted nanoplexes and an oligonucleotide effector of EGFP;
providing a Neuro-2A cells wherein the surface of the cell is targeted by the receptor-targeted nanoplexes;
contacting the cell of step b) with the pharmaceutical composition of step a),
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell, wherein the integration of SO1861 into the nanoplex caused a tremendous shift of the median fluorescence value, and wherein the high transfection efficiency
of the SO1861 sensitized LPDS-nanoplexes is corroborated by the fluorescence
image (page 85, right column, last paragraph, Fig. 10 legend, and Fig. 10).
Weng taught the RISC (RNA-Induced-Silencing Complex) is located in the cytosol (page 75-76 bridging paragraph). Weng taught to exert a silencing effect, siRNA has to escape from the endosomes/lysosomes into the cytosol because in lysosomes siRNA/DNA are degraded by nucleases (page 75-76 bridging paragraph). Weng taught: 1) If the endo-/lysosomal escape of the genetic cargo does not occur the siRNA/DNA is degraded within the lysosome thus leading to a therapeutic failure; 2) limited release of siRNA/DNA into the cytosol is one of the major obstacles for efficient siRNA/DNA delivery; and 3) development of innovative strategies to augment the endo-/lysosomal escape of siRNA/DNA and the delivery of a minimal amount of siRNA/DNA are desired for an efficient therapeutic response (page 75-76 bridging paragraph).
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody (page 279, left column, first paragraph). King taught hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating free doxorubicin payload (page 279, left column, first paragraph). King taught BR96-DOX conjugates produced antigen-specific antitumor activity and were more potent, were more active, and produced less systemic toxicity than unconjugated DOX in vivo(page 279, left column, first paragraph). King taught the branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a doxorubicin and antibody basis (abstract).
King taught the linear and branched hydrazone antibody payload conjugates were effective in cancer cells (Table 3).
Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid (pages 13-16, Schemes 1a-c). Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core (pages 23-25, Schemes 5a-b).
Regarding instant claims 57-60, 62, 64-65, 67-77, it would have been obvious for a person having ordinary skill in the art to take copending claims:
1-6, 11, 17, 21-23 of ‘760;
1, 4, 7-11, 13, 26, 32-34, and 43 of ‘193;
29-31, 37, 41, 45, 60, 62 of ‘163,
of a therapeutic combination comprising:
a) a nucleic acid of siRNA; and
b) a saponin of SO1861 attached to a binding molecule,
– and:
Prepare a pharmaceutical composition comprising a) an antibody covalently linked to an endosomal escape moiety; and separately b) an antibody covalently linked to an siRNA, and administer it for treatment of cancer as taught by Geall;
Use a VHH CD71 or EFGR targeting moiety as taught by Geall and Heukers;
Attach the endosomal escape saponin moiety at the C-23 aldehyde to an acid sensitive hydrazone linker of King that was a single or branched polymer for linking the payload; and
covalently conjugate the linear or branched polymer acid sensitive hydrazone linker that releases the SO1861 payload(s) to cause endosomal escape at: i) the C23 aldehyde of SO1861; or ii) the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861, as taught by Marciani
This is obvious because:
Geall taught separate siRNA and endosomal escape moieties on antibody conjugates were effective and the antibody as a sdAb and Heukers taught the bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells;
Weng taught the saponin SO1861: i) augments the escape of the genetic cargo out of the intracellular compartments into the cytosol; ii) integrated into a receptor targeted nanoplex improved DNA transfection and provides improved effector properties; and iii) in combination with siRNA increased siRNA silencing in cancer cells;
King taught immunoconjugates of monoclonal antibody BR96 and a doxorubicin payload with a single or branched polymer payload were effective in cancer cells and employed a hydrazone linkage to C-13 of DOX and a thioether linkage to the antibody, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the hydrazone linker would release the SO1861 payload in the endosomes/lysosomes, where SO1861 has its effects; and
i) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is at a carbonyl group of glucuronic acid on a first saccharide at the C3-OH of the aglycone core structure position, wherein the first saccharide comprises glucuronic acid; and 4ii) Marciani taught conjugation of moieties to a saponin wherein the conjugation site is an aldehyde at position C23 of the aglycone core.
There is a reasonable expectation of success because:
The compositions of Geall were effective and the bivalent biparatopic EGFR-targeted single domain antibody 7D12-9G8 was effective and the VHH causes faster accumulation at the tumor, a more homogeneous distribution within the tumor, and a more rapid clearance of unbound molecules, compared to an anti-EGFR monoclonal antibody and is known to go through endosomal clearance and kill cancer cells;
The saponin SO1861 would: i) augment the escape of the siRNA genetic cargo out of the intracellular compartments into the cytosol; ii) improve DNA transfection and provide improved effector properties; and iii) increase siRNA silencing in cancer cells to promote;
Single or branched hydrazone linkers are known to be effective, wherein hydrazone linkers of this nature are stable at normal physiological pH 7, but once internalized into the acidic compartment of endosomes/lysosomes, hydrolysis occurs liberating the free payload. Further, Weng taught SO1861 induces the release of the genetic cargo out of endosomes and lysosomes, wherein the lumen of the endosomes and lysosomes are acidified. Thus, the single or branched polymer hydrazone linker would release the SO1861 payload(s) in the endosomes/lysosomes, where SO1861 has its effects; and
i) and 4ii) the linear or branched polymer acid sensitive hydrazone linker connected at either the C23 aldehyde of SO1861 or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861 would connect to either of the carbonyls and release the payload under acidic conditions to allow the SO1861 to perform the endosomal escape of the siRNA.
This would produce a method of cancer treatment of a subject by silencing a protein in a cancer cell comprising administering a single pharmaceutical combination (instant claim 59) comprising two pharmaceutical compositions (instant claim 58) comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR targeted (instant claim 62 ) VHH 7D12-9G8 antibody (instant claims 60 ) covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claim 64 ); and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody immunoglobin binding fragment (instant claim 70) covalently linked to a linker and SO1861 (instant claims 68-69 ) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claim 65) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 67) wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape (instant claim 73 ), wherein the linker is covalently connected to linear or branched polymer acid sensitive hydrazone linker at either the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the aglycone core structure (instant claim 74) or the first glucuronic acid carbonyl saccharide at the C3beta-OH of SO1861 (instant claim 75), wherein EGFR is a second cell-surface receptor (instant claim 71 ), wherein the covalently branched polymer linker would comprise more than one saponin molecule (instant claim 76 ), wherein the EGFR molecules are present on the surface of the same cell (instant claims 57 and 77)
Regarding instant claim 78, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of ‘760, ‘193, or ‘163 and Geall, Heukers, Weng, and King above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition a second conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein EGFR is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR molecules are present on the surface of the same cell,
– and: include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR expressing cell to inside of said cell of Weng;
This is obvious because: 1) the method of Weng taught SO1861 was effective at transferring oligonucleotides into cells when targeted to the cell, Thus, the two compositions comprising SO1861 or an siRNA effector could be used for transferring nucleotides into the cell.
There is a reasonable expectation of success because: 1) SO1861 is a known endosomal escape agent that can effectively increase the effectiveness of oligonucleotide effector into the cell and the VHH would target the agents to the cells for internalization to the endosome..
This would produce an in vitro method for transferring an oligonucleotide effector molecule from outside an EGFR expressing cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a first pharmaceutical composition a first conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
providing a pharmaceutical composition comprising a second pharmaceutical composition a second conjugate comprising a single domain EGFR targeted VHH 7D12-9G8 antibody immunoglobin binding fragment covalently linked to a linker and SO1861 wherein the linker is a linear or branched polymer acid sensitive hydrazone linker that releases the payload(s) to cause endosomal escape, wherein EGFR is a second cell-surface receptor, wherein the covalently branched polymer linker would comprise more than one saponin molecule, wherein the EGFR molecules are present on the surface of the same cell,
providing a cell that expresses EGFR on the surface wherein the surface of the cell is targeted by the pharmaceutical compositions in a) and b);
contacting the cell of step c) in vitro with the pharmaceutical composition of step a) and the pharmaceutical composition of step b).
therewith establishing the transfer of the oligonucleotide effector from outside the cell into the cell.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-62, 64-65, and 67-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-6, 8-9, 11-14, 17, 21-26, and 54 of copending Application No. 18/012,760;
claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, 49-50 of copending Application No. 17/312,193; or
claims 29-31, 37, 39, 41, 45-50, 52, and 58-64 of copending Application No. 18/723,163;
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Tang J et al. (Oncotarget. 2016 7(23):34070–34083 reference of record).
The claims of copending ‘104, ‘476, ‘759, or ‘019 in view of Geall, Heukers, Weng, King, and Marciani teach the limitations of claims 57-60, 62, 64-65, and 67-78 for the reasons set forth above.
‘104, ‘476, ‘759, or ‘019, Geall, Heukers, Weng, King, and Marciani are discussed above.
‘104, ‘476, ‘759, or ‘019 did not teach the first conjugate comprises at least two sdAbs that were the same, but this is obvious in view of Tang.
Tang taught an effective method of administering a subject with cancer a monospecific bivalent CD7 single domain antibody conjugated immunotoxin PG002 that increased survival of the subject (abstract and Fig. 6), wherein the monospecific bivalent CD7 single domain antibody comprised the same single domain antibody (Fig. 4A). Tang taught a key property of CD7 for therapeutic applications in cancer cases is its rapid internalization after binding to an antibody or antibody derivative which makes it well suited for drug delivery (page 34071, left column, last paragraph). Tang taught to improve the cell-binding affinity and in vivo half-life of the monovalent single domain antibody-based immunotoxin PG001, as well as to potently induce leukemia cell apoptosis, construction of a bivalent nanobody-based immunotoxin with a longer half-life and greater cell-binding affinity was necessary, wherein the bivalent monospecific single domain conjugate PG002 was produced.
Regarding instant claim 61, it would have been obvious for a person having ordinary skill in the art to take the method of ‘104, ‘476, ‘759, or ‘019, Geall, Heukers, Weng, King, and Marciani above and in the pharmaceutical composition: – 1) exchange the EGFR targeting sdAb of the first and second conjugate with the monospecific bivalent CD7 single domain antibody of Tang.
This is obvious because: 1) Tang taught administering a subject with cancer a monospecific bivalent CD7 single domain antibody conjugated immunotoxin PG002 was effective at increasing survival of the subject, wherein the monospecific bivalent CD7 single domain antibody comprised the same single domain antibody.
There is a reasonable expectation of success because: 1) Tang taught a key property of CD7 for therapeutic applications in cancer cases is its rapid internalization after binding to an antibody or antibody derivative which makes it well suited for drug delivery and the monospecific bivalent CD7 was to improve the cell-binding affinity and in vivo half-life of the monovalent single domain.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Claims 57-60, 62-65, 67-73, and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-6, 8-9, 11-14, 17, 21-26, and 54 of copending Application No. 18/012,760;
claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, 43, 49-50 of copending Application No. 17/312,193; or
claims 29-31, 37, 39, 41, 45-50, 52, and 58-64 of copending Application No. 18/723,163;
in view of US 2017/0281795 (Geall AJ et al. reference of record), Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), King HD et al. (Bioconjugate Chem. 1999, 10, 2, 279–288 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Deken MM et al. (J Control Release. 2020 Apr 21;323:269–281 reference of record).
The claims of copending ‘104, ‘476, ‘759, or ‘019 in view of Geall, Heukers, Weng, King, and Marciani teach the limitations of claims 57-60, 62, 64-65, and 67-78 for the reasons set forth above.
‘104, ‘476, ‘759, or ‘019, Geall, Heukers, Weng, King, and Marciani are discussed above.
Geall taught the targeting antibody as trastuzumab or binding fragment thereof as trastuzumab which targets HER2 (page 66, [0343])
‘104, ‘476, ‘759, or ‘019 did not teach the first conjugate as a single embodiment of a HER2 targeting sdAb, but this is obvious in view of Deken.
Deken taught HER2-targeted nanobodies® VHHs 1D5 and 1D5-18A12 were conjugated to a photosensitizer and administered to subjects with cancer, wherein both VHH-PS conjugates potently and selectively induced cell death of HER2 overexpressing cells in vitro and in vivo (abstract). Deken taught the 18A12 VHH showed a slightly higher internalization rate as compared to 1D5, while the biparatopic VHH 1D5-18A12 showed a ten-fold increase in internalization, compared to 1D5 (page 274, right column, fourth paragraph). Deken taught internalization of the payload was achieved by employing a biparatopic VHH, which is known to promote receptor-mediated internalization (page 278, left column, last paragraph). The bivalent nanobody-PS in this study led to a higher internalization rate constant of the HER2, in comparison to a monovalent counterpart (page 278, left column, last paragraph).
Regarding instant claim 63, it would have been obvious for a person having ordinary skill in the art to take the method of ‘104, ‘476, ‘759, or ‘019 and Geall, Heukers, Weng, King, and Marciani above and in the pharmaceutical composition: – 1) exchange the EGFR targeting sdAb of the first and second conjugate with the single domain HER2 biparatopic VHH 1D5-18A12 antibody of Deken.
This is obvious because Geall taught the antibody could be an antibody that targets HER2 and: 1a) Deken taught the HER2-targeted VHH 1D5-18A12 conjugated to a toxic payload was effective when administered to subjects with cancer, wherein both the conjugate potently and selectively induced cell death of HER2 overexpressing cells in vitro and in vivo; and 1b) Deken taught the biparatopic VHH 1D5-18A12 was effectively internalized.
There is a reasonable expectation of success because: 1a) Deken taught the HER2-targeted VHH 1D5-18A12 conjugated to a toxic payload was effective when administered to subjects with cancer, wherein both the conjugate potently and selectively induced cell death of HER2 overexpressing cells in vitro and in vivo; and 1b) Deken taught the biparatopic VHH 1D5-18A12 was effectively internalized. Thus, the sdAb targeting HER2 internalize the siRNA and SO1861 for release.
Response to Arguments
Without conceding to the propriety of the rejection, Applicant respectfully requests that the rejection of instant claims 57-65 and 67-78 be held in abeyance until otherwise allowable patentable subject matter has been identified in the instant application.
In response, Applicant's arguments filed 1/20/2026 have been fully considered
but they are not persuasive. Independent claim 57 has been amended and the updated rejection is above. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see 37 CFR 1.111(b) and MPEP §714.02).
Conclusion
Claims 57-65 and 67-78 are rejected.
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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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643