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 57-59, 61, 64-65, and 67-76 are pending in the instant application.
Claims 77-78 are canceled.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/7/2026 has been entered.
Claim Objections and Rejections Withdrawn
The rejections to claims 77-78 are moot in view of claim cancelation.
The rejections to claims 57-59, 61, 64-65, and 67-76 under 35 USC §103 are withdrawn in view of claim amendment.
The rejections to claims 57-59, 61, 64-65, and 67-76 under Nonstatutory Double Patenting are withdrawn in view of claim amendment.
Claims Rejections Necessitated by 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.
Claim 76 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 76, an in vitro method is claimed for transferring an effector molecule comprising or consisting of a nucleic acid or xeno nucleic acid from outside a cell to inside said cell, but the method requires a conjugate that comprises a nucleic acid conjugated to a VHH that binds CD71. Thus, the claim is indefinite and metes and bounds are unclear for an effector molecule that consists of a nucleic acid or xeno nucleic acid because only a conjugate is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 67 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 67 requires selection of a modified quillaic acid or modified gypsogenin wherein the aldehyde group in position C-23 of quillaic acid is chemically modified by transformation into a hydrazone bond, but parental claim 57 already requires 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. Thus, the claim fails to further narrow the independent claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 75-76 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding instant claim 75, the method is not required to express CD71 or the target of the second conjugate, but the first conjugate comprises a VHH that targets CD71 conjugated to a nucleic acid and the second conjugate targets a second cell surface molecule conjugated to a saponin. If the disease does not express CD71 or the target of the second conjugate then the conjugates would not target the disease effectively;
Regarding instant claim 76, the cell is only required to express the cell surface molecule of the first conjugate, not the second conjugate. If the cell does not express CD71 and the target of the second conjugate then the cell would not be targeted by both conjugates.
Scope of the claimed genus
Regarding instant claim 75, a method of treating a disease in a patient in need thereof is claimed comprising administering an effective amount of a pharmaceutical combination comprising; i) a first conjugate comprising a VHH that binds CD71 covalently linked to a nucleic acid; and ii) a second conjugate which binds a second cell-surface molecule comprising a modified saponin, but the disease is not required to express CD71 or the target of the second conjugate;
Regarding instant claim 76, an in vitro method for transferring an effector molecule is claimed comprising providing first and second conjugates to a cell, but the cell is only required to express the cell surface molecule of the first conjugate, not the second conjugate.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
1)-2) The specification identifies A2058 cells which have low expression of HER2 and EGFR are not effectively treated with an HER2 or EGFR antibody conjugated to SO1861 in combination with a HER2 or EGFR antibody conjugated to an effector toxin molecule in Tables A6-A7 (pages 90-91). The specification showed the combination of EGFR targeted cetuximab conjugated to SO1861 and cetuximab conjugated to HSP27BNA oligo was effective at decreasing HSP27 mRNA in A431 tumors (page 96 Example 12 and Fig. 18). Table A6 identifies that A431 cells express high levels of EGFR (specification page 90). Thus, the specification identifies that only cells that express the cell surface targets of both conjugates are effectively targeted by the first and second conjugates.
State of the Relevant Art
1)-2) Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record) 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). The prior art has not taught that conjugates that bind cell surface molecules such as CD71 or other cell surface molecules are effective in diseases or at binding cells that do not express the cell surface targets of the conjugates.
Claims 75-76 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: 1) a method of treating a disease that expressed CD71 and the second cell surface molecule; and 2) an in vitro method for transferring an effector molecule comprising a nucleic acid or xeno nucleic acid from outside a cell that expresses CD71 and the second cell surface molecule, does not reasonably provide enablement for 1) a method of treating a disease that is not required to express CD71 and the second cell surface molecule; and 2) an in vitro method for transferring an effector molecule comprising a nucleic acid or xeno nucleic acid from outside a cell that is not required to express CD71 and the second cell surface molecule. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding instant claim 75, the method is not required to express CD71 or the target of the second conjugate, but the first conjugate comprises a VHH that targets CD71 conjugated to a nucleic acid and the second conjugate targets a second cell surface molecule conjugated to a saponin. If the disease does not express CD71 or the target of the second conjugate then the conjugates would not target the disease effectively;
Regarding instant claim 76, the cell is only required to express the cell surface molecule of the first conjugate, not the second conjugate. If the cell does not express CD71 and the target of the second conjugate then the cell would not be targeted by both conjugates.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Regarding instant claim 75, a method of treating a disease in a patient in need thereof is claimed comprising administering an effective amount of a pharmaceutical combination comprising; i) a first conjugate comprising a VHH that binds CD71 covalently linked to a nucleic acid; and ii) a second conjugate which binds a second cell-surface molecule comprising a modified saponin, but the disease is not required to express CD71 or the target of the second conjugate;
Regarding instant claim 76, an in vitro method for transferring an effector molecule is claimed comprising providing first and second conjugates to a cell, but the cell is only required to express the cell surface molecule of the first conjugate, not the second conjugate.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
1)-2) The specification identifies A2058 cells which have low expression of HER2 and EGFR are not effectively treated with an HER2 or EGFR antibody conjugated to SO1861 in combination with a HER2 or EGFR antibody conjugated to an effector toxin molecule in Tables A6-A7 (pages 90-91). The specification showed the combination of EGFR targeted cetuximab conjugated to SO1861 and cetuximab conjugated to HSP27BNA oligo was effective at decreasing HSP27 mRNA in A431 tumors (page 96 Example 12 and Fig. 18). Table A6 identifies that A431 cells express high levels of EGFR (specification page 90). Thus, the specification identifies that only cells that express the cell surface targets of both conjugates are effectively targeted by the first and second conjugates.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
1)-2) Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record) 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). The prior art has not taught that conjugates that bind cell surface molecules such as CD71 or other cell surface molecules are effective in diseases or at binding cells that do not express the cell surface targets of the conjugates.
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 57-59, 61, 64-65, 67-68, and 70-76 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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Yu X et al. (Nat Commun. 2019 Feb 4;10:574).
Regarding instant claims 57-59, 64-65, 67-68, and 70-75, 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 57-59, 64-65, 67-68, and 70-75, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-59, 64-65, 67-68, and 70-75, 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 pharmaceutical composition of a first conjugate comprising a sdAb-siRNA effector and a saponin that was a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside with a hydrazone bond conjugated to the endosomal escape moiety at a C23 of an aglycone core, but this is obvious in view of Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu.
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).
Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same (abstract and Fig. 2E).
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).
Firestone taught BR96-Dox is an immunoconjugate in which doxorubicin is linked via an acid-labile hydrazone to the chimeric MAb BR96 (abstract). Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free Dox (abstract). Firestone taught BR96-Dox was more effective at killing tumors in vivo with less toxicity and more activity when compared to untargeted Dox (abstract).
Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is reasonably stable at neutral pH, but released rapidly within lysosomes, where the pH is about 5 (page 252, right column, first paragraph).
Firestone taught BR96 DOX comprised a linker of 6-Maleimidocaproylhydrazone (page 253, left column, second paragraph).
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).
Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) (page 2, left to right bridging column). Yu taught an agent comprising melittin was specifically targeted to LSEC in vivo (page 3-4, bridging paragraph and Fig. 1).
Regarding instant claims 57-59, 61, 64-65, 67-68, and 70-75, 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 CD71 targeted single domain antibody for targeting CD71 expressing cancer cells, wherein the bivalent antibodies are the same in view of Geall, Niewoehner, and Heukers;
Exchange the endosomal escape molecule melittin for the endosomal escape molecule glycoside saponin SO1861 in view of Weng and Yu;
Exchange the attachment linker of the endosomal escape moiety for an acid sensitive hydrazone linker of Firestone for linking the payload;
covalently conjugate the acid sensitive hydrazone linker that releases the SO1861 payload to cause endosomal escape at the C23 aldehyde of SO1861 as taught by Marciani.
This is obvious because:
i) Geall taught the antibody as targeting CD71 with an antibody siRNA conjugate effectively and as a sdAb; ii) Heukers taught a 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; and iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a bivalent CD71 sdAb would be obvious and expected to be effective;
a) 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; and b) Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) and agents comprising melittin were specifically targeted to LSEC in vivo. Thus, exchange of one endosomal escape agent that has liver targeting properties for another would be obvious;
Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free payload effectively into the cancer cells. Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is stable at neutral pH, but released rapidly within lysosomes. 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
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:
i) Geall taught the antibody as targeting CD71 with an antibody siRNA conjugate effectively; ii) Heukers taught a 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; and iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a bivalent CD71 VHH sdAb would be obvious and expected to be effective;
a) 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; and b) exchange of an antibody-melittin conjugate for an antibody-SO1861 conjugate would decrease liver targeting due to melittin. Thus, tumors would be more specifically targeted with an effective agent that increases siRNA delivery to the cytosol of cancer cells for improved effector properties;
Hydrazone linkers are known to be effective, wherein hydrazone linkers are stable a neutral pH of 7, but once internalized into the acidic conditions, the payload is released into cancer cells. 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(s) in the endosomes/lysosomes, where SO1861 has its effects; and
an acid sensitive hydrazone linker connected at the C23 aldehyde of SO1861 would connect to 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 CD71 expressing 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 VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same (instant claim 61), covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claims 64-65); and
a second pharmaceutical composition comprising a second conjugate comprising a single domain CD71 targeted VHH antibody wherein the bivalent TfR VHH antibody is the same, covalently linked to a linker and a modified SO1861 (instant claims 71-74) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 68), wherein the first saccharide chain would comprise a the glucuronic acid unit comprising a carboxyl group (instant claim 70), and wherein the SO1861 linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 (instant claim 67) which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape (instant claims 57 and 75).
Regarding instant claim 76, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a single domain CD71 targeted VHH 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 a single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape
– and: include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside a 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 CD71 expressing cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a first pharmaceutical composition a first conjugate comprising a bivalent single domain CD71 targeted VHH antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide;
providing a pharmaceutical composition comprising a second pharmaceutical composition of a second conjugate comprising a bivalent single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape;
providing a cell that expresses 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.
Response to Arguments
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant argues the cited documents fail to teach a conjugate comprising a single-domain antibody is a VHH domain that can bind to CD71, wherein the first cell-surface molecule is CD71.
Applicant argues Geall is the only reference that attempts a two-conjugate approach (EGFR antibody-siRNA co-administered with EGFR antibody-melittin), but Geall's own data teaches away from it. Geall reports that EGFR antibody-melittin increased plasma clearance of the siRNA conjugate (pararaph [0689]) and that the co-administration "did not have a large impact on the tissue PK," while decreasing tumor uptake and increasing off-target liver accumulation (paragraph [0692]). These results would dissuade one of ordinary skill from pursuing a two-conjugate endosomal-escape strategy. None of the secondary references considers a two-conjugate combination.
The Examiner's path to the claimed second conjugate requires: replacing Geall's melittin with Weng's SO1861, modifying SO1861 at C-23 per Marciani, attaching it via hydrazone per Firestone, and conjugating to a binding molecule. Each step lacks motivation and a reasonable expectation of success:
- Geall teaches antibody-melittin conjugates. Melittin is a 26-amino-acid peptide, structurally and functionally unrelated to a saponin triterpene glycoside. Geall never teaches conjugating a saponin to a binding molecule.
- Weng teaches SO 1861 non-covalently associated with positively charged nanoplexes (see Weng, p. 77, left column). Weng explicitly does not teach covalent conjugation of SO1861 to any binding molecule. The formulation-dependent electrostatic association in Weng is fundamentally different from covalent conjugation via a hydrazone bond. Moreover, the vast differences in chemistry between melittin and SO 1861 provide no motivation for substitution.
- Firestone teaches hydrazone bonds for linking doxorubicin, a small-molecule chemotherapeutic, to antibodies. Firestone provides no teaching of using hydrazone chemistry to conjugate a saponin. Starting from Weng's free saponin, there is no bond between the saponin and any molecule to replace with a hydrazone linker.
- Marciani teaches saponin modification at C-23 for vaccine adjuvant purposes, not for covalent conjugation to a binding molecule for targeted intracellular delivery (see Marciani, pp. 23-25, Schemes 5a-b ). The Office Action identifies no teaching in Marciani that C-23 derivatization would predictably preserve or improve delivery performance in a binding molecule-saponin conjugate.
No single reference teaches a saponin-binding molecule conjugate via hydrazone at C- 23, and the six-reference combination does not remedy this gap.
None of the cited references teaches a VHH that binds CD71. Geall's CD71 work uses a Fab, not a VHH (see Office Action, p. 24, acknowledging Fig. 54 shows CD71-Fab). Heukers teaches VHH domains targeting EGFR only (see Heukers, p. 1442). Niewoehner teaches antiTfR Fab fragments for BBB transcytosis and reports that bivalent TfR binding leads to lysosomal sorting and degradation, counterproductive for effector molecule delivery (see Niewoehner, abstract and Fig. 2E). Thus, at most, combining Heukers and Niewoehner with Geall yields a CD71-targeted sdAb-siRNA-PEG single conjugate, with no motivation to provide a separate second conjugate comprising a modified saponin.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. Regarding Geall teaches away, Geall taught that a combination of a conjugate comprising an antibody KRAS siRNA and a conjugate comprising an antibody and the endosomal escape agent melittin effectively decreased KRAS mRNA in the tumor in vivo in Fig. 33.
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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. Thus, inclusion of the antibody conjugated endosomal escape agent with conjugate comprising an antibody KRAS siRNA was effective in tumors in vivo.
Regarding tissue PK and increasing off-target liver accumulation, as described in the obvious rational above, Yu X et al. (Nat Commun. 2019 Feb 4;10:574) taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) (page 2, left to right bridging column) and an agent comprising melittin was specifically targeted to LSEC in vivo (page 3-4, bridging paragraph and Fig. 1). Thus, exchange of melittin for the endosomal escape agent SO1861 would benefit from the known augmentation of escape of the genetic cargo out of the intracellular compartments into the cytosol taught by Weng (abstract). While melittin would be expected by a person having ordinary skill in the art to be responsible for the increased liver uptake, the exchange to SO1861 would improve the existing antibody-melittin conjugate by promoting endosomal escape in the absence of the known liver uptake problems with melittin.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding each step lacks motivation and a reasonable expectation of success; no single reference teaches a saponin-binding molecule conjugate via hydrazone at C-
23, and the six-reference combination does not remedy this gap; and none of the cited references teaches a VHH that binds CD71:
the obvious rational describes the motivation for combining the effective components for obviousness with a reasonable expectation of success above.
Further, regarding Geall and Weng – Geall taught melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]). 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 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.
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. Further, exchange of melittin would be beneficial in view of Yu. Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) (page 2, left to right bridging column). Yu taught an agent comprising melittin was specifically targeted to LSEC in vivo (page 3-4, bridging paragraph and Fig. 1). Thus, exchange of melittin for SO1861 would be expected to have less liver uptake in comparison. 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.
Regarding Firestone, Weng, and Maciani, Geall taught a second conjugate comprising an antibody covalently linked to melittin (page 148, [0689]), wherein melittin is an endosomolytic moiety that causes endosomal escape agent (page 148, [0689]). 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. Additionally, as described above, 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) and Firestone taught an acid-labile hydrazone conjugated to the chimeric MAb BR96 (abstract), wherein internalization of the antibody conjugate via endocytosis into lysosomes led to the acidic milieu of the lysozymes hydrolyzing the hydrazone linkage, releasing free Dox payload effectively (abstract). The hydrazone bond allows for conjugation of a payload to an antibody with acidic release within the lysosomal pathway. Further, Geall taught an acid cleavable linker as a hydrazone linker, which is susceptible to hydrolytic cleavage (Geall, page 82, [0507]). Thus, it is within the skill of a person having ordinary skill in the art to utilize a hydrazone linker in an antibody conjugate. Thus, a hydrazone linker would release the SO1861 payload form the antibody in the endosomes/lysosomes, where SO1861 has its effects. Thus, conjugation of an VHH antibody to an endosomal escape unit of SO1861 via a hydrazone linker is obvious with a reasonable expectation of success. As 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), conjugation of saponins at C23 would be obvious. A hydrazone bond at C23 would release the SO1861 molecule from an antibody in the endosomes/lysosomes, where SO1861 has its effect as described above and have a reasonable expectation of success.
Regarding a VHH that binds CD71 and Geal, Heukers, and Niewoehner, Geall taught targeting CD71 with an antibody siRNA conjugate (Fig. 54), wherein the CD71 targeting antibody siRNA conjugate effectively silenced HPRT expression (Fig. 86). Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same (abstract and Fig. 2E). 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). Thus, CD71-siRNA targeting antibodies and VHH antibodies are known to be effectively internalized. Further, as described above, combination with a second pharmaceutical composition comprising a second conjugate comprising a single domain CD71 targeted VHH antibody wherein the bivalent TfR VHH antibody is the same, covalently linked to a linker and a modified SO1861 which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA-, wherein the first saccharide chain would comprise a the glucuronic acid unit comprising a carboxyl group, and wherein the SO1861 linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape is obvious with a reasonable expectation of success as described above.
Applicant argues Example 10 of the application demonstrates that the claimed two-conjugate system achieves effective tumor cell killing using an ADC at sub-therapeutic levels in combination with a conjugated saponin. No cited reference predicts this synergistic result, further confirming that the combination would not have been obvious.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. Example 10 discloses the results of an antibody saponin of Cetuximab-SO1861 in combination with Trastuzumab-saporin or an anti-CD71 OKT-9-saporin. The instant specification disclosed that the CD71 monoclonal antibody was purchased from BioCell (Okt9, #BE0023). Biocell InVivoMAb anti-human CD71 OKT-9 catalog # BE0023 (https://bioxcell.com/pub/media/tds/BE0023-TDS.pdf) evidences that the BE0023 antibody is 150 kDa (page 1, Molecular Weight) which is not a VHH. Further, the instant specification taught saporin is a protein toxin (instant specification, page 37, first paragraph). Thus, the claims of synergy of Example 10 are not commensurate with the claimed subject matter. MPEP 716.02(d) requires unexpected results to be commensurate in scope with claimed invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. Thus, the claimed subject matter is not unexpected in view of Example 10.
Claims 57-59, 61, 64-65, and 67-76 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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.) Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Yu X et al. (Nat Commun. 2019 Feb 4;10:574). as applied to claims 57-59, 61, 64-65, 67-68, and 70-76 above, and further in view of Thermo Scientific et al. Instructions BMPH, EMCH, KMUH (https://documents.thermofisher.cn/TFS-Assets%2FLSG%2Fmanuals%2FMAN0011363_BMPH_EMCH_KMUH_UG.pdf 2015 reference of record).
Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu are described above.
Geall did not teach conjugation of the endosomal escape moiety at a C23 of an aglycone core through reaction with EMCH, but this is obvious in view of Thermo.
Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins (page 1, Introduction).
Regarding instant claim 69, it would have been obvious for a person having ordinary skill in the art to take the method of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above and in the pharmaceutical composition: – 1) covalently conjugate the SO1861 payload with EMCH at an aldehyde of SO1861 as taught by Thermo, which would be the C23 aldehyde of SO1861.
This is obvious because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone.
There is a reasonable expectation of success because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone. Thus, the acid sensitive hydrazone EMCH linker connected at the C23 aldehyde 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 would produce a method of cancer treatment of a subject by silencing a protein in a CD71 expressing cancer cell comprising administering a single pharmaceutical combination comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same, covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide; and
a second pharmaceutical composition of a second conjugate comprising a VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same, covalently linked to an EMCH linker and a modified SO1861 wherein the linker comprises an acid sensitive EMCH hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape.
Response to Arguments
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant argues the dependent claims are patentable over the cited references at least by virtue of their dependence from independent claim 57.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. The arguments regarding independent claim 57 are discussed 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 57-58 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 57-58, 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, 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,
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, and wherein the first binding sire and second binding site comprise an antibody that targeted CD71 in copending claim 45 (instant claims 57-58).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312,104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 64-65, and 67-74 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 57-58 for the reasons set forth above.
The claims of ‘661 are described above.
The claims of ‘661 further taught regarding instant claims 57-59, 64-65, and 67-74, 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,
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,
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,
wherein the first binding sire and second binding site comprise an antibody that targeted CD71 in copending claim 45,
wherein the effector moiety is an siRNA in copending claim 46,
wherein the first proteinaceous molecule comprises more than one covalently bound saponin via at least one oligomeric or polymeric scaffold in copending claim 50,
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.
The claims of ‘661 did not teach a single embodiment of a first and second molecule as sdAb that targeted CD71, wherein the first and second conjugate are provided in a single pharmaceutical composition, with an siRNA as the effector, wherein the saponin is SO1861, wherein the C23 position is reacted with N-e-maleimidocaproic acid hydrazide, but this is obvious in view of copending claims 43-44, 46, 53, and 55.
Regarding instant claims 57-59, 64-65, and 67-74, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition of: a) a first conjugate that comprised a VHH anti-CD71 conjugated to a saponin at C23; and b) a second conjugate that comprised a VHH anti-CD71 conjugated to an nucleic acid effector moiety of copending claims 41 and 45 – and: 1) use SO1861 as the saponin as taught in copending claim 43, covalently couple the linker N-e-maleimidocaproic acid hydrazide, which is an acid sensitive linker in copending claim 44, use siRNA as the effector moiety as taught in copending claim 46, 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, and wherein the first pharmaceutical composition and the second pharmaceutical composition are administered to the patient in need thereof in copending claim 55.
This is obvious with a reasonable expectation of success because copending claims 43-44, 46, 53, and 55 taught these embodiments and 1) SO1861 is the saponin; 2) the linker N-e-maleimidocaproic acid hydrazide is an acid sensitive linker; 3) siRNA is an effector moiety that can decrease protein expression; 4) a saponin 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 would release the SO1861 payload in the cells; and 5) administering the first and second pharmaceutical compositions would allow the diseased cells to be targeted with both the first and second compositions together.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, and 67-74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-57 of copending Application No.19/044,661 and further in view of Heukers R et al. (Nanomedicine 2014 10(7):1441-51 reference of record) and Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.).
The claims of copending ‘661 teach the limitations of claims 57-59, 64-65, and 67-74 for the reasons set forth above.
‘661 is described above.
‘661 did not teach the first conjugate comprises at least two sdAbs that were the same, but this is obvious in view of Heukers and Niewoehner.
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).
Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same (abstract and Fig. 2E).
Regarding instant claim 61, 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) exchange the targeting sdAb of the first and second conjugate with a monospecific bivalent CD71 single domain VHH antibody of Heukers and Niewoehner.
This is obvious because: 1a) Heukers taught a 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; and 1b) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a monospecific bivalent CD71 sdAb would be obvious and expected to be effective.
There is a reasonable expectation of success because: 1a) Heukers taught a 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; and 1b) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a monospecific bivalent CD71 sdAb would be obvious and expected to be effective.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, 67-68, and 70-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-2, 5, 7, 11, 13-14, 17, 23-26, and 28-29 of copending Application No. 17/312,104;
claims 1-2, 5, 8, 10-11, 16-19, 23-26, 29-30, 32, and 34 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;
claims 1-45 of copending Application No. 19/090,465
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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Yu X et al. (Nat Commun. 2019 Feb 4;10:574).
‘104 copending claims 1-2, 5, 7, 11, 13-14, 17, 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 saponin is covalently bound to the aldehyde in position C-23 and 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, 29-30, 32, and 34 claim a scaffold covalently bound to an endosomal escape enhancer saponin of a 12, 13-dehydrooleanane with an aldehyde at C23 covalently coupled to the scaffold via a hydrazone bond coupled to a proteinaceous 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 covalently bound to an endosomal escape enhancer saponin of a 12, 13-dehydrooleanane with an aldehyde at C23 covalently coupled to the scaffold via a hydrazone bond coupled to a proteinaceous carrier molecule in copending claim 1, wherein the biologically 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.
‘465 copending claims 1-45 claim a conjugate comprising a cell-surface molecule targeting molecule and at least one effector moiety and further comprising at least one covalently bound saponin in copending claim 1, wherein the at least one saponin is a 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 in copending claim 2, and wherein the cell-surface molecule targeting molecule comprises a VHH domain, and wherein the at least one effector moiety comprises an siRNA.
‘465 copending claims 1-45 claim a conjugate comprising a cell-surface molecule targeting molecule and at least one effector moiety and further comprising at least one covalently bound saponin in copending claim 1, wherein the at least one saponin is a 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 in copending claim 2, wherein the saponin is SO1861 in copending claim 5, wherein the cell surface molecule targeting molecule is a VHH in copending claim 8, wherein the cell surface molecule targeting molecule binds to a tumor cell-surface molecule of CD71 in copending claim 9, wherein the effector moiety is an siRNA in copending claim 12, wherein the at least one saponin at the C-23 aldehyde position is covalently coupled to linker N-e- maleimidocaproic acid hydrazide, which is covalently coupled via a thioether bond to a sulfhydryl group in the cell surface molecule targeting molecule of a cysteine in copending claim 18, wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane, with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta- OH group of the saponin, wherein the 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 and preferably via an amino-acid residue in the at least one effector moiety in copending claim 19, wherein the one cleavable linker is a hydrazone bond or a hydrazide bond subject to cleavage under acidic conditions in copending claim 24, wherein the at least one saponin is covalently bound to the polymeric or oligomeric structure of the scaffold, involving in the covalent bond the aldehyde function in position C-23 of the at least one saponin, when present, and/or involving in the covalent bond the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the at least one saponin, when present in copending claim 37, wherein the conjugate comprises 1-100 saponins in copending claim 41, wherein the composition further comprises a pharmaceutically acceptable excipient in copending claim 43, wherein the conjugate is used in the treatment or prevention of a cancer or an autoimmune disease in copending claim 45.
While the claims of ‘104, ‘476, ‘759, ‘019, and 465 taught embodiments of a VHH targeted CD71 targeted antibody covalently conjugated an siRNA and a saponin SO1861, wherein the bond is a hydrazone or hydrazine bond subject to cleavage under acidic conditions is attached at the C-23 aldehyde, they did not teach a single embodiment of the pharmaceutical combination, but this is obvious in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu.
Regarding instant claims 57-59, 64-65, 67-68, and 70-75, 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 57-59, 64-65, 67-68, and 70-75, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-59, 64-65, 67-68, and 70-75, 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).
Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same (abstract and Fig. 2E).
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).
Firestone taught BR96-Dox is an immunoconjugate in which doxorubicin is linked via an acid-labile hydrazone to the chimeric MAb BR96 (abstract). Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free Dox (abstract). Firestone taught BR96-Dox was more effective at killing tumors in vivo with less toxicity and more activity when compared to untargeted Dox (abstract).
Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is reasonably stable at neutral pH, but released rapidly within lysosomes, where the pH is about 5 (page 252, right column, first paragraph).
Firestone taught BR96 DOX comprised a linker of 6-Maleimidocaproylhydrazone (page 253, left column, second paragraph).
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).
Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) (page 2, left to right bridging column). Yu taught an agent comprising melittin was specifically targeted to LSEC in vivo (page 3-4, bridging paragraph and Fig. 1).
Regarding instant claims 57-59, 61, 64-65, 67-68, and 70-75, it would have been obvious for a person having ordinary skill in the art to take copending claims:
1, 2, 7, 14, 17, 26, 28 of ‘104;
1, 5, 8, 11, 17, 19, 23, 24, 26 of ‘476;
1, 5, 9, 13, 20, 22-23, and 35 of ‘759;
1, 5, 9, 11, 17, 19, 24, and 43 of ‘019; and
1-2, 5, 8-9, 12, 18-19, 24, 37, 43, and 45 of ‘465
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, 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 targeting moiety for CD71 expressing cancer cells as taught by the copending claims, Geall, Heukers, and Niewoehner;
Exchange the attachment linker of the endosomal escape moiety for an acid sensitive hydrazone linker of Firestone for linking the payload; and
covalently conjugate the acid sensitive hydrazone linker that releases the SO1861 payload to cause endosomal escape at the C23 aldehyde of SO1861 as taught by Marciani.
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, Weng taught SO1861 is an endosomal escape agent, and Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) and an agent comprising melittin was specifically targeted to LSEC in vivo. Thus, combination of a conjugate with SO1861 and a conjugate with siRNA would enhance siRNA endosomal escape in tumors;
i) Geall taught the antibody as targeting CD71 with an antibody siRNA conjugate effectively and as a sdAb; ii) Heukers taught a 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; and iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a bivalent CD71 sdAb would be obvious and expected to be effective;
Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free payload effectively into the cancer cells. Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is stable at neutral pH, but released rapidly within lysosomes. 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
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:
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. Thus, combination of a conjugate with SO1861 and a conjugate with siRNA would enhance siRNA endosomal escape in tumors;
i) Geall taught the antibody as targeting CD71 with an antibody siRNA conjugate effectively and as a sdAb; ii) Heukers taught a 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; and iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a bivalent CD71 sdAb would be obvious and expected to be effective;
Hydrazone linkers are known to be effective, wherein hydrazone linkers are stable a neutral pH of 7, but once internalized into the acidic conditions, the payload is released into cancer cells. 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(s) in the endosomes/lysosomes, where SO1861 has its effects; and
an acid sensitive hydrazone linker connected at the C23 aldehyde of SO1861 would connect to 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 CD71 expressing 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 VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same (instant claim 61), covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claims 64-65); and
a second pharmaceutical composition comprising a second conjugate comprising a VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same, covalently linked to a linker and a modified SO1861 (instant claims 71-74) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claims 66) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 68), wherein the first saccharide chain would comprise a the glucuronic acid unit comprising a carboxyl group (instant claim 70), and wherein the SO1861 linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 (instant claim 67) which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape (instant claims 57 and 75)
Regarding instant claim 76, 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, ‘019, or ‘465 and Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a single domain CD71 targeted VHH 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 a bivalent single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape
– and: include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside an 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 CD71 expressing cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a bivalent single domain CD71 targeted VHH antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide;
providing a pharmaceutical composition comprising a second pharmaceutical composition of a second conjugate comprising a bivalent single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape;
providing a cell that expresses 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
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, and 67-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-2, 5, 7, 11, 13-14, 17, 23-26, and 28-29 of copending Application No. 17/312,104;
claims 1-2, 5, 8, 10-11, 16-19, 23-26, 29-30, 32, and 34 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; or
claims 1-45 of copending Application No. 19/090,465
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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), and Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), Yu X et al. (Nat Commun. 2019 Feb 4;10:574) and Thermo Scientific et al. Instructions BMPH, EMCH, KMUH (https://documents.thermofisher.cn/TFS-Assets%2FLSG%2Fmanuals%2FMAN0011363_BMPH_EMCH_KMUH_UG.pdf 2015 reference of record).
The claims of copending ‘104, ‘476, ‘759, ‘019, and 465 in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu teach the limitations of claims 57-59, 61, 64-65, 67-68, and 70-76 for the reasons set forth above.
‘104, ‘476, ‘759, ‘019, and 465, Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu are discussed above.
The claims of ‘104, ‘476, ‘759, ‘019, and 465 did not teach conjugation of the endosomal escape moiety at a C23 of an aglycone core through reaction with EMCH, but this is obvious in view of Thermo.
Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins (page 1, Introduction).
Regarding instant claim 69, it would have been obvious for a person having ordinary skill in the art to take the method of ‘104, ‘476, ‘759, or ‘019 in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above and in the pharmaceutical composition: – 1) covalently conjugate the SO1861 payload with EMCH at an aldehyde of SO1861 as taught by Thermo, which would be the C23 aldehyde of SO1861.
This is obvious because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone.
There is a reasonable expectation of success because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone. Thus, the acid sensitive hydrazone EMCH linker connected at the C23 aldehyde 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
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, 67-68, and 70-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 57-65 and 67-78 of copending Application No. 18/012,741;
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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Yu X et al. Immune modulation of liver sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis. (Nat Commun. 2019 Feb 4;10:574).
‘741 copending claims 57-65 and 67-78 claim a pharmaceutical combination comprising: - a first conjugate comprising an effector molecule and a single-domain antibody for binding to a first cell-surface molecule (sdAb), wherein the effector molecule and the sdAb are covalently linked to each other and wherein the effector molecule comprises an oligonucleotide;
- a second conjugate comprising a quillaic acid or gypsogenin saponin with an aldehyde or an acid sensitive bond at C23, wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside, wherein the saponin and the binding molecule are covalently linked together;
‘741 taught a pharmaceutical combination comprising: - a first conjugate comprising an effector molecule and a single-domain antibody for binding to a first cell-surface molecule (sdAb), wherein the effector molecule and the sdAb are covalently linked to each other and wherein the effector molecule comprises an oligonucleotide; - a second conjugate comprising a quillaic acid or gypsogenin saponin with an aldehyde or an acid sensitive bond at C23, wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside, wherein the saponin and the binding molecule are covalently linked together in copending claim 57, wherein the pharmaceutical combination comprises two pharmaceutical compositions in copending claim 58, wherein the first conjugate and second conjugate are provided in a single pharmaceutical composition in copending claim 59, wherein the first conjugate is a VHH domain in copending claim 60, 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 cell surface receptor is CD71 in copending claim 62, wherein the first conjugate comprises an sdAb that can bind to CD71 in copending claim 63, wherein the effector molecule is an siRNA in copending claims 64, wherein the saponin is SO1861 in copending claims 68-69, wherein the saponin is covalently linked to the binding molecule via a linker that is an acid sensitive linker in copending claims 72-73, 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 74;
‘741 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 77.
‘741 taught an in vitro method for transferring an oligonucleotide effector molecule being an from outside a cell to inside said cell comprising: a) providing the first conjugate of the pharmaceutical combination above; b) providing the second conjugate of the pharmaceutical combination above; c) providing a cell which expresses (i) the first cell-surface molecule as recognized by the sdAb of the first conjugate and (ii) the second cell-surface molecule as recognized by the binding molecule of the second conjugate; d) contacting the cell of step c) in vitro with the first conjugate of step a) and the second conjugate of step b), therewith establishing the transfer of the effector molecule from outside the cell into said cell in copending claim 78.
‘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 bi-desmosidic 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 57, 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 72, 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 claims 61 and 62, 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, wherein the conjugate further comprises more than one saponin bound in copending claim 77;
‘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 78.
‘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 ‘741, ‘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 a single embodiment of the pharmaceutical combination wherein the bond is a hydrazone or hydrazine bond subject to cleavage under acidic conditions is attached at the C-23 aldehyde, but this is obvious in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu.
Regarding instant claims 57-60, 64-65, 67-68, and 70-75, 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, 64-65, 67-68, and 70-75, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-60, 64-65, 67-68, and 70-75, 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).
Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same (abstract and Fig. 2E).
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).
Firestone taught BR96-Dox is an immunoconjugate in which doxorubicin is linked via an acid-labile hydrazone to the chimeric MAb BR96 (abstract). Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free Dox (abstract). Firestone taught BR96-Dox was more effective at killing tumors in vivo with less toxicity and more activity when compared to untargeted Dox (abstract).
Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is reasonably stable at neutral pH, but released rapidly within lysosomes, where the pH is about 5 (page 252, right column, first paragraph).
Firestone taught BR96 DOX comprised a linker of 6-Maleimidocaproylhydrazone (page 253, left column, second paragraph).
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).
Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) (page 2, left to right bridging column). Yu taught an agent comprising melittin was specifically targeted to LSEC in vivo (page 3-4, bridging paragraph and Fig. 1).
Regarding instant claims 57-59, 61, 64-65, 67-68, and 70-75, it would have been obvious for a person having ordinary skill in the art to take copending claims:
57-64, 68-69, 72-74, and 77 of ‘741;
57-60, 62-64, 66, 68-72, 74, and 76 of ‘723; or
57-63, 65, 72-78 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 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, and administer it for treatment of cancer as taught by Geall;
Exchange the attachment linker of the endosomal escape moiety for an acid sensitive hydrazone linker of Firestone for linking the payload;
covalently conjugate the acid sensitive hydrazone linker that releases the SO1861 payload to cause endosomal escape at the C23 aldehyde of SO1861 as taught by Marciani.
This is obvious because:
i) 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 the antibody as targeting CD71 with an antibody siRNA conjugate effectively and as a sdAb; ii) Heukers taught a 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; iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same; iv) Weng taught SO1861 is an endosomal escape agent; and v) Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) and an agent comprising melittin was specifically targeted to LSEC in vivo. Thus, combination of a conjugate with SO1861 and a conjugate with siRNA would enhance siRNA endosomal escape in tumors
Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free payload effectively into the cancer cells. Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is stable at neutral pH, but released rapidly within lysosomes. 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
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:
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 CD71 targeted antibodies were effective and a conjugate with SO1861 and a conjugate with siRNA would enhance siRNA endosomal escape in tumors;
Hydrazone linkers are known to be effective, wherein hydrazone linkers are stable a neutral pH of 7, but once internalized into the acidic conditions, the payload is released into cancer cells. 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(s) in the endosomes/lysosomes, where SO1861 has its effects; and
an acid sensitive hydrazone linker connected at the C23 aldehyde of SO1861 would connect to 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 CD71 expressing 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 VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same (instant claim 61), covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claims 64-65); and
a second pharmaceutical composition comprising a second conjugate comprising a VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same, covalently linked to a linker and a modified SO1861 (instant claims 71-74) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claims 66) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 68), wherein the first saccharide chain would comprise a the glucuronic acid unit comprising a carboxyl group (instant claim 70), and wherein the SO1861 linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 (instant claim 67) which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape (instant claims 57 and 75).
Regarding instant claim 76, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of ‘741, ‘723, or ‘729 and Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a bivalent single domain CD71 targeted VHH 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 a bivalent single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape
– and: 1) use it in the in vitro method taught by: A) ‘741 copending claim 78; 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 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
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, and 67-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 57-65 and 67-78 of copending Application No. 18/012,741;
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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), Yu X et al. (Nat Commun. 2019 Feb 4;10:574), and Thermo Scientific et al. Instructions BMPH, EMCH, KMUH (https://documents.thermofisher.cn/TFS-Assets%2FLSG%2Fmanuals%2FMAN0011363_BMPH_EMCH_KMUH_UG.pdf 2015 reference of record).
The claims of copending ‘741, ‘723, or ‘729 in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu teach the limitations of claims 57-59, 61, 64-65, and 67-68, and 70-76 for the reasons set forth above.
‘741, ‘723, or ‘729, Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu are discussed above.
The claims of ‘741, ‘723, or ‘729 did not teach conjugation of the endosomal escape moiety at a C23 of an aglycone core through reaction with EMCH, but this is obvious in view of Thermo.
Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins (page 1, Introduction).
Regarding instant claim 69, it would have been obvious for a person having ordinary skill in the art to take the method of ‘741, ‘723, or ‘729, and Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above and in the pharmaceutical composition: – 1) covalently conjugate the SO1861 payload with EMCH at an aldehyde of SO1861 as taught by Thermo, which would be the C23 aldehyde of SO1861.
This is obvious because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone.
There is a reasonable expectation of success because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone. Thus, the acid sensitive hydrazone EMCH linker connected at the C23 aldehyde 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
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, and 67-68, 70-76 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 54-55 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; or
claims 22-37 and 39-41 of copending Application No. 18/012,715
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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), and Yu X et al. (Nat Commun. 2019 Feb 4;10:574).
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 55, 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 covalently coupled to the first proteinaceous molecule in copending claim 7, wherein the saponin is covalently coupled at the C3beta-OH glucuronic acids to the first proteinaceous molecule in copending claim 8, wherein the aldehyde at the C-23 position is covalently coupled to linker 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;
‘715 copending claims 22-37 and 39-41 claimed conjugates for transferring an endosomal escape enhancer saponin from outside a cell into said cell comprising a sdAb capable of binding to said cell and covalently bound by at least one endosomal escape enhancer saponin via a cleavable linker wherein the saponin is a quillaic acid or gypsogenin, wherein an aldehyde functional group is present at position C23 of the aglycone core is involved in the binding of the cleavable linker and wherein the cleavable linker comprises an acidic conditions cleavable bond adapted to release the at least one endosomal escape enhancer saponin in a free form and pharmaceutical combinations
‘715 taught a conjugate for transferring an endosomal escape enhancer saponin from outside a cell into said cell comprising a sdAb capable of binding to said cell and covalently bound by at least one endosomal escape enhancer saponin via a cleavable linker wherein the saponin is a quillaic acid or gypsogenin, wherein an aldehyde functional group is present at position C23 of the aglycone core is involved in the binding of the cleavable linker and wherein the cleavable linker comprises an acidic conditions cleavable bond adapted to release the at least one endosomal escape enhancer saponin in a free form in copending claim 22, wherein the conjugate is in a pharmaceutical combination further comprising a second pharmaceutical composition comprising an active pharmaceutical ingredient in copending claim 23, wherein the sdAb is a VHH in copending claim 24, wherein the conjugate comprises one to eight sdAb capable of binding the same binding sire on a cell surface molecule or wherein the at least one saponin is linked to two or more sdAb in copending claim 26, wherein the conjugate comprises 1-100 saponin moieties in copending claim 27, wherein the saponin is SO1861 in copending claim 30, wherein the acidic conditions bond is a hydrazone or hydrazide bond subject to cleavage in vivo at pH < 5.5 in copending claim 31, wherein the sdAb is a single or two sdAb of an anti-CD71 sdAb in copending claim 36-37, wherein the pharmaceutical combination comprises an AOC sdAb that can bind CD71 in copending claim 39, wherein the conjugate is in a pharmaceutical combination with a pharmaceutically acceptable excipient and further comprising a second pharmaceutical ingredient of a ligand drug conjugate of an anti-CD71 antibody conjugated to BNA or siRNA in copending claim 41.
‘760, ‘193, ‘163, or ‘715 did not teach a pharmaceutical composition of a first conjugate comprising a sdAb-siRNA effector and a second conjugate covalently linked to a saponin at the C23 aldehyde, but this is obvious in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu.
Regarding instant claims 57-60, 61, 64-65, 67-68, and 70-75, 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, 61, 64-65, 67-68, and 70-75, Geall taught the antibody as a single-domain antibody (sdAb) (page 1, [0019]). Regarding claims 57-60, 61, 64-65, 67-68, and 70-75, 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).
Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same (abstract and Fig. 2E).
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).
Firestone taught BR96-Dox is an immunoconjugate in which doxorubicin is linked via an acid-labile hydrazone to the chimeric MAb BR96 (abstract). Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free Dox (abstract). Firestone taught BR96-Dox was more effective at killing tumors in vivo with less toxicity and more activity when compared to untargeted Dox (abstract).
Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is reasonably stable at neutral pH, but released rapidly within lysosomes, where the pH is about 5 (page 252, right column, first paragraph).
Firestone taught BR96 DOX comprised a linker of 6-Maleimidocaproylhydrazone (page 253, left column, second paragraph).
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).
Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) (page 2, left to right bridging column). Yu taught an agent comprising melittin was specifically targeted to LSEC in vivo (page 3-4, bridging paragraph and Fig. 1).
Regarding instant claims 57-60, 62, 64-68, and 70-75, it would have been obvious for a person having ordinary skill in the art to take copending claims:
1-6, 11, 21-23, and 55 of ‘760;
1, 4, 7-11, 32-34, and 43 of ‘193;
29-31, 37, 41, 45, 60, 62 of ‘163, or
22-44, 26-27, 30-31, 36-37, 39, and 41 of ‘715
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 targeting moiety in view of the copending claims and/or Geall, Heukers, and Niewoehner; and
Exchange the attachment linker of the endosomal escape moiety for an acid sensitive hydrazone linker of Firestone for linking the payload;
covalently conjugate the acid sensitive hydrazone linker that releases the SO1861 payload to cause endosomal escape at the C23 aldehyde of SO1861 as taught by Marciani.
This is obvious because:
a) 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; b) 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; and c) Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) and an agent comprising melittin was specifically targeted to LSEC in vivo. Thus, combination of a conjugate with SO1861 and a conjugate with siRNA would enhance siRNA endosomal escape in tumors;
i) Geall taught the antibody as targeting CD71 with an antibody siRNA conjugate effectively and as a sdAb; ii) Heukers taught a 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; and iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a bivalent CD71 sdAb would be obvious and expected to be effective;
Firestone taught BR96 bound to tumor cells, then internalized via endocytosis into lysosomes, wherein the acidic milieu of the lysozymes hydrolyzed the hydrazone linkage, releasing free payload effectively into the cancer cells. Firestone taught conjugation of the monoclonal antibody to Dox by a hydrazone bond, wherein a hydrazone bond is stable at neutral pH, but released rapidly within lysosomes. 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
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:
a) 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; b) 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; and c) Yu taught melittin possesses an RXR sequence that targets liver sinusoidal endothelial cells (LSECs) and an agent comprising melittin was specifically targeted to LSEC in vivo. Thus, combination of a conjugate with SO1861 and a conjugate with siRNA would enhance siRNA endosomal escape in tumors;
i) Geall taught the antibody as targeting CD71 with an antibody siRNA conjugate effectively and as a sdAb; ii) Heukers taught a 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; and iii) Niewoehner taught a bivalent transferrin receptor (TfR or CD71) antibody leads to effective lysosomal targeting, wherein the bivalent TfR antibody is the same. Thus, a bivalent CD71 sdAb would be obvious and expected to be effective;
Hydrazone linkers are known to be effective, wherein hydrazone linkers are stable a neutral pH of 7, but once internalized into the acidic conditions, the payload is released into cancer cells. 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(s) in the endosomes/lysosomes, where SO1861 has its effects; and
an acid sensitive hydrazone linker connected at the C23 aldehyde of SO1861 would connect to 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 CD71 expressing 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 VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same (instant claim 61), covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide (instant claims 64-65); and
a second pharmaceutical composition comprising a second conjugate comprising a VHH single domain CD71 targeted antibody, wherein the bivalent TfR VHH antibody is the same, covalently linked to a linker and a modified SO1861 (instant claims 71-74) which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid (instant claims 66) with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA- (instant claim 68), wherein the first saccharide chain would comprise a the glucuronic acid unit comprising a carboxyl group (instant claim 70), and wherein the SO1861 linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 (instant claim 67) which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape (instant claims 57 and 75).
Regarding instant claim 76, it would have been obvious for a person having ordinary skill in the art to take the composition from the method of ‘760, ‘193, ‘163, or ‘715 and Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above of a pharmaceutical composition comprising two pharmaceutical compositions comprising:
a first pharmaceutical composition a first conjugate comprising a bivalent single domain CD71 targeted VHH 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 a bivalent single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 which is a bidesmosidic triterpene glycoside with an aglycone core structure of quillaic acid with a first saccharide chain of Gal-(1-2)-[Xyl-(1-3)]-GlcA wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape
– and: include the compositions in the effective in vitro method for transferring an oligonucleotide effector molecule from outside an 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 CD71 expressing cell to inside of said cell comprising:
providing a pharmaceutical composition comprising a first pharmaceutical composition a first conjugate comprising a bivalent single domain CD71 targeted VHH antibody covalently linked to an effector molecule wherein the effector molecule is an siRNA oligonucleotide;
providing a pharmaceutical composition comprising a second pharmaceutical composition of a second conjugate comprising a bivalent single domain CD71 targeted VHH antibody covalently linked to a linker and a modified SO1861 wherein the linker comprises an acid sensitive linker comprising a hydrazone bond linker connected at the C23 aldehyde of SO1861 which breaks under acidic conditions such that it forms an aldehyde function at C23 of the quillaic aglycone core structure to release the payload to cause endosomal escape;
providing a cell that expresses 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
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, 67-76 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 54-55 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;
claims 29-31, 37, 39, 41, 45-50, 52, and 58-64 of copending Application No. 18/723,163; or
claims 22-37 and 39-41 of copending Application No. 18/012,715
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), Niewoehner J et al. (Neuron 2014 81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.), Weng A et al. (Journal of Controlled Release 2015 206 75-90 reference of record), Firestone RA e al. (Journal of Controlled Release 1996 39 (2-3) 251-259 reference of record), US 2004/0242502 (Marciani D et al. reference of record), Yu X et al. (Nat Commun. 2019 Feb 4;10:574), and Thermo Scientific et al. Instructions BMPH, EMCH, KMUH (https://documents.thermofisher.cn/TFS-Assets%2FLSG%2Fmanuals%2FMAN0011363_BMPH_EMCH_KMUH_UG.pdf 2015 reference of record).
The claims of copending '760, '193, '163, or ‘715 in view of Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu teach the limitations of claims 57-59, 61, 64-65, 67-68, and 70-76 for the reasons set forth above.
'760, '193, '163, ‘715, Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu are discussed above.
'760, '193, '163, or ‘715 did not teach conjugation of the endosomal escape moiety at a C23 of an aglycone core through reaction with EMCH, but this is obvious in view of Thermo.
Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins (page 1, Introduction).
Regarding instant claim 69, it would have been obvious for a person having ordinary skill in the art to take the method of '760, '193, '163, or ‘715 and Geall, Heukers, Niewoehner, Weng, Firestone, Marciani, and Yu above and in the pharmaceutical composition: – 1) covalently conjugate the SO1861 payload with EMCH at an aldehyde of SO1861 as taught by Thermo, which would be the C23 aldehyde of SO1861.
This is obvious because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone.
There is a reasonable expectation of success because: 1i) Thermo taught EMCH (N-[ε-Maleimidocaproic acid) hydrazide is a heterobifunctional crosslinkers containing sulfhydryl-reactive maleimide and carbonyl-reactive hydrazide moieties, wherein hydrazide groups react with carbonyls (aldehydes and ketones) to form stable hydrazone bonds, wherein the EMCH crosslinker is useful for conjugating sulfhydryl-containing proteins; and 1ii) the structure of EMCH is included in the 6-Maleimidocaproic acid hydrazone linker of Firestone. Thus, the acid sensitive hydrazone EMCH linker connected at the C23 aldehyde 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
Applicant has amended the independent claim 57.
The updated to rejection is above.
Applicant requests that the provisionally rejection of the claims under the judicially created doctrine of obviousness-type double patenting as allegedly being unpatentable over the claims of co-pending applications Nos. 19/044,661, 17/312, 104, 17/312,476, 17/415,759, 17/312,019, 18/012,741, 18/012,723, 18/012,729, 18/012,760, 17/312,193 and 18/723,163 be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
In response, Applicant's arguments filed 7/7/2026 have been fully considered
but they are not persuasive. 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 57-59, 61, 64-65, and 67-76 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
