DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1-24 are pending.
Applicant’s election without traverse in the reply filed on May 27, 2026 of Invention I, encompassing claims 1-20 and directed to nanoparticles comprising renal cell carcinoma (RCC) therapeutics and targeting moieties is acknowledged. Claims 21-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention there being no allowable generic or linking claim. Applicant’s election of a targeting moiety having SEQ ID NO 1, and an HIF2a siRNA with SEQ ID NO 3, and conjugated to the nanoparticle by reaction with a functional group, is also acknowledged. Claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species there being no allowable generic or linking claim.
The elected species of a CD70-targeting peptide having SEQ ID NO 1 is free of the prior art. The examined genus was expanded to include anti-CD70 antibodies.
Claims 1-10 and 12-20 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency #1 - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Specifically on pages 23-24 are not identified with a SEQ ID NO.
Required response #1 – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency #2 - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that the scrambled CD27 fragment (page 23) is not in the sequence listing.
Required response #2 - Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 10 and 12-13. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Drawings
The drawings are objected to because the lines, shadings, numbers and letters of FIGs. 1A, 2A-2G, and 8-9 are not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the instant case, the text in FIGs noted above is very small and/or of poor resolution to permit satisfactory reproduction characteristics.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims 4 and 6-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites “wherein the CD70-targeting peptides conjugated includes a fragment of CD27 (CRKAAQCDPCIPG) having 5 to 12 amino acids or a peptide thereof with 1-7 conservative substitutions or additions”. The metes and bounds of the genus of included CD27 fragments is unclear. First, the peptide is in parentheses and it is not clear if this is preferred CD27 fragment, an example fragment, or defines the claimed CD27 fragment. Second, the recited fragment is 13 amino acids, but following the parenthetical fragment is “having 5-12 amino acids”. It is not clear if the entire 13 amino acid peptide in parentheses is allowed or if it must be only 5-12 amino acids. It is also not clear if “conservative” applies to “additions”, and if so what a “conservative addition” is.
To overcome this rejection is suggested that claim 4 recite “wherein the CD70-targeting peptide is SEQ ID NO 1 or a peptide thereof with 5 to 12 amino acid additions or conservative substitutions.”
Claim 6 recites, “wherein the CD70-targeting peptides is CD27 (CRKAAQCDPCIPG) (SEQ ID NO: 1) or a peptide thereof with 1-7 conservative substitutions of additions.” Similar to claim 4 above, it is not clear if the parenthetical peptide, which is also SEQ ID NO 1, is a preferred embodiment of the CD27 peptide or if claim 6 is limited to SEQ ID NO 1 or shorter peptides with the recited substitutions. It is also not clear if “conservative” applies to “additions”, and if so what a “conservative addition” is.
To overcome this rejection is suggested that claim 6 recite “wherein the CD70-targeting peptide is SEQ ID NO 1 or a peptide thereof with 1 to 7 amino acid additions or conservative substitutions.”
Claims 7-8 recite “The drug delivery system of claim 1, wherein anti-HIF2a siRNAs include…”. Claim 1 does not recite anti-HIF2a siRNAs; therefore, the reference to them in claims 7-8 lack proper and clear antecedent basis.
To overcome this rejection, it is suggested that claims 7-8 depend from claim 3, which recite “wherein the therapeutic for renal carcinoma includes anti-HIF2a siRNAs”.
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 1-10 and 12-20 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.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “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.”
Claim 1 analysis
Claim 1 recites “targeting peptides and/or targeting antibodies and/or targeting aptamers that target a renal carcinoma marker”, which represents a genus of molecules that are defined by their function of targeting a genus of molecules, mainly proteins, that are markers of renal carcinoma. A definition by function does not suffice to define the genus because it is only an indication of what the peptide/aptamer/antibody does, rather than what it is. To provide adequate written description and evidence of possession of the claimed peptide/aptamer/antibody genus, the instant specification in view of the art must structurally describe representative peptide/aptamer/antibody that function as a targeting moiety, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
The claimed genus: The Specification does not list any other markers to target except CD70, but other markers of renal cell carcinoma (RCC) have been described including AXL, BCAM, CDH2, CDH6, F3, HEG1, MME, SCL22A4 and SCL2A1 (Boysen et al., Neoplasia (2012), 14: 535-546; Table 2). Therefore, the claimed genus also includes peptides, aptamers and antibodies that target additional proteins other than CD70. For the reasons described below, Applicant has not sufficiently described the genus of targeting peptides, antibodies and aptamers that can predictably target the genus of renal carcinoma markers.
Species described in the Specification: Applicants have described a single targeting peptide derived from the extracellular domain of CD27 – RKAAQCDPCIPG – that is capable of targeting the CD70 renal carcinoma marker. Applicant do not explain why or how they chose the 12-amino acid peptide out of the 100+ amino acid extracellular domain of CD27. The N-terminal cytosine is not derived from CD27, and was likely included for conjugation purposes using the reactive -SH side chain. Importantly, the Specification does not provide guidance on how the skilled artisan could shorten, lengthen or alter the CRKAAQCDPCIPG peptide and still maintain CD70 targeting. Additionally, the specification does not disclose any additional antibodies, aptamers or peptides, either by structure or name, that can target CD70 or any other renal carcinoma structure. As such, as of the effective filing date of the claimed invention, it was not predictable 1) how to alter the singly disclosed peptide and maintain the claimed function, or 2) the structure of other targeting peptides, antibodies or aptamers that could target renal carcinoma cells/tumors.
State of the prior art: A few aptamers and antibodies are known that can be used to target drugs to renal carcinoma cells. For instance, Wajant discloses a human CD70-specific antibody 1F6 conjugated to chemotherapeutic agents (Expert Opinion on Therapeutic Targets (2016), 20: 959-973; Section 3). Taniguchi teaches that RGD-peptides can be used to target integrins upregulated in RCC (Taniguchi et al., Cancer Science (2022), 113: 2952-2961; page 2957, ¶5; Table 2). Ravichandran reviews the state of the art of aptamer-mediated drug delivery for cancer treatment (Ravichandran and Rengan, ACS Appl. Nano Mater. (2020), 3: 9542-9559). Ravichandran teaches a single 26-nt aptamer called AS1411 that targets upregulated nucleolin (Section 2.7.2). However, for each of antibodies, peptides and aptamers, the three-dimensional shape dictates the ability to bind to the target molecule. Thus, it is not predictable how to alter formerly disclosed peptides, aptamers, or peptides and still maintain the function of target binding. Additionally, antibodies, peptides, and aptamers that target other renal carcinoma markers like those disclosed in Boysen above have not been developed.
Although Applicants may argue that it is possible to screen for antibodies, peptides and aptamers that function as claimed, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies, peptides and aptamers yet to be discovered that may function as targeting moieties as claimed.
Regarding the disclosed CD27 peptide fragment, the crystal structure of the CD27-CD70 complex was recently solved (Liu et al., Journal of Biological Chemistry (2021), 297(4): 101102). Liu teaches the CD27 residues that interface with the CD70 extracellular domain (Fig 3). The claimed CD27 peptide is residues 58-68 of the full length CD27 protein. Interestingly, only residue, Ile66, is predicted to form contacts with CD70 (Fig 3). Liu does not perform any mutagenesis studies or provide any information on what residues outside of those depicted in Fig 3 are necessary or sufficient for CD70 targeting. Thus, Liu provides no information on what residues can be altered or removed from SEQ ID NO 1 and still maintain CD70 binding.
Given the lack of representative examples to support the full scope of the antibodies, peptides and aptamers encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of antibodies, aptamers and peptides that are capable of targeting CD70 or other renal carcinoma markers, the skilled artisan would reasonably conclude that the specification does not provide an adequate written description of antibodies, peptides and aptamers that function as required to practice the claimed invention.
Dependent claim analysis
Claim 2 only limits the marker to CD70. Other than the peptide fragment of CD27 with SEQ ID NO 1 and already developed anti-CD70 antibodies known in the art, the rest of the genus of CD70-binding aptamers, peptides and antibodies are completely unknown. Given the lack of predictable relationship between peptide/antibody/aptamer structure and their binding/targeting function, the skilled artisan would reasonably conclude that Applicant did not prosses genus as claimed.
Claims 3, 5, 7-10 and 12-20 do not limit the genus of targets or targeting moieties and are rejected for the reasons explained for claim 1.
Claims 4 and 6 limit the targeting genus to a CD70-targeting peptide that is “a fragment of CD27 (CRKAAQCDPCIPG) having 5-12 amino acids or peptide thereof with 1-7 conservative substitutions or additions.” Claims 4 and 6 are indefinite for the reasons explained above in paragraphs 13 and 15. For the purpose of this rejection, the claimed genus is interpreted as the CD70-targeting peptide comprising SEQ ID NO 1 or 5-12 amino acids of SEQ ID NO 1 with 1-7 conservative substitutions or any amino acid additions. Other than a peptide consisting of SEQ ID NO 1, it is not predictable what fragment/peptide of SEQ ID NO 1 would sustain CD70-targeting. It is also not predictable of which 1-7 amino acids could be substituted, even with “conservative substitutions” or where additional amino acids could be inserted and still maintain CD70-targeting. The Specification provides no guidance on which residues to retain, substitute, or add, and provides no studies on which residues are necessary and/or sufficient to provide CD70-targeting. Additionally, Liu’s teachings about the CD27-CD70 complex does not provide any insight since only one of the residues in SEQ ID NO 1 was shown to make contact with CD70. Given the lack of understanding in the art and disclosure in the Specification about how the peptide with SEQ ID NO 1 interacts with CD70, and the lack of a relationship between peptide structure and any binding/targeting function, the skilled artisan would reasonably conclude that Applicant did not possess genus of functional fragments of SEQ ID NO 1 or full length SEQ ID NO 1 with conservative substitutions or additions as claimed.
Claim Rejections - 35 USC § 102 - Taniguchi
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Taniguchi (Taniguchi et al., Cancer Science (2022), 113: 2952-2961, published June 30, 2026) and evidenced by Javid (Javid et al., Cancer Medicine (2023), 13:e6800) and Mena (Mena et al., Eur J Nucl Med Mol Imaging (2014) 41: 1879–1888).
Regarding claims 1 and 3, Taniguchi teaches ARO-HIF2 (i.e., a nanoparticle) is composed of HIF2 siRNA (i.e. an RCC therapeutic) targeting HIF2a and uses a proprietary targeting-RNAi molecule delivery platform which comprises targeting ligands, such as RGD motifs (i.e., a targeting peptide that targets a renal carcinoma marker) designed to transport siRNA to renal cancer cells (page 2957, ¶5; Table 2). Although Taniguchi teaches the RGD peptides target RCC cells, Taniguchi is silent about what protein on RCC cells, RGD peptides target.
Javid teaches that RGD peptides can bind to avb3, avb5 and a5b1 integrins (Table 6). Mena teaches avb3 and avb5 are upregulated in RCC tumors (i.e., avb3 and avb5 are RCC markers) (Abstract). Therefore, ARO-HIF2a inherently comprised a targeting peptide that targets a renal carcinoma maker.
Claim Rejections - 35 USC § 102 - Grosveld
Claims 1-2, 5, 12 and 19-20 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Grosveld (US 20230405146 A1, priority to at least November 5, 2021).
Regarding claims 1-2, Grosveld teaches nanoparticles conjugated to an antibody and comprising a payload (Abstract; Fig 3B). Grosveld teaches nanoparticles comprising a therapeutic payload conjugated to an anti-CD70 antibody for treating CD70+ tumors in renal cell carcinoma ([0077]). Grosveld teaches payloads include chemotherapeutic drugs (i.e., small molecule drugs) ([0215]) and DNA ([0216]).
Regarding claim 5, Grosveld teaches the nanoparticles are liposomes (Fig 3B, [0205]).
Regarding claim 12, Grosveld teaches the nanoparticles are micelles ([0205]).
Regarding claim 19, Grosveld teaches incorporating the payload (i.e., drug) in the core or conjugated to the nanoparticle ([0214]).
Regarding claim 20, as noted above for claims 1 and 12, Grosveld teaches nanoparticles that are micelles ([0205]) and used for treatment of renal cell carcinoma ([0077]).
Claim Rejections - 35 USC § 103 – Grosveld in view of others
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.
Claims 3, 9-10, 13 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Grosveld (US 20230405146 A1, priority to at least November 5, 2021), as applied claims 1-2, 5, 12 and 19-20 above and in view of Ma (Ma et al., Clinical Cancer Research (2022), 28: 5405-5418, published September 29, 2022) and Garcia (Cartón-Garcia et al., Biomedicines (2021), 9: 303, pages 1-24).
The teachings of Grosveld are recited above as for claims 1-2, 5, 12 and 19-20 and are incorporated here. Briefly, Grosveld teaches lipid-based nanoparticles comprising an anti-CD70 antibody to target the nanoparticles to renal carcinoma cells for treatment. Grosveld also teaches the nanoparticles can be used to deliver payloads including chemotherapy drugs, RNA and DNA to cancer cells ([0215]-[0216]).
Grosveld does not teach the payload is an siRNA or for inhibiting expression of HIF2a.
Ma teaches renal cell carcinoma (RCC) is characterized by inactivation of VHL and a concomitant increase in the oncogenic driver HIF2a, where in activates gene expression (page 5405, ¶1). Ma teaches delivering siRNAs targeting to HIF2a to RCC primary tumor cells, which reduced tumor cell growth (Fig 1A-D).
Garcia teaches oligonucleotide-based therapies for renal diseases and their delivery platforms (Abstract). Garcia teaches siRNA-based therapies targeting renal tissues show promising results (Section 2.1.1). Garcia teaches lipid-based nanoparticles can be used to deliver siRNAs to kidney tissues (Section 3.2.4, ¶1). Garcia teaches targeting ligands such as antibodies and aptamers can be conjugated to nanoparticles to enhance cell uptake and specificity (Section 3.2.4, ¶4).
Regarding claim 3, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have included Ma’s HIF2a-targeting siRNA in Grosveld’s lipid-based nanoparticle conjugated with anti-CD70 antibodies. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that a HIF2a-targeting siRNA could be included as payload in Grosveld’s nanoparticles because 1) Grosveld teaches generically that RNA can be a payload, and 2) Garcia teaches that siRNAs have been delivered to kidney tissues via lipid-based nanoparticles. One would have been motivated to do so because Ma teaches the siRNA is effective at reducing RCC tumor size.
Regarding claims 9-10, Grosveld teaches conjugating antibodies to the nanoparticle lipids via an -NH2 amino functional group or -SH thiol functional group (Fig 3B) via NHS-based conjugation ([0304]). Grosveld teaches that payloads can also be conjugated to the nanoparticle ([0214]). Ma teaches that anti-HIF2a siRNAs can be conjugated to a polymer-PEG-based delivery particle through a disulfide bond (i.e., via thiol- or amide- bond) (Fig 4a). Ma teaches the anti-HIF2a siRNA conjugated to the polymer/PEG nanoparticle resulted in greater knockdown of HIF2 (Fig. 4b).
It would have been obvious to one skilled in the art before the effective date of the claimed invention to have conjugated Ma’s HIF2a-targeting siRNA to a lipid of Grosveld’s lipid-based nanoparticle that is already conjugated via HNS esters with anti-CD70 antibodies. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that the Ma’s siRNA could be conjugated to the nanoparticle lipid because Ma teaches the siRNA can be conjugated to other delivery means including polymer/PEG nanoparticles. The skilled artisan would have been motivated to have done so because Ma teaches the siRNA conjugated to a polymer/PEG moiety increased knockdown of the target mRNA.
Regarding claims 13, Grosveld teaches the nanoparticles are comprised of a lipid (i.e., hydrophobic)-PEG (i.e., hydrophilic) shell (i.e., an amphiphile) (Fig 3b). As indicated above for claims 9-10, Grosveld teaches conjugating the antibodies to the lipid-PEG (i.e., a plurality of targeting peptide-conjugated amphiphiles) (Fig 3b). The obviousness of also conjugating Ma’s siRNA to Grosveld’s nanoparticles is recited above for claim 9.
Regarding claim 18, Grosveld teaches the nanoparticles in compositions with pharmaceutically acceptable carriers ([0261]).
Claims 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Grosveld (US 20230405146 A1, priority to at least November 5, 2021), Ma (Ma et al., Clinical Cancer Research (2022), 28: 5405-5418, published September 29, 2022) and Garcia (Cartón-Garcia et al., Biomedicines (2021), 9: 303, pages 1-24), as applied claims 1-3, 5, 9-10, 12-13 and 18-20 above, and further in view of Allen (Allen et al., Biochemica et Biophysica Acta (1995), 1237: 99-108).
The teachings of Grosveld, Ma and Garcia are recited above and applied as for claims 1-3, 5, 9-10, 12-13 and 18-20. Garcia also teaches liposomal-based delivery of oligonucleotides (Fig. 1B). Garcia teaches liposomes having a lipid biolayer (i.e., comprised of amphipathic phospholipids) (page 16, ¶4).
Grosveld, Ma and Garcia do not teach specific types of phospholipids or conjugated antibody or payload to a phospholipid.
Allen teaches the development of long-circulating formulations of liposomes comprised of PEG-disteroylphosphatidylethanolamine (PEG-DSPE) (Abstract). Allen teaches PEG-DSPE lipids conjugated to antibodies (page 102, ¶3). Allen teaches the PEG length was 2000 (page 10, ¶5). Allen teaches the liposomes comprising PEG-DSPE has increased circulation time and efficient drug loading.
Regarding claims 14-17, it would have been obvious to one skilled in the art before the effective date of the claimed invention to have used PEG-DSPE as the lipid in nanoparticles conjugated with the anti-CD70 antibody and Ma’s HIF2a-targeting siRNA. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that the PEG-DSPE could be used in siRNA- and antibody-conjugated liposomes for delivery to RCC cells, and been motivated to have done so, because Allen teaches PEG-DSPE liposomes have increased circulation time and are capable of targeting cancer cells.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Grosveld (US 20230405146 A1, priority to at least November 5, 2021), Ma (Ma et al., Clinical Cancer Research (2022), 28: 5405-5418, published September 29, 2022) and Garcia (Cartón-Garcia et al., Biomedicines (2021), 9: 303, pages 1-24), as applied claims 1-3, 5, 9-10, 12-13 and 18-20 above, and further in view of Kulisch (Kulisch et al., Dicer-Substrate siRNA Technology, BioRadiations 120) and Genbank (XM_011532698.2, EPAS1, mRNA reference sequence, available May 16, 2021).
The teachings of Grosveld, Ma and Garcia are recited above and applied as for claims 1-3, 5, 9-10, 12-13 and 18-20. Ma teaches an HIF2a siRNA that is a 20/21-mer with a sense and antisense strands (page 5406, ¶6).
Grosveld, Ma and Garcia do not teach the claimed siRNA comprising all of or a fragment of SEQ ID NO 2 or 3.
Kulisch teaches Dicer substrate siRNA Technology (title). Kulisch teaches longer dsRNAs are Dicer substrates which can facilitate loading the siRNA into the RISC complex (Fig 1; page 2, 13). Kulisch teaches the mechanism of Dicer-substrate siRNA mRNA targeting requires a double-stranded RNA comprising a guide strand that is 100% complementary to the target mRNA (i.e., an antisense strand), and a passenger strand that has the same sequence as the target mRNA (sense strand) (Fig 2). Kulisch teaches Dicer substrate siRNAs with 27-mer antisense strand and a 25-mer sense strand with a 2’ overhang on the 3’ end of the antisense strand (Fig 2). Kulisch teaches that an added benefit of Dicer-substrate siRNAs is their longevity of silencing (page 3, last ¶). Kulisch teaches siRNAs that are less than 30-nt in length does not activate the interferon-mediated inflammation pathway (page 3, 13).
Genbank teaches the mRNA reference sequence of EPAS1, which is also known as HIF2a (pages 2-3). Genbank teaches a sequence with 100% identity to Ma’s siRNA sense strand in the 3’UTR (positions 4791-4809). Genbank also teaches a sequence that is 100% identical to SEQ ID NO 2 in the 3’ UTR (positions 4731-4755). Genbank teaches the 3’ UTR is from position 2882 to 4918 (page 1), thus spanning 2037 nucleotides.
Regarding claims 7-8, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have designed and tried an HIF2a-targeting Dicer-substrate siRNA having a sense sequence with SEQ ID NO: 2 and guide/antisense strand with SEQ ID NO 3 in the anti-CD70 antibody conjugated nanoparticle rendered obvious above. It would have amounted to using Dicer-substrate siRNA design principles and the known HIF2a mRNA sequence to guide the design of a finite number of 27-29-mers with 100% complementarity to the HIF2a mRNA targeted to the same 3’UTR region as Ma. The possible number of Dicer substrate siRNAs that could be designed with 100% identity to the HIF2a mRNA 3’ UTR is 2017, a large but finite number. The skilled artisan would have predicted that Dicer-substrate siRNAs having SEQ ID NOs 2 and 3 could be designed from Ma’s siRNAs because 1) Ma’s siRNA also targets the 3’ UTR, which is 2000 nucleotides in length and 2) the claimed guide/passenger strands of the siRNAs have 100% complementary/identity to the known reference HIF2a RNA, which is also a known design principle for siRNAs taught by Kulisch. The skilled artisan would have been motivated to increase the length of Ma’s siRNA because Kulisch teaches Dicer substrate 27-30-mers have higher repression efficiencies than shorter siRNAs.
Conclusion
No claims are allowable.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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