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. Priority Receipt is acknowledged of certified copies of papers regarding Application Number CN 202110806912.8 as required by 37 CFR 1.55. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 07/15/2022 . It is noted, however, that applicant has not filed a certified copy of the CN2022108362378 application as required by 37 CFR 1.55. Applicant’s claim to priority from Foreign Applications CN202110806912.8 filed 07/16/2021 and CN2022108362378 filed 07/15/2022, and from International Application PCT/US2022/037519 filed 07/18/2022 and US Provisional Application No. 63/222,418 filed 07/16/2021 is hereby acknowledged. Election/Restrictions Applicant’s election of Invention Group I (claims 1-7 drawn to a composition comprising first and second siRNA duplexes targeting VEGFR2 and TGF β 1 ), and of SEQ ID NOs: 76 and 119 in Species Group A and of SEQ ID NOs: 23 and 33 in Species Group B (claims 1-7) in the reply filed on 03/02/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 6, 8-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and invention , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/02/2026 . Application Status This Application is a CON of International Application PCT/US2022/037519 filed 07/18/2022. Preliminary amendments to claims filed 06/20/2023 are hereby acknowledged. Claims 4-6 are currently amended. Claims 6, 8-12 are withdrawn from consideration. Therefore, claims 1- 5 and 7 are under consideration in this Office Action. Information Disclosure Statement The information disclosure statement (IDS) submitted on 03/07/2023 is hereby acknowledged . The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. However, t he listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Drawings The Drawings filed 03/07/2023 are hereby acknowledged and are acceptable. Nucleotide and/or Amino Acid Sequence Disclosures REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency - 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). See page s 10-12, 13, 31-33, 35 -37 ( No SEQ ID NO for amino acid sequences; only one SEQ ID NO present for sense and antisense strands ; No SEQ ID NO for sense and antisense strands with modifications). Required response – 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. Specification The disclosure is objected to because of the following informalities: the term “Tecentrip” should be read “Tecentri q ®” or “TECENTRIQ” (see page 38) . The term “ lipo2000” should be read “Lipofectamine™ 2000” (see pages 23 and 24). The term “MiiQ, Bio Rad” should be “MyiQ™, BioRad” (pages 19-20). The term “Cisplartin” should read “Cisplatin” (see page 39). Appropriate correction is required. The use of the term s “GraphPad Prism” (pages 25, 27, 29, 37, 39 and 40), “GemZar” (pages 37 and 40), “Tecentriq” (page 38), which are trade name s or mark s used in commerce, has been noted in this application. The term s should be accompanied by the generic terminology; furthermore the term s should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Claim Rejections - 35 USC § 102 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 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. Claims 1-3 and 7 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Lu (Lu, P.Y. et al. US 2013/0123330 A1, published May 16, 2013, cited on IDS filed 03/07/2023) . Regarding claim 1 , it recites “ A nanoparticle composition comprising a first siRNA duplex that targets VEGFR2, a second RNA duplex that targets TGF β 1 and a pharmaceutically acceptable carrier ”. Lu teaches “A composition comprising at least two different siRNA duplexes and a pharmaceutically acceptable carrier, wherein one of said siRNA duplexes binds to an mRNA molecule that encodes VEGF and the other of said siRNA duplexes binds to an mRNA molecule that encodes VEGFR2 ” (see page 26, claim 1). Lu further teaches “The composition of claim 1 further comprising an siRNA duplex that binds to an mRNA molecule that encodes TGFβ1 ” (see page 26, claim 2). Therefore, Lu teaches a composition that comprises both an siRNA duplex targeting VEGFR2 and an siRNA targeting TGFβ1 (see claims 1-2 and abstract). Lu also teaches that the composition is a nanoparticle (see [0019] and Figure 5). Regarding claim 2 , it recites “ wherein the pharmaceutical carrier is selected from the group consisting of a branched peptide, a polymer, a lipid, and a micelle ”. Lu teaches a Histidine-Lysine branched polymer for siRNA delivery (see [0019]). Lu further teaches that a pharmaceutically acceptable carrier can be a branched peptide, a polymer, a lipid, or a micelle (see [0046]). Regarding claim 3 , Lu further teaches that the Histidine-Lysine Polymer (HKP) is a polypeptide -based carrier (see [0058]). Regarding claim 7 , it recites “ The composition according to claim 1 comprising an HKP (+H) polypeptide ”. The Specification does not teach a specific definition for HKP(+H). However, the Specification teaches H3K4b(+H) as containing the unit KH3KH4[KH3] 2 K (see page 10, line 27). Lu teaches H3K( + H )4b with a structure of (R)K(R )-K(R )-(R )K(X) , wherein R= [KHHHKHHHHKHH-HKHHH] and X= C(O)NH2 (see [0097]). Therefore, Lu teaches an HKP(+H) structure. 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. 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. 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. Claim 4 is rejected under 35 U.S.C. § 103 as being unpatentable over Lu (Lu, P.Y. et al. US 2013/0123330 A1, published May 16, 2013, cited on IDS filed 03/07/2023) , as applied to claim 1 above, and in further view of Suhy (Suhy, D. et al. US 10,000,753 B2, published June 19, 2018), Lu(2) (Lu, P.Y. et al. US 8,735,567 B2, published May 27, 2014) , Chang (Chang, C. I. et al. “Asymmetruc shorter duplex siRNA structures trigger efficient gene silencing with reduced non specific effects”. Molecular Therapy, Vol. 17, No. 4 (2009), pp: 725-732) and Park (Park, J.H. et al. “Effect of siRNA with an asymmetric RNA/dTdT overhang on RNA interference activity”. Nucleic Acid Therapeutics, Vol. 24, No. 5 (2014), pp:364-371) . It is noted that the elements of claim 1 are anticipated by Lu. The rejection of claim 1 is described above and as follow: Regarding claim 1 , it recites “ A nanoparticle composition comprising a first siRNA duplex that targets VEGFR2, a second RNA duplex that targets TGF β 1 and a pharmaceutically acceptable carrier ”. Lu teaches “A composition comprising at least two different siRNA duplexes and a pharmaceutically acceptable carrier, wherein one of said siRNA duplexes binds to an mRNA molecule that encodes VEGF and the other of said siRNA duplexes binds to an mRNA molecule that encodes VEGFR2 ” (see page 26, claim 1). Lu further teaches “The composition of claim 1 further comprising an siRNA duplex that binds to an mRNA molecule that encodes TGFβ1 ” (see page 26, claim 2). Therefore, Lu teaches a composition that comprises both an siRNA duplex targeting VEGFR2 and an siRNA targeting TGFβ1 (see claims 1-2 and abstract). Lu also teaches that the composition is a nanoparticle (see [0019] and Figure 5). R egarding claim 4 , Lu does not teach a sequence from the group consisting of SEQ ID NOs: 41-130 for an antisense dsRNA targeting VEGFR2 and SEQ ID NOs: 1-40 for an antisense dsRNA targeting TGFβ1. However, a search for the sequence of SEQ ID NO: 76 lead to Suhy (US Patent No. 10,000,753 B2) . Suhy teaches two sequences SEQ ID NOs: 11 and 50 (see alignments below) that are 90.5% identical to instant Application’s SEQ ID NO s : 76 and 119 (Qy) as shown below . Result of alignment of SEQ ID NO: 76 (Qy) to Suhy’s SEQ ID NO: 11 (Db): US-14-759-401-11 Sequence 11, US/14759401 Patent No. 10000753 GENERAL INFORMATION APPLICANT: Benitec Biopharma Limited TITLE OF INVENTION: Age-related macular degeneration treatment FILE REFERENCE: M50054727:KAB CURRENT APPLICATION NUMBER: US/14/759,401 CURRENT FILING DATE: 2015-07-06 PRIOR APPLICATION NUMBER: US 61/750,086 PRIOR FILING DATE: 2013-01-08 NUMBER OF SEQ ID NOS: 150 SEQ ID NO 11 LENGTH: 21 TYPE: DNA ORGANISM: Homo sapiens Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 GGACTGGCTTTGGCCCAAT 19 ||||||||||||||||||| Db 3 GGACTGGCTTTGGCCCAAT 21 Result of alignment of SEQ ID NO: 119 (Qy) to Suhy’s SEQ ID NO: 50 (Db): US-14-759-401-50 Sequence 50, US/14759401 Patent No. 10000753 GENERAL INFORMATION APPLICANT: Benitec Biopharma Limited TITLE OF INVENTION: Age-related macular degeneration treatment FILE REFERENCE: M50054727:KAB CURRENT APPLICATION NUMBER: US/14/759,401 CURRENT FILING DATE: 2015-07-06 PRIOR APPLICATION NUMBER: US 61/750,086 PRIOR FILING DATE: 2013-01-08 NUMBER OF SEQ ID NOS: 150 SEQ ID NO 50 LENGTH: 21 TYPE: DNA ORGANISM: Homo sapiens Query Match 90.5%; Score 19; Length 21; Best Local Similarity 84.2%; Matches 16; Conservative 3; Mismatches 0; Indels 0; Gaps 0; Qy 1 ATTGGGCCAAAGCCAGTCC 19 |::|||||||||||||:|| Db 1 AUUGGGCCAAAGCCAGUCC 19 The alignment of Suhy’s SEQ ID NO: 11 to SEQ ID NO: 1 19 of instant Application shows that SEQ ID NO: 119 is complementary to Suhy’s SEQ ID NO: 11: US-14-759-401-11/c Sequence 11, US/14759401 Patent No. 10000753 GENERAL INFORMATION APPLICANT: Benitec Biopharma Limited TITLE OF INVENTION: Age-related macular degeneration treatment FILE REFERENCE: M50054727:KAB CURRENT APPLICATION NUMBER: US/14/759,401 CURRENT FILING DATE: 2015-07-06 PRIOR APPLICATION NUMBER: US 61/750,086 PRIOR FILING DATE: 2013-01-08 NUMBER OF SEQ ID NOS: 150 SEQ ID NO 11 LENGTH: 21 TYPE: DNA ORGANISM: Homo sapiens Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 ATTGGGCCAAAGCCAGTCC 19 ||||||||||||||||||| Db 21 ATTGGGCCAAAGCCAGTCC 3 Therefore, Suhy teaches a duplex siRNA comprising a sense and antisense strand targeting VEGFR2 mRNA and comprising sequences from SEQ ID NOs: 76 and 119. Lu(2) teaches combining multiple siRNAs for therapeutic use. Lu(2) teaches siRNA targeting TGFB1 mRNA (see Figures 11, 17, 19 and 21; see column s 7 and 8). Lu(2) teaches multiple siRNA targeting TGFB1 mRNA (see column 26, Table 2 ). In Table 2, the 21-mer No:3 is SEQ ID NO: 88 and the 23-mer No. 9 is SEQ ID NO: 104 ). A search for instant Application’s SEQ ID NO: 23 lead to SEQ ID NOs: 88 and 104 of Lu(2). Lu(2)’s SEQ ID NO: 88 (Db) has 90.5% sequence identity with instant Application SEQ ID NO: 23 (Qy) ; see below : US-12-741-645A-88 (NOTE: this sequence has 1 duplicate in the database searched. See complete list at the end of this report) Sequence 88, US/12741645A Patent No. 8735567 GENERAL INFORMATION APPLICANT: SIRNAOMICS, INC. TITLE OF INVENTION: MULTI-TARGETED RNAI THERAPEUTICS FOR SCARLESS WOUND TITLE OF INVENTION: HEALING OF SKIN FILE REFERENCE: SIR-005/P001-PCT CURRENT APPLICATION NUMBER: US/12/741,645A CURRENT FILING DATE: 2012-06-08 PRIOR APPLICATION NUMBER: PCT/US2008/012498 PRIOR FILING DATE: 2008-11-06 PRIOR APPLICATION NUMBER: 60/985,820 PRIOR FILING DATE: 2007-11-06 NUMBER OF SEQ ID NOS: 333 SEQ ID NO 88 LENGTH: 21 TYPE: DNA ORGANISM: Artificial Sequence FEATURE: OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 AACTATTGCTTCAGCTCCA 19 ||||||||||||||||||| Db 3 AACTATTGCTTCAGCTCCA 21 Lu(2) ’s SEQ ID NO: 104 (Db) has 90.5% sequence identity with instant Application’s SEQ ID NO: 23 (Qy); see below: US-12-741-645A-104 (NOTE: this sequence has 1 duplicate in the database searched. See complete list at the end of this report) Sequence 104, US/12741645A Patent No. 8735567 GENERAL INFORMATION APPLICANT: SIRNAOMICS, INC. TITLE OF INVENTION: MULTI-TARGETED RNAI THERAPEUTICS FOR SCARLESS WOUND TITLE OF INVENTION: HEALING OF SKIN FILE REFERENCE: SIR-005/P001-PCT CURRENT APPLICATION NUMBER: US/12/741,645A CURRENT FILING DATE: 2012-06-08 PRIOR APPLICATION NUMBER: PCT/US2008/012498 PRIOR FILING DATE: 2008-11-06 PRIOR APPLICATION NUMBER: 60/985,820 PRIOR FILING DATE: 2007-11-06 NUMBER OF SEQ ID NOS: 333 SEQ ID NO 104 LENGTH: 23 TYPE: DNA ORGANISM: Artificial Sequence FEATURE: OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide Query Match 90.5%; Score 19; Length 23; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 AACTATTGCTTCAGCTCCA 19 ||||||||||||||||||| Db 4 AACTATTGCTTCAGCTCCA 22 An alignment of Lu(2)’s SEQ ID NO: 88 (Db) with instant Application’s SEQ ID NO: 33 (Qy) shows that the sequences are complementary over 19 nucleobases, see below: Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 TGGAGCTGAAGCAATAGTT 19 ||||||||||||||||||| Db 21 TGGAGCTGAAGCAATAGTT 3 Therefore, LU(2) teaches sequences of TGFB1 that can be used to design and produce a dsRNA duplex targeting TGFB1 mRNA. However, Suhy and Lu(2) do not teach the whole sequences of SEQ ID NOs: 76 / 119 and 23/33. SEQ ID NO: 76 consists of the following sequence: “GGACTGGCTTTGGCCCAAT TT ” . SEQ ID NO: 119 consists of the sequence: “ATTGGGCCAAAGCCAGTCC TT ”. SEQ ID NO: 23 consists of the sequence : “AACTATTGCTTCAGCTCCA TT ”. SEQ ID NO: 33 consists of the sequence: “ TGGAGCTGAAGCAATAGTT TT ”. The sequences of instant Application comprise an extra double T compared to the sequences taught by Suhy and Lu(2). Chang teaches that asymmetric shorter duplex siRNAs trigger efficient gene silencing with reduced non-specific effects (see title and abstract). Chang teaches that the current standard for synthetic siRNA structures is a 19-base-pair duplex region with a 3’ overhang of 2 nucleotides (see abstract). Park teaches that accurate target recognition is dictated by thermodynamics that can be influenced by minor changes in the design of the siRNAs. Park teaches that adding an asymmetric RNA/deoxythymidine dinucleotide (dTdT) overhangs improves affinity of the RISC (RNA-induced silencing complexes) to the desired target, thereby increasing the specificity of target silencing (see title and abstract). Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention to have modified the sequences of the siRNAs taught by Suhy and Lu(2), adding an thymidine dinucleotide overhang to the sequences . It would have been obvious to design dsRNA as duplexes and substituted the siRNAs taught by Lu with the siRNAs of Suhy and Lu(2) modified by Chang/ Park. One with ordinary skills in the art, motivated in increasing the specificity of gene silencing, and therefore the efficiency as a result of decreasing off-targets effects, could have performed these modifications with a reasonable expectation of success and arrived at the claimed invention. Claim 5 is rejected under 35 U.S.C. § 103 as being unpatentable over Lu (Lu, P.Y. et al. US 2013/0123330 A1, published May 16, 2013, cited on IDS filed 03/07/2023) , as applied to claim 1 above, and in further view of Suhy (Suhy, D. et al. US 10,000,753 B2, published June 19, 2018), Lu(2) (Lu, P.Y. et al. US 8,735,567 B2, published May 27, 2014), Chang ( Chang, C. I. et al. “Asymmetruc shorter duplex siRNA structures trigger efficient gene silencing with reduced nonspecific effects”. Molecular Therapy, Vol. 17, No. 4 (2009), pp: 725-732 ), Park (Park, J.H. et al. “Effect of siRNA with an asymmetric RNA/dTdT overhang on RNA interference activity”. Nucleic Acid Therapeutics, Vol. 24, No. 5 (2014), pp:364-371) , Bennett (Bennett, C. F. et al. US 6,734,017 B2, published May 11, 2004) and Zewge (Zewge, D. et al. “High-Throughput chemical modification of oligonucleotides for systematic structure-activity relationship evaluation”. Bioconjugate Chemistry, Vol. 25 (2014), pp: 2222-2232) . It is noted that the elements of claim 1 are anticipated by Lu. The rejection of claim 1 is described above and as follow: Regarding claim 1 , it recites “ A nanoparticle composition comprising a first siRNA duplex that targets VEGFR2, a second RNA duplex that targets TGF β 1 and a pharmaceutically acceptable carrier ”. Lu teaches “A composition comprising at least two different siRNA duplexes and a pharmaceutically acceptable carrier, wherein one of said siRNA duplexes binds to an mRNA molecule that encodes VEGF and the other of said siRNA duplexes binds to an mRNA molecule that encodes VEGFR2 ” (see page 26, claim 1). Lu further teaches “The composition of claim 1 further comprising an siRNA duplex that binds to an mRNA molecule that encodes TGFβ1 ” (see page 26, claim 2). Therefore, Lu teaches a composition that comprises both an siRNA duplex targeting VEGFR2 and an siRNA targeting TGFβ1 (see claims 1-2 and abstract). Lu also teaches that the composition is a nanoparticle (see [0019] and Figure 5). Regarding claim 5 , Lu does not teach a sequence from the group consisting of SEQ ID NOs: 131-146 for an antisense dsRNA targeting VEGFR2 and SEQ ID NOs: 147-154 for an antisense dsRNA targeting TGFβ1. Instant Application’s SEQ ID NO: 135 correspond to a modified SEQ ID NO: 76 . Instant Application’s SEQ ID NO: 1 43 correspond to a modified SEQ ID NO: 1 19 . Instant Application’s SEQ ID NO: 147 correspond to a modified SEQ ID NO: 23 . Instant Application’s SEQ ID NO: 151 correspond to a modified SEQ ID NO: 33 . A search for the sequence of SEQ ID NO: 76 lead to Suhy (US Patent No. 10,000,753 B2). Suhy teaches two sequences SEQ ID NOs: 11 and 50 (see alignments below) that are 90.5% identical to instant Application’s SEQ ID NOs: 76 and 119 (Qy) as shown below. Result of alignment of SEQ ID NO: 76 (Qy) to Suhy’s SEQ ID NO: 11 (Db): US-14-759-401-11 Sequence 11, US/14759401 Patent No. 10000753 GENERAL INFORMATION APPLICANT: Benitec Biopharma Limited TITLE OF INVENTION: Age-related macular degeneration treatment FILE REFERENCE: M50054727:KAB CURRENT APPLICATION NUMBER: US/14/759,401 CURRENT FILING DATE: 2015-07-06 PRIOR APPLICATION NUMBER: US 61/750,086 PRIOR FILING DATE: 2013-01-08 NUMBER OF SEQ ID NOS: 150 SEQ ID NO 11 LENGTH: 21 TYPE: DNA ORGANISM: Homo sapiens Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 GGACTGGCTTTGGCCCAAT 19 ||||||||||||||||||| Db 3 GGACTGGCTTTGGCCCAAT 21 Result of alignment of SEQ ID NO: 119 (Qy) to Suhy’s SEQ ID NO: 50 (Db): US-14-759-401-50 Sequence 50, US/14759401 Patent No. 10000753 GENERAL INFORMATION APPLICANT: Benitec Biopharma Limited TITLE OF INVENTION: Age-related macular degeneration treatment FILE REFERENCE: M50054727:KAB CURRENT APPLICATION NUMBER: US/14/759,401 CURRENT FILING DATE: 2015-07-06 PRIOR APPLICATION NUMBER: US 61/750,086 PRIOR FILING DATE: 2013-01-08 NUMBER OF SEQ ID NOS: 150 SEQ ID NO 50 LENGTH: 21 TYPE: DNA ORGANISM: Homo sapiens Query Match 90.5%; Score 19; Length 21; Best Local Similarity 84.2%; Matches 16; Conservative 3; Mismatches 0; Indels 0; Gaps 0; Qy 1 ATTGGGCCAAAGCCAGTCC 19 |::|||||||||||||:|| Db 1 AUUGGGCCAAAGCCAGUCC 19 The alignment of Suhy’s SEQ ID NO: 11 to SEQ ID NO: 119 of instant Application shows that SEQ ID NO: 119 is complementary to Suhy’s SEQ ID NO: 11: US-14-759-401-11/c Sequence 11, US/14759401 Patent No. 10000753 GENERAL INFORMATION APPLICANT: Benitec Biopharma Limited TITLE OF INVENTION: Age-related macular degeneration treatment FILE REFERENCE: M50054727:KAB CURRENT APPLICATION NUMBER: US/14/759,401 CURRENT FILING DATE: 2015-07-06 PRIOR APPLICATION NUMBER: US 61/750,086 PRIOR FILING DATE: 2013-01-08 NUMBER OF SEQ ID NOS: 150 SEQ ID NO 11 LENGTH: 21 TYPE: DNA ORGANISM: Homo sapiens Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 ATTGGGCCAAAGCCAGTCC 19 ||||||||||||||||||| Db 21 ATTGGGCCAAAGCCAGTCC 3 Therefore, Suhy teaches a duplex siRNA comprising a sense and antisense strand targeting VEGFR2 mRNA and comprising sequences from SEQ ID NOs: 76 and 119. Lu(2) teaches combining multiple siRNAs for therapeutic use. Lu(2) teaches siRNA targeting TGFB1 mRNA (see Figures 11, 17, 19 and 21; see columns 7 and 8). Lu(2) teaches multiple siRNA targeting TGFB1 mRNA (see column 26, Table 2). In Table 2, the 21-mer No:3 is SEQ ID NO: 88 and the 23-mer No. 9 is SEQ ID NO: 104). A search for instant Application’s SEQ ID NO: 23 lead to SEQ ID NOs: 88 and 104 of Lu(2). Lu(2)’s SEQ ID NO: 88 (Db) has 90.5% sequence identity with instant Application SEQ ID NO: 23 (Qy); see below: US-12-741-645A-88 (NOTE: this sequence has 1 duplicate in the database searched. See complete list at the end of this report) Sequence 88, US/12741645A Patent No. 8735567 GENERAL INFORMATION APPLICANT: SIRNAOMICS, INC. TITLE OF INVENTION: MULTI-TARGETED RNAI THERAPEUTICS FOR SCARLESS WOUND TITLE OF INVENTION: HEALING OF SKIN FILE REFERENCE: SIR-005/P001-PCT CURRENT APPLICATION NUMBER: US/12/741,645A CURRENT FILING DATE: 2012-06-08 PRIOR APPLICATION NUMBER: PCT/US2008/012498 PRIOR FILING DATE: 2008-11-06 PRIOR APPLICATION NUMBER: 60/985,820 PRIOR FILING DATE: 2007-11-06 NUMBER OF SEQ ID NOS: 333 SEQ ID NO 88 LENGTH: 21 TYPE: DNA ORGANISM: Artificial Sequence FEATURE: OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 AACTATTGCTTCAGCTCCA 19 ||||||||||||||||||| Db 3 AACTATTGCTTCAGCTCCA 21 Lu(2)’s SEQ ID NO: 104 (Db) has 90.5% sequence identity with instant Application’s SEQ ID NO: 23 (Qy); see below: US-12-741-645A-104 (NOTE: this sequence has 1 duplicate in the database searched. See complete list at the end of this report) Sequence 104, US/12741645A Patent No. 8735567 GENERAL INFORMATION APPLICANT: SIRNAOMICS, INC. TITLE OF INVENTION: MULTI-TARGETED RNAI THERAPEUTICS FOR SCARLESS WOUND TITLE OF INVENTION: HEALING OF SKIN FILE REFERENCE: SIR-005/P001-PCT CURRENT APPLICATION NUMBER: US/12/741,645A CURRENT FILING DATE: 2012-06-08 PRIOR APPLICATION NUMBER: PCT/US2008/012498 PRIOR FILING DATE: 2008-11-06 PRIOR APPLICATION NUMBER: 60/985,820 PRIOR FILING DATE: 2007-11-06 NUMBER OF SEQ ID NOS: 333 SEQ ID NO 104 LENGTH: 23 TYPE: DNA ORGANISM: Artificial Sequence FEATURE: OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide Query Match 90.5%; Score 19; Length 23; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 AACTATTGCTTCAGCTCCA 19 ||||||||||||||||||| Db 4 AACTATTGCTTCAGCTCCA 22 An alignment of Lu(2)’s SEQ ID NO: 88 (Db) with instant Application’s SEQ ID NO: 33 (Qy) shows that the sequences are complementary over 19 nucleobases, see below: Query Match 90.5%; Score 19; Length 21; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 TGGAGCTGAAGCAATAGTT 19 ||||||||||||||||||| Db 21 TGGAGCTGAAGCAATAGTT 3 Therefore, LU(2) teaches sequences of TGFB1 that can be used to design and produce a dsRNA duplex targeting TGFB1 mRNA. However, Suhy and Lu(2) do not teach the whole sequences of SEQ ID NOs: 76/119 and 23/33. SEQ ID NO: 76 consists of the following sequence: “GGACTGGCTTTGGCCCAAT TT ” . SEQ ID NO: 119 consists of the sequence: “ATTGGGCCAAAGCCAGTCC TT ”. SEQ ID NO: 23 consists of the sequence : “AACTATTGCTTCAGCTCCA TT ”. SEQ ID NO: 33 consists of the sequence: “ TGGAGCTGAAGCAATAGTT TT ”. The sequences of instant Application comprise an extra double T compared to the sequences taught by Suhy and Lu(2). Chang teaches that asymmetric shorter duplex siRNAs trigger efficient gene silencing with reduced non-specific effects (see title and abstract). Chang teaches that the current standard for synthetic siRNA structures is a 19-base-pair duplex region with a 3’ overhang of 2 nucleotides (see abstract). Park teaches that accurate target recognition is dictated by thermodynamics that can be influenced by minor changes in the design of the siRNAs. Park teaches that adding an asymmetric RNA/deoxythymidine dinucleotide (dTdT) overhangs improves affinity of the RISC (RNA-induced silencing complexes) to the desired target, thereby increasing the specificity of target silencing (see title and abstract). Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention to have modified the sequences of the siRNAs taught by Suhy and Lu(2), adding an thymidine dinucleotide overhang to the sequences. It would have been obvious to design dsRNA as duplexes and substituted the siRNAs taught by Lu with the siRNAs of Suhy and Lu(2) modified by Chang/ Park. One with ordinary skills in the art, motivated in increasing the specificity of gene silencing, and therefore the efficiency as a result of decreasing off-targets effects, could have performed these modifications with a reasonable expectation of success and arrived at the claimed invention. However, the combination of Lu, Suhy, Lu(2) and Chang/Park does not teach the modifications of SEQ ID NOs: 135, 143, 147 and 151. However, Bennett also teaches antisense molecules against VEGFR2 mRNA; among others, Bennett teaches an antisense oligonucleotide comprising 19 nucleotides with 100% local similarity to SEQ ID NO: 119 (Qy) see alignment below: RESULT 2 US-09-967-655-27 Sequence 27, US/09967655 Patent No. 6734017 GENERAL INFORMATION APPLICANT: C. Frank Bennett APPLICANT: Andrew T. Watt TITLE OF INVENTION: ANTISENSE MODULATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2 TITLE OF INVENTION: EXPRESSION FILE REFERENCE: RTS-0227 CURRENT APPLICATION NUMBER: US/09/967,655 CURRENT FILING DATE: 2001-09-28 NUMBER OF SEQ ID NOS: 95 SEQ ID NO 27 LENGTH: 20 TYPE: DNA ORGANISM: Artificial Sequence FEATURE: OTHER INFORMATION: Antisense Oligonucleotide Query Match 90.5%; Score 19; Length 20; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 ATTGGGCCAAAGCCAGTCC 19 ||||||||||||||||||| Db 1 ATTGGGCCAAAGCCAGTCC 19 Bennett teaches that these antisense oligonucleotides against VEGFR2 mRNA can be modified, having a phosphate group (phosphorylation) at the 5’ end (see column 10, lines 49-55); a modified backbone comprising phospho ro thioates internucleo t ide linkages among other possibilities (see column 11, lines 12-24); Fluor o modifications at position 2’ (see column 12, lines 32-38); 2’ OME modifications (see column 40, “Example 5”, lines 41-55) . Zewge teaches using high-throughput chemical modification of oligonucleotides for systematic structure-activity relationship evaluation (see title). Zewge teaches that oligonucleotides can be modified at any position, on all residues, internal or terminal residues (see Figure 1) and can be linked together using click-chemistry (see Table 1) . In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “ The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability ” . KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007). It would have been obvious to one with ordinary skills, before the effective filing date of the claimed invention to have mass produced synthetic siRNA based on known sequences as taught by Lu, Suhy, Lu(2) and Bennett modified by Chang/Park, and modified these siRNAs as taught by Bennett, and selected the most effective ones using high-throughput method of screening. One with ordinary skills in the art, motivated in improving already known siRNAs and sequences could have performed these modifications with a reasonable expectation of success and arrived at the claimed invention. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT ALEXANDRA G DACE DENITO whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (703)756-4752 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday-Friday, 8:30-5:00EST. 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Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /A.D./ Examiner, Art Unit 1636 /NANCY J LEITH/ Primary Examiner, Art Unit 1636