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 .
Election/Restrictions
Applicant's election with traverse of Group II, claims 4-5 and 32-43, in the reply filed on 4 May 2026 is acknowledged. The traversal is on the ground(s) that claims 44 and 51 are drawn towards methods of administering the pharmaceutical composition of claim 43 to a subject, which is a pharmaceutical composition comprising the chimera of claim 4 and a pharmaceutically acceptable carrier. Accordingly, Applicant alleges that it will not be an undue burden to include claims 44 and 51 for search and examination.
This is not found persuasive. Because the method of claims 44 and 51 are drawn towards methods of reducing tumor burden in a subject via the administration of an aptamer-siRNA constrict of claim 4 that is not limited to a specific siRNA sequence, there is a non-prior art issue under 35 USC 112(a) that results in a burden when the method, and not the composition claim, is examined per MPEP 808.02. Because Applicant has not limited the siRNA sequence in claim 4 to any specific siRNA sequence, yet the aptamer-siRNA construct must possess a specific function in claims 44 and 51, there is both an enablement and written description issue that arises when claims 44 and 51 are examined because Applicant has not provided adequate written description nor enablement support for the extremely broad species of compositions comprising any siRNA sequence that can perform the specific claimed function of reducing tumor burden in a subject. Thus, there is a burden when examining the method claims of 44 and 51 that is not present when examining only the composition claims of claims 4 and 32.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-2 and 44-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 timely traversed the restriction (election) requirement in the reply filed on 4 May 2026.
Applicant’s election without traverse of the species of (j) NR4Aa and NR4A3 (see Claims 5 and 41-42), the aptamer-siRNA construct comprising aptamers that specifically bind to a protein of interest (see Claim 32), CTLA4 (see Claims 37 and 51), SEQ ID NO: 22 (see Claim 38), in the reply filed on 4 May 2026 is acknowledged.
Claims 39-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of an aptamer-siRNA construct that specifically binds to EPCAM, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4 May 2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
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 – Nucleotide and/or amino acid sequences appearing in the drawings, specifically in FIGS. 2A-3B, 11A-11C, 13A-13B, 15, 18A-18G, 25A, 26A, 27A-27C, 27E-27F, 28A, 30A-30C, and 34A-38B are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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.
Claim Objections
Regarding claims 32 and 34, MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.” Accordingly, the phrases “a.” and “b.” in the claims are objected to. Appropriate correction is required.
Claim Interpretation
Claims 4, 32, and 34 recite "a siRNA that is processed by cellular RNAi machinery to produce one or more siRNAs." This is a product-by-process claim. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by- process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (MPEP 2113(I)).
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.
(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.
Claim(s) 4, 32-34, 36, and 43 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018).
Regarding claims 4 and 32-34, for the purposes of examination the claims are interpreted as claiming the use of at least two individual, different, siRNAs that can be processed by cellular machinery to silence two different genes.
Liu is drawn towards an invention concerned with an aptamer platform capable of silencing one or more genes in vivo (Abstract). Liu teaches that the object of the invention is to treat cancer using non-antibody therapies that have reduced off-target effects via the targeting and silencing of known oncogenes (Col. 2, lines 55-62; Col 3, lines 4-18). Liu claims the use of a pharmaceutical composition comprising an aptamer-siRNA construct comprising: first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a target protein; and an siRNA construct between the first and second ends, wherein the siRNA construct is processed by cellular RNAi machinery to produce at least two different siRNAs that specifically inhibit expression of two or more different genes in a cell expressing the target protein (see Claim 1). Liu teaches the use of an aptamer-siRNA construct comprising two HER2 aptamers flanking an EGFR siRNA, or an HER2 and an HER3 aptamer, wherein the aptamers and siRNA molecules are linked to one another though the use of adenosine linkers (Col 3, lines 58-67; see Figs. 1A and 11A; see claims 1 and 4-5). Liu teaches that “the disclosed aptamer-siRNA construct can be processed by cellular machinery to produce separate and active siRNAs that inhibit expression of three different genes” and can “simultaneously silence EGFR, HER2, and HER3 in vivo” (Col. 3, lines 26-32).
Regarding claim 36, Liu teaches that the linkers may comprise 4 unpaired poly-adenosines present between the siRNA and aptamers (Col. 8, lines 20-25; see Fig. 1A and 11A). Liu teaches that the linkers help to warrant the siRNA cleavage with dicer, since dicer is able to measure and cut 21-25 nt RNA duplexes (Col. 8, lines 20-25).
Regarding claim 43, Liu teaches that the aptamer composition may be present within a pharmaceutical composition in order to downregulate at least two different genes in a target cell (Col. 3, lines 46-49).
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(s) 4-5, 32-34, 36, and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018) as applied to claims 4, 32-34, 36, and 43 above, and further in view of Li (PG Pub No. US 2007/0184459 A1) and Tiemann ("Dual-targeting siRNAs." Rna 16.6 (2010): 1275-1284).
Regarding claims 4 and 32-34, for the purposes of examination the claims are interpreted as claiming the use of a single siRNA molecule that can be processed by cellular machinery to silence two different genes.
Regarding claims 4, 32-34, 36, and 43, the applicable teachings of Liu are discussed above in the currently outstanding 35 USC 102 rejection of record.
Liu does not teach or suggest that a single siRNA molecule may be processed by cellular machinery to silence the expression of two or more genes (Claims 4, 32, and 34). Liu does not teach or suggest that the siRNA targets the different genes NR4A1 and NR4A3 (Claim 5). Liu does not teach or suggest that the siRNA construct can produce two siRNAs that inhibit the expression of three or more different genes (Claim 33).
Li is drawn towards an invention concerned with identifying agents useful for inhibiting cancer cells by binding to various nuclear receptor proteins (Abstract). Li teaches that knockdown of a number of nuclear receptor proteins expressed in cancerous tissue, as well as the genes or mRNA encoding such proteins, results in the death of the cancer cells, reduction in their size, a decrease in their growth or an increase in sensitization to undergo apoptosis ([0003]). Li teaches the use of siRNA sequences that are directed against NR4A1 resulted in the knockdown of NR4A1 mRNA and subsequent increase in apoptotic cell death of cancerous cells ([0047]; see Fig. 13). Similarly, Li teaches that the administration of siRNA targeting NR4A3 resulted in the knockdown of NR4A3 mRNA and the inhibition of growth of cancerous cells ([0239]-[0249]).
Tiemann is drawn towards a study concerned with dual-targeting siRNAs (Abstract). Tiemann teaches the design of a single dual-targeting siRNA molecule that can be processed by Dicer in order to silence the expression of two different genes (Abstract). Tiemann teaches the use of a single siRNA molecule that was able to target and knockdown the expression of both BCL6 and STAT3 simultaneously (pg. 1276, 1278; see Figure 1 and Table 1). Tiemann teaches that the dual-targeting siRNAs work as effectively as their mono-functional equivalents (pg. 1280). Tiemann teaches that an advantage of the dual-targeting design compared with two mono-functional siRNAs is that there are two fewer strands that compete for RISC entry, thereby minimizing potential off-targeting (pg. 1280).
Therefore, with regard to the claimed functional limitation that a single siRNA molecule silences the expression of two or more genes, or the claimed functional limitation wherein two or more siRNA molecules can silence three or more genes, it would have been obvious to have modified the siRNA sequences of Liu such that they could individually target two or more genes because it would have merely amounted to a simple substitution of one known functional siRNA construct for another to achieve predictable results. Because Tiemann teaches that the dual-targeting siRNA molecules performed the same function as mono-targeting siRNA molecules, one of ordinary skill in the art would have expected the substitution of one of Liu’s siRNA molecules for a single dual-targeting siRNA molecule to have predictably resulted in the silencing of two or more genes of interest. Additionally, because Tiemann teaches that dual-targeting siRNAs advantageously result in fewer strands that compete for RISC entry, one would have been motivated to have done so.
Further, with regard to the specific claimed target genes, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the dual-targeting siRNA sequence of Liu such that it targeted NR4A1 and NR4A3 because it would have merely amounted to a simple substitution of one known siRNA sequence for another to achieve predictable results. Because both Liu and Li utilized siRNA molecules for the knockdown of a target gene’s expression within a cell, then it would have been predictable to have used the NR4A1 and NR4A3 siRNA sequences of Li within the construct of Liu in order to achieve knockdown of NR4A1 and NR4A3 mRNA. Additionally, because Tiemann teaches that dual-guided siRNAs can target different genes and function as effectively as mono-targeting siRNA, one would have expected the dual-targeting siRNA molecule to have predictably performed the same function as mono-targeting siRNA that targets NR4A1 and NR4A3 individually. Since Li teaches that silencing NR4A1 and NR4A3 resulted in the death of cancerous cells, and Liu teaches that the siRNA-aptamer construct allows for the targeted delivery of siRNAs targeting oncogenes expressed from specific cells for the treatment of cancer, one would have been motivated to have utilized a dual-targeting siRNA construct within the siRNA-aptamer construct of Liu.
Claim(s) 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018) in view of Li (PG Pub No. US 2007/0184459 A1) and Tiemann ("Dual-targeting siRNAs." Rna 16.6 (2010): 1275-1284) as applied to claims 4-5, 32-34, 36, and 43 above, and further in view of Forrester (PG Pub No. WO 2018/163051 A1).
Regarding claim 35, Liu in view of Li and Tiemann renders obvious claims 4-5, 32-34, 36, and 43 as described above.
Liu in view of Li and Tiemann does not teach or suggest that the genes comprise UBB and UBC (Claim 35).
Forrester is drawn towards an invention concerned with reducing the expression level of a UBB and/or a UBC gene product to treat cancer (Abstract). Forrester teaches the use of siRNA molecules that can target and knockdown UBB and UBC mRNA ([00133]). Forrester teaches that in ovarian cancer cells, knockdown of either UBC or UBB individually is tolerated; however, silencing of these genes in combination results in synthetic lethality ([00151]; see Fig. 4A-4C).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the dual-targeting siRNA sequence of Liu in view of Li and Tiemann such that it targeted UBB and UBC because it would have merely amounted to a simple substitution of one known siRNA sequence for another to achieve predictable results. Because each of the siRNA molecules were used in a similar way (i.e., for the knockdown of a target gene’s expression within a cell) then it would have been predictable to have used the UBB and UBC siRNA sequences of Forrester within the construct of Liu in order to successfully achieve knockdown of UBB and UBC mRNA. Additionally, because Forrester teaches that silencing UBB and UBC resulted in the death of cancerous cells, one would have been motivated to do so.
Claim(s) 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018) in view of Li (PG Pub No. US 2007/0184459 A1) and Tiemann ("Dual-targeting siRNAs." Rna 16.6 (2010): 1275-1284) as applied to claims 4-5, 32-34, 36, and 43 above, and further in view of Herrmann ("CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells." The Journal of clinical investigation 124.7 (2014): 2977-2987).
Regarding claim 37, Liu in view of Li and Tiemann renders obvious claims 4-5, 32-34, 36, and 43 as described above.
Liu in view of Li and Tiemann does not teach or suggest that that the target protein comprises CTLA4 (Claim 37).
Herrmann is drawn towards a study concerned with the use of a covalently linked siRNA to an aptamer that selectively binds CTLA4, termed "CTLA4ᵃPt- siRNA", and allows for the gene silencing of STAT3 through the processing of the siRNA in tumor-associated and malignant CD8⁺ T cells (i.e., a construct comprising an aptamer that specifically binds at least one target protein on an immune cell and an siRNA that is processed by cellular machinery to produce one or more siRNAs) (Abstract, pg. 2977-2978; see Fig. 1 and Supplementary Fig. 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the aptamer and target protein of Liu in view of Li and Tiemann such that it was CTLA-4 because it would have merely amounted to a simple substitution of one known aptamer that can deliver an siRNA molecule to a target cell of interest for another to achieve predictable results. Because each of the aptamers were used in a similar way, namely for the knockdown of a target gene’s expression within a cell via the delivery of an siRNA molecule to the cell via an aptamer, then it would have been predictable to have used the CTLA-4 aptamer of Herrmann within the construct of Liu in order to predictably successfully achieve targeted delivery of siRNA molecules intended to suppress genes of interest within malignant T cells.
Claim(s) 38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018) in view of Li (PG Pub No. US 2007/0184459 A1) and Tiemann ("Dual-targeting siRNAs." Rna 16.6 (2010): 1275-1284) as applied to claims 4-5, 32-34, 36, and 43 above, and further in view of Khvorova (PG Pub No. US 2007/0031844 A1), Khvorova sequence alignment (accessed 22 June 2026), ATL68957 (sequence alignment published 27 November 2008), and Cui ("Down-regulation of MAP2K1 by miR-539 inhibits hepatocarcinoma progression." Biochemical and biophysical research communications 504.4 (2018): 784-791).
Regarding claim 38, Liu in view of Li and Tiemann renders obvious claims 4-5, 32-34, 36, and 43 as described above.
Liu in view of Li and Tiemann does not teach or suggest that that the construct comprises the nucleic acid sequence of SEQ ID NO: 22 (Claim 38).
Khvorova is drawn towards an invention concerned with methods of generating siRNA sequences that can be utilized to silence genes of interest (Abstract). Khvorova teaches the use of an siRNA sequence that has 100% identity to the claimed SEQ ID NO: 22 (see SEQ ID NO: 398652 attached sequence alignment).
ATL68957 is drawn towards a sequence alignment describing a human MAP2K mRNA target sequence for mdRNA in the field of RNA interference (pg. 1). ATL68957 teaches that the alignment is 19 nucleotides in length and comprises 100% identity to the claimed SEQ ID NO: 22 (pg. 3).
Cui is drawn towards a study concerned with the downregulation of MAP2K1 in hepatocellular carcinoma cells (Abstract). Cui teaches that cell viability of the cells was significantly decreased in MAP2K1 siRNA transfected cells in comparison to control (see Fig. 4C on pg. 788), indicating that MAP2K1 promoted the proliferation of hepatocellular carcinoma cells, and knockout of MAP2K1 inhibited the proliferation (pg. 787).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the siRNA sequence of Liu such that it comprised the claimed SEQ ID NO: 22 because it would have merely amounted to a simple substitution of one known siRNA sequence for another to achieve the predictable result of knocking down MAP2K mRNA. Because each of the siRNA molecules could be used in a similar way (i.e., for the knockdown of a target gene’s expression), and the claimed SEQ ID NO: 22 is a known RNAi target sequence present within MAP2K mRNA, then it would have been predictable to have used the claimed SEQ ID NO: 22 within the construct of Liu in order to successfully achieve knockdown of a MAP2K gene to which the claimed SEQ ID NO: 22 is targeted. Additionally, because Cui teaches that knockdown of MAP2K expression results in the inhibition of proliferation of cancerous cells, one would have been motivated to have done so.
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.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of copending Application No. 18/558,951 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claim anticipates the instant claim.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 4, copending claim 6 claims a therapeutic construct comprising a ligand that specifically binds at least one target protein and a cytotoxin that is processed by cellular RNAi machinery to produce one or more siRNAs wherein at least one of said siRNAs specifically inhibits the expression of two or more different genes.
Claim 32-36 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-7 of copending Application No. 18/558,951 (reference application) in view of Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 32-34, 36, and 43, copending claim 6 claims a therapeutic construct comprising a ligand that specifically binds at least one target protein and a cytotoxin that is processed by cellular RNAi machinery to produce one or more siRNAs wherein at least one of said siRNAs specifically inhibits the expression of two or more different genes.
Copending claim 6 does not claim that the siRNA comprises first and second ends comprising an aptamer (Claims 32 and 34). Copending claim 6 does not claim that three or more genes are inhibited by the chimeric siRNA molecule (Claim 33). Copending claim 6 does not claim that unpaired linkers comprising two to four adenines are between each aptamer and siRNA, and between each siRNA (Claim 36). Copending claim 6 does not claim a pharmaceutically acceptable carrier (Claim 43).
The applicable teachings of Liu are discussed above as applied to claims 4 and 32. Liu further teaches that using multiple aptamers specific to a cell surface protein increases efficiency of delivering the siRNAs to the targeted cell (Col 3, lines 24-26).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending composition such that it contained aptamers flanking the siRNAs that can inhibit the expression of three different genes via the use of linkers comprising 4 unpaired adenines, alongside the use of a pharmaceutically acceptable carrier, because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because the copending claims are directed towards a similar construct as Liu (i.e., an chimeric siRNA molecule that is directed towards a target protein present on a cell via the use of an aptamer), one of ordinary skill in the art would have expected the three siRNA sequences of Liu, alongside the aptamers of Liu, linked to one another via the use of 4 unpaired adenines to have predictably resulted in a functional chimeric siRNA construct that could be utilized to silence multiple genes when present within the copending claims. Additionally, since Liu teaches that the addition of multiple aptamers to the chimeric siRNA construct is beneficial, one would have been motivated to have done so.
Regarding claim 35, copending claim 7 claims that the different gens comprise UBB and UBC.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6 of copending Application No. 18/558,951 as applied to claim 4 above, further in view of Li (PG Pub No. US 2007/0184459 A1).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 5, copending claims 6 anticipates claim 4 as described above.
Copending claim 6 does not teach or suggest that the different genes comprise NR4A1 and NR4A3 (Claim 5).
The applicable teachings of Li are discussed above as applied to claim 5.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the 35 USC 103 rejection of claim 5 above.
Claim 37 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-7 of copending Application No. 18/558,951 in view of Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018) as applied to claims 32-36 and 43 above, further in view of Herrmann ("CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells." The Journal of clinical investigation 124.7 (2014): 2977-2987).
Regarding claim 8, copending claims 6-7 in view of Liu renders obvious claims 32-36 and 43 as described above.
Copending claims 6-7 in view of Liu does not teach or suggest that the target protein comprises CTLA4 (Claim 37).
The applicable teachings of Herrmann are discussed above as applied to claim 8.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the 35 USC 103 rejection of claim 37 above.
Claim 38 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-7 of copending Application No. 18/558,951 in view of Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018) as applied to claims 32-36 and 43 above, further in view of Khvorova (PG Pub No. US 2007/0031844 A1) and Khvorova sequence alignment (accessed 22 June 2026).
Regarding claim 38, copending claims 6-7 in view of Liu renders obvious claims 32-36 and 43 as described above.
Copending claims 6-7 in view of Liu does not teach or suggest that the construct comprises the claimed SEQ ID NO: 22 (Claim 38).
The applicable teachings of Khvorova and Khvorova sequence alignment are discussed above as applied to claim 38.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the 35 USC 103 rejection of claim 38 above.
Claims 4-5 and 32-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 8-9, and 18-19 of copending Application No. 18/289,519 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claim anticipates the instant claim.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 4 and 32-34, copending claim 5 claims an aptamer-siRNA chimera comprising: a) a first end and second end comprising an aptamer that specifically binds at least one target protein; and b) a siRNA construct between the first and second ends, wherein
the siRNA construct is processed by cellular RNAi machinery to produce one or more siRNAs wherein the siRNA molecule is selected from SEQ ID NO: 1 to SEQ ID NO: 594 from Table 1. Copending claim 6 claims that the siRNA construct is processed by cellular RNAi machinery to produce two siRNAs that specifically inhibit three or more different genes.
Regarding claim 5, copending claim 9 claims that the siRNA targets NR4A1 and NR4A3.
Regarding claim 35, copending claim 8 claims that the siRNA targets UBB and UBC.
Regarding claim 36, copending claim 18 claims identical limitations.
Regarding claim 37, copending claim 19 claims identical limitations.
Claim 38 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 8-9, and 18-19 of copending Application No. 18/289,519 as applied to claims 4-5 and 32-37 above, further in view of Khvorova (PG Pub No. US 2007/0031844 A1) and Khvorova sequence alignment (accessed 22 June 2026).
Regarding claim 38, copending claims 5, 8-9, and 18-19 anticipate instant claims 4-5 and 32-37 as described above.
Copending claims 5, 8-9, and 18-19 do not teach or suggest that the construct comprises the claimed SEQ ID NO: 22 (Claim 38).
The applicable teachings of Khvorova and Khvorova sequence alignment are discussed above as applied to claim 38.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the 35 USC 103 rejection of claim 38 above.
Claim 43 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 8-9, and 18-19 of copending Application No. 18/289,519 (reference application) as applied to claims 4-5 and 32-37 above, further in view of Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 43, copending claims 5, 8-9, and 18-19 anticipate instant claims 4-5 and 32-37 as described above.
Copending claims 5, 8-9, and 18-19 do not teach or suggest that the construct further comprises a pharmaceutical carrier (Claim 43).
The applicable teachings of Liu are discussed above as applied to claim 43.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the double patenting rejection of claim 43 over copending US Application No. 18/558, 951 above
Claims 4-5, 32-37 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16 of copending Application No. 18/558,945 in view of Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 4-5, 32-37, and 43, copending claim 16 claims a construct comprising: a) first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a target protein selected from PD-1,CTLA- 4, TIM-3 and LAG-3; b) an siRNA construct between the first and second ends, wherein the siRNA construct comprises a siRNA that targets one or more of NR4A2, NR4A1, NR4A2, NR4A3, VHL, ADORA2A, ADORA2B, PTPN2, CBLB, TOX, TOX2, YY1, BATF, PDCD1, TIGIT, LAG3, HAVCR2, CTLA4, NT5E and STAT3; and c) unpaired linkers comprising two to four adenines between each aptamer and siRNA and between each siRNA
Copending claim 6 does not claim that the siRNA can be utilized to inhibit the expression of two or more (Claims 4, 32, and 34), or three or more (Claim 33) different genes. Copending claim 6 does not claim a pharmaceutically acceptable carrier (Claim 43).
The applicable teachings of Liu are discussed above as applied to claims 4, 32, 34, and 43.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the double patenting rejection of claim 43 over copending US Application No. 18/558, 951 above
Claim 38 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16 of copending Application No. 18/558,945 as applied to claims 4-5, 32-37 and 43 above in view of Liu (US Patent No. 10,960,086 B2; published 30 March 2021, filed 28 December 2018), further in view of Khvorova (PG Pub No. US 2007/0031844 A1) and Khvorova sequence alignment (accessed 22 June 2026).
Regarding claim 38, copending claim 16 in view of Liu renders obvious instant claims 4-5, 32-37, and 43 as described above.
Copending claims 5, 8-9, and 18-19 do not teach or suggest that the construct comprises the claimed SEQ ID NO: 22 (Claim 38).
The applicable teachings of Khvorova and Khvorova sequence alignment are discussed above as applied to claim 38.
Therefore, it would have been obvious to have modified the copending application for the same reasons discussed above in the obviousness rationale utilized in the 35 USC 103 rejection of claim 38 above.
Conclusion
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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