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 .
Applicant’s election without traverse of group I and the species SEQ ID NO: 4, siRNA, SEQ ID NO: 5, and SEQ ID NO: 17 in the reply filed on 4/2/25 is acknowledged.
Claims 22-24, 27, and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/2/25.
The instant rejection is necessitated due to the modifications of instant SEQ ID NO: 4 that were not evident to the examiner in the claims.
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) 1, 8, 9, 11, 14-16, and 18-20 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Giangrande et al. (US 2018/0134746 A1).
Giangrande et al. teach an aptamer-siRNA chimera that is 100% identical in sequence to instant SEQ ID NO: 17 (see KU9, Figure 10, SEQ ID NO: 7618)(instant claims 1, 8, and 18) wherein the aptamer consists of the sequence instant SEQ ID NO: 4 and the siRNA strand consists of instant SEQ ID NO: 5 (instant claim 15); and therefore specifically binds to EphA2 as instantly claimed, absent evidence to the contrary. As stated in the MPEP (see MPEP 2112), something that is old does not become patentable upon the discovery of a new property.
Giangrande et al. teach: [0103] In certain embodiments, additional modifications are made to the aptamer portion. Additional modifications to the aptamer portion include 2′O-methyl modification of the pyrimidines. In other embodiments, all of the nucleotides in the aptamer are 2′O-methyl modified. Alternatively, the pyrimidines, or all the nucleotides, may be modified with 2′fluoros (both pyrimidines and purines).
Therefore, Giangrande et al. clearly teach that the pyrimidines in the aptamer may be modified with 2’-flouro, anticipating the modifications of the sequence of instant claim 1.
Giangrande et al. teach: [0106] In certain embodiments, the aptamer is linked to the entity by means of a linker. In certain embodiments, the linker is a binding pair. The linker meets the instant limitation of a spacer (instant claim 9). Design for the spacer to comprise a uracil is a matter of design choice given that there are only four options. Therefore, it would have been obvious to try incorporation of any of the four options given that the function is serving as a spacer (instant claim 11).
It is noted that the specification does not define “tail” and siRNAs have nucleotides at the 5’ and 3’ end that could be considered a tail because it is the end (instant claim 16).
Giangrande et al. teach a conjugate comprising the aptamer linked to a siRNA (claims 1, 2, 25, and 26). Giangrande et al. teach: [0096] The 2′-fluoro (2′-F) modification is compatible with siRNA function and also helps stabilize the duplex against nuclease degradation. Incorporation of 2′-F at pyrimidine positions maintains siRNA activity in vitro and in vivo pyrimidines may be modified with 2’-fluoros (instant claim 14).
Giangrande et al. teach that the sample may be solubilized in solution with the aptamer immobilized on a solid support [0122] (instant claim 19). When the therapeutic agents of the invention are prepared for administration, they are preferably combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form (claim 28) (instant claim 20).
Therefore, the claims are anticipated by Giangrande et al.
Response to Arguments
Applicant argues that although Giangrande et al. teach that the chemical modifications can be made to its aptamer, Giangrande et al. fails to disclose the presently claimed aptamer with the modifications. Contrary to applicant’s argument, Giangrande et al. is not required to explicitly demonstrate the modifications in each aptamer taught by Giangrande et al. Giangrande et al. clearly teaches that the pyrimidines of the aptamers taught by Giangrande et al. can be 2’ F modified.
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.
Claims 1, 8, 9, 11, 14, 16, 19, and 20 is/are rejected under 35 U.S.C. 103 as being obvious over Giangrande et al. (WO 2016/106387 A2), in view of McNamara et al. (Nature Biotechnology, 24, 8, 2006, 1005-1015), and Elbashir et al. (The EMBO Journal, 20, 23, 6877-6888, 2001).
Giangrande et al. teach an aptamer that is 100% identical to instant SEQ ID NO: 4 in sequence (see Histone H3/H4 specific RNA aptamer, SEQ:7618) and therefore specifically binds to EphA2 as instantly claimed, absent evidence to the contrary. As stated in the MPEP (see MPEP 2112), something that is old does not become patentable upon the discovery of a new property (instant claim 1).
Giangrande et al. teach that the sample may be solubilized in solution with the aptamer immobilized on a solid support (instant claim 19). When the therapeutic agents of the invention are prepared for administration, they are preferably combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form (instant claim 20).
Giangrande et al. teach: The present technology uses nucleic acid aptamer constructs that have been created to specifically inhibit the human H3 and H4 histones. In certain embodiments, the constructs are chemically modified (2'-fluoropyridines) RNA constructs making them nuclease resistant (page 15) (modifications of the sequence of instant claim 1).
Although Giangrande et al. does not explicitly teach that every pyrimidine is a 2’F pyrimidine, Giangrande et al. teaches that the constructs are chemically modified (2'-fluoropyridines) RNA constructs making them nuclease resistant. If not interpreted as fully modified 2’-F pyrimidine modified, it would have certainly been obvious to modify all pyrimidines with 2’F modifications as a matter of design choice with a reasonable expectation of the benefit of nuclease resistance as taught by Giangrande et al (instant claim 1).
Giangrande et al. teach a conjugate comprising the aptamer linked to a siRNA and teaches that 2'-F modification is compatible with siRNA function and also helps stabilize the duplex against nuclease degradation. Incorporation of 2'-F at pyrimidine positions maintains siRNA activity in vitro and in vivo (claims 1-5 and 25-27) (instant claims 8 and 14). The linker meets the instant limitation of a spacer (instant claim 9). It is noted that the specification does not define “tail” and siRNAs have nucleotides at the 5’ and 3’ end that could be considered a tail because it is the end (instant claim 16).
Should applicant intend for the “tail” to be an overhang, it was routine in the siRNA design art to incorporate a 3’-overhang for efficient triggers of sequence-specific mRNA degradation, as taught by Elbashir et al. Elbashir et al. teach that duplexes of 21 nt siRNAs with 2 nt 3’ overhangs were the most efficient triggers of sequence-specific mRNA degradation (abstract) and that the 2 nt 3’ overhang is critical for siRNA function (page 6884), offering motivation to include a 3’-overhang with a reasonable expectation of success (abstract) (instant claim 16).
Additionally, it was known to delivery siRNA-aptamer chimeras with a spacer, as evidenced by McNamara et al. (page 1012). Design for the spacer to comprise a uracil is a matter of design choice given that there are only four options. Therefore, it would have been obvious to try incorporation of any of the four options given that the function is serving as a spacer (instant claim 11).
Claim 16 is/are rejected under 35 U.S.C. 103 as being obvious over Giangrande et al. (US 2018/0134746 A1), in view of Elbashir et al. (The EMBO Journal, 20, 23, 6877-6888, 2001).
Giangrande et al. teach an aptamer-siRNA chimera that is 100% identical in sequence to instant SEQ ID NO: 17 (see KU9, Figure 10, SEQ ID NO: 7618)(instant claims 1, 8, and 18) wherein the aptamer consists of the sequence instant SEQ ID NO: 4 and the siRNA strand consists of instant SEQ ID NO: 5 (instant claim 15); and therefore specifically binds to EphA2 as instantly claimed, absent evidence to the contrary. As stated in the MPEP (see MPEP 2112), something that is old does not become patentable upon the discovery of a new property.
Giangrande et al. teach: [0103] In certain embodiments, additional modifications are made to the aptamer portion. Additional modifications to the aptamer portion include 2′O-methyl modification of the pyrimidines. In other embodiments, all of the nucleotides in the aptamer are 2′O-methyl modified. Alternatively, the pyrimidines, or all the nucleotides, may be modified with 2′fluoros (both pyrimidines and purines).
Therefore, Giangrande et al. clearly teach that the pyrimidines in the aptamer may be modified with 2’-flouro, anticipating the modifications of the sequence of instant claim 1.
Giangrande et al. teach: [0106] In certain embodiments, the aptamer is linked to the entity by means of a linker. In certain embodiments, the linker is a binding pair. The linker meets the instant limitation of a spacer (instant claim 9). Design for the spacer to comprise a uracil is a matter of design choice given that there are only four options. Therefore, it would have been obvious to try incorporation of any of the four options given that the function is serving as a spacer (instant claim 11).
It is noted that the specification does not define “tail” and siRNAs have nucleotides at the 5’ and 3’ end that could be considered a tail because it is the end (instant claim 16).
It is noted that all claims are anticipated by Giangrande et al., as set forth in the rejection under 35 USC 102, above. The instant rejection is for the circumstance if applicant intends for the tail to be an overhang.
Should applicant intend for the “tail” to be an overhang, it was routine in the siRNA design art to incorporate a 3’-overhang for efficient triggers of sequence-specific mRNA degradation, as taught by Elbashir et al. Elbashir et al. teach that duplexes of 21 nt siRNAs with 2 nt 3’ overhangs were the most efficient triggers of sequence-specific mRNA degradation (abstract) and that the 2 nt 3’ overhang is critical for siRNA function (page 6884), offering motivation to include a 3’-overhang with a reasonable expectation of success (abstract) (instant claim 16).
Giangrande et al. teach a conjugate comprising the aptamer linked to a siRNA (claims 1, 2, 25, and 26). Giangrande et al. teach: [0096] The 2′-fluoro (2′-F) modification is compatible with siRNA function and also helps stabilize the duplex against nuclease degradation. Incorporation of 2′-F at pyrimidine positions maintains siRNA activity in vitro and in vivo pyrimidines may be modified with 2’-fluoros (instant claim 14).
Giangrande et al. teach that the sample may be solubilized in solution with the aptamer immobilized on a solid support [0122] (instant claim 19). When the therapeutic agents of the invention are prepared for administration, they are preferably combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form (claim 28) (instant claim 20).
Response to Arguments
Applicant argues that the instant aptamer with all pyrimidines modified with 2’-F modifications resulted in an unexpected and advantageous effect on the decreased growth of cancer cells. The references do not need to teach the same benefit as demonstrated by applicant. The art clearly teaches the same aptamer sequence and offers motivation to modify all pyrimidines with 2’F modifications. Giangrande et al. (US 2018/0134746 A1) clearly anticipates each of these limitations and teaches the benefits of incorporating the modifications.
Applicant argues that although Giangrande et al. teach that the chemical modifications can be made to its aptamer, Giangrande et al. fails to disclose the presently claimed aptamer with the modifications. Contrary to applicant’s argument, Giangrande et al. is not required to explicitly demonstrate the modifications in each aptamer taught by Giangrande et al. Giangrande et al. clearly teaches that the pyrimidines of the aptamers taught by Giangrande et al. can be 2’ F modified.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8, 9, 11, 12, 14-16, and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,680,079 B2, in view of Elbashir et al. (The EMBO Journal, 20, 23, 6877-6888, 2001). Although the claims at issue are not identical, they are not patentably distinct from each other because US ‘079 B2 recites an aptamer-siRNA chimera that is 100% identical to instant SEQ ID NO: 17 (see KU9, claim 1) wherein the aptamer consists of instant SEQ ID NO: 4 and the siRNA strand consists of instant SEQ ID NO: 5; and therefore specifically binds to EphA2 as instantly claimed, absent evidence to the contrary. As stated in the MPEP (see MPEP 2112), something that is old does not become patentable upon the discovery of a new property.
Each claim set is directed to the same siRNA/aptamer chimera, wherein it would have been obvious to incorporate a uracil into the spacer as a matter of design choice given that there are four options and the purpose is only as a spacer. Additionally, Should applicant intend for the “tail” to be an overhang, it was routine in the siRNA design art to incorporate a 3’-overhang for efficient triggers of sequence-specific mRNA degradation, as taught by Elbashir et al (abstract). It would have been obvious to immobilize the aptamer on a solid support because this does not alter the structure of the aptamer and it was disclosed in the specification of US ‘079 B2 to immobilize the aptamer on a solid support, which further defines the recited compound.
The claims are obvious variations of each other.
The claims of US ‘079 B2 are as follows:
1. A nucleic acid molecule not more than 90 nucleotides in length comprising an aptamer, wherein the aptamer selectively binds with high affinity to extracellular histone 3 (H3) and 4 (H4), wherein the aptamer comprises a sequence with at least 95% identity to KU5 (SEQ ID NO: 10749), KU7 (SEQ ID NO: 7741), or KU9 (SEQ ID NO: 7839).
2. The nucleic acid molecule of claim 1, wherein the aptamer comprises one or more modified nucleotides.
3. The nucleic acid molecule of claim 2, wherein the modified nucleotide comprises 2′-O-methyl-; 2′-O-(2-methoxyethyl); 2-O-alkyl; 2-O-allyl; 2′-S-alkyl; 2′-S-allyl; 2′-fluoro-; 2′-amino; 2′-halo or 2-azido-ribose, a carbocyclic sugar analogue, an a-anomeric sugar; an epimeric sugar, wherein the epimeric sugar is arabinose, xylose or lyxose, a pyranose sugar, a furanose sugar, or sedoheptulose; 2′-fluoro-β-D-arabinonucleotide (FANA) modification; or a Locked nucleic acid (LNA).
4. The nucleic acid molecule of claim 3, wherein the one or more 2′-O-methyl modified nucleotides are alternated with un-modified RNA bases.
5. The nucleic acid molecule of claim 2, wherein the modified nucleotide is a 2′-fluoro pyrimidine and/or a 2′ O-methyl pyrimidine.
6. The nucleic acid molecule of claim 2, wherein the aptamer comprises an 2′OMe purine and a 2′-fluoro pyrimidine.
7. The nucleic acid molecule of claim 2, wherein the nucleic acid comprises a bridging phosphorothioate, and end cap that reverses the polarity of a chain and/or a linker.
8. A conjugate comprising the nucleic acid molecule of claim 1 linked to a therapeutic molecule.
9. The conjugate of claim 8, wherein the therapeutic molecule is an RNAi molecule.
10. The conjugate of claim 9, wherein the RNAi molecule is an siRNA molecule or an miRNA molecule.
11. A pharmaceutical composition comprising the nucleic acid molecule of claim 1 and a pharmaceutically acceptable carrier.
The claims are obvious variations of each other.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636