Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 03/30/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 12/31/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 03/30/2026, claims 1-25 are pending. Claims 1-6 and 21-25 are currently under examination. Claims 7-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
New Claim Rejections necessitated by claim amendments
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 21 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Place et al. (US Patent No. 12,104,157 of record), Manoharan et al. (US Patent No. 12,497,613 of record), Fantoni et al. ("A hitchhiker’s guide to click-chemistry with nucleic acids." Chemical Reviews 121.12 (2021): 7122-7154 of record) and Allerson et al. ("Fully 2 ‘-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA." Journal of medicinal chemistry 48.4 (2005): 901-904).
Regarding claims 21 and 22, Place et al. teach a double stranded polynucleotide wherein one strand having SEQ ID No. 8 is identical to instantly claimed SEQ ID No. 2 and can comprise modifications (col. 10 and Table 2). Place et. teach pharmaceutical compositions comprising the claimed polynucleotide (col. 11).
Manoharan et al. teach one or both strands of a double stranded RNA can have 1-5 phosphorothioate linkages at the terminal ends (see col. 16-17). Manoharan et al. teach one or both strands can have modifications such as 2’-F and 2’-OMe in an alternating pattern (col. 9-11).
With respect to attaching a GalNAc clicked cytindine to the end of the double stranded polynucleotide of Place et al., Fantoni et al. teach click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on multiple scientific disciplines, and its implementation within the nucleic acid field has enabled researchers to generate a wide variety of tools with application in biology, biochemistry, and biotechnology (abstract) and teach methods of use (see entire reference). Therefore, one of ordinary skill in the art, given Manoharan et al. teach GalNAc ligation to an oligonucleotide strand using click chemistry, would have been motivated and capable of conjugating the GalNAc ligand to the end of the double stranded oligonucleotide taught by Place et al.
Allerson et al. teach the alternating 2′-F/2′-OMe motif appears to be an attractive design for creating functionally active and stable RNA duplexes (see Figure 1, Table 1 and page 903 last para). Thus it would have been obvious to one of skill in the art to fully modify the strands of the dsRNA to increase the duplex stability. Because there was a finite number of identifiable and predictable solutions, either modification of one or both strands, a person of ordinary skill would have a good reason to pursue the known options within his or her technical grasp. KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007). Further, because Manoharan et al. teach the use of adding 1-5 phosphorothioate linkages at the ends of a strand of a double stranded polynucleotide, it would have been obvious to modify the double stranded polynucleotide with phosphorothioate linkages to determine the optimal number for stability and efficacy.
Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.
In further view of KSR, it would have been obvious for a skilled artisan to use the known motif of fully modified alternating 2′-F/2′-OMe to improve a dsRNA to increase the duplex stability. Moreover, there is an expectation of an advantage for using an oligonucleotide strand with 2’-F and 2’-OMe in an alternating pattern and thus a motivation to combine the prior art references (see MPEP 2144). Conclusive proof of efficacy is not required to show a reasonable expectation of success and obviousness does not require absolute predictability, but at least some degree of predictability is required (MPEP 2143.02).
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claim 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Place et al. (US Patent No. 12,104,157 of record), Manoharan et al. (US Patent No. 12,497,613 of record), Zimmermann, Tracy S., et al. "Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate." Molecular therapy 25.1 (2017): 71-78) and Fantoni et al. ("A hitchhiker’s guide to click-chemistry with nucleic acids." Chemical Reviews 121.12 (2021): 7122-7154 of record) .
Regarding claims 23, Place et al. teach a double stranded polynucleotide wherein one strand having SEQ ID No. 8 is identical to instantly claimed SEQ ID No. 2 and can comprise modifications (col. 10 and Table 2). Place et. teach pharmaceutical compositions comprising the claimed polynucleotide (col. 11).
Manoharan et al. teach one or both strands of the double stranded RNA can have 1-5 phosphorothioate linkages at the terminal ends (see col. 16-17). Manoharan et al. teach one or both strands can have modifications such as 2’-F and 2’-OMe in an alternating pattern (col. 9-11). Manoharan et al. further teach the double stranded RNA can be conjugated to a ligand via click chemistry (col. 43 lines 40-46) wherein the ligand can be GalNAc ligand (see col. 44-45).
With respect to attaching a GalNAc clicked cytindine to the end of the double stranded polynucleotide of Place et al., Fantoni et al. teach click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on multiple scientific disciplines, and its implementation within the nucleic acid field has enabled researchers to generate a wide variety of tools with application in biology, biochemistry, and biotechnology (abstract) and teach methods of use (see entire reference). Therefore, one of ordinary skill in the art, given Manoharan et al. teach GalNAc ligation to an oligonucleotide strand using click chemistry, would have been motivated and capable of conjugating the GalNAc ligand to the end of the double stranded oligonucleotide taught by Place et al.
Manoharan et al. do not teach a triantennary N-acetylgalactosamine (GalNAc) ligand.
Zimmermann et al. teach attachment of a triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates efficient hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing (page 71 col. 1). Zimmermann et al. teach utility of this GalNAc conjugate approach for efficient and potent hepatocellular siRNA delivery has provided a robust platform for the development of RNAi-based therapies in liver-based diseases, with GalNAc-siRNA conjugates in development for the treatment of hemophilia,23 acutehepaticporphyria,24 and hepatic infectious diseases,25 among others. (page 75 conclusion). It would have been obvious for one of skill in the art to use a triantennary N-acetylgalactosamine (GalNAc) ligand to attach to a dsRNA for efficient hepatocyte uptake.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claims 24 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Place et al. (US Patent No. 12,104,157 of record), Manoharan et al. (US Patent No. 12,497,613 of record), Wenge et al.(Synthesis of 2′-O-propargyl nucleoside triphosphates for enzymatic oligonucleotide preparation and “click” modification of DNA with Nile red as fluorescent probe." Bioconjugate Chemistry 24.3 (2013): 301-304), Pujari et al. ("Oligonucleotides with “clickable” sugar residues: synthesis, duplex stability, and terminal versus central interstrand cross-linking of 2′-O-propargylated 2-aminoadenosine with a bifunctional azide." The Journal of Organic Chemistry 79.10 (2014): 4423-4437) and Fantoni et al. ("A hitchhiker’s guide to click-chemistry with nucleic acids." Chemical Reviews 121.12 (2021): 7122-7154 of record) .
Regarding claims 24 and 25, Place et al. teach a double stranded polynucleotide wherein one strand having SEQ ID No. 8 is identical to instantly claimed SEQ ID No. 2 and can comprise modifications (col. 10 and Table 2). Place et. teach pharmaceutical compositions comprising the claimed polynucleotide (col. 11).
Manoharan et al. teach one or both strands of the double stranded RNA can have 1-5 phosphorothioate linkages at the terminal ends (see col. 16-17). Manoharan et al. teach one or both strands can have modifications such as 2’-F and 2’-OMe in an alternating pattern (col. 9-11). Manoharan et al. further teach the double stranded RNA can be conjugated to a ligand via click chemistry (col. 43 lines 40-46) wherein the ligand can be GalNAc ligand (see col. 44-45).
With respect to attaching a GalNAc clicked cytindine to the end of the double stranded polynucleotide of Place et al., Fantoni et al. teach click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on multiple scientific disciplines, and its implementation within the nucleic acid field has enabled researchers to generate a wide variety of tools with application in biology, biochemistry, and biotechnology (abstract) and teach methods of use (see entire reference). Therefore, one of ordinary skill in the art, given Manoharan et al. teach GalNAc ligation to an oligonucleotide strand using click chemistry, would have been motivated and capable of conjugating the GalNAc ligand to the end of the double stranded oligonucleotide taught by Place et al.
It is well known in the art that 2’-O-propargyl nucleotides can be used in conjugation using a click chemistry as taught by (Wenge et al. page 301 and Scheme 1) and Pujari et al. (see entire reference). One of skill in the art would have been capable of using this linker to attach a GalNac moiety given this was known in the art to be useful in click chemistry conjugation.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejection not reiterated in this Office Action is hereby withdrawn.
Maintained Rejections
Drawings
Color photographs and color drawings filed on 02/06/2023 are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Applicant request the drawings be maintained and reproduced in black and white form. This response is considered non-responsive. Applicant is required to submit a corrected drawings showing the indicated colored portions are in black and white. The Patent and Trademark Office no longer makes drawing changes. See 1017 O.G. 4. It is applicant's responsibility to ensure that the drawings are corrected. Corrections must be made in accordance with the instructions below.
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the colored drawings are still of record. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
The rejection of claims 1-6 under 35 U.S.C. 103 as being unpatentable over Place et al. (US Patent No. 12,104,157), Manoharan et al. (US Patent No. 12,497,613), Podbevsek et al. ("Solution-state structure of a fully alternately 2′-F/2′-OMe modified 42-nt dimeric siRNA construct." Nucleic acids research 38.20 (2010): 7298-7307) and Fantoni et al. ("A hitchhiker’s guide to click-chemistry with nucleic acids." Chemical Reviews 121.12 (2021): 7122-7154) is maintained for the reasons of record.
Applicant’s arguments are acknowledged but not found persuasive. Applicant argues the rejection relies on a hindsight combination of multiple references. In response, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The rejection takes into account knowledge that was within the level of one of ordinary skill. The sequence was known and the modifications of a dsRNA was known in the art and obvious.
Applicant argues that while Place may disclose a double stranded RNA having a sequence overlapping SEQ ID NO: 2, it does not teach or suggest the specific combination of alternating 2'-F/2'-OMe modifications, defined phosphorothioate linkages, a GaINAc moiety conjugated to cytidine via click chemistry, and an unmodified first strand forming a double stranded complex. The field of double stranded RNA therapeutics is highly unpredictable, and small variations in sequence, modification pattern, strand asymmetry, or conjugation site can substantially affect RISC loading, target knockdown efficiency, molecular stability, and off-target effects. Podbevsek and Manoharan do not provide guidance for applying the specific alternating 2'-F/2'-OMe pattern or the precise phosphorothioate linkage positions to the claimed sequences, and Fantoni does not teach the specific placement of a GaINAc moiety at the claimed terminus in combination with the claimed passenger strand structure. The cited references do not provide a reasonable expectation of success in achieving the claimed combination of features. The Office is reminded that the chemical arts are inherently unpredictable, especially when there is no reasonable expectation of similar properties. See MPEP § 2144.09(V).
Applicant’s argues that the field of dsRNA is highly unpredictable and small variants in sequence, modification pattern, strand asymmetry and conjugates site can substantially affect RISC loading target knockdown efficiency, molecular stability, and off-target effects. The prior art clearly teach these modifications improve the stability and target efficiency of dsRNA.. Further, Applicant has not provided any evidence that would lead one of skill in the art to believe that incorporating alternating 2'-F/2'-OMe modifications, defined phosphorothioate linkages, a GaINAc moiety conjugated to cytidine via click chemistry would cause the dsRNA of Place et al. to have decreased loading target knockdown efficiency, molecular stability, and off-target effects. MPEP 2145 states an argument does not replace evidence wherein evidence is necessary, such as in this case. Moreover the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). (see MPEP 716.01(c)).
As stated previously in the O.A., Manoharan et al. teach modified double stranded RNA agents that are capable of inhibition of expression of a target gene (abstract). Manoharan et al. teach one or both strands can have modifications such as 2’-F and 2’-OMe in an alternating pattern (col. 9-11). Podbevsek et al. teach the use of synthetic siRNAs consisting of solely standard nucleotides proved problematic with one of the main difficulties is the short half-life of unmodified RNA in serum due to the activity of endo- and exonucleases (page 7298). Podbevsek et al. teach the advantages of an oligonucleotide strand having modifications such as 2’-F and 2’-OMe wherein this modification pattern can increase stability of the molecule (see Fig 2 and conclusion). It would have been obvious to one of ordinary skill in the art to try modifying one or both strands of the double stranded polynucleotide taught by Place et al. with alternating modifications given Podbevsek et al. teach there was a design need to increase the stability of an oligonucleotide strand with 2’-F and 2’-OMe in an alternating pattern.
Applicant further argues the cited references do not provide a reasonable expectation of success in achieving the claimed combination of features. This argument is not convincing because Manoharan et al. teach how to make and use alternating 2’-F and 2’-OMe modification patterns and one of skill in the art would have been capable of substituting the nucleotides of SEQ ID No.2 with 2’-F and 2’-OMe in an alternating pattern.
The rejection is therefore maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a).
706.07(a) Final Rejection, When Proper on Second Action [R-07.2015]
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Second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Where information is submitted in an information disclosure statement during the period set forth in 37 CFR 1.97(c) with a fee, the examiner may use the information submitted, e.g., a printed publication or evidence of public use, and make the next Office action final whether or not the claims have been amended, provided that no other new ground of rejection which was not necessitated by amendment to the claims is introduced by the examiner. See MPEP § 609.04(b).
Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at 571-272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636
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