DETAILED ACTION
Receipt of Arguments/Remarks filed on June 16 2026 is acknowledged. Claims 4-5, 7-10, 12-17, 20-25, 28-36 and 44 were/stand cancelled. Claims 1, 3, 6, 41, 46 and 48 were amended. Claims 1- 3, 6, 11, 18-19, 26-27, 37-43, 45-48 are pending. Claims 2, 11,18-19, 26-27, 40 and 46-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 December 29 2025. Claims 1, 3, 6, 37-39, 41-43 and 45 are directed to the elected invention.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 16 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
The amendments filed June 16 2026 are sufficient to overcome the rejection of claims 1, 3, 6, 37-39, 41-43 and 45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The parentheses were removed from the claims, the such as language was removed from the claim, and the terminating group was clarified.
Claim Rejections - 35 USC § 103
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 of this title, 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.
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, 3, 6, 37-39, 41-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Hofmeister et al. (WO2019170731, published 9/12/19, cited on PTO Form 1449) in view of Clark et al. (PNAS, 2012), Hasegawa et al. (Carbohydrate Research 1980) and Manoharan et al. (USPGPUB No. 20180326070).
Applicant Claims
The instant application claims a compound of formula I.
The instant application claims an oligonucleotide comprising one or more compounds of formula (VI).
As elected the compound of formula I is IpT1:
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Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Hofmeister et al. is directed to nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same. Claimed is a compound of formula I:
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which is substantially similar to the instant claims (claim 1). A specific compound taught is IgT1 (compound 36) (Table A):
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. Claimed is an oligonucleotide comprising one or more compounds of formula (II):
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wherein L1 and L2 have the same definition as instantly claimed T1 and T2 (claim 35). As claimed R3 is N-acetyl-galactosamine (claim 48). A double stranded oligonucleotide comprising one or more of the compounds of formula II is claimed (claim 50). A small interfering RNA (siRNA) comprising one or more compounds of formula (II) (claim 51). Stability increase has been shown for siRNAs wherein the compounds of formula II are present at an overhang of the sense strand and antisense strand including siRNAs where the compounds of formula II are present at the 3’-end or 5’-end or both of the sense strand (page 48, lines 7-18). As claimed Y can be N-C(O)-R1 wherein R1 is a C1-C20 alkyl optionally substituted by one or more including -C(=J)- wherein J is O (claim 1). Y can be NR1 with R1 being C(O)m-R2-(O-CH2-CH2)p-R3 wherein p is 0, m is 1 and R2 is a C1-C20 alkylene group and R3 is a cell targeting moiety (claim 10; 21).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Hofmeister et al. teaches compounds similar to the instant claims, the difference between the compounds of Hofmeister et al. and the instant claims is Hofmeister et al. teaches a N-acetyl-galactosamine whereas the instant claim include a piperidine iminosugar (see box in compound 36 above). This deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
Clark et al. is directed to pharmacological chaperones for human α-N-acetylgalactosaminidase. DGJNAc, is the iminosugar analog of GalNAc:
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(page 17404, left column, last paragraph; Fig. 1).
Hasegawa et al. is directed to the synthesis of a 2-acetamido-5-amino-2,5-dideoxy-d-xylopyranosyl derivative. It is taught that there has been a great deal of activity in the synthesis of heterosugars in which the ring-oxygen atom of aldoses have been replaced by nitrogen, phosphorus or sulfur. These sugars are interesting, not only from the point of view of the chemistry involved, but also for their various, biological activities (page 277, introduction). A specific derivative taught is the di-N-acetyl-di-O-acetyl derivative (compound 12):
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(page 279; page 283). These are 2-amino sugar derivatives having nitrogen in the ring (page 277, introduction). Ligands include carbohydrates including galactose, N-acetyl-galactosamine, N-acetyl-glucosamine, mannose, fucose, etc. (page 79, lines 6-13).
Manoharan et al. is directed to carbohydrate conjugates as delivery agents for oligonucleotides. Taught are iRNA agents that are conjugated with at least one carbohydrate ligand such as monosaccharides (paragraph 0016). Monosaccharides include N-acetyl-galactosamine as well as imino sugar (ring oxygen replaced by nitrogen) (paragraph 0166). As shown in Figure 1, the monosaccharide can be conjugated via a CO, NH, O, S OC(O), NHC(O) or CH2.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Hofmeister et al., Clark et al., Hasegawa et al. and Manoharan et al. and utilize a compound of:
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as the targeting ligand in place of GalNAc as taught by Hofmeister et al. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring. Since Hofmeister et al. teaches the ligands can be carbohydrates and specifically point to sugars, one skilled in the art would have a reasonable expectation of success.
Regarding the elected species and claim 1, 3 and 6, as set forth above, 1pT1 is the same as instantly elected except for:
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. Hofmeister et al. teaches the linker between the ligand includes alkyl groups which can include a C(O). For ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of 1pT1 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, Hofmeister et al. teaches the compound can be a double stranded oligonucleotide comprising one or more of the compounds of formula II or a small interfering RNA (siRNA) comprising one or more compounds of formula (II). The compound of formula (VI) is the same as elected except for one of P1 or P2 (i.e. the ODMT or
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being the point of attachment to the oligonucleotide. This is also taught by Hofmeister et al. as Hofmeister et al. teaches in formula II L1 and L2 have the same definition as instantly claimed T1 and T2
Regarding claim 41, Hofmeister et al. teaches attachment of the compound to double stranded oligonucleotides.
Regarding claim 42, Hofmeister et al. teaches a RNAi which is double-stranded comprising a sense and antisense strand.
Regarding claims 43 and 45, Hofmeister et al. teaches that stability increase has been shown for siRNAs wherein the compounds of formula II are present at an overhang of the sense strand and antisense strand including siRNAs where the compounds of formula II are present at the 3’-end or 5’-end or both of the sense strand.
Response to Arguments
Applicants’ arguments filed June 16 2026 have been fully considered but they are not persuasive.
Applicants argue that (1) the Office has not established that the cited references teach or suggest any compounds of formula I, as recited in claim 1, or formula (V) as recited in claim 37, having an R3 of formula (II) where the N in the piperidine iminosugar is the linking point to the rest of the compound. The Office points to Clark as allegedly leading the skilled artisan to substitute N-acetyl-galactosamine taught by Hofmeister with an iminosugar analog of GalNAc. However, substituting the GalNAc with DGJNAc would not lead the skilled artisan to use the nitrogen of the iminosugar as directly linking to L. If the position of the ring-oxygen as shown in claim 48 of Hofmeister was directly swapped for nitrogen, this would lead to a different position of the nitrogen in the iminosugar, compared to formula (II) as recited in the present claims. The ring-oxygen in the 1gT1 compound of Hofmeister is at a different position in the molecule compared to the nitrogen in exemplary compound 1pT1. Swapping the ring-oxygen in 1gT1 would not produce the structure recited in the present claim. Nor has the office established that Hofmeister and Clark would provide any teaching or suggest that could lead the skilled artisan to shift the structure of the ring to match the structure of the present claims. Neither Hasegawa nor Manoharan supply the absent disclosure. Hasegawa fails to provide any guidance whatsoever on the position within the ring where the nitrogen should link to a monosaccharide. Manoharan fails to teach or suggest that nitrogen of an iminosugar can be the atom where conjugation occurs.
Regarding Applicants’ arguments, as indicated in the rejection Hofmeister et al. claims a compound of formula I:
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wherein Y is NR1 with R1 being C(O)m-R2-(OCH2CH3)p-R3 wherein p can be 0, m can be 1 and R2 can be a C1-C20 alkylene group and R3 is a cell targeting moiety (see claim 1; 11). This combination is exemplified in compound 1pT1 wherein R3 is N-acetyl-galactosamine (see for example 49). Therefore, when R3 is N-acetyl-galactosamine Applicants are correct this group is attached at C1-OH in N-acetyl-galactosamine amine. However, substituting GalNAc with a different ligand, such as DGJNAc does not necessarily mean that it has to be attached at the same position. In fact, the C1 of DGJNAc does not contain a hydroxy and therefore attachment at this position would be chemically more difficult. That is why the examiner pointed to the teachings of Hasegawa et al. and Manoharan. While Manoharan does not expressly teach the nitrogen of an imino sugar can be the atom where conjugation occurs, Manoharan specifically teaches the various types of chemical groups which can be used to conjugate a monosaccharide and these include C(O), NH, O, S, OC(O), NHC(O) or CH2. Since Clark et al. teaches compounds such as DGJNAc
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and Hasegawa et al. teaches
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which teaches that a C(O) group can be attached to the N of the ring, it is the examiners position that when attaching an imino sugar as an R3 group aka cell targeting moiety, one skilled in the art would recognize that the amino sugar can be attached via a C(O) attached to the N.
Even if Applicants disagree, Applicants’ attention is directed to MPEP 2144.09 which discusses close structural similarity between chemical compounds. Specifically it is stated: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). (emphasis added). Therefore six different positions on the imino sugar which could be utilized to attach to the rest of the structure. These are all position isomers and would all be expected to possess the same or similar activity. Therefore, the examiner cannot agree that the prior art does not suggest attachment at nitrogen.
Applicants argue that (2) the Office has not established that the skilled artisan would, at the time of filing, have reasonably predicted the beneficial effects that Applicant demonstrated for compound of the present claims in the working examples. Applicants point to examples 27-30, Table R and Figure 25, which shows exemplary siRNA1-3, comprising the compound falling within the scope of the claims successfully reduced the expression of target gene TTR both in hepatocytes and in vivo. Example 28 of the specification states that siRNA1-3 with trimeric piperidine-based ASGPR-binder still shows excellent potency and no obvious adverse effects were observed. Example 30 indicates that siRNA1-3 with a piperidine-derived ASGPPR-binder shows comparable in vivo knock-down activity relative to the GalNAc-derived control compound.
Regarding Applicants’ second argument, evidence the invention works is not evidence of an unexpected or unobvious effect. The prior art teaches that the claimed cell targeting moiety is an analog of GalNAc (see the teachings of Clark et al.). Therefore, the expectation would be that this compound would produce the same or similar effect. The word surprising never appears in the instant specification. The word unexpectedly appears once but this is in relation to guanosine-type ASGPR binders which are not the currently examined compounds. Therefore, the examiner cannot agree that the data in the instant specification establishes an unexpected effect as the data appears to show that the claimed compounds perform similarly to the GalNAc. MPEP 716.02(A) discusses evidence to show unexpected results. These include greater than expected results, superiority of a property shard with the prior art, presence of an unexpected property or absence of expected property. However, none of the data in the instant specification establishes any of these results. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
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, 3 and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11897911 in view of Clark et al. (PNAS, 2012), Hasegawa et al. (Carbohydrate Research 1980) and Manoharan et al. (USPGPUB No. 20180326070). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a compound of formula I.
As elected the compound of formula I is IpT1:
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Patent ‘911 claims a compound of formula I:
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wherein Y can be N-C(O)-R1 wherein R1 can be R2-R3 wherein R2 is a C1-C20 alkylene group and R3 is a cell targeting moiety (claim 1). Specific R3 claimed is:
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The difference between the instant claims and Patent ‘911 is that Patent ‘911 does not claim a nitrogen in the ring and this is the point of attachment via an amide. However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
Clark et al. is directed to pharmacological chaperones for human α-N-acetylgalactosaminidase. DGJNAc, is the iminosugar analog of GalNAc:
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(page 17404, left column, last paragraph; Fig. 1).
Hasegawa et al. is directed to the synthesis of a 2-acetamido-5-amino-2,5-dideoxy-d-xylopyranosyl derivative. It is taught that there has been a great deal of activity in the synthesis of heterosugars in which the ring-oxygen atom of aldoses have been replaced by nitrogen, phosphorus or sulfur. These sugars are interesting, not only from the point of view of the chemistry involved, but also for their various, biological activities (page 277, introduction). A specific derivative taught is the di-N-acetyl-di-O-acetyl derivative (compound 12):
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(page 279; page 283). These are 2-amino sugar derivatives having nitrogen in the ring (page 277, introduction). Ligands include carbohydrates including galactose, N-acetyl-galactosamine, N-acetyl-glucosamine, mannose, fucose, etc. (page 79, lines 6-13).
Manoharan et al. is directed to carbohydrate conjugates as delivery agents for oligonucleotides. Taught are iRNA agents that are conjugated with at least one carbohydrate ligand such as monosaccharides (paragraph 0016). Monosaccharides include N-acetyl-galactosamine as well as imino sugar (ring oxygen replaced by nitrogen) (paragraph 0166). As shown in Figure 1, the monosaccharide can be conjugated via a CO, NH, O, S OC(O), NHC(O) or CH2.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘911, Clark et al., Hasegawa et al. and Manoharan et al. and utilize a compound of:
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as the R3 in place of GalNAc as claimed by Patent ‘911. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds claimed in patent ‘911with C(O)-iminosugar would result in the elected compound.
Claims 37-39, 41-43 and 45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11897911 in view of Clark et al., Hasegawa et al. and Manoharan et al. as applied to claims 1, 3 and 6 above and in further view of Hofmeister et al. (WO2019170731, published 9/12/19, cited on PTO Form 1449). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims an oligonucleotide comprising one or more compounds of formula (VI).
As elected the compound of formula I is IpT1:
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The claims of Patent ‘911 are set forth above.
While Patent ‘911 claims B is a heterocyclic nucleobase, Patent ‘911 does not claim an oligonucleotide with the claimed compound. However, this deficiency is cured by Hofmeister et al.
Hofmeister et al. is directed to nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same. Claimed is a compound of formula I:
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which is substantially similar to the instant claims (claim 1). A specific compound taught is IgT1 (compound 36) (Table A):
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. Claimed is an oligonucleotide comprising one or more compounds of formula (II):
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wherein L1 and L2 have the same definition as instantly claimed T1 and T2 (claim 35). As claimed R3 is N-acetyl-galactosamine (claim 48). A double stranded oligonucleotide comprising one or more of the compounds of formula II is claimed (claim 50). A small interfering RNA (siRNA) comprising one or more compounds of formula (II) (claim 51). Stability increase has been shown for siRNAs wherein the compounds of formula II are present at an overhang of the sense strand and antisense strand including siRNAs where the compounds of formula II are present at the 3’-end or 5’-end or both of the sense strand (page 48, lines 7-18). As claimed Y can be N-C(O)-R1 wherein R1 is a C1-C20 alkyl optionally substituted by one or more including -C(=J)- wherein J is O (claim 1). Y can be NR1 with R1 being C(O)m-R2-(O-CH2-CH2)p-R3 wherein p is 0, m is 1 and R2 is a C1-C20 alkylene group and R3 is a cell targeting moiety (claim 10; 21).
Regarding claim 37-39, Hofmeister et al. teaches the compound can be a double stranded oligonucleotide comprising one or more of the compounds of formula II (which is the same as Patent ‘911) or a small interfering RNA (siRNA) comprising one or more compounds of formula (II). The compound of formula (VI) is the same as elected except for one of P1 or P2 (i.e. the ODMT or
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being the point of attachment to the oligonucleotide. This is also taught by Hofmeister et al. as Hofmeister et al. teaches in formula II L1 and L2 have the same definition as instantly claimed T1 and T2
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘911, Clark et al., Hasegawa et al., Manoharan et al. and Hofmeister et al. and utilize the compound of formula I with an oligonucleotide. One skilled in the art would have been motivated to utilize the compound with an oligonucleotide in order to increase stability as taught by Hofmeister et al.
Regarding claim 41, Hofmeister et al. teaches attachment of the compound to double stranded oligonucleotides.
Regarding claim 42, Hofmeister et al. teaches a RNAi which is double-stranded comprising a sense and antisense strand.
Regarding claims 43 and 45, Hofmeister et al. teaches that stability increase has been shown for siRNAs wherein the compounds of formula II are present at an overhang of the sense strand and antisense strand including siRNAs where the compounds of formula II are present at the 3’-end or 5’-end or both of the sense strand.
Claims 1, 3, 6, 37-39, 41-43 and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 11-12, 22, 28, 32, 35-36, 44,48 and 50-58 of copending Application No. 18532319 (USPGPUB No. 20240376137) in view of Clark et al., Hasegawa et al. and Manoharan et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘319 claims a compound of Formula I:
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wherein R3 is:
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(claims 1 and 28). Claimed is an oligonucleotide comprising one or more compounds of formula II (claim 35). A double stranded oligonucleotide is claimed (claim 50). A siRNA comprising the compound is claimed (claim 51).
The difference between the instant claims and copending ‘319 is that copending ‘319 does not claim a nitrogen in the ring and this is the point of attachment via an amide. However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
The teachings of Clark et al., Hasegawa et al. and Manoharan et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘319, Clark et al., Hasegawa et al .and Manoharan et al. and utilize a compound of:
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as R3 in place of GalNAc as taught by copending ‘319. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds of copending ‘319 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, copending ‘319 claims the compounds can be a double stranded oligonucleotide comprising one or more of the compounds of formula II or a small interfering RNA (siRNA) comprising one or more compounds of formula (II).
Regarding claim 41-43 and 45, copending ‘319 teaches attachment of the compound to double stranded oligonucleotides. Copending ‘319 teaches a RNAi which is double-stranded comprising a sense and antisense strand. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘319, Clark et al., Hasegawa et al .and Manoharan et al. and attach the compound at any position on the oligonucleotide.
Claims 1, 3, 6, 37-39, 41-43 and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 9, 11, 14-15, 19, 22-23, 25-26, 29, 32-33, 35-37 and 39 of copending Application No. 18248974 (USPGPUB No. 20240035029) in view of Clark et al., Hasegawa et al. and Manoharan et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘974 claims a double stranded RNA. The dsRNA includes a 5’ overhang, a 3’ overhang or both. One or both of the strands of the dsRNA comprise one or more compounds of Formula I:
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146
225
media_image13.png
Greyscale
wherein R3 is:
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119
152
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(claims 1; 22). A double stranded oligonucleotide is claimed (claim 22).
The difference between the instant claims and copending ‘974 is that copending ‘974 does not claim a nitrogen in the ring and this is the point of attachment via an amide. However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
The teachings of Clark et al., Hasegawa et al. and Manoharan et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘974, Clark et al., Hasegawa et al .and Manoharan et al. and utilize a compound of:
PNG
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157
176
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Greyscale
as R3 in place of GalNAc as taught by copending ‘974. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds of copending ‘974 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, copending ‘974 claims the compounds can be a double stranded oligonucleotide comprising one or more of the compounds of formula I.
Regarding claim 41-43 and 45, copending ‘974 claims attachment of the compound to double stranded oligonucleotides wherein the dsRNA comprises a sense and antisense strand. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘974, Clark et al., Hasegawa et al .and Manoharan et al. and attach the compound at any position on the oligonucleotide.
Claims 1, 3, 6, 37-39, 41-43 and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 9, 11, 15, 17-22, 30-31, 34-36 and 40-42 of copending Application No. 18248982 (USPGPUB No. 20230383294) in view of Clark et al., Hasegawa et al. and Manoharan et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘982 claims a double stranded RNA (claim 1). The dsRNA includes a 5’ overhang, a 3’ overhang or both (claim 11). One or both of the strands of the dsRNA comprise one or more compounds of Formula I:
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146
225
media_image13.png
Greyscale
wherein R3 is:
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348
407
media_image15.png
Greyscale
(claim 20; 22).
The difference between the instant claims and copending ‘982 is that copending ‘982 does not claim a nitrogen in the ring and this is the point of attachment via an amide. However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
The teachings of Clark et al., Hasegawa et al. and Manoharan et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘982, Clark et al., Hasegawa et al .and Manoharan et al. and utilize a compound of:
PNG
media_image7.png
157
176
media_image7.png
Greyscale
as R3 in place of GalNAc as taught by copending ‘982. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds of copending ‘982 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, copending ‘982 claims the compounds can be a double stranded oligonucleotide comprising one or more of the compounds of formula I.
Regarding claim 41-43 and 45, copending ‘982 claims attachment of the compound to double stranded oligonucleotides wherein the dsRNA comprises a sense and antisense strand. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘982, Clark et al., Hasegawa et al .and Manoharan et al. and attach the compound at any position on the oligonucleotide.
Claims 1, 3, 6, 37-39 and 41-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 15 and 17-28 of copending Application No. 17641014 (USPGPUB No. 20220372063) in view of Clark et al., Hasegawa et al. and Manoharan et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘014 claims a double stranded RNA comprising a sense and antisense strand that comprises one or more nucleotide analogs of formula I-A:
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158
263
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wherein R3 can be a heterocycle or a cell targeting agent (claim 1;7).
The difference between the instant claims and copending ‘014 is that copending ‘014 does not claim the instantly claimed R3 However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
The teachings of Clark et al., Hasegawa et al. and Manoharan et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘014, Clark et al., Hasegawa et al .and Manoharan et al. and utilize a compound of:
PNG
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157
176
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Greyscale
as R3 in copending ‘014. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds of copending ‘014 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, copending ‘014 claims the compounds can be a double stranded oligonucleotide comprising one or more of the compounds of formula I.
Regarding claim 41-43, copending ‘014 claims attachment of the compound to double stranded oligonucleotides wherein the dsRNA comprises a sense and antisense strand. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘014, Clark et al., Hasegawa et al .and Manoharan et al. and attach the compound at any position on the oligonucleotide.
Claims 1, 3, 6, 37-39 and 41-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-7, 9-21 and 23-39 of copending Application No. 17638339 (USPGPUB No. 20220290156) in view of Clark et al., Hasegawa et al. and Manoharan et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘339 claims a double stranded RNA comprising a sense and antisense strand (claim 1) that comprises one or more compounds of formula I:
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410
609
media_image17.png
Greyscale
wherein R3 can be formula II
PNG
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347
376
media_image18.png
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(claims 11; 14) The dsRNA includes a 5’ overhang, a 3’ overhang or both (claim 11). A 5’ and/or 3’ overhang is claimed (claim 10).
The difference between the instant claims and copending ‘339 is that copending ‘339 does not claim the instantly claimed R3 However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
The teachings of Clark et al., Hasegawa et al. and Manoharan et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘339, Clark et al., Hasegawa et al .and Manoharan et al. and utilize a compound of:
PNG
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157
176
media_image7.png
Greyscale
as R3 in copending ‘339. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds of copending ‘339 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, copending ‘339 claims the compounds can be a double stranded oligonucleotide comprising one or more of the compounds of formula I.
Regarding claim 41-43, copending ‘339 claims attachment of the compound to double stranded oligonucleotides wherein the dsRNA comprises a sense and antisense strand. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘339, Clark et al., Hasegawa et al .and Manoharan et al. and attach the compound at any position on the oligonucleotide.
Claims 1, 3, 6, 37-39 and 41-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-58 of copending Application No. 19407739 in view of Clark et al., Hasegawa et al. and Manoharan et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘739 claims a compound of formula I (claim 1):
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410
609
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Greyscale
wherein R3 can be formula III:
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113
173
media_image19.png
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(claim 27). An oligonucleotide comprising one or more compounds of formula II is claimed (claim 35). A double stranded oligonucleotide is claimed (claim 50).
The difference between the instant claims and copending ‘739 is that copending ‘739 does not claim the instantly claimed R3 However, this deficiency is cured by Clark et al., Hasegawa et al. and Manoharan et al.
The teachings of Clark et al., Hasegawa et al. and Manoharan et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘739, Clark et al., Hasegawa et al .and Manoharan et al. and utilize a compound of:
PNG
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157
176
media_image7.png
Greyscale
as R3 in copending ‘739. One skilled in the art would have been motivated to utilize this compound as Clark et al. teaches that a similar compound DGJNAc is an iminosugar analog of GalNAc and Manoharan et al. teaches that both GalNAc and imino sugars are known to be used as monosaccharides for conjugation to oligonucleotides. Hasegawa et al. teaches that replacement of the oxygen with a nitrogen in aldose sugars has been of great interest not only from the point of view of the chemistry involved, but also for their various, biological activities and specifically teaches that compound 12 is a specific derivative of 2-amino sugars with nitrogen in the ring.
Regarding the elected species and claim 1, 3 and 6, for ease of synthesis, the use of a carbonyl to couple the nitrogen with a C(O). There is a reasonable expectation of success as Manoharan et al. suggests that NHC(O) can be utilized to conjugate sugar moieties. Therefore replacement of the sugar moiety and one of the carbons of the compounds of copending ‘739 with C(O)-iminosugar would result in the elected compound.
Regarding claim 37-39, copending ‘739 claims the compounds can be a double stranded oligonucleotide comprising one or more of the compounds of formula I.
Regarding claim 41-43, copending ‘739 claims attachment of the compound to double stranded oligonucleotides wherein the dsRNA comprises a sense and antisense strand. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘739, Clark et al., Hasegawa et al .and Manoharan et al. and attach the compound at any position on the oligonucleotide.
Response to Arguments
Applicant's arguments filed June 16 2026 are acknowledged. The rejections are maintained since applicant has not made any substantive arguments traversing the rejection.
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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