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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 28, 2025 has been entered.
Status of Claims/Rejections
Currently, claims 58 and 61-65 are pending and under examination on the merits in the instant application.
Any rejections not repeated herein are withdrawn, and the following rejections are the only rejections applied in this application.
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.
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 58 and 60-65 are rejected under 35 U.S.C. 103 as being unpatentable over Seth et al. (WO 2015/042447 A1, of record) in view of Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record) and Gryaznov et al. (US 2020/0270611 A1, of record).
Seth discloses compound 230 at page 203 as reproduced below, wherein “CM” represents a cleavable bond or cleavable moiety such as “phosphodiester” and “Nucleotide(s)” represents double-stranded siRNA, which can comprise chemical modifications including phosphorothioate linking groups, 2’-O-methyl, and 2’-F modifications, wherein the GalNAc conjugate “is attached to the sense strand in an siRNA compound.” See pages 3, 34-39, 78-79, 96, and 203.
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Seth teaches that the linker that links the trivalent moiety to the nucleotides can have the following structure at page 65, wherein each n is 1-20 and “L” is a phosphorous linking group.
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Seth does not teach that the trivalent linker comprises a tris-based linker/scaffold.
Prakash teaches that a trivalent GalNAc conjugate comprising tris-based trivalent linker/scaffold (“5’-tris-GN3”) and a trivalent GalNAc conjugate comprising triacid-based trivalent linker/scaffold (“5’-triacid GN3” or “5’-TA-GN3”) “exhibits similar binding affinity” to ASGR (asialoglycoprotein receptor) and the antisense oligonucleotide containing 5’-tris-GN3 and that containing 5’-TA-GN3 also “exhibited similar potency”. See page 2723; Figure 2.
Prakash discloses the structure of a trivalent GalNAc conjugate comprising tris-based linker in Figure 9 as shown below.
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Prakash teaches that different triantennary GalNAc moieties were synthesized and tested in order “to determine the optimal tether length and linker chemistry” and that “a hexylamino PO linker between the GalNAc cluster and the ASO is sufficient to liberate the parent ASO by metabolism”. See pages 2726 and 2728.
Gryaznov discloses at page 49 that the linker that links a trivalent GalNAc moiety to the 3’ end of an oligonucleotide comprises a C8 linker moiety and a C6 amine linker moiety as shown below.
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Grayznov teaches that the linker moiety includes “a C2-C10 alkyl moiety”. See paragraph 0097.
Grayznov teaches that the oligonucleotide can be “an siRNA oligonucleotide.” See paragraphs 0030 and 0059.
It would have been obvious to one of ordinary skill in the art before the effective filing date to replace the triacid-based trivalent linker/scaffold in Seth’s compound 230 with Prakash’s tris-based trivalent linker/scaffold. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make an alternative GalNAc conjugate having similar potency and binding affinity to ASGR that can be used for siRNA molecule delivery as compound 230, because the GalNAc moiety having tris-based trivalent linker/scaffold and that having triacid-based trivalent linker/scaffold were known to have “similar binding affinity” to ASGR (asialoglycoprotein receptor) as well as “similar potency” as reported by Prakash, and because it was an art-recognized goal and a normal desire of relevant artisans to make different GalNAc moieties with varying tether/linker structures in order “to determine the optimal tether length and linker chemistry.” It would also have been obvious to one of ordinary skill in the art to use n=5 for Seth’s linker structure reproduced above at page 5 because each n was taught to be 1-20, thereby providing a finite number of linker structures, especially when the linker comprises a hexylamino PO linker thus the second n is fixed at 5 while varying the number of first n, because the hexylamino PO linker when attached to an oligonucleotide was taught to be “sufficient to liberate” the attached oligonucleotide as disclosed by Prakash, and further because linker structures having a hexylamino PO linker with a varying number of first “n” within “1-20” were known to be suitable for providing a suitable spatial separation between the oligonucleotide and the trivalent GalNAc moiety as evidenced by Seth’s compound 230 as well as Prakash’s 5’-THA-GN3 ASO having a hexylamino PO linker with the first “n” being 3, and further evidenced by Gryaznov’s GalNAc moiety comprising a hexylamino PO linker with the first “n” being 8. Taken together, one of ordinary skill in the art would have reasonably obtained the instantly claimed compound structure in view of the combined teachings of Seth, Prakash, and Gryaznov and the level of skills/techniques disclosed therein.
In view of the foregoing, claims 58 and 61-65 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on May 28, 2025 have been fully considered but they are not persuasive. Applicant argues that the claims are not obvious because Seth’s compound relied on the instant rejection is not structurally identical to the claimed compound. In response, it is noted that the instant rejection is not an anticipation rejection under 35 U.S.C.102 thus there is no legal requirement that Seth’s compound should not differ from the claimed compound. Further, it is noted that applicant cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Prakash fails to cure the deficiencies of Seth because Prakash’s teachings pertaining to similarities between tris-GN3- and triacid-GN3-based linkers are insufficient to show that one skilled in the art would be motivated to modify Seth’s compound to arrive at the claimed subject matter by stating that the examiner’s reasoning “is contrary to the standard set by” Virtek Vision Int’l ULC v. Assembly Guidance Sys., Inc., 97 F.4th 882 (Fed. Cir. 2024). In response, it is noted that the fact pattern in the Virtek caselaw is not at all analogous to that in the instant rejection. The reversal of the obviousness rejection in the relatively brief, concise decision by the Federal Circuit was based on the Court’s finding that the obviousness rejection was improperly established on the finding that the two systems – angular direction system and 3D coordinate system – were merely “known to be used” or “both such measurement systems were known”, which by itself was found insufficient to support the obviousness because there was no articulated rationale/reason for substituting the one-camera angular direction system in the prior art with the two-camera 3D coordinate system. That is, the Court found that the obviousness rejection of record and the expert declaration of record did not “articulate” a motivation for the substitution. In fact, the Court expressly noted that the statement “testifying “I’m not sure I can find” a reason to combine” in the expert deposition of the cross-appellant. See page 8. By contrast, the obviousness of the claimed subject matter is not merely established on the fact that the two different linkers/scaffolds in GalNAc3 were “known” but rather, the instant ground of rejection is established on a clearly articulated reason/rationale as to why one of ordinary skill in the relevant art would have been motivated to replace Seth’s triacid-based trivalent linker/scaffold with Prakash’s tris-based trivalent linker/scaffold, wherein the motivation is “to make an alternative GalNAc conjugate having similar potency and binding affinity to ASGR that can be used for siRNA molecule delivery as compound 230” and “because it was an art-recognized goal and a normal desire of relevant artisans to make different GalNAc moieties with varying tether/linker structures in order “to determine the optimal tether length and linker chemistry.”” Since there is no analogy between the ground of rejection in the instant application and that in Virteck for the reasons stated above, applicant’s arguments alleging no motivation in view of Virteck are not found persuasive. Again, note that the instant obviousness rationale is not established merely on the finding that two linker types were “known” as interpreted by applicant, who alleged that the examiner made “an error”. In addition, since the fact pattern between the obviousness rationale in the instant rejection and that in Virtek are not analogous, applicant’s assertion that the examiner’s rationale “is contrary to the standard” in Virtek is not found persuasive.
Applicant argues that the examiner’s motivation rationale “is also incorrect in view of Sharma” because one skilled in the art would appreciate that the target-binding efficacy would be greatly affected with “even minor changes”. As an initial matter, “Sharma” is not even cited or relied on in making the instant rejection. Hence, it is unclear what relevance “Sharma” has in showing applicant’s asserted nonobviousness of the rejected claims. Further, applicant’s generic statement that the target-binding efficacy was expected by relevant artisans to be greatly different with “even minor changes” does not specifically support applicant’s implied assertion that the modifications incorporated into Seth’s compound in view of the teachings of Prakash and Gryaznov were expected in the relevant prior art to impair target-binding efficacy of the GalNAc3 conjugate moiety, thereby fails to address the instant ground of rejection. Furthermore, it was expressly noted in the Office action of record mailed on January 28, 2025 that there is no teaching in “Sharma” that a PEG spacer in Seth’s compound and the instantly claimed compound should be avoided. Hence, the examiner is not persuaded by applicant’s argument that the examiner’s motivation rationale is “incorrect in view of Sharma.”
Applicant argues that the claims are not obvious in view of the §1.132 declaration filed on May 28, 2025. Since applicant has merely reiterated the declaration, the examiner will address the declaration. The declaration under 37 CFR 1.132 filed May 28, 2025 is insufficient to overcome the instant rejection for the following reasons:
The declarant states that the claimed compound is “superior” to Seth’s compound because the claimed compound’s precursor showed “a higher predicted solubility” (-1.71 vs. -1.94 in LogS), which provides “several crucial advantages” such as “improved stock solution preparation for the post-synthetic conjugation process.” The declarant further states that the claimed compound enables use of “less organic solvent”, thereby avoiding “increased processing costs and negative environmental impacts”, which thus is “a more commercially beneficial GalNAc conjugate-precursor.” In making the aforementioned statements, the declarant points out three references. Since a legible copy of each of the references is not submitted for examiner’s consideration, the examiner cannot consider/verify the teachings of the references.
Now, applicant’s attention is directed to the fact that the rejected claims in the instant case are not directed to a method of synthesizing the claimed compound or precursor thereof or a method of conjugating the GalNAc3 moiety. The claims are directed to a finalized compound comprising an RNA duplex conjugated to the GalNAc3 moiety/linker/scaffold shown in the claimed “structure” at the 3’ end of the second strand (sense strand). Furthermore, the claims do not require use of “less organic solvent” with reduced “costs” and “negative environmental impacts”. That is, the alleged “advantages” that are asserted to be “commercially beneficial” are not commensurate in scope with the rejected claims. Note that “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” See MPEP 716.02. Moreover, the LogS of -1.71 is only about 1.7 times more soluble than the LogS of -1.94 thus, the difference in solubility between the claimed compound’s precursor and Seth’s compound’s precursor is not significantly different, and there is no objective evidence demonstrating that the two LogS values are of statistical significance. Even better, both LogS values are considered soluble. Hence, even if the claims were to expressly recite and require the LogS value of -1.71 for the claimed compound or precursor thereof, such property is not deemed “superior” compared to Seth’s compound.
The declarant continues to focus on and compare “synthesis” of the claimed compound’s precursor and Seth’s compound’s precursor. In response, applicant’s attention is again directed to the fact that the instantly rejected claims are not directed to a method of synthesizing the claimed compound or precursor thereof thus, any difference in “synthesis” and “total yield” between the two precursors bears no merit in providing objective evidence of nonobviousness of the claimed subject matter. Again, note that the rejected claims are not directed to a precursor, but a finalized, finished product comprising an RNA duplex conjugated to the GalNAc3 moiety/linker/scaffold shown in the claimed “structure” at the 3’ end of the sense strand. As such, the potential “economically” beneficial aspect of synthesizing the claimed compound’s precursor having a total yield of about 16% over 9 steps is not commensurate in scope with the rejected claims.
The declarant makes a conclusory statement that the claimed compound’s precursor has “unexpected”, “improved technical effects”. In response, the examiner finds that this statement is not corroborated by any factual, objective evidence commensurate in scope with the claims.
The declarant concludes that the “results” pertaining to the LogS values and total yields “emphasize that even minor changes in molecular design can impact important properties of GalNAc conjugate compounds and precursors thereof.” As an initial matter, the rejected claims are not directed to a precursor of a GalNAc conjugate as repeatedly noted hereinabove. Further, the “results” described in the declaration are not commensurate in scope with the rejected claims as explained in detail hereinabove. Furthermore, there is no evidence or disclosure in the instant specification that the “solubility” and the “total yields” of the “precursor” of the claimed compound are “important properties”. As such, the declarant’s personal opinion pertaining to the unclaimed features of the rejected claims is not found to support the asserted nonobviousness of the rejected claims directed to a finalized, not intermediate or precursor, compound comprising an RNA duplex whose 3’ end of the sense strand is conjugated to the GalNAc3 conjugate moiety illustrated in claim 58.
In view of the foregoing, the instant rejection is hereby reiterated.
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 58 and 61-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 13-18, and 21-39 of U.S. Patent No. 10,995,336 B2 in view of Seth et al. (WO 2015/042447 A1, of record), Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record), and Gryaznov et al. (US 2020/0270611 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘336 patent claims drawn to an Serpina1-targeting dsRNA agent, “wherein said sense strand comprises an ASGPR ligand”, which is “one or more GalNAc derivatives attached through a bivalent or trivalent branched linker”, and the agent also comprises two or more 2’-fluoro modifications. It would have been obvious to use a GalNAc3 conjugate structure comprising the instantly claimed linker for the “GalNAc derivatives” claimed in the ‘336 patent claims because the techniques and elements necessary to arrive at the claimed GalNAc3 conjugate structure were known, available, and prima facie obvious in view of the teachings of Seth, Prakash, and Gryaznov as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Response to Arguments
Applicant's arguments filed on May 28, 2025 have been fully considered but they are not persuasive. Applicant argues that the ‘336 patent claims and the cited secondary references “do not teach or suggest the compound of the amended claims.” In response, it is noted that the claims filed on May 28, 2025 are not “amended” as there is no claimed with the “amended” status. Applicant argues that the cited references do not cure the deficiencies of the ‘336 patent claims because the examiner’s motivation rationale “does not meet the correct standard” and “is incorrect in view of Sharma.” In response, applicant’s arguments are not found persuasive for the same reasons provided in the §103 rejection above. Applicant argues that the claims are not obvious in view of the §1.132 declaration filed on May 28, 2025. In response, the declaration is not found persuasive to support the nonobviousness of the claimed subject matter, which is not a precursor of the conjugate or a synthesis/conjugation method as explained in detail above in the §103 rejection.
Accordingly, this rejection is hereby reiterated.
Claims 58 and 61-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-17, 19-29, and 31-41 of U.S. Patent No. 11,504,391 B1 in view of Seth et al. (WO 2015/042447 A1, of record), Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record), and Gryaznov et al. (US 2020/0270611 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘391 patent claims that recite and require a dsRNA molecule comprising an ASGPR ligand, which is “one or more GalNAc derivatives attached through a bivalent or trivalent branched linker”, and the agent also comprises two or more 2’-fluoro modifications. It would have been obvious to use a GalNAc3 conjugate structure comprising the instantly claimed linker for the “GalNAc derivatives” claimed in the ‘391 patent claims because the techniques and elements necessary to arrive at the claimed GalNAc3 conjugate structure were known, available, and prima facie obvious in view of the teachings of Seth, Prakash, and Gryaznov as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Response to Arguments
Applicant's arguments filed on May 28, 2025 have been fully considered but they are not persuasive. Applicant argues that the ‘391 patent claims and the cited secondary references “do not teach or suggest the compound of the amended claims.” In response, it is noted that the claims filed on May 28, 2025 are not “amended”. Applicant argues that the cited references do not cure the deficiencies of the ‘391 patent claims because the examiner’s motivation rationale “does not meet the correct standard” and “is incorrect in view of Sharma.” In response, applicant’s arguments are not found persuasive for the same reasons provided in the §103 rejection above. Applicant argues that the claims are not obvious in view of the §1.132 declaration filed on May 28, 2025. In response, the declaration is not found persuasive to support the nonobviousness of the claimed subject matter, which is not a precursor of the conjugate or a synthesis/conjugation method as explained in detail above in the §103 rejection.
Accordingly, this rejection is hereby reiterated.
Claims 58 and 61-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12-26, 34-47, 50-63, 82-93, and 96-109 of U.S. Patent No. 11,725,207 B2 in view of Seth et al. (WO 2015/042447 A1, of record), Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record), and Gryaznov et al. (US 2020/0270611 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘207 patent claims that recite and require an Serpina1-targeting dsRNA agent, “wherein said sense strand comprises an ASGPR ligand”, which is “one or more GalNAc derivatives attached through a bivalent or trivalent branched linker”, and the agent also comprises two or more 2’-fluoro modifications. It would have been obvious to use a GalNAc3 conjugate structure comprising the instantly claimed linker for the “GalNAc derivatives” claimed in the ‘207 patent claims because the techniques and elements necessary to arrive at the claimed GalNAc3 conjugate structure were known, available, and prima facie obvious in view of the teachings of Seth, Prakash, and Gryaznov as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Response to Arguments
Applicant's arguments filed on May 28, 2025 have been fully considered but they are not persuasive. Applicant argues that the ‘207 patent claims and the cited secondary references “do not teach or suggest the compound of the amended claims.” In response, it is noted that the claims filed on May 28, 2025 are not “amended”. Applicant argues that the cited references do not cure the deficiencies of the ‘336 patent claims because the examiner’s motivation rationale “does not meet the correct standard” and “is incorrect in view of Sharma.” In response, applicant’s arguments are not found persuasive for the same reasons provided in the §103 rejection above. Applicant argues that the claims are not obvious in view of the §1.132 declaration filed on May 28, 2025. In response, the declaration is not found persuasive to support the nonobviousness of the claimed subject matter, which is not a precursor of the conjugate or a synthesis/conjugation method as explained in detail above in the §103 rejection.
Accordingly, this rejection is hereby reiterated.
Claims 58 and 61-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 14, and 16-40 of copending Application No. 17/937,256 in view of Seth et al. (WO 2015/042447 A1, of record), Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record), and Gryaznov et al. (US 2020/0270611 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘256 claims drawn to a dsRNA agent comprising “one or more GalNAc molecules attached through a bivalent or trivalent branched linker” to the “3’ end of the sense strand”, and the agent also comprises “at least four 2’-fluoro modifications” and terminal “phosphorothioate internucleotide linkages”. It would have been obvious to use a GalNAc3 conjugate structure comprising the instantly claimed linker for the “GalNAc molecules” claimed in the ‘256 claims because the techniques and elements necessary to arrive at the claimed GalNAc3 conjugate structure were known, available, and prima facie obvious in view of the teachings of Seth, Prakash, and Gryaznov as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Claims 58 and 61-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8-9, 12-14, 42-43, and 48-51 of copending Application No. 18/106,166 in view of Seth et al. (WO 2015/042447 A1, of record), Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record), and Gryaznov et al. (US 2020/0270611 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘166 claims drawn to a double-stranded RNA (dsRNA) comprising “2’-Me or 2’-F modifications”, “two consecutive abasic nucleotides in the 5’ terminal region” of the sense strand, and “phosphorothioate internucleotide linkages” in the 5’ terminal region of the antisense strand. It would have been obvious to attach a GalNAc3 conjugate to the 3’ end of the sense strand (“second strand”) of the dsRNA claimed in the ‘166 claims in order to improve in vivo intracellular delivery of the dsRNA because a GalNAc3 conjugate was known to improve in vivo intracellular delivery of an siRNA molecule thus it was an art-recognized goal to make an siRNA- GalNAc3 conjugate as evidenced by the teachings of Seth and Gryaznov. Further, the techniques and elements necessary to arrive at the claimed GalNAc3 conjugate structure including the linker were known, available, and prima facie obvious in view of the teachings of Seth, Prakash, and Gryaznov as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Claims 58 and 61-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/624,912.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the ‘912 claims that recite and require an siRNA oligomer conjugated to ligand moieties, which are defined to read on the structure claimed in the instant case as evidenced by “Formula (IX)” and “3’-GalNAc-T2 conjugates” disclosed in the ‘912 specification. See pages 121 and 157-158.
Claims 58 and 61-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-20 of copending Application No. 18/640,905.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the ‘905 claims that recite and require an siRNA oligomer conjugated to GalNAc ligands and derivatives thereof, which are defined to read on the structure claimed in the instant case as evidenced by “3’-GalNAc-T2 conjugates” disclosed in the ‘905 specification. See page 218.
Claims 58 and 61-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/644,183 in view of Seth et al. (WO 2015/042447 A1, of record), Prakash et al. (Journal of Medicinal Chemistry, 2016, 59:2718-2733, of record), and Gryaznov et al. (US 2020/0270611 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘917 claims drawn to an Serpina1-targeting dsRNA agent, “wherein said sense strand comprises an ASGPR ligand”, which is “one or more GalNAc derivatives attached through a bivalent or trivalent branched linker”, and the agent also comprises two or more 2’-fluoro modifications. It would have been obvious to use a GalNAc3 conjugate structure comprising the instantly claimed linker for the “GalNAc derivatives” claimed in the ‘917 claims because the techniques and elements necessary to arrive at the claimed GalNAc3 conjugate structure were known, available, and prima facie obvious in view of the teachings of Seth, Prakash, and Gryaznov as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Potential Double Patenting
Claims 58 and 61-65 would be provisionally rejected over the claims of Application Nos. 18/869,034, 18/876,959, and 18/879,713 that are currently under preexam processing as the instant claims would have been obvious over the siRNA conjugated to one or more GalNAc ligands claimed in the ‘034, ‘959, and ‘713 applications.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635