DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 14, 2025 has been entered.
Status of Claims/Rejections
Currently, claim 10 is pending and under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn, and the following rejections are the only rejections applied in this application.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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claim 10 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rana et al. (US 2006/0069050 A1, of record).
Rana discloses an in vivo method of silencing a target mRNA encoding a protein associated with a pathological condition in a cell of a subject for therapeutic applications such as “for treating a disease or disorder associated with the activity of a protein specified by a target mRNA in a subject” comprising administering a target mRNA-specific non-canonical siRNA at “an amount sufficient for degradation of the target mRNA to occur” in the subject, wherein the non-canonical siRNA comprises “an antisense strand of about 21 nucleotides (e.g., 19, 20, 21, or 22 nucleotides) and corresponding sense strand of at least 10, 11, 12, 13, 14, 15, 16, 17, 18 to 19 nucleotides”, wherein “siRNAs comprising a sense strand of 14, 15, or 16 nucleotides are particularly effective”. See paragraphs 0055, 0058, 0062-0063, 0075, and 0086-0087; claims 1-3, 5, and 37. See claims 1, 5, and 37 reproduced below, wherein underline has been added for emphasis.
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Rana teaches that non-canonical siRNAs “having a non-canonical length (i.e., being shorter than 21 nucleotides) or non-canonical overhang (i.e., lacking a 3’ dTdT overhang) are as effective as [canonical] RNAi/gene silencing agents”, wherein the non-canonical overhangs encompass “sense strand shortening and/or deletion of the dTdT end”. See paragraphs 0007, 0017, and 0037.
Rana demonstrates that a non-canonical siRNA having a shortened sense strand hybridized with a 21-mer antisense strand forming a 16-bp duplex and a 5-nt 3’ overhang in the antisense strand provides RNAi activity. See the following reproduced from Figure 7.
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It would have been obvious to one of ordinary skill in the art at the time the invention was made to practice Rana’s in vivo method of administering a non-canonical 16-bp siRNA formed by a 21-nt antisense strand and a 16-nt sense strand with “at least one non-canonical end” for therapeutic applications because use of a non-canonical siRNA comprising an antisense strand of “21 nucleotides” and a shorter sense strand of “16 nucleotides” forming a 16-bp duplex for RNAi-mediated target silencing was already practiced in the art as evidenced by Rana as demonstrated in Figure 7 reproduced above, and because Rana expressly taught that the non-canonical siRNA comprises a non-canonical 3’ end “lacking a 3’ dTdT overhang” in addition to the sense strand shortening. Since the non-canonical 16-bp siRNA design having a 5-nt 3’ overhang in the 21-nt antisense strand was already demonstrated to have RNAi activity in the art as evidenced by Rana, and since “deletion of the dTdT end”, thereby “lacking a 3’ dTdT overhang” in the sense strand was additionally suggested with “sense strand shortening” by Rana, one of ordinary skill in the art would have had a reasonable expectation of success in making an using a non-canonical 16-bp duplex forming a 5-nt 3’ overhang in the antisense strand of 21 nucleotides in length duplexed with a sense strand of 16 nucleotides in length for therapeutic applications in a subject.
Accordingly, claim 10 taken as a whole would have been prima facie obvious at the time the invention was made.
Claim 10 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Li et al. (US 2009/0208564 A1, of record).
Li discloses a method of silencing target expression in a target cell in vivo for therapeutic purposes comprising administering to an animal or a subject an asymmetric siRNA comprising a first strand (antisense strand that is “complementary to a target mRNA sequence”) and a second strand, wherein “the first strand has a length of 21 nucleotides” and “the second strand has a length of 14-16 nucleotides”, wherein the asymmetric siRNA has a blunt end at the 5’ end of the first strand (thus antisense strand) and a 3’-overhang at the 3’ end of the antisense strand. See paragraphs 0009-0010 and 0014; claims 1-2, 6-7, and 23-33. See also Figure 2B reproduced below.
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It would have been obvious to one of ordinary skill in the art at the time the invention was made to practice Li’s in vivo method by administering an asymmetric siRNA of 16-bp duplex formed by a 21-nt antisense strand and a 16-nt sense strand forming the structure in Figure 2B reproduced above because use of such asymmetric siRNA satisfying the instantly claimed structural limitations for target silencing in vivo in a subject for therapeutic purposes was expressly suggested and taught by Li as described above, wherein the sense strand length of “16 nucleotides” is one of three clearly identified sense strand length options (“a length of 14-16 nucleotides”) forming an asymmetric siRNA with an antisense strand having “a length of 21 nucleotides”, wherein the asymmetric siRNA in Figure 2B was one of a finite number of clearly identified asymmetric siRNA structures disclosed in Li (see for instance Figures 1A-2D), one of ordinary skill in the art would have reasonably pursued the known asymmetric siRNA design options and would have reasonably succeeded in making and using the asymmetric siRNA of 16-bp duplex formed by a 21-nt antisense strand and a 16-nt sense strand forming the structure in Figure 2B for therapeutic purposes.
Accordingly, claim 10 taken as a whole would have been prima facie obvious at the time the invention was made.
Response to Arguments
Applicant's arguments filed on October 14, 2025 have been fully considered but they are not persuasive. Applicant argues that neither Rana nor Li teaches the claimed method because the cited art does not teach “which” of the siRNA structures in the cited art has “desirable properties” for the therapeutic in vivo use thus fails to teach that the asymmetric structure recited in claim 10 “would be a desirable compound” for the claimed method. In response, applicant appears to require that the cited art must show therapeutic in vivo effects for a disclosed siRNA structure in Rana and Li in order to render claim 10 obvious under §103. Applicant’s attention is directed to the fact that a working example is not required for obviousness under §103, and furthermore, all that is required for obviousness is a reasonable, not absolute, expectation of success. In the instant case, applicant did not provide any objective, factual rebuttal evidence that supports that the literal teachings/disclosures in Rana and Li pertaining to the therapeutic use of the asymmetric siRNAs are not credible, thereby failing to provide a reasonable expectation of success when a person of ordinary skill in the art practices the therapeutic application of the prior art’s asymmetric siRNAs in a target cell of a subject.
Applicant’s attention is further directed to the fact that the word “therapy” is recited only as an intended use “for therapy”, wherein the claimed method is expressly directed to “silencing the expression of a target gene in a cell of a subject”. There is no teaching in Rana or Li that the disclosed asymmetric siRNAs cannot have the function of “silencing the expression of a target gene in a cell of a subject” when applied for the purpose of therapy, nor has applicant provided evidence showing that the prior art’s asymmetric siRNAs cannot be used to silence target gene expression in a cell of a subject. Again, applicant’s attention is directed to the fact that the instant specification in and of itself is completely silent regarding any working example commensurate in scope with the instantly claimed in vivo method to the extent that the word “therapy” is merely mentioned twice in passing in the phrase “gene therapy”. See page 1 disclosing the following: “As RNAi can be used to suppress target gene expression as described above, it has drawn a great deal of attention as a method applicable to gene therapy” (emphasis added). See also page 34 for the following: “Thus, the siRNA structure according to the present invention can substitute for prior art siRNA molecules and can be advantageously used in siRNA-based gene silencing techniques such as gene therapy.” (emphasis added). Note that the aforementioned disclosure at page 1 expressly acknowledges on the record that RNAi that suppresses target expression was known to be “applicable to gene therapy” in the prior art and the aforementioned disclosure at page 34 merely discloses that “gene therapy” application is purely based on “siRNA-based gene silencing”. Taken together, the intended use “for therapy” recited in claim 10 is expressly acknowledged to be possible purely due to the target gene silencing function of an siRNA molecule. Now, as repeatedly noted above, applicant did not provide any scientific rationale or any objective, factual evidence showing that the prior art’s asymmetric siRNA that inhibits target expression would fail to suppress target expression in a subject’s cell for intended use in therapy when the asymmetric siRNA is taught to be useful in therapeutic applications by the cited art, consistent with applicant’s own acknowledgement of the prior art knowledge at page 1 such that RNAi that suppresses target gene expression has been recognized “as a method applicable to gene therapy”.
Applicant points out Examples 13-16 of the instant specification and argues that asymmetric siRNA structures have “good serum stability,” “low off-target effects,” and “do not saturate the RNAi machinery.” Applicant further argues that the instantly claimed structure would be readily envisioned to have “these effects” although the instantly claimed structure was not tested in Examples 13-16. Applicant even goes further to state that the in vitro tests in Examples 13-16 “clearly pertain to therapeutic properties of the siRNA.” In response, claim 10 merely recites “silencing the expression of a target gene in a cell of a subject for therapy”, wherein the method comprises “administering a small interfering RNA molecule” to the subject, wherein the claim is completely silent regarding the “effects” in Examples 13-16. Hence, claim 10 does not require “these effects” mentioned by applicant. Furthermore, the “effects” in Examples 13-16 are described for “the 16+3A siRNA structure” and “the 17+2A and 15+4A structures”, which are not the 16+5A structure claimed in the instant case comprising “a 21 nucleotide (nt) antisense strand” and “a 16 nucleotide sense strand”. Further, Examples 13-16 have nothing to do with the instantly claimed method as they pertain to in vitro 10% FBS solution and HeLa cell line examples using structures that do not satisfy the claimed siRNA molecule’s structural requirements. Hence, what is described in Examples 13-16 is not commensurate in scope with claim 10. It is unclear how or why Examples 13-16 can possibly show evidence that is sufficient to overcome the §103 rejections. If applicant meant to assert that Examples 13-16 provide secondary evidence such as unexpected results, applicant’s attention is directed to the fact that unexpected results must be compared to the prior art’s compound’s activity or “effects”, not to “19+2 siRNA” as done in Examples 13-16. Applicant’s attention is further directed to the fact that unexpected results must be commensurate in scope with the rejected claim, which is an in vivo method of silencing target expression in a subject’s cell comprising administering “to the subject” the claimed siRNA molecule structure.
In view of the foregoing, applicant’s arguments are not found persuasive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-15 of U.S. Patent No. 9,260,470 in view of Rana (US 2005/0020521 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claim would have been obvious over the ‘470 patent claims. It would have been obvious to one of ordinary skill in the art to remove the “bulge” in the asymmetric, blunt-ended siRNA molecule of the ‘470 patent claims and introduce a perfect base pair into the asymmetric, blunt-ended siRNA molecule comprising a 21-nt antisense strand and a 16-nt sense strand forming a 5-nt 3’ overhang sequence in the antisense strand in order to improve the target silencing efficiency in view of the teachings of Rana such that a duplex having a bulge provides reduced target silencing compared to a perfectly base-paired duplex (see Figures 15B, 15C, and 17). Further, since asymmetric siRNAs were known to be useful for therapeutic applications as taught by Rana (see claim 37; paragraphs 0055, 0058, 0062-0063, 0075, and 0086-0087), one of ordinary skill in the art would have reasonably deemed that the methods of the ‘470 claims that require delivery of the asymmetric siRNA “into a cell” can be practiced for therapeutic applications wherein the “cell” is in a subject in need of treatment.
Response to Arguments
Applicant's arguments filed on October 14, 2025 have been fully considered but they are not persuasive. Applicant argues that the siRNA molecule used in the methods of the ‘470 patent claims does not have the structural features of the instantly claimed siRNA. In response, applicant’s attention is directed to the fact that the instant rejection is an obviousness-type double patenting rejection, wherein the instantly claimed siRNA structure is deemed obvious over the teachings of Rana as explained above. Applicant further argues that claims 12-15 of the ‘470 patent are not “claims for use in therapy” thus patentably distinct from the instant claim reciting “for therapy”. In response, applicant’s attention is directed to the fact that the method claims of the ‘470 patent as broadly written do not whatsoever exclude in vivo methods, nor are they strictly limited to in vitro methods as there is no recitation that the cell is in vitro. Now, as explained above, use of an asymmetric siRNA for therapeutic applications was already known in the prior art as evidenced by Rana. Again, note that this rejection is not an anticipation-type but an obviousness-type double patenting rejection.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-19 of U.S. Patent No. 10,590,423 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant genus claim is anticipated by the ‘423 patent claims drawn to an AMD treatment method comprising administering an asymmetric, blunt-ended MyD88-targeting siRNA molecule comprising a 21-nt antisense strand and a 16-nt sense strand.
Response to Arguments
Applicant's arguments filed on October 14, 2025 have been fully considered but they are not persuasive. Applicant contends that a “two-way test” must be conducted in order to properly show that the conflicting claims are not distinct from each other. In response, applicant’s attention is directed to the fact that a two-way test is not required in making double patenting rejections because a “two-way test is to be applied only when the applicant could not have filed the claims in a single application and the Office is solely responsible for any delays.” (original emphasis in italics; emphasis added in bold). See MPEP §804. Hence, applicant’s contention is found baseless as there is no evidence supporting the two required conditions.
Applicant additionally contends that the two-way test is required because “applicant does not have complete control over the rate of progress of a patent application through the Office.” Contrary to applicant’s contention, it was applicant’s own decision, prior to the issuance of the ‘423 patent on March 17, 2020, to choose an appeal process by filing a notice of appeal on October 16, 2019 with the prior awareness/understanding that the entire appeal process until the Board’s decision is not an expedited process. Hence, applicant had significant contribution to the rate of prosecution of the instant application thus the examiner strongly disagrees with applicant’s contention that applicant has nothing to do with the rate of the prosecution of this application. See Pierce v. Allen B. DuMont Laboratories, Inc., 297 F.2e 323, 131 USPQ 340 (3d. Cir. 1961) and In re Emert, 124 F. 3d 1458, 44 USPQ2d 1149 (Fed. Cir. 1997), wherein the courts ruled that a two-way test is not required “when applicant had significant control over the rate of prosecution of the application at issue.”
It is further noted that applicant expressly stated on the record that “Applicant is not the cause in the delayed issuance of this Application.” Applicant’s personal opinion is not objective evidence, and applicant is invited to seek the Board’s review of the propriety of all of the non-provisional nonstatutory double patenting rejections.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-21 of U.S. Patent No. 10,829,761 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant genus claim is anticipated by the ‘761 patent claims drawn to a idiopathic pulmonary fibrosis treatment method comprising administering an asymmetric, blunt-ended CTGF mRNA-targeting siRNA molecule comprising a 21-nt antisense strand and a 16-nt sense strand.
Response to Arguments
Applicant's arguments filed on October 14, 2025 have been fully considered but they are not persuasive. Applicant contends that a “two-way test” must be conducted in order to properly show that the conflicting claims are not distinct from each other. In response, applicant’s attention is directed to the fact that a two-way test is not required in making double patenting rejections because a “two-way test is to be applied only when the applicant could not have filed the claims in a single application and the Office is solely responsible for any delays.” (original emphasis in italics; emphasis added in bold). See MPEP §804. Hence, applicant’s contention is found baseless as there is no evidence supporting the two required conditions.
Claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 17/927,427.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant genus claim is anticipated by the ‘427 claims drawn to an AMD treatment method comprising administering an asymmetric, blunt-ended MyD88-targeting siRNA molecule comprising a 21-nt antisense strand and a 16-nt sense strand.
Response to Arguments
Applicant's arguments filed on October 14, 2025 have been fully considered but they are not persuasive. Applicant argues that the rejection should be withdrawn in view of MPEP 804. In response, applicant’s attention is directed to the fact that the instant rejection is not the only outstanding rejection in the instant application.
Claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-16 of copending Application No. 18/265,603.
The ‘603 application shares the same assignee as the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant genus claim is anticipated by the ‘603 claims drawn to a retinal disease treatment method comprising administering an asymmetric, blunt-ended ROR-beta-targeting siRNA molecule comprising a 21-nt antisense strand and a 16-nt sense strand.
Response to Arguments
Applicant's arguments filed on October 14, 2025 have been fully considered but they are not persuasive. Applicant argues that the rejection should be withdrawn in view of MPEP 804. In response, applicant’s attention is directed to the fact that the instant rejection is not the only outstanding rejection in the instant application.
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