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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on November 7, 2025.
Currently, claims 30-35, 119-121, and 123-133 are pending and under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 7, 2025 has been considered by the examiner, except foreign patent document citation numbers 1 and 2, which are in non-English language and are not provided with English language translation.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112
Claims 31-35, 125-127, and 130 remain rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement for the reasons as set forth in the Office action mailed on July 7, 2025 and for the reasons set forth below.
Applicant's arguments filed on November 7, 2025 have been fully considered but they are not persuasive. Applicant argues that the claims as amended are sufficient to overcome the rejection by pointing out working examples, Figures 45-47 and 49-51, Table 8, and the post-filing Smeyers et al. reference (2021) that discloses “the discovery of C9ORF72 as the most frequent cause of FTC and ALS in 2011.” In response, it is interesting to note that even the fully chemically modified “c9-241” (the single species satisfying the claimed di-branched oligonucleotide) failed to reduce C9ORF7 mRNA with a statistical significance in the cervical and lumbar spinal cord in C9ALS mouse model compared to PBS and/or NTC, wherein claim 35 specifically requires that the unmodified di-branched siRNA as encompassed by the claim “causes a decrease in C9ORF72 gene mRNA in the spinal cord”, wherein “the spinal cord” encompasses the cervical and lumbar spinal cord. See Figure 45A reproduced below.
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Furthermore, “c9-241” also failed to decrease C9ORF72 total mRNA with any statistical significance in the prefrontal cortex, somato-sensory cortex, cerebellum, brainstem, motor cortex, striatum, thalamus, and the hippocampus in C9ALS mouse model compared to the negative controls as shown in Figure 45B and also failed to decrease C9ORF72 total mRNA with a statistical significance in the cerebellum, brainstem, motor cortex, striatum, thalamus, and hippocampus after one month of the administration as shown in Figure 48B and 49B.
Regarding the disease isoform specific mRNA reduction, Figure 46A shows that c9-241 provided statistically insignificant reduction in the cervical, thoracic, and lumbar spinal cord in C9ALS mouse model, and Figure 46B shows an increased expression level of the disease isoform specific mRNA by c9-241 in the prefrontal cortex and little or no significant reductions in the somato-sensory cortex, cerebellum, and brainstem. Therefore, the Figures pointed out by applicant do expressly demonstrate that the fully chemically modified di-branched oligonucleotide comprising two guide strands complementary to SEQ ID NO:5 does not display any scientifically valuable/significant in vivo reduction in C9ORF72 mRNA expression in the brain/spinal cord regions that are associated with ALS and frontotemporal dementia (FTD) when tested in the ALS9 mouse model. Hence, the Figures are far from describing the required limitation pertaining to “administering the di-branched oligonucleotide causes a decrease in C9ORF72 gene mRNA in the brain” and “in the spinal cord” thus, the Figures pointed out by applicant are far from supporting the required structure-function correlation for the claimed di-branched oligonucleotide including the single species of “c9-241” within the claimed genus. As such, the working examples, Figures, and Table 8 pointed out by applicant are insufficient to adequately describe the instantly claimed ALS and FTD treatment method that is performed in “a patient in need of such treatment or management” in light of the little or no reduction in C9ORF72 mRNA expression in the pathologically affected CNS regions in the mouse model of ALS and FTD. Moreover, it is highly questionable as to how a di-branched oligonucleotide that is chemically unmodified or minimally modified as broadly written in the instant case (see claims 31-35 and 125-127) can be possibly deemed adequately described to be used in the claimed in vivo ALS and FTD treatment methods when the instant application itself demonstrates little or no reduction in C9ORF72 mRNA in many regions of the brain and spinal cord in the C9ALS mice treated with a fully chemically modified di-branched siRNA “c9-241”, which consists of two of the 20-mer antisense strand of SEQ ID NO:4 and two of the 15-mer sense strand of SEQ ID NO:440 (a chemically modified version of SEQ ID NO:5), wherein each strand has the specific modification pattern named “P3” disclosed in paragraph 0500.
Regarding the post-filing reference that is asserted to have been attached with applicant’s remarks, it is noted that a copy of the review article has not been submitted for examiner’s consideration. It is noted that applicant’s brief summary of the review article at best appears to teach “the discovery of C9ORF72 as the most frequent cause of FTC and ALS in 2011.” It is noted that the mere “discovery” of the pathogenic link between C9ORF72 and FTD and ALS is not sufficient to support that the instant co-inventors had possession of the instantly claimed ALS and FTD treatment method comprising administering the claimed di-branched oligonucleotide as of the filing date sought in the instant application, especially in view of the unimpressive, negative data disclosed in the instant application pertaining to the in vivo performance of “c9-241”, the only species within the claimed genus of the oligonucleotides, in reducing total C9ORF72 mRNA in the affected brain/spinal cord regions as amply explained hereinabove.
In view of the foregoing, this rejection is maintained.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 131-133 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 131-133 depend from claim 31, wherein claim 131 merely recites that the guide strand of the two duplexes comprises at least a 5-mer overhang that is complementary to nucleotide positions 1-5 of SEQ ID NO:2 without clearly specifying the guide strand nucleotide sequence and the sense strand nucleotide sequence as well as chemical modifications thereof, and claims 132-133 merely recite each of the disease types in claim 31. As such, claims 131-133 are not drawn to an ALS/FTD treatment method comprising administering c9-241, which is the only di-branched oligonucleotide species within the claimed genus to be delivered to the C9ALS mouse model with resultant effects of little or no significant levels of target decrease in many of the brain regions and the spinal cord, but rather with a noticeably increased expression level of the pathological isoform mRNA in the prefrontal cortex in the C9ALS mouse model as shown in Figure 46B.
Accordingly, the instant specification fails to adequately describe the claimed method in such a way to reasonably convey that the instant co-inventors had possession of the claimed method as of the filing date sought in the instant application.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 30-35, 119-121, and 123-133 are rejected under 35 U.S.C. 103 as being unpatentable over Freier et al. (US 2016/0251655 A1, applicant’s citation) in view of Khvorova et al. (US 2017/0312367 A1, of record).
Freier discloses a method of inhibiting C9ORF72 pathogenic mRNA in cells in vitro with an antisense oligonucleotide of SEQ ID NO:211 (5’-TTCTTCTGGTTAATCTTTAT), which inhibits C9ORF72 pathogenic mRNA by 11%, wherein Freier’s SEQ ID NO:211 comprises a 15-mer sequence (see the underlined) that is fully complementary to SEQ ID NO:5 claimed in the instant case. See Table 8.
Freier teaches that an antisense compound hybridizing to C9ORF72 includes “single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNA”, wherein inhibition of C9ORF72 is useful for treating ALS and FTD. See paragraphs 0002-0004 and 0027.
Freier does not teach inhibiting C9ORF72 pathogenic mRNA in cells or in a patient with a double-stranded antisense compound comprising two linked double-stranded siRNAs each comprising SEQ ID NO:211 and a 15-mer sense strand sequence.
Khvorova exemplifies a “di-branched” composition comprising two fully chemically modified siRNA duplexes each consisting of a 20-mer antisense strand and a 15-mer sense strand, forming a blunt end at the 3’ end of the sense strand, which is linked to the 3’ end of the other sense strand via a linker. See the following structure in Figure 1:
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Khvorova teaches that the “di-branched” composition comprising two siRNA duplexes is able to “promote potent silencing of therapeutic targets” and “results in unexpectedly high in vivo efficacy” and is successfully delivered in a “non-toxic”, “metabolically stable” manner to the brain and/or the spinal cord via intracerebroventricular (ICV) injection or intrathecal (IT) injection, wherein the siRNA duplexes effectively inhibit target mRNA expression in the brain and/or the spinal cord, and wherein the di-branched composition “efficiently and stably delivered small RNAs to multiple regions of the brain” and “exhibit therapeutic potential for many hard to treat disease and overcome present challenges in employing RNA therapeutics.” See paragraphs 0006-0013, 0082-0089, 0180, 0187, and 0243.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Freier’s method by replacing the single-stranded antisense compound of SEQ ID NO:211 with Khvorova’s di-branched siRNA duplex structure. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to improve the target silencing level in the C9ORF72 pathogenic mRNA in cells because Khovorva’s di-branched siRNA duplex structure was taught to “promote potent silencing of therapeutic targets”. As such, one of ordinary skill in the art would have reasonably applied Khovorva’s di-branched siRNA duplex structure to Freier’s antisense compound comprising SEQ ID NO:211 that provided only 11% inhibition level in the C9ORF72 pathogenic mRNA, thereby obtaining and using a di-branched dsRNA structure comprising two fully chemically modified siRNA structures comprising an RNA sequence counterpart (5’-UUCUUCUGGUUAAUCUUUAU) of Freier’s SEQ ID NO:211 and a 15-mer sense strand (5’-GAUUAACCAGAAGAA) forming a 3’ blunt end at the sense strand and a 5-mer overhang sequence (5’-UUUAU) at the 3’ end of the antisense strand so that the di-branched dsRNA structure mimics the structure in Khvorova’s Figure 1. It is noted that the 3’-overhang sequence (5’-UUUAU) is complementary to 5’-AUAAA at positions 1-5 of SEQ ID NO:2.
It would also have been obvious to one of ordinary skill in the art to try testing the di-branched dsRNA structure rendered obvious above in a disease animal model for the potential of treating ALS and FTD. One of ordinary skill in the art would have been motivated to test the therapeutic potential with a reasonable expectation of success because inhibition of C9ORF72 was known to be useful for treatment of ALS and FTD as taught by Freier, and because Khvorova’s di-branched dsRNA structure was expressly taught and suggested to be particularly useful to “efficiently and stably” to be delivered to the spinal cord as well as “multiple regions of the brain” via IT and ICV injection routes with “high in vivo efficacy” thus “exhibit therapeutic potential” in a “non-toxic”, “metabolically stable” manner as taught by Khvorova. That is, one of ordinary skill in the relevant art would have reasonably recognized the benefits/advantages of utilizing Khvorova’s di-branched dsRNA structure in in vivo therapeutic applications for CNS disease treatment purpose and as such, the ordinarily skilled artisan would have reasonably been motivated to test the therapeutic potential of Khvorova’s di-branched structure targeting C9ORF72 in an animal model in vivo for treatment of CNS diseases – ALS and FTD – that are deemed to be treatable by double-stranded antisense compounds that inhibit C9ORF72 as taught by Freier.
In view of the foregoing, claims 30-35, 119-121, and 123-133 taken as a whole would have been prima facie obvious before the effective filing date.
Double Patenting
The text of the judicially created doctrine not included in this action can be found in a prior Office action.
Claims 30-35, 119-121, and 123-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,799,591 B2 in view of Freier et al. (US 2016/0251655 A1, applicant’s citation) and Khvorova et al. (US 2017/0312367 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed by and/or rendered obvious over the ‘591 patent claims drawn to a method of delivering a di-branched oligonucleotide comprising two siRNA duplexes into the brain and/or spinal cord of a patient having a neurodegenerative disease. It would have been obvious to one of ordinary skill in the art to deem a patient having ALS and FTD as satisfying the patient claimed in the ‘591 patent claims in view of the art-recognized knowledge that ALS and FTD are neurodegenerative diseases as taught by Freier (see paragraph 0003). As such, it would have been obvious to design the di-branched oligonucleotide of the ‘591 patent claims to target C9ORF72 pathogenic sequence and to design the oligonucleotide to have the art-recognized structure and chemical modifications of Khvorova’s di-branched dsRNA structure for the purpose of treating a patient with ALS and FTD that is encompassed by the ‘591 patent claims, wherein the combination of Freier and Khvorova renders obvious the antisense (or guide) strand sequence and the sense strand sequence of the instant claims as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Claims 30-35, 119-121, and 123-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,896,669 B2 in view of Freier et al. (US 2016/0251655 A1, applicant’s citation) and Khvorova et al. (US 2017/0312367 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed by and/or rendered obvious over the ‘669 patent claims drawn to a method of “intrathecally, or intracerebroventricularly administering” a di-branched oligonucleotide comprising two siRNA duplexes into the CNS of a subject. It would have been obvious to one of ordinary skill in the art to deem the subject having ALS and FTD as satisfying the subject claimed in the ‘669 patent claims in view of the art-recognized knowledge that ALS and FTD are CNS diseases as taught by Freier (see paragraph 0003). As such, it would have been obvious to design the di-branched oligonucleotide of the ‘669 patent claims to target C9ORF72 pathogenic sequence and to design the oligonucleotide to have the art-recognized structure and chemical modifications of Khvorova’s di-branched dsRNA structure for the purpose of treating a patient with ALS and FTD that is encompassed by the ‘669 patent claims, wherein the combination of Freier and Khvorova renders obvious the antisense (or guide) strand sequence and the sense strand sequence of the instant claims as explained in the §103 rejection above, which is fully incorporated by reference herein thus will not be repeated.
Claims 30-35, 119-121, 123-130, and 132-133 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 63-86 of copending Application No. 19/172,533 in view of Khvorova et al. (US 2017/0312367 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed by and/or rendered obvious over the ‘533 claims drawn to a method of treating or managing “a disease- or disorder-associated [with] nucleotide repeat sequence within a C9orf72gene” comprising administering a “branched oligonucleotide compound” comprising an oligonucleotide having a substantial complementarity to SEQ ID NO:4 (5’-AAGAUUAACCAGAAGAAAAC), wherein the underlined 15-mer is 100% identical to SEQ ID NO:5 claimed in the instant case. It is noted that the disease broadly claimed in the ‘533 claims is described to read on ALS and FTD in paragraph 0219 of the ‘533 specification, and furthermore, claims 71 and 86 of the ‘533 application recite “amyotrophic lateral sclerosis” and “frontotemporal dementia.” It would have been obvious to provide ICV or IT injection when performing the administering step of the ‘533 claims as such injection routes were known to provide direct delivery as evidenced by the teachings of Khvorova, who also taught that the di-branched dsRNA is fully chemically modified.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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