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 October 9, 2025.
Currently, claims 46, 92, 122, 129-133, and 135-146 are pending in the instant application. Claims 143-144 are withdrawn from further consideration as being drawn to a nonelected invention, there being no allowable linking claim. Accordingly, claims 46, 92, 122, 129-133, 135-142, and 145-146 are 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 October 9, 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Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Response to Arguments
Applicant’s arguments with respect to previous grounds of rejection have been considered but are moot because they do not pertain to the new grounds of rejection, which are necessitated by claim amendments filed on October 9, 2025.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 141-142 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The instant claims depending from claim 46 recite that “nucleotides of each antisense strand are connected via at least one phosphodiester internucleoside linkage and at least one phosphorothioate internucleoside linkage.” It is noted that claim 46 as amended already requires that each antisense strand comprises “at least one phosphodiester internucleoside linkage and at least one phosphorothioate internucleoside linkage”. As such, the limitation “(3)” recited in claims 141-142 fail to further limit the subject matter of claim 46. In addition, claim 46 as currently amended require that “nucleotides at positions 1 to 8” in the 3’ end of at least one antisense strand are connected by phosphorothioate linkages.” As such, the generic recitation of “at least one phosphorothioate” linkage in an antisense strand in “(3)” of claims 141-142 broadens the specific number of a plurality of phosphorothioate linkages in the antisense strand, thereby failing to further limit and include all limitations of the subject matter of claim 46.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 141-142 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. This is a new matter rejection.
In the remarks filed on October 9, 2025, applicant states that the amendments in claim 141 are supported by the specification and claims as originally filed. Contrary to applicant’s argument, the limitation newly recited in claim 141 and claim 142 is not described or supported by the specification or claims as originally filed. It is noted that Figure 23 illustrates a structure satisfying the limitations within the claimed genus, wherein such structure does not have alternating modification pattern “at all positions except positions 5 and 18” as now required by claims 141-142. See Figure 23 reproduced below.
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There is no other di-branched structure adequately described in the instant specification or claimed in the original claims that resembles or reads on the structure claimed in claims 141-142. Accordingly, the subject matter as exactly arranged and required by claims 141-142 is not described in the specification and claims as originally filed thus introduces new matter.
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 46, 92, 122, 129-133, 135-140, and 145-146 are rejected under 35 U.S.C. 103 as being unpatentable over Rigo (US 2017/0349897 A1, of record) in view of Khvorova et al. (US 2019/0024082 A1) and Maier et al. (US 2017/0275626 A1, of record).
Rigo teaches making “C9ORF72 specific inhibitor” compounds, especially “antisense compounds” comprising a nucleotide sequence that is complementary to at least 12 nucleotides of C9ORF72, which are “capable of specifically inhibiting the expression of C9ORF72 mRNA”, wherein the “antisense compounds” that function as a “C9ORF72 specific inhibitor” include “siRNAs” and inhibition of C9ORF72 is useful for treating neurodegenerative diseases such as ALS. See paragraphs 0002, 0027, 0040, 0206, and 0244.
Rigo demonstrates that C9ORF72-targeting oligonucleotide, ISIS No. 806680 (SEQ ID NO:50; 5’-TGGTTAATCTTTATCAGGTC), which is complementary to a 14-mer sequence of SEQ ID NO:2 claimed in the instant case provides 71% and 59% in vivo inhibition of pathogenic human C9ORF72 mRNA expression in the spinal cord and the cortex, respectively, of transgenic mice. See Tables 6 and 11.
Rigo does not teach the instantly claimed structure for the “siRNAs” functioning as a “C9ORF72 specific inhibitor”.
Khvorova teaches making a di-branched siRNA molecule comprising two linked siRNA molecules, which are linked at the two 3’ ends of the two sense strands by a linker. See Figure 13.
Khvorova teaches that the antisense strand comprises “8 phosphorothioated nucleotides” at positions “1-8 from the 3’ end” of the 20-mer antisense strand “are each connected to adjacent nucleotides via phosphorothioate linkages.” See “7-13-7” in Figure 5 and Table 1; paragraph 0013. See also Formula I.
Khvorova discloses that the “7-13-7” having “8 phosphorothioated nucleotides” in the 3’ end of the antisense strand “provided superior distribution in vivo”. See paragraph 0204.
Khovorva demonstrates that the siRNA comprising eight consecutive phosphorothioate linked nucleotides in the 3’ end region of the antisense strand and at least 3 consecutive 2’-O-methyl modified nucleotides in the 3’ end of the sense strand provides the greatest level of target mRNA expression inhibition in the primary cortical neurons. See “5-15-5” in FIG. 5 and 9A-9B.
Khvorova discloses that the “5-15-5” siRNA is “conducive to efficacious silencing”. See paragraph 0204.
Khvorova teaches that the sense strand comprises “at least four consecutive 2’-methoxy-nucleotides” in the overhang region and that the antisense strand in the duplex region excluding the overhang regions has “alternating 2’-methoxy-nucleotides and 2’-fluoro-nucleoties.” See paragraph 0011.
Maier teaches that the vinylphosphonate group at the 5’ terminus of the antisense strand of a chemically modified siRNA molecule improved in vivo efficacy of the chemically modified siRNA molecule such that the “efficacy of chemically modified siRNAs can be improved with 5’-trans-vinylphosphonate (5’-E-VP) which mimics natural phosphate well.” See paragraphs 0713 and 0717; Figures 21A-21B.
It would have been obvious to one of ordinary skill in the art before the effective filing date to incorporate the di-branched structure and the chemical modifications of the siRNA molecule of Khvorova into a C9ORF72-targeting siRNA molecule comprising an RNA counterpart of Rigo’s antisense sequence of SEQ ID NO:50. 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 siRNA molecule that is reasonably expected to provide a relatively high level of C9ORF72 inhibition in the cortical neurons in vivo, because making a C9ORF72-targeting siRNA molecule for in vivo therapeutic use was an art-recognized goal as taught by Rigo, wherein Rigo’s SEQ ID NO:50 provided effective in vivo inhibition of C9ORF72 expression in the brain and the spinal cord, and because Khvorova’s siRNA molecule whose antisense strand comprises eight consecutive nucleotides linked by phosphorothioate linkages in the 3’ end and whose sense strand comprises a region of three consecutive 2’-O-methyl nucleotides in the 3’ end provided the highest level of target mRNA expression inhibition in cortical neurons, thereby providing a reasonable expectation that Khvorova’s phosphorothioate linkage modification in the 3’ end region of the antisense strand and the 2’-O-methyl modification in the 3’ end region of the sense strand would improve C9ORF72 inhibition level in the cortical neurons, wherein the di-branched structure taught by Khvorova would have been expected to further improve the level of C9ORF72 inhibition by the combination of two siRNAs instead of one siRNA. It would also have been obvious to incorporate an alternating 2’-F and 2’-O-methyl modification pattern into each of the antisense strand of the di-branched structure such that all odd numbered positions (thus including position 5) are modified with 2’-F while all even numbered positions (thus including position 18) are modified with 2’-O-methyl because Khvorova expressly suggested incorporating alternating 2’-F/2’-O-methyl modification pattern in the antisense strand, wherein one of ordinary skill in the art would have readily recognized that there are only two design options for making such alternating modification pattern: 2’-F at every odd position with 2’-O-methyl at every even position or 2’-F at every even position with 2’-O-methyl at every odd position. Hence, one of ordinary skill in the art would have reasonably pursued the known, readily predictable alternating modification pattern and would have succeeded in obtaining the instantly claimed modification pattern. One of ordinary skill in the art would have also have been motivated to incorporate a 5’-E-VP modification at the 5’ end of the antisense strand of the di-branched siRNA molecule as modified above in order to further improve the in vivo efficacy of the siRNA molecule in view of the teachings of Maier. Since the di-branched siRNA rendered obvious in the instant rejection satisfies the structural limitations set forth in claim 46, it necessarily follows that the antisense strand would inherently possess the functionality of enhancing target degradation via nuclease degradation as recited in claims 136 and 140 and also the functionality of inhibiting C9ORF72 expression by at least 50% as recited in claim 138, absent objective evidence to the contrary.
In view of the foregoing, claims 46, 92, 122, 129-133, 135-140, and 145-146 taken as a whole would have been prima facie obvious before the effective filing date.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are rejected under 35 U.S.C. 103 as being unpatentable over Rigo (US 2017/0349897 A1, of record) in view of Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter), and Khvorova et al. (US 2017/0312367 A1, of record; Khvorova (2017) hereinafter).
Rigo teaches making “C9ORF72 specific inhibitor” compounds, especially “antisense compounds” comprising a nucleotide sequence that is complementary to at least 12 nucleotides of C9ORF72, which are “capable of specifically inhibiting the expression of C9ORF72 mRNA”, wherein the “antisense compounds” that function as a “C9ORF72 specific inhibitor” include “siRNAs” and inhibition of C9ORF72 is useful for treating neurodegenerative diseases such as ALS. See paragraphs 0002, 0027, 0040, 0206, and 0244.
Rigo demonstrates that C9ORF72-targeting oligonucleotide, ISIS No. 806680 (SEQ ID NO:50; 5’-TGGTTAATCTTTATCAGGTC), which is complementary to a 14-mer sequence of SEQ ID NO:2 claimed in the instant case provides 71% in vivo inhibition of pathogenic human C9ORF72 mRNA expression in the spinal cord of transgenic mice. See Tables 6 and 11.
Rigo does not teach the instantly claimed structure for the “siRNAs” functioning as a “C9ORF72 specific inhibitor”.
Khvorova (2016) discloses “HTT10150-ASP-P2” comprising eight consecutive nucleotides in the 3’ end of the 20-mer antisense strand that are connected to the next nucleotides via phosphorothioate linkages. See Figure 17 for the following siRNA comprising seven consecutive phosphorothioate linkages resulting in eight consecutive nucleotides at positions 1-8 from the 3’ end of the antisense strand are linked by the phosphorothioate linkages.
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Khvorova (2016) demonstrates that the above structure having eight consecutive nucleotides linked by phosphorothioate linkages in the 3’ end of the 20-mer antisense strand whose 5’ end has a phosphate group results in a long-lasting (28 days) target mRNA expression in the mouse brain after a single injection. See Figures 39B and 39D.
Khvorova (2016) teaches that the 5’ end of the antisense strand is modified to comprise “5’(E)-vinylphosphonate (5’-E-VP)”, which “significantly enhances retention of guide strand in tissues” and “is expected to further increase duration of effect in vivo.” See paragraph 0198.
Khvorova (2013) discloses making and using a chemically modified asymmetric siRNA comprising 2’-O-methyl (thus 2’-methoxy) and 2’-F modifications for effective target inhibition, wherein the asymmetric siRNA has a longer antisense strand. See Figure 41 showing an siRNA Duplex ID “12984” having three consecutive 2’-O-methyl (thus 2’-methoxy) modifications in the passenger (thus sense) strand (see the arrows) as well as a 3’ terminal cholesterol conjugate and a 2’-F modification at position 5 and a 2’-O-methyl modification at position 18 in the guide (thus antisense) strand (see the arrows), which provided a significant level of target inhibition such as 80% target mRNA reduction at 1 mM. See the chemical modifications for Duplex ID “12984” targeting Mapk4k as reproduced below from Figure 41, wherein the left column is of the sense strand and the right column is of the antisense strand.
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Khvorova (2017) teaches that a fully modified di-branched siRNA structure comprising a 20-mer antisense strand is effectively delivered to the brain tissues (e.g., cortex) and provides target silencing both in mRNA and protein expression in the brain tissues and also exhibits “unexpected improvement in distribution, in vivo efficacy and safety.” See Figures 1, 9, 13A, and 32A-32B; paragraph 0082.
Khvorova (2017) discloses that a single injection of the di-branched siRNA “induces robust silencing in both the striatum and cortex of mouse brain”, wherein such “level of efficacy has never been demonstrated previously for non-conjugated siRNAs.” See paragraph 0188.
It would have been obvious to one of ordinary skill in the art before the effective filing date to incorporate the siRNA chemical modifications of Khvorova (2016) and Khvorova (2013) into a C9ORF72-targeting siRNA molecule comprising a 20-mer RNA counterpart of Rigo’s antisense sequence of SEQ ID NO:50 and formulate the chemically modified siRNA molecule as the di-branched structure disclosed in Khvorova (2017). One of ordinary skill in the art would have been motivated to incorporate seven consecutive phosphorothioate linkages linking eight nucleotides in the 3’ end of a 20-mer RNA counterpart of Rigo’s SEQ ID NO:50 when making a “C9ORF72 specific inhibitor” that is an “siRNA” in order to improve silencing activity and duration of the C9ORF72-targeting siRNA when delivered to the brain, because the brain was an art-recognized delivery site and the site of action of an “C9ORF72 specific inhibitor” including siRNAs as evidenced by the teachings of Rigo, who indeed demonstrated inhibition of pathogenic C9ORF72 expression in the brain by the 20-mer SEQ ID NO:50 that is complementary to at least 14 consecutive nucleotides in SEQ ID NO:2 claimed in the instant case, and because the fully chemically modified siRNA structure having eight consecutive nucleotides linked by phosphorothioate linkages in the 3’ end of the 20-mer antisense strand was known to be effectively delivered to the brain and provide a long-term target inhibition in the brain as evidenced by Khvorova (2016). One of ordinary skill in the art would have been further motivated, with a reasonable expectation of success, to replace the 5’-phosphate group at the 5’ end of the 20-mer RNA counterpart of Rigo’s SEQ ID NO:50 modified to comprise seven consecutive phosphorothioate linkages at the 3’ end with a 5’-E-VP group in order to “further increase duration of effect in vivo” and also to enhance “retention of guide strand in tissues”, thereby making an siRNA molecule capable of providing a prolonged, effective inhibition of the pathogenic C9ORF72 expression in the brain in view of the benefits/advantages of replacing a 5’ phosphate group with a 5’-E-VP group in the antisense strand of a modified siRNA molecule as taught by Khvorova (2016).
It would also have been obvious to further incorporate a 2’-fluoro RNA into position 5 and a 2’-O-methyl RNA into position 18 of the antisense strand comprising an RNA counterpart of Rigo’s SEQ ID NO:50 and three consecutive 2’-O-methyl RNAs into a sense strand comprising a region of complementary to the antisense strand in order to make an siRNA molecule that is reasonably expected to provide a relatively high level of C9ORF72 inhibition in vivo, because Khvorova (2013)’s siRNA molecules having the instantly claimed 2’-F and/or 2’-O-methyl chemical modifications in the antisense strand and the sense stand were known to provide a significant inhibition (e.g., 80%, 90%) of target expression as disclosed by Khvorova (2013). One of ordinary skill in the art would have been further motivated to utilize the di-branched siRNA molecule structure of Khvorova (2017) by linking two of the above-modified C9ORF72-targeting siRNA molecule in order to enhance the in vivo distribution, efficacy, and safety of the therapeutically useful siRNA molecule because the di-branched structure without any delivery agent conjugate was shown to provide “unexpected improvement in distribution, in vivo efficacy and safety” as well as “robust silencing” in the brain after a single injection as taught by Khvorova (2017) thus one of ordinary skill in the art would have reasonably deemed that the di-branched siRNA structure without a delivery conjugate would be suitable and desirable for the C9ORF72-targeting siRNA molecule for its potential use in treating CNS diseases. Since the di-branched siRNA rendered obvious in the instant rejection satisfies the structural limitations set forth in claim 46, it necessarily follows that the antisense strand would inherently possess the functionality of enhancing target degradation via nuclease degradation as recited in claims 136 and 140 and also the functionality of inhibiting C9ORF72 expression by at least 50% as recited in claim 138, absent objective evidence to the contrary.
In view of the foregoing, claims 46, 92, 122, 129-133, 135-140, and 145-146 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 46, 92, 122, 129-133, 135-140, and 145-146 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 10,478,503 B2 in view of Rigo (US 2017/0349897 A1, of record), Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘669 patent claims drawn to a branched oligonucleotide comprising two linked dsRNAs via a linker, wherein the 5’ end of the antisense strand comprises a 5’-E-VP and “the antisense strand is complementary to a target mRNA in a neuronal cell.” It would have been obvious to design the antisense strand of the branched oligonucleotide of the ‘503 patent claims to be complementary to C9ORF72, in particular, at least a 14-mer of SEQ ID NO:2 claimed in the instant case and also to incorporate the modifications of Khvorova (2016) and Khvorova (2013) because making an siRNA targeting C9ORF72 in the brain for neurodegenerative disease treatment was an art-recognized goal as evidenced by Rigo, who taught in vivo efficacy of an antisense sequence (SEQ ID NO:50) targeting at least a 14-mer sequence in SEQ ID NO:2 claimed in the instant case, and because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 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 Rigo (US 2017/0349897 A1, of record), Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘591 patent claims that require a branched oligonucleotide comprising two linked dsRNAs via a linker, wherein the antisense strand is complementary to “a target mRNA in a neuronal cell.” It would have been obvious to design the antisense strand of the branched oligonucleotide of the ‘591 patent claims to be complementary to C9ORF72, in particular, at least a 14-mer of SEQ ID NO:2 claimed in the instant case and also to incorporate modifications of Khvorova (2016) and Khvorova (2013) because making an siRNA targeting C9ORF72 in the brain for neurodegenerative disease treatment was an art-recognized goal as evidenced by Rigo, who taught in vivo efficacy of an antisense sequence (SEQ ID NO:50) targeting at least a 14-mer sequence in SEQ ID NO:2 claimed in the instant case, and because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-29 of U.S. Patent No. 11,279,930 B2 in view of Rigo (US 2017/0349897 A1, of record), Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘930 patent claims drawn to a branched oligonucleotide comprising two linked dsRNAs via a linker, wherein the antisense strand comprises at least 85% 2’-O-methyl (thus methoxy) as well as non-methoxy modifications, which are 2’-F, and wherein the sense strand comprises at least 80% 2’-O-methyl (thus methoxy) modifications. It would have been obvious to design the antisense strand of the branched oligonucleotide of the ‘930 patent claims to be complementary to C9ORF72, in particular, at least a 14-mer of SEQ ID NO:2 claimed in the instant case and also to incorporate modifications of Khvorova (2016) and Khvorova (2013) because making an siRNA targeting C9ORF72 in the brain for neurodegenerative disease treatment was an art-recognized goal as evidenced by Rigo, who taught in vivo efficacy of an antisense sequence (SEQ ID NO:50) targeting at least a 14-mer sequence in SEQ ID NO:2 claimed in the instant case, and because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,896,669 B2 in view of Rigo (US 2017/0349897 A1, of record), Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘669 patent claims that require a branched oligonucleotide comprising two linked dsRNAs via a linker, wherein the 5’ end of the antisense strand comprises a 5’-E-VP and the siRNAs are 80-100% chemically modified. It would have been obvious to design the antisense strand of the branched oligonucleotide of the ‘669 patent claims to be complementary to C9ORF72, in particular, at least a 14-mer of SEQ ID NO:2 claimed in the instant case and also to incorporate modifications of Khvorova (2016) and Khvorova (2013) because making an siRNA targeting C9ORF72 in the brain for neurodegenerative disease treatment was an art-recognized goal as evidenced by Rigo, who taught in vivo efficacy of an antisense sequence (SEQ ID NO:50) targeting at least a 14-mer sequence in SEQ ID NO:2 claimed in the instant case, and because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-20 of U.S. Patent No. 12,297,430 B2 in view of Rigo (US 2017/0349897 A1, of record), Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘430 patent claims drawn to a branched oligonucleotide comprising two linked dsRNAs via a linker, wherein the antisense strand comprises at least 85% 2’-O-methyl (thus methoxy) as well as non-methoxy modifications, which are 2’-F. It would have been obvious to design the antisense strand of the branched oligonucleotide of the ‘430 patent claims to be complementary to C9ORF72, in particular, at least a 14-mer of SEQ ID NO:2 claimed in the instant case and also to incorporate modifications of Khvorova (2016) and Khvorova (2013) because making an siRNA targeting C9ORF72 in the brain for neurodegenerative disease treatment was an art-recognized goal as evidenced by Rigo, who taught in vivo efficacy of an antisense sequence (SEQ ID NO:50) targeting at least a 14-mer sequence in SEQ ID NO:2 claimed in the instant case, and because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-17 of U.S. Patent No. 12,344,839 B2 in view of Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter) and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘839 patent claims drawn to a branched oligonucleotide comprising two linked, chemically modified C9ORF72-targeting dsRNAs via a linker, wherein the dsRNAs are targeted to SEQ ID NO:1, 2, or 4, which comprises at least 14 consecutive nucleotides of SEQ ID NO:2 claimed in the instant case, wherein the antisense strand comprises 2’-methoxy at positions 2-4 from the 3’ end of a 20-mer antisense strand (guide strand), thereby reading on a 2’-methoxy at position 18 of the antisense strand. It would have been obvious to incorporate modifications of Khvorova (2016) and Khvorova (2013) because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45-59 of Application No. 18/396,613 in view of Rigo (US 2017/0349897 A1, of record), Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter), and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘613 claims drawn to a branched oligonucleotide comprising two linked dsRNAs via a linker, wherein the 5’ end of the antisense strand comprises a 5’-E-VP and the siRNAs are 80-100% chemically modified. It would have been obvious to design the antisense strand of the branched oligonucleotide of the ‘613 claims to be complementary to C9ORF72, in particular, at least a 14-mer of SEQ ID NO:2 claimed in the instant case and also to incorporate modifications of Khvorova (2016) and Khvorova (2013) because making an siRNA targeting C9ORF72 in the brain for neurodegenerative disease treatment was an art-recognized goal as evidenced by Rigo, who taught in vivo efficacy of an antisense sequence (SEQ ID NO:50) targeting at least a 14-mer sequence in SEQ ID NO:2 claimed in the instant case, and because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 46, 92, 122, 129-133, 135-140, and 145-146 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 63-86 of Application No. 19/172,533 in view of Khvorova et al. (WO 2016/161388 A1, applicant’s citation; Khvorova (2016) hereinafter) and Khvorova et al. (US 2013/0131141 A1, of record; Khvorova (2013) hereinafter).
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 ‘533 claims that require a branched oligonucleotide comprising two linked, chemically modified C9ORF72-targeting dsRNAs via a linker, wherein the dsRNAs are targeted to SEQ ID NO:1, 2, or 4, which comprises at least 14 consecutive nucleotides of SEQ ID NO:2 claimed in the instant case. It would have been obvious to incorporate modifications of Khvorova (2016) and Khvorova (2013) because the chemical modifications of Khvorova (2016) and Khvorova (2013) including the newly added eight consecutive 3’-terminal nucleotides being linked by phosphorothioate linkages in the antisense strand were known to improve siRNA activity/potency as explained in the §103 rejection above, which is fully incorporated by reference herein.
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.
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/DANA H SHIN/Primary Examiner, Art Unit 1635