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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 10/28//2025 is acknowledged. Claims 1-40,42,48 and 52 were/stand cancelled. Claims 41 and 43-45 were amended. Claims 41,43-47,49-51,53-58 are pending. Claims 49-51 and 53-58 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/04/2024. Claims 41 and 43-47 are directed to the elected invention and are under examination.
Response to Arguments
Applicant’s arguments and amendments, see page 5, filed 10/28/2025, with respect to the objection to claim 45 has been fully considered and is persuasive due to the amendment to claim 45 adding “the” in line 4 before “2-FANA AON”. Therefore, the rejection has been withdrawn.
Applicant’s arguments and amendments, see page 5, filed 10/28/2025, with respect to the 35 U.S.C. 112(b) rejection of claim 41 has been fully considered and is persuasive due to the amendment to claim 41 correcting the antecedent basis issue. Therefore, the rejection has been withdrawn.
The following rejections and/or objections are either reiterated or newly applied and are necessitated by amendment. They constitute the complete set presently being applied to the instant application.
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 43 and 44 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.
In the previous claims filed on 05/19/2025, claim 43 previously depended on claim 42, and neither claim recited Formula 7. Claim 44 depended on claim 41 which recited the positions according to Formula 7, but did not recite that the AON comprises SEQ ID NO: 199. Therefore, in the previous claim set, claim 43 further limited claim 42 because claim 42 did not recite Formula 7, and claim 44 further limited claim 41 because claim 41 did not recite SEQ ID NO: 199. However, now claim 41 has been amended to incorporate the limitations regarding SEQ ID NO: 199 and the recited internucleotide linkages between the nucleotides of the 2’-FANA modified nucleotides recited in now canceled claim 42 with the limitations that were previously recited regarding the positioning of 2’-FANA modified nucleotides of claim 41, and claim 43 was amended to depend on claim 41 rather than claim 42. Therefore, because claim 41 now requires the recited AON comprising SEQ ID NO: 199 and the positioning of the 2’-FANA modified nucleotides according to Formula 7 (found in Table 1, page 14 of instant Specification and shown below), claim 43 does not further limit claim 41 and is broader in scope. Formula 7 requires 5 2’-FANA modified nucleotides at the 5’ end and 5 2’-FANA modified nucleotides at the 3’ end flanking a sequence of 11 deoxyribonucleotide residues. Therefore the limitations of claim 43 reciting from about 1-20 2’-deoxy-2’-fluoro-D-arabinonucleotides at the 5’ end and from about 1-20 2’-deoxy-2’-fluoro-D-arabinonucleotides at the 3’ end, flanking a sequence comprising from about 1 to about 20 deoxyribonucleotide residues does not further limit and is broader in scope.
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Claim 44 depends on amended claim 1 which now recites “said AON comprising SEQ ID NO: 199”. Claim 44 recites wherein the 2’-FANA AON comprises at least 10, at least 11….or at least 25, successive nucleotides of SEQ ID NO: 199, or a sequence complementary thereto. Therefore, because claim 41 requires the AON to comprise 100% identity to SEQ ID NO: 1, and claim 44 requires a sequence that is less than 100% identity to SEQ ID NO: 1, claim 44 does not include all the limitations of the claim upon which it depends and does not further limit and is therefore broader in scope.
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 § 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 41,43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Barsoum et al. (US 2016122760, Published 5 May 2016) in view of Damha et al. (WO 0220773, Published 14 March 2002) and NCBI Reference Sequence Accession number NM_014009 (Chatila et al., J Clin Invest. 15 Dec 2000; 106(12):R75-R81).
Claim Interpretation: Claim 41 is being interpreted as requiring the AON to comprise 100% identity to SEQ ID NO: 199. Claims 43 and 44 do not further limit claim 41 as explained in the 35 U.S.C. 112(d) rejection above, and therefore art that meets the limitations of claim 41 also meets the limitations of claims 43 and 44.
Regarding claim 41, Barsoum et al. teach single stranded oligonucleotides that target a PRC2-associated region of FOXP3 gene and which are useful for treatment of diseases associated with aberrant immune cell activation such as autoimmune or inflammatory diseases or disorders (paragraph 0005). Barsoum et al. teach the single stranded oligonucleotides comprise at least one nucleotide modified at the 2’-position of the sugar which are routinely incorporated into oligonucleotides (paragraph 0140), that modified oligonucleotides are known which are based on arabinonucleotide or modified arabinonucleotide residues, and that the 2’-arabino modification is 2’-fluoro-D-arbainonucleic acid (FANA) (paragraph 0145).
Barsoum et al. teach gapmer oligonucleotides of formula 5’-X-Y-Z-3’ with X and Z as flanking regions around a gap region Y, wherein the gap region Y is a contiguous stretch of nucleotides (e.g. a region of at least 6 DNA nucleotides which are capable of recruiting RNAse), and the Y region is flanked both 5’ and 3’ by regions X and Z comprising high-affinity modified nucleotides (e.g. 1-6 modified nucleotides, and are more preferably 1-5 nucleotides) (paragraph 0190). Therefore, Barsoum et al. teach modified antisense oligonucleotides that target Foxp3, and which may have a gapmer configuration with a gap of at least 6 DNA nucleotides (and therefore encompasses a DNA gap of 11 nucleotides), flanked on the 5’ and 3’ regions by 5 modified nucleotides, and that the modified oligonucleotides can be based on 2’-fluoro-D-arbainonucleic acid (FANA).
Barsoum et al. teach sequences of the sense strand of the target gene, which include SEQ ID NO: 41187 (pages 48-49). SEQ ID NO: 41187 of Barsoum et al. is 15 nucleotides in length, and is complementary to nucleotides 7-21 of instant SEQ ID NO: 199. See alignment below, wherein Qy is instant SEQ ID NO: 199 and Db is SEQ ID NO: 41187 of Barsoum et al.:
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Barsoum et al. teach antisense oligonucleotides targeting human Foxp3, including SEQ ID NO: 41052 in Table 2, page 36.
Barsoum et al. do not teach an AON comprising SEQ ID NO: 199 and do not explicitly teach that the antisense oligonucleotide that targets Foxp3 has 2’-FANA modified nucleotides positioned according to Formula 7 and the recited internucleotide linkages between the nucleotides of the 2’-FANA modified nucleotides recited in instant claim 41. Formula 7 is shown in the instant specification as:
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wherein X represents a nucleotide, and bolded and underlined nucleotides represent 2’-FANA modified nucleotides (Page 14, Table 1 and paragraph 0080).
Before the effective filing date, Damha et al. taught novel oligonucleotide chimeras used as therapeutic agents to selectively prevent gene transcription and expression in a sequence specific manner, using oligonucleotides constructed from arabinonucleotide or modified arabinonucleotide residues, flanking a series of deoxyribose nucleotide residues of variable length to hybridize to and induce cleavage of (via RNaseH activation) the complementary RNA (Field of Invention, page 1 lines 6-19). Damha et al. taught mixed backbone or “gapmer” oligonucleotides have been synthesized, but oligonucleotides comprised of 2’-OMe RNA alone are unable to
elicit RNaseH degradation of the target RNA, that eukaryotic RNaseH requires substantially larger DNA gaps (7 DNA nucleotides or more for optimal degradation activity), and that antisense activity of [2’-OMe RNA]-[PS-DNA]-[2’OMe RNA] chimera oligonucleotides are highly dependent on DNA gap size (pages 6-7).
Damha et al. taught it would be highly desirable to provide oligonucleotides constructed from arabinonucleotide or modified arabinonucleotide residues flanking a series of deoxyribose nucleotide residues of variable length for the sequence-specific inhibition of gene expression via association to (and RNaseH mediated cleavage of) complementary mRNA, which is the aim of the invention of Damha et al. (pages 7-8). Damha et al. taught the discovery that antisense hybrid chimeras, specifically constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides (FANA) flanking a defined sequence constructed from DNA are superior to antisense hybrid chimeras constructed from (OMeNA) flanking a defined sequence of DNA (page 8, lines 13-18).
Damha et al. provides the following structure of their antisense hybrid chimeras on page 9, which also shows phosphorothioate internucleotide linkages between the nucleotides of the 2’-FANA modified nucleotides in the wings, as well as between the nucleotides in the DNA gap:
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Damha et al. taught the gapmer antisense oligonucleotides of the invention exhibit a number of desirable properties including that they bind to and cleave ssRNA by activating RNaseH, and that the gapmer wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides in particular were found to have excellent affinity towards RNA targets compared to gapmers with wings comprised of 2’-O-methylribonucleotides and significantly better than that of identical sequence DNA, and the wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides were found to better effect sequence-specific inhibition of intracellular gene expression than the same-sequence DNA oligonucleotides (page 16, lines 15-26), and are excellent models of antisense oligonucleotide agents that can serve as therapeutics or tools for studying gene expression in cells and organisms (page 17, lines 3-5). Example 2, pages 20-21 show that antisense oligonucleotides constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides flanking a series of ten DNA residues all joined with phosphorothioate bonds (S-FANA gapmer, ID#1 in Table 1) provided at least 90% inhibition of cell luciferase activity and the results shown in Figure 1 show the S-FANA gapmer with a 10 DNA gap is a significantly better inhibitor of X1/5 cell luciferase activity expression than any of PO-DNA, S-DNA, PO-FANA or S-FANA (page 21, lines 6-16).
Barsoum et al. and Damha et al. do not teach an AON comprising 100% identity to SEQ ID NO: 199.
However, before the effective filing date, the human Foxp3 mRNA sequence was publicly available as evidenced by the NCBI Reference Sequence Accession number NM_014009 (Homo sapiens forkhead box P3 (FOXP3), transcript variant 1 mRNA). The human Foxp3 gene sequence (NM_014009) was taught by Chatila et al. (J Clin Invest. 15 Dec 2000; 106(12):R75-R81) more than one year prior to the effective filing date of the instant application, and the human Foxp3 mRNA sequence is shown below.
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As seen in the alignment below, the antisense oligonucleotide of instant SEQ ID NO: 199 (Qy) is complementary to nucleotides 1800-1780 of the human Foxp3 gene sequence (NM_014009) (Db):
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In addition, the region of alignment of the antisense oligonucleotide sequence of Barsoum et al. to the human Foxp3 gene sequence of NM_014009 is shown below and provides additional support that it is an obvious region of the target Foxp3 gene to target with an antisense oligonucleotide. Qy is SEQ ID NO: 41052 of Barsoum et al. and Db is positions 1645-1659 of the human Foxp3 gene:
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the Foxp3 antisense oligonucleotides of Barsoum et al. which are Foxp3 antisense oligonucleotide gapmers comprising at least a 6 DNA gap flanked on the 5’ and 3’ regions by 5 modified nucleotides, with the teachings of Dahma et al. regarding the positions and structure of the gapmer (the wings of the gapmer are specifically 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides with phosphorothioate internucleotide linkages between the nucleotides of the 2’-FANA modified nucleotides in the wings, that flank a series of DNA residues of variable length), and to choose any of the 21 nucleotide regions of the target human Foxp3 gene sequence to produce antisense oligonucleotides that target these 21 nucleotide regions with a reasonable expectation of success. There would be a reasonable expectation of success, because both Barsoum et al. and Dahma et al. teach gapmer antisense oligonucleotides, including gapmers with a variable number of DNA residues in the gap, flanked by modified nucleotides, Barsoum et al. teaches the modified nucleotides may be FANA (paragraph 0145), and Dahma et al. teaches the gapmer structure of 2’-FANA modified nucleotides flanking a DNA gap of variable lengths. One of ordinary skill in the art would have been motivated to provide a Foxp3 antisense oligonucleotide with 2’FANA modified nucleotides positioned according to instant formula 7, because Dahma et al. teach the benefits of and desirable properties of a gapmer with wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides flanking a DNA gap, including that they bind to and cleave ssRNA by activating RNaseH, were found to have excellent affinity towards RNA targets compared to gapmers with wings comprised of 2’-O-methylribonucleotides and significantly better than that of identical sequence DNA, the wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides were found to better effect sequence-specific inhibition of intracellular gene expression than the same-sequence DNA oligonucleotides (page 16, lines 15-26), as well as that eukaryotic RNaseH requires substantially larger DNA gaps (7 DNA nucleotides or more for optimal degradation activity), and because Dahma et al. demonstrates that antisense oligonucleotides constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides flanking a series of ten DNA residues all joined with phosphorothioate bonds (S-FANA gapmer, ID#1 in Table 1) provided at least 90% inhibition of cell luciferase activity and is a significantly better inhibitor (Example 2, pages 20-21 and Fig. 1).
It would have been obvious to provide a gapmer with an 11 DNA gap as in instant Formula 7, based on the number of DNAs in the gap taught in both Barsoum et al and Dahma et al. above (at least 6, or 7 or more, and including a 10 DNA gap) to determine the effect of the length of the 11 DNA gap on RNaseH degradation and Foxp3 gene expression. An ordinary artisan could have arrived at the positioning and length of the segments in instant formula 7 from the teachings of Barsoum et al. and Dahma et al. since the combination teaches a Foxp3 antisense oligonucleotide gapmer with at least a 6 DNA gap (Barsoum et al.) and Dahma et al. teach eukaryotic RNaseH requires substantially larger DNA gaps (7 DNA nucleotides or more for optimal degradation activity) and also teaches a gapmer with a 10 DNA gap with superior properties, and therefore encompasses an 11 DNA gap, flanked by 5 modified nucleotides which are 2’FANA modified nucleotides, because SEQ ID NO: 199 is complementary to human Foxp3 mRNA at positions 1800-1780 as evidenced by the NCBI Reference Sequence Accession number NM_014009. Additionally, as Barsoum et al. teach specific antisense oligonucleotide sequences that target Foxp3 including SEQ ID NO: 41052 that targets a region of Foxp3 that is near the region that instant SEQ ID NO:199 targets as shown in the above alignment, it would be obvious to target this region of the human Foxp3 mRNA sequence with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide an antisense oligonucleotide comprising SEQ ID NO: 199 since the sequence is complementary to positions 1800-1780 of the human Foxp3 mRNA sequence which was known before the effective filing date, and Barsoum et al. teach antisense oligonucleotide sequences targeting Foxp3 that may be used for treatment of diseases or disorders associated with aberrant immune cell activation (autoimmune or inflammatory diseases or disorders).
Additionally, as explained in the 103 rejection above, Barsoum et al. teach modified antisense oligonucleotides that target Foxp3, and which may have a gapmer configuration with a gap of at least 6 DNA nucleotides (and therefore encompasses a DNA gap of 11 nucleotides), flanked on the 5’ and 3’ regions by 5 modified nucleotides, and that the modified oligonucleotides can be based on 2’-fluoro-D-arbainonucleic acid (FANA) and therefore teaches the limitations of the antisense oligonucleotide length and gapmer arrangement. One of ordinary skill in the art would have been motivated to provide an antisense oligonucleotide comprising SEQ ID NO: 199 which requires residues 1-5 and 17-20 to be FANA modified bases with phosphorothioate linkages, residues 6-16 are residues with a phosphorothioate linkage, and residue 21 is a FANA modified base (which is the same FANA modification pattern as in Formula 7 of instant claim 41), in order to provide an improved antisense oligonucleotide targeting Foxp3 mRNA that has improved properties of binding to and cleaving ssRNA by activating RNaseH, and that the gapmer wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides in particular were found to have excellent affinity towards RNA targets as taught by Damha et al. and because Damha et al. teach the structure of their antisense hybrid chimeras on page 9 which shows phosphorothioate internucleotide linkages between the nucleotides of the 2’-FANA modified nucleotides in the wings, as well as between the nucleotides in the DNA gap. In addition, Damha et al. provides such motivation because antisense oligonucleotides constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides flanking a series of ten DNA residues all joined with phosphorothioate bonds (S-FANA gapmer, ID#1 in Table 1) provided at least 90% inhibition of cell luciferase activity and the results shown in Figure 1 show the S-FANA gapmer with a 10 DNA gap is a significantly better inhibitor of X1/5 cell luciferase activity expression than any of PO-DNA, S-DNA, PO-FANA or S-FANA (page 21, lines 6-16).
Accordingly, the limitations of claims 41,43 and 44 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 45-47 are rejected under 35 U.S.C. 103 as being unpatentable over Barsoum et al. (US 2016122760, Published 5 May 2016) in view of Damha et al. (WO 0220773, Published 14 March 2002).
Claim Interpretation: It is noted that Claims 45-47 do not recite Formula 7, or that the oligonucleotide comprises SEQ ID NO: 199.
Regarding claim 45-57, Barsoum et al. teach single stranded oligonucleotides that target a PRC2-associated region of FOXP3 gene and which are useful for treatment of diseases associated with aberrant immune cell activation such as autoimmune or inflammatory diseases or disorders (paragraph 0005). Barsoum et al. teach the single stranded oligonucleotides comprise at least one nucleotide modified at the 2’-position of the sugar which are routinely incorporated into oligonucleotides (paragraph 0140), that modified oligonucleotides are known which are based on arabinonucleotide or modified arabinonucleotide residues, and that the 2’-arabino modification is 2’-fluoro-D-arbainonucleic acid (FANA) (paragraph 0145).
Barsoum et al. teach gapmer oligonucleotides of formula 5’-X-Y-Z-3’ with X and Z as flanking regions around a gap region Y, wherein the gap region Y is a contiguous stretch of nucleotides (e.g. a region of at least 6 DNA nucleotides which are capable of recruiting RNAse), and the Y region is flanked both 5’ and 3’ by regions X and Z comprising high-affinity modified nucleotides (e.g. 1-6 modified nucleotides, and are more preferably 1-5 nucleotides) (paragraph 0190). Therefore, Barsoum et al. teach modified antisense oligonucleotides that target Foxp3, and which may have a gapmer configuration with a gap of at least 6 DNA nucleotides (and therefore encompasses a DNA gap of 11 nucleotides), flanked on the 5’ and 3’ regions by 5 modified nucleotides, and that the modified oligonucleotides can be based on 2’-fluoro-D-arbainonucleic acid (FANA).
Regarding the limitations of the AON comprising at least 5 successive nucleotides of SEQ ID NO: 199 or a sequence complementary thereto in claims 45-47, Barsoum et al. teach sequences of the sense strand of the target gene, which include SEQ ID NO: 41187 (pages 48-49). SEQ ID NO: 41187 of Barsoum et al. is 15 nucleotides in length, and is complementary to nucleotides 7-21 of instant SEQ ID NO: 199.
See alignment below, wherein Qy is instant SEQ ID NO: 199 and Db is SEQ ID NO: 41187 of Barsoum et al.:
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Regarding the pharmaceutical composition of claims 45-47, Barsoum et al. teach oligonucleotides of the invention can be formulated for administration to a subject for treating a condition, and the oligonucleotide compound of the invention can be combined with a carrier material (paragraphs 0207-0208).
Barsoum et al. does not teach wherein internucleotide linkages between nucleotides of the 2’-FANA modified nucleotides are those as recited in claim 45.
However, before the effective filing date, Dahma et al. taught novel oligonucleotide chimeras used as therapeutic agents to selectively prevent gene transcription and expression in a sequence specific manner, using oligonucleotides constructed from arabinonucleotide or modified arabinonucleotide residues, flanking a series of deoxyribose nucleotide residues of variable length to hybridize to and induce cleavage of (via RNaseH activation) the complementary RNA (Field of Invention, page 1 lines 6-19). Dahma et al. taught mixed backbone or “gapmer” oligonucleotides have been synthesized, but oligonucleotides comprised of 2’-OMe RNA alone are unable to
elicit RNaseH degradation of the target RNA, that eukaryotic RNaseH requires substantially larger DNA gaps (7 DNA nucleotides or more for optimal degradation activity), and that antisense activity of [2’-OMe RNA]-[PS-DNA]-[2’OMe RNA] chimera oligonucleotides are highly dependent on DNA gap size (pages 6-7).
Dahma et al. taught it would be highly desirable to provide oligonucleotides constructed from arabinonucleotide or modified arabinonucleotide residues flanking a series of deoxyribose nucleotide residues of variable length for the sequence-specific inhibition of gene expression via association to (and RNaseH mediated cleavage of) complementary mRNA, which is the aim of the invention of Dahma et al. (pages 7-8). Dahma et al. teach the discovery that antisense hybrid chimeras, specifically constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides (FANA) flanking a defined sequence constructed from DNA are superior to antisense hybrid chimeras constructed from (OMeNA) flanking a defined sequence of DNA (page 8, lines 13-18).
Dahma et al. provides the following structure of their antisense hybrid chimeras on page 9, which also shows phosphorothioate internucleotide linkages between the nucleotides of the 2’-FANA modified nucleotides in the wings, as well as between the nucleotides in the DNA gap:
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Dahma et al. teach the gapmer antisense oligonucleotides of the invention exhibit a number of desirable properties including that they bind to and cleave ssRNA by activating RNaseH, and that the gapmer wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides in particular were found to have excellent affinity towards RNA targets compared to gapmers with wings comprised of 2’-O-methylribonucleotides and significantly better than that of identical sequence DNA, and the wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides were found to better effect sequence-specific inhibition of intracellular gene expression than the same-sequence DNA oligonucleotides (page 16, lines 15-26), and are excellent models of antisense oligonucleotide agents that can serve as therapeutics or tools for studying gene expression in cells and organisms (page 17, lines 3-5). Example 2, pages 20-21 show that antisense oligonucleotides constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides flanking a series of ten DNA residues all joined with phosphorothioate bonds (S-FANA gapmer, ID#1 in Table 1) provided at least 90% inhibition of cell luciferase activity and the results shown in Figure 1 show the S-FANA gapmer with a 10 DNA gap is a significantly better inhibitor of X1/5 cell luciferase activity expression than any of PO-DNA, S-DNA, PO-FANA or S-FANA (page 21, lines 6-16).
It would have been obvious to one of ordinary skill in the art to provide a pharmaceutical composition comprising a modified antisense oligonucleotide comprising at least one 2’-FANA and a pharmaceutically acceptable carrier, wherein the AON binds to Foxp3 and the AON comprises at least 5 successive nucleotides of SEQ ID NO: 199 or a sequence complementary thereto and modify based on the teachings of Dahma et al. regarding the 2’-FANA modified nucleotides joined by phosphorothioate bonds with a reasonable expectation of success. One of ordinary skill in the art would be motivated to provide the AON in a pharmaceutical composition with a carrier in order to provide a composition for administration to a subject for treatment because Barsoum et al. teach oligonucleotides of the invention can be formulated for administration to a subject for treating a condition, and the oligonucleotide compound of the invention can be combined with a carrier material (paragraphs 0207-0208). As explained above, it would be obvious that the AON would comprise at least 5 contiguous nucleotides of SEQ ID NO: 199 or a sequence complementary thereto, because Barsoum et al. teach SEQ ID NO: 41187 is the sense strand of the target gene and is 15 nucleotides in length, and SEQ ID NO: 41187 is complementary to nucleotides 7-21 of instant SEQ ID NO: 199. An ordinary artisan would be able to obtain an antisense oligonucleotide comprising 15 successive nucleotides that is complementary to the sense target strand of SEQ ID NO: 41187 with a reasonable expectation of success in order to target Foxp3 mRNA. The ordinary artisan would be motivated to provide the AON in the pharmaceutical composition with at least one 2’-deoxy-2’-fluoro-D-arabinonucleotide modified nucleotide and wherein internucleotide linkages between nucleotides of the 2’-FANA modified nucleotides are phosphorothioate bonds, as well as a hybrid chimera AON comprising at least one 2’-FANA modified nucleotide and at least one unmodified deoxyribonucleotide, and the limitations of the 2’FANA AON comprising about 1-20 2’-FANA at the 5’ end and from about 1-20 2’-FANA at the 3’ end flanking a sequence comprising about 1-20 deoxyribonucleotide residues in claim 47 because Dahma et al. each the benefits of and desirable properties of a gapmer with wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides flanking a DNA gap, including that they bind to and cleave ssRNA by activating RNaseH, were found to have excellent affinity towards RNA targets compared to gapmers with wings comprised of 2’-O-methylribonucleotides and significantly better than that of identical sequence DNA, the wings comprised of beta-D-2’-deoxy-2’-F-arabinofuranose nucleotides were found to better effect sequence-specific inhibition of intracellular gene expression than the same-sequence DNA oligonucleotides (page 16, lines 15-26), as well as that eukaryotic RNaseH requires substantially larger DNA gaps (7 DNA nucleotides or more for optimal degradation activity), and because Dahma et al. demonstrates that antisense oligonucleotides constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides flanking a series of ten DNA residues all joined with phosphorothioate bonds (S-FANA gapmer, ID#1 in Table 1) provided at least 90% inhibition of cell luciferase activity and is a significantly better inhibitor (Example 2, pages 20-21 and Fig. 1), and would make obvious the limitations of claims 45-47.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments- 35 U.S.C. 103 Rejections
Applicant’s arguments and amendments, filed 10/28/2025 regarding the 35 U.S.C. 103 rejection of claims 41 and 44-47 as unpatentable over Barsoum et al and Dahma et al. have been fully considered and are partially persuasive. Therefore, the 35 U.S.C. 103 rejection of claims 41 and 44 as unpatentable over Barsoum et al and Dahma et al. has been withdrawn. However claims 45-47 remain rejected under 35 U.S.C. 103 as unpatentable over Barsoum et al and Dahma et al. Regarding claims 41 and 44, a new ground of rejection is made in view of the amendments to claim 41. Regarding the 35 U.S.C. 103 rejection of claim 43 as unpatentable over Barsoum et al., Dahma et al. and NCBI Accession No. NM-014009 deposited by Chatila et al. the arguments have been fully considered but they are not persuasive.
Regarding the rejection of claims 41 and 44-47 over Barsoum et al. and Damha et al., Applicant argues on pages 7-8 that the Examiner has relied on impermissible hindsight reconstruction of Applicant’s invention in the rejection. Applicant argues that Barsoum discloses thousands of sequences that may or may not be useful for silencing FoxP3 and is more concerned with creating siRNAs rather than antisense sequences, and that the modifications of Dahma does not rectify this deficiency. Applicant argues there would be undue experimentation to test thousands of different compounds to arrive at the present invention and the Examiner acknowledges that neither of the references teach sequences that are 100% identical to SEQ ID NO: 199. Applicant argues that citing references which merely indicate the isolated elements in the claims are known is not sufficient for concluding the claimed combination would have been obvious and cites Ex parte Hiyamizu and Ex parte Levengood, and that here, as in Levengood, the references cited as evidence of obviousness “fall short of providing the motivation or suggestion to assembly their teachings into a viable process”.
As stated above, claims 45-47 remain rejected under 35 U.S.C. 103 as unpatentable over Barsoum et al and Dahma et al. Claims 41,43 and 44 are rejected under 35 U.S.C. 103 as unpatentable over Barsoum et al. and Dahma et al. and NCBI Accession No. NM-014009 deposited by Chatila et al. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As the argument of obviousness is not based on applicant’s disclosure, but rather from what was known in the state of the art at the time of the effective filing date and sufficient motivation is provided for combining the references, this argument of improper hindsight reasoning is not persuasive. In addition, the examiner has cited numerous motivations and suggestions as why one would be motivated to combine the teachings of the references and why there would be a reasonable expectation of success. Regarding applicants’ argument about the number of disclosed sequences of Barsoum and undue experimentation, Barsoum et al. teaches antisense oligonucleotides targeting the same gene as the instant claims, and claims 45-47 does not recite that the AON “comprises SEQ ID NO: 199” and only requires at least 5 successive nucleotides of SEQ ID NO: 199 or a sequence complementary thereto. Barsoum et al. teach sequences of the sense strand of the target gene, which include SEQ ID NO: 41187 (pages 48-49). SEQ ID NO: 41187 of Barsoum et al. is 15 nucleotides in length, and is complementary to nucleotides 7-21 of instant SEQ ID NO: 199. While the sequence is present in a list, it meets the instant claim limitations regarding the sequence complementary to SEQ ID NO: 199 and does not have to be derived. A skilled artisan would merely have to pick the sequence from the list of suitable sequences taught by Barsoum et al.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Barsoum et al. and Dahma teach 2’-FANA modifications and modification patterns that were known in the art before the effective filing date, and reasons for motivation of why an ordinary artisan would want to include 2’-FANA sugar modifications in an antisense oligonucleotide as well as an antisense oligonucleotide chimera comprising 2’-FANA and deoxyribonucleotides. Both Barsoum et al. and Dahma et al. teach gapmer antisense oligonucleotides, including gapmers with a variable number of DNA residues in the gap, flanked by modified nucleotides, Barsoum et al. teaches the modified nucleotides may be FANA (paragraph 0145), and Dahma et al. teaches the gapmer structure of 2’-FANA modified nucleotides flanking a DNA gap of variable lengths. For instance Damha et al. taught antisense oligonucleotides constructed from 2’-deoxy-2’-fluoro-beta-D-arabinonucleotides flanking a series of ten DNA residues all joined with phosphorothioate bonds (S-FANA gapmer, ID#1 in Table 1) provided at least 90% inhibition of cell luciferase activity and the results shown in Figure 1 show the S-FANA gapmer with a 10 DNA gap is a significantly better inhibitor of X1/5 cell luciferase activity expression than any of PO-DNA, S-DNA, PO-FANA or S-FANA (page 21, lines 6-16).
In addition, claims 45-47 do not require a particular formula or sequence of the 2’-FANA AON, and merely require at least one 2’-FANA modified nucleotide and an internucleotide linkage recited in claim 45 between nucleotides of the 2’-FANA modified nucleotides and claim 46 requires at least one unmodified deoxyribonucleotide and claim 47 provides a range of the number of 2’-FANAs flanking a range of the number of deoxyribonucleotides. Therefore, the examiner is maintaining the 103 rejection of claims 45-47 as unpatentable over Barsoum et al. and Dahma et al.
Regarding the rejection of claim 43 as unpatentable over Barsoum et al. and Damha et al. further in view of NCBI Reference Sequence NM_014009 (Chatila et al.), applicant argues on page 8 that claim 43 has been amended to depend from claim 41 which was not included in the first 103 rejection and claim 42 has been canceled. Applicant argues that the claim now requires the criteria for formula 7 to be met and the specific modification pattern present, and therefore the modified AON disclosed by claim 43 is not disclosed nor could be derived from the references cited by the examiner, and the deficiencies of Barsoum et al. and Damha et al. are disclosed above and the addition of Chatila that disclose the full length sequence of Foxp3 does not rectify these deficiencies. Applicant cites In re Lee, In re Dow Chem. Co. regarding using that which the inventor taught against its teacher, and suggestion to combine references must not be derived by hindsight.
The response to Applicant’s arguments regarding Barsoum et al. and Damha et al. as pertinent to claims 41,43 and 44 has been described above. The examiner has supplied sequences regarding the target gene sequence of FoxP3 being known and references regarding design of FoxP3 antisense gapmer oligonucleotides containing 2’-FANA modification patterns and FoxP3 antisense sequences, as well as support and motivations within the cited references. Regarding the argument citing In re Lee, In re Dow Chem. Co. and hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). For these reasons, amended claims 41,43 and 44 are rejected under 103 as unpatentable over Barsoum et al. and Damha et al. further in view of NCBI Reference Sequence NM_014009 (Chatila et al.).
Conclusion
Claims 41 and 43-47 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636