DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/12/2026 has been entered.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 05/12/2026 is acknowledged. Claims 46,47 and 51 were cancelled. Claims 41,43-45,49,50 and 53-56 were amended. Claims 49,50 and 53-58 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 43-45 are directed to the elected invention and are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). In the instant case, claim 43 recites a modified oligonucleotide sequence without reciting the SEQ ID NO. While this depends on claim 41 which recites SEQ ID NO: 199, claim 43 is still required to recite a sequence identifier for sequence compliance.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Declaration Under 37 C.F.R. 1.132
The Declaration under 37 CFR 1.132 filed 05/12/2026 is insufficient to overcome the rejection of claims 41 and 43-45 based upon 35 U.S.C. 103 as set forth in the last Office action.
A Declaration is due full consideration and weight for all that it discloses. Declarations are reviewed for the following considerations: 1) whether the Declaration presents a nexus such as a side-by-side or single-variable comparison (In re Huang, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996)), 2) whether the Declaration presents a comparison to the closest art, 3) whether the Declaration is commensurate in scope with the scope of the claims (In re Kulling, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)), 4) whether the Declaration shows the difference in results are in fact unexpected and unobvious and of both statistical and practical significance (Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)), and 5) whether the prima facie case is sufficiently strong that allegedly superior results are insufficient to overcome the case for obviousness (Pfizer Inc. v. Apotex, Inc., 82 USPQ2d 1321, 1339 (Fed. Cir. 2007)).
Regarding the above considerations, the Declaration does not provide a side-by-side or single-variable comparison of the instant claimed sequence to the closest prior art. In addition, the Declaration is not commensurate in scope with the instant claims, as while the Declaration at point 8 states that the AON identified as “ASO 16” in the provided publication, “Antisense targeting of FOXP3+ Tregs to boost anti-tumor immunity”, corresponds to the AON recited in pending claim 41 comprising SEQ ID NO: 199, it cannot be determined from the article whether that AON also comprises the modifications as recited in claims 41 and 43. In addition, claim 41 is now broader than it was previously, as it has been amended to also encompass a sequence complementary to SEQ ID NO: 199 or a sequence having 98% identity to SEQ ID NO: 199, and as the Declaration states, the ASO 16 in the publication corresponds to SEQ ID NO: 199. Therefore, it cannot be said that any supposed unexpected results of the ASO 16 in the publication are commensurate in scope with the instant claims which recite specific modifications and also encompasses sequences having 98% identity thereto, or a sequence complementary thereto that may not have those same results or effects.
Regarding point 4), whether the Declaration shows the difference in results are in fact unexpected and unobvious and of both statistical and practical significance, upon reviewing the points and Figures referenced in the Declaration, it appears the Declaration shows that the invention works as it should rather than any unexpected and unobvious results. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716. For instance, in Figure 1F of the publication provided in the Declaration, ASO 11, ASO 15, ASO 16, ASO 17 and ASO 29 all reduced FOXP3 mRNA compared to the Scramble, and ASO 17 had even better activity than ASO 16. These ASO’s performed to such a similar degree, that the activity of ASO 16 does not appear unexpected or of both statistical and practical significance. The same is true for the results in Figure 2E, where ASO’s 15,16,21,23 and 29 all reduced FoxP3 mRNA expression in primary cancer samples compared to scramble, and the amount of reduction achieved by ASO16, while better, is not significantly better than the other ASOs. "Applicants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). MPEP 716.02(b).
Withdrawn Rejections
Applicant’s arguments and amendments, see page 6, filed 05/12/2026 with respect to the rejection(s) of claim(s) 43 and 44 under 35 U.S.C. 112(d) have been fully considered and are persuasive due to the amendments to claims 43 and 44 such that the issues in the 35 U.S.C. 112(d) rejection discussed in the final rejection have been corrected. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 44 which now recites “The AON of claim 41 present in a pharmaceutically acceptable composition” and therefore based on this amendment is rejected under 35 U.S.C. 112(d). See the new rejection below.
Applicant’s arguments and amendments, see pages 10-11, filed 05/12/2026 with respect to the rejection(s) of claim(s) 45 under 35 U.S.C. 103 as unpatentable over Barsoum et al. and Damha et al. have been fully considered and are persuasive due to the amendments to claim 45 and the change in dependency to now amended claim 43 and therefore the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claim 45 to depend on claim 43 which has been amended to recited the specific sequence and modifications and claim 45 is now rejected under 35 U.S.C. 103 as unpatentable over Barsoum et al. in view of Damha et al. and NCBI Reference Sequence Accession number NM_014009 (Chatila et al.) along with claims 41,43 and 44. See the 103 rejection below.
Drawings
The drawings are objected to because the drawings are objected to because Figure 1-Figure 22 recite “Figure 1”, “Figure 2”…. “Figure 9A”, “Figure 9B”, etc. See 37 CFR 1.84(u). (u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." For example, “Figure 1” should be “FIG. 1”, and “Figure 9A” should be “FIG. 9A”. All of the figures should be corrected to be labeled correctly.
In addition, many of the figures are not clear and legible, including Figures 1-6,10,11,12B,15A,16A,18 and 19A, and therefore more legible replacement figures should be provided.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claim 44 is 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.
Claim 44 depends on amended claim 41, and claim 44 recites, “The AON of claim 41 present in a pharmaceutically acceptable composition”. Claim 41 does not further limit the AON of claim 1 as required by 35 U.S.C. 112(d) stated above.
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.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 41 and 43-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 recites “2’-FANA modified nucleotides positioned according to Formula 7”. See MPEP 2173.05(s). “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted)”. In the instant case, Formula 7 should be provided in the claim for the claim to be complete.
In addition, claim 41 as amended now recites “a sequence complementary thereto or having at least 98% identity therewith”. The metes and bounds of the claim are not clear because claim 41 recites a modified antisense oligonucleotide which binds to a Foxp3 mRNA, said AON comprising SEQ ID NO: 199, a sequence complementary thereto or having at least 98% identity therewith, and therefore as the claim is reciting an antisense oligonucleotide that binds to Foxp3 mRNA, it is unclear how the antisense oligonucleotide could comprise a sequence complementary to SEQ ID NO: 199, which is the sequence of the antisense oligonucleotide. It seems that a sequence complementary to SEQ ID NO: 199 would be the target mRNA sequence and not the sequence of the AON. Therefore, this limitation is unclear and indefinite.
Claims 43-45 are included in the rejection as they depend from claim 41 and do not correct the issue.
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 and 43-45 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: Amended claim 41 now encompasses a modified AON which binds to Foxp3 mRNA, said AON comprising SEQ ID NO: 199, a sequence complementary thereto (which reads on 2 or more nucleotides complementary to SEQ ID NO: 199), or 98% identity to SEQ ID NO: 199.
Regarding claims 41 and 43, 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 teach 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 claim Interpretation above, where claim 41 as amended encompasses a sequence complementary to SEQ ID NO: 199, which reads on 2 or more nucleotides complementary to SEQ ID NO: 199, and therefore SEQ ID NO: 41187 of Barsoum et al. meets this limitation. 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. also 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 or a sequence having at least 98% identity therewith, 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, or that the modifications consist of [FANA U]*[FANA U]*[FANA U]*[FANA G]*[FANA A]*G*T*G*T*A*C*T*G*A*G*G*[FANA C]*[FANA A]*[FANA G]*[FANA G]*[FANA C], wherein * is phosphorothioate bond recited in amended claim 43. Instant 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).
In addition, 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 nucleotides 1-21 of 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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Regarding claims 44 and 45, no additional ingredients are recited other than the AON of claim 41, and therefore, art that teaches the limitations of claim 41 teaches the limitations of claims 44 and 45. Nevertheless, 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, which reads on a pharmaceutical composition (paragraphs 0207-0208).
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 and between the nucleotides in the DNA gap 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 based on the Foxp3 mRNA sequence being publicly available 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 flanked on the 5’ and 3’ regions by 5 modified nucleotides, and teaches modified nucleotides include 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 with an 11 DNA gap 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. 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). Therefore, an ordinary artisan could have arrived at the positioning and length of the segments in instant formula 7 as well as the modification pattern of instant claim 43 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 therefore encompasses an 11 DNA gap.
Regarding the sequence, an ordinary artisan could have arrived at a sequence comprising or consisting of instant SEQ ID NO: 199 based on Barsoum et al. teaching 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 and therefore it would be obvious to target this region of the human Foxp3 mRNA sequence, and as SEQ ID NO: 199 is complementary to positions 1800-1780 of the human Foxp3 mRNA sequence which was known before the effective filing date, one of ordinary skill in the art would have been able to design a 21-mer targeting that region of the Foxp3 sequence knowing the Foxp3 mRNA sequence and being near the region targeted by antisense sequence of Barsoum et al. with a reasonable expectation of success.
Accordingly, the limitations of claims 41 and 43-45 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant’s arguments and amendments, filed 05/12/2026 regarding the 35 U.S.C. 103 rejection of claims 41,43 and 44 as unpatentable over Barsoum et al. in view of Dahma et al. and NCBI Accession No. NM-014009 deposited by Chatila et al. have been fully considered but they are not persuasive. In addition, claim 45 was previously rejected as unpatentable over Barsoum et al. in view of Damha et al. and the rejection was withdrawn as stated above based on the amendments to claim 45 which now depends on amended claim 43 and therefore claim 45 is now rejected along with claims 41,43 and 44 as unpatentable over Barsoum et al. in view of Damha et al. and NCBI Reference Sequence Accession number NM_014009 (Chatila et al.).
Applicant refers to the Declaration on page 8 of remarks and states the development of therapeutically effective FOXP3-targeting AONs was highly sequence-dependent and unpredictable and 19 different FOXP3 targeting AON candidates were designed and screened and only a small subset demonstrated significant biological activity and selectivity, and the cited references do not establish that a person having ordinary skill in the art would have reasonably expected the specific AONs presently claimed with the specific modifications in claim 43 to exhibit favorable biological properties demonstrated by the Applicant and the cited references do not provide a reasonable expectation that the specifically modified AONs presently claimed would selectively target FOXP3 while maintaining unexpectedly favorable biological activity demonstrated in the Declaration. Applicant argues the Declaration demonstrates the claimed AON selectively reduced FOXP3 expression without significantly affecting FOXP1, FOXP2, or FOXP4 (Declaration paragraph 8), unexpectedly rapid impairment of Treg suppressive activity, substantial inhibitory activity in primary human cancer samples, enhanced sensitive in intratumoral Tregs, significant inhibition of tumor growth in vivo (Dec. paragraphs 9-13), which would not have been expected from the cited references. Applicant argues the rejection improperly assumes that disclosures of complementary target region and generalized gapmer chemistry would have rendered the presently claimed AON predictable, however the Declaration demonstrates that successful FOXP3 antisense target required more than identifying a complementary target sequence, and depended on highly unpredictable interactions between sequence selection, target regions, oligonucleotide chemistry, biological selectivity and functional activity.
This is not found persuasive. The lack of persuasiveness of the Declaration has been explained above but will also be included herein. The Declaration does not provide a side-by-side or single-variable comparison of the instant claimed sequence to the closest prior art. In addition, the Declaration is not commensurate in scope with the instant claims, as while the Declaration at point 8 states that the AON identified as “ASO 16” in the provided publication, “Antisense targeting of FOXP3+ Tregs to boost anti-tumor immunity”, corresponds to the AON recited in pending claim 41 comprising SEQ ID NO: 199, it cannot be determined from the article whether that AON also comprises the modifications as recited in claims 41 and 43. In addition, claim 41 is now broader than it was previously, as it has been amended to also encompass a sequence complementary to SEQ ID NO: 199 (which reads on 2 or more nucleotides complementary to the sequence) or a sequence having 98% identity to SEQ ID NO: 199, and as the Declaration states, the ASO 16 in the publication corresponds to SEQ ID NO: 199. Therefore, it cannot be said that any supposed unexpected results of the ASO 16 in the publication are commensurate in scope with the instant claims which recite specific modifications and also encompasses sequences having 98% identity thereto, or a sequence complementary thereto that may not have those same results or effects.
Regarding whether the Declaration shows the difference in results are in fact unexpected and unobvious and of both statistical and practical significance, upon reviewing the points and Figures referenced in the Declaration, it appears the Declaration shows that the invention works as it should rather than any unexpected and unobvious results. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716. For instance, in Figure 1F of the publication provided in the Declaration, ASO 11, ASO 15, ASO 16, ASO 17 and ASO 29 all reduced FOXP3 mRNA compared to the Scramble, and ASO 17 had even better activity than ASO 16. These ASO’s performed to such a similar degree, that the activity of ASO 16 does not appear unexpected or of both statistical and practical significance. The same is true for the results in Figure 2E, where ASO’s 15,16,21,23 and 29 all reduced FoxP3 mRNA expression in primary cancer samples compared to scramble, and the amount of reduction achieved by ASO16, while better, is not significantly better, or unexpectedly better than the other ASOs, and based on the similar degree of performance does not appear to be of statistical and practical significance. Based on this data, there appear to be other FoxP3 antisense oligonucleotides with different sequences, and other unknown modifications that also achieve similar results to the instant claimed ASO, which does not support that the instant sequence and modifications are unexpectedly better and of statistical and practical significance. "Applicants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). MPEP 716.02(b).
Applicant argues on pages 9-10 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”. 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.
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.
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).
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. For these reasons, amended claims 41 and 43-45 are rejected under 103 as unpatentable over Barsoum et al. in view of Damha et al. and NCBI Reference Sequence NM_014009 (Chatila et al.).
Conclusion
Claims 41 and 43-45 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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