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 .
Election/Restrictions
Applicant’s election of group I, and SEQ ID NO 2 in the reply filed on 10/10/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 12, 14 and 16 require SEQ ID NO 3 which has a different sequence.
Claims 12, 14, 16, 18, 21, 23, 25-28, 30, 32 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/10/2025.
Claims 1, 3, 6-7, 9, 11, 17 are being examined.
The claim objections have been withdrawn in view of the amendment to the claims.
Priority
The instant application was filed 05/04/2023 is a National Stage entry of PCT/US2021/058010 with an international filing date: 11/04/2021 and claims priority from Provisional Application 63110225 , filed 11/05/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/20/2026 is being considered by the examiner.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 6-7, 17 is/are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Bennnett (US20030232977).
With regards to claims 1, 3 , Bennett discloses an antisense oligonucleotide comprising a sequence that binds to a target sequence on an MRNA that encodes TRA2.beta (para [0006]; human splicing factor R/S-rich 10 (also known as SFRS10; TRA2-BETA; TRA2B; htra2-beta-1; htra2- beta1"; para (0017); "The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding splicing factor R/S-rich 10, and which modulate the expression of splicing factor R/S-rich 10"), wherein the antisense oligonucleotide further comprises a 2'-O-methoxyethy! modification (para [0051]; "improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2'-methoxyethoxy (2'-O-CH2CH2OCH3, also known as 2'-O-(2-methoxyethyl) or 2'-MOE)"; para [0283}; "All compounds in Table 1 are chimeric oligonucleotides ("gapmers") 20 nucleotides in length, composed of a central “gap” region consisting of ten 2'-deoxynucleotides, which is flanked on both sides (5' and 3' directions) by five-nucleotide "wings". The wings are composed of 2'-methoxyethyl (2'-MOE) nucleotides. The internucleoside (backbone) linkages are phosphorothioate (P=S) throughout the oligonucleotide"). .
With regards to claim 4, Bennett teaches, “The internucleoside (backbone) linkages are phosphorothioate (P.dbd.S) throughout the oligonucleotide. “ (0283).
With regards to claim 5, Bennet claims, “wherein the modified internucleoside linkage is a phosphorothioate linkage.” (claim 4)
With regards to claim 7, Bennett teaches “Both controls are 2'-O-methoxyethyl gapmers (2'-O-methoxyethyls shown in bold) with a phosphorothioate backbone.” (0260)
MPEP 2111 states: Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) “adapted to” or “adapted for” clauses;
(B) “wherein” clauses; and
(C) “whereby” clauses.
The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 283 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”). In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id.
Claim 17 recites, “wherein binding of the antisense oligonucleotide to the pre-mRNA increases TRA23-PE inclusion.”
Thus the broadest reasonable interpretation is the oligonucleotide of claim 1 provides for this outcome.
Thus the teachings of claim 1 anticipate the claim.
Response to Arguments
The response traverses the rejection asserting, “Claim 1 requires an ASO comprising a nucleotide sequence that "binds to an intronic splicing silencer sequence on a precursor messenger ribonucleic acid (pre-mRNA) of an mRNA that encodes TRA2p3." This limitation is not a generic TRA2p3-targeting requirement. It demands that the ASO bind to a specific functional element within a pre-mRNA: an intronic splicing silencer (ISS) sequence. An ISS is a distinct regulatory element that suppresses exon inclusion; binding to it achieves a mechanistically specific outcome distinct from general antisense knockdown of TRA2p3 mRNA. Bennett discloses ASOs targeting nucleic acids encoding TRA2p broadly, and Table 1 of Bennett lists chimeric gapmer oligonucleotides comprising a central ten-deoxynucleotide gap flanked by five-nucleotide 2'-MOE wings. However, Bennett does not disclose or suggest an ASO designed to bind an intronic splicing silencer sequence on a TRA2p pre-mRNA. The reference is directed to general antisense reduction of TRA2p expression, which is a different mechanism from ISS-targeted splicing modulation. Nothing in Bennett identifies an ISS target site, discloses ASO sequences that map to an ISS, or describes any effect on pre-mRNA splicing through ISS engagement. Because the "intronic splicing silencer sequence" limitation of claim 1 is absent from Bennett both expressly and inherently, the reference cannot anticipate.” This argument has been thoroughly reviewed but is not considered persuasive as the Bennett teaches,” [0019] It is preferred to target specific nucleic acids for antisense. "Targeting" an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding splicing factor R/S-rich 10. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5'-AUG (in transcribed mRNA molecules; 5'-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the "AUG codon," the "start codon" or the "AUG start codon". A minority of genes have a translation initiation codon having the RNA sequence 5'-GUG, 5'-UUG or 5'-CUG, and 5'-AUA, 5'-ACG and 5'-CUG have been shown to function in vivo. Thus, the terms "translation initiation codon" and "start codon" can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, "start codon" and "translation initiation codon" refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding splicing factor R/S-rich 10, regardless of the sequence(s) of such codons.” Bennett further teaches, “[0022] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as "introns," which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as "exons" and are spliced together to form a continuous mRNA sequence. mRNA splice sites, i.e., intron-exon junctions, may also be preferred target regions, and are particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular mRNA splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. mRNA transcripts produced via the process of splicing of two (or more) mRNAs from different gene sources are known as "fusion transcripts". It has also been found that introns can be effective, and therefore preferred, target regions for antisense compounds targeted, for example, to DNA or pre-mRNA. 0023] It is also known in the art that alternative RNA transcripts can be produced from the same genomic region of DNA. These alternative transcripts are generally known as "variants". More specifically, "pre-mRNA variants" are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and extronic regions. [0024] Upon excision of one or more exon or intron regions or portions thereof during splicing, pre-mRNA variants produce smaller "mRNA variants". Consequently, mRNA variants are processed pre-mRNA variants and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as "alternative splice variants". If no splicing of the pre-mRNA variant occurs then the pre-mRNA variant is identical to the mRNA variant.” Thus the teachings are Bennett are not limited to Traf2Beta encoding sequences but encompass preMRNA and introns. Further with response to targeting the intronic silencer sequence, the specification recites intronic spacer 5 times and provides no definition. Thus the broadest reasonable interpretation is any nucleic acid sequence encompassed by Traf2Beta, absent a specific definition. Further it is noted the teachings of Bennett are not limited to Table 1, but Bennet also teaches tables 2 and 3 and provides guidance on how to target and design oligonucleotides. Thus the rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 3, 6-7, 9, 11, 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bennett (US20030232977), Grellscheid (PLoS Genet 7(12): e1002390. doi:10.1371/journal.pgen.1002390) and hd86g01.x1 NCI_CGAP_GC6 Homo sapiens cDNA clone IMAGE:2916432 3' similar to TR:O15449 O15449 HTRA2-BETA-2, mRNA sequence (https://www.ncbi.nlm.nih.gov/nuccore/AW515680, Jan 7, 2011) .
With regards to claims 1, 3 , Bennett discloses an antisense oligonucleotide comprising a sequence that binds to a target sequence on an MRNA that encodes TRA2.beta (para [0006]; human splicing factor R/S-rich 10 (also known as SFRS10; TRA2-BETA; TRA2B; htra2-beta-1; htra2- beta1"; para (0017); "The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding splicing factor R/S-rich 10, and which modulate the expression of splicing factor R/S-rich 10"), wherein the antisense oligonucleotide further comprises a 2'-O-methoxyethy! modification (para [0051]; "improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2'-methoxyethoxy (2'-O-CH2CH2OCH3, also known as 2'-O-(2-methoxyethyl) or 2'-MOE)"; para [0283}; "All compounds in Table 1 are chimeric oligonucleotides ("gapmers") 20 nucleotides in length, composed of a central “gap” region consisting of ten 2'-deoxynucleotides, which is flanked on both sides (5' and 3' directions) by five-nucleotide "wings". The wings are composed of 2'-methoxyethyl (2'-MOE) nucleotides. The internucleoside (backbone) linkages are phosphorothioate (P=S) throughout the oligonucleotide"). .
Bennett does not specifically teach SEQ ID NO 2.
However, Grellscheid teaches, “The Sfrs10 gene itself is alternatively spliced to five mRNA isoforms encoding at least 2 protein isoforms . The major isoform encodes full length Tra2β protein. Full length Tra2β protein regulates its own levels through activating splicing inclusion of a poison exon (exon 2) into a second mRNA isoform.”
Further hd86g01.x1 NCI_CGAP_GC6 Homo sapiens cDNA clone IMAGE:2916432 3' similar to TR:O15449 O15449 HTRA2-BETA-2, mRNA sequence teaches nucleotides 408-442 which comprise SEQ ID NO 2.
Therefore it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims to target the Tra2β poison exon comprising SEQ ID NO 2. The artisan would be motivated to target Tra2β with an antisense oligonucleotide to further characterize the how inhibition of Tra2β affects splicing and/or spermatogenesis. The artisan would have a reasonable expectation of success as the artisan is merely targeting known sequence identified in the art by 2’-MOE and phosphorothioate as they play a role in oligonucleotide stability.
With regards to claim 4, Bennett teaches, “The internucleoside (backbone) linkages are phosphorothioate (P.dbd.S) throughout the oligonucleotide. “ (0283).
With regards to claim 5, Bennet claims, “wherein the modified internucleoside linkage is a phosphorothioate linkage.” (claim 4)
With regards to claim 7, Bennett teaches “Both controls are 2'-O-methoxyethyl gapmers (2'-O-methoxyethyls shown in bold) with a phosphorothioate backbone.” (0260)
MPEP 2111 states: Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) “adapted to” or “adapted for” clauses;
(B) “wherein” clauses; and
(C) “whereby” clauses.
The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 283 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”). In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id.
Claim 17 recites, “wherein binding of the antisense oligonucleotide to the pre-mRNA increases TRA23-PE inclusion.”
Thus the broadest reasonable interpretation is the oligonucleotide of claim 1 provides for this outcome.
Response to Arguments
The response begins traversing the rejection for the reasons set forth with respect to the 102 rejection. These arguments are not persuasive for the reasons of record.
The response continues by asserting, “Grellscheid teaches poison exon autoregulation and does not identify any ISS within TRA2p pre-mRNA; the NCBI sequence is an unannotated 554-nucleotide cDNA that does not identify any ISS, any splicing regulatory motif, or any basis for selecting a 35-nucleotide subsequence as an ASO target. Because the ISS-targeting limitation of claim 1 does not appear in any of the cited references, alone or in combination. This argument has been thoroughly reviewed but is not considered persuasive as the specification recites intronic spacer 5 times and provides no definition. Thus the broadest reasonable interpretation is any nucleic acid sequence encompassed by Traf2Beta, absent a specific definition.
Further in NCBI sequence comprises SEQ ID NO 2 as identified in the rejection. Further the rejection states, “The artisan would be motivated to target Tra2β with an antisense oligonucleotide to further characterize the how inhibition of Tra2β affects splicing and/or spermatogenesis.” First, MPEP 716.01(c) makes clear that "The arguments of counsel cannot take the place of evidence in the record. In re Schulze , 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long - felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant."
This should not be construed as an invitation for providing evidence. As further stated in the MPEP 716.01 regarding the timely submission of evidence:
A) Timeliness.
Evidence traversing rejections must be timely or seasonably filed to be entered and entitled to consideration. In re Rothermel, 276 F.2d 393, 125 USPQ 328 (CCPA 1960). Affidavits and declarations submitted under 37 CFR 1.132 and other evidence traversing rejections are considered timely if submitted:
(1) prior to a final rejection,
(2) before appeal in an application not having a final rejection, or
(3) after final rejection and submitted
(i) with a first reply after final rejection for the purpose of overcoming a new ground of rejection or requirement made in the final rejection, or
(ii) with a satisfactory showing under 37 CFR 1.116(b) or 37
CFR 1.195, or
(iii) under 37 CFR 1.129(a).
Summary
No claims are allowed.
The 2’-MOE appears to require the hand of man as searching revealed 2’-MOE is a second generation nucleotide modification.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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