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 without traverse of claims 198-215 with species election of SEQ ID NO:1591 in the reply filed on August 28, 2025 is acknowledged.
Status of Claims
Claims 198-217 are currently pending in the instant application. Claims 203 and 216-217 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Accordingly, claims 198-202 and 204-215 are under examination on the merits in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 30, 2022, August 15, 2023, January 8, 2025, and September 2, 2025 have been considered by the examiner.
Note that the IDS filed on August 15, 2023 contains WO 94/14226 A1, which appears to pertain to “brushless DC motor systems” useful “in thrust vector control of rocket engines.” Since the examiner does not see any relevance of the WO document to the subject matter of the instant application, this reference is not considered. Applicant is required to point out a relevant portion of the WO document for the examiner to consider the document in the next response if applicant wishes the examiner to consider the document. In addition, the non-English language foreign patent publication, WO 2005/021570 A1 submitted without an English language translation, is considered only insofar as its English language title and abstract contained within the non-English language WO document.
Claim Objections
Claim 198 is objected to because of the following informalities: “85” line 1 should be “85%”. Appropriate correction is required.
Claim Rejections - Improper Markush Grouping
Claims 198-202 and 204-215 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination of process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP §706.03(y).
Note that “the phrase "Markush claim” means any claim that recites a list of alternatively useable species regardless of format.” See MPEP §2173.05(h).
The list of two alternatively recited target nucleotide sequences of SEQ ID NO:1339 (470 nucleotides in length) and SEQ ID NO:1341 (55,361 nucleotides in length) is improper because the 55,361-mer sequence of SEQ ID NO:1341 shares about 8% sequence with SEQ ID NO:1339, wherein such low sequence homology level is far from being a substantial structural feature shared by the two species. In fact, an oligonucleotide complementary to positions 1-15 of SEQ ID NO:1341 is incapable of being complementary to any portion of SEQ ID NO:1339 due to the low sequence homology shared by the two sequence species. As such, there is no common use flowing from a substantial structural feature shared by both SEQ ID NOs.
The Markush grouping of the different SEQ ID NO species recited in claims 201-202 is improper because the alternatives defined by the Markush grouping do not share a significant nucleotide sequence commonly shared by all of the alternatively recited SEQ ID NOs thus the species lack a common use flowing from a substantially shared nucleotide sequence. For instance, SEQ ID NO:1451 and applicant’s elected SEQ ID NO:1591 share little or no nucleotide sequence homology.
The Markush grouping of different spacers represented by Formula (I), Formula (I’), Formula (Ia), Formula (Ia’), Formula (II), Formula (II’), Formula (Iia), Formula (Iia’), Formula (III), Formula (III’), Formula (IIIa), and Formula (IIIa’) is improper because the alternatives within the grouping do not all share a significant structural similarity. For instance, see and compare Formula (Iia’) to Formula (III’) as shown below.
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To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternatives within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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 198, 200, 204, 206-207, 209-213, and 215 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 198 recites “(i.e., one or more)” in line 4. It is unclear whether the parenthetical recitation is part of the claimed invention, thereby rendering the claimed metes and bounds unclear. It is also unclear how “one or more” differs from “at least one” in “at least one (i.e., one or more)”.
Claim 200 recites the limitation "wherein every segment" in line 1. There is insufficient antecedent basis for this limitation in the claim. Note that claim 198 does not recite “segment”.
Claim 204 recites “oligonucleotide units in length.” It is unclear what is meant by the word “units” thus it is unclear what is meant by the phrase “oligonucleotide units”. Since paragraph 00213 of the specification appears to define “oligonucleotide unit” as either a nucleoside or a spacer of the oligonucleotide, the numerical values recited in claim 204 will be interpreted as the minimum length of the entirety of the oligonucleotide comprising a spacer (a spacer is counted as one unit) of claim 198.
Claim 206 recites that “the spacer is located between positions 7 and 11 of the oligonucleotide.” It is unclear whether the single spacer is linking the specific two positions 7 and 11 of the oligonucleotide or whether the single spacer is meant to be present in any (e.g., between 9 and 10) of the recited position range of the oligonucleotide.
Claims 207 and 209-213 recite that “the second spacer is located between positions 14 and 22 of the oligonucleotide.” It is noted that claims 207 and 209-213 do not particularly point out the position(s) of the “first” spacer. Hence, it is unclear how the two spacers (e.g., first and second) should be positioned with respect to each other. Further, it is unclear whether the second spacer is linking the specific two positions 14 and 22 of the oligonucleotide such that the two positions are directly linked by a single long spacer or whether the second spacer is meant to be present in any one of the recited position range of the oligonucleotide.
Claim 212 recites the limitation "first or second spacer" in multiple lines including line 2. There is insufficient antecedent basis for the “first” spacer limitation in the claim.
Claim 213 recites “(i.e., one or more)” in line 1. It is unclear whether the parenthetical recitation is part of the claimed invention, thereby rendering the claimed metes and bounds unclear. It is also unclear how “one or more” differs from “at least one” in “at least one (i.e., one or more)”.
Claim 215 recites “(e.g., tcDNA)” in line 6. It is unclear whether the parenthetical recitation is part of the claimed invention or merely exemplary thus is not required. Hence, the aforementioned parenthetical recitation renders the claimed metes and bounds unclear.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 198-202 and 204-215 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are broadly drawn to an “oligonucleotide comprising a sequence that is between 85 and 98% complementary to an equal length portion of any one of SEQ ID NO:1339 or SEQ ID NO:1341” “or to a 15 to 50 contiguous nucleobase portion thereof”.
It is found that the instantly claimed genus of oligonucleotides is not adequately supported by the instant specification for the following reasons:
1. The length of the oligonucleotide
The claims as broadly written at best specify that the oligonucleotide comprises a sequence that is complementary to the minimum length of 15 contiguous nucleotides and the maximum length of 50 contiguous nucleotides of the target SEQ ID NO, wherein such limitation does not limit the length of the oligonucleotide per se as the length range (“15 to 50”) pertains to the complementarity region in the target SEQ ID NO with the open-ended transitional phrase “comprising” in “oligonucleotide comprising a sequence”. As such, the claimed oligonucleotide is not limited to any specific length. Now, it is noted that the instant specification appears to at best describe that the oligonucleotides targeting the claimed target should be at least 19 oligonucleotide units in length and at most 25 oligonucleotide units in length comprising both nucleobases and spacers (see the claim interpretation in the §112(b) rejection above), wherein the 19-25 oligonucleotide units in the oligonucleotide species disclosed in the instant specification are far from representing the substantial length variations of the claimed oligonucleotide that is not limited to any particular length or length range. Further, the oligonucleotide units of 19-25 disclosed in the instant specification are also insufficient to represent the target sequence complementarity length range of “15 to 50” as broadly claimed. That is, the limited lengths of the oligonucleotide species disclosed in the specification are not a representative number of substantial variations of oligonucleotide length species providing the modulation of the human STMN2 pre-mRNA, which is the function provided by the claimed “oligonucleotide”.
2. The type of the spacer
Regarding the genus of “spacer” included in the claimed oligonucleotide, the instant specification at best describes incorporation of a spacer that is Formula (I), wherein X is O and n is 1, except for SEQ ID NO:1649 having Formula (I), wherein X is O and n is 2. This single spacer structure of Formula (I) incorporated into the oligonucleotides, in particular applicant’s elected SEQ ID NO:1591, is not a representative number of species reflecting the substantially different types of spacers encompassed by the genus. Now, it is noted that the instant specification expressly demonstrates spacer position-dependent STMN2-modulating activity of oligonucleotides that provide variable levels of STMN2-modulating levels depending on the spacer species that are incorporated into the same nucleotide positions into the oligonucleotides having the same nucleotide sequence. For instance, Table 15 shows that SEQ ID NO:1649 comprising two spacers of Formula (I) with n=2 at positions 8 and 16 rescued STMN2-FL to 71% and reduced STMN2 cryptic exon level to 21%, whereas SEQ ID NO:1633 comprising two spacers of Formula (I) with n=1 at positions 8 and 16 rescued STMN2-FL to 83% and reduced STMN2 cryptic exon level to 10%. In light of the variability within Formula (I) that differs only in the number of “n”, the two species of Formula (I) incorporated into the oligonucleotide species of 19-25 oligonucleotide units in length are not deemed a representative number of species reflecting the substantial variations of spacers encompassed by the claims including but not limited to Formula (I), Formula (I’), Formula (Ia), Formula (Ia’), Formula (II), Formula (II’), Formula (Iia), Formula (Iia’), Formula (III), Formula (III’), Formula (IIIa), and Formula (IIIa’).
3. The position and number of spacers
The broad claims recite “wherein the oligonucleotide comprises a spacer”, and some dependent claims recite positions (e.g., “between positions 7 and 11”, “between positions 14 and 22”) as well as number (e.g., “a second spacer”) of the spacers included in the claimed oligonucleotide having the function of modulating STMN2.
Applicant’s elected species of SEQ ID NO:1591 is a 25-mer with two spacers of Formula (I) with X is O and n is 1 at positions 8 and 19 compared to the non-spacer oligonucleotide of SEQ ID NO:237. See the following reproduced from Table 11.
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The specification describes that “a STMN2 parent oligonucleotide with SEQ ID NO: 237 reduced STMN2 transcript with cryptic exon levels by 93%...SEQ ID NO: 1591 reduced STMN2 transcript with cryptic exon levels by 96%. Here, SEQ ID NO: 1591 exhibited similar reduction of STMN2 transcripts with cryptic exon in comparison to SEQ ID NO: 237 (without two spacers.)” See paragraph 00487. The specification also discloses that the spacer-containing SEQ ID NO:1591 and the oligonucleotide of SEQ ID NO:237 without the spacers “increased STMN-FL levels by 225% (rescued to 104%).” See paragraph 00488. Hence, it appears that the presence of spacers in the STMN2-modulating oligonucleotides is not intended to reduce the STMN2 modulating activity compared to the oligonucleotides without spacers.
Now, it is noted that the instant specification expressly demonstrates a high level of unpredictability in STMN2 modulation activity that is highly dependent on the positions of the spacer as shown by the comparison between SEQ ID NO:1598 increased levels of STMN-FL to 0.72 at 200 nM and SEQ ID NO:1599 increased levels of STMN-FL to only 0.1 at the same concentration. See the following reproduced from Table 13 for the two SEQ ID NOs that are 21 oligonucleotide units in length.
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See also the following portion of Table 13 showing the variable levels of STMN-FL by 200 nM of SEQ ID NOs:173, 1418, 1613, 1614, and 1615, wherein the oligonucleotides containing spacers significantly reduced decreased the levels of STMN-FL (0.73, 0.2, 0.13, 0.12) compared to the parent oligonucleotide without any spacers (SEQ ID NO:173), wherein the spacer-containing oligonucleotides do show a substantial variability in the oligonucleotide activity that is highly dependent on the positions of the spacers within the oligonucleotides of 25 oligonucleotide units.
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Note that SEQ ID NO:1591 elected by applicant is also 25 oligonucleotide units in length comprising two spacers at positions 8 and 19, which provided similar or almost identical function as the parent oligonucleotide (SEQ ID NO:237) without spacers as explained above, whereas SEQ ID NOs:1418 and 1613-1615 that are 25 oligonucleotide units in length comprising three spacers at various positions significantly reduced the oligonucleotide function compared to the parent oligonucleotide (SEQ ID NO:173) without spacers. Hence, the specification itself demonstrates that the oligonucleotide function is highly dependent on the number of spacers at least for the maximum length of oligonucleotides disclosed in the instant application.
The specification also discloses, “In addition to GC content, the location of spacers relative to guanine and cytosine nucleobases can also impact the performance of the STMN2 AON.” (emphasis added). See paragraph 00495, which in particular teaches that a spacer positioned “immediately preceding a guanine base” can improve the performance of the AON. Hence, it appears that a spacer’s position that is dependent on the nucleobase within an oligonucleotide highly impacts the intended function. Taken together, it appears clear that the oligonucleotide’s intended function is highly unpredictable and highly position-dependent, wherein the specific positions 8 and 19 for two spacers within a 25-mer oligonucleotide that did not negatively impact the original, parent oligonucleotide’s function as demonstrated by applicant’s elected SEQ ID NO:1591 are not representative number of spacer positions/numbers within the claimed genus that represent the structure-function correlation of the claimed oligonucleotide.
In view of the foregoing, it is concluded that the instant specification fails to adequately describe a representative number of oligonucleotide species within the claimed genus thus fails to reasonably convey that the instant co-inventors had possession of the entire genus as of the filing date sought in the instant application.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 198-199, 201-202, 204-206, and 213-215 are rejected under 35 U.S.C. 103 as being unpatentable over Bui et al. (US 2021/0252039 A1, of record) in view of Fragall et al. (BMC Medical Genetics, 2011, 12:141) and Van Ness et al. (WO 98/13527 A2).
Bui discloses an antisense compound that is an 18-mer oligonucleotide of SEQ ID NO:123 (ISIS 1186672), which is 5’-GCACACATGCTCACACAG, which increases human STMN2 expression by 166% compared to control, wherein the oligonucleotide is modified with 2’-MOE and phosphorothioate linkages, wherein the “hybridization of the antisense compound to the target nucleic acid results in alteration of splicing of the target nucleic acid.” See Table 2; paragraph 0215.
It is noted that Bui’s SEQ ID NO:123 is 100% complementary to an 18-mer sequence at nucleotide positions 244-261 of SEQ ID NO:1339 claimed in the instant case and is 100% identical to the first 18-mer sequence of applicant’s elected species of SEQ ID NO:1591 except position 8.
Bui does not teach replacing a base in SEQ ID NO:123 with a spacer.
Fragall teaches that that an antisense oligonucleotide of a 19-mer (“H25A (+95+119)”) comprising a mismatched base in the middle region (between positions 11-12) with respect to the target pre-mRNA provides efficient pre-mRNA splicing modulation such that the 19-mer “performed better” in modulating splicing with a target pre-mRNA that does not form a base pair between positions 11-12 compared with a target pre-mRNA that forms a perfect base pair at all 19 positions, wherein Fragall thus reports that “the mismatched H25A (+95+119) oligomer performed so effectively in the patient cells in comparison to the mutation specific H25A (+95+A+119).” See pages 1-3 and 6; Table 1.
Van Ness teaches that an abasic moiety (e.g., apurinic or apyrimidine moiety) such as C3-spacer or dSPACER introduces “a mismatched site” as it “lacks the coding information thus fails to base pair.” See pages 67-68.
It would have been obvious to one of ordinary skill in the art before the effective filing date to introduce an abasic spacer in the middle region such as at nucleotide position 8, 9, 10, or 11 of Bui’s 18-mer oligonucleotide of SEQ ID NO:123. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to investigate whether the introduction of a mismatched site via an abasic spacer in the middle position of the STMN2 splicing modulating oligonucleotide of Bui’s SEQ ID NO:123 would further enhance the splicing modulating efficacy of Bui’s SEQ ID NO:123, thereby further increasing the expression level of STMN2, because experimental investigation of the efficacy of pre-mRNA splicing modulating oligonucleotides comprising a mismatched base in the middle region was an art-recognized goal as evidenced by Fragall, who reported that the “mismatched” 19-mer antisense oligonucleotide that is designed to form a non-base pair in the middle portion (between positions 11-12) with the target pre-mRNA “performed better” or “performed so effectively” compared to when the 19-mer forms a perfectly matched base pair formation with the target pre-mRNA, and because a mismatched site was known to be created with the presence of an abasic spacer that “fails to base pair” with a complementary base as taught by Van Ness, which would have thus reasonably led one of ordinary skill in the art to deem the presence of mismatched base or non-base-paired base in the middle of a splicing modulating oligonucleotide can be created with the presence of an art-recognized abasic spacer that does not form a base pair. Hence, one of ordinary skill in the art would have reasonably obtained an 18-mer oligonucleotide that is at least about 94% complementary to an 18-mer portion of SEQ ID NO:1339 and is at least about 94% identical to an 18-mer portion of SEQ ID NO:1591, wherein the oligonucleotide comprises an abasic spacer at any one of the positions 8-11, thereby resulting in at most 7-10 linked nucleoside segments within Bui’s 18-mer oligonucleotide that is modified with phosphorothioate linkages and 2’-MOE, wherein such oligonucleotide rendered obvious fully satisfies all structural limitations set forth in claims 198-199, 201-202, 204-206, and 213-215.
Accordingly, claims 198-199, 201-202, 204-206, and 213-215 taken as a whole would have been prima facie obvious before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 198-202 and 204-215 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 4, 10, 12, 19-29, 31, and 35-36 of copending Application No. 17/616,350 in view of Fragall et al. (BMC Medical Genetics, 2011, 12:141) and Van Ness et al. (WO 98/13527 A2).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘350 claims drawn to an oligonucleotide comprising SEQ ID NO:237, SEQ ID NO:1181, or SEQ ID NO:1423, each of which fully satisfies applicant’s elected SEQ ID NO:1591 claimed in the instant case. It would have been obvious to incorporate at least one abasic spacer into the 25-mer oligonucleotide claimed in the ‘350 claims because the presence of a mismatched base in a splicing modulating oligonucleotide was known to improve the efficacy of the oligonucleotide as taught by Fragall, and because an abasic spacer was known to be functionally equivalent to a mismatched base as the spacer “fails to base pair” as taught by Van Ness. When introducing one spacer into the 25-mer oligonucleotide of the ‘350 claims, one of ordinary skill in the art would have tried introducing it to nucleotide positions 11, 12, 13, or 14 in the middle region of the oligonucleotide as a mismatched base in the middle portion was tested to be effective as evidenced by Fragall. When introducing two spacers into the 25-mer oligonucleotide of the ‘350 claims, it would have been obvious for one of ordinary skill in the art to try equally spaced two base positions such as positions 8 and 16 so that the three segments separated by the two spacers would be about an equal length within the 25-mer oligonucleotide because such equal length would mimic the single mismatch placed in the middle region of Fragall’s oligonucleotide, resulting in two segments of about an equal length.
Claims 198-202 and 204-215 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 15-70, 105-126, and 132 of copending Application No. 18/715,682 in view of Bui et al. (US 2021/0252039 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over and encompassed by the ‘682 claims drawn to an oligonucleotide that “comprises a spacer” having the structure of “Formula (I)” at two positions selected from 5, 7, 8, 11, 15, 17, and 19 and a method of using the oligonucleotide for the treatment of ALS and FTD. It would have been obvious to reasonably envision that the spacer-containing oligonucleotide claimed in the ‘682 claims is targeted to STMN2 because antisense oligonucleotides targeting STMN2 RNA was known to be useful in treating ALS and FTD as taught by Bui (see paragraph 0002), who disclosed many species of oligonucleotides that target SEQ ID NO:1339 including SEQ ID NO:123, wherein Bui taught that the oligonucleotides can be up to 50 nucleotides in length. See paragraph 0182. As such, the instant claims drawn to an STMN2-targeting oligonucleotide comprising one or two spacers of Formula I would have been prima facie obvious over the ‘682 claims in view of the teachings of Bui.
Claims 198-202 and 204-215 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-233 of copending Application No. 18/715,684.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the ‘684 claims that are drawn to and require a splice-switching oligonucleotide that “comprises a spacer” having the structure of “Formula (I)” at two positions selected from 7, 8, 9, 10, and 11, wherein the oligonucleotide is targeted to “STMN2” and is SEQ ID NO:1591, which is 100% identical to applicant’s elected SEQ ID NO:1591 claimed in the instant case.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635