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 .
Applicant’s response of 07/27/2026, including replacement drawings, has been received and entered into the application file.
Claims 9 and 16 were amended in the claim set filed 07/27/2026.
Claims 10 and 13 were canceled in the claim set filed 07/27/2026.
Claims 1-9, 11-12, and 14-18 are pending, of which claims 1-8 and 17-19 were previously withdrawn.
Accordingly, claims 9, 11-12, and 14-16 are pending and under consideration.
Election/Restrictions
Applicant’s previous election without traverse of claims 9-16 (Group II) in the reply filed on 02/10/2026 is acknowledged. Acknowledgment is further made of Applicant’s election of SEQ ID NO: 5. In view of the results from searching the prior art, the species election requirement was previously withdrawn.
Claims 1-8 and 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 02/10/2026.
Claims 10 and 13 were canceled in the claim set filed 07/27/2026.
Accordingly, claims 9, 11-12, and 14-16 are pending and under consideration.
Status of Prior Objections/Rejections
RE: Drawings
►The drawings were previously objected to for various informalities.
The replacement sheets filed 07/27/2026 have obviated the basis of the objection of record. The objection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(a)
►Claims 9-16 were previously 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 amended claim set filed 07/27/2026 has obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(b)
►Claims 9 and 16 were previously 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.
The amended claim set filed 07/27/2026 has obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claims 9 and 12-16 were previously rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2019/0300879 A1 (hereinafter Khurana; of record; as cited in the IDS filed 05/23/2023).
Applicant has traversed the rejection of record, asserting that Khurana does not disclose the combination of claimed features in the amended claims.
In response, this is found persuasive. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claim 10 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0300879 A1 (hereinafter Khurana; of record; as cited in the IDS filed 05/23/2023) as applied to claim 9 above, and further in view of Askari and McDonnell, 1996 (hereinafter Askari).
►Claims 10 and 11 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0300879 A1 (hereinafter Khurana; of record; as cited in the IDS filed 05/23/2023) as applied to claim 9 above, and further in view of US 2023/0272433 A1 (hereinafter Amendola; effectively filed 09/29/2020), Stenvang and Kauppinen, 2008 (hereinafter Stenvang), Chan et al., 2006 (hereinafter Chan), and Askari and McDonnell, 1996 (hereinafter Askari), as evidenced by Liu et al., 2021 (hereinafter Liu).
Applicant has traversed the rejection of record, asserting that the cited art does not disclose or motivate the combination of claimed features in the amended claims.
In response, this is found persuasive. The rejection of record is hereby withdrawn.
RE: Double Patenting
►Claims 9 and 13 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 14, and 19 of U.S. Patent No. 9,458,459 B2.
►Claims 9, 15, and 16 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 5 of U.S. Patent No. 11,028,389 B2.
►Claim 9 was previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of U.S. Patent No. 12,104,152 B2.
►Claims 9, 10, 13, and 14 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 13-15 of U.S. Patent No. 12,104,152 B2 in view of Askari and McDonnell, 1996 (hereinafter Askari).
The cancellation of claims 10 and 13 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that the amended instant claims are patentably distinct from the cited patents, as none of the cited patents disclose this combination of claimed features.
In response, while it is found persuasive that the cited patents do not disclose the combination of claimed features in the amended claim set, the prior art supplies those features not disclosed in the cited patents. Accordingly, while the rejection of record is hereby withdrawn, new grounds of rejection necessitated by amendment are set forth below.
Additionally, the rejection of record regarding claims 9, 10, 13, and 14 over U.S. Patent No. 12,104,152 B2 in view of Askari and McDonnell, 1996 is hereby withdrawn.
New/Maintained Grounds of Objection/Rejection
Claim Rejections - 35 USC § 112(a)
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 9, 12, and 14-16 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Amended instant claim 9 is drawn to a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and an oligonucleotide that is between 24 and 29 nucleotides long and that is complementary to a Let-7c microRNA binding sequence in a utrophin mRNA 3’-untranslated region (UTR) having the sequence of SEQ ID NO: 8, wherein the oligonucleotide comprises a 24 nucleotide sequence that is complementary to SEQ ID NO: 5, which is itself complementary to SEQ ID NO: 8. Therefore, the invention is drawn to an oligonucleotide that is simultaneously complementary to a UTR sequence as well as to an oligonucleotide comprising SEQ ID NO: 5, which is itself complementary to the UTR sequence. Instant claim 11 is not included in this rejection, as it recites that the oligonucleotide comprises SEQ ID NO: 5, which is complementary to instant SEQ ID NO: 8.
Breadth of the claims: The claims are broadly drawn to an oligonucleotide that is simultaneously complementary to a UTR sequence as well as to an oligonucleotide comprising SEQ ID NO: 5, which is itself complementary to the UTR sequence.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The instant specification discloses that the oligonucleotide taught therein comprises the nucleic acid sequence of SEQ ID NO: 5 (paragraphs [0009] and [0050]). The specification teaches that said oligonucleotide can be designated as an antisense oligonucleotide or antisense molecule of the microRNA that binds to a microRNA binding sequence (paragraphs [0006] and [0025]). One of ordinary skill in the art would be aware that an oligonucleotide complementary to an antisense oligonucleotide that binds to a microRNA binding site must be the microRNA binding site, and further supplying such an oligonucleotide would have no functional impact.
Predictability and state of the art: The prior art teaches that the approach of regulating activity by blocking miRNA binding sites is well-known as miRNA-masking, wherein antisense oligonucleotides mask the binding site of the target miRNA (reviewed in Stenvang (of record): see page 69, column 2, paragraph 1). This methodology is notably distinct from that of amended instant claim 9, which requires an oligonucleotide that corresponds to the microRNA binding site.
Amount of experimentation necessary: The quantity of experimentation required to make the instant invention is large. One would not be able to rely upon either the instant specification or the prior art for guidance in designing an oligonucleotide capable of regulating utrophin expression wherein said oligonucleotide corresponds to a microRNA binding site in the UTR of utrophin.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 9, 12, and 14-16 are not considered to be enabled by the instant disclosure.
Claim Rejections - 35 USC § 112(d)
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 11 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 11 depends from claim 9, which requires an oligonucleotide that is complementary to SEQ ID NO: 8 and complementary to SEQ ID NO: 5. However, claim 11 requires that the oligonucleotide comprises SEQ ID NO: 5. It is not possible for a sequence to be both complementary to and comprise the same sequence. It would be remedial to amend the complementarity limitations such that it is clear whether Applicant is claiming SEQ ID NO: 5 or a sequence complementary thereto.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The 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 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0300879 A1 (hereinafter Khurana; of record; as cited in the IDS filed 05/23/2023) in view of US 2023/0272433 A1 (hereinafter Amendola; effectively filed 09/29/2020; of record), Wang, 2011 (hereinafter Wang), Stenvang and Kauppinen, 2008 (hereinafter Stenvang; of record), Chan et al., 2006 (hereinafter Chan; of record), and Askari and McDonnell, 1996 (hereinafter Askari; of record), as evidenced by Liu et al., 2021 (hereinafter Liu; of record).
With regard to claim 11, which recites “the composition of claim 9, wherein the oligonucleotide has a sequence comprising SEQ ID NO: 5,” as previously set forth, Khurana discloses methods for enhancing utrophin protein production in a cell by inhibiting a utrophin microRNA molecule, said methods comprising administering pharmaceutical compositions that include an antisense oligonucleotide that specifically hybridizes to a microRNA binding sequence in a utrophin mRNA 3’ UTR, thereby inhibiting the binding of the microRNA to the 3’-UTR utrophin mRNA (abstract; paragraph [0011]). Such inhibited microRNAs include Let-7c, as instantly claimed (paragraphs [0011] and [0013]). The pharmaceutical compositions disclosed in Khurana further comprise at least one pharmaceutically acceptable excipient, and the antisense oligonucleotide targeting the Let-7c microRNA binding sequence is provided in an amount effective in a human subject to inhibit the binding of Let-7 microRNA with its utrophin mRNA 3’-UTR binding sequence (paragraph [0013]), thereby increasing utrophin production (abstract), as instantly claimed.
As previously set forth, and similar to Khurana, Amendola discloses methods of enhancing utrophin expression in a cell by inducing mutations within a target sequence comprising a utrophin regulatory element (such as a Let7c binding site, as instantly claimed) using a gene editing enzyme (paragraphs [0001], [0006], and [0033]). The target sequences comprising utrophin repressor binding sites disclosed therein include SEQ ID NOs: 18 and 26 (Table 1; paragraph [0046]). As shown in the alignment of the Appendix, instant SEQ ID NO: 8 comprises both SEQ ID NOs: 18 and 26 of Amendola, both of which comprise the Let-7c binding site (Table 1; paragraphs [0045] and [0046]). Thus, the disclosure of Khurana establishes that blocking Let-7c binding to the 3’-UTR of utrophin via antisense oligonucleotides upregulates utrophin expression (abstract; paragraphs [0010] and [0013]), while Amendola similarly discloses disruption of Let7c binding, as well as the known binding sequence of Let-7c, which is comprised within instant SEQ ID NO: 8. As is known to those of ordinary skill in the art, the approach of regulating activity by blocking miRNA binding sites is well-known as miRNA-masking, wherein antisense oligonucleotides mask the binding site of the target miRNA (reviewed in Stenvang: see page 69, column 2, paragraph 1), such as the Let7c target site disclosed in Amendola.
While neither Khurana nor Amendola disclose the instantly claimed SEQ ID NO: 5, the principles of design for such antisense oligonucleotides blocking miRNA (i.e. Let-7c) binding are well known such that a person of ordinary skill in the art would have arrived at a finite, testable number of antisense oligonucleotides targeting the known Let-7c binding site, thereby arriving at instant SEQ ID NO: 5. These design principles are reviewed in Wang. A person of ordinary skill in the art would have been motivated, prior to the effective filing date of the instant application, to apply the design principles of Wang to the Let-7c binding site disclosed in Amendola for purposes of blocking Let-7c binding, thereby upregulating utrophin expression as per Khurana.
To emphasize this rationale, as shown in the alignment of the Appendix, SEQ ID NO: 5 is capable of binding to the disclosed Let7c target site of Amendola (SEQ ID NOs: 18 and 26; see Table 1). Therefore, given that the target sequence comprising instant SEQ ID NO: 5 (within the UTR corresponding to instant SEQ ID NO: 8) was disclosed in Amendola, design of suitable antisense oligonucleotides per the methods of Wang would predictably generate a limited number of antisense oligonucleotides targeting said sequence, including instant SEQ ID NO: 5. As set forth previously, antisense DNA oligonucleotides such as instant SEQ ID NO: 5 are well-known in the art and function in the same manner as antisense RNA oligonucleotides, as reviewed in Askari (see in particular page 316, column 2, paragraph 2).
Accordingly, it is considered that although the prior art does not teach SEQ ID NO: 5, the prior art provides all of the guidance required to arrive at SEQ ID NO: 5.
As reviewed in Chan, antisense oligonucleotide drugs have been approved for in vivo therapeutic use, and other antisense oligonucleotide drugs are in clinical trials (see section ANTISENSE OLIGONUCLEOTIDE DRUGS IN CLINICAL TRIALS). The same is not true of CRISPR-based gene editing tools, such as those disclosed in Amendola (paragraph [0052]). While Liu has a post-filing publication date, it is applied as an evidentiary reference that is representative of the state of the art at the time of filing. At the time of filing, applying CRISPR editing to patients in vivo was an underdeveloped and unpredictable topic in the art. As reviewed in Liu, there are a number of hurdles to overcome before in vivo CRISPR therapy is commonplace, including editing efficiency, effective delivery of the editing machinery, off target effects, and immunogenicity (see sections “Editing efficiency,” “Delivering methods,” “Off-target effects,” and “Immunogenicity”). Therefore, in the interest of therapeutically targeting utrophin regulatory element sequences known in the field (for example SEQ ID NO: 18 of Amendola) in patients in need thereof, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant invention to design antisense oligonucleotides (such as DNA antisense oligonucleotides, as reviewed in Askari) per the methods of Wang, as motivated by Khurana, to predictably arrive at a limited number of antisense oligonucleotide sequences targeting the Let7c binding sequence disclosed in Amendola, said limited number including instant SEQ ID NO: 5. Antisense oligonucleotides produced via these methods would predictably block Let-7c binding and increase utrophin expression, as disclosed in Khurana and supported by Amendola. One would have been motivated to practice these methods in order to produce therapeutic antisense oligonucleotides for in vivo use in patients in need thereof, as the CRISPR editing disclosed in Amendola was an underdeveloped and unpredictable topic in the art at the time of filing, with no CRISPR drugs approved for in vivo use in patients.
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.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 13 of U.S. Patent No. 9,458,459 B2 (of record) in view of US 2019/0300879 A1 (hereinafter Khurana; of record; as cited in the IDS filed 05/23/2023) in view of US 2023/0272433 A1 (hereinafter Amendola; effectively filed 09/29/2020; of record), Wang, 2011 (hereinafter Wang), Stenvang and Kauppinen, 2008 (hereinafter Stenvang; of record), Chan et al., 2006 (hereinafter Chan; of record), and Askari and McDonnell, 1996 (hereinafter Askari; of record), as evidenced by Liu et al., 2021 (hereinafter Liu; of record).
Claim 13 of patent ‘459 is drawn to a pharmaceutical composition, recited to “compris[e] an antisense oligonucleotide that specifically hybridizes to a micro-RNA binding sequence in a 3’ UTR of a utrophin mRNA and inhibits the binding of the microRNA molecule to the 3’ UTR utrophin mRNA, wherein said microRNA is selected from the group consisting of Let-7c…and at least one pharmaceutically acceptable excipient.”
In comparison, instant claim 11 recites “the composition of claim 9, wherein the oligonucleotide has a sequence comprising SEQ ID NO: 5,” as previously set forth, both the patented application and Khurana disclose methods for enhancing utrophin protein production in a cell by inhibiting a utrophin microRNA molecule, said methods comprising administering pharmaceutical compositions that include an antisense oligonucleotide that specifically hybridizes to a microRNA binding sequence in a utrophin mRNA 3’ UTR, thereby inhibiting the binding of the microRNA to the 3’-UTR utrophin mRNA (abstract; paragraph [0011]). Such inhibited microRNAs include Let-7c, as instantly claimed (paragraphs [0011] and [0013]). The pharmaceutical compositions disclosed in Khurana further comprise at least one pharmaceutically acceptable excipient, and the antisense oligonucleotide targeting the Let-7c microRNA binding sequence is provided in an amount effective in a human subject to inhibit the binding of Let-7 microRNA with its utrophin mRNA 3’-UTR binding sequence (paragraph [0013]), thereby increasing utrophin production (abstract), as instantly claimed.
As previously set forth, and similar to Khurana, Amendola discloses methods of enhancing utrophin expression in a cell by inducing mutations within a target sequence comprising a utrophin regulatory element (such as a Let7c binding site, as instantly claimed) using a gene editing enzyme (paragraphs [0001], [0006], and [0033]). The target sequences comprising utrophin repressor binding sites disclosed therein include SEQ ID NOs: 18 and 26 (Table 1; paragraph [0046]). As shown in the alignment of the Appendix, instant SEQ ID NO: 8 comprises both SEQ ID NOs: 18 and 26 of Amendola, both of which comprise the Let-7c binding site (Table 1; paragraphs [0045] and [0046]). Thus, the disclosure of Khurana establishes that blocking Let-7c binding to the 3’-UTR of utrophin via antisense oligonucleotides upregulates utrophin expression (abstract; paragraphs [0010] and [0013]), while Amendola similarly discloses disruption of Let7c binding, as well as the known binding sequence of Let-7c, which is comprised within instant SEQ ID NO: 8. As is known to those of ordinary skill in the art, the approach of regulating activity by blocking miRNA binding sites is well-known as miRNA-masking, wherein antisense oligonucleotides mask the binding site of the target miRNA (reviewed in Stenvang: see page 69, column 2, paragraph 1), such as the Let7c target site disclosed in Amendola.
While neither Khurana nor Amendola disclose the instantly claimed SEQ ID NO: 5, the principles of design for such antisense oligonucleotides blocking miRNA (i.e. Let-7c) binding are well known such that a person of ordinary skill in the art would have arrived at a finite, testable number of antisense oligonucleotides targeting the known Let-7c binding site, thereby arriving at instant SEQ ID NO: 5. These design principles are reviewed in Wang. A person of ordinary skill in the art would have been motivated, prior to the effective filing date of the instant application, to apply the design principles of Wang to the Let-7c binding site disclosed in Amendola for purposes of blocking Let-7c binding, thereby upregulating utrophin expression as per Khurana.
To emphasize this rationale, as shown in the alignment of the Appendix, SEQ ID NO: 5 is capable of binding to the disclosed Let7c target site of Amendola (SEQ ID NOs: 18 and 26; see Table 1). Therefore, given that the target sequence comprising instant SEQ ID NO: 5 (within the UTR corresponding to instant SEQ ID NO: 8) was disclosed in Amendola, design of suitable antisense oligonucleotides per the methods of Wang would predictably generate a limited number of antisense oligonucleotides targeting said sequence, including instant SEQ ID NO: 5. As set forth previously, antisense DNA oligonucleotides such as instant SEQ ID NO: 5 are well-known in the art and function in the same manner as antisense RNA oligonucleotides, as reviewed in Askari (see in particular page 316, column 2, paragraph 2).
Accordingly, it is considered that although the prior art does not teach SEQ ID NO: 5, the prior art provides all of the guidance required to arrive at SEQ ID NO: 5.
As reviewed in Chan, antisense oligonucleotide drugs have been approved for in vivo therapeutic use, and other antisense oligonucleotide drugs are in clinical trials (see section ANTISENSE OLIGONUCLEOTIDE DRUGS IN CLINICAL TRIALS). The same is not true of CRISPR-based gene editing tools, such as those disclosed in Amendola (paragraph [0052]). While Liu has a post-filing publication date, it is applied as an evidentiary reference that is representative of the state of the art at the time of filing. At the time of filing, applying CRISPR editing to patients in vivo was an underdeveloped and unpredictable topic in the art. As reviewed in Liu, there are a number of hurdles to overcome before in vivo CRISPR therapy is commonplace, including editing efficiency, effective delivery of the editing machinery, off target effects, and immunogenicity (see sections “Editing efficiency,” “Delivering methods,” “Off-target effects,” and “Immunogenicity”). Therefore, in the interest of therapeutically targeting utrophin regulatory element sequences known in the field (for example SEQ ID NO: 18 of Amendola) in patients in need thereof, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant invention to design antisense oligonucleotides (such as DNA antisense oligonucleotides, as reviewed in Askari) per the methods of Wang, as motivated by Khurana and the patented application, to predictably arrive at a limited number of antisense oligonucleotide sequences targeting the Let7c binding sequence disclosed in Amendola, said limited number including instant SEQ ID NO: 5. Antisense oligonucleotides produced via these methods would predictably block Let-7c binding and increase utrophin expression, as disclosed in Khurana and the patented application and supported by Amendola. One would have been motivated to practice these methods in order to produce therapeutic antisense oligonucleotides for in vivo use in patients in need thereof, as the CRISPR editing disclosed in Amendola was an underdeveloped and unpredictable topic in the art at the time of filing, with no CRISPR drugs approved for in vivo use in patients.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,028,389 B2 (hereinafter Khurana; of record) in view of US 2023/0272433 A1 (hereinafter Amendola; effectively filed 09/29/2020; of record), Wang, 2011 (hereinafter Wang), Stenvang and Kauppinen, 2008 (hereinafter Stenvang; of record), Chan et al., 2006 (hereinafter Chan; of record), and Askari and McDonnell, 1996 (hereinafter Askari; of record), as evidenced by Liu et al., 2021 (hereinafter Liu; of record
Claim 1 of patent ‘389 is drawn to a pharmaceutical composition, recited to “compris[e] an antisense oligonucleotide that specifically hybridizes to a Let-7c microRNA binding sequence in a 3’-UTR of a utrophin mRNA 3’ untranslated region (UTR) and inhibits the binding of the Let-7c microRNA to the utrophin mRNA 3’-UTR and at least one pharmaceutically acceptable excipient, wherein the antisense oligonucleotide is present in an amount effective in a human subject to inhibit the binding of Let-7 microRNA with its utrophin mRNA 3’-UTR binding sequence…”.
In comparison, instant claim 11 recites “the composition of claim 9, wherein the oligonucleotide has a sequence comprising SEQ ID NO: 5,” as previously set forth, both the patented application and Khurana disclose methods for enhancing utrophin protein production in a cell by inhibiting a utrophin microRNA molecule, said methods comprising administering pharmaceutical compositions that include an antisense oligonucleotide that specifically hybridizes to a microRNA binding sequence in a utrophin mRNA 3’ UTR, thereby inhibiting the binding of the microRNA to the 3’-UTR utrophin mRNA (abstract; paragraph [0011]). Such inhibited microRNAs include Let-7c, as instantly claimed (paragraphs [0011] and [0013]). The pharmaceutical compositions disclosed in Khurana further comprise at least one pharmaceutically acceptable excipient, and the antisense oligonucleotide targeting the Let-7c microRNA binding sequence is provided in an amount effective in a human subject to inhibit the binding of Let-7 microRNA with its utrophin mRNA 3’-UTR binding sequence (paragraph [0013]), thereby increasing utrophin production (abstract), as instantly claimed.
As previously set forth, and similar to Khurana, Amendola discloses methods of enhancing utrophin expression in a cell by inducing mutations within a target sequence comprising a utrophin regulatory element (such as a Let7c binding site, as instantly claimed) using a gene editing enzyme (paragraphs [0001], [0006], and [0033]). The target sequences comprising utrophin repressor binding sites disclosed therein include SEQ ID NOs: 18 and 26 (Table 1; paragraph [0046]). As shown in the alignment of the Appendix, instant SEQ ID NO: 8 comprises both SEQ ID NOs: 18 and 26 of Amendola, both of which comprise the Let-7c binding site (Table 1; paragraphs [0045] and [0046]). Thus, the disclosure of Khurana establishes that blocking Let-7c binding to the 3’-UTR of utrophin via antisense oligonucleotides upregulates utrophin expression (abstract; paragraphs [0010] and [0013]), while Amendola similarly discloses disruption of Let7c binding, as well as the known binding sequence of Let-7c, which is comprised within instant SEQ ID NO: 8. As is known to those of ordinary skill in the art, the approach of regulating activity by blocking miRNA binding sites is well-known as miRNA-masking, wherein antisense oligonucleotides mask the binding site of the target miRNA (reviewed in Stenvang: see page 69, column 2, paragraph 1), such as the Let7c target site disclosed in Amendola.
While neither Khurana nor Amendola disclose the instantly claimed SEQ ID NO: 5, the principles of design for such antisense oligonucleotides blocking miRNA (i.e. Let-7c) binding are well known such that a person of ordinary skill in the art would have arrived at a finite, testable number of antisense oligonucleotides targeting the known Let-7c binding site, thereby arriving at instant SEQ ID NO: 5. These design principles are reviewed in Wang. A person of ordinary skill in the art would have been motivated, prior to the effective filing date of the instant application, to apply the design principles of Wang to the Let-7c binding site disclosed in Amendola for purposes of blocking Let-7c binding, thereby upregulating utrophin expression as per Khurana.
To emphasize this rationale, as shown in the alignment of the Appendix, SEQ ID NO: 5 is capable of binding to the disclosed Let7c target site of Amendola (SEQ ID NOs: 18 and 26; see Table 1). Therefore, given that the target sequence comprising instant SEQ ID NO: 5 (within the UTR corresponding to instant SEQ ID NO: 8) was disclosed in Amendola, design of suitable antisense oligonucleotides per the methods of Wang would predictably generate a limited number of antisense oligonucleotides targeting said sequence, including instant SEQ ID NO: 5. As set forth previously, antisense DNA oligonucleotides such as instant SEQ ID NO: 5 are well-known in the art and function in the same manner as antisense RNA oligonucleotides, as reviewed in Askari (see in particular page 316, column 2, paragraph 2).
Accordingly, it is considered that although the prior art does not teach SEQ ID NO: 5, the prior art provides all of the guidance required to arrive at SEQ ID NO: 5.
As reviewed in Chan, antisense oligonucleotide drugs have been approved for in vivo therapeutic use, and other antisense oligonucleotide drugs are in clinical trials (see section ANTISENSE OLIGONUCLEOTIDE DRUGS IN CLINICAL TRIALS). The same is not true of CRISPR-based gene editing tools, such as those disclosed in Amendola (paragraph [0052]). While Liu has a post-filing publication date, it is applied as an evidentiary reference that is representative of the state of the art at the time of filing. At the time of filing, applying CRISPR editing to patients in vivo was an underdeveloped and unpredictable topic in the art. As reviewed in Liu, there are a number of hurdles to overcome before in vivo CRISPR therapy is commonplace, including editing efficiency, effective delivery of the editing machinery, off target effects, and immunogenicity (see sections “Editing efficiency,” “Delivering methods,” “Off-target effects,” and “Immunogenicity”). Therefore, in the interest of therapeutically targeting utrophin regulatory element sequences known in the field (for example SEQ ID NO: 18 of Amendola) in patients in need thereof, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant invention to design antisense oligonucleotides (such as DNA antisense oligonucleotides, as reviewed in Askari) per the methods of Wang, as motivated by Khurana and the patented application, to predictably arrive at a limited number of antisense oligonucleotide sequences targeting the Let7c binding sequence disclosed in Amendola, said limited number including instant SEQ ID NO: 5. Antisense oligonucleotides produced via these methods would predictably block Let-7c binding and increase utrophin expression, as disclosed in Khurana and the patented application and supported by Amendola. One would have been motivated to practice these methods in order to produce therapeutic antisense oligonucleotides for in vivo use in patients in need thereof, as the CRISPR editing disclosed in Amendola was an underdeveloped and unpredictable topic in the art at the time of filing, with no CRISPR drugs approved for in vivo use in patients.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of U.S. Patent No. 12,104,152 B2 (of record) in view of in view of US 2019/0300879 A1 (hereinafter Khurana; of record; as cited in the IDS filed 05/23/2023) in view of US 2023/0272433 A1 (hereinafter Amendola; effectively filed 09/29/2020; of record), Wang, 2011 (hereinafter Wang), Stenvang and Kauppinen, 2008 (hereinafter Stenvang; of record), Chan et al., 2006 (hereinafter Chan; of record), and Askari and McDonnell, 1996 (hereinafter Askari; of record), as evidenced by Liu et al., 2021 (hereinafter Liu; of record).
Claim 1 of patent ‘152 recites “an oligonucleotide comprising one or more arabinonucleotides, wherein the oligonucleotide specifically hybridizes to a Let-7c microRNA binding sequence in a utrophin mRNA 3’ untranslated region (UTR) and inhibits the binding of the Let-7c microRNA to the utrophin mRNA 3’-UTR,” while claim 6 of patent ‘152 recites “a pharmaceutical composition comprising the oligonucleotide of claim 1 and at least one pharmaceutically acceptable excipient.”
In comparison, instant claim 11 recites “the composition of claim 9, wherein the oligonucleotide has a sequence comprising SEQ ID NO: 5,” as previously set forth, both the patented application and Khurana disclose methods for enhancing utrophin protein production in a cell by inhibiting a utrophin microRNA molecule, said methods comprising administering pharmaceutical compositions that include an antisense oligonucleotide that specifically hybridizes to a microRNA binding sequence in a utrophin mRNA 3’ UTR, thereby inhibiting the binding of the microRNA to the 3’-UTR utrophin mRNA (abstract; paragraph [0011]). Such inhibited microRNAs include Let-7c, as instantly claimed (paragraphs [0011] and [0013]). The pharmaceutical compositions disclosed in Khurana further comprise at least one pharmaceutically acceptable excipient, and the antisense oligonucleotide targeting the Let-7c microRNA binding sequence is provided in an amount effective in a human subject to inhibit the binding of Let-7 microRNA with its utrophin mRNA 3’-UTR binding sequence (paragraph [0013]), thereby increasing utrophin production (abstract), as instantly claimed.
As previously set forth, and similar to Khurana, Amendola discloses methods of enhancing utrophin expression in a cell by inducing mutations within a target sequence comprising a utrophin regulatory element (such as a Let7c binding site, as instantly claimed) using a gene editing enzyme (paragraphs [0001], [0006], and [0033]). The target sequences comprising utrophin repressor binding sites disclosed therein include SEQ ID NOs: 18 and 26 (Table 1; paragraph [0046]). As shown in the alignment of the Appendix, instant SEQ ID NO: 8 comprises both SEQ ID NOs: 18 and 26 of Amendola, both of which comprise the Let-7c binding site (Table 1; paragraphs [0045] and [0046]). Thus, the disclosure of Khurana establishes that blocking Let-7c binding to the 3’-UTR of utrophin via antisense oligonucleotides upregulates utrophin expression (abstract; paragraphs [0010] and [0013]), while Amendola similarly discloses disruption of Let7c binding, as well as the known binding sequence of Let-7c, which is comprised within instant SEQ ID NO: 8. As is known to those of ordinary skill in the art, the approach of regulating activity by blocking miRNA binding sites is well-known as miRNA-masking, wherein antisense oligonucleotides mask the binding site of the target miRNA (reviewed in Stenvang: see page 69, column 2, paragraph 1), such as the Let7c target site disclosed in Amendola.
While neither Khurana nor Amendola disclose the instantly claimed SEQ ID NO: 5, the principles of design for such antisense oligonucleotides blocking miRNA (i.e. Let-7c) binding are well known such that a person of ordinary skill in the art would have arrived at a finite, testable number of antisense oligonucleotides targeting the known Let-7c binding site, thereby arriving at instant SEQ ID NO: 5. These design principles are reviewed in Wang. A person of ordinary skill in the art would have been motivated, prior to the effective filing date of the instant application, to apply the design principles of Wang to the Let-7c binding site disclosed in Amendola for purposes of blocking Let-7c binding, thereby upregulating utrophin expression as per Khurana.
To emphasize this rationale, as shown in the alignment of the Appendix, SEQ ID NO: 5 is capable of binding to the disclosed Let7c target site of Amendola (SEQ ID NOs: 18 and 26; see Table 1). Therefore, given that the target sequence comprising instant SEQ ID NO: 5 (within the UTR corresponding to instant SEQ ID NO: 8) was disclosed in Amendola, design of suitable antisense oligonucleotides per the methods of Wang would predictably generate a limited number of antisense oligonucleotides targeting said sequence, including instant SEQ ID NO: 5. As set forth previously, antisense DNA oligonucleotides such as instant SEQ ID NO: 5 are well-known in the art and function in the same manner as antisense RNA oligonucleotides, as reviewed in Askari (see in particular page 316, column 2, paragraph 2).
Accordingly, it is considered that although the prior art does not teach SEQ ID NO: 5, the prior art provides all of the guidance required to arrive at SEQ ID NO: 5.
As reviewed in Chan, antisense oligonucleotide drugs have been approved for in vivo therapeutic use, and other antisense oligonucleotide drugs are in clinical trials (see section ANTISENSE OLIGONUCLEOTIDE DRUGS IN CLINICAL TRIALS). The same is not true of CRISPR-based gene editing tools, such as those disclosed in Amendola (paragraph [0052]). While Liu has a post-filing publication date, it is applied as an evidentiary reference that is representative of the state of the art at the time of filing. At the time of filing, applying CRISPR editing to patients in vivo was an underdeveloped and unpredictable topic in the art. As reviewed in Liu, there are a number of hurdles to overcome before in vivo CRISPR therapy is commonplace, including editing efficiency, effective delivery of the editing machinery, off target effects, and immunogenicity (see sections “Editing efficiency,” “Delivering methods,” “Off-target effects,” and “Immunogenicity”). Therefore, in the interest of therapeutically targeting utrophin regulatory element sequences known in the field (for example SEQ ID NO: 18 of Amendola) in patients in need thereof, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant invention to design antisense oligonucleotides (such as DNA antisense oligonucleotides, as reviewed in Askari) per the methods of Wang, as motivated by Khurana and the patented application, to predictably arrive at a limited number of antisense oligonucleotide sequences targeting the Let7c binding sequence disclosed in Amendola, said limited number including instant SEQ ID NO: 5. Antisense oligonucleotides produced via these methods would predictably block Let-7c binding and increase utrophin expression, as disclosed in Khurana and the patented application and supported by Amendola. One would have been motivated to practice these methods in order to produce therapeutic antisense oligonucleotides for in vivo use in patients in need thereof, as the CRISPR editing disclosed in Amendola was an underdeveloped and unpredictable topic in the art at the time of filing, with no CRISPR drugs approved for in vivo use in patients.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
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