DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10th, September, 2025 has been entered.
Claim Status
Claims 1-4, 6, 8, 11-13, 15-17, 20-22, 25, 27, 29-30, 32 and 34-35 are pending.
Claims 22, 25, 27, 30, 32 and 34-35 are withdrawn.
Claims 1-4, 6, 8, 11-13, 15-17, 20-21, and 29 are under examination.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims 1-4, 6, 8 and 21 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced by NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 4, 12-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claims 1 and 3 above, and in further view of Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 7 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claims 1 and 3 above, and in further view of Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
The rejection of claim 11 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced by NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claim 1 above, and in further view of Olson et al. (WO-2019/152609-A1; published 8th, August, 2019 with priority to 31st, January, 2018; henceforth “Olson”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 16 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claims 1 and 3 above, in view of Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as applied to claims 4 and 7 above, and in further view of NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 17 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claim 1 above, and in further view of Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) and Warnock et al. (Methods Mol Biol. 2011:737:1-25.; henceforth “Warnock”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 29 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claim 1 above, and in further view of Ahern et al. (The Scientist Magazine (1995); accessed at https://www.the-scientist.com/technology/biochemical-reagents-kits-offer-scientists-good-return-on-investment-58425) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 4, 12-13 and 15 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claims 1 and 3 above, and in further view of Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”) as applied to claims 1 and 3 above, and in further view of Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
New Claim Rejections - 35 USC § 112(b)
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.
Claim 8 is 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 8 recites “the gRNA is encoded by a polynucleotide comprising the sequence of SEQ ID NO: 19 or SEQ ID NO: 20,” which is a descriptive limitation of the gRNA based on the polynucleotide that encodes it. However, claim 1, upon which claim 8 depends, recites one or more vectors encoding a composition, the composition comprising a gRNA. Since claim 8 does not recite a limitation drawn to the vectors, which are the required elements of claim 1, upon which claim 8 depends, it is unclear what is encompassed by the claim.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
New 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6, 8, 12-13, 15 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”), Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”).
Regarding claims 1-2, Li discloses a CRISPR/Cas-based genome editing system comprising multiple vectors (donor vector and Cas9 and sgRNA vector; “TALEN- or CRISPR-Mediated Exon 44 Knockin” pg. 125 col. 1 last para.) encoding a composition, the composition comprising:
(a) a guide RNA (gRNA) (sgRNA) targeting an intron that is in junction with an exon of a mutant dystrophin gene (intron 45 Figure S2);
(b) a Cas protein; and
(c) a donor sequence comprising Exon 44 of a wild-type dystrophin gene (exon 44 “knockin of the missing exon 44” pg. 144 col. 1; Figure s2A, 4; pg. 147 “Correction of the Full-Length Dystrophin Protein with a Donor Template”)(see also Figures 2 and S2).
However, regarding claims 1-2, Li does not disclose the gRNA and the donor sequence are encoded by one vector.
Nevertheless, regarding claims 1-2, Lee teaches vectors for CRISPR gene editing that encode both the donor sequence and the gRNA (“guide RNA and donor DNA were fused together” pg. 2 4th para.).
Therefore, regarding claims 1-2, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the CRISPR/Cas-based genome editing system of Li and combine the know prior art element of the fusing the guide RNA and donor DNA into one vector of Lee to obtain the predictable result of a vector for delivering gRNA and donor sequences. One of ordinary skill would have been motivated to do so as taught by Lee to increase gene editing and simplify the system (“guide RNA and donor DNA were fused together” pg. 2 4th para.). Regarding the reasonable expectation of success, Lee evidences successful gene editing with a vector that encodes both the donor sequence and the gRNA (“three times more editing than cells exposed to the original CRISPR system” pg. 2 4th para.).
Regarding claims 1-2 and 4, although Li teaches preparation of a CRISPR Cas-9 system to restore the full-length DMD gene by knocking in a commonly deleted Exon (“Exon 44”; Summary; pg. 144 col. 1 3rd para; pg. 147 col. 1-2; pg. 149 col. 2 1st para; Figure 2), Li is silent to preparation of a CRISPR Cas-9 system to restore the full-length DMD gene by knocking in a commonly deleted Exon 52.
Nevertheless, regarding claims 1-2 and 4, Echigoya teaches deletions in a Exon 52 are a common deletion in DMD (pg. 4 1st para. 1; Figure 1).
Additionally, regarding claims 1-2 and 4, Hsu teaches preparation of a CRISPR Cas-9 system for targeting Exon 52 issues in DMD (pg. 74-75, pg. 83, pg. 163).
Therefore, regarding claims 1-2 and 4, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the system as suggested by Li in view of Lee, and simply substitute the known element of the Exon 52 sequence of Echigoya for the Exon 44 donor sequence of Li and obtain the predictable result of a system for knocking in Exon 52. One of ordinary skill would have been motivated to do so as taught by Li to genetically correct the dystrophin gene (pg. 144 col. 1) in the case of the common patients with a deletion in Exon 52 of Echigoya. Specifically, Li teaches replacement of Exon 44, which is the third or fourth most common deletion in DMD patients (pg. 147 col. 1 last para), with a CRISPR Cas 9 system, which restores the full length dystrophin mRNA to the same length as that of a healthy control (pg. 149), and therefore provides a reasonable expectation of success in preparing a CRISPR/Cas-based genome editing system for a specific Exon replacement in DMD. Preparation of a system for knocking in exon 52 would further require redesign of the guide RNAs to target the correct insertion location of exon 52 to similarly insert the missing Exon, and Hsu evidences a reasonable expectation of success in targeting Exon 52 with CRISPR Cas9 system components (pg. 72, 74, 83, 163).
Regarding claims 1-2, as stated above, Echigoya and Hsu make obvious and provide a reasonable expectation of success for preparing a CRISPR Cas-9 system for knocking in Exon 52. As stated above, preparation of such a system would further require redesign of the guide RNAs to target the correct insertion location of exon 52 to similarly insert the missing Exon.
Regarding claims 1-2 and 4, although LI teaches targeting an intron that is in junction with an exon of the mutant dystrophin gene, Li, Lee Echigoya are silent to the gRNA targeting intron 51 which is in junction with exon 52 of the mutant dystrophin gene (instant claim 4).
Nevertheless, regarding claims 1-2 and 4, Li teaches insertion of a missing exon using a gRNA that targets an intron that is in junction with the adjacent exon of the mutant dystrophin gene, and is adjacent to the location of the missing exon (intron 45 which is adjacent to Exon 45; pg. 144 col. 1 2nd para, col. 2 last para; pg. 145 col. 1 2nd para; pg. 147 col. 2 1st para; pg. 149 col. 2 2nd para.; pg. 152 col. 1 last para; Figures 4, 6; pg. S14 3rd para).
Additionally, regarding claims 1-2 and 4, as stated above, Echigoya teaches and makes obvious the donor sequence of Exon 52.
Therefore, regarding claims 1-2 and 4, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the system as suggested by Li in view of Lee, Echigoya and Hsu, and combine the known prior art element of a gRNA targeting an intron that is in junction with the adjacent exon of the mutant dystrophin gene of Li to obtain the predictable result of a CRISPR System for restoring the DMD transcript. One of ordinary skill would have been motivated to do so as taught by Li to genetically correct the dystrophin gene (pg. 144 col. 1). The intron that is in junction with the adjacent exon of the mutant dystrophin gene for the suggested replacement Exon 52 would be the location of Intron 51. Regarding the reasonable expectation of success, Li evidences preparing a system for insertion of a missing exon using a gRNA that targets an intron that is in junction with the adjacent exon of the mutant dystrophin gene, and is adjacent to the location of the missing exon (intron 45 which is adjacent to Exon 45; pg. 144 col. 1 2nd para, col. 2 last para; pg. 145 col. 1 2nd para; pg. 147 col. 2 1st para; pg. 149 col. 2 2nd para.; pg. 152 col. 1 last para; Figures 4, 6; pg. S14 3rd para).
However, regarding claims 1-2, 12-13 and 15, although Li teaches the donor sequence of Li is flanked by spacer sequences (“nuclease-targeting site” Figure 4), Li, Lee, and Echigoya are silent to whether the two spacer sequences independently comprise the sequence of SEQ ID NO: 25.
Nevertheless, regarding claims 1-2, 12-13 and 15, Hsu teaches the spacer sequence of SEQ ID NO: 25 (Seq ID No: 60235 of Hsu is a 100% match to instant SEQ ID NO: 25) as part of a CRISPR-Cas system for targeting Intron 51 for treating DMD, and Hsu teaches preparation of CRISPR-Cas systems for knocking-in donor templates for treating DMD (pg. 159 Section 8.3).
Therefore, regarding claims 1-2, 12-13 and 15, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the CRISPR/Cas-based genome editing system as suggested by Li in view of Lee, Echigoya and Hsu and simply substitute the known prior art element of the sequence (Seq ID No: 60235 of Hsu is a 100% match to instant SEQ ID NO: 25) that targets intron 51 of Hsu for the spacer sequences of Li to obtain the predictable result of a donor sequence for targeting intron 51. One of ordinary skill would have been motivated to do so as taught by Hsu to target Intron 51, as targeting this intron is made obvious by Echigoya and Hsu above, and to treat DMD, as taught by Li and Hsu. One of ordinary skill would also have been motivated to choose the spacer sequence of Hsu from the finite number of predictable identified sequences presented by Hsu for targeting intron 51. Regarding the reasonable expectation of success, Li evidences donor sequences with spacer sequences that target an intron (Figure 4) and Hsu evidences vectors comprising spacer sequences that target introns in the DMD gene (pg. 96-97 “targeting domain”; pg. 181-186 “Examples of gRNAs in Genome Editing Methods; Example 3).
Regarding claims 1-2, it is noted that instant SEQ ID NO:25 is the reverse-complement of instant SEQ ID NO: 17 and therefore SEQ ID NO: 25 “targets and binds the polynucleotide sequence of SEQ ID NO: 17” (instant claims 1-2) as claimed. Therefore, the sequence of Seq ID No: 60235 taught by and made obvious by Hsu above, which comprises a 100% match to instant SEQ ID NO: 25 also “targets and binds the polynucleotide sequence of SEQ ID NO: 17” and meets instant claim limitations.
Regarding claim 3, further to the discussion of claim 1 above, Li teaches the donor sequence comprises spacer sequences (“nuclease-targeting site” Figure 4). Because the donor sequence is able to be knocked-in, these spacer sequences flank the donor sequences.
Regarding claim 6, further to the discussion of claims 1 and 4 above, Li teaches the exon of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene (“deletion of dystrophin exon 44” pg. 144) and similarity the exon 52 suggested and made obvious by Echigoya and Hsu above has a deletion in Exon 52 (pg. 4 1st para. 1; Figure 1).
Regarding claim 8, further to the discussion of claim 1 above, the gRNA of sequence of Seq ID No: 60235 taught by and made obvious by Hsu above, which comprises a 100% match to instant SEQ ID NO: 25 is capable of being encoded by a polynucleotide comprising the sequence of SEQ ID NO: 19 and therefore meets instant claims.
Regarding claim 13, further to the discussion of claims 1, 3, and 12 above, Because the donor sequence is double stranded, it comprises the same spacer sequence on the opposite strand and therefore meets the limitation of the two gRNA spacers are identical.
Regarding claim 21, further to the discussion of claim 1 above, Li teaches the molar ratio between gRNA and donor sequences is 1:1 (5 mg of donor vector: 5 mg for sgRNA ; “TALEN- or CRISPR-Mediated Exon 44 Knockin” pg. 152 col. 1).
Hence, the claimed invention as a whole was prima facie obvious.
Examiner’s Remark
Applicant’s amendments necessitated the new grounds of rejection above. Nevertheless, for the sake of compact prosecution, arguments considered pertinent to the new grounds of rejection are addressed below.
Applicant’s arguments, filed 10th, September, 2025, have been fully considered but are not found persuasive.
Response to Arguments
Applicant argues “Li does not disclose, teach, or suggest the claimed gRNAs. NCBI DMD and Lee do not cure this deficiency” (pg. 7)
In response, the gRNA’s are suggested and made obvious by Hsu above in the new grounds of rejection for the reasons stated above.
Applicant argues “Li does not disclose, teach, or suggest the claimed gRNAs. NCBI_DMD, Lee, Echigoya, and Hsu do not cure this deficiency. There is no teaching or suggestion in the combination of references to pursue a system as claimed, or that it would be successful in restoring dystrophin function. Applicant submits that the claims are patentable over the cited references” (pg. 7-8).
In response, the gRNA’s are suggested and made obvious by Hsu above in the new grounds of rejection for the reasons stated above.
Further in response, regarding the reasonable expectation of success (i.e. Applicant’s argument that it would not “be successful in restoring dystrophin function”). Instant claims are drawn to a product, not a method. Applicant is directed to MPEP 2143.02 which states that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, while the prior art suggests the reason for modification, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result, is not necessarily required. In the instant case, the combination of the prior art of record provides a reasonable expectation of success in combining or modifying prior art disclosures to meet the limitations of the claimed invention because the prior art provides a reasonable expectation of success in preparing the product as claimed. The effect of “be successful in restoring dystrophin function” is a motivation to combine, but is not a required structural element of claimed limitations. Li evidences preparation of a CRISPR-Cas system comprising multiple vectors encoding a composition, the composition comprising: (a) a guide RNA (gRNA) (sgRNA) targeting an intron that is in junction with an exon of a mutant dystrophin gene (intron 45 Figure S2); (b) a Cas protein; and (c) a donor sequence comprising Exon 44 of a wild-type dystrophin gene (exon 44 “knockin of the missing exon 44” pg. 144 col. 1; Figure s2A, 4; pg. 147 “Correction of the Full-Length Dystrophin Protein with a Donor Template”)(see also Figures 2 and S2). The prior art of Lee provides a reasonable expectation of success for a gRNA and a donor sequence encoded by one vector (“guide RNA and donor DNA were fused together” pg. 2 4th para.). The prior art of Hsu provides a reasonable expectation of success for targeting intron 51 and Exon 52. Therefore, in view of all of the art of record, one of ordinary skill would have had a reasonable expectation of success in preparing the structural requirements of the claimed system, which are the required elements of the claims.
It is noted that Applicant repeatedly refers to claim 8 as “non-rejected claim 8” (pg. 8).
In response, claim 8 was rejected in the previous office action, and claim 8 is rejected above in the present office action with a new grounds of rejection in view of Applicant’s amendments. Claim 8 is not “non-rejected.”
New Claim Rejections - 35 USC § 103
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”), Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as applied to claim 1 above, and in further view of Olson et al. (WO-2019/152609-A1; published 8th, August, 2019 with priority to 31st, January, 2018; henceforth “Olson”). The teachings of Li, Lee, Echigoya and Hsu above are hereby incorporated in their entirety.
Regarding claim 11, further to the discussion of claim 1 above, although Li teaches as Streptococcus Cas9 cDNA sequence (“Supplemental Experimental Procedures”) that encodes a Cas9 protein, Li, Lee, Echigoya and Hsu are silent to the Streptococcus aureus sequence that encodes the Cas9 protein comprising the sequence of SEQ ID NO: 2.
Nevertheless, regarding claim 11, Olson teaches a CRISPR/Cas-based genome editing system for treating DMD comprising a vector that encodes a Cas protein that comprises the sequence of SEQ ID NO:2 (SEQ ID NO: 873 of Olson is a 100% match to instant SEQ ID NO:2; see also pg. 26 3rd para, pg. 42 last para and claim 17) which provides advantages over wildtype or full length Cas9 (pg. 21 3rd para.).
Therefore, regarding claim 11, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the CRISPR/Cas-based genome editing system as suggested by Li in view of Lee, Echigoya and Hsu and simply substitute the known prior art element of the Streptococcus aureus sequence that encodes the Cas9 protein comprising the sequence of SEQ ID NO: 2 of Olson for the Streptococcus pyogenes sequence of Li to obtain the predictable result of a vector for encoding a Cas9 nuclease. One of ordinary skill would have been motivated to do so because Olson teaches S. Pyogenes and S. Aureus Cas 9 as known suitable Cas9 alternatives (pg. 26 2nd para.; pg. 42 last para. ). One of ordinary skill would also have been motivated to do so as taught by Olson because the small version of a Cas9 from the bacterium Staphylococcus aureus provides advantages over wildtype or full length Cas9 (pg. 21 3rd para.). Regarding the reasonable expectation of success, Li evidences vectors as part of a CRISPR/Cas-based genome editing system with sequences encoding Staphylococcus Cas9 (Figure 4).
Hence, the claimed invention as a whole was prima facie obvious.
New Claim Rejections - 35 USC § 103
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”), Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as applied to claim 1 above, and in further view of NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/). The teachings of Li, Lee, Echigoya and Hsu above are hereby incorporated in their entirety.
Regarding claim 16, further to the discussion of claim 1 above, as stated above, Li, Echigoya and Hsu make obvious preparation of a CRISPR system for insertion of Exon 52 to correct the mutant DMD gene in a patient lacking Exon 52.
However, regarding claim 16, Li, Lee, Echigoya and Hsu are silent to a donor sequence comprising Exon 52 that comprises SEQ ID NO: 21.
Nevertheless, regarding claim 16, SEQ ID NO:21 is a 100% match to the wildtype human Exon 52 sequence, as evidenced by NCBI_DMD.
Therefore, regarding claim 16, it would have been obvious to a person of ordinary skill in the at before the effective filing date of the claimed invention to prepare the system as suggested by Li in view of Lee, Echigoya and Hsu, and combine the known prior art element of the wildtype human Exon 52 sequence of NCBI_DMD to obtain the predictable result of a CRISPR system comprising a wildtype donor sequence for correction of the DMD gene. One of ordinary skill would have been motivated to do so as taught by Li to genetically correct the dystrophin gene (pg. 144 col. 1) in the case of Exon 52 deletion of patient of Echigoya. Regarding the reasonable expectation of success, Li evidences preparing a donor construct comprising a wildtype DMD exon sequence (pg. 144 col. 1 2nd para, col. 2 last para; pg. 145 col. 1 2nd para; pg. 147 col. 2 1st para; pg. 149 col. 2 2nd para.; pg. 152 col. 1 last para; Figures 4, 6; pg. S14 3rd para).
Hence, the claimed invention as a whole was prima facie obvious.
New Claim Rejections - 35 USC § 103
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”), Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as applied to claim 1 above, and in further view of Warnock et al. (Methods Mol Biol. 2011:737:1-25.; henceforth “Warnock”). The teachings of Li, Lee, Echigoya and Hsu above are hereby incorporated in their entirety.
Regarding claim 17, further to the discussion of claim 1 above, Li, Lee and Echigoya are silent to viral vectors.
Nevertheless, regarding claim 17, Hsu teaches a CRISPR/Cas-based genome editing system comprising multiple AAV vectors encoding a composition, the composition comprising
(a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene (pg. 4-14, 16-37, 39, 41-47, 51-59, 64-71, 88, 91, 94-96, 99-100, 102-113, 119-120, 123, 126, 135-136, 138, 142, 147-156, 158-159, 161-168, 170, 181-197, 202, 207-210, 219-240; claims 1, 5-7, 11, 18, 23-28, 32, 35, 39-42, 47, 53; Tables 10-16)
(b) a Cas protein (pg. 4-7, 9, 17, 19, 23, 25, 29-37, 39-41, 60, 65, 71, 74-77, 91, 94-96, 100, 103, 105, 106, 108, 109, 119-122, 123, 125-136, 138-162, 164-170, 175-176, 181, 182, 184, 186-198, 202-203, 207, 208-209, 222-223, 225-228, 235; claims 1, 4-7, 11, 13-15, 19-22, 24-28, 35, 39, 44, 47, 53).
Therefore, regarding claim 17, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the system of Li in view of Lee, Echigoya and Hsu, and simply substitute the known element of the AAV vectors system of Hsu for the non-viral vectors of Li to obtain the predictable result of a vector system for expressing CRISPR Cas components. One of ordinary skill would have been motivated to do so as taught by Warnock because viral vectors are the most effective means of gene transfer to modify a specific cell type or tissue and can be manipulated to express therapeutic genes (abstract). Regarding the reasonable expectation of success, Hsu evidences preparation of viral vectors encoding a composition comprising a guide RNA and a Cas protein (Table 4; Example 6).
Hence, the claimed invention as a whole was prima facie obvious.
New Claim Rejections - 35 USC § 103
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Stem Cell Reports. 2015 Jan 13;4(1):143-154. Epub 2014 Nov 26.; henceforth “Li”) as evidenced NCBI_DMD (accessed at: https://www.ncbi.nlm.nih.gov/nuccore/NG_012232.1/) in view of Lee et al. (Elife. 2017 May 2:6:e25312.; henceforth “Lee”), Echigoya et al. (J Pers Med. 2018 Dec 7;8(4):41.; henceforth “Echigoya”) and Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) as applied to claim 1 above, and in further view of Ahern et al. (The Scientist Magazine (1995); accessed at https://www.the-scientist.com/technology/biochemical-reagents-kits-offer-scientists-good-return-on-investment-58425). The teachings of Li, Lee, Echigoya and Hsu above are hereby incorporated in their entirety.
Regarding claim 29, further to the discussion of claim 1 above, Li, Lee and Echigoya are silent to a kit comprising the system.
Nevertheless, regarding claim 29 Ahern teaches preparation of Kits to allow the product to be readily used in research by other scientists to accelerate the research process and allow them to spend more time on their primary research focus, rather than preparing reagents, as taught by Ahern (pg. 3-5).
Additionally, regarding claim 29, Hsu teaches kits comprising CRISPR-Cas components (pg. 31 2nd -3rd para.).
Therefore, regarding claim 29, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the system of Li in view of Lee and combine the known prior art element of making the contents into a kit of Ahern to obtain the predictable result of creation of a kit. One of ordinary skill would have been motivated to do so as taught by Ahern because making the system into a kit would allow the product to be readily used in research by other scientists to accelerate the research process and allow them to spend more time on their primary research focus, rather than preparing reagents, as taught by Ahern (pg. 3-5). Regarding the reasonable expectation of success, Hsu evidences kits comprising CRISPR Cas components (pg. 31 2nd -3rd para.).
Hence, the claimed invention as a whole was prima facie obvious.
Withdrawn Double Patenting
Withdrawn Non-Statutory Double Patenting
U.S. Co-pending Application No. 17/921,316
The provisional rejection of claim 7 on the ground of nonstatutory double patenting as being unpatentable over claims of 1-2, 9, 13, 17, 23, 25, 27-28 and 38 of copending application No. 17/921,316 (claims filed 10th, July, 2023) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
The provisional rejection of claims 12-13 and 15 on the ground of nonstatutory double patenting as being unpatentable over claims of 1-2, 9, 13, 17, 23, 25, 27-28 and 38 of copending application No. 17/921,316 (claims filed 10th, July, 2023) as applied to claims 1 and 3 above, and in further view of Hsu et al. (WO-2016/161380-A1; see IDS filed 6th, May, 2022; henceforth “Hsu”) are withdrawn in view of Applicant’s amendments and in view of the new grounds of rejection below.
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.
Non-Statutory Double Patenting
U.S. Co-pending Application No. 17921316
Claims 1-4, 6, 8, 11-13, 15-17, 21, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of 1-2, 9, 13, 23, 25, 27-28 and 38 of copending application No. 17/921,316 (claims filed 10th, July, 2023).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the CRISPR/Cas-based genome editing system anticipates or makes obvious the CRISPR/Cas-based genome editing system of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claims 1-2, U.S. Co-pending App ‘316 claims a CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition, the composition comprising:
(a) a guide RNA (gRNA) targeting an intron (intron 51) that is in junction with an exon of a mutant dystrophin gene;
(b) a Cas protein or a fusion protein comprises comprising the Cas protein; and
(c) a donor sequence comprising exon 52 of the wild-type dystrophin gene (claim 1).
Regarding claims 1-2, Co-pending claims 1-2 of U.S. Co-pending App ‘316 specifies hybridizing to a target sequence within intron 51, which is an anticipatory species of the instantly claimed “intron that is in junction with an exon,” and thereby make it obvious.
Regarding claim 1, one of ordinary skill would have at once envisaged the gRNA and the donor sequence are encoded by one vector from the limited genus of vector configurations claimed by U.S. Co-pending App ‘316.
Regarding claims 1-2, 12 and 15, further to the discussion of claims 1 and 3 above, as stated above, U.S. Co-pending App ‘316 claims a target of intron 51.
Regarding claims 1-2, 12-13 and 15, U.S. Co-pending App ‘316 claims one or vectors comprising SEQ ID NO: 57 of U.S. Co-pending App ‘316. The claimed SEQ ID NO: 57 of U.S. Co-pending App ‘316 comprises a sequence 100% identical to instant SEQ ID NO: 17 as well as sequence 100% identical to instant SEQ ID NO: 19 which encodes a gRNA 100% identical to instant SEQ ID NO: 25. The gRNA 100% identical to instant SEQ ID NO: 25 “targets and binds the polynucleotide sequence of SEQ ID NO: 17” (instant claims 1-2) as claimed.
Regarding claim 3, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims the fragment of the functional dystrophin gene (exon 52 of the wild-type dystrophin gene) is flanked by two gRNA spacers and/or PAM sequences (claim 9).
Regarding claim 3, U.S. Co-pending App ‘316 claims the donor sequence is flanked on both sides by a gRNA spacer and/or a PAM sequence (claim 9), the fragment being flanked on both sides is an anticipatory species of “flanked by two gRNA spacers and/or PAM sequences,” and thereby makes it obvious.
Regarding claim 4, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims the gRNA targets an intron that is in junction with an exon of the mutant dystrophin gene (intron 51 or intron 44; claim 1).
Regarding claim 4, U.S. Co-pending App ‘316 claims the gRNA hybridizes to a target sequence within intron 51 or intron 44, which are anticipatory species of the instantly claimed “an intron that is in junction with an exon of the mutant dystrophin gene,” and thereby make it obvious.
Regarding claim 6, further to the discussion of claims 1 and 4 above, U.S. Co-pending App ‘316 claims the exon (Exon 52) of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene (claim 13).
Regarding claim 6, U.S. Co-pending App ‘316 claims “exon 52 of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene” which is an anticipatory species of the instantly claimed “the exon of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene,” and thereby makes it obvious.
Regarding claim 7, further to the discussion of claims 1 and 4 above, U.S. Co-pending App ‘316 claims the exon is exon 52 (Exon 52; claim 1).
Regarding claim 8, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims a vector which includes a sequence that encodes the gRNA that comprises the sequence of SEQ ID NO: 19 (claimed SEQ ID NO: 57 of claim 27) vector comprises instant SEQ ID NO: 19.
Regarding claim 11, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims the Cas protein comprises an amino acid sequence of SEQ ID NO: 2 (SEQ ID NO: 19 of U.S. Co-pending App ‘316 is a 100% match to instant SEQ ID NO: 2) (claim 23).
Regarding claim 13, further to the discussion of claims 1 and 12 above, although U.S. Co-pending App ‘316 does not claim a literal recitation of two gRNA spacers are identical, the vectors claimed by U.S. Co-pending App ‘316 are double stranded, and therefore comprise two of the identical gRNA spacers that flank the donor sequence, one on each strand.
Regarding claim 16, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims the donor sequence comprises the polynucleotide of SEQ ID NO: 21 (claimed SEQ ID NO: 58 vector of U.S. Co-pending App ‘316 comprises the donor sequence of SEQ ID NO: 21) (claim 27).
Regarding claim 16, claimed SEQ ID NO: 58 vector of U.S. Co-pending App ‘316 is an anticipatory species of the instantly claimed “the donor sequence comprises the polynucleotide of SEQ ID NO: 21” and thereby makes it obvious.
Regarding claim 17, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims the vector is a viral vector (claim 25).
Regarding claim 17, U.S. Co-pending App ‘316 claims the vector is an “AAV vector” (claim 25), which is an anticipatory species of the instantly claimed “viral vector,” and thereby makes it obvious.
Regarding claim 21, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims the molar ratio between gRNA and donor sequence is 1: 1, or from 5: 1 to 1: 10, or from 1: 1 to 1 :5 (claim 28).
Regarding claim 29, further to the discussion of claim 1 above, U.S. Co-pending App ‘316 claims a kit comprising the system of claim 1 (claim 38).
Since the instant application claims are anticipated by or obvious over cited application claims, said claims are not patentably distinct.
Claim Objections
Claim 20 is objected to because it is dependent on rejected claim 1.
Examiner’s Remark
As previously indicated, SEQ ID NO: 23-24 are free of the prior art. However, as stated above, claim 20, which includes the limitation of the polynucleotide sequence of SEQ ID NO: 23 or 24, is not allowable because it is dependent on a rejected claim and is therefore objected to.
Sequences comprising SEQ ID NO:19 are free of the prior art.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632