Notice of Pre-AIA or AIA Status
The examiner prosecuting the application has changed.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Applicant’s response and claim amendments filed on 10/29/2025 are received and entered.
In response to the most recent action, claims 3 and 20 are cancelled without prejudice. Claims 1, 4, 6, 8, 15-16, 18, 22-25, 27, 31, and 33-37 are currently pending. Claims 24-25, 27, 31, and 33-36 are withdrawn as being drawn to a non-elected invention. Claim 1 is amended herein.
Claims 1, 4, 6, 8, 15-16, 18, 22-23, and 37 are currently under examination of the merits.
Any rejections/objections NOT repeated/presented here are withdrawn.
New Rejections
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 6, 8, 15-16, 18, 22-23, and 37 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Police et. al. (US 20210363521 A1; Published: 11/25/2021; EFD: 11/9/2017).
Regarding claim 1, Police discloses CRISPR/Cas systems and compositions which target the dystrophin gene comprising (a) a first nucleic acid encoding (i) a first guide RNA (gRNA) comprising a DNA targeting sequence that is complementary to a target sequence comprising a human DMD gene and (ii) a second gRNA comprising a DNA targeting sequence that is complementary to a target sequence comprising a human DMD gene (abstract; [0013). Police teaches , in some examples, Cas9 mRNA is formulated in a lipid nanoparticle (see paragraph 0436) and where options are available to deliver the Cas9 nuclease as a DNA plasmid, as mRNA, or as a protein (see paragraph 0437). Police further discloses that the nucleic acid encoding a DNA-targeting nucleic acid of the disclosure and/or a site-directed polypeptide can be packaged into or on the surface of delivery vehicles for delivery to cells [0415]. Police discloses that delivery vehicles contemplated include, but are not limited to, nanospheres, liposomes, quantum dots, nanoparticles, polyethylene glycol particles, hydrogels, micelles, viral vectors, lipid nanoparticles (LNPs), or synthetic polymers ([0417]; and [0799]).
Police discloses that the site-directed polypeptide can be administered to a cell or a patient as either: one or more polypeptides, or one or more mRNAs encoding the polypeptide [0258].
Police discloses that the disclosed site-directed polypeptide can be flanked at the N-terminus, the C-terminus, or both the N-terminus and C-terminus by one or more nuclear localization signals (NLSs) (see paragraph 0386).
Police also teaches where chemically modified mRNA delivered in vivo can be used to achieve improved therapeutic effects. Using chemical modifications, it was found just substituting just one quarter of the uridine and cystine residues resulted in a significant decrease in toll-like receptor mediated recognition of mRNA in mice. By reducing the activation of the innate immune system, these modifications can be used effectively to increase the stability and longevity of the mRNA in vivo (see paragraph 0377).
Furthermore, Police teaches where the expression vector can also comprise appropriate sequence for amplifying expression. The expression vector can also include nucleotide sequences encoding non-native tags (e.g. hemagglutinin tag (HA tag)) (see paragraph 0401).
Regarding claim 6, Police discloses that in some cases, the disclosed Cas9 mRNA, and sgRNA targeting one or two loci in target genes, and donor DNA are each separately formulated into lipid nanoparticles, or are all co-formulated into one lipid nanoparticle [0435].
Regarding claim 8, Police discloses that the disclosed polynucleotides can be delivered by non-viral delivery vehicles including, but not limited to, nanoparticles, liposomes, ribonucleoproteins, positively charged peptides, small molecule RNA-conjugates, aptamer-RNA chimeras, and RNA-fusion protein complexes [0419]. Police further discloses that some exemplary non-viral delivery vehicles are described in Peer and Lieberman, Gene Therapy, 18: 1127-1133 (2011), for example, polymer lipid hybrid nanoparticles such as stable nucleic acid–lipid particles (SNALPs) are B100 nm nontargeted liposomes with low cationic lipid content that incorporate the cargo and are coated with a diffusible polyethylene glycol–lipid (PEG–lipid) conjugate [0419].
Regarding claim 15, Police discloses that gRNA pairs that target exon 51 for deletion by cutting the gene twice, one gRNA cutting at the 5′ end of exon 51 and the other gRNA cutting at the 3′ end of exon 51 for correction of the mutant dystrophin gene ([0024]; [0551]).
Regarding claim 16, Police discloses gRNAs to make double-strand cuts that facilitate insertion of a new sequence from a polynucleotide donor template to replace a sequence in exon 51 [0553].
Regarding claim 18, Police discloses that the expression of more than one of the disclosed gRNAs allows for the introduction of double-stranded breaks in the target gene, and further disclose gRNA pairs that delete exon 51 by cutting the gene twice, one gRNA cutting at the 5′ end of exon 51 and the other gRNA cutting at the 3′ end of exon 51 ([0458]; [0551]).
Regarding claim 22, Police discloses that in some of the above applications, the disclosed methods can be employed to induce DNA cleavage, DNA modification, and/or transcriptional modulation in mitotic or post-mitotic cells in vivo and/or ex vivo and/or in vitro, and that because the disclosed guide RNAs provide specificity by hybridizing to target DNA, a mitotic and/or post-mitotic cell of interest in the disclosed methods can include a cell from any organism including cells within skeletal or cardiac muscle tissue ([0025]; [0445).
Regarding claim 23, Police teaches that the disclosed CRISPR/Cas systems can be formulated into pharmaceutical compositions by combination with appropriate pharmaceutically acceptable carriers or diluents ([0500]; [0026]).
Regarding claim 37, Police teaches that their disclosure provides kits for carrying out the described methods [0510]. Police discloses that a kit can include one or more of a DNA-targeting nucleic acid, a polynucleotide encoding a DNA-targeting nucleic acid, a site-directed polypeptide, a polynucleotide encoding a site-directed polypeptide, and/or any nucleic acid or proteinaceous molecule necessary to carry out the aspects of the methods disclosed, or any combination thereof [0510].
In view of the foregoing, claims 1, 6, 8, 15-16, 18, 22-23, and 37 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Police.
Response to Arguments
Applicant’s arguments filed on 10/29/2025 have been fully considered but they are not persuasive. Applicant argues that after amendments, Police does not disclose, and certainly does not enable, an mRNA with all these features combined. First, the current rejection is not a matter of enablement, but, of prior art. Contrary to applicants’ arguments Police, teaches a composition comprising a lipid nanoparticle and a DNA targeting system can be delivered to a muscle cell, wherein the DNA targeting system comprises at least one gRNA molecule targeting a fragment of a mutant dystrophin gene. Furthermore, Police teaches where options to deliver the Cas9 nuclease includes delivering as a mRNA (see paragraph 0436 and 0437). If one were to argue a matter of enablement, then the invention of the instant application would also fall under such consideration.
Second, applicant amends the claim to recite wherein the “polynucleotide encoding the Cas9 nuclease is mRNA” and argues that Police does not disclose an mRNA with all these features combined. Regarding claim 1, Police teaches a CRISPR/Cas9 system for targeting a human DMD gene, wherein the Cas9 nuclease can be delivered as mRNA (see paragraph 0436 and 0437). Furthermore, Police teaches the site direct (Cas9) polypeptide can be administered to the cell or patient in the form of mRNA (see paragraph 0258) and where the disclosed site-directed polypeptide can be flanked at the N-terminus, the C-terminus, or both the N-terminus and C-terminus by one or more nuclear localization signals (NLSs). Police teaches the limitations of the newly amended claim 1, wherein the mRNA is modified with a uridine substitution (see paragraph 0377) and where the expression vector can also include nucleotide sequences encoding HA tags (see paragraph 0401). As all the limitations of the composition are fully taught by Police, regardless of the structure the composition is recited in, Police fully anticipates the claims listed above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Police et. al. (US 20210363521 A1; Published: 11/25/2021; EFD: 11/9/2017) as applied to claim 1 above, and further in view of Olson et. al. (US 20200370042 A1; Published: 11/26/2020; EFD: 1/31/2018).
Regarding claim 4, The teachings of Police as applied to claim 1 are discussed above.
Regarding claim 4, Police teaches in claim 1 where the CRISPR/Cas9 system comprises of a first gRNA targeting sequence and a second gRNA targeting (see paragraph 0014), indicating the use of two gRNA molecules. Furthermore, Police experimentally teaches dual or pairwise combinations of SaCas9 gRNAs to delete exon 51 in human DMD gene in in vitro cultured myoblasts (see paragraph 0846).
Police does not teach wherein the first gRNA molecule is encoded by a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 110, and the second gRNA molecule is encoded by a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 111.
However, Olson teaches nucleotide sequences that have 100% similarity to SEQ ID NO: 110 and SEQ ID NO: 111 (see alignment below). Olson further teaches methods for treating or preventing Duchene Muscular Dystrophy (DMD) in a subject in need thereof, the method comprising administering to the subject the disclosed Cas9 nuclease or a sequence encoding a Cas9 nuclease, and the disclosed gRNAs or a sequence encoding the gRNAs, wherein the gRNAs target a splice donor or splice acceptor site of the mutant dystrophin gene ([0008]; [0037]).
Furthermore, Olson teaches that in some embodiments, at least a first sequence encoding a gRNA and a second sequence encoding a gRNA may be packaged into an AAV vector (see paragraph 0110) and wherein the invention also includes a method for inducing select skipping and/or reframing of a DMD exon, the method comprising of contacting a cell with one or more compositions of the disclosure wherein the guide RNA and the second guide RNA form a complex with the Cas9 protein to disrupt a dystrophin splice site and induces selective skipping (see paragraph 0140). Here, the two gRNAs target different sites such as the start and end of an exon, indicating different targeting domains, in order to skip said exon.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Police’s CRISPR/Cas systems and compositions which target the dystrophin gene with Olson’s sequences encoding gRNAs that target the dystrophin gene by swapping out the SEQ ID NOs of the first and second gRNA with SEQ ID NO: 110 and 111 of Olson. The skilled artisan would have been motivated to use Olson’s gRNAs because Olson teaches that such gRNAs can be used for treating or preventing Duchene Muscular Dystrophy (DMD) in a subject in need thereof (see paragraph 0008) and that multiple gRNAs can be used in tandem to splice out a DMD exon in an attempt to modify dystrophin gene expression to treat DMD (see paragraph 0140).
In view of the foregoing, claim 4 is rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Response to Arguments
Applicant’s arguments filed on 10/29/2025 have been fully considered but they are not persuasive. Applicant argues that the amendments made to the claim render the primary art of Police null. However, as indicated in the new rejection necessitated by amendments, Police teaches all the limitations of claim 1, including the combined modifications of a NLS at the N or C terminal, a HA tag, and a uridine substitution. Therefore, Police anticipates the structural limitations of the claims.
Regarding claim 4, Applicant argues the combination of Police and Olson does not teach or suggest the pairs of gRNAs recited in claim 4. Examiner disagrees as both Police and Olson teaches the use of gRNA pairs, wherein the gRNA molecules comprise of different targeting domains. With regards to Police, Police recites in claim 1 wherein the CRISPR system comprises of a first and a second gRNA with distinct SEQ ID NOs. Given that they are distinct SEQ ID NOs, it is clear that the first and second gRNAs would have different targeting domains as they target different sequences. This is further experimentally taught in Police where seven different pairwise combinations of SaCas9 gRNAs to delete exon 51 in human DMD gene in in vitro cultured myoblasts (see paragraph 0846), indicating that different pairs of gRNAs target different portions of exon 51 in order to delete the exon.
Regarding claim 4, Olson teaches where two different guide RNAs can be used to form a complex with the Cas9 protein to disrupt a dystrophin splice site and induces selective skipping (see paragraph 0140). It is known to one with ordinary skill in the art that exon skipping involves one sequence targeting the start of an exon and a second targeting the end of the exon, in order to skip or splice out the exon, therefore indicating the two guide RNAs have different targeting domains. Therefore, both Police and Olson clearly describe the use of pairs of gRNAs that comprise of different targeting domains and one would be motivated to swap the SEQ ID NOs of Police with that of Olson as Olson teaches that such gRNAs can be used for treating or preventing Duchene Muscular Dystrophy (DMD) in a subject in need thereof (see paragraph 0008) and that multiple gRNAs can be used in tandem to splice out a DMD exon in an attempt to modify dystrophin gene expression to treat DMD (see paragraph 0140).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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