DETAILED ACTION
The examiner prosecuting this application has changed.
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 .
Priority
This application is a 371 of PCT/US2021/029378 04/27/2021 which claims benefit of 63/118,299 11/25/2020 and claims benefit of 63/016,712 04/28/2020.
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on January 27, 2026.
Currently, claims 15-18, 22, 24-25, 28, and 30-37 are pending in the instant application. Claims 1-14, 19-21, 23, 26-27, and 29 are now cancelled by applicant in amended claim set submitted 01/27/2026 in response to the non-final office action with notification date 08/11/2025. Claim 30-37 are newly added claims included in amended claim set submitted 01/27/2026. Applicant’s statement that: “claim 30 is supported, e.g., by prior claim 13, page 35, lines 21- 21; page 36, lines 1-23. Claim 31 is supported, e.g., page 46, lines 25-26. Claims 32 and 33 are supported, e.g. on page 46, lines 26 – 31; claim 34 is supported, e.g., page 1, lines 20-30. Claim 36 and 37 are supported, e.g., page 50, lines 1-17; the language in claim 15 and 28 is supported, e.g., by original claim 1, original claim 3, original claims 20 and 21, page 20, lines 24-15, page 35, lines 10-15; page 46, lines 27 – 31; Claim 24 is amended to refer to the rAAV of claim 15;” and that “no new matter is added by this amendment,” is acknowledged. The examiner finds support for all limitation in all currently pending claims within the provisional application, 63/016,712, filed on 04/28/2020.
Accordingly, claims 15-18, 22, 24-25, 28, and 30-37 are under examination on the merits in the instant application with an effective filing date of 04/28/2020.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Withdrawn Objections and Rejections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
New Objections/Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
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.
Claims 32-33 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. Independent claim 15 recites that the target sequence is located at chr15: 25,278,409-25,333,728 (hg38 genome assembly) and/or in a sequence of UBE3A-ATS complementary to the region between the UBE3A 3'UTR and SNORD109B ORF on chromosome 15. Dependent claims 32-33 merely restate these alternatives and therefore do not add any further limitation, as it is inherent that when a CRISPR system is targeted to a region that a modification will ensue at the targeted location; therefore, rendering them improper dependent claims. 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 15-18, 22, 24,32-35, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Zylka et. al., (US 20210054370 A1; Published: 02/25/2021; EFD: 02/27/2018) in view of Limberis et. al., (US 20180243416 A1; Published: 08/30/2018; EFD: 02/28/2017) and Hinderer et. al., (Human Gene Therapy, pg. 285-298, Vol. 29, No. 3, 2018, provided in IDS)..
Regarding claim 15-17, 25, and 30-31, Zylka discloses that in some embodiments the CRISPR-associated endonuclease (Cas9) and the one or more guide RNAs that are capable of targeting UBE3A-ATS can be introduced into the subject as a nucleic acid molecule, which can be present, e.g., in a nucleic acid construct, as naked DNA, as a plasmid and/or as a viral vector [0007] [0030][0071]. In some embodiments, the nucleic acid molecule of the invention can be in an adeno-associated virus (AAV) vector comprising a nucleotide sequence encoding the nuclease and gRNA of the invention. In some embodiments, the AAV vector can comprise one or more engineered capsid proteins. Zylka further discloses that the vector of the disclosed invention can comprise a vector genome that has been optimized relative to a wild type vector genome, e.g., to enhance the activity of viral cis elements required for replication, packaging and/or delivery, etc., as would be well known in the art [0051]. Zylka discloses that such an optimized vector can comprise an optimized transcription cassette, optimized terminal repeats, etc., as would be well known in the art [0051]. Zylka further discloses that in particular embodiments, the nucleic acid molecule is in an AAV9 vector (that optionally comprises engineered capsid proteins) and that exemplary capsid proteins include, but are not limited to, chimeric capsid proteins that are not typically found in nature, and are engineered to enhance tissue and cell delivery and/or to enhance transduction, etc., as are known in the art [0071].
Regarding claims 18 and 37, Zylka discloses that in some embodiments, the promoter upstream of the nucleotide sequence encoding Cas9 can be a cell-type specific promoter such as, but not limited to, synapsin (i.e., to drive expression in neurons) and/or a ubiquitous promoter (e.g., cytomegalovirus (CMV) and/or a chicken beta-acting (CBA) hybrid (CBh) promoter) [0049].
Regarding claim 22, Zylka discloses compositions (e.g., pharmaceutical compositions) of the CRISPR-associated endonuclease, the guide RNA molecule(s), vector, nucleic acid construct, nucleic acid molecule, nanoparticle or microparticle, etc., of the disclosed invention in a pharmaceutically acceptable carrier and/or a suitable diluent known in the art [0063-0065][0098]. See also claims 20, 22, 24. And 26-27.
Regarding claims 15-17, 24-25, 28, 30, and 32-36, Zylka discloses a method of treating Angelman Syndrome (AS) in a subject in need thereof, comprising administering to the subject an effective amount of a vector comprising a transcription cassette (expression cassette) comprising a gene editing system, for example, a catalytically active or inactive CRISPR associated endonuclease (including SaCas9 and SpCas9) and one or more than one guide RNA (gRNA) capable of targeting a target nucleotide sequence in UBE3A-ATS on a paternal allele in cells of a human subject in need such as a neuron and thereby unsilencing the paternal UBE3A, see [0007][0008][0013][0017-0022][0030][0032-0035][0047][0053][0049][0051][0071][0121-0122] and claims 1-2. Zylka further discloses that the target nucleotide sequence is the entire nucleotide sequence of human UBE3A-ATS or any contiguous region of at least about ten nucleotides of the nucleotide sequence of UBE3A-ATS [0042], and that “the gRNA molecule(s) of the invention can comprise a nucleotide sequence that is complementary to any target nucleotide sequence in UBE3A-ATS, wherein the target nucleotide sequence can be SNORD116, SNORD115 and/or IPW or any portion thereof [0043]. Specifically, Zylka teaches that “the target nucleotide sequence is the entire nucleotide sequence of human UBE3A-ATS (SEQ ID NO:1) or any contiguous region of at least about ten nucleotides (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, etc., including any number of nucleotides up to the total number of nucleotides in SEQ ID NO:1 not expressly set forth herein) of the nucleotide sequence of SEQ ID NO:1, and that this human sequence (SEQ ID NO:1) encompasses the 3′end of the IPW transcript, through all the snord115 repeats, and ends just before the annotated 3′UTR of UBE3A. See [0041-0043]. Zylka further discloses a target nucleotide sequence wherein the target nucleotide sequence in UBE3A-ATS is in one or more SNORD109B genes (see claim 9). Zylka also discloses a method of treating the symptoms of Angelman syndrome including developmental delays, severe intellectual disabilities, lack of speech, debilitating seizures, and problems with movement and balance [0101].
Regarding claims 15, 30, and 36, Zykla teaches “Cas9 is guided by a mature crRNA that contains about 20 base pairs (bp) of unique target sequence (called spacer) and a trans-activated small RNA (tracrRNA) that serves as a guide for ribonuclease III-aided processing of pre-crRNA. The crRNA:tracrRNA duplex directs Cas9 to target DNA via complementary base pairing between the spacer on the crRNA and the complementary sequence (called protospacer) on the target DNA. Cas9 isolated from Streptococcus pyogenes (SpCas9) recognizes a trinucleotide (NGG) protospacer adjacent motif (PAM) to specify the cut site (the 3rd nucleotide from PAM). The crRNA and tracrRNA can be expressed separately or engineered into an artificial fusion small guide RNA (sgRNA, also referred to as “gRNA”) via a synthetic stem loop (AGAAAU) to mimic the natural crRNA/tracrRNA duplex.” See [0028].
Regarding claims 15-18, 24, 30, 32-34, and 37, Zylka teaches “ Cas9 expression can be restricted by using the neuron-specific promoter, hSyn1. In the event that Cas9 is expressed in non-neuronal cells, the underlying biology provides an additional layer of restriction: In nonneuronal cells, there is a boundary element that truncates Ube3a-ATS within the PWS critical region (FIGS. 2A-2B). In neurons, Ube3a-ATS extends beyond this boundary element and silences paternal Ube3a via a transcriptional collision mechanism (FIGS. 2A-2B). By focusing on gRNAs that target Ube3a-ATS downstream of this boundary element, one can restrict changes in paternal Ube3a expression to neurons.” See [0111]. Zylka teaches that their targeting gRNA distal to the “PWS critical rejoin” “did not alter the levels of upstream genes (Snrpn, Snord116; FIG. 4) and caused “downregulation of Snord115 and the 3′ Ube3a-ATS region (FIG. 4).” See [0112-0113]. Zylka further teaches that “other effective gRNAs target Snord116 genes (Tables 1-5), reproducing results with an ASO targeted to Snord116,” and that “while Snord116 genes are highly redundant, their complete deletion is linked to PWS pathogenesis, making them a risky target for the treatment of AS.” See [0114].
Zylka does not disclose the AAV capsid is an AAVhu68.
Limberis discloses a non-replicating recombinant adeno-associated associated virus (rAAV) having an AAV capsid wherein the rAAV has an AAVhu68 capsid. See claims 1 and 17 and rest of publication.
Hinderer teaches that neurotropic adeno-associated virus (AAV) serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously (i.v.) at high doses (abstract). Hinderer further teaches that an AAV9 variant (AAVhu68) resulted in widespread transduction of spinal motor neurons (abstract).
Regarding claim 15, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize an adeno-associated virus (AAV) vector comprising an AAVhu68 capsid for delivery of the CRISPR components in the methods of Zylka. Zylka expressly teaches delivery of CRISPR components via AAV vectors for targeting UBE3A-ATS in neurons. Limberis teaches recombinant AAV vectors comprising AAVhu68 capsids, and Hinderer teaches that AAVhu68 exhibits enhanced transduction efficiency in central nervous system (CNS) cells, including neurons. Accordingly, a skilled artisan would have been motivated to substitute the AAV capsid of Zylka with the AAVhu68b capsid of Limberis, with a reasonable expectation of improved neuronal transduction efficiency, which is directly relevant to Zykla’s goal of treating Angelman syndrome in neuronal cells.
Claims 15-18, 22, 24-25, 28, and 30-37 are rejected under 35 U.S.C. 103 as being unpatentable over Zylka et. al., (US 20210054370 A1; Published: 02/25/2021; EFD: 02/27/2018) in view of Limberis et. al., (US 20180243416 A1; Published: 08/30/2018; EFD: 02/28/2017) and Hinderer et. al., (Human Gene Therapy, pg. 285-298, Vol. 29, No. 3, 2018, provided in IDS) as applied to claims 15-18, 22, 24, 32-35, and 37 above, and further in view of Galiveti et. al., (Sci Rep 4, 6445, 2014), Ran et. al., (Nature, 520, 186-191, 2015) and Zhang (US 8697359 B1, Published: 04/15/2014, provided in IDS).
The teachings of Zykla are incorporated herein by reference to the preceding 103 rejection.
Zykla does not teach a packaging cell per se; the modification is an insertion, deletion or inversion per se; or a guide RNA comprising SEQ ID NOs: 1, 2,3,4,5,6,7,8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 per se.
The teachings of Limberis, and Hinderer are incorporated herein by reference to the preceding 103 rejection.
Limberis further teaches “a packaging host cell for production a viral vector,” and that “stable AAV packaging cells can also be made.” See [0162].
Galiveti teaches: “Based on exonic sequences and genomic location, U-UBE3A-ATS transcript could be divided into two parts. The first is the proximal region, which harbors intronic SNORD64, SNORD107, SNORD108, SNORD109A genes and SNORD116 cluster. It is composed of different exons including U-exons and repetitive IPW116 subtypes (Figure 1). The second region is UBE3A-ATS transcript, which harbors intronic SNORD109B and the SNORD115 cluster and extends distally to overlap the UBE3A gene in cis-antisense orientation (Figure 1). There are reports suggesting that the expression of UBE3A-ATS is restricted to the brain, whereas the proximal transcript could be identified in other tissues,” see Expression analysis of U-UBE3A-ATS and UBE3A genes. Galiveti teaches “the transcript containing intronic copies of SNORD115 embedded by IPW115 exons (previously known as IPW-G1 and IPW-G2) and the SNORD109B together with the distal part of UBE3A antisense region (UBE3A-ATS) is restricted to neurons (Figure 1).” Whereas, “SNORD64, SNORD107, SNORD108, SNORD109A, SNORD116 and their hosting exons of U-UBE3A-ATS RNA (including IPW116 exons: previously known as IPW-A1 and IPW-A2) are ubiquitously expressed in human tissues,” see introduction paragraph 1. Galiveti further teaches “additional regulatory elements or differential processing of the distal region of the U-UBE3A-ATS transcript (UBE3A-ATS),” see Figure 2C and discussion paragraph 2.
Ran teaches that “Staphylococcus aureus (SaCas9) produced indels with efficiency comparable to those of SpCas9” and that “SaCas9 achieves the highest editing efficiency in mammalian cells, with guides between 21 and 23 nucleotides long,” wherein “SaCas9 cleaves genomic targets most efficiently with NNGRRT,” which is the SaCas9 PAM sequence (emphasis added, see page 187). , Ran demonstrates in vivo genome editing by incorporating “SaCas9 and its sgRNA into an AAV vector” or by packaging sgRNA into “AAV-SaCas9,” which “is able to mediate efficient and rapid editing” (See pages 189-190). Ran illustrates a nucleotide sequence alignment between a 21-mer target preceded by NNGRRT PAM sequence and a 21-mer “SaCas9” guide RNA that is designed to be homologous to the target sequence, which is fused to a “tracrRNA” or “SaCas9 sgRNA scaffold,” see Figure 2a copied below:
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Zhang teaches “packaging cells are typically used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and .psi.2 cells or PA317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line may also be infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences.” See column 24 lines 57-67 and column 25 lines 1-15. Zhang further teaches that when employing CRISPR enzymes to cleave a target polynucleotide, “repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide.” See column 7 lines 50-54.
Regarding claims 15, 30 and 36, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select guide RNA sequences targeting the claimed region between SNORD109B and the 3’-UTR of UBE3A (i.e., chr15: 25,278,409-25,333,728 (hg38 genome assembly)) arriving at the specific recited guide RNA sequences (SEQ ID NOs: 1-32). Zykla teaches that the guide RNAs may target any contiguous region of UBE3A-ATS (defined as SEQ ID NO: 1 in Zykla), which includes regions encompassing SNORD109B and extending to the 3’-UTR of UBE3A. Alignment of SEQ ID NOs: 1-32 to SEQ ID NO: 1 of Zykla result in a 100% identity score for each, demonstrating that the claimed sequence by Zykla comprises the gRNA sequences claimed in the instant case. Zykla expressly teaches that gRNA should be designed to target sequences within this distal region to avoid disrupting the SNORD116 gene cluster, thereby inducing Prader Willi Syndrome. Galiveti further teaches that the distal region of UBE3A-ATS, beginning near SNORD115 (immediately upstream of SNORD109B) and extending to overlap UBE3A 3’-UTR in antisense orientation, is a structurally and functionally relevant region associated with neuronal expression and genomic imprinting regulation of UBE3A. Ran teaches that guide RNAs for CRISPR systems are designed by identifying target sequences adjacent to appropriate PAM motifs (e.g., NNGRRT for SaCas9), thereby providing a predictable and routine method for identifying guide RNAs within a given target region. Accordingly, a skilled artisan would have been motivated to scan the disclosed target region for suitable SaCas9 PAM sites and generate corresponding guide RNA sequences using well-established design principles. This process would have yielded a finite number of candidate guide RNA sequences, including those encompassed by SEQ ID NOs: 1-32. The identification of such sequences would have involved no more than routine optimization and screening, with a reasonable expectation of success in achieving CRISPR-mediated modification of the target sequence. Therefore, the claimed guide RNA sequences that target a location at chr15: 25,278,409-25,333,728 (hg38 genome assembly) and/or in a sequence of UBE3A-ATS complementary to the region between the UBE3A 3'UTR and SNORD109B ORF on chromosome 15, represent predictable solutions within the scope of the prior art. "[W]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp." KSR, 550 U.S. at 421, 82 USPQ2d at 1397." MPEP 2143.
Regarding claims 25 and 31, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the CRISPR/Cas methods employed by Zylka would results in modification of the target UBE3A-ATS sequence, including insertions, deletions, or other mutations. Ran teaches that CRISPR/Cas9 systems introduce double-strand breaks that are repaired by cellular mechanisms resulting in indels, and Zhang further teaches that such repair can results in insertions, deletions, or substitutions. Thus, a skilled artisan would have had reasonably expected that targeting UBE3A-ATS using CRISPR as taught by Zylka would inherently result in such sequence modifications.
Regarding claim 28, see teachings of Zykla above.
Regarding claim 30, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a packaging cell in culture to produce the AAV vector particles. Zylka teaches the use of AAV vectors, while Limberis and Zhang teach that AAV vectors are conventionally produced in packaging cells via co-transfection of vector genomes and helper constructs. As viral vector production using packaging cells was a standard and well-understood technique in the art, a skilled artisan would have been motivated to employ such conventional systems to generate the AAV vectors of Zylka with a reasonable expectation of success.
Further regarding claim 30, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize an adeno-associated virus (AAV) vector comprising an AAVhu68 capsid for delivery of the CRISPR components in the methods of Zylka. Zylka expressly teaches delivery of CRISPR components via AAV vectors for targeting UBE3A-ATS in neurons. Limberis teaches recombinant AAV vectors comprising AAVhu68 capsids, and Hinderer teaches that AAVhu68 exhibits enhanced transduction efficiency in central nervous system (CNS) cells, including neurons. Accordingly, a skilled artisan would have been motivated to substitute the AAV capsid of Zylka with the AAVhu68b capsid of Limberis, with a reasonable expectation of improved neuronal transduction efficiency, which is directly relevant to Zykla’s goal of treating Angelman syndrome in neuronal cells.
Response to Arguments and Amendments
Applicant’s amendments and remarks filed January 27, 2026 have been fully considered. Claims 20-21, previously rejected under 35 U.S.C 103, have been cancelled, and the limitations directed to the AAVhu68 capsid have been incorporated into the independent claim 15. Likewise, Applicant canceled claims 1-7, 9-10, and 13, previously rejected under 35 U.S.C. 102, and either incorporated the limitations into independent claim 15 or added newly independent and dependent claims containing these limitations. For example, the limitation of “the target sequence is located at chrl5: 25,278,409-25,333,728 (hg38 genome assembly) and/or in a sequence of UBE3A-ATS complementary to the region between the UBE3A 3'UTR and SNORD109B ORF on chromosome 15” in canceled claim 7 is now incorporated into independent claim 15 and new independent claim 30. In view of these amendments, the prior 35 U.S.C. 102 and 35 U.S.C. 103 rejections have been withdrawn.
However, the newly amended claims have been re-evaluated, and a new ground of rejection under 35 U.S.C. 103 necessitated by amendments is set forth herein, which addresses the amended limitations and Applicant’s remarks.
Applicant remarks that Zylka does not disclose an AAV vector having an AAVhu68 capsid, especially in combination with the claimed vector genome elements, and that the secondary references do not relate to gene editing or Angelman syndrome. These arguments are not persuasive. The previous and new 35 U.S.C. 103 rejections rely on the combined teachings of the references, not any single reference alone. Zykla teaches CRISPR-based methods using AAV vectors to treat Angelman syndrome. Limberis teaches AAVhu68 capsids, and Hinderer teaches that AAVhu68’s effectiveness in neuronal transduction. A skilled artisan would have been motivated to apply known AAV variants with improved tropism to enhance delivery of the CRISPR system in the methods of Zykla.
Applicant’s argument that Limberis and Hinderer do not relate to gene editing or Angelman syndrome is also not persuasive, as references may be combined for all that they reasonably teach, including general delivery technologies applicable across therapeutic contexts.
With respect to the claimed target region and the guide RNA sequences, Zykla teaches and claims targeting any contiguous region of UBE3A-ATS (defined as SEQ ID NO: 1), and Galiveti identifies that this distal region taught by Zykla beginning near SNORD115 (immediately upstream of SNORD109B) and extending toward UBE3A 3’UTR as structurally and functionally relevant. Ran further teaches routine methods for designing guide RNAs within a target region. Accordingly, the claimed region and gRNA sequences represent a selection from a finite number of predictable solutions within a known target sequence.
Therefore, the combination of references renders the claimed invention obvious.
Conclusion
No claim is 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 COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached Monday - Friday 10:30am-7:00pm.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635