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 .
DETAILED ACTION
Election/Restriction
Applicant’s election of Group I, claims 190-216, drawn to a composition comprising heterologous nucleic acids, a eukaryotic cell comprising heterologous nucleic acids and a pharmaceutical composition thereof, in the reply filed on 01/14/2026 is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
The requirement is still deemed proper and is therefore made FINAL.
Claims 217-219 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
In the reply filed on 01/14/2026, Applicant further elects the species of the position of the D sequence in claim 191, the species of the second donor nucleic acid sequence does not comprise a second nuclease recognition sequence in claim 198, and the species of a first portion of the first transgene and a second portion of the first transgene in claim 204.
Claims 192, 199, 205, 206, 208 and 209 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 190-219 are pending.
Claims 192, 199, 205-206, 208-209 and 217-219 are withdrawn.
Claims 190-191, 193-198, 200-204, 207 and 210-216 are considered on the merits.
Priority
This application is a CON of 17/630,064 (filed on 01/25/2022), which is a 371 of PCT/US2020/043628 (filed on 07/24/2020), which claims benefit from application 62/878,529 (filed on 07/25/2019). The priority claim of the instant application has been granted and the earliest benefit date is 07/25/2019 from the application 62/878,529.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/15/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Furthermore, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., page 66). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “www” can be replaced with “world wide web” as the URL code. See MPEP § 608.01.
Claim Objections
Claims 198, 200 and 214 are objected to because of the following informalities:
Claim 198 ends with “,.”, which contains a typographical error. It is recommended to remove the comma.
Claim 200 does not end with a period. MPEP 608.01(m) states “Each claim begins with a capital letter and ends with a period.”
Claim 214 recites “said eukaryotic cells of claim 213”. Since claim 213 is directed to a eukaryotic cell, the phrase should be changed to “said eukaryotic cell of claim 213”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 191, 195-196, 200-201, 207 and 210-211 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 191 recites “said 5’ homology arm” in line 3. There is insufficient antecedent basis for this limitation in the claim because this limitation is directed to “said first polynucleotide” in lines 1-2, however, base claim 190 is silent on a 5’ homology arm in the first polynucleotide.
Claim 195 recites a eukaryotic cell “of interest”, which renders the claim indefinite because the phrase is a subjective term. A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. See MPEP § 2173.05(b). Claims 210-211 are rejected as being dependent from claim 195 but not resolving the ambiguity.
Claim 196 recites “said endogenous nuclease recognition sequence” in line 2. There is insufficient antecedent basis for this limitation in the claim because base claim 190 is silent on an endogenous nuclease recognition sequence. It is recommended to change its dependency to be dependent from claim 195.
Claims 200 and 201 both recite “said endogenous nuclease recognition sequence”. There is insufficient antecedent basis for the limitation in the claims because base claims 198 and 190 are silent on an endogenous nuclease recognition sequence.
Claim 207 recites “said second transgene” in the last line. There is insufficient antecedent basis for this limitation in the claim because base claims 204, 202 and 190 are silent on a second transgene.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 213-216 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Bak et al., (Cell Reports. 2017; 20: 750-756).
With respect to claim 213, Bak teaches CRISPR-mediated integration of large gene cassettes using two AAV donor vectors into primary human T cells and CD34+ hematopoietic stem and progenitor cells (see e.g., Highlights and abstract), thus teaches a eukaryotic cell and a population of eukaryotic cells.
In regard to (a) a first polynucleotide, Bak teaches a first polynucleotide “Donor A” comprising a first heterologous nucleic acid sequence comprising (i) a first donor nucleic acid sequence (see e.g., Part A of the transgene in Fig 1), comprising a first nuclease recognition sequence for a first engineered nuclease (see an sgRNA target site marked by a red box in Fig 1); and (ii) a first homology region positioned 3’ downstream of the first nuclease recognition sequence (see the stuffer DNA in white box after the sgRNA target site and the right homology arm after the stuffer DNA in Fig 1). It is noted that this stuffer DNA is used as a homology arm for donor B (see Fig 1 legend), thus this stuffer DNA and the right homology arm are examined as a first homology region.
In regard to (b) a second polynucleotide, Bak teaches a second polynucleotide “Donor B” comprising a second heterologous nucleic acid sequence comprising: (i) a 5’ homology arm having homology to at least a portion of the first donor nucleic acid sequence (see the 5’ homology arm in Donor B that has homology to a portion of Part A of the transgene in Fig 1) and to a 5’ portion of the first nuclease recognition sequence (see Fig 2A and 2B for the 5’ homology arm in Donor B that has homology to the 5’ portion of the sgRNA target site); (ii) a 3’ homology arm having homology to a 3’ portion of the first nuclease recognition sequence (see Fig 2A and 2B for the 3’ homology arm in Donor B that has homology to the 3’ portion of the sgRNA target site) and to the first homology region (see Fig 1 and Fig 2A for the 3’ homology arm in Donor B that has homology to the stuffer DNA in Donor A); and (iii) a second donor nucleic acid sequence positioned between the 5’ homology arm and the 3’ homology arm (see e.g., Part B of the transgene in Fig 1).
In regard to (c) the first engineered nuclease or nucleic acids encoding the nuclease, Bak teaches Cas9 protein and Cas9 mRNA (e.g., p. 754, right col, para 1).
With respect to claim 214, as stated supra, Bak teaches primary human T cells and CD34+ hematopoietic stem and progenitor cells (see e.g., abstract), thus teaches a population of eukaryotic cells comprising a plurality of the eukaryotic cell of claim 213.
With respect to claim 215 and claim 216 directed to a pharmaceutical composition, it is noted that the limitation “pharmaceutical" is interpreted as intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Thus, the limitation “a pharmaceutical composition” is reasonably interpreted as a composition that is capable for performing the intended “pharmaceutical” use as recited in the preamble. In the instant case, e.g., Bak teaches in a CFU assay that the electroporated and transduced human T cells are cultured for 12-16 days and then washed in PBS (p. 755, para 1). Thus, Bak teaches a composition comprising a pharmaceutically-acceptable carrier (e.g., PBS) and the eukaryotic cell/cells (i.e., human T cells) that is capable for pharmaceutical use.
Accordingly, Bak anticipates instant claims.
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 190-191, 193-198, 200-203 and 210-212 are rejected under 35 U.S.C. 103 as being unpatentable over Bak et al., (Cell Reports. 2017; 20: 750-756) in view of Wang et al., (J Virol. 1996;70(3):1668-1677).
With respect to claim 190, Bak teaches CRISPR-mediated integration of large gene cassettes using two AAV donor vectors into primary human T cells and CD34+ cells (see e.g., Highlights and abstract), thus teaches a composition (e.g., a T cell).
In regard to (a) a first polynucleotide, Bak teaches a first polynucleotide “Donor A” comprising a first heterologous nucleic acid sequence comprising (i) a first donor nucleic acid sequence (see e.g., Part A of the transgene in Fig 1), comprising a first nuclease recognition sequence for a first engineered nuclease (see an sgRNA target site marked by a red box in Fig 1); and (ii) a first homology region positioned 3’ downstream of the first nuclease recognition sequence (see the stuffer DNA in white box after the sgRNA target site and the right homology arm after the stuffer DNA in Fig 1). It is noted that this stuffer DNA is used as a homology arm for donor B (see Fig 1 legend), thus this stuffer DNA and the right homology arm are examined as a first homology region.
In regard to (b) a second polynucleotide, Bak teaches a second polynucleotide “Donor B” comprising a second heterologous nucleic acid sequence comprising: (i) a 5’ homology arm having homology to at least a portion of the first donor nucleic acid sequence (see the 5’ homology arm in Donor B that has homology to a portion of Part A of the transgene in Fig 1) and to a 5’ portion of the first nuclease recognition sequence (see Fig 2A and 2B for the 5’ homology arm in Donor B that has homology to the 5’ portion of the sgRNA target site); (ii) a 3’ homology arm having homology to a 3’ portion of the first nuclease recognition sequence (see Fig 2A and 2B for the 3’ homology arm in Donor B that has homology to the 3’ portion of the sgRNA target site) and to the first homology region (see Fig 1 and Fig 2A for the 3’ homology arm in Donor B that has homology to the stuffer DNA in Donor A); and (iii) a second donor nucleic acid sequence positioned between the 5’ homology arm and the 3’ homology arm (see e.g., Part B of the transgene in Fig 1).
In regard to (c) the first engineered nuclease or nucleic acids encoding the nuclease, Bak teaches Cas9 protein and Cas9 mRNA (e.g., p. 754, right col, para 1).
In regard to the first and the second polynucleotides being comprised within a first and second recombinant AAVs, Bak teaches the two donors are delivered as two AAV vectors (e.g., p. 751, para 1, also see abstract and Highlights).
However, Bak is silent on the AAVs comprising only one D sequence.
Wang constructs and assays a number of recombinant AAV genomes containing deletions-substitutions within the viral inverted terminal repeat (ITR) (see e.g., Fig 1) and teaches that two palindromic hairpin structures and one D-sequence (i.e., pXS-23 in Fig 1) are sufficient for efficient rescue and preferential replication of the AAV DNA (see abstract, also see p. 1673, last para for pXS-23 producing virions and see p. 1674, last para for the virions produced from pXS-23 plasmid is infectious and biologically active).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV vectors disclosed by Bak, by substituting the AAVs with the AAV construct comprising two hairpin structures and one D-sequence as taught by Wang with a reasonable expectation of success. Since Wang has reduced to practice an AAV construct that comprises two hairpin structures and one D-sequence and demonstrates that this AAV construct is sufficient for replication of the AAV DNA and for producing progeny virions that are infectious and biologically active (see above), one of ordinary skill in the art would have had a reason to substitute with Wang’s AAV construct comprising only one D sequence in the composition of Bak in order to produce infectious AAV virions for transducing Bak’s cells.
Furthermore, since Bak’s AAV constructs and Wang’s AAV construct comprising only one D sequence, are for the same purpose (i.e., to produce AAV virions for transducing cells), these AAV constructs are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Wang’s AAV construct comprising only one D sequence for Bak’s AAV constructs. See MPEP 2144.06.
With respect to claim 191 directed to the position of the D sequence, as stated supra, Wang teaches two palindromic hairpin structures and one D-sequence are sufficient for efficient rescue and preferential replication of the AAV DNA (see e.g., abstract, also see Fig 8 a-e and legend for a model for the rescue and selective replication of the AAV genome, in which the D sequence is positioned within a 5’ inverted terminal repeat (ITR) next to the hairpin structure).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the D sequence being positioned within a 5” ITR as suggested by Wang with a reasonable expectation of success. Since Wang teaches a AAV construct having two palindromic hairpin structures and one D-sequence are sufficient for efficient rescue and preferential replication of the AAV DNA (see e.g., abstract) and exemplifies the D sequence being positioned within a 5’ ITR in a model for the rescue and selective replication of the AAV genome (see Fig 8), one of ordinary skill in the art would have had a reason to choose the D sequence being positioned within a 5” ITR in order to obtain sufficient replication of the AAV genome. Furthermore, since Wang only teaches two options of the position of the only one D sequence (i.e., within the 5’ ITR or the 3’ ITR), one of ordinary skill in the art would have immediately envisioned the taught option of positioning the D sequence within the 5’ ITR among the limited genus of options as taught by Wang. See MPEP 2131.02 (III).
With respect to claim 193 directed to the first nuclease recognition sequence being positioned at the 3’ end of the first donor nucleic acid sequence, as stated supra, Bak teaches the first nuclease recognition sequence (i.e., the sgRNA target site in red box in Fig 1) is positioned at the 3’ end of the first donor nucleic acid sequence (i.e., the Part A of the transgene in Fig 1).
With respect to claim 194 directed to the engineered nuclease being a CRISPR system nuclease, as stated supra, Bak teaches the engineered nuclease is a CRISPR/Cas9 system nuclease Cas9 (see e.g., abstract).
With respect to claim 195 and claim 200 directed to the first nuclease being capable of binding and cleaving the first nuclease recognition sequence and an endogenous nuclease recognition sequence normally present in the genome of a eukaryotic cell, as stated supra, Bak teaches a eukaryotic cell (e.g., a T cell, see abstract), and teaches the first nuclease is capable of binding and cleaving the first nuclease recognition sequence (see Fig 1 “Locus after 1st HR”) and an endogenous nuclease recognition sequence normally present in the genome of a cell (see Fig 1 “Targeted locus”).
With respect to claim 196 and claim 201 directed to the first nuclease recognition sequence being identical to the endogenous nuclease recognition sequence, Bak teaches the same sgRNA target site in Donor A and in the targeted locus (see e.g., Fig 1 legend and Fig 2A and 2B legend).
With respect to claim 197 directed to the nucleic acid encoding the nuclease being mRNA, as stated supra, Bak teaches Cas9 mRNA (e.g., p. 754, right col, para 1).
With respect to claim 198 directed to the second donor nucleic acid sequence does not comprise a second nuclease recognition sequence, Bak teaches the second donor nucleic acid sequence positioned between the 5’ homology arm and the 3’ homology arm (see e.g., Part B of the transgene in Fig 1) does not comprise a second nuclease recognition sequence. It is noted that although the 5’ homology arm and the 3’ homology arm each comprise a portion of the first nuclease recognition sequence (see e.g., Fig 2A and 2B), those portions do not pair to generate a second nuclease recognition sequence (see Fig 2A last row for a “sgRNA site Δ”).
With respect to claim 202 directed to the first donor nucleic acid sequence comprising a first transgene, as stated supra, Bak teaches the first donor nucleic acid sequence comprises a portion of a large transgene (see e.g., Part A of the transgene in Fig 1).
With respect to claim 203 directed to the first donor nucleic acid sequence comprising a first promoter that is operably linked to the first transgene, Bak teaches the first donor nucleic acid sequence comprises a first promoter (e.g., a SFFV promoter) that is operably linked to the first transgene (i.e., a portion of GFP, see Fig 2A).
With respect to claim 210 and claim 211, Bak teaches the first heterologous nucleic acid sequence (i.e., Donor A in Fig 2A and 2B) further comprises (a) a 5’ homology arm that is homologous to a sequence 5’ upstream of the endogenous nuclease recognition sequence and to a 5’ portion of the endogenous nuclease recognition sequence (see e.g. Fig 2A and 2B Donor A left homology arm “LHA”); and (b) the first homology region (i.e., the stuffer DNA and the right homology arm as discussed above, it is noted that this first homology region is equivalent to a 3’ homology arm) that is homologous to a sequence 3’ downstream of the endogenous nuclease recognition sequence and to a 3’ portion of the endogenous nuclease recognition sequence (see Fig 2A and 2B Donor A the stuffer DNA and the right homology arm). Bak teaches the 5’ homology arm and the 3’ homology arm flank the first heterologous nucleic acid sequence (see Fig 2A).
With respect to claim 212 directed to the composition being a eukaryotic cell, as stated supra, Bak teaches the composition being primary human T cells and CD34+ cells (see e.g., abstract), thus teaches a eukaryotic cell (e.g., a T cell).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 204 and 207 are rejected under 35 U.S.C. 103 as being unpatentable over Bak et al., (Cell Reports. 2017; 20: 750-756) in view of Wang et al., (J Virol. 1996;70(3):1668-1677), as applied to claims 202 and 190 above, and further in view of Ghosh et al., (Hum Gene Ther. 2011;22(1):77-83).
It is noted that since the limitation of “said second transgene” in claim 207 lacks antecedent basis, claim 207 is examined based on the limitations that are the same as those in base claim 204.
With respect to claim 204, Bak teaches the first donor nucleic acid sequence (e.g., Donor A in Fig 1) comprises, from 5’ to 3’, a first portion of the first transgene (see e.g., Part A of the transgene in Fig 1), the first recognition sequence (see e.g., the first sgRNA target site in red box in Fig 1) and the first homology region (e.g., the stuffer DNA and the right homology arm in Fig 1 as discussed above). Bak teaches the second donor nucleic acid sequence (e.g., Donor B in Fig 1) comprises, from 5’ to 3’, the 5’ homology arm (see Fig 1 left homology arm) and a second portion of the first transgene (see Part B of the transgene in Fig 1). Bak teaches the 5’ homology arm in Donor B comprises, from 5’ to 3’, a sequence having homology to at least a portion of the first transgene (see e.g., Fig 2A LHA in Donor B having homology to a portion of GFP(A)), and a sequence having homology to a 5’ portion of the first nuclease recognition sequence (see Fig 2A and 2B for homology to a 5’ portion of the sgRNA target site). Bak teaches insertion of the second donor nucleic acid sequence into the first nuclease recognition sequence would generate a sequence comprising, from 5’ to 3’, the first portion of the first transgene (e.g., GFP(A) in Fig 2A), the 5’ portion of the first nuclease recognition sequence (see Fig 2B the PAM sequence in red and a “T” in purple in Donor B which is a 5’ portion of the first nuclease recognition sequence), and the second portion of the first transgene (see GFP(B) in Fig 2A).
Bak teaches to seamlessly integrate the two portions of the transgene, “GFP is split at a PAM site... Donor A carries a truncated GFP sequence that ends after the PAM site identified in the GFP gene….Note that the last codon (Pro) of the truncated GFP sequence is maintained with the fusion to the sgRNA target sequence. …The two homology arms flank the remaining part of GFP and an mCherry expression cassette—see (A)—that, upon seamless HR of donor B, will reconstitute a functional GFP open reading frame” (see Fig 2B legend), indicating that the functional reconstitution of the open reading frame depends on both (1) the presence of a PAM site in the open reading frame and (2) the ability to maintain the last codon after fusion to the sgRNA target sequence, which may not be applicable to all transgenes.
However, Bak is silent on a first untranslated sequence in the first donor sequence, a second untranslated sequence in the second donor sequence, or the 5’ homology arm comprising a sequence having homology to the first untranslated sequence, nor teach the first and the second untranslated sequence are introns comprising splice donor and acceptor sequences in claims 204 and 207.
Bak acknowledges existing methods for expression of long transgenes split between two AAV vectors include an approach where two vectors are designed with splice donor and acceptor in each vector so that the full-length mRNA transcript is produced (e.g., p. 753, left col.).
Ghosh teaches an efficient transgene reconstitution with hybrid dual AAV vectors carrying bridging sequences in which the expression cassette is split into the two independent AAV vectors (see e.g., abstract). Ghosh teaches the first donor sequence comprises a first untranslated sequence (see e.g., Fig 3A last row in which a 1/3 tail bridging sequence is downstream of the first portion of the transgene 5’-LacZ and further comprises a splice donor “SD” at its 5’ end), thus teaches a first untranslated sequence in the first donor sequence, that is a first intron sequence (e.g., the 1/3 tail bridging sequence) comprising a splice donor sequence at its 5’ end in claims 204 and 207. Ghosh teaches the second donor sequence comprises the same 1/3 tail bridging sequence (see e.g., Fig 3A last row, which is equivalent to a sequence having homology to the first untranslated sequence in the 5’ homology arm) and further comprises a splice acceptor (see “SA” in Fig 3A last row, which is equivalent to a second untranslated sequence that is a second intron sequence comprising a splice acceptor sequence at its 3’ end, that is upstream of the second portion of the transgene 3’-LacZ). It is noted that the claimed second untranslated sequence that is a second intron sequence comprising a splice acceptor sequence at its 3’ end in claims 204 and 207 is examined as a splice acceptor taught by Ghosh. Ghosh teaches robust reconstitution is achieved from a 0.26-kb and a 0.27-kb bridging sequence-mediated homologous recombination (e.g., abstract and p. 77, right col.), indicating the splice donor sequence and the splice acceptor sequence are capable of being recognized by a splicing complex, and the first intron sequence (i.e., the bridging sequence) and the second intron sequence (i.e., the splice acceptor) are capable of being spliced from the first polynucleotide upon insertion of the second donor nucleic acid sequence (i.e., trans-splicing, see e.g., p. 77, left col) and expression of said first transgene (e.g., the LacZ transgene, see e.g., Fig 4) in claims 204 and 207.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the first and the second polynucleotide suggested by Bak in view of Wang, by combining a first untranslated sequence being an intron comprising a splice donor sequence at its 5’ end downstream of the first portion of the first transgene in the first donor nucleic acid sequence, and combining a sequence having homology to the first untranslated sequence in the 5’ homology arm and a second untranslated sequence being an intron comprising a splice acceptor sequence at its 3’ end upstream of the second portion of the first transgene in the second donor nucleic acid sequence as suggested by Ghosh with a reasonable expectation of success. Since Bak indicates that the functional reconstitution of the open reading frame depends on both (1) the presence of a PAM site in the open reading frame and (2) the ability to maintain the last codon after fusion to the sgRNA target sequence, which may not be applicable to all transgenes (see above), and since Ghosh reduces to practice a trans-splicing approach by incorporating a splice donor and a splice acceptor in each split vector that obtains robust reconstitution and that does not rely on the sequence of the transgenes, one of ordinary skill in the art would have had a reason to combine the teaching of Ghosh in the AAV donor vectors of Bak in view of Wang in order to broaden the application of Bak’s approach to any transgene.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631