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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-4, 6, 9, 11, 15-17, 20-25, 28-29, 33, 39, and 43) and MYO7A recited in claim 33 as the species in the reply filed on 11/04/2025 is acknowledged.
Claims 35-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/04/2025.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Status of Claims
Claims 1-3, 11, 15-17, 20-25, 28-29, 33, 35-39, 43, and 51 are pending.
Claims 35-38 are withdrawn.
Claims 1-3, 11, 15-17, 20-25, 28-29, 33, 39, 43, and 51 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 05/10/2022, 09/28/2022, 12/06/2024, 04/11/2025, 04/28/2025, 05/08/2026, and 07/22/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Figures 21D, 22C, and 23C or the corresponding description of the drawings do not contain SEQ ID NOs for nucleic acid sequences present in the drawings.
Claim Objections
Applicant is advised that should claim 17 be found allowable, claim 21 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). It is unclear as currently drafted how a system for expressing a target protein is different than a composition for expressing a target protein.
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 39 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 39 recites that one or both of the first and second RNA molecules comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to a synthetic intron provided in any one of SEQ ID NOs: including SEQ ID NOs: 5 and 6. However, the specification identifies SEQ ID NOs: 5 and 6 as N-terminal and C-terminal coding sequences respectively, used to express full-length YFP. See specification pg. 14. The specification separately identifies synthetic-intron sequences in its YFP constructs. For example SEQ ID NO: 171 is identified as comprising the 5’ YFP coding sequence segment as nucleotides 3730-4224 and separately identifies the 5’ synthetic intron sequence as nucleotides 4425-4294. Mapping SEQ ID NO: 5 to SEQ ID NO: 171 confirms this arrangement with SEQ ID NO: 5 aligning to positions 3736-4224, see alignment below:
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Similarly, the 3’ synthetic intron sequence of SEQ ID NO: 172 is identified as nucleotides 637-706 and separately the 3’ YFP coding sequence is identified as nucleotides 707-940.
Therefore, it is unclear how a synthetic intron may have the recited sequence identity to SEQ ID NO: 5 or SEQ ID NO: 6, which are defined by the specification as coding sequences, rather than to the separately identified synthetic-intron regions. Accordingly, the scope of the claim can not be determined with reasonable certainty.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 39 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
Claim 39 recites that one or both of the first and second RNA molecules comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to a synthetic intron provided in any one of numerous SEQ ID NOs. This recitation encompasses a broad genus of synthetic intron sequences differing by up to 20% from each recited reference sequence.
For example, the specification identifies SEQ ID NO: 3 as a 5′ intronic sequence and SEQ ID NO: 4 as a 3′ intronic sequence that can be used to express a desired full-length protein. The specification further states that an N-terminal portion of the target protein can be added at nucleotide 1 of SEQ ID NO: 3 and a C-terminal portion of the target protein can be added at nucleotide 382 of SEQ ID NO: 4. SEQ ID NO: 3 is 404 nucleotides long and SEQ ID NO: 4 is 382 nucleotides long. See specification pages 5-6. Accordingly, the claimed lower endpoint of 80% identity encompasses sequences having approximately 80 non-identical nucleotide positions relative to SEQ ID NO: 3 and approximately 76 non-identical nucleotide positions relative to SEQ ID NO: 4, without accounting for the further sequence variation potentially encompassed by insertions and deletions.
The specification discloses particular synthetic-intron sequences and selected construct embodiments, but does not identify which nucleotide positions in SEQ ID NOs. 3 and 4 may be substituted, deleted, or inserted, individually or in combination, while retaining the sequence and structural features necessary for use as a synthetic intron in the claimed composition/system. In particular, the claimed system includes a first RNA having a splice donor and dimerization domain and a second RNA having a dimerization domain, branchpoint sequence, polypyrimidine tract, and splice acceptor, wherein the dimerization domains associate to facilitate RNA trans-splicing and expression of a full-length target protein. The specification does not disclose a representative number of species or common structural characteristics sufficient to demonstrate possession of the full genus of synthetic intron sequences having as little as 80%, 85%, 90%, or 95% sequence identity to for example SEQ ID NO: 3 or SEQ ID NO: 4 in the claimed system.
The materiality of the sequence variation is confirmed by the state of the art. Hotzel I, et al., (WO 2016/004370 A1, in IDS) teaches a related two-pre-mRNA trans-splicing platform in which defined complementary hybridizing sequences on the two transcripts bring a 5′ splice site and a 3′ splice site into proximity for trans-splicing. See pages 13–15. Hotzel further teaches defined sequence and positional requirements for the relevant intronic region, including a 5′ splice site, a polypyrimidine tract positioned between the second hybridizing sequence and the 3′ splice site, and intronic splice enhancers positioned between the 5′ splice site and first hybridizing sequence and between the second hybridizing sequence and the 3′ splice site. See pages 4–5 and 13-15. For example, Hotzel identifies a 5′ splice-site sequence of GTAAGA, specific PPT sequences, and ISE G-runs comprising three or more consecutive guanines, including nine consecutive guanines. See pages 4–5.
Thus, the art confirms that RNA trans-splicing depends on defined sequence components, their relative position, and their ability to form the requisite intermolecular and intramolecular RNA association and splice-site architecture. The specification does not reasonably convey possession of the extensive genus of sequences encompassed by 80% 85%, 90%, or 95% identity to each of the numerous recited reference sequences, including SEQ ID NOs. 3 and 4. The specification therefore fails to provide adequate written-description support for the full scope of claim 39.
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.
Claims 1-3, 11, 15, 17, 21-24, 29, 33, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, 12-18, 21-22, and 26 of U.S. Patent No. 12,448,636. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to the same two-component, RNA trans-splicing system in which separate synthetic nucleic acid molecules encode separate portions of a target protein, include donor- and acceptor-side splice elements, and include interacting RNA dimerization domains formed from complementary RNA hairpins having loops that hybridize while avoiding intramolecular annealing.
Regarding claim 1, ’636’s claim 1 recites a first synthetic nucleic acid molecule encoding an N-terminal portion of a target protein comprising a splice junction at the 3’end, a splice donor, and a first RNA-hairpin dimerization domain; and a second synthetic nucleic acid molecule encoding a second RNA-hairpin dimerization domain, a branchpoint sequence, a polypyrimidine tract, a splice acceptor, and a C-terminal target-protein portion, wherein the first and second loops hybridize and avoid intramolecular annealing. Claim 22 of the ’636 patent further recites first and second promoters 5′ to the respective sequences, and claim 26 recites plural first and second RNA hairpins. The instant claim’s recitation of first and second promoter-driven RNA molecules and one or more hairpins in the dimerization domains therefore represents no more than an obvious restatement or aggregation of the system already claimed in the ’636 patent.
Regarding claim 2, claim 4 of the ’636 patent expressly recites that the first and second loops comprise hypodiverse sequences.
Regarding claim 3, claim 1 of the ’636 patent expressly requires that the first and second loops avoid intramolecular annealing.
Regarding claim 11, claim 6 of the ’636 patent expressly recites that the target protein is a protein associated with disease or a therapeutic protein.
Regarding claim 15, claim 12 of the ’636 patent recites a DISE and/or ISE 3′ to the splice donor and 5′ to the first dimerization domain, and an ISE 3′ to the second dimerization domain and 5′ to the branchpoint sequence, or combinations thereof. Those are the same enhancer arrangements recited in the instant claim.
Regarding claim 17, claim 22 of the ’636 patent recites a first promoter 5′ to the first synthetic nucleic-acid sequence and a second promoter 5′ to the second dimerization domain. Selecting the same promoter for both constructs or selecting different promoters for the respective constructs would have been an obvious design choice in the already claimed two-promoter system.
Regarding claims 21 and 22, claims 1, 13, 18, and 22 of the ’636 patent recite the same two-nucleic-acid trans-splicing system and expressly recites introduction into a cell, reconstitution of the N-terminal and C-terminal RNA portions into a full-length coding sequence, and expression in the cell.
Regarding claims 23 and 24, claims 14 and 15 of the ’636 patent expressly recite that the first and second synthetic nucleic-acid molecules are part of first and second viral vectors and that the viral vectors are AAVs.
Regarding claim 29, claim 16 of the ’636 patent recites first and second dimerization domains each no more than 1000 nt and a recombination efficiency of at least 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, or 90%; and claim 26 recites plural first and second RNA hairpins. The additional recited overlapping size and efficiency ranges in the instant claim do not provide patentable distinction over the same domain-size and recombination-efficiency system.
Regarding claim 33, claim 17 of the ’636 patent expressly recites dystrophin, myosin VIIA, clotting factor VIII, and ABCA4 among the target proteins.
Regarding claim 43, claim 1 of the ’636 patent recites the same two-synthetic-nucleic-acid system for expressing a target protein, including a first target-protein portion followed by a splice donor and first RNA-hairpin dimerization domain, and a second RNA-hairpin dimerization domain followed by a branchpoint, polypyrimidine tract, splice acceptor, and C-terminal target-protein portion, wherein the loop regions hybridize and avoid intramolecular annealing. Claim 12 of the ’636 patent further recites that the first synthetic nucleic-acid molecule may include a DISE, an ISE, or both, positioned 3′ to the splice donor and 5′ to the first dimerization domain; and that the second synthetic nucleic-acid molecule may include an ISE positioned 3′ to the second dimerization domain and 5′ to the branchpoint sequence. Claim 22 of the ’636 patent recites first and second promoters positioned 5′ to the respective first and second RNA-encoding sequences. The instant claim 43 does not recite a patentably distinct invention because it recites the same system and the same donor-side DISE/ISE and acceptor-side ISE arrangements. The recitation of “at least one ISE sequence” on the second RNA does not patentably distinguish over the ’636 patent’s recitation of an ISE in the same location.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13, 16, and 22 of U.S. Patent No. 12,448,636 in view of Trapani et al., (Adeno-Associated Viral Vectors as a Tool for Large Gene Delivery to the Retina, Genes 2019, 10, 287, in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the ’636 patent claims the same split-nucleic-acid, RNA-reconstitution system and expressly recognizes that the N-terminal and C-terminal RNA portions are combined into a full-length coding sequence after introduction into a cell.
‘636 does not claim any of the alternative further limitations of claim 16; for example, an in frame degron protein degradation tag.
Trapani teaches that dual-AAV systems can produce unwanted truncated proteins from the individual 5′ and 3′ half-vectors and teaches use of a C-terminal CL1 degron, a 16-amino-acid destabilizing peptide, to selectively degrade a truncated product from the 5′ half-vector without affecting full-length protein reconstitution. See pgs. 7–8, section 4 (“Limitations of Dual AAV Vectors”).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to incorporate a degron sequence into the first and/or second split expression construct of the system claimed in the ’636 patent so that an undesired protein fragment expressed from an unjoined or nonrecombined transcript is destabilized and degraded.
A PHOSITA would have been motivated because the ’636 patent claims the same split-transcript system and Trapani expressly identifies expression of unwanted truncated products from individual half-vectors as a known drawback of dual-vector large-gene systems. Trapani further teaches that a CL1 degron selectively reduces such truncated-product expression while retaining full-length reconstitution.
A PHOSITA would have had a reasonable expectation of success because Trapani reports that inclusion of the short C-terminal CL1 degron mediates selective degradation of the unwanted 5′ half-vector product without affecting full-length protein reconstitution, thereby demonstrating that a degron can be used compatibly with a split-gene reconstitution platform.
Claims 25 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14–15 and 22 of U.S. Patent No. 12,448,636 in view of Trapani et al., (Adeno-Associated Viral Vectors as a Tool for Large Gene Delivery to the Retina, Genes 2019, 10, 287, in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the ’636 patent expressly recites first and second promoter-containing synthetic nucleic-acid molecules packaged in separate viral vectors, including AAVs.
‘636 does not claim that the first and second DNA molecules have a size selected from the groupings recited in claims 25 and 28.
Trapani teaches that AAV cargo capacity is limited to approximately 5 kb and that large transgenes are routinely divided between two AAV vectors to ensure efficient and robust transfection. Trapani teaches each carrying a respective portion of the coding sequence, with each DNA molecule total size not exceeding the approximate 5kb limit, and thus combined not exceeding 10kb. See pgs. 1–4, sections 1 and 2.
It would have been obvious to a PHOSITA before the effective filing date to select the recited individual construct, coding-sequence, and RNA sizes for the split AAV system of the ’636 patent.
A PHOSITA would have been motivated because AAV packaging capacity imposes a known size constraint, and the reason for splitting a gene across two AAV vectors is to accommodate a target coding sequence that exceeds the approximately 5 kb capacity of a single AAV vector. Trapani teaches that dual AAV vectors are used to deliver portions of large transgenes and can support delivery of approximately 9 kb transgenes.
A PHOSITA would have had a reasonable expectation of success because the size of the individual vector genomes and split coding sequences is a predictable design parameter constrained by known AAV packaging capacity and the known size of the selected target transgene. Trapani identifies split point and vector design as optimization considerations in the dual-AAV system.
Claim 51 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, and 22 of U.S. Patent No. 12,448,636 in view of Hotzel I, et al., (WO 2016/004370 A1, in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ’636 patent recites the same two-synthetic-nucleic-acid, RNA-trans-splicing system with first and second RNA-hairpin dimerization domains, a splice donor on the first RNA, and a branchpoint, polypyrimidine tract, and splice acceptor on the second RNA. Claim 12 of the ’636 patent further recites a DISE and/or ISE 3′ to the first splice donor and 5′ to the first dimerization domain, and an ISE 3′ to the second dimerization domain and 5′ to the branchpoint sequence. Claim 22 of the ’636 patent recites first and second promoters for the respective first and second synthetic nucleic-acid molecules.
The ’636 patent does not expressly recite that the first RNA contains a DISE, a first ISE, and a second ISE, nor does it expressly recite that the second RNA contains three ISE sequences, as required by instant claim 51.
Hotzel teaches a substantially analogous, two-RNA, hybridization-driven pre-mRNA trans-splicing system, see abstract and entire claim set. In Hotzel, a first transcript includes a 5′ splice site, 5ss1, and a first hybridizing sequence, HS1. Hotzel teaches an intronic splice enhancer, ISE1, positioned between 5ss1 and HS1. See claim set, pgs. 4–5; pgs. 13–16, Fig 1. Hotzel further teaches a second transcript having a second hybridizing sequence, HS2, a 3′ splice site, 3ss2, and a second polypeptide-encoding sequence. Hotzel teaches a PPT between HS2 and 3ss2 and an ISE2 between HS2 and 3ss2. See pgs. 4–5; pgs. 13-16. Hotzel teaches that the ISEs can be G-runs of at least three consecutive guanines, including a G-run of nine consecutive guanines, and reports experiments evaluating the effect of adding ISE sequences on expression. See pgs 4–5; pg. 13-16, Figs. 1, 4–6, and 8.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to include additional ISE sequences in the donor-side and acceptor-side intronic regions of the RNA trans-splicing system claimed in the ’636 patent, including providing more than one ISE in each respective intronic region.
A PHOSITA would have been motivated because the ’636 patent teaches DISE and/or ISE elements in precisely the donor-side and acceptor-side regions used in the instant claim, and Hotzel teaches that ISEs are placed in corresponding positions in a two-transcript system to promote hybridization-driven trans-splicing. Hotzel also identifies ISE addition as a variable affecting expression output.
A PHOSITA would have had a reasonable expectation of success because Hotzel provides concrete ISE positions relative to the donor, hybridizing region, PPT, and 3′ splice site; identifies G-run ISE sequences; and reports expression data from constructs containing the ISE sequences. Accordingly, selecting the number and arrangement of enhancer motifs within the known donor-side and acceptor-side intronic intervals would have been a predictable optimization of known splice-enhancer elements for their established function of improving splicing efficiency.
Claims 1-3, 11, 15, 17, 20–25, 28-29, 33, 43, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-3, 7-10, 13, and 16-17 of copending Application No. 19/331,661. Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the claims of the reference application are directed to the same multi-vector system for expressing a target protein by RNA trans-splicing between separately expressed split transcripts. In each, a first vector/genome includes a promoter, an N-terminal target-protein coding portion, a splice donor, and a first RNA-hairpin dimerization domain; and a second vector/genome includes a promoter, a second RNA-hairpin dimerization domain, a branchpoint sequence, a polypyrimidine tract, a splice acceptor, and a C-terminal target-protein coding portion. The respective hairpin domains hybridize to facilitate formation of a full-length mRNA encoding the target protein.
The reference application further recites multiple non-self-hybridizing hairpins, donor-side and acceptor-side DISE/ISE arrangements, viral vectors including AAVs, target proteins associated with disease or therapy, disease-specific target proteins, and introduction of the two vectors into a cell to form a full-length mRNA. The instant claims recite the same invention or obvious variants thereof, including the same/different promoter alternative, routine vector-size and target-protein selections, and routine optimization of the number of intronic splice enhancer elements.
Claims 1–3, 11, 15–17, 20–22, 25, 28–29, 33, 39, 43, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1–4, 10, 13, 15–17, 33–34, 36–37, 40, 59, 64, and 67 of copending Application No. 18/289,166. Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the claims of the reference application are directed to the same two-synthetic-DNA-molecule RNA trans-splicing platform. In each, a first promoter-driven DNA molecule encodes an N-terminal portion of a target protein, a splice donor, and a first RNA-hairpin dimerization domain, and a second promoter-driven DNA molecule encodes a second RNA-hairpin dimerization domain, a branchpoint sequence, a polypyrimidine tract, a splice acceptor, and a C-terminal portion of the target protein. The corresponding RNA dimerization domains hybridize to facilitate joining/reconstitution of a full-length target-protein coding RNA.
The reference application limits the recited target protein to a nucleic-acid editing protein, including a Cas nuclease, zinc-finger nuclease, or TALEN. That limitation does not render the instant claims patentably distinct because the instant claims broadly encompass a “target protein,” including the nucleic-acid editing-protein species claimed in the reference application.
The reference application further recites kissing-loop and hypodiverse-region interactions, direct and indirect binding by base-pairing, RNA hairpin dimerization domains, splice-enhancer arrangements, synthetic intron limitations with the same sequences corresponding to the same SEQ ID NOs, suppression of expression from nonrecombined RNA intermediates, promoter selections, full-length coding-RNA reconstitution, dimerization-domain sizes, RNA sizes, coding-sequence sizes, and recombination-efficiency ranges. The instant claims recite the same invention or obvious variations thereof, including use of the same or different promoters, synthetic introns, routine optimization of splice-enhancer number/placement, and selection of the claimed target protein and size parameters.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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 M-F 7:30am - 6:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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