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 .
Applicant’s response of 01/20/2026 has been received and entered into the application file.
Claims 1, 3, 22, 27, and 29-33 were amended in the claim set filed 01/20/2026.
Claims 1-44 are pending, of which claims 29 and 31-44 were previously withdrawn.
Information Disclosure Statement
Receipt of an information disclosure statement on 01/20/2026 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Election/Restrictions
Applicant previously elected Group I (claims 1-28 and 30) with traverse in the reply filed on 09/24/2025. While this requirement was upheld in the previous action, upon further consideration, the restriction requirement between Groups I and II and between Groups III and IV is hereby withdrawn. For purposes of examination, previous Groups I and II are now Group I (claims 1-30) and previous Groups III and IV are now Group II (claims 31-44).
Accordingly, Group I (claims 1-30) are pending and under consideration.
Claims 31-44 (Group II) stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09/24/2025.
Furthermore, because a claimed invention previously withdrawn from consideration under 37 CFR 1.142 has been rejoined, the restriction requirement between Groups I and II and between Groups III and IV as set forth in the Office action mailed on 08/19/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Status of Prior Objections/Rejections
RE: Claim Objections
►Claims 27, 28, and 30 were previously objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only.
The amendments to claims 27, 28, and 30 have obviated the basis of the objection of record. Therefore, the objection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 112
►Claims 1, 3, 5-28, and 30 were previously 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.
The amendments to claims 3 and 22 to limit the claimed percent identity threshold to “at least 90% identity to SEQ ID NO: 2” are inherited by the remaining previously rejected claims and have obviated the basis of the rejection of record. Therefore, the rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claims 1, 3, 5, 9, 10, 16, and 23-26 were previously rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2019/0192691 A1 (hereinafter Barrett).
The amendments to instant claims 1 and 3 to limit the claimed percent identity threshold to “at least 90% identity to SEQ ID NO: 2” are inherited by the remaining previously rejected claims and have obviated the basis of the rejection of record. Therefore, the rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claims 6, 7, 12, 13, and 15 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett) as applied to claims 3, 5, 9, and 10 (see section Claim Rejections - 35 USC § 102), and further in view of Karumuthil-Melethil et al., 2016 (hereinafter Karumuthil-Melethil).
Claims 6, 7, 12, 13, and 15 all directly or indirectly depend from instant claim 3. As set forth above, the amendments to instant claim 3 have obviated the basis of the rejection of record. Therefore, the rejection of record is hereby withdrawn. However, new grounds of rejection are set forth below.
►Claim 8 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett) in view of Karumuthil-Melethil et al., 2016 (hereinafter Karumuthil-Melethil) as applied to claim 7, and further in view of Azzoni et al., 2007 (hereinafter Azzoni).
Claim 8 indirectly depends from instant claim 3. As set forth above, the amendments to instant claim 3 have obviated the basis of the rejection of record. Therefore, the rejection of record is hereby withdrawn. However, new grounds of rejection are set forth below.
►Claim 11 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett) as applied to claim 10 (see section Claim Rejections - 35 USC § 102), and further in view of WO 2017/218450 A1 (hereinafter Gray; as cited in the IDS dated 01/20/2023).
Claim 11 indirectly depends from instant claim 3. As set forth above, the amendments to instant claim 3 have obviated the basis of the rejection of record. Therefore, the rejection of record is hereby withdrawn. However, new grounds of rejection are set forth below.
►Claim 14 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett) as applied to claim 10 (see section Claim Rejections - 35 USC § 102), and further in view of US 2004/00029106 A1 (hereinafter Samulski).
Claim 14 indirectly depends from instant claim 3. As set forth above, the amendments to instant claim 3 have obviated the basis of the rejection of record. Therefore, the rejection of record is hereby withdrawn. However, new grounds of rejection are set forth below.
►Claims 17-22 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett) as applied to claim 3 above (see section Claim Rejections - 35 USC § 102), and further in view of Levitt et al., 1989 (hereinafter Levitt), Karumuthil-Melethil et al., 2016 (hereinafter Karumuthil-Melethil), and WO 2017/218450 A1 (hereinafter Gray; as cited in the IDS dated 01/20/2023).
Claims 17-21 all directly depend from instant claim 3. As set forth above, the amendments to instant claim 3 have obviated the basis of the corresponding rejection of record. Additionally, the amendments to instant claim 22 have obviated the basis of the corresponding rejection of record. Therefore, the rejection of record is hereby withdrawn. However, new grounds of rejection are set forth below.
RE: Double Patenting
►Claims 1-7, 9-10, 12, 17-19, and 22-26 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-8 of copending Application No. 18/683,101 (reference application; corresponds to US 2024/0342314 A1).
Applicant has asserted that the patent term filing date of the instant application pre-dates the patent term filing date of copending application 18/683,101 and accordingly, when the provisional non-statutory double patenting rejection is the only rejection remaining in the present application, the rejection should be withdrawn in accordance with MPEP § 1504.06 and 1490(VI)(D).
In response, the provisional non-statutory double patenting rejection of record is not the only rejection remaining in the present action. Accordingly, the rejection of record is maintained and set forth below.
New/Maintained Grounds of Objection/Rejection
Claim Objections
Claims 2 and 4 are objected to because of the following informalities:
Claims 2 and 4 both recite “the human SLC13A5 open reading frame comprises the nucleotide of SEQ ID NO:2” (bolded emphasis added), which does not comport with standard grammatical and/or linguistic conventions, as it lacks a space following the colon denoting the claimed sequence identifier. In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to recite “the human SLC13A5 open reading frame comprises the nucleotide of SEQ ID NO: 2” (bolded and underlined emphasis added).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 27 and 28 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
With regard to claim 27, which recites “a transformed cell comprising the polynucleotide of claim 1,” the broadest reasonable interpretation of the term “cell” embraces a human having the cell. Neither the instant claim language nor the disclosure of the instant specification precludes this interpretation. In fact, the instant specification explicitly discloses that the transformed cell may be an in vivo cell (page 28, lines 1-4), which broadly embraces a human subject having the cell. Instant claim 28 directly depends from claim 27 and also does not preclude the interpretation of the instant claim language embracing a human having the cell. It would be remedial to amend the instant claims to recite “an isolated transformed cell” (bolded emphasis added) and “the isolated transformed cell” (bolded emphasis added) to avoid the claims embracing a human organism.
Claim Rejections - 35 USC § 112
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 29 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 enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Instant claim 29 is drawn to a non-human transgenic animal comprising the polynucleotide of claim 1, which is recited to comprise a human SLC13A5 open reading frame that is codon-optimized for expression in a human cell and has at least 90% identity to instant SEQ ID NO: 2. As recited at instant claim 29, the non-human transgenic animal may alternatively comprise an expression cassette comprising said polynucleotide, a vector comprising said polynucleotide and/or said expression cassette, and/or a transformed cell comprising said polynucleotide, said expression cassette, and/or said vector.
Breadth of the claims: The claim broadly encompasses any transgenic non-human animal, wherein said transgenic non-human animal comprises a human SLC13A5 open reading frame that is codon-optimized for expression in a human cell and has at least 90% identity to instant SEQ ID NO: 2. Numerous transgenic non-human animals are known in the art and include, but are not limited to, Drosophila melanogaster (reviewed in Venken et al., 2016), Caenorhabditis elegans (reviewed in Nance and Frøkjær-Jensen, 2019), Mus musculus (reviewed in Gurumurthy and Lloyd, 2019), Rattus norvegicus (reviewed in Meek et al., 2017), Gallus gallus domesticus (reviewed in Bahrami et al., 2019), Danio rerio (reviewed in Lin et al., 2016), and Taeniopygia guttata (reviewed in Heston and White, 2017). The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claim.
Guidance of the specification and existence of working examples: The instant specification discloses in vivo intrathecal administration of AAV9/USP-hSLC13A5opt to SLC13A5 knockout mice (page 40, line 31-page 41, line 4), wherein such a treatment reduces EEG activity to normal levels, reduces seizure susceptibility, and reduces seizure-related death in SLC13A5 knockout mice (page 41, lines 5-29). However, the disclosure of treating SLC13A5 knockout mice with a vector comprising the instantly claimed polynucleotide comprising instant SEQ ID NO: 2 does not read on a transgenic mouse as accepted in the field, as evidenced by Gurumurthy and Lloyd, 2019. Gurumurthy and Lloyd, 2019 disclose that the accepted definition of a transgenic mouse is “a genetically engineered mouse created by the pronuclear injection of recombinant DNA (transgene), which typically inserts at a random location in the genome” (Box 1). The instant specification does not disclose any evidence that the therapeutic vector set forth above (AAV9/UsP-hSLC13A5opt) was inserted into the mouse genome, random or otherwise. Furthermore, the instant specification does not disclose experimentation with any other animal than the mice set forth above.
Predictability and state of the art: Regarding the claimed non-human transgenic animal comprising the human codon-optimized SLC13A5 open reading frame of the instant invention, the phenotype of said non-human transgenic animal is not disclosed in the instant specification (as set forth above) and would not have been predictable at the time of filing. While SLC13A5 expression has been implicated in liver fat metabolism in that its inhibition improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice (reported in Brachs et al., 2016: e.g. abstract; page 1081, column 1, paragraph 3-page 1081, column 2, paragraph 1), as supported by the instant specification (page 2, lines 7-8), this phenotype is not further contemplated by the instant specification. In fact, the instant specification discloses that while the function of this transporter is extensively studied in liver cells, its function in the human brain is largely unknown and thus the instant application is drawn to optimized SLC13A5 genes, expression cassettes, and vectors capable of providing therapeutic levels of SLC13A5 expression for treating disorders such as citrate transporter disorder, which causes seizures in affected patients (page 2, lines 7-8; page 2, lines 9-10; page 2, lines 18-21). SLC13A5 is a member of the solute carrier (SLC) superfamily, which also includes SLC6A15, the hippocampal overexpression of which has been reported to generate mice with lower anxiety and depressive behaviors after chronic social stress (Aykaç and Şehirli, 2020: abstract; page 183, column 2, paragraph 3). Post-filing art further implicates SLC13A5 in behavioral phenotypes, specifically that its overexpression in mouse forebrain neurons results in an autistic-like phenotype with jumping stereotypy (Rigby et al., 2022: abstract). The instant specification is entirely silent as to the autistic-like behaviors that are reported in post-filing art discussing SLC13A5 overexpression.
When considering the predictability of this invention, one has to remember that many of the phenotypes examined in transgenic and knockout models are influenced by the genetic background in which they are studied and the effect of allelic variation and the interaction between the allelic variants (reviewed in Chandler et al., 2013; e.g. Figures 1 and 2, Box 1). Further, the state of the art for transgenics is unpredictable because the method of gene transfer typically relies on random integration of the transgene construct. Insertional inactivation of endogenous genes and position effects can dramatically influence the phenotype of the resultant transgenic animal (reviewed in Chandler et al., 2013; e.g. page 361, column 2, paragraph 4-page 632, column 1, paragraph 4).
Further, the particular genetic elements required for optimal expression varies from species to species. Therefore, constructs that use heterologous genetic elements (i.e. a ubiquitous promoter driving expression of a human codon-optimized SLC13A5 open reading frame in mice) will not always confer the desired phenotype in a mouse. Our lack of understanding of essential genetic control elements makes it difficult to design transgenes with predictable behavior (reviewed in Gama Sosa et al., 2010; e.g. page 95, column 2, paragraph 2).
Finally, different transgenic animal systems all require different considerations regarding methods of generating said transgenic animals and have different rates of success. It is thus accepted in the field that tools for generating transgenic animals must be empirically validated in the model organism of choice and that in vivo results do not always mirror in vitro results (Heston and White, 2017; e.g. page 705, column 1, paragraph 1).
Therefore, in the absence of specific guidance and working examples, the production of any non-human transgenic organism with the breadth of the scope as claimed in claim 29 is unpredictable.
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.
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 1-5, 9, 10, 16, 23-28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett; of record) in view of Inouye et al., 2015 (hereinafter Inouye), as evidenced by Nakamura et al., 2000 (hereinafter Nakamura).
With regard to claim 1, which recites “a polynucleotide comprising a human SLC13A5 open reading frame, wherein the human SLC13A5 open reading frame is codon-optimized for expression in a human cell, and wherein the human SLC13A5 open reading frame comprises a nucleotide sequence having at least 90% identity to SEQ ID NO: 2,” as previously set forth, Barrett discloses codon-optimized polynucleotides with open reading frames encoding therapeutic effector molecules and payload constructs for enhanced expression in human cells and for treatment of patients in need (paragraphs [0027], [0031], [0033], [0042], [0044], [0051], [0170]-[0176], and [0652]; claims 53-57 and 66-68). Barrett further discloses that the payload of the invention may be a nucleic acid sequence corresponding to SEQ ID NO: 182881 and encoding SLC13A5 (paragraph [0103], page 459). As shown in Appendix I, SEQ ID NO: 182881 of Barrett is 63.4% identical to instant SEQ ID NO: 2. Thus, while Barrett does not disclose a polynucleotide comprising a nucleotide sequence having at least 90% identity to instant SEQ ID NO: 2, Barrett does disclose therapeutic, codon-optimized polynucleotides comprising open reading frames encoding molecules such as SLC13A5. Methods of codon-optimizing sequences, specifically methods of human codon-optimizing, are well-known in the art (supported by the disclosure of the instant specification: page 21, lines 11-12).
For example, Inouye discloses human codon optimization of genes resulting in improved protein expression in mammalian cells (abstract; Table 2; Figures 2 and 4). Per Inouye, this “human codon-optimized method” comprises altering the proportions of usage of each codon to closely match human codon usage, avoiding usage of nucleotide sequences corresponding to rare codons, restriction enzyme sites, recognition sites of transcription factors, cryptic splice sites, and polyadenylation signal sequences, as well as increasing GC content (page 47, column 1, paragraph 2). Such methods are straightforward to those of ordinary skill in the art, as human codon usage proportions have been reported in the art, as evidenced by Nakamura (see entire reference; as cited in Inouye: page 47, column 1, paragraph 2). The human codon usage table disclosed in Nakamura was publicly available prior to the effective filing date of the claimed invention, as evidenced by the Wayback Machine, which lists an availability date of 12/04/2007 for said table. The current human codon usage table is identical to that of the table available prior to the effective filing date of the claimed invention.
Furthermore, comparing the methods of the instant invention to the methods of Inouye reveals substantial overlap, as the specification discloses “in human codon-optimization one or more codons in a coding sequence are replaced by codons that occur more frequently in human cells for the same amino acid”, increasing total GC content, and removing regulatory sequences such as Kozak sequences, as well as removing cryptic splice donor or acceptor sites (page 12, lines 12-14), as disclosed in Inouye. Per the instant specification, “a codon-optimized gene exhibits improved protein expression…at a detectably greater level in a cell compared with the level of expression of the protein provided by the wild-type gene in an otherwise similar cell” (page 12, lines 19-22), as is also disclosed in Inouye.
Accordingly, Barrett and Inouye (as evidenced by Nakamura) collectively disclose each and every limitation of instant claim 1, as set forth in greater detail below.
With regard to claim 2, which recites “the human SLC13A5 open reading frame [of the polynucleotide of claim 1] comprises the nucleotide sequence of SEQ ID NO: 2,” as set forth above, while Barrett does not disclose a polynucleotide comprising the nucleotide sequence of instant SEQ ID NO: 2, Barrett does disclose therapeutic, codon-optimized polynucleotides comprising open reading frames encoding molecules such as SLC13A5. Methods of codon-optimizing sequences, specifically methods of human codon-optimizing, are known in the art. For example, as set forth above, Inouye discloses the “human codon-optimized method,” which comprises altering codon usage proportions to more closely match human codon usage and eliminating certain sequences such as cryptic splice sites and transcription factor recognition sites (page 47, column 1, paragraph 2), thereby resulting in improved protein expression in mammalian cells (Table 2; Figures 2 and 4), as in the instant specification (page 12, lines 4-22). Accordingly, Barrett and Inouye (as evidenced by Nakamura) collectively disclose each and every limitation of instant claim 2, as set forth in greater detail below.
With regard to claim 3, which recites “an expression cassette comprising a polynucleotide comprising a human SLC13A5 open reading frame, wherein the human SLC13A5 open reading frame is codon-optimized for expression in a human cell, and wherein the human SLC13A5 open reading frame comprises a nucleotide sequence having at least 90% identity to SEQ ID NO: 2,” Barrett further discloses expression vectors comprising the polynucleotide sequence comprising an SLC13A5 open reading frame as set forth above, as well as a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]). Per the instant specification, expression vectors are synonymous with expression constructs and expression cassettes, all of which “are for the expression of the exogenous gene in the target cell, and generally have a promoter sequence that drives expression of the exogenous gene” (page 15, lines 21-24). Thus, it is considered that the expression vector of Barrett reads on the instantly claimed expression cassette. Accordingly, Barrett discloses the additional limitations of instant claim 3.
With regard to claim 4, which recites “the human SLC13A5 open reading frame [of the expression cassette of claim 3] comprises the nucleotide sequence of SEQ ID NO: 2,” as set forth above, while Barrett does not disclose a polynucleotide comprising the nucleotide sequence of instant SEQ ID NO: 2, Barrett does disclose therapeutic, codon-optimized polynucleotides comprising open reading frames encoding molecules such as SLC13A5, as well expression vectors comprising the same. Methods of codon-optimizing sequences, specifically methods of human codon-optimizing, are known in the art. For example, Inouye discloses human codon optimization of genes by selecting only preferentially used human codons (abstract), resulting in improved protein expression in mammalian cells (Table 2; Figures 2 and 4). Accordingly, Barrett and Inouye collectively disclose each and every limitation of instant claim 4, as set forth in greater detail below.
With regard to claim 5, which recites “the human SLC13A5 open reading frame [of the expression cassette of instant claim 3] is operably linked to a promoter,” as set forth above regarding instant claim 3, Barrett discloses expression vectors comprising said polynucleotide sequence comprising an open reading frame, as well as a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]). Per the instant specification, the term “operably linked” denotes functional linkage between nucleic acids, such as initiating and/or mediating transcription (page 11, lines 28-33). Accordingly, Barrett discloses the additional limitations of instant claim 5.
With regard to claim 9, which recites “the expression cassette of claim 3, further compris[es] at least one adeno-associated virus (AAV) inverted terminal repeat (ITR),” as set forth above regarding instant claims 3 and 5, Barrett discloses expression vectors comprising the instantly claimed polynucleotide sequence as well as a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]). Barrett further discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors comprising at least one or two inverted terminal repeats (paragraphs [0500] and [0513]). Accordingly, Barrett discloses the additional limitations of instant claim 9.
With regard to claim 10, which recites “the expression cassette of claim 9, wherein the expression cassette comprises two AAV ITRs,” as set forth above regarding instant claim 9, Barrett discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors comprising at least one or two inverted terminal repeats (paragraphs [0500] and [0513]). Accordingly, Barrett discloses the additional limitations of instant claim 10.
With regard to claim 16, which recites “the expression cassette [of claim 3] is a self-complementary AAV genome,” as set forth above, Barrett discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors comprising at least one or two inverted terminal repeats (paragraphs [0500] and [0513]). Barrett further discloses that the AAV vectors taught therein may be self-complementary AAV vectors, which facilitate rapid expression of the therapeutic payload polynucleotide in cells (paragraph [0510]). Accordingly, Barrett discloses the additional limitations of instant claim 16.
With regard to claim 23, which recites “a vector comprising the polynucleotide of claim 1 or the expression cassette of claim 3,” as set forth above, Barrett discloses both expression vectors comprising an open reading frame and a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]), as well as delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors comprising at least one or two inverted terminal repeats (paragraphs [0500] and [0513]). Accordingly, Barrett discloses the additional limitations of instant claim 23.
With regard to claim 24, which recites “the vector [of claim 23] is a viral vector,” the recombinant AAV vectors disclosed in Barrett and set forth above are viral vectors (paragraphs [0483], [0500], and [0513]). Accordingly, Barrett discloses the additional limitations of instant claim 24.
With regard to claim 25, which recites “the vector [of claim 23] is an AAV vector,” as set forth above, Barrett discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors (paragraphs [0500] and [0513]). Accordingly, Barrett discloses the additional limitations of instant claim 25.
With regard to claim 26, which recites “the AAV vector [of claim 25] is an AAV9 vector,” as set forth above, Barrett discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors (paragraphs [0500] and [0513]). Barrett further discloses that these rAAV vectors may utilize the AAV9 serotype capsid (paragraphs [0500], [0501], and [0503]). Accordingly, Barrett discloses the additional limitations of instant claim 26.
With regard to claim 27, which recites “a transformed cell comprising the polynucleotide of claim 1, an expression cassette comprising said polynucleotide, [or] a vector comprising said polynucleotide and/or said expression cassette,” as set forth above, Barrett and Inouye collectively disclose the polynucleotide of instant claim 1, as well as vectors comprising the same. Barrett further discloses that the invention taught therein also provides a cell comprising any of the expression vectors described therein (paragraph [0037]). Accordingly, Barrett discloses the additional limitations of instant claim 27.
With regard to claim 28, which recites “the polynucleotide, expression cassette, and/or vector [of the transformed cell of claim 27] is stably incorporated into the cell genome,” as set forth above, Barrett discloses therapeutic, codon-optimized polynucleotides comprising open reading frames encoding molecules such as SLC13A5, as well expression vectors and transformed cells comprising the same. The polynucleotide constructs of Barrett may be delivered via lentiviral or retroviral vectors that facilitate integration of a transgene in target cells (paragraphs [0490], [0491], and [0516]). Accordingly, Barrett discloses the additional limitations of instant claim 28.
With regard to claim 30, which recites “a pharmaceutical composition comprising the polynucleotide of claim 1, an expression cassette comprising said polynucleotide, [or] a vector comprising said polynucleotide and/or said expression cassette,” as set forth above, Barrett and Inouye collectively disclose the polynucleotide of instant claim 1, as well as vectors comprising the same. Barrett further discloses that the invention taught therein also provides pharmaceutical compositions comprising one or more of the effector modules or systems described therein (paragraph [0337]). Accordingly, Barrett discloses the additional limitations of instant claim 30.
In summary, Barrett discloses therapeutic polynucleotides comprising open reading frames encoding molecules such as SLC13A5, wherein said therapeutic polynucleotides are codon optimized to enhance gene expression in the targeted host organism, specifically in humans, as Barrett discloses that the targeted cells taught therein are preferably human cells such as regulatable human T cells engineered to express effector molecules, such as SLC13A5 as set forth above (paragraphs [0042], [0171], and [0652]). Such methods of human codon optimization are known in the art, as disclosed in Inouye. Inouye discloses a method of codon optimization termed the “human codon-optimized method,” which comprises altering codon usage proportions to more closely match human codon usage (taught in Nakamura) and eliminating certain sequences such as cryptic splice sites and transcription factor recognition sites, thereby resulting in improved protein expression in mammalian cells (abstract; page 47, column 1, paragraph 2; Table 2; Figures 2 and 4). Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to codon optimize the open reading frames as disclosed in Barrett to enhance expression of the same via known codon-optimization methods, such as the methods disclosed in Inouye to predictably enhance expression of the therapeutic SLC13A5 open reading frame in human cells. One would have been motivated to make such a modification in order to receive the expected benefit of providing a codon-optimized nucleic acid construct encoding SLC13A5 capable of expressing at higher levels than wild-type SLC13A5 in human cells, thereby providing enhanced therapeutic benefit.
Claims 6, 7, 12, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett; of record) in view of Inouye et al., 2015 (hereinafter Inouye), as evidenced by Nakamura et al., 2000 (hereinafter Nakamura), as applied to claims 3, 5, 9, and 10 above, and further in view of Karumuthil-Melethil et al., 2016 (hereinafter Karumuthil-Melethil; of record).
The disclosures of Barrett and Inouye (as evidenced by Nakamura) are described above and applied as before. However, these disclosures do not teach the additional components of the expression cassette of instant claim 3 set forth in instant claims 6, 7, 12, 13, and 15.
With regard to claim 6, which recites “the promoter [of the expression cassette of claim 5] is a UsP promoter,” as set forth above regarding instant claim 3, Barrett discloses expression vectors comprising said polynucleotide sequence comprising an open reading frame, as well as a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]). However, Barrett does not disclose the instantly claimed UsP promoter. This deficiency is cured by Karumuthil-Melethil, which discloses a novel capsid and cassette design capable of efficiently transducing cells (abstract). The AAV vectors disclosed in Karumuthil-Melethil comprise a short synthetic and ubiquitous promoter derived from the JeT promoter and a synthetic intron, which is referred to as the UsP promoter or the JeTI promoter (page 511, column 2, paragraph 4-page 512, column 1, paragraph 1; Figure 1). Karumuthil-Melethil further discloses that the UsP promoter construct taught therein displays ubiquitous expression throughout the central nervous system when incorporated into a therapeutic self-complementary AAV vector (page 519, column 1, paragraph 1). Accordingly, Karumuthil-Melethil discloses each and every additional limitation of instant claim 6.
With regard to claim 7, which recites “the human SLC13A5 open reading frame [of the expression cassette of claim 3] is operably linked to a polyadenylation signal,” Karumuthil-Melethil further discloses that the AAV vectors taught therein comprise an SV40 polyA signal, which facilitates expression of the gene encoded therein (page 511, column 2, paragraph 4-page 512, column 1, paragraph 1; Figure 1). Accordingly, Karumuthil-Melethil discloses each and every additional limitation of instant claim 7.
With regard to claim 12, which recites “the two AAV ITRs [of the expression cassette of claim 10] have different nucleotide sequences,” as shown in Figure 1 of Karumuthil-Melethil, the AAV constructs comprising the expression cassettes taught therein include both a mutant ITR and a wild-type AAV2 ITR flanking the disclosed expression cassette elements (Figure 1). As is known to those of ordinary skill in the art, a mutant ITR must necessarily comprise a different nucleotide sequence than a wild-type ITR. Accordingly, Karumuthil-Melethil discloses each and every additional limitation of instant claim 12.
With regard to claim 13, which recites “one of the two AAV ITRs [of the expression cassette of claim 10] is a modified ITR,” as set forth above, Figure 1 of Karumuthil-Melethil illustrates that the AAV constructs comprising the expression cassettes taught therein include both a mutant ITR and a wild-type AAV2 ITR flanking the disclosed expression cassette elements (Figure 1). As is known to those of ordinary skill in the art, a mutant ITR must necessarily be an ITR modified from its wild-type sequence. Accordingly, Karumuthil-Melethil discloses each and every additional limitation of instant claim 13.
With regard to claim 15, which recites “at least one of the AAV ITRs [of the expression cassette of claim 9] is an AAV2 ITR,” as set forth above, Figure 1 of Karumuthil-Melethil illustrates that the AAV constructs comprising the expression cassettes taught therein include both a mutant ITR and a wild-type AAV2 ITR flanking the disclosed expression cassette elements (Figure 1). Accordingly, Karumuthil-Melethil discloses each and every additional limitation of instant claim 15.
Given that Barrett and Inouye (as evidenced by Nakamura) collectively disclose the instantly claimed expression cassette, as set forth above, and that Karumuthil-Melethil discloses AAV vectors (including self-complementary AAV vectors) suitable for therapeutic use comprising the ubiquitous UsP promoter, AAV ITRs comprising a mutant ITR and a wild-type AAV2 ITR, as well as an SV40 polyA signal to facilitate expression of the gene encoded therein, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the expression cassette disclosed in Barrett and Inouye to comprise the UsP promoter, the SV40 polyA signal, and the ITRs disclosed in Karumuthil-Melethil to predictably ubiquitously express the therapeutic genes encoded therein, particularly in the central nervous system. One would have been motivated to make such a modification in order to receive the expected benefit of providing a vector capable of ubiquitously expressing the therapeutic genes encoded therein, particularly in the central nervous system.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett; of record) in view of Inouye et al., 2015 (hereinafter Inouye), as evidenced by Nakamura et al., 2000 (hereinafter Nakamura), as applied to claim 3 above, further in view of Karumuthil-Melethil et al., 2016 (hereinafter Karumuthil-Melethil; of record) as applied to claim 7 above, and further in view of Azzoni et al., 2007 (hereinafter Azzoni; of record).
The combined disclosures of Barrett, Inouye (as evidenced by Nakamura), and Karumuthil-Melethil are described above and applied as before. However, these disclosures do not teach the synthetic polyadenylation signal of instant claim 8.
With regard to claim 8, which recites “the polyadenylation signal [of the expression cassette of claim 7] is a synthetic polyadenylation signal,” as set forth above, Barrett discloses expression vectors comprising said polynucleotide sequence comprising an open reading frame, as well as a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]), while Karumuthil-Melethil discloses that the AAV vectors taught therein comprise an SV40 polyA signal to facilitate expression of the gene encoded therein (page 511, column 2, paragraph 4-page 512, column 1, paragraph 1; Figure 1). However, neither Barrett nor Karumuthil-Melethil disclose a synthetic polyadenylation signal, as instantly claimed. This deficiency is cured by Azzoni, which discloses that synthetic polyadenylation signals (and sequences) significantly improve nuclease resistance and overall stability, which may facilitate higher transfection levels as a direct result of increased resistance (abstract; page 393, column 1, paragraph 3; page 400, column 2, paragraph 1; page 402, column 1, paragraph 2). Accordingly, Azzoni discloses each and every additional limitation of instant claim 8.
Given that Barrett, Inouye (as evidenced by Nakarmua), and Karumuthil-Melethil collectively disclose the instantly claimed expression cassette comprising a human SLC13A5 open reading frame operably linked to a polyadenylation signal (as set forth above), and that Azzoni discloses that the synthetic polyadenylation signals disclosed therein facilitate higher transfection levels as a direct result of increased resistance (i.e. to nucleases), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the expression cassette collectively disclosed in Barrett, Inouye, and Karumuthil-Melethil such that it comprises the synthetic polyadenylation signal taught in Azzoni in place of the SV40 polyadenylation signal taught in Karumuthil-Melethil to predictably facilitate higher transfection levels directly resulting from increased resistance (i.e. to nucleases) of therapeutic vectors conferred by said synthetic polyadenylation signal. One would have been motivated to make such a modification in order to receive the expected benefit of facilitating higher transfection levels directly resulting from increased resistance (i.e. to nucleases) of therapeutic vectors conferred by said synthetic polyadenylation signal.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett; of record) in view of Inouye et al., 2015 (hereinafter Inouye) as evidenced by Nakamura et al., 2000 (hereinafter Nakamura), as applied to claims 3, 9, and 10 above, and further in view of WO 2017/218450 A1 (hereinafter Gray; as cited in the IDS dated 01/20/2023; of record).
The disclosures of Barrett and Inouye (as evidenced by Nakamura) are described above and applied as before. However, these disclosures do not teach the two identical AAV ITRs of instant claim 11.
With regard to claims 11 and 12, which respectively recite “the two AAV ITRs [of the expression cassette of claim 10] have the same nucleotide sequence,” or “different nucleotide sequences,” as set forth above, Barrett discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors comprising at least one or two inverted terminal repeats (ITRs) (paragraphs [0500] and [0513]). However, Barrett does not specifically disclose whether these ITRs have the same or different nucleotide sequences. This deficiency is cured by Gray, which discloses polynucleotides comprising an optimized CLN1 open reading frame, as well as expression cassettes and viral vectors comprising the same, for delivering said optimized open reading frame to a human cell for expression in said human cell (abstract; paragraphs [0007] and [0008]). Gray specifically discloses that the expression cassettes taught therein may comprise two AAV ITRs with the same or different nucleotide sequences, both combinations of which may be part of codon-optimized expression cassettes capable of expressing polynucleotides in human cells (paragraphs [0008] and [0108]). Thus, Gray discloses expression cassettes comprising a codon-optimized open reading frame and two AAV ITRs, which may be different or identical to each other, wherein said expression cassettes are capable of expressing codon-optimized polynucleotides in human cells (paragraphs [0008] and [0108]). Therefore, Gray discloses that expression cassettes comprising two different or identical AAV ITRs are both capable of expressing codon-optimized polynucleotides in human cells, thereby disclosing each and every additional limitation of instant claims 11 and 12.
Given that Barrett and Inouye (as evidenced by Nakamura) collectively disclose the instantly claimed expression cassette comprising two AAV ITRs, as set forth above, and that Gray discloses therapeutic expression cassettes comprising a codon-optimized open reading frame as well as two AAV ITRs (with identical or different nucleotide sequences), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the therapeutic construct disclosed in Barrett and Inouye such that it comprises two AAV ITRs (as disclosed in Barrett) with either identical or different nucleotide sequences (as disclosed in Gray) to predictably express a codon-optimized open reading frame nucleic acid sequence in a human cell. One would have been motivated to make such a modification in order to receive the expected benefit of expressing a codon-optimized open reading frame nucleic acid sequence in a human cell.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett; of record) in view of Inouye et al., 2015 (hereinafter Inouye) as evidenced by Nakamura et al., 2000 (hereinafter Nakamura), as applied to claim 3, 9, and 10 above, and further in view of US 2004/00029106 A1 (hereinafter Samulski; of record).
The disclosures of Barrett and Inouye (as evidenced by Nakamura) are described above and applied as before. However, these disclosures do not teach the ITR D-element deletion of instant claim 14.
With regard to claim 14, which recites “one of the two AAV ITRs [of the expression cassette of claim 10] is a D-element deletion modified ITR,” as set forth above, Barrett discloses delivery of the payload polynucleotide sequences taught therein via recombinant AAV vectors comprising at least one or two inverted terminal repeats (ITRs) (paragraphs [0500] and [0513]). However, Barrett does not disclose that one of the two AAV ITRs is a D-element deletion modified ITR. However, this deficiency is cured by Samulski, which discloses improved parvovirus-based gene delivery vectors such as AAV vectors with non-resolvable terminal repeat sequences (paragraphs [0003]-[0005] and [0013]). Samulski discloses that these sequences may be rendered non-resolvable by deletion of the D-element (paragraphs [0076], [0202], and [0204]). Samulski discloses that the resulting AAV vectors generated therein are improved parvovirus gene delivery vectors that address the requirement for complementary strand synthesis by conventional AAV gene delivery vectors (paragraph [0007]). Accordingly, Samulski discloses each and every additional limitation of instant claim 14.
Given that Barrett and Inouye collectively disclose the instantly claimed expression cassette comprising two AAV ITRs, as set forth above, and that Samulski discloses improved parvovirus gene delivery vectors (specifically AAV vectors) comprising non-resolvable terminal repeat sequences generated by deletion of the D-element, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the therapeutic construct disclosed in Barrett and Inouye such that it comprises an ITR with a deleted D-element (as disclosed in Samulski) to predictably generate an improved gene delivery vector to effectively deliver the polynucleotide within said cassette. One would have been motivated to make such a modification in order to receive the expected benefit of generating an improved gene delivery vector to effectively deliver the polynucleotide within said cassette.
Claims 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0192691 A1 (hereinafter Barrett; of record) in view of Inouye et al., 2015 (hereinafter Inouye) as evidenced by Nakamura et al., 2000 (hereinafter Nakamura), as applied to claim 3 above, and further in view of Levitt et al., 1989 (hereinafter Levitt; of record), Karumuthil-Melethil et al., 2016 (hereinafter Karumuthil-Melethil; of record), and WO 2017/218450 A1 (hereinafter Gray; as cited in the IDS dated 01/20/2023; of record).
The disclosures of Barrett and Inouye (as evidenced by Nakamura) are described above and applied as before. However, these disclosures do not teach the additional limitations regarding the structure of the expression cassette of instant claims 17-21.
With regard to claim 17, which recites “the expression cassette [of claim 3] comprises a promoter, the human SLC13A5 open reading frame, and a polyadenylation site,” as set forth above regarding instant claim 3, Barrett and Inouye collectively disclose a codon-optimized human SLC13A5 open reading frame comprising a nucleotide sequence having at least 90% identity to SEQ ID NO: 2. Barrett further discloses expression vectors (or cassettes, as per the instant specification and set forth above) comprising said polynucleotide sequence comprising an open reading frame, as well as a promoter to drive expression of the same (paragraphs [0036], [0484], [0485], and [0488]). While Barrett does disclose that the polynucleotides taught therein comprise at least one RNA-binding motif to facilitate polyadenylation mediated by RNA binding proteins (paragraphs [0156] and [0157]), Barrett does not disclose the instantly claimed polyadenylation site. This deficiency is cured by Gray, which (as set forth above) discloses polynucleotides comprising an optimized CLN1 open reading frame, as well as expression cassettes and viral vectors comprising the same, for delivering said optimized open reading frame to a cell or a subject, thereby treating diseases such as infantile neuronal lipofuscinosis (abstract; paragraph [0007]). Gray further discloses that the expression cassettes taught therein may also comprise a polyadenylation site (paragraph [0109]; claims 19 and 20). Levitt discloses that poly(A) sites are critical for producing stable mRNA from any given nucleotide sequence encoding a gene of interest and further that poly(A) sites display dramatically different efficiencies in producing stable mRNA from different genes (abstract; page 1019, column 1, paragraph 1-page 1019, column 2, paragraph 1). Accordingly, Gray and Levitt disclose each and every additional limitation of instant claim 17.
With regard to claim 18, which recites “the expression cassette [of claim 3] comprises an AAV ITR, a promoter, the human SLC13A5 open reading frame, a polyadenylation site, and an AAV ITR,” as set forth above, the expression vectors of Barrett are further disclosed to comprise at least one or two AAV ITRs in addition to the previously addressed polynucleotide sequence and promoter (paragraphs [0036], [0484], [0485], [0488], [0500], and [0513]). Additionally, as set forth above, Gray discloses therapeutic expression cassettes comprising a polyadenylation site (paragraph [0109]; claims 19 and 20), while Levitt discloses that poly(A) sites are critical for producing stable mRNA (abstract; page 1019, column 1, paragraph 1-page 1019, column 2, paragraph 1). Accordingly, Barrett, Gray, and Levitt collectively disclose each and every additional limitation of instant claim 18.
With regard to claim 19, which recites “the expression cassette [of claim 3] comprises an AAV ITR, a UsP promoter, the human SLC13A5 open reading frame, a synthetic polyadenylation site, and an AAV ITR,” as set forth above, Barrett, Gray, and Levitt collectively disclose an expression cassette comprising two AAV ITRs, a human SLC13A5 open reading frame, a promoter, and a polyadenylation site. As set forth above, the AAV vectors disclosed in Karumuthil-Melethil comprise a short synthetic and ubiquitous promoter derived from the JeT promoter and a synthetic intron, which is referred to as the UsP promoter or the JeTI promoter (page 511, column 2, paragraph 4-page 512, column 1, paragraph 1; Figure 1). Karumuthil-Melethil further discloses that the UsP promoter construct taught therein displays ubiquitous expression throughout the central nervous system when incorporated into a therapeutic self-complementary AAV vector (page 519, column 1, paragraph 1). Additionally, Levitt discloses the generation of a synthetic poly(A) site that functions with full efficiency when placed at the appropriate location within the queried gene region (Figure 1; page 1019, column 2, paragraph 2-page 1020, column 1, paragraph 1; page 1023, column 2, paragraph 1). Accordingly, Barrett, Gray, Levitt, and Karumuthil-Melethil collectively disclose each and every additional limitation of instant claim 19.
With regard to claim 20, which recites “the expression cassette [of claim 3] comprises an AAV ITR, a UsP promoter, the human SLC13A5 open reading frame, a synthetic polyadenylation site, and an AAV2 ITR,” as set forth above, Barrett, Gray, Levitt, and Karumuthil-Melethil collectively disclose an expression cassette comprising two AAV ITRs, a human SLC13A5 open reading frame, a UsP promoter, and a synthetic polyadenylation site. Additionally, as set forth above, Figure 1 of Karumuthil-Melethil illustrates that the AAV constructs comprising the expression cassettes taught therein include both a mutant ITR and a wild-type AAV2 ITR flanking the disclosed expression cassette elements (Figure 1). Accordingly, Barrett, Gray, Levitt, and Karumuthil-Melethil collectively disclose each and every additional limitation of instant claim 20.
With regard to claim 21, which recites “the expression cassette [of claim 3] comprises a modified AAV2 ITR, a UsP promoter, the human SLC13A5 open reading frame, a synthetic polyadenylation site, and a wildtype AAV2 ITR,” as set forth above, Barrett, Gray, Levitt, and Karumuthil-Melethil collectively disclose an expression cassette comprising two AAV ITRs (one of which is an AAV2 ITR), a human SLC13A5 open reading frame, a UsP promoter, and a synthetic polyadenylation site. While Karumuthil-Melethil discloses that the AAV constructs taught therein comprise both a mutant ITR and a wild-type AAV2 ITR, Karumuthil-Melethil does not disclose from which AAV serotype the mutant ITR was derived. However, this deficiency is cured by Gray. As set forth above, Gray discloses therapeutic expression cassettes, said cassettes comprising a mutant AAV2 ITR and a wild-type AAV2 ITR (paragraph [0170]; Figure 1). Accordingly, Barrett, Gray, Levitt, and Karumuthil-Melethil collectively disclose each and every additional limitation of instant claim 21.
Given that Barrett and Inouye (as evidenced by Nakamura) collectively disclose therapeutic codon-optimized polynucleotides comprising an SLC13A5 open reading frame, as well as expression vectors/cassettes comprising the same (in addition to AAV ITRs and a promoter), that Gray discloses therapeutic expression cassettes comprising a polyadenylation site (taught to be critical for producing stable mRNA in Levitt) and a mutant AAV2 ITR, that Levitt discloses a fully efficient synthetic poly(A) site, and that Karumuthil-Melethil discloses AAV constructs comprising a mutant ITR, a wild-type AAV2 ITR, and a UsP promoter, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the expression cassettes of Barrett to comprise the (synthetic) polyadenylation sites taught in Gray and Levitt, the UsP promoter disclosed in Karumuthil-Melethil, and the mutant AAV2 ITR disclosed in Gray to predictably and ubiquitously produce a stable, therapeutic mRNA from said expression vector, particularly in the central nervous system (as disclosed in Karumuthil-Melethil). One would have been motivated to make such a modification in order to receive the expected benefit of providing a vector capable of ubiquitously producing a stable, therapeutic mRNA from said expression vector, particularly in the central nervous system.
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.
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Claims 1-7, 9-10, 12, 17-19, 22-26, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-9 of copending Application No. 18/683,101 (reference application; corresponds to US 2024/0342314 A1; of record). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed subject matter reads on the subject matter of copending claims 1-4 and 6-8, as set forth in greater detail below.
Copending application ‘101 is drawn to an rAAV vector comprising a codon-optimized SLC13A5 nucleic acid sequence (corresponding to SEQ ID NO: 3 and encoding SEQ ID NO: 1 claimed therein), a promoter sequence (corresponding to SEQ ID NO: 21 claimed therein), a polyA sequence, two AAV ITRs of different nucleotide sequences, and an AAV capsid protein such as the AAV9 capsid (copending claims 1-4, 7, and 8). Copending claim 6 further recites that the rAAV vector comprises the nucleic acid sequence of SEQ ID NO: 38. Copending claim 9 recites a pharmaceutical composition comprising the rAAV vector of copending claim 7, which is set forth above.
Regarding the instant application, the subject matter claimed therein is also drawn to AAV vectors comprising a polynucleotide (instant claims 1 and 2) or an expression cassette (instant claims 3 and 4) encoding human SLC13A5 and an AAV9 capsid (instant claims 23-26), as well as a pharmaceutical composition comprising said vector (instant claim 30). The expression cassette (of the instantly claimed vector) is further recited to comprise a UsP promoter (instant claims 5 and 6), a polyadenylation signal or site (instant claims 7 and 17-19), as well as two AAV ITRs (instant claims 9 and 10) with different nucleotide sequences (instant claim 12). Additionally, the expression cassette claimed therein is recited to comprise the nucleotide sequence of instant SEQ ID NO: 5, or a sequence at least about 90% identical thereto (instant claim 22).
Thus, both the copending and instant applications are drawn to codon-optimized SLC13A5 nucleic acid sequences (defined as SEQ ID NO: 3 in copending application ‘101 and as SEQ ID NO: 2 in the instant application), as well as vectors comprising the same. As shown in Appendix II, copending SEQ ID NO: 3 is 100% identical to instant SEQ ID NO: 2. Accordingly, both the copending and instant applications are drawn to the same codon-optimized SLC13A5 nucleic acid sequence. Additionally, the AAV vector of the copending application (which comprises the nucleic acid sequence of SEQ ID NO: 38) comprises 100% identity to the instantly claimed expression cassette sequence (instant SEQ ID NO: 5), as shown in Appendix III. Furthermore, while the copending application does not recite that the promoter claimed therein is a UsP promoter (as in instant claims 6 and 19) the promoter sequence of SEQ ID NO: 21 claimed therein (copending claim 4) comprises 100% identity to instant SEQ ID NO: 3 (as shown in Appendix IV), which is disclosed to correspond to the UsP promoter in the instant specification (page 24, lines 3-9). Accordingly, the promoter of copending claim 4 is considered to read on the instantly claimed UsP promoter (instant claims 6 and 19).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Claims 2 and 4 are objected to.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637