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 .
Status of Claims
Claims 7, 17-20, 23, 33, 40, 42-46 and 51-56 are pending following the Reply filed 03/02/2026. Claims 1, 5-6, 24, 39 and 41 have been cancelled. Claims 7, 17-20, 23, 33 and 40 have been amended without introducing new matter. Claims 52-56 have been added without introducing new matter. Claims 42-46 and 51 remain withdrawn. Accordingly, claims 7, 17-20, 23, 33, 40 and 52-56 are presently considered.
Election/Restriction
The restriction requirement filed on 07/16/2025 is maintained, and Applicant’s election of Group I in the Reply filed 09/04/2025 remains in effect. Newly added claims 52-56 read upon the elected invention of Group I and are considered herein.
Withdrawn
The objections to the drawings are withdrawn in light of the replacement drawings filed 03/02/2026.
Any objection to or rejection of claims 1, 5-6, 24, 39 or 41 is moot because the claims are cancelled.
The objection to claim 17 is withdrawn in light of the amendments.
The written description rejection under 35 U.S.C. 112(a) is withdrawn in light of the amendments. In particular, independent claim 7 has been amended to require the nucleic acid sequence of SEQ ID NO: 2. See Response to Arguments for further discussion.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Venditti et al. (US 20160040150 A1; cited in the IDS filed 03/15/2023), hereafter, “Venditti”.
Regarding claim 7, Venditti teaches a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMMUT) consisting of a polynucleotide comprising the nucleic acid sequence of SEQ ID NO: 1 (see claim 1, part (a)). As shown in the following alignment, instant SEQ ID NO: 2 (top) is identical to Venditti’s SEQ ID NO: 1 (bottom):
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Hence, Venditti teaches a synthetic methylmalonyl-CoA mutase polynucleotide (synMMUT) comprising the nucleic acid sequence of instant SEQ ID NO: 2.
Venditti teaches an expression vector comprising the synthetic polynucleotide of claim 1 (see claim 7) and discloses that the vector used for gene therapy comprises an expression cassette comprising the synthetic polynucleotide (see pg. 8, para. [0076]). Hence, Venditti teaches a gene expression cassette comprising the synthetic polynucleotide.
Venditti teaches the expression vector is AAV2/8-HCR-hAAT-synMUT-RBG (see claim 8). Figure 7 of Venditti presents a map of the AAV-HCR-hAAT-synMUT construct (see pg. 2, para. [0036]), as shown below:
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Hence, Venditti teaches the gene expression cassette comprising (a) a 5’-inverted terminal repeat sequence (5’-ITR) sequence and a 3’-inverted terminal repeat sequence (3’-ITR) sequence, which meets the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 18, 20, 23, 40 and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venditti as applied to claim 7 above, and further in view of Carrillo-Carrasco et al. (“Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction”, Human Gene Therapy, 21(9): 1147-1154 (2010); cited in the IDS filed 03/15/2023 at Doc. No. A25), hereafter, “Carrillo”.
Regarding claim 18, Venditti teaches a recombinant expression vector comprising a synthetic methylmalonyl-CoA mutase polynucleotide, as discussed above. Venditti teaches methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in the mitochondrial localized enzyme methylmalonyl-CoA mutase (MUT) (see pg. 1, para. [0005]), and that the synthetic human methylmalonyl-CoA mutase (synMUT) can be used via viral-mediated gene delivery to restore MUT function in MMA patients (see pg. 1, para. [0006]). Venditti further teaches an adeno-associated viral (AAV) gene therapy vector, AAV2/8-HCR-hAAT-synMUT-RBG (see Abstract).
Venditti further teaches that the human codon-optimized methylmalonyl-CoA mutase (synMUT) was cloned into AAV2-HCR-hAAT-RBG and packaged into rAAV8 (see pg. 9, para. [0092]), and hence, meets the limitation of a “recombinant adeno-associated virus (rAAV)”.
Venditti does not explicitly teach said rAAV comprises an AAV “capsid”.
However, Venditti teaches that compositions of the disclosure may comprise a therapeutically effective amount of “a viral particle” produced by or obtained from a vector comprising the synMUT transgenes (see pg. 8, para. [0082]). Venditti teaches the rAAV was packaged into rAAV8 “as previously described” in “Carrillo-Carrasco, et al. 2010 Hum Gene Ther 21:1147-54” (see pg. 9, para. [0092]). Examiner notes that the term “viral particles” is subsequently used in Venditti’s Examples to refer to the composition in the steps that follow the “packaging” step (see pg. 9, para. [0092]). Hence, the use of this term would reasonably suggest to a person of ordinary skill that the packaging “into rAAV8” involves a viral capsid (i.e., “packaging into an rAAV8 capsid”), because without a capsid, the only “particles” would be the genetic material itself.
Nonetheless, Carrillo, which is directly referenced by Venditti, teaches that methylmalonic acidemia is a severe metabolic disorder caused by a deficiency of the ubiquitously expressed mitochondrial enzyme, methylmalonyl-CoA mutase (MUT) and discloses that a recombinant adeno-associated virus serotype 8 expressing the Mut gene under the control of a promoter was sufficient to rescue Mut-deficient mice (see Abstract). Regarding the construction and production of rAAVs, Carrillo explicitly states that “the vector genomes were packaged into an AAV8 capsid” (see pg. 1148, col. 2, para. 1).
It would have been obvious at the time of filing to have arrived at the claimed invention by combining the teachings of Venditti and Carrillo, because both references pertain to solving the same problem by the same methods, wherein Venditti explicitly relies upon Carrillo’s teachings as they relate to rAAV packaging. A person of ordinary skill in the art would have recognized from Carrillo that the packaging of rAAV into AAV8, taught by Venditti, refers to the packaging of the recombinant viral genome into an AAV8 capsid. One would have been motivated to do so, in accordance with the teachings of both disclosures, because both references teach that viral-mediated delivery of MUT may be effective to treat methylmalonic acidemia, a severe metabolic disorder. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103). Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g. MPEP 2121(I)) for all that it discloses (see, e.g., MPEP 2123(I)-(II)).
Regarding claim 20, Venditti and Carrillo teach the AAV capsid is from an AAV of serotype 8 (AAV8), as discussed above.
Regarding claim 23, Venditti and Carrillo teach the AAV capsid is from an AAV of serotype 8 (AAV8), as discussed above.
Regarding claim 40, Venditti teaches a composition comprising the synthetic polynucleotide and a pharmaceutically acceptable carrier (see pg. 2, para. [0023]). Venditti also teaches the pharmaceutical composition may comprise a therapeutically effective amount of a vector comprising the synMUT transgenes (see pg. 8, para. [0082]). Hence, Venditti teaches a composition comprising the recombinant expression vector and a pharmaceutically acceptable carrier.
Regarding claim 53, the claim is obvious for the same reasons as claims 23 and 40.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venditti as applied to claim 7 above, and further in view of Logan et al. (US 2018/0142260 A1; cited on Form 892), hereafter, “Logan”.
Regarding claim 56, Venditti teaches a recombinant expression vector comprising a synthetic methylmalonyl-CoA mutase polynucleotide, as discussed above. Venditti teaches methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in the mitochondrial localized enzyme methylmalonyl-CoA mutase (MUT) (see pg. 1, para. [0005]), and that the synthetic human methylmalonyl-CoA mutase (synMUT) can be used via viral-mediated gene delivery to restore MUT function in MMA patients (see pg. 1, para. [0006]). Venditti further teaches an adeno-associated viral (AAV) gene therapy vector, AAV2/8-HCR-hAAT-synMUT-RBG (see Abstract).
Venditti teaches the gene expression cassette comprising the synthetic polynucleotide and the viral genome comprising a 5’-ITR and 3’-ITR, as discussed regarding claim 7. Venditti discloses an AAV2/8-HCR-hAAT-RBG vector that contained terminal repeats from AAV serotype 2 flanking the expression cassette (see pg. 9, para. [0092]).
Venditti does not teach wherein the 5’-ITR and 3’-ITR are independently selected from SEQ ID NOs: 4, 5, and 22.
Interpretation: The examiner notes that if the ITRs are “independently selected” that they may each comprise the same or different SEQ ID NOs.
Logan’s disclosure relates to promoters derived from the AAV anti-sense strand, their use in the expression of one or more heterologous coding sequences, and isolated polynucleotides, vectors and recombinant viruses comprising the promoters (see Abstract). Logan’s disclosure also relates to enhancers derived from the AAV anti-sense strand, their use in increasing the expression of one or more heterologous coding sequences, and isolated polynucleotides, vectors and recombinant viruses comprising the enhancers (see Abstract). Logan teaches that the expression of heterologous coding sequences is widely used across many fields and industries, in particular the medical and biotechnology industries, typically in order to treat a disease or condition, generally referred to as gene therapy (see pg. 1, para. [0003]).
Logan teaches that the adeno-associated virus (AAV) is a replication-deficient parvovirus, the single-stranded DNA genome of which is about 4.7 kb in length including 145 nucleotide inverted terminal repeat (ITRs), which play a role in the integration of the AAV DNA into the host cell genome, and AAV can be exploited to introduce heterologous coding sequences into cells (see pg. 1, para. [0004]). Logan teaches that recombinant AAVs containing a genome that lacks some or most of the native AAV genome and instead contains one or more heterologous coding sequences flanked by the ITRs have been successfully used in gene therapy settings (see pg. 1, para. [0005]).
Logan teaches that in such vectors, the 5’ ITR and 3’ ITR may be derived from AAV viruses of the same or different serotypes and can comprise the AAV2 ITR set forth in SEQ ID NO: 32 (see pg. 2, para. [0019]). As shown in the following alignment, instant SEQ ID NO: 5 (top) is identical to Logan’s SEQ ID NO: 32 (bottom):
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It would have been obvious at the time of filing for a person of ordinary skill to have arrived at the claimed invention by combining the teachings of Venditti and Logan because both disclosures teach methods to introduce heterologous coding sequences into cells using AAV vectors comprising AAV serotype 2 ITRs. One would have been motivated to do so, because Logan teaches that ITRs play a role in the integration of heterologous sequences into cells which can be used for gene therapy. Therefore, one would have recognized that the AAV ITRs taught by Logan could be used in the expression cassette taught by Venditti, in order to treat patients suffering from MMA. As each claimed element (i.e., AAV, MUT, ITR) was commonly known in the art at the time of filing, one could have combined each element by known methods, while recognizing that the results of the combination would have been predictable. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venditti and Carrillo as applied to claims 7, 18, 20, 23, 40 and 53 above, and further in view of Logan (previously cited) and Williams et al. (US 20150275221 A1; previously cited), hereafter, “Williams”.
Regarding claim 19, Venditti, Carrillo and Logan all teach recombinant adeno-associated virus (rAAV) expression vectors, as discussed above.
Logan teaches that vectors may also include a gene whose expression confers a detectable marker such as a drug resistance gene, which allows for selection and maintenance of the host cells (see pg. 9, para. [0085]). Logan teaches that the recombinant AAV is produced by using a cell line that stably expresses some of the necessary components for AAV virion production (see pg. 11, para. [0098]). For example, a plasmid comprising AAV genes and a selectable marker, such as a neomycin resistance gene, can be integrated into the genome of the packaging cells (see pg. 11, para. [0098]). Logan teaches that the advantages of this method are that the cells are selectable and are suitable for large-scale production of the recombinant AAV (see pg. 11, para. [0098]).
Logan does not explicitly teach the rAAV vector comprising a kanamycin resistance gene.
Williams’ disclosure relates to the production and use of covalently closed circular recombinant DNA molecules, such as viral vectors, and to vector modifications that improve expression of said DNA molecules (see Abstract). Williams teaches that the vector is a gene delivery vehicle which includes viral vectors, such as “adenovirus related virus”, which Williams teaches are well known in the art (see pg. 22, para. [0186]). Here, the phrase “adenovirus related virus” is understood to be equivalent to the phrase “adenovirus-associated virus” (AAV). Williams’s disclosure further relates to a family of eukaryotic expression plasmids useful for gene therapy and for improving the expression of plasmid encoded therapeutic genes (see pg. 1, para. [0003]). Williams teaches an example of a selectable marker is a kanamycin resistance gene (kanR) (see pg. 18, para. [0181]; pg. 21, para. [0185]) and discloses a vector comprising kanR (see pg. 42, para. [0328]).
It would have been obvious at the time of filing for a person of ordinary skill to have arrived at the claimed invention by substituting the neomycin resistance gene taught by Logan with the kanamycin resistance gene taught by Williams, because both resistance genes are taught to function as selectable markers which Logan teaches are needed for the selection and maintenance of host cells used to produce vectors for gene therapy. One would have recognized that the antibiotic resistant gene used as a selectable marker merely serves the function of maintaining the cell line used to produce the recombinant vectors, and the kanamycin resistance gene could be used for the same purpose as the selectable markers taught be Logan. One would have recognized that the only difference when using the antibiotic resistance gene taught by Williams (i.e., KanR) is the antibiotic used in maintaining the cell line (i.e., kanamycin). Here, the use of any antibiotic resistant gene with its corresponding antibiotic would be expected to render the same effect, so long as the host cell was susceptible to the antibiotic, and it was within the ordinary skill in the art at the time of filing to have made the appropriate selection. Therefore, one would have recognized that the results of making such a substitution would have been predictable, and there would have been a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (B) simple substitution of one known element for another to obtain predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venditti, as applied above, and further in view of Williams (previously cited), Alexander et al. (US 2019/0365926 A1; cited on Form 892), hereafter, “Alexander”, GenBank U32510.1 (cited on Form 892), and Minshull et al. (US 20170101646 A1; cited on Form 892), hereafter, “Minshull”.
Regarding claim 17, Venditti teaches a recombinant expression vector comprising a synthetic methylmalonyl-CoA mutase polynucleotide, as discussed regarding claim 7. Venditti teaches methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in the mitochondrial localized enzyme methylmalonyl-CoA mutase (MUT) (see pg. 1, para. [0005]), and that the synthetic human methylmalonyl-CoA mutase (synMUT) can be used via viral-mediated gene delivery to restore MUT function in MMA patients (see pg. 1, para. [0006]). Venditti further teaches an adeno-associated viral (AAV) gene therapy vector, AAV2/8-HCR-hAAT-synMUT-RBG (see Abstract). Figure 7 of Venditti presents a map of the AAV-HCR-hAAT-synMUT construct (see pg. 2, para. [0036]), as shown and further annotated (“a-f”) below:
[AltContent: textbox ( (a) (b) (f) (a))]
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Hence, Venditti teaches the gene expression cassette comprising (a) a 5’-inverted terminal repeat sequence (5’-ITR) sequence and a 3’-inverted terminal repeat sequence (3’-ITR) sequence, (b) a human alpha-anti-trypsin (hAAT) promoter sequence, and (f) a polyadenylation sequence.
Venditti does not explicitly disclose the nucleic acid sequence corresponding to the human alpha-anti-trypsin promoter.
Alexander teaches polynucleotides and vectors that can be used for the expression of a transgenes in cells, such as liver cells, which can be useful in gene therapy (see Abstract). Alexander teaches that the expression of transgenes is useful for gene therapy, wherein the transgene is generally introduced into the target cells of a subject for expression in those cells, typically in order to treat a disease or condition (see pg. 1, para. [0003]). Alexander teaches that gene therapy has been used both experimentally and in the clinic to treat a range of conditions and diseases, and can be performed using viral vectors (see pg. 1, para. [0004]). Alexander teaches that to facilitate expression of the transgene in the host cell, the transgene is typically contained in a construct that also contains various regulatory elements necessary to
express the transgene, such as, promoters, enhancers, initiation signals, termination signals, introns and other regulatory elements, which must function together to facilitate not only stable expression of the transgene in the target cell, but also expression at levels that are sufficient to effect therapy (see pg. 1, para. [0005]).
Alexander teaches polynucleotides comprising functional AAV inverted terminal repeats (ITRs) flanking the transgene and regulatory elements (see pg. 7, para. [0066]), including
an ApoE enhancer and hAAT promoter (see pg. 7, para. [0070]). Alexander teaches that the enhancer is a nucleotide region comprising a sequence capable of increasing the level of transcription of a transgene from the promoter (see pg. 3, para. [0034]). Alexander teaches the hAAT promoter may comprise the sequence set forth in SEQ ID NO: 4 (see pg. 5, para. [0050]). As shown in the following alignment, Alexander’s SEQ ID NO: 4 (bottom) comprises a sequence that is identical to instant SEQ ID NO: 8 (top):
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Regarding limitation (c), Venditti teaches the synMUT could be placed under the transcriptional control of a ubiquitous or tissue-specific promoter, with a 5’ intron, polyadenylation signal, and mRNA stability element, such as the woodchuck post-transcriptional regulatory element (see pg. 8, para. [0077]).
Venditti does not explicitly teach the nucleic acid sequence corresponding to the intron.
Williams’ disclosure relates to the production and use of covalently closed circular recombinant DNA molecules, such as viral vectors, and to vector modifications that improve expression of said DNA molecules (see Abstract). Williams teaches that the vector is a gene delivery vehicle which includes viral vectors, such as “adenovirus related virus”, which Williams teaches are well known in the art (see pg. 22, para. [0186]). Here, the phrase “adenovirus related virus” is understood to be equivalent to the phrase “adenovirus-associated virus” (AAV). Williams’s disclosure further relates to a family of eukaryotic expression plasmids useful for gene therapy and for improving the expression of plasmid encoded therapeutic genes (see pg. 1, para. [0003]).
Williams teaches that vector modifications in plasmid therapies, such as the inclusion of an intron, are highly correlative with improved in vivo expression (see pg. 1, para. [0009]). Williams discloses SEQ ID NO: 5 which is a human beta-globin murine IgG chimeric intron (see pg. 15, para. [0101]) for insertion into the vector to create an intron (see pg. 45, para. [0335]). As shown in the following alignment, Williams’ SEQ ID NO: 5 (bottom) comprises a sequence that is identical to instant SEQ ID NO: 12 (top):
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Regarding limitation (d), Alexander teaches polynucleotides comprising functional AAV inverted terminal repeats (ITRs) flanking the transgene and regulatory elements (see pg. 7, para. [0066]), including an ApoE enhancer and hAAT promoter (see pg. 7, para. [0070]). Alexander teaches that the enhancer is a nucleotide region comprising a sequence capable of increasing the level of transcription of a transgene from the promoter (see pg. 3, para. [0034]).
Alexander does not explicitly disclose the nucleic acid sequence corresponding to the ApoE enhancer.
GenBank U32510.1 is identified as the “Structure of the hepatic control region of the human apolipoprotein E” (see “Title”). As shown in the following alignment, GenBank U23510.1 (bottom) comprises a sequence that is identical to instant SEQ ID NO: 11 (top):
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Regarding limitation (e), Alexander teaches the polynucleotides can include various posttranscriptional regulatory elements that can function to increase the expression level of a transgene, including a viral posttranscriptional regulatory element, such as the hepatitis B virus posttranscriptional regulatory element (see pg. 7, para. [0062]). As previously discussed, Venditti teaches the synMUT could be placed under the transcriptional control of a ubiquitous or tissue-specific promoter, with a 5’ intron, polyadenylation signal, and mRNA stability element, such as the woodchuck post-transcriptional regulatory element (see pg. 8, para. [0077]).
Alexander and Venditti do not explicitly teach the nucleic acid sequence corresponding to the post-transcriptional regulatory element.
Minshull teaches polynucleotide vectors for high expression of heterologous genes, which can be used in a gene transfer system for stably introducing nucleic acids into the DNA of a cell, which can be used in methods for gene therapy (see Abstract). Minshull provides vector configurations that are particularly advantageous for the expression of genes in mammalian systems (see pg. 2, para. [0010]). Minshull teaches that the components of the gene transfer system may be transfected into one or more cells by inserting the components into a viral vector and contacting the viral vector with the cell (see pg. 13, para. [0126]). Minshull teaches that the viral vector can include any of a variety of viral vectors known in the art, including an adenovirus vector or an adeno-associated viral vector (see pgs. 13-14, para. [0126]).
Minshull teaches that particularly advantageous gene transfer polynucleotides for the transfer of genes for expression into mammalian cells comprise one or more of an expression enhancer that enhances RNA export from the nucleus, such as the woodchuck hepatitis post-transcriptional regulatory element (WPRE) or the hepatis B virus post-transcriptional regulatory element (HPRE), represented by SEQ ID NO: 868 (see pg. 15, para. [0135]). As shown in the following alignment, instant SEQ ID NO: 15 (top) is identical to Minshull’s SEQ ID NO: 868 (bottom):
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Regarding limitation (f), Venditti teaches the expression cassette may comprise a polyadenylation signal, as discussed above. Venditti discloses that the AAV2/8-HCR-hAAT-RBG vector contains the rabbit beta-globin polyadenylation (RBG) signal (see pg. 9, para. [0092]). Alexander teaches that the polynucleotides for gene therapy can comprise additional elements to help facilitate stable and strong expression of the transgene, including transcriptional termination signals (see pg. 6, para. [0060]). Alexander teaches that such transcriptional termination signals include polyadenylation signal sequences, such as the rabbit beta-globin (RBG) poly(A) (see pg. 6, para. [0061]).
Williams teaches that commonly utilized poly A signals are derived from the rabbit beta-globin (see pg. 19, para. [0184]). Williams discloses plasmids comprising the rabbit beta-globin polyadenylation signal, including SEQ ID NO: 30, which include the polyadenylation site (see pg. 56, “SEQ ID NO 30”). As shown in the following alignment, Williams’ SEQ ID NO: 30 (bottom) comprises a sequence that is identical to instant SEQ ID NO: 17 (top):
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It would have been obvious for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of the above references, because all references relate to the use of viral vectors comprising gene expression cassettes encoding therapeutic genes useful for gene therapy. One would have recognized that Venditti teaches an AAV-based expression cassette comprising (a) ITRs, (b) an hAAT promoter, (c) an intron, (d) hepatic control elements, and (f) a polyadenylation sequence. One would have recognized that Alexander also teaches AAV vectors comprising (a) ITRs, (b) hAAT promoters, (c) introns, (d) ApoE enhancer elements, (e) hepatitis B post transcriptional response elements, and (f) polyadenylation signals. One would have recognized from Alexander and Williams that vector modifications, such as the inclusion of an intron, can improve the expression of therapeutic genes, and would have been motivated to apply these teachings to the rAAV vector of Venditti to provide an effective gene therapy to MMA patients. As one could have combined each of these known elements (i.e., promoter, enhancer, ITR, MUT, polyA signal, etc.) using known methods with no change in their respective functions, one would have recognized the results of the combination to have been predictable. One would have also recognized that these elements could be included in a variety of different vectors designed to express various transgenes for therapy, and they would have had a reasonable expectation of success at applying such modifications to Venditti. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Claim(s) 33, 52 and 54-55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venditti, Logan, Williams and Alexander, as applied above, and further in view of GenBank LT727126.1 (cited on Form 892) and Slepushkin et al. (US 2019/0062783 A1; cited on Form 892), hereafter, “Slepushkin”.
Regarding claim 33, Venditti teaches a recombinant expression vector comprising a synthetic methylmalonyl-CoA mutase polynucleotide, as discussed above. Venditti teaches methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in the mitochondrial localized enzyme methylmalonyl-CoA mutase (MUT) (see pg. 1, para. [0005]), and that the synthetic human methylmalonyl-CoA mutase (synMUT) can be used via viral-mediated gene delivery to restore MUT function in MMA patients (see pg. 1, para. [0006]). Venditti further teaches an adeno-associated viral (AAV) gene therapy vector, AAV2/8-HCR-hAAT-synMUT-RBG (see Abstract). Venditti teaches an expression vector comprising the synthetic polynucleotide (see claim 7) and discloses that the vector used for gene therapy comprises an expression cassette comprising the synthetic polynucleotide (see pg. 8, para. [0076]).
Venditti teaches that compositions of the disclosure may comprise a therapeutically effective amount of “a viral particle” produced by or obtained from a vector comprising the synMUT transgenes (see pg. 8, para. [0082]). Venditti teaches the rAAV was packaged into rAAV8 “as previously described” (“Carrillo-Carrasco, et al. 2010 Hum Gene Ther 21:1147-54”) (see pg. 9, para. [0092]). Examiner notes that the term “viral particles” is subsequently used in Venditti’s Examples to refer to the composition in the steps that follow the “packaging” step (see pg. 9, para. [0092]). Hence, the use of this term would reasonably suggest to a person of ordinary skill that the packaging “into rAAV8” involves a viral capsid (i.e., “packaging into an rAAV8 capsid”), because without a capsid, the only “particles” would be the genetic material itself. Furthermore, Alexander teaches that “recombinant AAV” or “rAAV” refer to a virus that includes an AAV capsid shell encapsidating an AAV genome.
In view of the instant specification (see, e.g., Table 2 on pgs. 47-69), instant SEQ ID NO: 18 comprises the following components:
(1) a 5’ ITR sequence, represented by instant SEQ ID NO: 5, as shown in the following alignment (bottom) with instant SEQ ID NO: 18 (top):
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(2) the elongation factor 1 α long promoter (EF1L), represented by instant SEQ ID NO: 6, as shown in the following alignment (bottom) with instant SEQ ID NO: 18 (top):
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(3) chimeric intron (“Intron C”), represented by instant SEQ ID NO: 12 (see also pg. 9, para. [0042]), as shown in the following alignment (bottom) with instant SEQ ID NO: 18 (top):
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(4) the synthetic methylmalonyl-CoA mutase polynucleotide, represented by instant SEQ ID NO: 2 (previously discussed), as shown in the following alignment (bottom) with instant SEQ ID NO: 18 (top) (Note: for the sake of brevity, the middle section of the alignment has been omitted and only the first and last rows are shown):
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69
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(…)
(5) the polyadenylation sequence of rabbit polyA, represented by instant SEQ ID NO: 17 (see also pg. 9, para. [0045]), as shown in the following alignment (bottom) with instant SEQ ID NO: 18 (top):
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306
628
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(6) a 3’ ITR sequence, represented by instant SEQ ID NO: 22, as shown in the following alignment (bottom) with instant SEQ ID NO: 18 (top):
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(7) a 5’ region spanning base pairs 1-2693, which will be further discussed below as it relates to the prior art of Alexander and Slepushkin.
As previously discussed, Figure 7 of Venditti shows a map of the AAV-HCR-hAAT-synMUT construct, as shown below:
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Regarding (1) the 5’ ITR sequence, Venditti teaches the vector genome comprising an AAV 5’-inverted terminal repeat sequence, as shown above. Logan teaches that recombinant AAVs containing a genome that lacks some or most of the native AAV genome and instead contains one or more heterologous coding sequences flanked by ITRs have been successfully used in gene therapy settings (see pg. 1, para. [0005]). Logan teaches that in such vectors, the 5’ ITR and 3’ ITR may be derived from AAV viruses of the same or different serotypes and can comprise the AAV2 ITR set forth in SEQ ID NO: 32 (see pg. 2, para. [0019]). As discussed regarding claim 56, instant SEQ ID NO: 5 is identical to Logan’s SEQ ID NO: 32. Hence, it would have been obvious to have selected this sequence for the 5’ ITR for the same reasons discussed regarding claim 56.
Regarding (2) the elongation factor 1 α long promoter (EF1L), Williams teaches that vectors may utilize a diversity of promoters, including the elongation factor-1 α (EF1 α) promoter (see pg. 47, para. [0342]).
Williams does not explicitly disclose a nucleic acid sequence for the EF-1α promoter.
GenBank LT727126.1 is identified as a mammalian expression vector comprising “pEF1” which is understood to be an EF-1α promoter (see “DEFINITION”). As shown in the following alignment, this vector (bottom) comprises a sequence that is identical to instant SEQ ID NO: 18 (top), which is the same region corresponding to instant SEQ ID NO: 6 (EF1L):
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Hence, it would have been obvious to have selected this sequence comprising the EF-1α promoter.
Regarding (3) the chimeric intron (“Intron C”) represented by instant SEQ ID NO: 12, Williams teaches that vector modifications in plasmid therapies, such as the inclusion of an intron, are highly correlative with improved in vivo expression (see pg. 1, para. [0009]). Williams discloses SEQ ID NO: 5 which is a human beta-globin murine IgG chimeric intron (see pg. 15, para. [0101]) for insertion into the vector to create an intron (see pg. 45, para. [0335]). As discussed regarding claim 17, Williams’ SEQ ID NO: 5 comprises a sequence that is identical to instant SEQ ID NO: 12. Therefore, it would have been obvious to have selected this sequence to create an intron for the same reasons discussed regarding claim 17(c).
Regarding (4) the synthetic methylmalonyl-CoA mutase polynucleotide, Venditti teaches SEQ ID NO: 1 which is identical to instant SEQ ID NO: 2, as previously discussed.
Regarding (5) the polyadenylation sequence of rabbit polyA represented by instant SEQ ID NO: 17, Venditti teaches the AAV2/8-HCR-hAAT-RBG vector contains the “rabbit β-globin polyadenylation (RBG) signal” (see pg. 9, para. [0092]), as also shown in Figure 7 above. Alexander teaches that the polynucleotides for gene therapy can comprise additional elements to help facilitate stable and strong expression of the transgene, including transcriptional termination signals (see pg. 6, para. [0060]).
Alexander teaches that such transcriptional termination signals include polyadenylation signal sequences, such as the rabbit beta-globin (RBG) poly(A) (see pg. 6, para. [0061]). Williams teaches that commonly utilized poly A signals are derived from the rabbit beta-globin (see pg. 19, para. [0184]). Williams discloses plasmids comprising the rabbit beta-globin polyadenylation signal, including SEQ ID NO: 30, which include the polyadenylation site (see pg. 56, “SEQ ID NO 30”). As discussed regarding claim 17, Williams’ SEQ ID NO: 30 comprises a sequence that is identical to instant SEQ ID NO: 17. Hence, it would have been obvious to have selected this sequence for the polyadenylation signal for the same reasons discussed regarding claim 17(f).
Regarding (6) the 3’ ITR sequence, Venditti teaches the vector genome comprising an AAV 3’-inverted terminal repeat sequence, as shown above. Logan teaches that recombinant AAVs containing a genome that lacks some or most of the native AAV genome and instead contains one or more heterologous coding sequences flanked by ITRs have been successfully used in gene therapy settings (see pg. 1, para. [0005]). Logan teaches that in such vectors, the 5’ ITR and 3’ ITR may be derived from AAV viruses of the same or different serotypes and can comprise the AAV2 ITR set forth in SEQ ID NO: 32 (see pg. 2, para. [0019]). As discussed regarding claim 56, instant SEQ ID NO: 5 is identical to Logan’s SEQ ID NO: 32. Hence, it would have been obvious to have selected this sequence for the 3’ ITR.
Regarding (7) the region spanning base pairs 1-2693 of instant SEQ ID NO: 18, Logan teaches that vectors may also include a gene whose expression confers a detectable marker such as a drug resistance gene, which allows for selection and maintenance of the host cells (see pg. 9, para. [0085]). Logan teaches that the recombinant AAV is produced by using a cell line that stably expresses some of the necessary components for AAV virion production (see pg. 11, para. [0098]). For example, a plasmid comprising AAV genes and a selectable marker, such as a neomycin resistance gene, can be integrated into the genome of the packaging cells (see pg. 11, para. [0098]). Logan teaches that the advantages of this method are that the cells are selectable and are suitable for large-scale production of the recombinant AAV (see pg. 11, para. [0098]). Williams teaches an example of a selectable marker is a kanamycin resistance gene (kanR) (see pg. 18, para. [0181]; pg. 21, para. [0185]) and discloses a vector comprising kanR (see pg. 42, para. [0328]). As discussed regarding claim 19, it would have been obvious to have substituted the neomycin resistance gene taught by Logan with the kanamycin resistance gene taught by Williams, because both resistance genes are taught to function as selectable markers for maintaining host cell lines for the production of the vectors.
Williams does not explicitly disclose the nucleic acid sequence corresponding to the kanamycin resistance gene.
However, Alexander also teaches vectors may include a gene whose expression confers a detectable marker such as a drug resistance gene, which allows for selection and maintenance of the host cells (see pg. 9, para. [0083]). Alexander discloses an exemplary polynucleotide vector having a sequence set forth in SEQ ID NO: 27 (see pg. 9, para. [0084]). As shown in the following alignment, Alexander’s SEQ ID NO: 27 (bottom) comprises a sequence that is 98.3% identical to base pairs 1 to 2417 of instant SEQ ID NO: 18 (top):
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It should be noted that this sequence contains several regions that are identical to instant SEQ ID NO: 18, including the regions comprising base pairs 1-908, 941-1360 and 1750-2417.
Slepushkin teaches that the expression of heterologous genes in cells is desirable for many therapeutically relevant applications, and one method of introducing a heterologous gene into a cell involves the use of transfer vectors which, when transfected into a host cell, induce the host cell to produce viral particles including the heterologous gene (see pg. 1, para. [0002]). Slepushkin teaches that viruses useful in such methods include lentiviruses, adenoviruses and adeno-associated viruses, and there exists a need for improved vectors suitable for rapid and efficient production of viruses that are useful for inducing heterologous gene expression in target cells (see pg. 1, para. [0002]). Slepushkin teaches a lentiviral transfer vector including an EF1a promoter, a heterologous nucleic acid sequence, a post-transcriptional regulatory element, such as a hepatitis B virus isolate bba6 PRE (HPRE), an SV40 polyA tail, and a kanamycin resistance gene (see pg. 3, para. [0015]-[0016]). Slepushkin teaches that the kanamycin resistance gene is used as a selectable marker (see pg. 9, para. [0077]).
Slepushkin discloses SEQ ID NO: 88 which represents “Kan-R” (see pg. 63, Table 5, “Kan-R”). As shown in the following alignment, instant SEQ ID NO: 18 (top) comprises a sequence that is identical to Slepushkin’s SEQ ID NO: 88 (bottom):
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Therefore, base pairs 941-1750 of instant SEQ ID NO: 18 encode the kanamycin resistant gene.
Further, Slepushkin discloses a vector comprising this same region, which is represented by SEQ ID NO: 50 (see pg. 45, para. [0449]). As shown in the following alignment, Slepushkin’s SEQ ID NO: 50 (bottom) comprises a sequence that is identical to base pairs 1-1867 of instant SEQ ID NO: 18 (top):
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Hence, it would have been obvious to have included this element because both Williams and Slepushkin teach that the kanamycin resistance gene can be used as a selectable marker, which Logan and Alexander teach is useful for maintaining cell lines for producing the AAV expression vector. Therefore, a person having ordinary skill would have sought out a polynucleotide comprising this sequence, which is disclosed by Slepushkin.
In view of Applicant’s Examples (see instant specification at pgs. 41-46), there is no disclosure of any element comprised by SEQ ID NO: 18, other than those specifically discussed above, as being critical to the claimed invention. As the construction of AAV expression vectors comprising the elements discussed above (i.e., Kan-R, ITRs, EF1L promoter, chimeric intron, synMUT, rabbit polyA) appear to be well-known in the art, it would have required no more than routine optimization for a person of ordinary skill to have arrived at the claimed sequence of SEQ ID NO: 18.
Therefore, it would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Venditti, Logan, Williams, Alexander and Slepushkin, because all references teach methods of making and using viral vectors encoding therapeutic polypeptides for use in gene therapy. One would have been particularly motivated to combine these teachings to provide a viral vector with increased expression, as well as a selectable marker for mass producing the vector, which could be used to treat methylmalonic acidemia as taught by Venditti. As each claimed element (i.e., promoter, enhancer, ITR, MUT, polyA signal, antibiotic resistance gene, etc.) are taught by the references to have the same function in combination as they do separately, a person of skill would have recognized these elements to be suitable for constructing a vector for use in gene therapy and would have had a reasonable expectation of success. As one could have combined each of these elements using known methods, with no change in their respective functions, one would have recognized the results of this combination to have been predictable. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 52, Venditti teaches that compositions of the disclosure may comprise a therapeutically effective amount of “a viral particle” produced by or obtained from a vector comprising the synMUT transgenes, wherein the rAAV is packaged into rAAV8, as discussed above. Alexander teaches that recombinant AAVs (rAAVs) include AAV8 and “recombinant AAV” refers to a virus that includes an AAV capsid shell encapsidating an AAV genome (see pg. 3, para. [0039]). Alexander also teaches that typically the encoded AAV capsids are liver-trophic, such as, capsids from AAV serotype 8 (see pg. 16, para. [0088]). Hence, it would have been obvious for the AAV capsid to have been from an AAV of serotype 8.
Regarding claim 54, Venditti teaches a composition comprising the synthetic polynucleotide and a pharmaceutically acceptable carrier (see pg. 2, para. [0023]). Venditti also teaches the pharmaceutical composition may comprise a therapeutically effective amount of a vector comprising the synMUT transgenes (see pg. 8, para. [0082]). Hence, Venditti teaches a composition comprising the recombinant expression vector and a pharmaceutically acceptable carrier.
Regarding claim 55, the claim is obvious for the same reasons as claims 52 and 54.
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.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,719,080 (Venditti ‘080) in view of U.S. Patent No. 9,944,918 B2 (Venditti ‘918). This is an obvious-type rejection.
Note: Venditti ‘918 is a continuation-in-part of application No. 14/773,885, which is also a patented case (US 9,719,080 B2). Venditti ‘080 and the Venditti reference used in the rejections under 35 U.S.C. 103 are both publications of application No. 14/773,885 and contain the same disclosure.
Regarding instant claim 7, claim 1 of 9,719,080 recites a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMUT) selected from the group that includes SEQ ID NO: 1, which is identical to instant SEQ ID NO: 2 of the present disclosure. Claim 7 of Venditti ‘080 recites “An expression vector comprising the synthetic polynucleotide of claim 1.”
Venditti ‘918 discloses a gene expression cassette comprising the synMUT and 5’- and 3’-ITRs (see Fig. 7).
The Abstracts of Venditti ‘080 and Venditti ‘918 both recite: “Synthetic polynucleotides encoding human methylmalonyl-CoA mutase (synMUT) and exhibiting augmented expression in cell culture and/or in a subject are described herein. An adeno-associated viral (AAV) gene therapy vector encoding synMUT under the control of a liver-specific promoter (AAV2/8-HCR-hAAT-synMUT-RBG) successfully rescued the neonatal lethal phenotype displayed by methylmalonyl-CoA mutase-deficient mice, lowered circulating methylmalonic acid levels in the treated animals, and resulted in prolonged hepatic expression of the product of synMUT transgene in vivo, human methylmalonyl-CoA mutase (MUT).” Hence, both references disclose the same utility, are in the same field of endeavor, relate to solving the same problem, and would have been obvious to combine. Furthermore, a person of ordinary skill would have been motivated to do so, because Venditti ‘918 teaches an AAV gene therapy vector that successfully rescued MUT-deficient mice and the claims of Venditti ‘080 relate to solving the same problem.
Hence, it would have been obvious to have provided an expression cassette comprising the synMMUT and 5’- and 3’-ITRs.
Claim(s) 18, 20, 23, 40 and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,719,080 (Venditti ‘080) in view of U.S. Patent No. 9,944,918 B2 (Venditti ‘918), and further in view of Carrillo.
Regarding claim 18, Venditti ‘918 teaches a recombinant expression vector comprising a synthetic methylmalonyl-CoA mutase polynucleotide, as discussed above. Venditti teaches methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in the mitochondrial localized enzyme methylmalonyl-CoA mutase (MUT) (see col. 1, lines 40-44), and that the synthetic human methylmalonyl-CoA mutase (synMUT) can be used via viral-mediated gene delivery to restore MUT function in MMA patients (see col. 2, lines 3-10). Venditti further teaches an adeno-associated viral (AAV) gene therapy vector, AAV2/8-HCR-hAAT-synMUT-RBG (see Abstract). Figure 7 of Venditti presents a map of the AAV-HCR-hAAT-synMUT construct (see col. 4, lines 66-67), as shown in the rejection under 35 USC 103. Hence, Venditti ‘918 teaches the vector genome comprising a 5’-inverted terminal repeat sequence (5’-ITR) sequence, a promoter sequence, a coding sequence for MMUT, and a 3’-inverted terminal repeat sequence (3’-ITR) sequence.
Venditti ‘918 further teaches that the human codon-optimized methylmalonyl-CoA mutase (synMUT) was cloned into AAV2-HCR-hAAT-RBG and packaged into rAAV8 (see col. 19, lines 23-25), and hence, meets the limitation of a “recombinant adeno-associated virus (rAAV)”.
Venditti ‘918 does not explicitly teach said rAAV comprises an AAV “capsid”.
However, Venditti ‘918 teaches that compositions of the disclosure may comprise a therapeutically effective amount of “a viral particle” produced by or obtained from a vector comprising the synMUT transgenes (see col. 17, lines 21-25). Venditti teaches the rAAV was packaged into rAAV8 “as previously described” in “Carrillo-Carrasco, et al. 2010 Hum Gene Ther 21:1147-54” (see col. 19, lines 23-25). Examiner notes that the term “viral particles” is subsequently used in Venditti’s Examples to refer to the composition in the steps that follow the “packaging” step (see col. 19, lines 34-39). Hence, the use of this term would reasonably suggest to a person of ordinary skill that the packaging “into rAAV8” involves a viral capsid (i.e., “packaging into an rAAV8 capsid”), because without a capsid, the only “particles” would be the genetic material itself.
Nevertheless, Carrillo, which Venditti ‘918 directly references, teaches that methylmalonic acidemia is a severe metabolic disorder caused by a deficiency of the ubiquitously expressed mitochondrial enzyme, methylmalonyl-CoA mutase (MUT) and discloses that a recombinant adeno-associated virus serotype 8 expressing the Mut gene under the control of a promoter was sufficient to rescue Mut-deficient mice (see Abstract). Regarding the construction and production of rAAVs, Carrillo explicitly states that “the vector genomes were packaged into an AAV8 capsid” (see pg. 1148, col. 2, para. 1). Hence, the claim is obvious over Venditti ‘080 in further view of Venditti ‘918 and Carrillo for the same reasons discussed in the rejection under 35 USC 103 in view of Venditti and Carrillo.
Regarding claim 20, Venditti ‘918 and Carrillo teach the AAV capsid is from an AAV of serotype 8 (AAV8), as discussed above.
Regarding claim 23, Venditti ‘918 and Carrillo teach the AAV capsid is from an AAV of serotype 8 (AAV8), as discussed above.
Regarding claim 40, Venditti ‘918 discloses a composition comprising the synthetic polynucleotide and a pharmaceutically acceptable carrier (col. 3, lines 49-51).
Regarding instant claim 53, Venditti ‘918 discloses a composition comprising the recombinant expression vector and a pharmaceutically acceptable carrier (see col. 3, lines 49-51; col. 17, lines 21-25).
Claim(s) 56 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,719,080 (Venditti ‘080) in view of U.S. Patent No. 9,944,918 B2 (Venditti ‘918), and further in view of Logan et al. (US 2018/0142260 A1; cited on Form 892), hereafter, “Logan”.
Regarding claim 56, Venditti ‘918 discloses a gene expression cassette comprising the synMUT and 5’- and 3’-ITRs, as discussed above. Hence, the claim is obvious over Venditti ‘080 and Venditti ‘918 in further view of Logan for the same reasons discussed under 35 U.S.C. 103.
Claim(s) 19 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,719,080 (Venditti ‘080) in view of U.S. Patent No. 9,944,918 B2 (Venditti ‘918), and Carrillo as applied to claims 7, 18, 20, 23, 40 and 53 above, and further in view of Logan (previously cited) and Williams et al. (US 20150275221 A1; previously cited), hereafter, “Williams”.
Regarding claim 19, Venditti ‘918 teaches the vector genome comprising a 5’-inverted terminal repeat sequence (5’-ITR) sequence, a promoter sequence, a coding sequence for MMUT, and a 3’-inverted terminal repeat sequence (3’-ITR) sequence, as discussed above. Hence, the claim is obvious over Venditti ‘080 and Venditti ‘918 in further view of the above cited references for the same reasons discussed under 35 U.S.C. 103.
Claim(s) 17 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,719,080 (Venditti ‘080) in view of U.S. Patent No. 9,944,918 B2 (Venditti ‘918), and further in view of Williams (previously cited), Alexander et al. (US 2019/0365926 A1; cited on Form 892), hereafter, “Alexander”, GenBank U32510.1 (cited on Form 892), and Minshull et al. (US 20170101646 A1; cited on Form 892), hereafter, “Minshull”.
Regarding claim 17, Venditti ‘918 teaches the vector genome comprising a 5’-inverted terminal repeat sequence (5’-ITR) sequence, a (hAAT) promoter sequence, a coding sequence for MMUT, and a 3’-inverted terminal repeat sequence (3’-ITR) sequence., as discussed above. Hence, the claim is obvious over Venditti ‘080 and Venditti ‘918 in further view of the above cited references for the same reasons discussed under 35 U.S.C. 103.
Claim(s) 33, 52 and 54-55 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,719,080 (Venditti ‘080) in view of U.S. Patent No. 9,944,918 B2 (Venditti ‘918), Logan, Williams and Alexander, as applied above, and further in view of GenBank LT727126.1 (cited on Form 892) and Slepushkin et al. (US 2019/0062783 A1; cited on Form 892), hereafter, “Slepushkin”.
Regarding claims 33, 52 and 54-55, Venditti ‘918 teaches the vector genome comprising a 5’-inverted terminal repeat sequence (5’-ITR) sequence, a promoter sequence, a coding sequence for MMUT, and a 3’-inverted terminal repeat sequence (3’-ITR) sequence. Hence, the claims are obvious over Venditti ‘080 and Venditti ‘918 in further view of the above cited references for the same reasons discussed under 35 U.S.C. 103.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080). This is an obvious-type rejection.
Regarding instant claim 7, claim 1 of Venditti ‘918 recites a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMUT) selected from the group that includes SEQ ID NO: 1, which is identical to instant SEQ ID NO: 2 of the present disclosure. Claim 7 of Venditti ‘918 recites “An expression vector comprising the synthetic polynucleotide of claim 1.” Venditti ‘080 further discloses a gene expression cassette comprising the synMUT (see Fig. 7).
As discussed above, both references disclose the same utility, are in the same field of endeavor, relate to solving the same problem, and would have been obvious to combine. Furthermore, a person of ordinary skill would have been motivated to do so, because Venditti ‘080 teaches an AAV gene therapy vector that successfully rescued MUT-deficient mice which directly relates to the claims of Venditti ‘918.
Claim(s) 18, 20, 23, 40 and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of Carrillo.
As noted above, Venditti ‘080 contains the same disclosure as the Venditti reference used in the rejections under 35 U.S.C. 103. Therefore, the claim(s) are obvious over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of the references cited above, for at least the same reasons discussed under 35 U.S.C. 103.
Claim(s) 56 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of Logan et al. (US 2018/0142260 A1; cited on Form 892), hereafter, “Logan”.
As noted above, Venditti ‘080 contains the same disclosure as the Venditti reference used in the rejections under 35 U.S.C. 103. Therefore, the claim(s) are obvious over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of the references cited above, for at least the same reasons discussed under 35 U.S.C. 103.
Claim(s) 19 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and Carrillo as applied to claims 7, 18, 20, 23, 40 and 53 above, and further in view of Logan (previously cited) and Williams et al. (US 20150275221 A1; previously cited), hereafter, “Williams”.
As noted above, Venditti ‘080 contains the same disclosure as the Venditti reference used in the rejections under 35 U.S.C. 103. Therefore, the claim(s) are obvious over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of the references cited above, for at least the same reasons discussed under 35 U.S.C. 103.
Claim(s) 17 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of Williams (previously cited), Alexander et al. (US 2019/0365926 A1; cited on Form 892), hereafter, “Alexander”, GenBank U32510.1 (cited on Form 892), and Minshull et al. (US 20170101646 A1; cited on Form 892), hereafter, “Minshull”.
As noted above, Venditti ‘080 contains the same disclosure as the Venditti reference used in the rejections under 35 U.S.C. 103. Therefore, the claim(s) are obvious over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of the references cited above, for at least the same reasons discussed under 35 U.S.C. 103.
Claim(s) 33, 52 and 54-55 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), Logan, Williams and Alexander, as applied above, and further in view of GenBank LT727126.1 (cited on Form 892) and Slepushkin et al. (US 2019/0062783 A1; cited on Form 892), hereafter, “Slepushkin”.
As noted above, Venditti ‘080 contains the same disclosure as the Venditti reference used in the rejections under 35 U.S.C. 103. Therefore, the claim(s) are obvious over claims 1 and 7 of U.S. Patent No. 9,944,918 B2 (Venditti ‘918) in view of U.S. Patent No. 9,719,080 (Venditti ‘080), and further in view of the references cited above, for at least the same reasons discussed under 35 U.S.C. 103.
Response to Arguments
Regarding the written description rejection under 35 U.S.C. 112(a), Applicant argues that (now independent) claim 7 recites that the expression cassette comprises the nucleic acid sequence of SEQ ID NO: 2. The OA appears to indicate that SEQ ID NO: 2 is adequately disclosed (see OA, page 10). Thus present claim 7 and those of its dependent claims subject to the written description rejection no longer recite the subject matter alleged by the OA to lack description and do not present subject matter lacking adequate written description. Applicant argues the same rationale for (now independent) claim 33, which recites that the vector now comprises the nucleotide sequence of SEQ ID NO: 18.
Applicant’s arguments have been fully considered and they are persuasive.
Accordingly, the rejection under 35 U.S.C. 112(a) has been withdrawn.
Regarding the rejections under 35 U.S.C. 102, Applicant argues that respect to claim 7, the claim has been amended to remove reference to “chicken beta-actin promoter” in part (b). Accordingly, the basis for rejecting claim 7 no longer applies.
Applicant’s arguments have been fully considered but they are not persuasive.
As discussed in the present rejection, Venditti teaches limitation (a) of the claim.
Applicant further argues that with respect of claims 17, 18 and 40, the claims have been amended in a manner such that the they are no longer anticipated by Venditti.
Applicant’s arguments have been fully considered and they are persuasive.
Accordingly the rejection of claims 17, 18 and 40 under 35 U.S.C. 102 has been withdrawn.
Regarding the rejections under 35 U.S.C. 103, Applicant argues that the claims have been amended or cancelled such that the basis of the rejections are moot.
Applicant’s arguments have been fully considered but they are not persuasive.
While the amendments to the claims may have changed the basis for the rejections(s) and/or necessitated a new ground of rejection, the claims stand rejected for the reasons discussed under 35 U.S.C. 103.
However, the examiner agrees that any rejection of a cancelled claim is moot.
Regarding the Double Patenting rejections under 35 U.S.C. 101, Applicant argues that the claims have been amended or cancelled such that the basis of the rejections are moot. Accordingly, the DP rejections of the claims should be withdrawn.
Applicant’s arguments have been fully considered but they are not persuasive.
While the amendments to the claims may have changed the basis for the rejections(s) and/or necessitated a new ground of rejection, the claims stand rejected for the reasons discussed under Double Patenting.
However, the examiner agrees that any rejection of a cancelled claim is moot.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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