DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of claims 1, 2, 11, 23, 38, 40, 41, 70, and 71 (Group I) in the reply filed on 10/28/2025 is acknowledged. Furthermore, Applicant elected the following species: a human synapsin 1 promoter (claim 2), an rAAV virion comprising sequences with at least 95% identity to SEQ ID NOs: 54, 42, 10, 34, and 48 (claim 23), an rAAV virion of embodiment bb (claim 40), and an rAAV virion comprising a vector genome comprising a polynucleotide sequence that shares at least 90% identity with SEQ ID NO: 57.
Claims 42, 47, 51, 53, 56, 59, 64, and 68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/28/2025.
Accordingly, claims 1, 2, 11, 23, 38, 40, 41, 70, and 71 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest effective filing date to which the instant application is entitled is 07/23/2020.
Information Disclosure Statement
Receipt of an information disclosure statement on 07/21/2023 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings are objected to because:
With regard to Figures 10A and 10B, the accompanying legend does not clearly facilitate the interpretation of said Figures. Unlike Figures 10C-10F, which clearly depict the symbols in the legend, Figures 10A and 10B are much harder to interpret as currently presented. It would be remedial to update Figures 10A and 10B (or the associated legend) such that they are clearly interpretable.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 2, 11, 23, and 40 are objected to because of the following informalities:
Claims 2, 11, 23, and 40 are objected to for reciting “i.”, “ii.”, etc. or “a.”, “b.”, “c.”, etc. to distinguish components of the claimed virion by including a period at the end of the identifier of each claimed component. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. It would be remedial to replace “i.”, “ii.”, etc. with “(i)”, “(ii)”, etc., and “a.”, “b.”, “c.”, etc. with “(a)”, “(b)”, “(c)”, etc., as appropriate.
Claim 2 is further objected to for incorrectly numbering the claimed components of the virion, grammatical errors, and improperly recited acronyms. The component identified by “ii.” is listed twice, both as a neuron-specific promoter and a pan-neuronal promoter. Additionally, the recitation of “the synapsin 1 promoter is a human synapsin 1 (hSYN) promoter that shares at least 70%, at least 80%, at least 90% identity, at least 95% at least 99% identity to SEQ ID NO: 3; or…the promoter is an eSYN promoter that shares at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 64” (bolded and underlined emphasis added) is grammatically improper. The bolded “identity” is misplaced, thereby introducing a typographical error. The sequence identity recitations should be structured as recited regarding the eSYN promoter. Furthermore, the underlined portions of text should include commas and the conjunction “or” separating the recited identity thresholds in order to comport with standard grammatical and/or linguistic conventions. The instant claim omits these commas and one of the conjunctions (“or”). Finally, claim 2 recites several acronyms, including the CAG promoter, the CMV promoter, and the eSYN promoter, none of which are properly identified prior to the recitation of the corresponding acronyms. When reciting acronyms, it is proper to first identify the species that is being acronymized to ensure clarity. It would be remedial to amend the instant claim such that the claimed components are correctly numbered and that the claim language comports with standard grammatical and/or linguistic conventions.
Claim 11 is further objected to for grammatical errors when reciting “the polynucleotide sequence encoding the eEF1A2 protein shares at least 70%, at least 80%, at least 90% identity to SEQ ID NO: 2; and/or ii. the eEF1A2 protein shares at least 70%, at least 80%, at least 90% identity, at least 95% at least 99% identity to SEQ ID NO: 1.” The bolded “identity” is misplaced, thereby introducing a typographical error. The sequence identity recitations should be structured as recited in “i.” of instant claim 11. Furthermore, the underlined portions of text should include commas and the conjunction “or” separating the recited identity thresholds in order to comport with standard grammatical and/or linguistic conventions. The instant claim omits these commas and one of the conjunctions (“or”). It would be remedial to amend the instant claim such that the claim language comports with standard grammatical and/or linguistic conventions.
Claim 23 is further objected to for reciting “a hGH polyadenylation site” (bolded emphasis added). The article “a” is grammatically improper when preceding words articulated with an initial vowel sound. While “hGH” is spelled such that it recites a consonant letter “h”, the pronunciation of the “h” in “hGH” nonetheless begins with a vowel sound. It would be remedial to update the instant claim language to be grammatically proper.
Claim 40 is further objected to for reciting components such as promoters corresponding to each recited expression cassette without an appropriate preceding article such as “a.” For example, elected expression cassette bb recites “hSYN promoter, Kozak, the polynucleotide sequence encoding eEF1A2 or a functional variant thereof, and pAGH-Hs,” which does not comport with standard grammatical and/or linguistic conventions. It would be remedial to amend the instant claim such that the article “a” (or another appropriate article) precedes each recited species, as is consistent with standard grammatical and/or linguistic conventions. Additionally, claim 40 recites “Kozak” in the expression cassettes of “w.”, “y.”, “bb.”, and “dd.”. As recited at instant claim 23, the proper term known to those of ordinary skill in the art is “Kozak sequence.” It would be remedial to amend the instant claim such that the claim recites the proper term “Kozak sequence” in place of “Kozak.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1, 2, 11, 23, 38, 40, 70, and 71 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 2, 11, 23, 38, 40, 70, and 71 are drawn to a set of recombinant adeno-associated virus (rAAV) virions comprising a polynucleotide sequence encoding an eEF1A2 protein or a functional variant thereof. Additionally, claim 40 is drawn to such an rAAV virion, further comprising an AAV9 capsid or functional variant thereof. Finally, claims 2 and 11 both recite sequences with at least 70% identity to the claimed hSYN and eSYN promoters (claim 2) and to the claimed eEF1A2 polynucleotide or polypeptide (claim 11). The rejected claims thus comprise a set of rAAV virions that comprise polynucleotide and/or polypeptide sequences, as well as functional variants thereof (which necessarily encompasses a set of sequences with a large number of variable residues), all of which/all variants of which must effectively perform the functions of the claimed eEF1A2 protein and/or the claimed promoters.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes an eEF1A2 polypeptide sequence defined by SEQ ID NO: 1 and an eEF1A2 polynucleotide sequence defined by SEQ ID NOs: 2 and 4-8. No description is provided of an eEF1A2 polypeptide sequence other than SEQ ID NO: 1, nor is any description provided of any hSYN or eSYN promoter sequences other than SEQ ID NOs: 3 and 64, respectively. No description is provided of any AAV9 capsid sequence other than SEQ ID NO: 15.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the eEF1A2 polynucleotide sequence variants of SEQ ID NOs: 2 and 4-8. While the eEF1A2 polynucleotide sequences defined by SEQ ID NOs: 2 and 4-8 do exhibit sequence variation (as shown in the multiple sequence alignment of Appendix I), a substantial portion of nucleotides is conserved between all of these sequences. As is known to those of ordinary skill in the art, nucleotide sequences are ultimately translated into amino acid sequences that determine the structure and biochemical function of the protein encoded therein (reviewed in Molecular Biology of the Cell, 2002). Thus, alterations to the nucleotide sequence necessarily have implications for the encoded protein structure and function. As reviewed in Goldstein and Pollock, 2016, alterations to the nucleotide sequence (i.e. synonymous versus non-synonymous) may result in conservative or non-conservative amino acid substitutions, which are respectively more and less likely to be functionally accepted in the protein produced from translation of said nucleotide sequence. The instant specification is silent as to the essentiality of any of the conserved nucleotides in SEQ ID NOs: 2 and 4-8. Accordingly, while the claim language encompasses a set of sequences with a large number of variable residues in eEF1A2, hSYN promoter, eSYN promoter, and AAV9 capsid sequences, the few sequences of the instant disclosure are not necessarily predictive of any sequence satisfying the instant claim limitations encompassing a set of sequences with a large number of variable residues . Thus, it is impossible for one to extrapolate from the few examples described herein those sequences that would necessarily meet the structural/functional characteristics of the rejected claims.
Regarding the recited limitation of “a functional variant thereof,” under broadest reasonable interpretation, the recitation of “a functional variant thereof” is considered to encompass a genus of functional variants that are functionally related by not necessarily structurally related. The breadth of interpretations encompassed by this limitation is even broader than the breadth of interpretations encompassed by the recited sequence percent identities. As set forth above, the instant disclosure provides only a few examples from which it is impossible for one to extrapolate those sequences that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of sequences that would meet the requirements of the instantly claimed eEF1A2, hSYN promoter, eSYN promoter, and AAV9 capsid sequences.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 2, 11, 23, 38, 40, 70, and 71.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 41 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 recites “the vector genome [of the rAAV virion of claim 1] comprises, consists essentially of, or consists of a polynucleotide sequence that shares at least 90%...identity to any one of SEQ ID NOs: 55-58 or 68-68” (bolded emphasis added). However, “comprises” and “consists of” have fundamentally different meanings that respectively invoke an open-ended composition (comprises) or a closed composition (consists of). While the instant specification discloses that the terms “include” and “comprise” are used synonymously (paragraph [0054]), the instant specification is silent as to the definition of “consists of” as used therein. Accordingly, both “comprises” and “consists of” are interpreted according to their ordinary definitions, which are fundamentally different, as set forth above. Additionally, the recitation of “consists essentially of” is not defined in the instant specification. Given that the ordinary definition of “consists of” invoked a closed composition, the recitation of “consists essentially of” is indefinite, as this phrase necessarily implies that the composition recited therein comprises components not explicitly recited. Accordingly, one of ordinary skill in the art would not be reasonable apprised of the bounds of protection sought in the instant claim language.
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, 2, 11, 38, 70, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Ruest et al., 2002 in view of Chang and Wang, 2007, US 2018/0311290 A1 (hereinafter Sena-Esteves), and NCBI Entry NM_001958.4 (hereinafter NCBI), as evidenced by Khalyfa et al., 2001.
With regard to claim 1, which recites “a recombinant adeno-associated virus (rAAV) virion, comprising a capsid and a vector genome, wherein the vector genome comprises a polynucleotide sequence encoding an eEF1A2 protein or a functional variant thereof, operatively linked to a promoter,” Ruest et al., 2002 discloses adenoviral delivery of the eEF1A-2/S1 gene via a recombinant adenovirus expressing the same to cultured myotubes, which was found to rescue said cultured myotubes from apoptotic cell death induction (page 5419, column 1, paragraph 1; page 5419, column 2, paragraph 4). The Examiner notes that Khalyfa et al., 2001 discloses that eEF1A2-/S1 the eEF1A-2 gene (S1) (abstract). Accordingly, the adenoviral delivery of the eEF1A-2/S1 gene disclosed in Ruest et al., 2002 is considered to read on the instantly claimed polynucleotide sequence encoding an eEF1A2 protein or a functional variant thereof. Ruest et al., 2002 further sets forth that the switch from eEF1A-1/EF-1α to eEF1A-2/S1 may deliver a translation elongation factor that also prevents accidental cell death from occurring in long-lived, terminally differentiated cells such as myotubes via a noncanonical protective function, and speculates that this protective function may also be found in heart cells and neurons (page 5424, column 1, paragraph 4-page 5424, column 2, paragraph 1). This speculation was later empirically supported, as Chang and Wang, 2007 disclose that eEF1A-2 in adult neurons provides not only necessary support for peptide elongation, but also supports extreme protection from oxidative stress by working together with peroxiredoxin in these long-lived, terminally differentiated cells, where accidental triggering of apoptotic death would be catastrophic (page 276, column 1, paragraph 1). However, despite collectively establishing that eEF1A2 expression (i.e. by adenoviral-mediated delivery) protects long-lived, terminally differentiated cells from accidental apoptosis, neither Ruest et al., 2002 nor Chang and Wang, 2007 disclose the instantly claimed rAAV virion.
This deficiency is cured by Sena-Esteves, which discloses methods for treating central nervous system diseases, said methods comprising administering an rAAV virion comprising a capsid containing a nucleic acid under the control of (i.e. operatively linked to) a promoter (paragraphs [0019] and [0021]). Thus, Sena-Esteves discloses therapeutic rAAV virions comprising a polynucleotide sequence operatively linked to a promoter. While Sena-Esteves does not disclose that the polynucleotide sequence taught therein encodes an eEF1A2 protein, as instantly claimed, this deficiency is cured by NCBI, which discloses the human polynucleotide sequence encoding eEF1A2.
Accordingly, Ruest et al., 2002, Chang and Wang, 2007, Sena-Esteves, and NCBI (as evidenced by Khalyfa et al., 2001) collectively disclose the rAAV virion of instant claim 1, as set forth in greater detail below.
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With regard to claim 2, which recites “the rAAV virion of claim 1, wherein the promoter is:…a synapsin 1 (hSYN) promoter that shares at least 70%...identity to SEQ ID NO: 3,” as set forth above, Sena-Esteves discloses therapeutic rAAV virions for the treatment of central nervous system diseases (paragraphs [0019] and [0021]). Sena-Esteves further discloses that exemplary promoters for use in the therapeutic rAAV virions taught therein include the Synapsin 1 promoter represented by SEQ ID NO: 13, which is specific for neurons (paragraphs [0019] and [0080]). As shown in the alignment below, the Synapsin 1 promoter represented by SEQ ID NO: 13 of Sena-Esteves comprises 100% identity to instant SEQ ID NO: 3. Accordingly, Sena-Esteves discloses each and every additional limitation of instant claim 2.
With regard to claim 11, which recites “the rAAV virion of claim 1, wherein:…the polynucleotide sequence encoding the eEF1A2 protein shares at least 70%...identity to SEQ ID NO: 2,” as set forth above, NCBI discloses the polynucleotide sequence encoding human eEF1A2. This sequence comprises 100% identity to instant SEQ ID NO: 2, as shown in Appendix II. Accordingly, NCBI discloses each and every additional limitation of instant claim 11.
With regard to claim 38, which recites “the capsid [of the rAAV virion of claim 1] is an AAV9 capsid,” as set forth above, Sena-Esteves discloses therapeutic rAAV virions for the treatment of central nervous system diseases (paragraphs [0019] and [0021]). Sena-Esteves further discloses that the rAAV virions taught therein comprise an AAV9 capsid, which is empirically shown to facilitate expression of transgenes in neurons and astrocytes (paragraph [0020]; Example 10). Accordingly, Sena-Esteves discloses each and every additional limitation of instant claim 38.
With regard to claims 70 and 71, which respectively recite “a pharmaceutical composition comprising the rAAV virion of claim 1” and “a kit comprising the rAAV virion of claim 1 and instructions for use,” as set forth above, Sena-Esteves discloses therapeutic rAAV virions for the treatment of central nervous system diseases (paragraphs [0019] and [0021]). Sena-Esteves further discloses that the rAAV virions taught therein may be delivered as part of pharmaceutical compositions or provided as a kit including instructions for use of the same (paragraphs [0016], [0017], and [0146]). Accordingly, Sena-Esteves discloses each and every additional limitation of instant claims 70 and 71.
Given that Ruest et al., 2002 discloses that adenoviral delivery of the eEF1A-2/S1 gene (such as the polynucleotide sequence disclosed in NCBI) to long-lived, terminally differentiated cells such as myotubes protects said cells from accidental cell death, that Chang and Wang, 2007 disclose that eEF1A2 performs the same function in adult neurons (another type of long-lived, terminally differentiated cells), and that Sena-Esteves discloses therapeutic rAAV virions comprising a therapeutic nucleic acid under the control of a promoter (such as the instantly claimed human synapsin 1 promoter) for treatment of central nervous system diseases (delivered as a pharmaceutical composition or packaged into a kit), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to construct the rAAV virion disclosed in Sena-Esteves such that it delivers a polynucleotide sequence encoding eEF1A2 (such as the polynucleotide sequence disclosed in NCBI) to predictably protect neurons in the central nervous system from accidental cell death, as disclosed in Ruest et al., 2002 and Chang and Wang, 2007. One would have been motivated to make such a modification in order to receive the expected benefit of protecting neurons in the central nervous system from accidental cell death.
Claims 23 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Ruest et al., 2002 in view of Chang and Wang, 2007, US 2018/0311290 A1 (hereinafter Sena-Esteves), and NCBI Entry NM_001958.4 (hereinafter NCBI), as evidenced by Khalyfa et al., 2001 as applied to claim 1 above, and further in view of US 2020/0010851 A1 (hereinafter Keravala), US 2019/0247516 A1 (hereinafter Cotney), US 2003/0224508 A1 (hereinafter Ill), WO 2019/210325 A1 (hereinafter Rocket; as cited in the IDS filed 07/21/2023), and WO 2019/028273 A1 (hereinafter Minshull).
The combined disclosures of Ruest et al., 2002, Chang and Wang, 2007, Sena-Esteves, NCBI, and Khalyfa et al., 2001 are described above and applied as before. However, these disclosures do not teach the vector genome sequences of instant claim 23 or the vector genome expression cassette of instant claim 40.
With regard to claim 23, which recites “the vector genome [of the rAAV virion of claim 1] comprises: i. a polyadenylation (polyA) site, optionally wherein the polyA sequence is…a hGH polyadenylation site…[that] shares at least 95% identity to SEQ ID NO: 54; ii. a WPRE(x) element, optionally wherein the WPRE(x) element shares:…at least 95% identity to SEQ ID NO: 42…iii. a Kozak sequence, optionally wherein the Kozak sequence is SEQ ID NO: 10; iv. A 5’ untranslated region (UTR), optionally wherein the 5’ UTR shares at least 95% identity to…SEQ ID NO: [34]…; and/or v. a 3’ untranslated region (UTR), optionally wherein the 3’ UTR shares at least 95% identity to…SEQ ID NO: [48],” as set forth above, Ruest et al., 2002, Chang and Wang, 2007, Sena-Esteves, NCBI, and Khalyfa et al., 2001 collectively disclose the rAAV virion of instant claim 1. However, these disclosures do not teach the instantly claimed sequences. These deficiencies are cured by the various secondary references, as set forth below.
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Keravala discloses therapeutic AAV vectors for the treatment of mammalian diseases, particularly human diseases (paragraph [0007]). The therapeutic AAV vectors disclosed in Keravala are further disclosed to comprise an HGH polyadenylation site corresponding to SEQ ID NO: 14 that is necessary for proper transcript processing (paragraphs [0029], [0118], and [0152]), which is 100% identical to instant SEQ ID NO: 54, as shown in the alignment below. Accordingly, the disclosure of Keravala is considered to read on the instantly claimed hGH polyadenylation site corresponding to instant SEQ ID NO: 54.
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Cotney also discloses therapeutic AAV vectors, said vectors delivering of nucleic acid constructs to treat neurological disorders (paragraphs [0003], [0015]-[0020], and [0176]). The therapeutic AAV vectors disclosed in Cotney are further disclosed to comprise a WPRE element corresponding to SEQ ID NO: 1631 that creates a tertiary structure which enhances gene expression and may be operatively linked to the therapeutic gene (paragraph [0161]). As shown in the alignment below, SEQ ID NO: 1631 of Cotney comprises 100% identity to instant SEQ ID NO: 42. Accordingly, the disclosure of Cotney is considered to read on the instantly claimed WPRE(x) element corresponding to instant SEQ ID NO: 42.
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Ill discloses nucleic acid sequences which exhibit increased expression of a protein of interest, as well as vectors to deliver said nucleic acid sequences to cells, thereby promoting expression of the same within said cells (paragraph [0009]). Ill further discloses that the nucleic acid seuqences taught therein comprise an optimized translation initaiton site derived from the canonical Kozak sequence and corresponding to SEQ ID NO: 8 (paragraph [0109]). As shown in the alignment below, SEQ ID NO: 8 of Ill is 100% identical to instant SEQ ID NO: 10. Accordingly, the disclosure of Ill is considered to read on the instantly claimed Kozak sequence corresponding to instant SEQ ID NO: 10.
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Rocket also discloses therapeutic AAV gene therapy vectors comprising a 5’ UTR, such as SEQ ID NO: 67, as a transcript stabilizing element (page 3, lines 17-18; page 67, lines 10-13; Figure 1; table 6). As shown in the alignment below, SEQ ID NO: 67 of Rocket comprises 100% identity to instant SEQ ID NO: 34. Accordingly, the disclosure of Rocket is considered to read on the instantly claimed 5’ UTR corresponding to instant SEQ ID NO: 34.
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Finally, Minshull also discloses AAV vectors for gene therapy that comprise 5’ and 3’ UTRs to facilitate translational initiation and/or contribute to mRNA stability, thereby enhancing gene expression (abstract; paragraph [0081]). One such 3’ UTR is disclosed to correspond to the human globin 3’ UTR defined as SEQ ID NO: 579, which is 100% identical to instant SEQ ID NO: 48, as shown in the alignment below. Accordingly, the disclosure of Minshull is considered to read on the instantly claimed 3’ UTR corresponding to instant SEQ ID NO: 48.
With regard to claim 40, which recites “the vector genome [of the rAAV virion of claim 1] comprises an expression cassette, the expression cassette comprising, in 5’ to 3’ order:…bb. [an] hSYN promoter, [a] Kozak [sequence], the polynucleotide sequence encoding eEF1A2 or a functional variant thereof, and pAGH-Hs,” as set forth above, Ruest et al., 2002, Chang and Wang, 2007, Sena-Esteves, NCBI, and Khalyfa et al., 2001 collectively disclose the rAAV virion of instant claim 1. Furthermore, Sena-Esteves discloses that the therapeutic nucleic acids delivered by the AAV vectors taught therein are preceded by a promoter sequence such as the neuronal Syn1 promoter represented by SEQ ID NO: 13 (paragraphs [0019], [0021], and [0080]). As set forth above, one such therapeutic nucleic acid may encode eEF1A2, as disclosed in Ruest et al., 2002, Chang and Wang, 2007, and NCBI. Additionally, the AAV expression constructs taught therein are disclosed to comprise a Kozak sequence and a polyadenylation signal (paragraph [0104]). As set forth above, Ill discloses an optimized translation initiation sequence (i.e. Kozak sequence) that facilitates optimal translation of the sequence under the control of (i.e. downstream of) the said Kozak sequence (paragraph [0109]). Finally, Keravala discloses that the therapeutic AAV vectors taught therein comprise an hGH polyadenylation site that is necessary for proper transcript processing (paragraphs [0029], [0118], and [0152]). Per the instant specification, the instantly claimed pAGH-Hs corresponds to instant SEQ ID NO: 54, which is an hGH polyadenylation site (Table 6). As depicted in Figure 1 of Sena-Esteves, polyA sites are typically placed at the 3’ end of a nucleic acid construct. Accordingly, the cited art collectively discloses an expression cassette for a therapeutic rAAV virion in which the therapeutic polynucleotide encoding eEF1A2 is placed under the control of an hSYN promoter, preceded by a Kozak sequence, and followed by a polyA site, as instantly claimed.
Given that Ruest et al., 2002, Chang and Wang, 2007, Sena-Esteves, NCBI, and Khalyfa et al., 2001 collectively disclose the rAAV virion of instant claim 1 (as set forth above, and that Keravala, Cotney, Ill, Rocket, and Minshull all disclose expression of therapeutic nucleic acids and/or therapeutic AAV vectors, respectively specifically disclosing an hGH polyA site with 100% identity to instant SEQ ID NO: 54, a WPRE element with 100% identity to SEQ ID NO: 42, an optimized Kozak sequence with 100% identity to instant SEQ ID NO: 10, a 5’ UTR with 100% identity to instant SEQ ID NO: 34, and a 3’ UTR with 100% identity to instant SEQ ID NO: 48, said elements respectively being necessary for proper transcript processing, enhancing gene expression, optimizing translation initiation, and contributing to transcript stability it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to construct the rAAV virion collectively disclosed by Ruest et al., 2002, Chang and Wang, 2007, Sena-Esteves, NCBI, and Khalyfa et al., 2001 (as set forth above) such that it comprises the elements disclosed in Keravala, Cotney, Ill, Rocket, and Minshull in the order suggested by Sena-Esteves, Ill, and Keravala to predictably produce an rAAV virion capable of robust expression of the therapeutic nucleic acid encoding eEF1A2 therein. One would have been motivated to make such a modification in order to receive the expected benefit of robustly expressing the therapeutic nucleic acid encoding eEF1A2 therein.
Conclusion
No claims are allowed.
Claims 2, 11, 23, and 40 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./ Primary Examiner, Art Unit 1637
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117
598
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1041
595
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Appendix I: Multiple Sequence Alignment of SEQ ID NOs: 2 and 4-8
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1017
550
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Greyscale
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647
533
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Greyscale
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35
736
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Greyscale
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1008
760
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81
738
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Appendix II: NCBI NM_001958.4 vs. Instant SEQ ID NO: 2
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851
761
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