DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10, 16, in the reply filed on 6/8/2026 is acknowledged.
Claims 11-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/8/2026.
Claims status
Claims 1-16 is/are currently pending with claims 11-15 is/are withdrawn. Claims 1-10, 16 is/are under examination.
Information Disclosure Statement
The listing of references in the specification, such as from pages 34-39, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 1-5 are objected to because of the following informalities: Claims recite incorrect abbreviation for nicotinamide mononucleotide adenylyl transferase 2 as NMNTA2. Correct abbreviation is NMNAT2, as used in the specification Appropriate correction is required.
Claims 10 is objected to because of the following informalities: Claim recites an AAV virus particle comprising a vector of claim 1. For the sake of uniformity across the claim set, following language is recommended: “An AAV virus particle comprising [[a]] the mammalian AAV vector of claim 1”. Appropriate correction is required.
Claims 16 is objected to because of the following informalities: Claim recites the vector of claim 1. For the sake of uniformity across the claim set, following language is recommended: “the mammalian AAV vector”. Appropriate correction is required.
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.
Claims 3 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites “NMNTA2 protein comprises an exon 6 deletion” (emphasis). Proteins do not comprise exons, so a protein comprising an exon deletion is unclear. Even if the claim is interpreted such that the exon deletion is in the nucleotide sequence encoding the protein, the phrase “an exon 6” remains unclear since protein coding sequence tend to comprise only one exon of specified number such the nucleotide sequence encoding NMNAT2 comprises the exon 6. Thus, it is unclear if the claim requires a deletion of any residue in exon 6 or deletion of entire exon 6. If deletion of any residue in exon 6 is intended, upto entire exon, following language is appropriate: “a deletion in exon 6 the exon 6 deletion”. For the purpose of compact prosecution, the claim(s) 3 is/are interpreted as “the sequence encoding the NMNAT2 protein comprises a deletion in exon 6
Claim 8 recites the limitation "a promoter variant" in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 8 is/are interpreted as “[[a]] the promoter
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 depends from claim 1 and recites “wherein the mammalian vector is a mammalian viral vector”. This broadens the scope of claim 1 that is limited to a specific mammalian viral vector i.e. mammalian AAV vector.
Claim 16 depends from claim 1 and recites specific vector sequences. Claim 1 requires the vector to comprise a sequence encoding NMNAT2 from human however claim 16 broadens the scope of claim 1 by reciting SEQ ID NO: 11 that comprises a sequence encoding NMNAT2 from mouse and not human (see page 43 from the specification that discloses “SEQ ID NO: 11 AAV vector with mouse NMNAT2 sequence”).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-10, 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 1 is directed to an AAV vector that embraces γ-synuclein promoters from any species or any functional fragment thereof and sequences encoding human NMNAT2 protein or any of their variants. Although the claim does not recite any specific structure for the claimed promoters or their functional fragments, the claim requires the sequences to perform the function of promoting expression of an operably linked coding sequence in retinal ganglion cells (RGC) of any species. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters from any species or any functional fragment thereof in combination with sequences that encode any variant of human NMNAT2 protein.
Of note, all AAVs are mammalian - in that they naturally infect mammals.
Claim 2 limits the sequences encoding human NMNAT2 protein to sequences that encode specific variants of human NMNAT2. The claim does not recite any specific structure for the variants however requires the variants to perform the function of extending the half-life of the encoded protein in vivo in comparison to its wild type form. Claim does not limit the promoters or their fragments of claim 1. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters from any species or any functional fragment thereof in combination with sequences that encode variants of human NMNAT2 protein that extend its in vivo half-life.
Claim 3, in view of interpretation presented in the U.S.C.112b rejection above, limits the sequences encoding human NMNAT2 protein to sequences that encode specific variants of human NMNAT2 which comprise any deletion in exon 6. Claim does not limit the promoters or their fragments of claim 1. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters from any species or any functional fragment thereof in combination with sequences that encode any variant of human NMNAT2 protein that comprises any deletion in exon 6.
Claim 4 limits the sequences encoding human NMNAT2 protein to sequences that encode the wild type protein. Claim does not limit the promoters or their fragments of claim 1. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters from any species or any functional fragment thereof in combination with sequences that encode wild-type human NMNAT2 protein.
Claim 5 limits the sequences encoding human NMNAT2 protein to sequences that are at least 95% identical to SEQ ID NOs: 5 or 6. Claim does not limit the promoters or their fragments of claim 1. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters from any species or any functional fragment thereof in combination with sequences that encode human NMNAT2 protein at least 95% identical to SEQ ID NOs: 5 or 6.
Claim 6 limits the promoter of claim 1 to be from any murine species which embraces several hundred species. Claim does not limit the variants of human NMNAT2 protein of claim 1. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters from any murine species or any functional fragment thereof in combination with sequences that encode any variant of human NMNAT2 protein.
Claim 7 limits the promoter of claim 1 to comprise a sequence of any of SEQ ID NOs: 1-4 or any variant of these sequences. Due to the use of the article “a”, claim 7 embraces any fragments of the recited sequences. Claim does not limit the variants of human NMNAT2 protein of claim 1. Thus, the claim embraces an expansive array of vectors that comprise γ-synuclein promoters that are any fragment or variant of SEQ ID NOs: 1-4 in combination with sequences that encode any variant of human NMNAT2 protein. Of note, substitution of the article “a” with “the” would limit the sequences to the specifically recited SEQ IDs and not their fragments.
Claim 8, in view of interpretation presented in the U.S.C.112b rejection above, limits the promoter of claim 1 to sequences that are at least 95% identical to SEQ ID NOs: 1-4. Claim does not limit the variants of human NMNAT2 protein of claim 1. Thus, the claim embraces an vectors that comprise γ-synuclein promoters that are 95% identical to SEQ ID NOs: 1-4 in combination with sequences that encode any variant of human NMNAT2 protein.
Claims 9 and 10 do not limit the promoter or the sequence encoding the human NMNAT2 protein. Thus, these claims embrace an expansive array of vectors that comprise γ-synuclein promoters from any species or any functional fragment thereof in combination with sequences that encode any variant of human NMNAT2 protein.
Claim 16 limits the vector of claim 1 to comprise a sequence of any of SEQ ID NOs: 11, 14, 15. Due to the use of the article “a”, claim 16 embraces any fragments of the recited sequences. Thus, the claim embraces an expansive array of vectors that comprise any fragment of the recited sequences. Of note, substitution of the article “a” with “the” would limit the sequences to the specifically recited SEQ IDs and not their fragments.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by “whatever characteristics sufficiently distinguish it).
Regarding γ-synuclein promoters from any species and any fragments thereof, the instant specification is limited to γ-synuclein promoters and fragments from only mouse species ([0037-0038], Examples, Figures). These promoters were known in the art to perform the function of promoting expression of an operably linked coding sequence in at least human and mouse RGC (see Abstract in Wang et al. J. Neurosci., May 13, 2020 • 40(20):3896–3914). Although the specification discloses these sequences as from “murine” species, the structure disclosed belongs to only mouse species while murinae is a large subfamily of old world rats and mice that comprise highly diverse species totaling at least 561 (see Diversity in Murinae in PTO892). The specification does not disclose γ-synuclein promoters from any other species, other than mouse, let alone its functional fragments. Thus, the specification does not reduce to practice or disclose the structural details of the expansive array of claimed γ-synuclein promoters from any species and any fragments thereof. Furthermore, the specification does not provide sufficient guidance regarding the structure of disclosed mouse γ-synuclein promoter or the claimed γ-synuclein promoters from other species, such that a skilled artisan could envision functional fragments of these promoters embraced by the claims. Even the fragments of mouse γ-synuclein promoter (SEQ 2-4) do not characterize the promoter to identify the fragments that would retain the claimed function, other than the specifically disclosed fragments. Although it appears that the 0.27kb fragment (SEQ ID NO: 4) of the mouse γ-synuclein promoter likely comprises the core promoter region, the promoter region is not sufficiently characterized such that the varied fragments embraced could be envisioned. Wang, that disclosed the fragments of mouse γ-synuclein promoter, teaches that each of the fragment of the full-length promoter is weaker for transgene expression and critically for RGC specificity, and there are likely yet unidentified regulatory elements in the full-length of promoter (page 3908, col. 1, para 2). Thus, the disclosure and the prior art do not provide a clear structure-function relationship between the sequence of the mouse γ-synuclein promoter and its function such that its fragments could be envisioned. Other than the mouse γ-synuclein promoter, human γ-synuclein promoter was known in the art (taught by Wang) however this promoter is a significantly weaker driver of transgene expression in both mouse and human RGCs (Figure 3 and 6 in Wang), and again, is not characterized at all such that a clear structure-function relationship between the sequence of the human γ-synuclein promoter and its function was known such that its fragments could be envisioned. Such information is wholly lacking for γ-synuclein promoter from other species, including other murine species.
Regarding fragments or variants of SEQ ID NO: 1-4, only sequences that are identical to SEQ ID NO: 1-4 are described. No fragments or variants are described. As noted above, mouse γ-synuclein promoter of SEQ ID NO: 1 and its specific truncations SEQ ID NOs: 2-4 were known in the art (Wang) and also disclosed in the instant specification. However, the promoter region is not sufficiently characterized such that it the varied fragments embraced could be envisioned. The disclosure and the prior art do not provide a clear structure-function relationship between the sequence of the mouse γ-synuclein promoter and its function such that its fragments or fragments of SEQ ID NO: 1-4 that provide for the claimed function could be envisioned.
Thus, the specification only provides support for mouse γ-synuclein promoter of SEQ ID NO: 1 and its fragments of SEQ ID NO: 2-4.
Regarding human NMNAT2 protein or any of its variants, including variants required to have an extended half-life or any deletion in exon 6, the instant specification is limited to wild type human NMNAT2 (SEQ ID NO: 5) and a single variant that comprises a deletion of the entire exon 6 lending to an increase in half-life (SEQ ID NO:6). The specification does not disclose human NMNAT2 variants, other than SEQ ID NO: 6 which is a result of exon 6 deletion. Thus, the specification does not reduce to practice or disclose the structural details of the expansive array any variants of human NMNAT2.
However, prior art of Milde et al (PLoS Bio, April 2013, Vol. 11) described variants of human NMNAT2 protein each with mutation is exon 6 or deletion of entire exon 6 that reduce membrane localization of the NMNAT2 protein, increase its half-life and neurite protective effects (Figure 2, 3, 5 and 6; Table 1). Milde also provides guidance regarding the structure of the amino acid residues transcribed by exon 6 such that human NMNAT2 protein variants with variation in residues encoded by exon 6 could be envisioned. However, human NMNAT2 protein variants that comprise variations from the wild type protein, as broadly claimed, were not known in the art or disclosed in the specification. The structure of the remainder of human NMNAT2 protein, outside of residues transcribed by exon 6, is not characterized such that an artisan could envision variants of human NMNAT2 protein, other than exon 6 variants, that could function as NMNAT2 protein or extend its half-life.
Thus, the specification only provides support for sequences encoding human NMNAT2 protein and sequences encoding human NMNAT2 protein with mutations in exon 6.
Therefore, the claimed invention is not adequately described for its entire embraced scope. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date.
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.
Claim(s) 1-3, 5-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al (Frontiers of Cell. Neuro., Vol. 15, Oct. 2021; IDS 5/9/2024) as evidence by Milde et al (PLoS Bio, April 2013, Vol. 11) and Wang et al (J. Neurosci., May 13, 2020 • 40(20):3896–3914).
Of note, the prior art reference has a publication date prior to the EFD of the instant Application. The prior art reference has ten named inventors and shares one inventor with the inventive entity of the instant Application. Thus, the inventive entity of the prior art and the instant Application are not the same. See MPEP 2136.04.
Regarding claims 1, 9 and 10, Liu discloses a composition comprising an AAV2 viral vector comprising mouse Sncg promoter and a sequence encoding human NMNAT2 with exon 6 deletion (Figure 1; Materials and Methods: Adeno-Associated Virus Production and Intravitreal Injection). Liu discloses that the promoter drives transgene expression specifically in in RGCs (Figure 1).
Regarding claim 2, 3, Liu discloses that the encoded human NMNAT2 with exon 6 deletion in their vector has an extended half-life in comparison to the wild type (Abstract).
Regarding claim 5, Liu discloses that the encoded human NMNAT2 with exon 6 deletion is by Milde (page 4, col. 1, last para) that evidences that human NMNAT2 with exon 6 deletion has the sequence at least 95% identical to SEQ ID NO: 6 (Figure S1A and S1B in Milde showing wild type human NMNAT2 with exon 6 residues highlighted and NMNAT delta exon 6 mutant noted in Table below). See sequence alignment below.
Regarding claim 6, Liu discloses mouse Sncg promoter (Figure 1).
Regarding claims 7 and 8, Liu discloses the source of mouse Sncg promoter as Wang (page 4, col. 2, para 1) that evidences that mouse Sncg has the sequence of SEQ ID NO: 1 (Figure 1-1 in Wang mScng-1.45kB). See sequence alignment in PTO-892.
Therefore, Liu anticipates the claimed invention.
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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) 4 and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu, as evidenced by Milde and Wang, as applied to claim 1 above, further in view of Milde.
The teachings of Liu as applied to claim 1 above are relied upon for the instant rejection.
Liu teaches the composition of claim 1 wherein the sequence encodes a human NMNAT2 protein variant. Liu does not teach the wild type NMNAT2, as recited in claim 4 or a sequence that is at least 95% identical to SEQ ID NO: 5 recited in claim 5.
Milde teaches the sequence of wild type NMNAT2 that is at least 95% identical to SEQ ID NO: 5 (as required by claims 4 and 5; Figure S1A in Milde showing wild type human NMNAT2; see sequence alignment below).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the sequence encoding human NMNAT2 variant of Liu with sequence encoding the wild type human NMNAT2, as taught by Milde. An ordinary artisan would be motivated to make such a substitution because Liu teaches expression of human NMNAT2 variant was not efficacious in their model and there is a possibility that “that overexpression of wild type NMNAT2 may have neuroprotection in the EAE mice” (page 9, col. 2, para 1). An ordinary artisan would reasonably expect to make such substitution by using routine molecular biology approaches such as taught by Liu (Methods: Adeno-Associated Virus Production and Intravitreal Injection) and Milde (Methods: DNA constructs) replacing sequence encoding the variant protein with a sequence encoding the wild type protein. Milde provides DNA constructs comprising these sequences.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
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Claim(s) 1-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (J. Neurosci., May 13, 2020 • 40(20):3896–3914) and Milde et al (PLoS Bio, April 2013, Vol. 11) in view of John et al (US 2018/0344719 A1; Dec. 6, 2018).
Regarding claims 1, 6, 9 and 10, Wang teaches compositions comprising AAV virus vectors comprising mouse Sncg promoter and its fragments which promote expression of an operably linked coding sequence in RGCs (as required by claim 1, 6, 9, 10; Materials and Methods: Constructs, AAV production; Figure 1-6).
Regarding claims 7 and 8, Wang teaches mouse Sncg promoter of sequence that is identical to SEQ ID NO: 1 and its fragments with sequences identical to SEQ ID NO: 2-4 (Figure 1-1 teaches mSncg-1.45kb which is identical to SEQ ID NO: 1, mSncg-1.03b which is identical to SEQ ID NO: 2, mSncg-0.66kb which is identical to SEQ ID NO: 3; mSncg-0.27kb which is identical to SEQ ID NO: 4; See sequence alignment in PTO-892).
Wang drives the expression of Cas9 enzyme under their mouse Sncg promoters for gene therapy purposes (Figure 8).
Wang does not drive the expression of wild type human NMNAT2 protein or its variant in RGCs and thus does not teach an AAV vector comprising a sequence encoding wild type human NMNAT2 protein or its variant, as recited in claims 1-5.
Milde teaches DNA constructs comprising sequences that encode wild type human NMNAT2 protein or its variant that lacks exon 6 and thus has an extended half-life (as required by claims 1-3; Figure 6; Materials and Methods: DNA constructs). Milde teaches the sequence of wild type human NMNAT2 protein that is at least 95% identical to SEQ ID NO: 5 (as required by claims 4 and 5; Figure S1A in Milde showing wild type human NMNAT2; see sequence alignment above). Milde also teaches the sequence of the human NMNAT2 protein variant that is at least 95% identical to SEQ ID NO: 6 (as required by claims 4 and 5; Figure S1A and S1B in Milde showing wild type human NMNAT2 with exon 6 residues highlighted and NMNAT delta exon 6 mutant noted in Table below; see sequence alignment above).
John teaches AAV gene therapy to alleviate glaucoma wherein the AAV vector increases the expression of enzymes in the NAD pathway resulting in increase in NAM [0123, 0129]. John teaches age-dependent decline in NAD sensitizes RGCs to glaucoma and other neurodegenerative diseases [308] and overexpression of enzymes such as NMNAT1, NMNAT2 and NMNAT3 could increase intracellular NAD levels for therapeutic effect [0025-0032]. John tests the ability of NMNAT enzymes to provide therapeutic effect in glaucoma by delivering an AAV viral vector comprising a generic CMV promoter driving the expression of NMNAT1 (Example 7, Figure 24).
Regarding NMNAT2, John teaches that “NMNAT2 is emerging as an important NAD producing enzyme in axons and protects from axon degeneration. Ongoing stress negatively impacts Nnmat2 expression in RGCs (q<0.05 in D2 glaucoma Group 4, the final stage detected before glaucomatous degeneration). This decline may be important in the transition to axon degeneration in glaucoma. NMNAT2 expression is decreased in brains with Alzheimer's disease and has a highly variable depression in aged postmortem human brains, which may contribute to the variable vulnerability to these conditions.” [0215]
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the sequence encoding the Cas9 protein in Wang’s AAV vector with the sequence encoding wild type or variant human NMNAT2, as taught by Milde, to arrive at AAV vector wherein mouse Sncg promoter or its fragment drive the expression of wild type or variant human NMNAT2 in RGCs. An ordinary artisan would be motivated to make such a substitutions based on the teachings of Wang regarding the strength and specificity of their mouse Sncg promoter and its fragments in targeting RGCs specifically in comparison to ubiquitous and other neuronal promoters (Figure 1, 2, 6), teachings of Milde regarding the neuroprotective effects of wild type and variant human NMNAT2 (Figure 4, 5) and further in view of teachings from John that teaches that AAV based overexpression of NMNAT enzymes in RGCs can be therapeutic (Example 7) and NMNAT2 is emerging as a key therapeutic target related to not only glaucoma but other neurodegenerative disorders. An ordinary would reasonably expect to make such a substitution by using routine molecular biology approaches such as taught by Wang (Materials and Methods: Constructs, AAV production) and Milde (Methods: DNA constructs) replacing sequence encoding the Cas9 protein with a sequence encoding the wild type or variant human NMNAT2 protein. Milde provides DNA constructs comprising these sequences.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
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