DETAILED ACTION
Claims 1-4, 6-13 and 16-24 are currently pending.
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 invention Group I (claims 1-4, 6-13 and 16-18) in the reply filed on 4/20/2026 is acknowledged.
Claims 19-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 4/20/2026.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US2022/074791, filed August 11, 2022, which claims the benefit of provisional application No. 63/232,420, filed August 12, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 2/12/2024, 2/29/2024 and 8/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification (pages 54-57) 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 Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 1-4, 6 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bolukbasi et al. (see IDS 2/12/24; “Bolukbasi”), as evidenced by SnapGene (pEGFP-N1 vector map; see PTO-892 (“SnapGene”).
Bolukbasi is directed to studies of 25 nucleotide “zipcode” sequence that enrich mRNA in microvesicles and when this sequence was incorporated into the 3’ UTR of a reporter message it led to enrichment of the reporter mRNA in microvesicles (MVs) (Abstract).
Regarding claims 1-2, Bolukbasi teach the incorporation of a 25 nucleotide (nt) zipcode sequence into a plasmid expression vector comprising the enhanced green fluorescent protein (EGFP, polynucleotide encoding nucleic acid of interest), i.e., pEGFP-N1-3UTR-25nt. The resulting plasmid expresses EGFP mRNA fused to this potential zipcode, followed by a polyA addition site (operably linked) (pg. 2, col 1, 1st full paragraph). Thus, Bolukbasi teaches an expression vector comprising a polynucleotide encoding a nucleic acid of interest operably linked to an extracellular vesicle-targeting zip code sequence, thus anticipating claims 1-2.
Regarding claim 3, Bolukbasi teaches the EGFP polynucleotide is operably linked a poly(A) signal, and the zipcode sequence is located between the EGFP polynucleotide and the poly(A) signal.
As to the polynucleotide being operably linked to a promoter, it is noted that SnapGene evidences that Bolukbasi’s disclosed pEGFP-N1 plasmid comprises the CMV promoter operably linked to EGFP. Thus, Bolukbasi’s teaching anticipates claim 3.
Regarding claim 4, Bolukbasi at Figure 1 teaches the 25 nt zip code sequence for NM_003614.1 is: ACCCTGCCGCCTGGACTCCGCCTGT.
Instant SEQ ID NO: 1 comprises the nucleotide sequence of:
accctgccgc ctggactccg cctgt.
Bolukbasi’s teaching anticipates claim 4.
Regarding claim 6, Bolukbasi teaches plasmid pEGFP-N1-3UTR-25nt, thus anticipating claim 6.
Regarding claim 10, Bolukbasi teaches a functional nucleic acid, i.e., EGFP, thus anticipating claim 10.
Claim(s) 1-4, 6 and 10 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Saydam et al., (WO 2013/109713; see PTO-892) (“Saydam”), as evidenced by SnapGene (pEGFP-N1 vector map; see PTO-892 (“SnapGene”).
Saydam teaches of an isolated nucleic acid molecule comprising a 25 nucleotide first nucleic acid sequence 5'- ACCCTGCCGCCTGGACTCCGCCTGT-3' (SEQ ID NO: 22), operably linked to a second, heterologous nucleic acid sequence, wherein the isolated nucleic acid molecule is DNA in the context of an expression vector, or RNA selected from the group consisting of mRNA, shRNA, and ncRNA. Additionally, Saydam teaches a microvesicle (MV) preparation comprising said RNA and methods of delivering the RNA to a subject (Abstract and [0007]-[0010]).
Regarding claims 1-2, Saydam teach the incorporation of a 25 nucleotide (nt) zipcode sequence into a plasmid expression vector comprising the enhanced green fluorescent protein (EGFP, polynucleotide encoding nucleic acid of interest), i.e., pEGFP-N1-3UTR-25nt. The resulting plasmid expresses EGFP mRNA fused to this potential zipcode, followed by a polyA addition site (operably linked) ([0025], [0087]; Figure 3 A).
Saydam teaches the suitable heterologous (second) nucleic acid sequence for linkage to the zip code sequence is one that is recognized for functional use by a cell. Such a DNA molecule will typically contain a coding sequence comprising an open reading frame (ORF) that is suitable for translation into a protein, and the ORF is operatively linked to the appropriate regulatory sequences (TATA box, poly A site, etc) for transcription into an RNA by cellular transcription machinery. Such an RNA molecule (e.g., an mRNA) will likewise contain the appropriate sequences for function within the cell ([0039]).
Thus, Saydam teaches an expression vector, i.e., pEGFP-N1-3UTR-25nt, comprising a polynucleotide encoding a nucleic acid of interest (second nucleic acid) operably linked to an extracellular vesicle-targeting zip code sequence (first nucleic acid), thus anticipating claims 1-2.
Regarding claim 3, Saydam teaches the EGFP polynucleotide is operably linked a poly(A) signal, and the zipcode sequence is located between the EGFP polynucleotide and the poly(A) signal ) ([0025], [0087]).
As to the polynucleotide being operably linked to a promoter, it is noted that SnapGene evidences that Saydam’s disclosed pEGFP-N1 plasmid comprises the CMV promoter operably linked to EGFP. Thus, Saydam’s teaching anticipates claim 3.
Regarding claim 4, Saydam teaches the 25 nt zip code sequence for SEQ ID NO: 22 is: ACCCTGCCGCCTGGACTCCGCCTGT.
Instant SEQ ID NO: 1 comprises the nucleotide sequence of:
accctgccgc ctggactccg cctgt.
Saydam’s teaching anticipates claim 4, as evidenced by the sequence alignment conducted using ABSS, as copied below (see PTO-892):
PNG
media_image1.png
206
674
media_image1.png
Greyscale
Regarding claim 6, Saydam exemplifies plasmid pEGFP-N1-3UTR-25nt, thus anticipating claim 6.
Regarding claim 10, Saydam teaches a functional nucleic acid, i.e., EGFP, thus anticipating claim 10.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claim(s) 7, 11-12 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Saydam, as evidenced by SnapGene, as applied to claim(s) 1-4, 6 and 10 above.
The teaching of Saydam, as evidenced by SnapGene is set forth above.
Regarding claims 7, 16 and 17, Saydam exemplifies plasmid vector pEGFP-Nl-3UTR-25nt ([0107]). Saydam does not further exemplify the vector is an adeno-associated virus (AAV) vector (claim 7), or a virus particle comprising the expression vector (claim 16), or wherein the virus particle is an AAV particle, an adenovirus particle, a herpesvirus particle, or a baculovirus particle (claim 17).
However, Saydam teaches the nucleic acid molecules of the invention can be present in the context of an expression vector ([0055]), including plasmid or virus vectors ([0056]), the constructs may be integrated and packaged into non-replicating, defective viral genomes like adenovirus (i.e., adenovirus particle), adeno-associated virus (AAV) (i.e., AAV particle), or herpes simplex virus (HSV) (i.e., herpesvirus particle), for infection or transduction into cells ([0058]).
Thus, Saydam does render obvious an expression vector is an adeno-associated virus vector (AAV virus particle), that is, Saydam teaches the limitations required by the current claims and as all limitations are found in one reference it is held that an expression vector is an adeno-associated virus vector (AAV virus particle), is within the scope of the teachings of Saydam, and thus renders the invention of claims 7, 16 and 17 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion that the expression vector is an adeno-associated virus vector (AAV virus particle). Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Saydam.
Regarding claims 11 and 12, and the limitation the expression vector encodes a therapeutic protein that is a secreted protein (claim 11), or the therapeutic protein is a non-secreted protein (claim 12), it is noted Saydam teaches that the nucleic acid (i.e., DNA) is linked to the zip code sequence in a manner that is sufficient to promote enrichment of a transcribed RNA into microvesicles when transcription of the appropriate DNA strand upon transcription in a cell. Subsequently, the zip code sequence promotes enrichment of the RNA into microvesicles produced by the cell in which the RNA is present. Such linkage is referred to herein as operative, with respect to the promotion of enrichment of a transcribed RNA into microvesicles. Saydam teaches the heterologous (second) nucleic acid sequence linked to the zip code sequence is one that is recognized for functional use by a cell, encoding sequence (e.g., an open reading frame) for transcription to RNA and thereafter translation into a protein. The RNA molecule (e.g., an mRNA) will likewise contain the appropriate sequences for function within the cell. That function will depend upon the nature of the RNA molecule [0038]-[0039]. Saydam teaches an embodiment wherein the nuclei acid is a therapeutic nucleic acid (DNA or RNA) encodes a protein, and can be used for gene therapy, i.e., a therapeutic protein. The targeted delivery of the microvesicles, comprising the nucleic acid molecules, promotes the expression of the therapeutic nucleic acid, and therefore producing a therapeutic protein, in specific cells types or specific locations within a subject [0049].
Thus, Saydam does render obvious an expression vector that encodes a therapeutic protein, that is, Saydam teaches the limitation required by the current claims and as said limitation is found in one reference it is held that an expression vector that encodes a therapeutic protein is within the scope of the teachings of Saydam. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion that the expression vector encodes a therapeutic protein. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Saydam.
Further regarding claims 11 and 12 and the limitations therapeutic protein that is a secreted protein (claim 11), or the therapeutic protein is non-secreted (claim 12), it is noted that Saydam, at FIG. 3B illustrates cytosolic expression (i.e., non-secreted expression) of EGFP, and Saydam further teaches that microvesicles are naturally secreted by various cell types ([0063]) and microvesicles participate in horizontal transfer of proteins between cells ([0094]), which reads on secreted proteins.
Thus, Saydam has established that microvesicles can carry secreted and non-secreted proteins, thus meeting the limitations of claims 11 and 12.
Regarding claim 18, Saydam teaches delivering a therapeutic nucleic acid (e.g., RNA) via a nucleic acid expression vector to a subject by engineering the nucleic acid for targeting into microvesicles, generating the microvesicles in vitro, and thereafter delivering the microvesicles (i.e., pharmaceutically acceptable carrier) to the subject in one or more forms ([0071]-[0072],[0102], [0113]), thus meeting the limitation of claim 18.
Claim(s) 8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Saydam, as evidenced by SnapGene, as applied to claims 1-4, 6 and 10 above, and further in view of Addelman (Agreement takes a new therapy for rare brain disease to next stage, 28 June 2018, 5 pages; see PTO-892) (“Addelman”), as evidenced by Bennett et al., (Journal of Structural Biology 213 (2021) 107795, pages 1-14; see PTO-892) (“Bennett”).
The teaching of Saydam, as evidenced by SnapGene is set forth above.
Regarding claims 8 and 13, it is noted that although Saydam renders obvious the constructs comprising therapeutic proteins may be integrated and packaged into adeno-associated virus (AAV) (i.e., AAV particle), as discussed above, Saydam does not further comment on the AAV serotype (claim 8) or that the therapeutic protein is HGSNAT or SMN1.
However, Addelman discusses efforts at the University of Manchester that are directed to gene therapies that deliver therapeutic proteins, i.e., HGSNAT, for treating mutations in the HGSNAT gene cause the inherited neurodegenerative lysosomal storage disease Sanfilippo disease type C. Addelman teaches the gene therapy employs an AAV vector called AAV-TT (AAV-true type) (pages 1-4).
Bennett evidences that the AAV-TT is a modified AAV2 serotype (Abstract).
Thus Addelman, as evidenced by Bennett, has established it was known at the time of filing that AAV vectors comprising AAV 2 serotype, could be employed for packaging expression vectors encoding therapeutic proteins for treating Sanfilippo disease type C, specifically wherein the therapeutic protein is HGSNAT.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare AAV serotype 2 expression vector constructs comprising therapeutic proteins, wherein the therapeutic protein is HGSNAT for treatment of Sanfilippo disease type C.
The person of ordinary skill in the art would have been motivated to modify the AAV vector construct of Saydam wherein the expression vector comprises the therapeutic protein HGSNAT is packaged in AAV-TT (comprising AAV serotype 2) in order to deliver a gene therapy for treating children with the rare brain disease Sanfilippo disease type C, as taught by Addelman, for the predictable result of successfully providing therapeutic relief, thus meeting the limitation of claims 8 and 13.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Saydam and Addelman because each of these teachings are directed at gene therapies.
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Saydam, as evidenced by SnapGene, as applied to claims 7, 11-12 and 16-18 above, and further in view of McCarty et al., (Molecular Therapy, Vol. 16, Issue 10, October 2008, Pages 1648-1656; see PTO-892) (“McCarty”) and Ware et al (Molecular Therapy Vol. 20, Supplement 1, S123, May 2012, Abstract 312; see PTO-892) (“Ware”).
The teaching of Saydam, as evidenced by SnapGene, is set forth above.
Regarding claim 9, it is noted that although Saydam renders obvious AAV vectors, Saydam does not further comment on self-complementary AAV vectors. However, McCarty is directed to self-complementary AAV vectors and teaches that numerous preclinical studies have demonstrated the efficacy of recombinant adeno-associated virus (rAAV) gene delivery vectors, however, the efficiency of these vectors, in terms of the number of genome-containing particles required for transduction, is hindered by the need to convert the single-stranded DNA (ssDNA) genome into double-stranded DNA (dsDNA) prior to expression. McCarty teaches the use of self-complementary AAV vectors can circumvent the conversion into double-stranded DNA through packaging of an inverted repeat genome that can fold into dsDNA without the requirement for DNA synthesis or base-pairing between multiple vector genomes, and although the coding capacity of the vector is reduced, small protein-coding genes (up to 55 kd), and any currently available RNA-based therapy, can be accommodated and the increases in efficiency gained with self-complementary AAV (scAAV) are wide-ranging (Abstract).
Ware has demonstrated gene therapy for lysosomal storage diseases using systemic delivery of self-complementary AAV (scAAV) vectors of serotypes AAV 9 and AAVrh74. The vectors were compared for delivery to the CNS and expression of SGSH enzyme in MPS IIIA mice. By 10 days post-injection, SGSH activity levels had reached 14% of normal in the brains of scAAV9-treated mice, and 26% in scAAVrh74-treated mice. Both vectors yielded supranormal levels of SGSH activity in liver, and high levels in other somatic tissues. GAG storage in brain tissue was reduced to normal levels in AAVrh74-treated mice within 10 days, and reduced by 60% in AAV9-treated mice.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute using a self-complementary AAV for the AAV vector disclosed by Saydam since AAV vectors are known to be effective for delivery of therapeutic proteins. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of AAV vector for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Additionally, McCarty notes the use of scAAV vectors circumvents the conversion into double-stranded DNA and improves transduction efficiency, thus one would be motivated to substitute the self-complementary AAV vector for the prior art AAV vector for the predictable result of improving the efficiency of the gene therapy.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Saydam with McCarty and Ware because each of these teachings are directed at gene therapies.
Claim(s) 7, 11-12 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bolukbasi, as evidenced by SnapGene, as applied to claims 1-4, 6 and 10 above, and further in view of Saydam (set forth above).
The teaching of Bolukbasi, as evidenced by SnapGene, is set forth above.
Regarding claims 7, 16 and 17, it is noted that Bolukbasi does not further teach the expression vector is an adeno-associated virus vector (AAV vector) (claim 7), or a virus particle (claim 16), or an adenovirus particle, a herpesvirus particle or a baculovirus particle (claim 17).
However, Saydam, like Bolukbasi, is directed to employing expression vectors comprising a polynucleotide encoding a nucleic acid of interest (second nucleic acid) operably linked to an extracellular vesicle-targeting zip code sequence (first nucleic acid) for targeting to microvesicles, and Saydam teaches the nucleic acid expression vectors ([0055]) include plasmid or virus vectors ([0056]), the constructs may be integrated and packaged into non-replicating, defective viral genomes like adenovirus (i.e., adenovirus particle), adeno-associated virus (AAV) (i.e., AAV particle), or herpes simplex virus (HSV) (i.e., herpesvirus particle), for infection or transduction into cells ([0058]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute using an adeno-associated virus (AAV) (i.e., AAV particle) for packaging of the nucleic acid disclosed by Bolukbasi since Saydam acknowledges that the expression vector comprising zip code sequence can be selected from a variety of vectors including AAV viral particle vectors since they are known to be effective for delivery of therapeutic proteins. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of expression vector for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Bolukbasi with Saydam because each of these teachings are directed at gene therapies that employ zip code sequences for targeting microvesicles.
Regarding claims 11 and 12, and the limitation the expression vector encodes a therapeutic protein that is a secreted protein (claim 11), or the therapeutic protein is a non-secreted protein (claim 12), it is noted Bolukbasi does not further comment on the vector encoding a therapeutic protein. However, Saydam teaches that the nucleic acid (i.e., DNA) linked to the zip code sequence can encode sequences (e.g., an open reading frame) for transcription to RNA and thereafter translation into a protein [0038]-[0039]. Saydam teaches an embodiment wherein the nuclei acid is a therapeutic nucleic acid (DNA or RNA) that encodes a protein, and can be used for gene therapy, i.e., a therapeutic protein. The targeted delivery of the microvesicles, comprising the nucleic acid molecules, promotes the expression of the therapeutic nucleic acid, and therefore producing a therapeutic protein, in specific cells types or specific locations within a subject [0049].
Thus, Saydam has established it was known to use the expression vectors for encoding a therapeutic protein. Therefore, it would have been prima facie obvious to substitute sequence encoding a therapeutic protein, as taught by Saydam since AAV vectors are known to be effective for delivery of therapeutic proteins. Therefore, one of ordinary skill in the art would recognize this as simply substituting one nucleic acid of interest for another ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Further regarding claims 11 and 12 and the limitations therapeutic protein that is a secreted protein (claim 11), or the therapeutic protein is non-secreted (claim 12), it is noted that Saydam, at FIG. 3B illustrates cytosolic expression (i.e., non-secreted expression) of EGFP, and Saydam further teaches that microvesicles are naturally secreted by various cell types ([0063]) and microvesicles participate in horizontal transfer of proteins between cells ([0094]), which reads on secreted proteins.
Thus, Saydam has established that microvesicles can carry secreted and non-secreted proteins, thus meeting the limitations of claims 11 and 12.
Regarding claim 18, Saydam teaches delivering a therapeutic nucleic acid (e.g., RNA) via a nucleic acid expression vector to a subject by engineering the nucleic acid for targeting into microvesicles, generating the microvesicles in vitro, and thereafter delivering the microvesicles (i.e., pharmaceutically acceptable carrier) to the subject in one or more forms ([0071]-[0072],[0102], [0113]), thus meeting the limitation of claim 18.
Claim(s) 8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Bolukbasi, in view of Saydam, as evidenced by SnapGene, as applied to claims 7, 11-12 and 16-18 above, and further in view of Addelman (set forth above; see PTO-892) (“Addelman”), as evidenced by Bennett et al., (set forth above; see PTO-892) (“Bennett”).
The teaching of Bolukbasi, in view of Saydam, as evidenced by SnapGene is set forth above.
Regarding claims 8 and 13, it is noted that although Saydam renders obvious the constructs comprising therapeutic proteins may be integrated and packaged into adeno-associated virus (AAV) (i.e., AAV particle), as discussed above, Saydam does not further comment on the AAV serotype (claim 8) or that the therapeutic protein is HGSNAT or SMN1.
However, Addelman discusses efforts at the University of Manchester that are directed to gene therapies that deliver therapeutic proteins, i.e., HGSNAT, for treating mutations in the HGSNAT gene cause the inherited neurodegenerative lysosomal storage disease Sanfilippo disease type C. Addelman teaches the gene therapy employs an AAV vector called AAV-TT (AAV-true type) (pages 1-4).
Bennett evidences that the AAV-TT is a modified AAV2 serotype (Abstract).
Thus Addelman, as evidenced by Bennett, has established it was known at the time of filing that AAV vectors comprising AAV 2 serotype, could be employed for packaging expression vectors encoding therapeutic proteins for treating Sanfilippo disease type C, specifically wherein the therapeutic protein is HGSNAT.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare AAV serotype 2 expression vector constructs comprising therapeutic proteins, wherein the therapeutic protein is HGSNAT for treatment of Sanfilippo disease type C.
The person of ordinary skill in the art would have been motivated to modify the AAV vector construct of the prior art wherein the expression vector comprises the therapeutic protein HGSNAT is packaged in AAV-TT (comprising AAV serotype 2) in order to deliver a gene therapy for treating children with the rare brain disease Sanfilippo disease type C, as taught by Addelman, for the predictable result of successfully providing therapeutic relief, thus meeting the limitation of claims 8 and 13.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Addelman with the cited prior art because each of these teachings are directed at gene therapies.
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Bolukbasi, in view of Saydam, as evidenced by SnapGene, as applied to claims 7, 11-12 and 16-18 above, and further in view of McCarty et al., (set forth above; see PTO-892) (“McCarty”) and Ware et al (set forth above; see PTO-892) (“Ware”).
The teaching of Bolukbasi, in view of Saydam, as evidenced by SnapGene, is set forth above.
Regarding claim 9, it is noted that although Saydam renders obvious AAV vectors, Saydam does not further comment on self-complementary AAV vectors. However, McCarty is directed to self-complementary AAV vectors and teaches that numerous preclinical studies have demonstrated the efficacy of recombinant adeno-associated virus (rAAV) gene delivery vectors, however, the efficiency of these vectors, in terms of the number of genome-containing particles required for transduction, is hindered by the need to convert the single-stranded DNA (ssDNA) genome into double-stranded DNA (dsDNA) prior to expression. McCarty teaches the use of self-complementary AAV vectors can circumvent the conversion into double-stranded DNA through packaging of an inverted repeat genome that can fold into dsDNA without the requirement for DNA synthesis or base-pairing between multiple vector genomes, and although the coding capacity of the vector is reduced, small protein-coding genes (up to 55 kd), and any currently available RNA-based therapy, can be accommodated and the increases in efficiency gained with self-complementary AAV (scAAV) are wide-ranging (Abstract).
Ware has demonstrated gene therapy for lysosomal storage diseases using systemic delivery of self-complementary AAV (scAAV) vectors of serotypes AAV 9 and AAVrh74. The vectors were compared for delivery to the CNS and expression of SGSH enzyme in MPS IIIA mice. By 10 days post-injection, SGSH activity levels had reached 14% of normal in the brains of scAAV9-treated mice, and 26% in scAAVrh74-treated mice. Both vectors yielded supranormal levels of SGSH activity in liver, and high levels in other somatic tissues. GAG storage in brain tissue was reduced to normal levels in AAVrh74-treated mice within 10 days, and reduced by 60% in AAV9-treated mice.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute using a self-complementary AAV for the AAV vector disclosed by the cited prior art since AAV vectors are known to be effective for delivery of therapeutic proteins. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of AAV vector for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Additionally, McCarty notes the use of scAAV vectors circumvents the conversion into double-stranded DNA and improves transduction efficiency, thus one would be motivated to substitute the self-complementary AAV vector for the prior art AAV vector for the predictable result of improving the efficiency of the gene therapy.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of the cited prior art with McCarty and Ware because each of these teachings are directed at gene therapies.
Conclusion
No claim is allowed. No claim is free of prior art.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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