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 .
Priority
This application claims benefit to US provisional 63/545,351 (filed on 10/23/2023) and claims benefit to US provisional 63/456,632 (filed on 04/03/2023).
Claim Status
Claims 1-2,5-6,10-11,14,16,28-29,32-33,36-39,42,45-47,49,52,55-56 and 58-59 are pending and have been examined on the merits.
Claim Rejections - 35 USC § 112
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 47 and 52 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.
Regarding claim 47, claim 47 is drawn to method of which the only active step is to substitute an arbitrary plasmid, pAAV-RC1, with the rep-cap plasmid of claim 2 in manufacture of an rAAV. However, because there is no step of providing a cell with pAAV-RC1, and physically removing the pAAV-RC1 plasmid and replacing it with the rep-cap plasmid of claim 2 (it is not clear such would be enabled), it is unclear if the method requires anything other than a mental step of deciding to use the rep-cap plasmid of claim 2 instead of the pAAV-RC1 plasmid. Thus it appears the method ultimately only requires an active step of providing a cell with the rep-cap plasmid of claim 2. It is unclear what the claim requires besides the rep-cap plasmid being used with a cell to produce an rAAV. The metes and bounds of the claim are unclear, therefore it is rendered indefinite.
For examination purposes with respect to prior art, any rep-cap plasmid that reads on the plasmid of claim 2, that is used to create rAAV, will be considered within the metes and bounds of claim 47.
Regarding claim 52, the phrase, “wherein the rep-cap plasmid has an arrangement according to Figure 1, Figure 5, Figure 6, or Figure 7,” renders the claim indefinite because the phrase refers to Figures, therefore it is unclear what the arrangement for the plasmids is. MPEP 2173.05(s) states “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608 (bd. Pat. App. & Inter. 1993) (citation omitted).” The information from Figures 1, 5, 6 or 7 pertinent to the claims does not qualify as an exception to circumstance. It is unclear what information from the Figures is to be read into the claim can be incorporated into the claims. It is not clear what the claim requires nor what the metes and bounds of the limitation is and any interpretation leads to the claims being indefinite.
For examination purposes with respect to prior art, any plasmid arrangement that has the components of set forth by claim 2, will be considered within the metes and bounds of claim 52.
Appropriate correction or clarification is required.
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.
Claims 1, 36-38, and 46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goeden et al (WO 2022/2221397 A2).
Goeden et al disclosed plasmids and methods for producing plasmids (See, Abstract).
Regarding claim 1, Goeden et al teach an embodiment with a AAV rep-cap plasmid comprising an AAV2 rep gene, a cap gene, a tetracycline-inducible expression system in between the AAV2 rep gene and cap gene, and an AAV5 p41 promoter (See, ¶0003). This reads on, an AAV rep-cap plasmid comprising… : (a) polynucleotide encoding AAV rep protein, (b) a tetracycline system, (c) an AAV promoter, (d) polynucleotide encoding an AAV capsid protein.
Goeden et al disclosed that that tetracycline system and the AAV5 p41 promoter are inserted between the rep gene and the gene encoding the capsid protein (See, ¶0008). This reads on the orientation of plasmid, as it has elements a) through d) in the order specified in 5’ to 3’.
Regarding claim 36, following the discussion above, Goeden teaches the plasmid can contain helper genes or a secondary plasmid with helper genes can be introduced simultaneously with the Rep-Cap plasmid into a cell, where the helper genes include E4, E2a, or VA (See, ¶0004). The cell the AAV plasmid is introduced to make an rAAV can be a cell from a mammal, embryonic stem cell, or human embryonic kidney 293 (HEK293) cell (See, ¶0005). This reads on, a method of manufacturing a rAAV comprising… (I) introducing a mammalian cell, which HEK293 cells are, (a) a rep-cap plasmid of claim 1, (b) a helper plasmid comprising…E4, E2a and or VA… Goeden et al also teaches a third plasmid that includes a gene of interest flanked by inverted terminal repeats and the Rep-cap plasmids of the invention can be introduced into a cell with helper genes plasmid and the plasmid with transgene of interest, such that rAAV is produced that can be used for gene therapy (See, ¶0002). This reads on, (c) a transgene plasmid comprising a transgene of interest flanked by inverse terminal repeats, wherein the introducing step is under conditions that permit formation of rAAV. Goeden et al teaches in example 2 the manufacturing where the HEK293 cells are scaled up, transfected and then the cells are collected for further processing (See, ¶0027). This reads on, (II) collecting the rAAV.
Regarding claim 37, following the discussion above, the rep-cap plasmid of claim 36 and claim 1 has a AAV P41 promoter; therefore this reads on, wherein the AAV promoter is an AAV P41 promoter.
Regarding claim 38, following the discussion above, Goeden et al teaches the use of HEK293 cell for rAAV manufacture, this reads on, wherein the mammalian cell is HEK-293 cell.
Regarding claim 46, following the discussion above, Goeden et al teaches that the rAAV is transduced with the rep-cap plasmid of claim 1, which has an AAV5 promoter of AAV p41, helper plasmids and transgene plasmid. As the plasmid has an AAV5 p41 promoter, which is a constitutive promotor from AAV5, it is not required for the tet-system, also a part of a plasmid to be induced to produce rAAV1 virus. Therefore, this reads on, wherein (a) rep-cap plasmid comprises a Tet-On system; and (b) the production of the rAAV1 virus is achieved without inducing the Tet-on system.
Therefore, claims 1, 36-38, and 46 are anticipated by Goeden et al.
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.
Claims 2,10,28,32,42,47,52,55-56, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Goeden et al (WO 2022/2221397 A2) as applied to claims 1, 36-38, and 46, and in view of Kim et al (Theranostics, 2019); evidenced by Van Vliet et al (Methods in molecular biology, 2008).
The teachings of Goeden et al are set forth above.
Regarding claim 2, following the discussion above, Goeden et al an embodiment a AAV rep-cap plasmid comprising an AAV2 rep gene, a cap gene, a tetracycline-inducible expression system in between the AAV2 rep gene and cap gene, and an AAV5 p41 promoter. This reads on, and the AAV promoter is an AAV P41 promoter.
Goeden et al does not teach that the AAV capsid protein is an AAV1 capsid protein.
Goeden et al disclosed that Rep-cap plasmids of the invention can be modified by substituting or modifying an existing capsid gene to encode a targeting protein to provide the plasmid a preferred target for specific cell or tissue administration (See, ¶0008).
Kim et al teaches the use of recombinant viral vector to transfect Slc26A4 (pendrin) cDNA (See, Abstract). Kim et al teaches that the use of rAAV with ITR of AAV2, capsid of AAV1, a CMV promoter that was packaged with Slc26a4 cDNA and turbo GFP (tGFP) for gene delivery for hereditary hearing loss (See, Methods p 7186).
Van Vliet et al teaches that the transduction efficiency of select AAV serotypes and it shows that for inner ear / cochlear AAV1 and AAV2 are more efficient (See, Table 2.1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the AAV plasmid of Goeden et al such that the capsid protein be AAV1, as taught by Kim et al. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have been motivated to make this modification by the disclose of Goeden et al to modify the capsid for optimal delivery and by Van Vliet et al as AAV1/AAV2 are efficient for inner ear/cochlear transduction. One would have had a reasonable expectation of success evidenced by Kim et al and Van Vliet et al.
Regarding claim 10, following the discussion above, Goeden et al teaches the exemplary plasmid has all the components mentioned above. Goeden et al disclosed that the tetracycline-inducible expression system comprising tetracycline controlled transactivator (tTA) – Tetracycline response element (TRE)-based inducible application loop to increase virus production is exemplified in SEQ ID NO: 1 with a tet8 TRE and SEQ ID NO: 2 with a tet6 TRE. This reads on, wherein the Tet-Off system comprises 5’ to 3’ orientation: (a) polynucleotide encoding tTA….; and (b) a polynucleotide comprising 1 to 12 tet operator (tetO) sequences. The tetO sequence is a 19 nucleotide sequence found in both plasmid nucleotide sequences.
Regarding claim 28, following the discussion above, Goeden et al disclosed a p41 promoter with sequence 100% query match with instant application SEQ ID NO: 8. (See, APPENDIX for alignment). This reads on, wherein the p41 promoter has the sequence of SEQ ID NO: 8.
Regarding claim 32, following the discussion above, Goeden et al disclosed an embodiment where the poly adenylation sequence is inserted between the rep gene and the gene encoding the capsid (See, ¶0008). This reads on, …further comprises a poly A signal sequence located between the first and second polynucleotide.
Regarding claim 42 and 56, following the discussion above, Goeden et al does not teach the cell further comprising a transgene of interest that encodes a protein that is normally expressed in the human ear.
Kim et al teaches the use of recombinant viral vector to transfect Slc26A4 (pendrin) cDNA (See, Abstract). Kim et al teaches that the use of rAAV with ITR of AAV2, capsid of AAV1, a CMV promoter that was packaged with Slc26a4 cDNA and turbo GFP (tGFP) for gene delivery for hereditary hearing loss (See, Methods p 7186).
Given that Goeden et al and Kim et al teach gene delivery vectors, it would have been prima facie obvious to a person having ordinary skill in the art to substitute the transgene of Goeden et al to the solute carrier family 26; member 4 (Pendrin) (Slc26A4) of Kim et al for a similar purpose. The use of Slc26A4 transgene would have predictable results of success evidenced by Kim et al. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding claim 47, following the discussion above, the claimed method as is has no active step besides substituting a pAAV-RC1 in manufacture with the rep-cap plasmid of claim 2. As the rep-cap plasmid of claim 2 has been rendered obvious above, claim 47 is included in the rejection due the availability of the plasmid for the substitution in the method.
Regarding claim 52, following the discussion above, as the claim is indefinite as described above about the plasmid arrangement, this claim is included in the rejection of claim 2, as the plasmid as all the components in the orientation required.
Regarding claim 55 and 58-59, following the discussion above Goeden et al disclosed a cell comprising a rep-cap plasmid of claim 2, when making rAAV with HEK293 cells. This also reads on, wherein the cell is a mammalian cell of claim 58 and wherein the mammalian cell is a HEK-293 cell of claim 59.
Therefore, claims 2,10,28,32,42,47,52, 55-56, and 58-59 are rendered obvious by Goeden et al in view of Kim et al and evidenced by Van Vliet et al.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Goeden et al (WO 2022/2221397 A2) and Kim et al (Theranostics, 2019) as applied to claims 2,10,28,42,47,52,55-56, and 58-59 above, and further in view of Chew et al (WO 2021/251905A1).
The teachings of Goeden et al and Kim et al are set forth above.
Regarding claim 5, Goeden et al nor Kim et al teach a polynucleotide encoding the AAV rep protein with sequence of SEQ ID NO: 3.
Chew et al disclosed a method for assessing the transduction efficiency and specificity of vectors at a single cell level for AAV vectors used in gene delivery into a subject (See, Abstract and ¶0021). Chew et al teaches SEQ ID NO: 12, a rep gene sequence for capsid REP gene sequence of plasmid. This is a 100% query match for instant SEQ ID NO: 3 (See, APPENDIX for alignment).
Given that Goeden et al and Chew et al teach gene delivery vectors, it would have been prima facie obvious to a person having ordinary skill in the art to substitute the AAV rep protein sequence of the AAV2 rep protein of Goeden et al to that of SEQ ID NO: 12 of Chew et al for a similar purpose. The use of SEQ ID NO: 12 rep protein sequence would have predictable results of success evidenced by Chew et al. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Therefore, claim 5 is rendered obvious by Goeden et al and Kim et al, in view of Chew et al.
Claims 11 is rejected under 35 U.S.C. 103 as being unpatentable over Goeden et al (WO 2022/2221397 A2) and Kim et al (Theranostics, 2019) as applied to claims 2,10,28,42,47,52,55-56, and 58-59 above, and further in view of Bisgrove et al (US2012129254-A1).
The teachings of Goeden et al and Kim et al are set forth above.
Regarding claim 11, Goeden et al teaches …wherein the first polynucleotide has at least 80% sequence identity to SEQ ID NO: 6. Goeden et al disclosed SEQ ID NO: 5, a tetracycline controlled transactivator (tTA) and a 100% query match for instant SEQ ID NO: 6 (See, APPENDIX for alignment).
Goeden et al nor Kim et al teach a polynucleotide having an amino acid sequence of… SEQ ID NO: 20.
Bisgrove et al disclosed an invention with inducible expression system such as the Tet- ON/OFF system (See, abstract and ¶0056). Bisgrove et al teaches SEQ ID NO: 7, Tet-On amino acid sequence for this inducible system. This is a 100% query match for instant SEQ ID NO: 20 (See, APPENDIX for alignment).
Given that Goeden et al and Bisgrove et al teach inducible Tet system for AAV vectors, it would have been prima facie obvious to a person having ordinary skill in the art to substitute the tTA sequence of the Tet-system of Goeden et al to that of SEQ ID NO: 7 of Bisgrove et al for a similar purpose. The use of SEQ ID NO: 7 tTA amino acid sequence would have predictable results of success evidenced by Bisgrove et al. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Therefore, claim 11 is rendered obvious by Goeden et al and Kim et al, in view of Bisgrove et al.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Goeden et al (WO 2022/2221397 A2) and Kim et al (Theranostics, 2019) as applied to claims 2,10,28,42,47,52,55-56, and 58-59 above, and further in view of Lim et al (WO 00/52179).
The teachings of Goeden et al and Kim et al are set forth above.
Regarding claim 14, Goeden et al nor Kim et al teach wherein each tetO sequence has the sequence of SEQ ID NO: 4, wherein each tetO sequence is separated from an adjacent tetO sequence by 0-20 nucleotides.
Lim et al disclosed an invention with molecular switch system methods and compositions to regulate gene expression (See, abstract). Lim et al teaches an expression system with a promoter repeats of tetO elements and a fusion protein and a TetR DNA binding domain that binds to tetracycline to induce expression (See, p15 lines 1-5). Lim et al also teaches SEQ ID NO: 5, tetO DNA response element nucleic acid sequence for this inducible system. This is a 100% query match for instant SEQ ID NO: 4 (See, APPENDIX for alignment).
Given that Goeden et al and Lim et al teach inducible Tet system for gene expression, it would have been prima facie obvious to a person having ordinary skill in the art to substitute the tetO sequence of the Tet-system of Goeden et al to that of SEQ ID NO: 5 of Lim et al for a similar purpose. The use of SEQ ID NO: 5 tetO nucleic acid sequence would have predictable results of success evidenced by Lim et al. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Therefore, claim 14 is rendered obvious by Goeden et al and Kim et al, in view of Lim et al.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Goeden et al (WO 2022/2221397 A2) and Kim et al (Theranostics, 2019) as applied to claims 2,10,28,42, 47,52,55-56, and 58-59 above, and further in view of Wilson et al (WO 2000/28061 A2).
The teachings of Goeden et al and Kim et al are set forth above.
Regarding claim 29, Goeden et al nor Kim et al teach wherein the polynucleotide encoding an AAV1 capsid protein encodes an amino acid sequence of SEQ ID NO: 9.
Wilson et al disclosed an invention with nucleic acid sequences of AAV serotype I as vectors and host cells containing the sequences or functional fragments (See, Abstract). Wilson et al also teaches SEQ ID NO: 3, an AAV1 capsid. This is a 100% query match for instant SEQ ID NO: 9 (See, APPENDIX for alignment).
Given that Goeden et al and Wilson et al teach inducible AAV vectors for gene delivery, it would have been prima facie obvious to a person having ordinary skill in the art to substitute AAV1 capsid sequence of Goeden et al to that of SEQ ID NO: 3 of Wilson et al for a similar purpose. The use of SEQ ID NO: 3 AAV1 sequence would have predictable results of success evidenced by Wilson et al. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Therefore, claim 29 is rendered obvious by Goeden et al and Kim et al, in view of Wilson et al.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Goeden et al (WO 2022/2221397 A2) as applied to claims 1, 36-38, and 46 above, and further in view of Dobnik et al (Frontiers in microbiology, 2019).
The teachings of Goeden et al are set forth above.
Regarding claim 45, following the discussion above, Goeden et al does not teach wherein the viral yield is at least 1 x 1011 vg/mL as measured using ddPCR of clarified lysate.
Dobnik et al teaches that droplet digital PCR (ddPCR) performs better than quantitative PCR (qPCR) for measuring AAV viral vectors and optimizing process for production for gene therapy (See, Abstract). Dobnik et al teaches a method of clarifying HEK293T AAV transduced cells that was in lysis buffer. The lysate was centrifuged and supernatant collected, the clarified lysate was used for more processing in columns (See, Methods, p2). Dobnik et al teaches various ways to increase resulting vector genomes or titers with ddPCR including pretreatment with DNase, denaturation, and using restriction enzymes (See, 8 and figure 4).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Goeden et al such that the viral yield is at least 1x 1011 vg/mL, measured by ddPCR as taught by Dobnik et al. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have been motivated to make this modification by the teachings of Dobnik et al, to increase vector genome/ titers for improved gene delivery/therapy. One would have had a reasonable expectation of success evidenced by Dobnik et al.
Therefore, claim 45 is rendered obvious by Goeden et al in view of Dobnik et al.
Allowable Subject Matter
Claims 6,16,33,39, objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
APPENDIX
SEQUENCE ALIGNMENTS
RE: Claim 5
Query (Qy), SEQ ID NO: 3 vs Database (Db) WO2021/251905 A1 SEQ ID NO: 12
PNG
media_image1.png
236
626
media_image1.png
Greyscale
RE: Claim 28
Query (Qy), SEQ ID NO: 8 vs Database (Db) WO 2022/221397A2 SED ID NO: 8
PNG
media_image2.png
486
624
media_image2.png
Greyscale
RE: Claim 11
Query (Qy), SEQ ID NO: 6 vs Database (Db) WO 2022/221397 A2 SED ID NO: 5
PNG
media_image3.png
233
612
media_image3.png
Greyscale
Query (Qy), SEQ ID NO: 20 vs Database (Db) US2012129254-A1SEQ ID NO: 7
PNG
media_image4.png
486
616
media_image4.png
Greyscale
RE: Claim 14
Query (Qy), SEQ ID NO: 4 vs Database (Db) WO 00/52179 AAA75181 SEQ ID NO: 5
PNG
media_image5.png
145
611
media_image5.png
Greyscale
RE: Claim 29
Query (Qy), SEQ ID NO: 9 vs Database (Db) WO 2000/28061 A2 SEQ ID NO: 3
PNG
media_image6.png
565
616
media_image6.png
Greyscale
Prosecution Insights