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 II (claims 1-12 and 25-28 in the reply filed on 10/27/2025 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The species election of AA Vrh.79 is acknowledged in the reply filed on 10/27/2025.
Claims 1-12 and 25-28 are pending.
Claims 9-11 and 25-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group or species, there being no allowable generic or linking claim.
Claims 1-8 and 12 are examined on the merits.
Specification
The disclosure is objected to because of the following informalities: The tables on pages 57, 59, 62 and 66 of the instant specification lack identifiers.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites “PCSK9”. When an abbreviation is first introduced it should be described using the full name.
Claim 3 is objected to because of the following informalities: the claim recites “the nucleotide sequence that encodes a PCSK9 comprises”. The claim should recite “the nucleotide sequence that encodes a PCSK9-targeting meganuclease comprises”.
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.
Claim 7 is 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 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.
Regarding claim 7: The claim recites “the vector genome comprises a nucleic acid sequence of SEQ ID NO: 13 or sequence sharing at
least 80% therewith”.
Seq ID NO: 13 is a nucleic acid sequence comprising 1866
nucleotides. The broadest reasonable interpretation of the claim limitation “sharing at least 80% therewith” is a nucleic acid sequence that can differ from Seq ID NO: 13 by up to 20% (about 373 nucleotides) compared to Seq ID NO: 13.
Thus the claimed genus of vectors is broad, as up to 373 nucleotides of the claimed vector can be any of the four nucleotides at any of the 1866 positions within the claimed vector sequence.
Teachings of the instant specification
The instant specification provides some guidance as to the composition of the claimed vector sequences.
The instant specification teaches the vector can comprise a “weak promoter” such as the promoter sequences of Seq ID NO:6-8 (p2 ln15-20).
The instant specification teach Figures 1B and 6A, schematic representations of AAV constructs that are used in examples 1 and in mouse experiments (p3 ln 20-25, Examples 1 and 2).
The instant specification disclose working examples of rAAV vectors in examples 1-4. Example 3 teach multiple AAV vectors but does not disclose the nucleotide sequences for said vectors (p66 Table). Example 4 is a working example of the vector genome of Seq ID NO: 13 (p74 ln20-25).
The state of the art:
It is well known in the art that an AAV vector genome comprises nucleic acid sequences encoding functional regions, for example regulatory sequences such as promoters and nucleic acid sequences which encode transgenes, such as the PCSK9 meganuclease of the instant invention. It is also well known in the art that the effect of nucleic acid substitutions on polynucleotide activity is not predictable for nucleic acids which comprise protein coding sequences.
Regarding nucleic acid sequences which encode proteins (such as the PCSK9 meganuclease of the instant invention), Alberts et al (The Shape and Structure of Proteins (2002) Molecular Biology of the Cell 4th edition p1-19) teach only a very small fraction of the vast set of conceivable polypeptide chains would adopt a single, stable three-dimensional conformation (p7 ¶3).
Thus the effect changing nucleotides which comprise amino acid coding sequences without guidance is unpredictable as to whether or not the changes in the nucleotide sequence would change the encoded protein structure such that it would still fold correctly to enable the encoded protein to perform the intended function. Thus trial-and error experimentation is required when implementing nucleotide sequence changes to protein coding sequences such as the sequence which encodes the PCSK9 meganuclease of Seq ID NO:13.
The art teaches some sequence requirements for meganucleases. Takeuchi et al (Methods Mol Biol (2015)1239;1-30) teach meganucleases possess a single conserved amino acid motif comprising 9 residues (p2 ¶3). Takeuchi also teach to retarget meganucleases, variant endonucleases are screened using a two-plasmid cleavage assay to identify variants that are active in cells (p2 ¶4). Thus, identification of meganuclease variants with changed activity requires trial-and-error experimentation to screen many variants to identify meganucleases with the desired traits.
Thus, while nucleic acid sequences encoding meganuclease sequences are known, there is not sufficient guidance in the art for changes of up to 20% of the nucleic acid sequence encoding the polypeptides and the effects of such changes are unpredictable.
This supports the effect of changes of up to 20% of the nucleotide residues encoding the PCSK9 meganuclease of the instant invention must be experimentally tested using trial and error experimentation.
Therefore, the species examples provided in the art are not of a large enough breadth to impart predictability on the genus as claimed and the art does not provide sufficient guidance for the sequences as claimed.
Conclusion
As described supra, the instant specification discloses a nucleic acid sequences encoding an AAV vector which encodes a PCSK9 meganuclease.
However a single nucleotide sequence encoding a protein is not sufficient guidance to predict the large genus of PCSK9 meganuclease variants that are at least 80% identical to the coding sequence of seq ID NO:13, as claimed, in view of the unpredictability of nucleic acid substitutions as evidenced by the art.
Furthermore, the instant specification provides no guidance as how to avoid losing key structural or binding components of the encoded meganuclease, or regulatory regions of the vector (such as promoter sequences), and the art does not remedy this deficiency.
One of ordinary skill in the art would understand that protein function requires correct protein structure (folding). One of ordinary skill in the art would also understand that the effect of nucleic acid substitutions in the nucleic acid coding sequence of proteins can have unpredictable effects on the encoded proteins structure and thus function.
Thus, while nucleotide sequences encoding meganucleases are known in the art, the effect of changes of up to 20% of those sequences must be tested empirically to determine how the sequence change affects protein function. Furthermore, one of ordinary skill in the art would understand that changes of up to 20% of other regions of the AAV vector genome, such as a promoter sequence, would also require empirical testing to determine how the sequence change affects promoter function.
MPEP states “[a] specification may call for a reasonable amount of experimentation to make and use a patented invention. What is reasonable in any case will depend on the nature of the invention and the underlying art”.
In the case of the instant claims, trial and error and/or laborious screening methods are required to identify rAAV genome variants as claimed and the species examples provided in the instant specification and art are not of a large enough breadth to impart predictability on the genus as claimed.
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 1-8 and 12 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.
Regarding claim 1: The claim recites “a PCSK9 meganuclease”. This is indefinite because PCSK9 typically refers to proprotein convertase subtilisin/kexin type 9 which is associated with cholesterol metabolism but not known as a meganuclease (Peterson et al (Journal of Lipid Research (2008) 49:0-5); p0 col1 ¶1). Thus it is unclear what a PCSK9 meganuclease refers to.
For purposes of compact prosecution the claim is interpreted as “a PCSK9-targeting meganuclease”.
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 1, 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Bartsevich et al (WO 2018/195449 A1) in view Wang et al (US 11779656 B2) and Wu et al (American Society of Gene and Cell Therapy (2010 18:1;80-86).
Regarding claim 1: Bartsevich teach engineered meganucleases which recognize and cleave a recognition sequence within the human PCSK9 gene (abstract). Bartsevich teach the AAV8.TBG.PI.PCS7-8x.88WPRE.bGH vector, a recombinant AAV vector comprising a meganuclease and comprising a capsid and AAV inverted terminal repeats (p61 [0231]). Bartsevich further teach the 5’ ITR and 3’ ITR flank the coding sequence for the PCSK9 meganuclease and regulatory sequences (p61 [0231]).
Bartsevich teach the PCSK9 meganuclease comprises the amino acid sequence of sequence 6 (claim 17). Sequence 6 of Bartsevich comprises 97% sequence identity to amino acid sequence of Seq ID NO: 16 of the instant invention. This reads on a PCSK9 meganuclease comprising at least 95% identity to Seq ID NO: 16 of the instant claim.
The sequence alignment of Seq ID NO: 16 of the instant invention (Qy) and Seq ID 6 (Db) is shown below:
Best Local Similarity 100.0%;
Matches 354; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 11 MNTKYNKEFLLYLAGFVDGDGSIFARIKPSQRSKFKHKLHLVFAVYQKTQRRWFLDKLVD 70
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MNTKYNKEFLLYLAGFVDGDGSIFARIKPSQRSKFKHKLHLVFAVYQKTQRRWFLDKLVD 60
Qy 71 EIGVGYVLDSGSVSFYSLSEIKPLHNFLTQLQPFLKLKQKQANLVLKIIEQLPSAKESPD 130
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EIGVGYVLDSGSVSFYSLSEIKPLHNFLTQLQPFLKLKQKQANLVLKIIEQLPSAKESPD 120
Qy 131 KFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLPGSVGGLSPSQASSAASSASSSPGS 190
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLPGSVGGLSPSQASSAASSASSSPGS 180
Qy 191 GISEALRAGAGSGTGYNKEFLLYLAGFVDGDGSIYARIKPVQRAKFKHELVLGFDVTQKT 250
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GISEALRAGAGSGTGYNKEFLLYLAGFVDGDGSIYARIKPVQRAKFKHELVLGFDVTQKT 240
Qy 251 QRRWFLDKLVDEIGVGYVYDKGSVSAYRLSQIKPLHNFLTQLQPFLKLKQKQANLVLKII 310
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QRRWFLDKLVDEIGVGYVYDKGSVSAYRLSQIKPLHNFLTQLQPFLKLKQKQANLVLKII 300
Qy 311 EQLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLSEKKKSSP 364
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 EQLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLSEKKKSSP 354
Bartsevich teach one approach to prevent meganuclease expression in viral packaging cells include placing the meganuclease under the control of a tissue-specific promoter that is not active in the packaging cells (p49 [206]). Bartsevich further teach the AAV vector comprises a liver-specific human thyroxine binding globulin (TBG) promoter (p61 [0231]).
Bartsevich do not teach the thyroxine binding globulin promoter comprises the sequence of Seq ID NO:7 of claim 1.
Wang teach an rAAV vector with a promoter driving expression of a human transgene (abstract). Wang further teach a promoter of a small size is desirable for vectors with large inserts (p38 col10 ln 34-40). As such Wang teach a shortened version of the thyroxin binding globulin promoter can be used. Wang teach the sequence of the shortened thyroxin binding promoter is sequence 8 (p38, col1 ln 40-45), which is 100% identical to Seq ID NO: 7 of the instant invention.
The alignment of Seq ID NO: 7 of the instant invention (Qy) and Sequence 8 of Wang (Db) is shown below:
Query Match 100.0%; Score 113; Length 176;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CTTTGAAAATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAACTAAGAGTGCTCTAG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 64 CTTTGAAAATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAACTAAGAGTGCTCTAG 123
Qy 61 TTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTCTGAGAGA 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 124 TTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTCTGAGAGA 176
It would have been obvious to one of ordinary skill in the art to adapt the product of Bartsevich drawn to an rAAV by using a promoter sequence of a shortened thyroxine binding globulin (TBG) promoter as disclosed by Seq ID NO: 8 of Wang.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by Bartsevich with the promoter taught by Wang for the purposes of using a shortened promoter because Wu teach a substantial limitation of AAV vectors is their small packaging capacity, which is generally considered to be less than 5kb (p80 col1 ¶1). Therefore, a shortened promoter would result in more cargo capacity in the rAAV for additional cargo sequence and would allow for a more flexible rAAV.
One would have had a reasonable expectation of success because Wang discloses expression of a transgene using the disclosed promoter (Fig 21) and one of ordinary skill in the art would understand that exchanging functional components in rAAV expression systems is standard molecular biology practice.
One of ordinary skill in the art would also understand that AAV expression vectors have limited cargo capacity and would recognize a shorter promoter sequence would provide more space in an expression vector for additional transgene elements.
Regarding claim 5: The teachings of Bartsevich are discussed supra. Bartsevich do not teach the vector comprises a polyadenylation signal.
Wang teach the vector comprises a polyadenylation signal (p38 col 10 ln 3-10). Wang further teach that an expression cassette may contain sequences to promote efficient RNA processing and that a polyA sequence stabilizes cytoplasmic mRNA (p39 col11 ln 38-45).
It would have been obvious to one of ordinary skill in the art to adapt the rAAV of Bartsevich by including a polyA signal as taught by Wang.
One of ordinary skill in the art would have been motivated to modify the rAAV of Bartsevich by including a polyA signal as taught by Wang for the purposes of stabilizing cytoplasmic RNA.
One would have had a reasonable expectation of success because Wang teach polyA signals stabilize cytoplasmic mRNA and mediates termination of transcripts, and one of ordinary skill in the art would understand that exchanging functional components in rAAV expression systems is standard molecular biology practice.
Regarding claim 7: The instant claim recites “the vector
genome comprises a nucleic acid sequence of SEQ ID NO: 13”. Claim language such as that of claim 7 encompasses nucleic acids that comprise the full-length sequence of SEQ ID NO: 13 or nucleic acid sequences that comprise any portion of SEQ ID NO: 13. Thus the claim is anticipated by any nucleic acid comprising any dinucleotide or larger oligonucleotide which is a portion of SEQ ID NO: 13.
If the claim were amended to recite “the vector genome comprises the nucleic acid sequence of SEQ ID NO: 13” the examiner would interpret the claims to encompass only nucleic acids that comprise the full length of the specified SEQ ID NO:, with or without additional nucleotides at either or both ends.
Seq ID NO:13 is a nucleotide sequence comprising 1866 bp. Nucleotides 206-311 of Seq ID NO:13 are 100% identical to Seq ID NO: 7 of the instant disclosure.
As discussed supra, Bartsevich and Wang teach the vector genomic sequence comprises the sequence of the shortened thyroxin binding promoter, i.e. Wang teach sequence 8 (p38, col1 ln 40-45), which is 100% identical to Seq ID NO: 7 of the instant invention, and thus also 100% identical to nucleotides 205-311 of the instant Seq ID No:13.
Thus, as discussed supra, the teachings of Bartsevich and Wang render obvious the genome sequence of instant claim 7 because Seq ID NO: 8, as taught by Wang, comprises 100% sequence identity with a nucleic acid sequence of Seq ID NO:13 (nucleotides 206-311 of Seq ID NO: 13).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over Bartsevich et al (WO 2018/195449 A1) in view Wang et al (US 11779656 B2) and Wu et al (American Society of Gene and Cell Therapy (2010 18:1;80-86) as applied to claims 1, 5 and 7 above, and further in view of Jantz et al (US 2016/0017372 A1).
Regarding claim 2: As discussed supra, Bartsevich teaches Sequence 6, which comprises 97% sequence identity to the amino acid sequence of seq ID NO: 16 of the instant invention.
Bartsevich do not teach the amino acid sequence of Seq ID NO:16 of the instant invention.
Seq ID NO: 16 of the instant invention comprises 364 amino acid residues. Seq ID NO: 6 of Wang comprises 100% sequence identity with residues 11-364 of the instant seq ID NO: 6.
Bartsevich do not teach the promoter comprises residues 1-10 of Seq ID NO:16, which comprises the amino acid sequence “MAPKKKRKVH”.
Jantz teach methods for inserting genes into chromosomal DNA of mammalian cells, meganucleases and vectors (abstract, p1 [0002]). Jantz further teach an engineered nuclease is fused to a nuclear localization signal to facilitate nuclear uptake, and that “MAPKKKRKV” (Seq ID NO: 36 of Jantz) is the SV40 NLS sequence which is preferably fused to the N-terminus of the protein (p12 [0112]). Jantz further teach multiple embodiments of nucleases with an N-terminal fusion to an NLS, which comprise the sequence “MAPKKKRKVH” at the N-terminus (e.g. Seq ID NOs:9-10 of Jantz).
It would have been obvious to one of ordinary skill in the art to adapt the rAAV of Bartsevich by including the sequence “MAPKKKRKVH” at the N-terminus of the meganuclease as taught by Jantz. Furthermore, it would have been obvious to modify the rAAV vector to comprise a nucleic acid sequence encoding the amino acid sequence of the meganuclease with the N-terminal NLS, as encoding the nucleic acid sequence of a desired transgene (amino acid sequence) in an expression vector is well known in the art.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by Bartsevich with the NLS sequence as taught by Jantz to facilitate nuclear uptake of the nuclease, which one of ordinary skill in the art would understand would increase the efficiency of the nuclease because the target DNA is in the nucleus.
One would have had a reasonable expectation of success because Jantz discloses multiple embodiments of the NLS sequence “MAPKKKRKVH” fused to the N-terminus of meganucleases, and one of ordinary skill in the art would understand that exchanging functional components in rAAV expression systems is standard molecular biology practice.
Regarding claims 3 and 4: The claim is interpreted as requiring a nucleotide sequence that encodes a PCSK9 targeted meganuclease having at least 95% sequence identity to nucleotides 1089-2183 of Seq ID NO: 15.
Nucleotides 1089-2183 of Seq ID NO:15 encode the amino acid sequence of seq ID No:16 which is rendered obvious by the teachings of Bartsevich and Jantz, as discussed supra.
The nucleotide encoding an amino acid sequence would be obvious to one of ordinary skill in the art as nucleotide codon sequences are well known in the art. One would be motivated to use the nucleic acid coding sequence of an amino acid sequence to encode the desired amino acid sequence in an expression vector. One would have a reasonable expectation of success because encoding the nucleic acid sequence of the amino acid sequence of a transgene is common molecular biology practice.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
While Bartsevich and Jantz do not disclose a specific nucleic acid sequence which encodes the amino acid sequence, one of ordinary skill in the art would understand nucleic acid sequences encoding amino acid sequences are well known in the art and it would be obvious to use a nucleic acid sequence encoding the amino acid sequence of a desired transgene in an AAV expression vector. Furthermore, there would be a limited number of obvious nucleic acid sequences which one of ordinary skill in the art would use to encode the amino acid sequence.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Bartsevich et al (WO 2018/195449 A1) in view Wang et al (US 11779656 B2) and Wu et al (American Society of Gene and Cell Therapy (2010 18:1;80-86) as applied to claims 1 and 5 and 7 above, and further in view of Choi et al (Curr Gene Ther (2005) 5:3;1-20).
Regarding claim 6: The teachings of Bartsevich are discussed supra. While Bartsevich teach the 5’ ITR and 3’ ITR flank the coding sequence for the PCSK9 meganuclease and regulatory sequences (p61 [0231]), Bartsevich do not teach the 5’ ITR and 5’ ITR are from AAV2.
Choi teach AAV2 is the best characterized among naturally discovered AAV serotypes (p3 ¶2). Choi also teach the host cell response to the AAV2 ITR is best understood (p6 ¶4).
It would have been obvious to one of ordinary skill in the art to adapt the invention of Bartsevich drawn to an rAAV vector by using an AAV2 5’ ITR and an AAV2 3’ ITR as taught by Choi.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by Bartsevich by using an AAV2 5’ ITR and an AAV2 3’ ITR as taught by Choi because Choi teach AAV2 is the best characterized serotype and the host cell response to the AAV2 ITR is the best understood.
One would have had a reasonable expectation of success because Choi teach the AAV2 ITR is well characterized, well understood, and many previous studies use AAV2 ITR, and thus results would be predictable.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Bartsevich et al (WO 2018/195449 A1) in view Wang et al (US 11779656 B2) and Wu et al (American Society of Gene and Cell Therapy (2010 18:1;80-86) as applied to claims 1, 5 and 7 above, and further in view of Wilson et al (WO 2019/169004 A1).
Regarding claim 8: : The teachings of Bartsevich are discussed supra. Bartsevich do not teach the AAV capsid is an AAVrh.79 capsid.
Wilson teach an rAAV vector comprising AAV capsid (abstract). Wilson further teach an rAAV comprising an AAVrh79 capsid (p3 ln25-30). Figure 17E teaches an rAAV comprising AAVrh79 capsid b5250 has superior expression following intramuscular administration into macaques compared to the other rAAV tested (p94 ln15-18, Fig 17E).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Bartsevich drawn to an rAAV vector by using an AAVrh79 capsid as taught by Wilson.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by Bartsevich by using an AAVrh79 capsid, as taught by Wilson because Wilson teach AAVrh79 b5250 is highly expressed following intramuscular administration into macaques and one of ordinary skill in the art would understand that a highly expressed vector is desirable because lower titers of AAV could be used which would result in a more cost effective vector that would be less likely to cause an adverse response in the subject.
One would have had a reasonable expectation of success because Wilson discloses successful use of rAAV vectors comprising an AAVrh79 capsid.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Bartsevich et al (WO 2018/195449 A1) in view Wang et al (US 11779656 B2) and Wu et al (American Society of Gene and Cell Therapy (2010 18:1;80-86) as applied to claims 1, 5 and 7 above, and further in view of Havel (EPR (2018) 6; p1-12).
Regarding claim 12: The teachings of Bartsevich are discussed supra. Bartsevich also teach that the AAV vector is prepared in a pharmaceutical composition and administered as a single infusion (p61 [0232]).
Bartsevich do not explicitly teach the pharmaceutical composition is an aqueous composition.
Havel teach that for delivery of pharmaceuticals, aqueous solubility is an obvious requirement if the route of administration is intravenous, and that aqueous vehicles are highly preferred to minimize off-target effects due to dosing vehicle (p2 ¶3).
It would have been obvious to one of ordinary skill in the art to adapt the invention of Bartsevich drawn to an rAAV vector by preparing the rAAV vector in an aqueous pharmaceutical composition for intravenous administration as taught by Havel.
One of ordinary skill in the art would have been motivated to modify the composition as taught by Bartsevich to include an aqueous liquid suitable for intravenous administration as taught by Havel because Havel teach that an aqueous vehicle is preferred when intravenous injection is used as the route of administration.
One would have had a reasonable expectation of success because Havel teach aqueous solubility of a compound is a requirement for intravenous injection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 2, 7 and 9 of copending Application No. 18/726,190 (reference application, hereafter referred to as ‘190) in view of Wang et al (US 11779656 B2), Wu et al (American Society of Gene and Cell Therapy (2010 18:1;80-86), Choi et al (Curr Gene Ther (2005) 5:3;1-20), Bartsevich et al (WO 2018/195449 A1) and Havel (EPR (2018) 6; p1-12).
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application renders obvious the invention as claimed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1-2: Claim 1 of ‘190 recites a recombinant AAV comprising (a) an AAV capsid (first AAV rh79 capsid) and (b) a vector genome comprising AAV terminal repeats (a 5’ IDR and a 3’ ITR), a nucleotide sequence that encodes a PCSK9 meganuclease (a meganuclease that targets PCSK9) having the sequence of Seq ID NO: 3 of ‘190.
Seq ID NO:3 of ‘190 shares 100% identity with Seq ID NO:16 of the instant claim 1 (as shown below) and thus reads on the nucleotide sequence encoded by the vector genome.
Query 1 MAPKKKRKVHMNTKYNKEFLLYLAGFVDGDGSIFARIKPSQRSKFKHKLHLVFAVYQKTQ 60
MAPKKKRKVHMNTKYNKEFLLYLAGFVDGDGSIFARIKPSQRSKFKHKLHLVFAVYQKTQ
Sbjct 1 MAPKKKRKVHMNTKYNKEFLLYLAGFVDGDGSIFARIKPSQRSKFKHKLHLVFAVYQKTQ 60
Query 61 RRWFLDKLVDEIGVGYVLDSGSVSFYSLSEIKPLHNFLTQLQPFLKLKQKQANLVLKIIE 120
RRWFLDKLVDEIGVGYVLDSGSVSFYSLSEIKPLHNFLTQLQPFLKLKQKQANLVLKIIE
Sbjct 61 RRWFLDKLVDEIGVGYVLDSGSVSFYSLSEIKPLHNFLTQLQPFLKLKQKQANLVLKIIE 120
Query 121 QLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLPGSVGGLSPSQASSA 180
QLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLPGSVGGLSPSQASSA
Sbjct 121 QLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLPGSVGGLSPSQASSA 180
Query 181 ASSASSSPGSGISEALRAGAGSGTGYNKEFLLYLAGFVDGDGSIYARIKPVQRAKFKHEL 240
ASSASSSPGSGISEALRAGAGSGTGYNKEFLLYLAGFVDGDGSIYARIKPVQRAKFKHEL
Sbjct 181 ASSASSSPGSGISEALRAGAGSGTGYNKEFLLYLAGFVDGDGSIYARIKPVQRAKFKHEL 240
Query 241 VLGFDVTQKTQRRWFLDKLVDEIGVGYVYDKGSVSAYRLSQIKPLHNFLTQLQPFLKLKQ 300
VLGFDVTQKTQRRWFLDKLVDEIGVGYVYDKGSVSAYRLSQIKPLHNFLTQLQPFLKLKQ
Sbjct 241 VLGFDVTQKTQRRWFLDKLVDEIGVGYVYDKGSVSAYRLSQIKPLHNFLTQLQPFLKLKQ 300
Query 301 KQANLVLKIIEQLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLSEKK 360
KQANLVLKIIEQLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLSEKK
Sbjct 301 KQANLVLKIIEQLPSAKESPDKFLEVCTWVDQIAALNDSKTRKTTSETVRAVLDSLSEKK 360
Query 361 KSSP 364
KSSP
Sbjct 361 KSSP 364
Claim 1 of ‘190 also recites regulatory sequences that direct expression of the PCK9 meganuclease. Claim 7 of ‘190 discloses the transgene (meganuclease) is under control of a TBG promoter.
Copending ‘190 do not teach the regulatory sequences comprise a TBG-S1-F113 promoter of Seq ID NO:7 of the instant application.
Wang teach an rAAV vector with a promoter driving expression of a human transgene (abstract). Wang further teach a promoter of a small size is desirable for vectors with large inserts (p38 col10 ln 34-40). As such Wang teach a shortened version of the thyroxin binding globulin promoter can be used. Wang teach the sequence of the shortened thyroxin binding promoter is sequence 8 (p38, col1 ln 40-45), which is 100% identical to Seq ID NO: 7 of the instant invention.
The alignment of Seq ID NO: 7 of the instant invention (Qy) and Sequence 8 of Wang (Db) is shown below:
Query Match 100.0%; Score 113; Length 176;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CTTTGAAAATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAACTAAGAGTGCTCTAG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 64 CTTTGAAAATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAACTAAGAGTGCTCTAG 123
Qy 61 TTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTCTGAGAGA 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 124 TTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTCTGAGAGA 176
It would have been obvious to one of ordinary skill in the art to adapt the vector system of copending ‘190 drawn to an rAAV by using a promoter sequence of a shortened thyroxine binding globulin (TBG) promoter as disclosed by Seq ID NO: 8 of Wang.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by ‘190 with the promoter taught by Wang for the purposes of using a shortened promoter because Wu teach a substantial limitation of AAV vectors is their small packaging capacity, which is generally considered to be less than 5kb (p80 col1 ¶1). Therefore, a shortened promoter would provide more cargo capacity in the rAAV for additional cargo sequence and would allow for a more flexible and efficient rAAV.
One would have had a reasonable expectation of success because Wang discloses expression of a transgene using the disclosed promoter (Fig 21) and one of ordinary skill in the art would understand that exchanging functional components in rAAV expression systems is standard molecular biology practice.
One of ordinary skill in the art would also understand that AAV expression vectors have limited cargo capacity and would recognize a shorter promoter sequence would provide more space in an expression vector for additional transgene elements, and allow for a more versatile expression vector.
While ‘190 do not disclose a specific nucleic acid sequence which encodes the PCSK9 sequence, one of ordinary skill in the art would understand a nucleic acids encoding an amino acid sequences are well known in the art and it would be obvious to use a nucleic acid sequence encoding the amino acid sequence of a desired transgene in an AAV expression vector and there would be a limited number of obvious nucleic acid sequences which one of ordinary skill in the art would use.
Regarding claims 3-4: Copending claim 2 of ‘190 recites the sequence encoding the meganuclease comprises nucleotides 1089-2183 of Seq ID NO:2. Seq ID NO:2 of ‘190 comprises 100% sequence identity with Seq ID NO:15 of the instant application, thus nt 1089-2183 of copending Seq ID NO:2 comprise 100% identity with nt 1089-2183 of the instant seq ID 15, as required for the instant claims 3-4.
Query 1 CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTT 60
Query 61 GGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 61 GGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACT 120
Query 121 AGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACGTAGCCATGCTCT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 121 AGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACGTAGCCATGCTCT 180
Query 181 AGGAAGATCGGAATTCGCCCTTAAGCTAGCAGGTTAATTTTTAAAAAGCAGTCAAAAGTC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 181 AGGAAGATCGGAATTCGCCCTTAAGCTAGCAGGTTAATTTTTAAAAAGCAGTCAAAAGTC 240
Query 241 CAAGTGGCCCTTGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 241 CAAGTGGCCCTTGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCA 300
Query 301 CAAACATTCCAGATCCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCCAAGTGGCCCTTGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 301 CAAACATTCCAGATCCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCCAAGTGGCCCTTGG 360
Query 361 CAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCACAAACATTCCAGAT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 361 CAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCACAAACATTCCAGAT 420
Query 421 CCGGCGCGCCAGGGCTGGAAGCTACCTTTGACATCATTTCCTCTGCGAATGCATGTATAA 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 421 CCGGCGCGCCAGGGCTGGAAGCTACCTTTGACATCATTTCCTCTGCGAATGCATGTATAA 480
Query 481 TTTCTACAGAACCTATTAGAAAGGATCACCCAGCCTCTGCTTTTGTACAACTTTCCCTTA 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 481 TTTCTACAGAACCTATTAGAAAGGATCACCCAGCCTCTGCTTTTGTACAACTTTCCCTTA 540
Query 541 AAAAACTGCCAATTCCACTGCTGTTTGGCCCAATAGTGAGAACTTTTTCCTGCTGCCTCT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 541 AAAAACTGCCAATTCCACTGCTGTTTGGCCCAATAGTGAGAACTTTTTCCTGCTGCCTCT 600
Query 601 TGGTGCTTTTGCCTATGGCCCCTATTCTGCCTGCTGAAGACACTCTTGCCAGCATGGACT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 601 TGGTGCTTTTGCCTATGGCCCCTATTCTGCCTGCTGAAGACACTCTTGCCAGCATGGACT 660
Query 661 TAAACCCCTCCAGCTCTGACAATCCTCTTTCTCTTTTGTTTTACATGAAGGGTCTGGCAG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 661 TAAACCCCTCCAGCTCTGACAATCCTCTTTCTCTTTTGTTTTACATGAAGGGTCTGGCAG 720
Query 721 CCAAAGCAATCACTCAAAGTTCAAACCTTATCATTTTTTGCTTTGTTCCTCTTGGCCTTG 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 721 CCAAAGCAATCACTCAAAGTTCAAACCTTATCATTTTTTGCTTTGTTCCTCTTGGCCTTG 780
Query 781 GTTTTGTACATCAGCTTTGAAAATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAAC 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 781 GTTTTGTACATCAGCTTTGAAAATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAAC 840
Query 841 TAAGAGTGCTCTAGTTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 841 TAAGAGTGCTCTAGTTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTC 900
Query 901 TGAGAGACTGCAGAAGTTGGTCGTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGAC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 901 TGAGAGACTGCAGAAGTTGGTCGTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGAC 960
Query 961 AGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCT 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 961 AGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCT 1020
Query 1021 GATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCAGG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1021 GATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCAGG 1080
Query 1081 CGGCCGCCATGGCACCGAAGAAGAAGCGCAAGGTGCATATGAATACAAAATATAATAAAG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1081 CGGCCGCCATGGCACCGAAGAAGAAGCGCAAGGTGCATATGAATACAAAATATAATAAAG 1140
Query 1141 AGTTCTTACTCTACTTAGCAGGGTTTGTAGACGGTGACGGTTCCATCTTTGCCAGGATCA 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1141 AGTTCTTACTCTACTTAGCAGGGTTTGTAGACGGTGACGGTTCCATCTTTGCCAGGATCA 1200
Query 1201 AGCCTAGTCAACGTAGTAAGTTCAAGCACAAGCTGCATCTCGTTTTCGCTGTCTATCAGA 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1201 AGCCTAGTCAACGTAGTAAGTTCAAGCACAAGCTGCATCTCGTTTTCGCTGTCTATCAGA 1260
Query 1261 AGACACAGCGCCGTTGGTTCCTCGACAAGCTGGTGGACGAGATCGGTGTGGGTTACGTGC 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1261 AGACACAGCGCCGTTGGTTCCTCGACAAGCTGGTGGACGAGATCGGTGTGGGTTACGTGC 1320
Query 1321 TGGACTCTGGCAGCGTCTCCTTTTACTCGCTGTCCGAGATCAAGCCTTTGCATAAttttt 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1321 TGGACTCTGGCAGCGTCTCCTTTTACTCGCTGTCCGAGATCAAGCCTTTGCATAATTTTT 1380
Query 1381 taacacaactacaaccttttctaaaactaaaacaaaaacaagcaaatttagttttaaaaa 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1381 TAACACAACTACAACCTTTTCTAAAACTAAAACAAAAACAAGCAAATTTAGTTTTAAAAA 1440
Query 1441 TTATTGAACAACTTCCGTCAGCAAAAGAATCCCCGGACAAATTCTTAGAAGTTTGTACAT 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1441 TTATTGAACAACTTCCGTCAGCAAAAGAATCCCCGGACAAATTCTTAGAAGTTTGTACAT 1500
Query 1501 GGGTGGATCAAATTGCAGCTCTGAATGATTCGAAGACGCGTAAAACAACTTCTGAAACCG 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1501 GGGTGGATCAAATTGCAGCTCTGAATGATTCGAAGACGCGTAAAACAACTTCTGAAACCG 1560
Query 1561 TTCGTGCTGTGCTAGACAGTTTACCAGGATCCGTGGGAGGTCTATCGCCATCTCAGGCAT 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1561 TTCGTGCTGTGCTAGACAGTTTACCAGGATCCGTGGGAGGTCTATCGCCATCTCAGGCAT 1620
Query 1621 CCAGCGCCGCATCCTCGGCTTCCTCAAGCCCGGGTTCAGGGATCTCCGAAGCACTCAGAG 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1621 CCAGCGCCGCATCCTCGGCTTCCTCAAGCCCGGGTTCAGGGATCTCCGAAGCACTCAGAG 1680
Query 1681 CTGGAGCAGGTTCCGGCACTGGATACAACAAGGAATTCCTGCTCTACCTGGCGGGCTTCG 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1681 CTGGAGCAGGTTCCGGCACTGGATACAACAAGGAATTCCTGCTCTACCTGGCGGGCTTCG 1740
Query 1741 TCGACGGGGACGGCTCCATCTATGCCCGTATCAAGCCGGTTCAGCGGGCTAAGTTCAAGC 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1741 TCGACGGGGACGGCTCCATCTATGCCCGTATCAAGCCGGTTCAGCGGGCTAAGTTCAAGC 1800
Query 1801 ACGAGCTGGTTCTCGGGTTCGATGTCACTCAGAAGACACAGCGCCGTTGGTTCCTCGACA 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1801 ACGAGCTGGTTCTCGGGTTCGATGTCACTCAGAAGACACAGCGCCGTTGGTTCCTCGACA 1860
Query 1861 AGCTGGTGGACGAGATCGGTGTGGGTTACGTGTATGACAAGGGCAGCGTCTCCGCGTACC 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1861 AGCTGGTGGACGAGATCGGTGTGGGTTACGTGTATGACAAGGGCAGCGTCTCCGCGTACC 1920
Query 1921 GTCTGTCCCAGATCAAGCCTCTGCACAACTTCCTGACCCAGCTCCAGCCCTTCCTGAAGC 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1921 GTCTGTCCCAGATCAAGCCTCTGCACAACTTCCTGACCCAGCTCCAGCCCTTCCTGAAGC 1980
Query 1981 TCAAGCAGAAGCAGGCCAACCTCGTGCTGAAGATCATCGAGCAGCTGCCCTCCGCCAAGG 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1981 TCAAGCAGAAGCAGGCCAACCTCGTGCTGAAGATCATCGAGCAGCTGCCCTCCGCCAAGG 2040
Query 2041 AATCCCCGGACAAGTTCCTGGAGGTGTGCACCTGGGTGGACCAGATCGCCGCTCTGAACG 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2041 AATCCCCGGACAAGTTCCTGGAGGTGTGCACCTGGGTGGACCAGATCGCCGCTCTGAACG 2100
Query 2101 ACTCCAAGACCCGCAAGACCACTTCCGAAACCGTCCGCGCCGTTCTAGACAGTCTCTCCG 2160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2101 ACTCCAAGACCCGCAAGACCACTTCCGAAACCGTCCGCGCCGTTCTAGACAGTCTCTCCG 2160
Query 2161 AGAAGAAGAAGTCGTCCCCCTAAGGTAC 2188
||||||||||||||||||||||||||||
Sbjct 2161 AGAAGAAGAAGTCGTCCCCCTAAGGTAC 2188
Regarding claim 5: The teachings of ‘190 are discussed supra. ‘190 do not teach the rAAV comprises a polyadenylation signal.
Wang teach an rAAV vector that comprises a polyadenylation signal (p38 col 10 ln 3-10). Wang further teach that an expression cassette may contain sequences to promote efficient RNA processing and that a polyA sequence stabilizes cytoplasmic mRNA (p39 col11 ln 38-45).
It would have been obvious to one of ordinary skill in the art to adapt the rAAV of ‘190 by including a polyA signal as taught by Wang.
One of ordinary skill in the art would have been motivated to modify the rAAV of ‘190 by including a polyA signal as taught by Wang for the purposes of stabilizing cytoplasmic RNA.
One would have had a reasonable expectation of success because Wang teach polyA signals stabilize cytoplasmic mRNA and mediates termination of transcripts, and one of ordinary skill in the art would understand that exchanging functional components in rAAV expression systems is standard molecular biology practice.
Regarding claim 6: The teachings of ‘190 are discussed supra. Copending ‘190 teach 5’ and 3’ ITRs, however ‘190 do not teach the ITRs are derived from AAV2.
Choi teach AAV2 is the best characterized among naturally discovered AAV serotypes (p3 ¶2). Choi also teach the host cell response to the AAV2 ITR is best understood (p6 ¶4).
It would have been obvious to one of ordinary skill in the art to adapt the invention of ‘190 drawn to an rAAV vector by using an AAV2 5’ ITR and an AAV2 3’ ITR as taught by Choi.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by ‘190 to use an AAV2 5’ ITR and an AAV2 3’ ITR as taught by Choi because Choi teach AAV2 is the best characterized serotype and the host cell response to the AAV2 ITR is the best understood.
One would have had a reasonable expectation of success because Choi teach the AAV2 ITR is well characterized, well understood, and many previous studies use AAV2 ITR, and thus results would be predictable.
Regarding claim 7: The teachings of ‘190 are discussed supra. ‘190 does not teach the vector genome comprises a nucleic acid sequence with at least 80% sequence identity with Seq ID No: 13 of the instant invention.
As discussed supra, the instant claim recites “the vector
genome comprises a nucleic acid sequence of SEQ ID NO: 13”. Claim language such as that of claim 7 encompasses nucleic acids that comprise the full-length sequence of SEQ ID NO: 13 or nucleic acid sequences that comprise any portion of SEQ ID NO: 13. Thus the claim is anticipated by any nucleic acid comprising any dinucleotide or larger oligonucleotide which is a portion of SEQ ID NO: 13.
If the claim were amended to recite “the vector genome comprises the nucleic acid sequence of SEQ ID NO: 13” the examiner would interpret the claims to encompass only nucleic acids that comprise the full length of the specified SEQ ID NO:, with or without additional nucleotides at either or both ends.
Seq ID NO:13 is a nucleotide sequence comprising 1866 bp. Nucleotides 206-311 of Seq ID NO:13 are 100% identical to Seq ID NO: 7 of the instant disclosure.
As discussed supra, Bartsevich and Wang teach the vector genomic sequence comprises the sequence of the shortened thyroxin binding promoter, i.e. Wang teach sequence 8 (p38, col1 ln 40-45), which is 100% identical to Seq ID NO: 7 of the instant invention.
Thus, as discussed supra, the teachings of Bartsevich and Wang render obvious the genome sequence of instant claim 7 because Seq ID NO: 8, as taught by Wang, comprises 100% sequence identity with a nucleic acid sequence of Seq ID NO:13 (nucleotides 206-311 of Seq ID NO: 13).
Regarding claim 8: Claim 1 of copending ‘190 teach the AAV capsid is an AAV rh79 capsid.
Regarding claim 12: The teachings of ‘190 are discussed supra. ‘190 also teaches administration of the rAAV in humans (claim 9). Administration of a vector to a human requires a pharmaceutical composition comprising the rAAV.
‘190 do not teach the pharmaceutical composition is an aqueous liquid suitable for intravenous administration.
Bartsevich teach an rAAV vector is prepared in a pharmaceutical composition and administered as a single infusion (p61 [0232]). Bartsevich do not explicitly teach the pharmaceutical composition is an aqueous composition.
Havel teach that for delivery of pharmaceuticals, aqueous solubility is an obvious requirement if the route of administration is intravenous, and that aqueous vehicles are highly preferred to minimize off-target effects due to dosing vehicle (p2 ¶3).
It would have been obvious to one of ordinary skill in the art to adapt the invention of ‘190 drawn to an rAAV vector by preparing the rAAV vector in an aqueous pharmaceutical composition for intravenous administration as taught by Batsevich.
One of ordinary skill in the art would have been motivated to modify the rAAV as taught by ‘190 to include the rAAV vector in a pharmaceutical composition comprising an aqueous liquid suitable for intravenous administration as taught by Batsevich and Havel because Batsevich teach that the intravenous injection of the rAAV vector is effective, and Havel teach that an aqueous vehicle is preferred when intravenous injection is used as the route of administration.
One would have had a reasonable expectation of success because Bartsevich teach administration of the rAAV was effective (Fig 7, p62 [0234]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA LYNNE MORRIS SPENCER whose telephone number is (571)272-3328. The examiner can normally be reached Monday-Friday 9:00-5:00.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631 spencerandrea
/TAEYOON KIM/Primary Examiner, Art Unit 1631