DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election without traverse of Group I (claims 1-13 and 17-20) in the reply filed on 01/06/2026 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)).
Election of the following species on the reply filed on 01/06/2026 is acknowledged: 1) SEQ ID NO: 3 (murine IR-1 element);
2) BSEP (if required, SEQ ID NO. 8); and
3) a method of treatment
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2021/087437, filed 12/22/2021.
Applicant’s claim for the benefit of a prior-filed parent application EP20306684.0, filed on 12/23/2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. The certified copy of the Foreign priority document is acknowledged.
Thus, the earliest possible priority for the instant application is 12/23/2020.
Claims Status
Claim 14 is cancelled, claims 17-21 were newly added, claims 4, 8, 15-17, 19 and 21 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-13 and 17-20 have been considered on the merits.
Claim Objections
Claims 5 and 7 are objected to because of the following informalities: Claim 5 recites “murine IR-1 element”. Claim 7 recites “BSEP”. When an abbreviation is introduced for the first time it should be accompanied by the full description. Appropriate correction is required.
Claim 12 is objected because the claim recites “a nucleic acid construct”. Amending the claim to recite “the nucleic acid construct” would overcome this objection.
Claim Rejections - 35 USC § 112
Claims 1-3, 5-7, 9-13, 18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1: The claim recites the term “promoter”. The instant specification defines the term as “a regulatory element that directs the transcription of a nucleic acid to which it is operably linked” (p12 ln10-11).
The claim requires a functional variant having at least 95% identity to Seq ID NO:1.
The instant specification defines “functional variant” is a variant of SEQ ID NO: 1 that exhibits a promoter activity of SEQ ID NO: 1 (p14 ln 13-15)).
Seq ID NO: 1 is a 222 bp nucleic acid sequence which encodes sequence of the murine ABCB11 promoter (alignment below; Query is Seq ID NO:1 and Sbjct is promoter sequence of Mus musculus ABCB11 gene; Genbank AY039785.1):
Query 1 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2267 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 2326
Query 61 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2327 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 2386
Query 121 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2387 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 2446
Query 181 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 222
||||||||||||||||||||||||||||||||||||||||||
Sbjct 2447 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 2488
The broadest reasonable interpretation at least 95% identity to seq ID No: 1 is a nucleic acid sequence that can differ from Seq ID NO: 1 by up to 5% (~11 residues) compared to Seq ID NO: 1.
Teachings of the instant specification
The instant specification provides guidance as to the composition of the claimed nucleotide sequences. The instant specification teaches Seq ID NO: 1 is the minimal mouse ABCB11 (BSEP) promoter (p55 ln25-30). The instant specification teaches Seq ID NO: 1 comprises the last 145 nucleotides of the regulatory region fo ABCB11 (BSEP) and a 5’ untranslated region of ABCB11 (p12 ln5-6).
The instant specification further teaches the functional variant functional variant has a sequence comprising at least 50, 60, 70, 80, 90, 100, 110, 25 120, 130, 140, 150, 160, 170, 180, 190, 200 consecutive nucleotides of SEQ ID NO: 1 (p16 ln 22-25).
The state of the art:
It is well known in the art that the effect of nucleic acid substitutions on polynucleotide activity is not predictable for promoter sequences. Vooght et al (Clinical Chemistry (2009) 55:4;1-11) teach not every promoter sequence variation affects transcriptional regulation, and that the location and nature of the mutation can disrupt normal processes (transcription factor recruitment) and result in decrease or increased translation (mRNA level) (p1 col2 ¶2).
Regarding the ABCB11 promoter, Lang et al (Drug Metabolism and Disposition (2006) 34;1582-1599) test 27 genetic variants identified in the ABCB11 promoter (p1589 col2 ¶2). Lang teach 13 different ABCB11 promoter constructs were tested to determine the effect of mutations on promoter function (p1596 col2 ¶3). Lang teach two of the constructs show ~50% reduced activity (p1596 col2 ¶3). The constructs showing reduced activity had 3 and 4 nucleotide changes (Fig 5).
Thus Lang teach a small number of nucleotide changes in the human ABCB11 promoter can reduce promoter activity and the effects of such changes must be experimentally determined.
Conclusion
As described supra, the instant specification provides Seq ID NO: 1 as a single species of the broad genus of nucleic acid constructs comprising functional variants of Seq ID NO: 1 comprising at least 95% identity to Seq ID NO: 1.
However the single species of promoter disclosed in the instant specification is not sufficient to predict the genus of functional variants of Seq ID NO: 1 comprising at least 95% identity to Seq ID NO: 1 in view of unpredictability as demonstrated by the art.
Furthermore, the instant specification provides no guidance as how to avoid losing key structural or binding components of promoter sequences with nucleic acid substitutions or changes of up to 11 residues and the art does not provide a remedy.
One of ordinary skill in the art would understand that functional promoter sequences require binding to nucleic acid sequences (e.g. genomic DNA) and often amino acid sequences (e.g. transcription factors) for a functional system. One of ordinary skill in the art would also understand that the effect of nucleic acid substitutions in the promoter sequence can have unpredictable effects on the promoter structure and thus function.
This demonstrates that, while ABCB11 promoter variants are known in the art, the effect of changes to promoter sequences must be tested empirically 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 claim 1, trial and error and/or laborious screening methods are required to identify functional promoter variants as claimed and the species examples provided in the art are not of a large enough breadth to impart predictability on the genus as claimed.
Note claims 2-3, 5-7, 9-13, 18 and 20 depend from claim 1 and fail to cure the deficiency.
Regarding claim 18: The claim recites “a variant having at least 80% identity to Seq ID NO: 8”.
Seq ID NO: 8 is a nucleic acid sequence comprising 3966 nucleotides. The broadest reasonable interpretation of at least 80% identity to seq ID No: 8 is a nucleic acid sequence that can differ from Seq ID NO: 8 by up to 20% (~793 residues) compared to Seq ID NO: 8.
The instant specification teaches Seq ID NO: 8 is a codon optimized sequence of the human ABCB11 gene (p49 ln 13-15). The translated amino acid sequence of Seq ID NO: 8 comprises 100% sequence identity with the human ABCB11 amino acid sequence (see below; Query is seq ID NO: 8 and Sbjct is human ABCB11 (NCBI NP_003733.2; human bile salt export pump)
Query 1 MSDSVILRSIKKFGEENDGFESDKSYNNDKKSRLQDEKKGDGVRVGFFQLFRFSSSTDIW 180
MSDSVILRSIKKFGEENDGFESDKSYNNDKKSRLQDEKKGDGVRVGFFQLFRFSSSTDIW
Sbjct 1 MSDSVILRSIKKFGEENDGFESDKSYNNDKKSRLQDEKKGDGVRVGFFQLFRFSSSTDIW 60
Query 181 LMFVGSLCAFLHGIAQPGVLLIFGTMTDVFIDYDVELQELQIPGKACVNNTIVWTNSSLN 360
LMFVGSLCAFLHGIAQPGVLLIFGTMTDVFIDYDVELQELQIPGKACVNNTIVWTNSSLN
Sbjct 61 LMFVGSLCAFLHGIAQPGVLLIFGTMTDVFIDYDVELQELQIPGKACVNNTIVWTNSSLN 120
Query 361 QNMTNGTRCGLLNIESEMIKFASYYAGIAVAVLITGYIQICFWVIAAARQIQKMRKFYFR 540
QNMTNGTRCGLLNIESEMIKFASYYAGIAVAVLITGYIQICFWVIAAARQIQKMRKFYFR
Sbjct 121 QNMTNGTRCGLLNIESEMIKFASYYAGIAVAVLITGYIQICFWVIAAARQIQKMRKFYFR 180
Query 541 RIMRMEIGWFDCNSVGELNTRFSddinkindaiadQMALFIQRMTSTICGFLLGFFRGWK 720
RIMRMEIGWFDCNSVGELNTRFSDDINKINDAIA DQMALFIQRMTSTICGFLLGFFRGWK
Sbjct 181 RIMRMEIGWFDCNSVGELNTRFSDDINKINDAIA DQMALFIQRMTSTICGFLLGFFRGWK 240
Query 721 LTLVIISVSPLIGIGAATIGLSVSKFTDYELKAYAKAGVVADEVISSMRTVAAFGGEKRE 900
LTLVIISVSPLIGIGAATIGLSVSKFTDYELKAYAKAGVVADEVISSMRTVAAFGGEKRE
Sbjct 241 LTLVIISVSPLIGIGAATIGLSVSKFTDYELKAYAKAGVVADEVISSMRTVAAFGGEKRE 300
Query 901 VERYEKNLVFAQRWGIRKGIVMGFFTGFVWCLIFLCYALAFWYGSTLVLDEGEYTPGTLV 1080
VERYEKNLVFAQRWGIRKGIVMGFFTGFVWCLIFLCYALAFWYGSTLVLDEGEYTPGTLV
Sbjct 301 VERYEKNLVFAQRWGIRKGIVMGFFTGFVWCLIFLCYALAFWYGSTLVLDEGEYTPGTLV 360
Query 1081 QIFLSVIVGALNLGNASPCLEAFATGRAAATSIFETIDRKPIIDCMSEDGYKLDRIKGEI 1260
QIFLSVIVGALNLGNASPCLEAFATGRAAATSIFETIDRKPIIDCMSEDGYKLDRIKGEI
Sbjct 361 QIFLSVIVGALNLGNASPCLEAFATGRAAATSIFETIDRKPIIDCMSEDGYKLDRIKGEI 420
Query 1261 EFHNVTFHYPSRPEVKILNDLNMVIKPGEMTALVGPSGAGKSTALQLIQRFYDPCEGMVT 1440
EFHNVTFHYPSRPEVKILNDLNMVIKPGEMTALVGPSGAGKSTALQLIQRFYDPCEGMVT
Sbjct 421 EFHNVTFHYPSRPEVKILNDLNMVIKPGEMTALVGPSGAGKSTALQLIQRFYDPCEGMVT 480
Query 1441 VDGHDIRSLNIQWLRDQIGIVEQEPVLFSTTIAENIRYGREDATMEDIVQAAKEANAYNF 1620
VDGHDIRSLNIQWLRDQIGIVEQEPVLFSTTIAENIRYGREDATMEDIVQAAKEANAYNF
Sbjct 481 VDGHDIRSLNIQWLRDQIGIVEQEPVLFSTTIAENIRYGREDATMEDIVQAAKEANAYNF 540
Query 1621 IMDLPQQFDTLVgegggqmsggqkqRVAIA RALIRNPKILLLDMATSALDNESEAMVQEV 1800
IMDLPQQFDTLVGEGGGQMSGGQKQRVAIA RALIRNPKILLLDMATSALDNESEAMVQEV
Sbjct 541 IMDLPQQFDTLVGEGGGQMSGGQKQRVAIA RALIRNPKILLLDMATSALDNESEAMVQEV 600
Query 1801 LSKIQHGHTIISVAHRLSTVRAADTIIGFEHGTAVERGTHEELLERKGVYFTLVTLQSQG 1980
LSKIQHGHTIISVAHRLSTVRAADTIIGFEHGTAVERGTHEELLERKGVYFTLVTLQSQG
Sbjct 601 LSKIQHGHTIISVAHRLSTVRAADTIIGFEHGTAVERGTHEELLERKGVYFTLVTLQSQG 660
Query 1981 NQALNEEDIKDATEDDMLARTFSRGSYQDSLRASIRQRSKSQLSYLVHEPPLAVVDHKST 2160
NQALNEEDIKDATEDDMLARTFSRGSYQDSLRASIRQRSKSQLSYLVHEPPLAVVDHKST
Sbjct 661 NQALNEEDIKDATEDDMLARTFSRGSYQDSLRASIRQRSKSQLSYLVHEPPLAVVDHKST 720
Query 2161 YEEDRKDKDIPVQEEVEPAPVRRILKFSAPEWPYMLVGSVGAAVNGTVTPLYAFLFSQIL 2340
YEEDRKDKDIPVQEEVEPAPVRRILKFSAPEWPYMLVGSVGAAVNGTVTPLYAFLFSQIL
Sbjct 721 YEEDRKDKDIPVQEEVEPAPVRRILKFSAPEWPYMLVGSVGAAVNGTVTPLYAFLFSQIL 780
Query 2341 GTFSIPDKEEQRSQINGVCLLFVAMGCVSLFTQFLQGYAFAKSGELLTKRLRKFGFRAML 2520
GTFSIPDKEEQRSQINGVCLLFVAMGCVSLFTQFLQGYAFAKSGELLTKRLRKFGFRAML
Sbjct 781 GTFSIPDKEEQRSQINGVCLLFVAMGCVSLFTQFLQGYAFAKSGELLTKRLRKFGFRAML 840
Query 2521 GQDIAWFDDLRNSPGALTTRLATDASQVQGAAGSQIGMIVNSFTNVTVAMIIAFSFSWKL 2700
GQDIAWFDDLRNSPGALTTRLATDASQVQGAAGSQIGMIVNSFTNVTVAMIIAFSFSWKL
Sbjct 841 GQDIAWFDDLRNSPGALTTRLATDASQVQGAAGSQIGMIVNSFTNVTVAMIIAFSFSWKL 900
Query 2701 SLVILCFFPFLALSGATQTRMLTGFASRDKQALEMVGQITNEALSNIRTVAGIGKERRFI 2880
SLVILCFFPFLALSGATQTRMLTGFASRDKQALEMVGQITNEALSNIRTVAGIGKERRFI
Sbjct 901 SLVILCFFPFLALSGATQTRMLTGFASRDKQALEMVGQITNEALSNIRTVAGIGKERRFI 960
Query 2881 EALETELEKPFKTAIQKANIYGFCFAFAQCIMFIANSASYRYGGYLISNEGLHFSYVFRV 3060
EALETELEKPFKTAIQKANIYGFCFAFAQCIMFIANSASYRYGGYLISNEGLHFSYVFRV
Sbjct 961 EALETELEKPFKTAIQKANIYGFCFAFAQCIMFIANSASYRYGGYLISNEGLHFSYVFRV 1020
Query 3061 ISAVVLSATALGRAFSYTPSYAKAKISAARFFQLLDRQPPISVYNTAGEKWDNFQGKIDF 3240
ISAVVLSATALGRAFSYTPSYAKAKISAARFFQLLDRQPPISVYNTAGEKWDNFQGKIDF
Sbjct 1021 ISAVVLSATALGRAFSYTPSYAKAKISAARFFQLLDRQPPISVYNTAGEKWDNFQGKIDF 1080
Query 3241 VDCKFTYPSRPDSQVLNGLSVSISPGQTLAFVGSSGCGKSTSIQLLERFYDPDQGKVMID 3420
VDCKFTYPSRPDSQVLNGLSVSISPGQTLAFVGSSGCGKSTSIQLLERFYDPDQGKVMID
Sbjct 1081 VDCKFTYPSRPDSQVLNGLSVSISPGQTLAFVGSSGCGKSTSIQLLERFYDPDQGKVMID 1140
Query 3421 GHDSKKVNVQFLRSNIGIVSQEPVLFACSIMDNIKYGDNTKEIPMERVIAAAKQAQLHDF 3600
GHDSKKVNVQFLRSNIGIVSQEPVLFACSIMDNIKYGDNTKEIPMERVIAAAKQAQLHDF
Sbjct 1141 GHDSKKVNVQFLRSNIGIVSQEPVLFACSIMDNIKYGDNTKEIPMERVIAAAKQAQLHDF 1200
Query 3601 VMSLPEKYETNVGSQGSQLSRGEKQRIAIA RAIVRDPKILLLDEATSALDTESEKTVQVA 3780
VMSLPEKYETNVGSQGSQLSRGEKQRIAIA RAIVRDPKILLLDEATSALDTESEKTVQVA
Sbjct 1201 VMSLPEKYETNVGSQGSQLSRGEKQRIAIA RAIVRDPKILLLDEATSALDTESEKTVQVA 1260
Query 3781 LDKAREGRTCIVIAHRLSTIQNADIIAVMAQGVVIEKGTHEELMAQKGAYYKLVTTGSPI 3960
LDKAREGRTCIVIAHRLSTIQNADIIAVMAQGVVIEKGTHEELMAQKGAYYKLVTTGSPI
Sbjct 1261 LDKAREGRTCIVIAHRLSTIQNADIIAVMAQGVVIEKGTHEELMAQKGAYYKLVTTGSPI 1320
Query 3961 S 3963
S
Sbjct 1321 S 1321
Teachings of the instant specification
The instant specification provides some guidance as to the composition of the claimed nucleotide sequences. The instant specification teaches Seq ID 8 is a codon-optimized version of AABCB11 cDNA (p49 ln 13-20). The instant specification further teaches a transgene having at least 80% identity to SEQ ID NO: 8 (p4 cln 14-15).
Teachings of the art
Lang et al (Drug Metabolism and Disposition (2006) 34;1582-1599) teach protein encoded by the ABCB11 gene comprises multiple transmembrane regions and the location of some known variants in the human gene (Fig 1b).
Lang further teach attempts to predict the functional consequence of known nonsynonymous variants of ABCB11 were not consistent between five different prediction methods tested (p1589 col2 ¶3; p1590 col1 ¶2).
Thus Lang teach predicting the functional consequence of even two or three nonsynonymous changes in the amino acid sequence of ABCB11 is unpredictable, and thus the functional consequence of an ABCB11 variant comprising up to 20% changes (~793 residues) in the nucleic acid sequence encoding the protein would be unpredictable and require trial-and-error experimentation.
Conclusion
As described supra, the instant specification provide a single example of the species for the broad genus of “a variant having at least 80% identity to Seq ID NO: 8”.
However the single species of nucleic acid sequence disclosed in the instant specification is not sufficient to predict the genus of variants having at least 80% identity to Seq ID NO: 8 in view of unpredictability as demonstrated by the art.
Furthermore, the instant specification provides no guidance as how to avoid losing key structural or binding components of the encoded ABCB11 transporter with nucleic acid substitutions or changes of up to 793 residues and the art does not provide a remedy.
One of ordinary skill in the art would understand that functional ABC transporter requires a specific structure to perform its function (Lang Fib 1b). One of ordinary skill in the art would also understand that the effect of nucleic acid substitutions in the coding sequence of the protein can have unpredictable effects on the transporter structure and thus function.
This demonstrates that, while ABCB11 variants are known in the art, the effect of changes to nucleic acid sequences encoding the protein must be tested empirically to determine how the sequence change affects transporter 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 claim 1, trial and error and/or laborious screening methods are required to identify functional transporter variants as claimed and the species examples provided in the art are not of a large enough breadth to impart predictability on the genus as claimed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 is considered indefinite because the claim recites “transgene”. The instant specification defines transgene as “exogenous DNA or cDNA encoding a gene product” (p17 ln 24-26).
The term “transgene” is therefore interpreted to mean any gene, because any gene is exogenous DNA depending of the context of the gene. For example, any mammalian gene can be encoded in an AAV expression vector and would thus be considered a transgene according to the definition supra.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 recites the nucleic acid of claim 1, which as discussed supra, comprises “at least one” of the required sequence, Seq ID NO: 3. Thus claim 1 as written is considered to already fulfill the claim limitations of claim 5 and claim 5 is not considered to further limit the subject matter.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
If the claim were amended to recite “further comprises at least one additional murine IR- element, of Seq ID NO: 3” the rejection as written would be overcome.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 5-6 and 12-13 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to a judicial exception (specifically a natural product) without significantly more.
The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
Regarding claims 1, and 12: Claims 1 and 12 are drawn to a product (in this case the nucleic acid construct of claim 1 and the host cell of claim 12 are each considered a product).
Claim 1 requires a nucleic acid construct comprising a bile acid inducible promoter having a length of less than 500 bp and comprising nucleic acid sequence of seq ID NO: 1 (or a functional variant having at least 95% identity to Seq ID NO:1) which is operably linked to a therapeutic transgene.
As discussed supra, the term “transgene” is interpreted to mean any gene, because any gene is exogenous DNA depending of the context of the gene. For example, any mammalian gene can be encoded in an AAV expression vector and would thus be considered a transgene according to the definition supra.
The instant specification defines “nucleic acid construct” as “to a man-made nucleic acid molecule resulting from the use of recombinant DNA technology. A” (p17 ln 15-20).
A “man-made-gene” is considered product-by-process. MPEP 2113 reads "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
Furthermore, MPEP 2106.04(c) reads “If the claim includes a nature-based product that does not exhibit markedly different characteristics from its naturally occurring counterpart in its natural state, then the claim recites a "product of nature" exception, and requires further analysis in Step 2A Prong Two to determine whether the claim as a whole integrates the exception into a practical application”.
The language “comprising” as recited in claim 1 is open claim language and thus the claim is interpreted to require the nucleic acid sequence of Seq ID NO: 1 (or a sequence comprising at least 95% identity thereof), but does not exclude additional nucleic acid sequence.
Step 1: Is claim directed to a statutory category of invention?
Yes, the claim is drawn to a product (a nucleic acid and a cell), which is a statutory category of invention (Step 1: YES).
Step 2A, Prong 1: Does the claim recite a product of nature judicial exception (JE)?
The recited nucleic acid exists in nature.
Claim 1 requires a promoter comprising the sequence of Seq ID NO:1. Seq ID NO:1 is a nucleic acid sequence that shares 100% identity with the naturally occurring murine promoter for ABCB11, see below (Query is Seq ID NO:1 and Sbjct is Mus musculus ABCB11 promoter; Genbank AY039785.1):
Query 1 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2267 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 2326
Query 61 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2327 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 2386
Query 121 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2387 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 2446
Query 181 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 222
||||||||||||||||||||||||||||||||||||||||||
Sbjct 2447 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 2488
Claim 1 requires the promoter sequence comprising Seq ID NO: 1 to be operably linked to a therapeutic transgene. The murine ABCB11 promoter is operably linked to the murine ABCB11 gene. Per the discussion supra, the murine ABCB11 gene is considered a therapeutic transgene because it can be present in an AAV vector and furthermore can be used therapeutically. Noe et al (Journal of Hepatology (2005) 43;1-8) identify mutations which cause disfunction of ABCB11 in humans and an ABCB11-/- mouse model is taught by Wang et al (Eur J Clin Invest (2010) 40:6;1-21), thus the ABCB11 gene can be used therapeutically.
The claimed nucleic acid construct is therefore considered indistinguishable from the naturally occurring nucleic acid construct in the mouse genome which comprises the ABCB11 promoter linked to the ABCB11 gene. Furthermore, the naturally occurring mouse genome comprising a nucleic acid construct indistinguishable form the construct of Claim 1 naturally exists in a mouse cell. The claimed nucleic acid and cell are identical to naturally occurring nucleic acids and cells, thus there is no marked difference between the claim and product of nature.
Thus the claim does recite a product of nature judicial exception (Step 2A, Prong 1: YES).
Step 2A, Prong 2: Does the claim recite additional elements that integrate the JE into a practical application?
The claims does not integrate the product into a practical application because the claim is to the nucleic acid or cell, per se, not a method of use. (Step 2A, Prong 2: NO).
Step 2B: Are there additional elements that add significantly more to the ‘product of nature judicial exception' ?
Claims 1 and 12 do not include additional elements that add significantly more to the product of nature.
Claim 5 requires Seq ID NO: 3, which is found in the natural mouse promoter of ABCB11 (bold underline sequence of Seq ID NO:1 below) and therefore not considered an additional element which adds significantly more to the product of nature.
Ggttcctgctttgagtatgttcgacctttcctctcatgtcactgaactgtgctagatctggactttaggccattgacctataagcaaatagatagtgttcttaaaaaagcctgatttctgttcaatgctttattaccatgaaaactgaacttggaaaggggtgtacaaccctgactttccacagtggcgtctctcgcttctcctggctccctcaaattcaca
Claim 6 recites “the promoter is less than 450 bp” and depends on claim 1 which requires the nucleic acid sequence of Seq ID NO: 1. As noted above, the nucleic acid sequence of Seq ID NO: 1 is identical to the naturally occurring murine promoter for ABCB11. As Seq ID NO: 1 comprises 222 nucleotides, this reads on a length of less than 450 bp as required by the claim. Thus claim 6 is not considered an additional element which add significantly more to the product of nature.
Claim 13 recites a pharmaceutical composition comprising the nucleic construct of claim 1. A composition comprising a product is not considered to contribute an additional element which adds significantly more to the product of nature.
Claim 2 requires a poly(a) signal sequence Seq ID NO:10, which is not found in the natural mouse genome and therefore is considered an additional element which adds significantly more to the product of nature.
Claim 3 requires the nucleic acid to comprise 5’ and 3’ ITR sequences of an AAV, which is not found in a natural mouse genome and thus is considered to add significantly more to the product of nature.
Claim 7 requires the promoter to be linked to human BSEP (also called ABCB11). As evidenced by Bell et al (JLR (2025) 66:7;1-15) human and mouse ABCB11 share 82% identity at the amino acid level (p4 col2 ¶2). Thus the nucleic acid sequence encoding the claimed promoter and transgene would differ from the naturally occurring murine sequence. Therefore claim 7 is considered an additional element which adds significantly more to the product of nature.
Claims 9-11 and 20 recite an expression vector and viral particle comprising the nucleic acid of claim 1. These are considered additional elements which adds significantly more to the product of nature.
Claim 18 requires a transgene comprising Seq Id NO: 8 of the instant disclosure, which is the codon optimized nucleic acid sequence of human ABCB11 (instant specification p56 ln20). This is considered an additional element which adds significantly more to the product of nature because the murine ABCB11 promoter is not naturally on the same nucleic acid sequence as the human ABCB11 gene sequence.
In conclusion, claims 1, 5-6 and 12-13 do not recite any elements which add significantly more to the product of nature in addition to the nucleic acid construct, therefore there are no additional elements that add significantly more to the judicial exception (Step 2B: NO).
Claims 1, 5-6 and 12-13 are patent ineligible.
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.
Claims 1, 5-6 and 12-13 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Figge et al (Journal of Biologica Chemistry (2004) 279:4;2790-2799) and as evidenced by GenBank AY039785.1 (GenBank AY039785.1 [online]. GenBank [retrieved on 06/11/2026]. Retrieved from the Internet: <URL: https://www.ncbi.nlm.nih.gov/nucleotide/AY039785.1?report=genbank&log$=nucltop&blast_rank=5&RID=2P5U9EBT014).
Regarding claim 1, 5-6 and 12-13: Claim 1 requires a nucleic acid construct comprising a bile acid inducible promoter having a length of less than 500 bp and comprising nucleic acid sequence of seq ID NO: 1 (or a functional variant having at least 95% identity to Seq ID NO:1) which is operably linked to a therapeutic transgene.
As discussed supra, the term “transgene” is interpreted to mean any gene, because any gene is exogenous DNA depending of the context of the gene. For example, any mammalian gene can be encoded in an AAV expression vector and would thus be considered a transgene according to the definition supra.
The language “comprising” as recited in claim 1 is open claim language and thus the claim is interpreted to require the nucleic acid sequence of Seq ID NO: 1 (or a sequence comprising at least 95% identity thereof), but does not exclude additional nucleic acid sequence.
The instant specification defines “nucleic acid construct” as “to a man-made nucleic acid molecule resulting from the use of recombinant DNA technology. A” (p17 ln 15-20).
A “man-made-gene” is considered product-by-process. MPEP 2113 reads "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
As discussed supra in the rejection under 101, the claimed nucleic acid construct of claims 1, 5-6 and 12-13 is indistinguishable from the nucleic acid sequence of an unmodified mouse genome. Thus any art that teaches a wild-type mouse reads on the nucleic acid sequence as claimed.
As discussed supra, the natural mouse ABCB11 promoter is operably linked to the mouce ABCB11 gene, and thus is considered operably linked to a therapeutic transgene.
Figge teach a transgenic mouse with overexpression of ABCB11 gene has one to two intact copies of the ABCB11 gene in comparison to wild-type controls (p2793 col2 ¶2; Fig 1A). The wild type mouse genome which expresses ABCB11 driven by the endogenous ABCB11 promoter reads on the nucleic acid as claimed because it comprises the ABCB11 promoter sequence which comprises 100% identity with the instant Seq ID NO: 1; see below (Query is Seq ID NO:1 and Sbjct is Mus musculus ABCB11 gene; Genbank AY039785.1):
Query 1 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2267 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 2326
Query 61 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2327 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 2386
Query 121 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2387 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 2446
Query 181 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 222
||||||||||||||||||||||||||||||||||||||||||
Sbjct 2447 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 2488
Thus claims 1, 5-6 and 12-13 are anticipated by Figge et al.
Claims 1, 5-6 and 12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated Wang et al (Eur J Clin Invest (2010) 40:6;1-21) and as evidenced by Vooght et al (Clinical Chemistry (2009) 55:4;1-11).
Regarding claims 1, 5-6 and 12: Claim 1 requires a nucleic acid construct comprising a bile acid inducible promoter having a length of less than 500 bp and comprising nucleic acid sequence of seq ID NO: 1 (or a functional variant having at least 95% identity to Seq ID NO:1) which is operably linked to a therapeutic transgene.
As discussed supra, the term “transgene” is interpreted to mean any gene, because any gene is exogenous DNA depending of the context of the gene. For example, any mammalian gene can be encoded in an AAV expression vector and would thus be considered a transgene according to the definition supra.
The language “comprising” as recited in claim 1 is open claim language and thus the claim is interpreted to require the nucleic acid sequence of Seq ID NO: 1 (or a sequence comprising at least 95% identity thereof), but does not exclude additional nucleic acid sequence.
The instant specification defines “nucleic acid construct” as “to a man-made nucleic acid molecule resulting from the use of recombinant DNA technology. A” (p17 ln 15-20).
A “man-made-gene” is considered product-by-process. MPEP 2113 reads "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
Wang teach a nucleic acid construct comprising a bile acid inducible promoter comprising nucleic acid sequence Seq ID NO: 1.
Wang teach ABCB11 transgenic mice (ABCB11.Tg) which overexpress ABCB11 (p2 ¶2). Wang teach ABCB11 cDNA was cloned in front of the minimal promoter sequence for ABCB11 (-376/+64 bp) (p7 ¶5). As discussed supra, the ABCB11 protein encoded by ABCB11 cDNA is considered a therapeutic transgene.
As evidenced by Vooght, -376/+64 bp refers to the nucleotides 376 bp upstream and 64 bp downstream relative to the transcriptional start site of the gene (p1 col2 ¶4), thus Wang teach a 440 bp promoter sequence of ABCB11 operably linked to ABCB11 (a therapeutic transgene).
As evidenced by Genbank AY039785.1, the mouse ABCB11 gene promoter sequence transcription start (position +1) is at position 2302 (ATG).
The sequence taught by Wang comprises 376 nucleotides upstream of the transcription start (position 2302) is position 1926. Alignment of the ABCB11 sequence comprising taught by Wang, comprising nucleotides 1926-2488 of AY039785.1, shares 100% sequence identity with Seq ID NO: 1 of the instant invention (Query is the instant Seq ID NO: 1; Sbjct is positions 1926-2488 of AY039785.1, the mouse ABCB11 promoter):
Thus the promoter sequence as recited by Wang (-376/+64) bp of the comprises a 222 bp sequence identical to the instant Seq ID NO: 1:
Query 1 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2267 GGTTCCTGCTTTGAGTATGTTCGACCTTTCCTCTCATGTCACTGAACTGTGCTAGATCTG 2326
Query 61 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2327 GACTTTAGGCCATTGACCTATAAGCAAATAGATAGTGTTCTTAAAAAAGCCTGATTTCTG 2386
Query 121 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2387 TTCAATGCTTTATTACCATGAAAACTGAACTTGGAAAGGGGTGTACAACCCTGACTTTCC 2446
Query 181 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 222
||||||||||||||||||||||||||||||||||||||||||
Sbjct 2447 ACAGTGGCGTCTCTCGCTTCTCCTGGCTCCCTCAAATTCACA 2488
Thus claims 1, 5-6 and 12 are anticipated by Wang.
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 2-3, 9-11, 13 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Eur J Clin Invest (2010) 40:6;1-21) as applied to claims 1, 5-6 and 12 above, and further in view of Sauca et al (WO 2016097219A1).
Claims 1, 5-6 and 12 are anticipated by Wang and thus are also rendered obvious (see above).
Regarding claims 2-3, 9-11 and 20: The teachings of Wang are discussed supra. Wang do not teach the nucleic acid construct comprises a poly(A) signal sequence of Seq ID NO: 10 or is encoded in an AAV8 expression vector.
Sauca teach AAV vectors for gene therapy for inherited disorders caused by absent or reduced function of the ATP transporter ATP7B (abstract, p1 ln 12-20). Sauca teach an AAV vector encoding wild type ATP7B followed by a poly(A) signal sequence and flanked by 5’ and 3’ ITR (Figure 1). Sauca teach the AAV viral particle comprises capsid proteins from an AAV8 serotype (p19 ln30-33).
Sauca teach a poly(A) signal is important for the nuclear export, translation and stability of mRNA (p15 ln15-23). Sauca further teach the a poly(A) sequence comprises nucletides 4877-4932 of Seq ID NO: 1 as taught by Sauca. The poly(A) sequence taught by Sauca (4877-4932 of Seq ID NO: 1) shares 100% identity with Seq ID NO: 10 of the instant invention (Qy is Seq ID NO:10, Db is Seq ID NO: 1 of Sauca):
Qy 1 AATAAAGACCTCTTATTTTCATTCATCAGGTGTGGTTGGTTTTTTTGTGTGGGGGC 56
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4877 AATAAAGACCTCTTATTTTCATTCATCAGGTGTGGTTGGTTTTTTTGTGTGGGGGC 4932
It would have been obvious to one of ordinary skill in the art to adapt the nucleic acid taught by Wang, drawn to the promoter sequence of ABCB11 operably linked to expressing ABCB11 of by incorporating the nucleic acid construct in an AVV8 expression vector comprising 5’ and 3’ ITR and a poly(A) signal as taught by Sauca.
Sauca teach treating a mouse model of the disease intravenously with the therapeutic vector, which requires a pharmaceutical composition comprising the nucleic acid construct (p27 col26 ln 30-35). Sauca further teach treatment with the gene therapy vector reduced the disease phenotype (Cu content in the liver) (col27 ln 25-35).
One of ordinary skill in the art would have been motivated to modify the nucleic acid construct as taught by Wang by incorporating it into an AAV8 expression vector comprising a poly(A) signal sequence, 5’ and 3’ ITR, generating viral particles and a pharmaceutical composition comprising the nucleic acid construct as taught by Sauca, because Sauca teach the expression of the wild type type gene would theoretically reverse all disease-related abnormalities and rescue the symptoms of disease caused by mutations. Sauca further teach that administration of a pharmaceutical composition comprising viral particles comprising the gene therapy vector reduces the disease phenotype in a mouse model. One of ordinary skill in the art would have recognized that incorporation of the nucleic acid construct taught by Wang, the ABCB11 promoter operably linked to the ABCB11 transporter, generation of viral particles comprising the nucleic acid construct and subsequent administration of the viral particles in a pharmaceutical composition would theoretically reverse all disease-related abnormalities and rescue the symptoms of disease caused by mutations in the ABCB11 transporter.
One would have had a reasonable expectation of success because incorporating known promoter and gene sequences in an known AAV expression vector and generating viral particles requires standard molecular biology methods which are well known in the art and thus the outcome would be predictable.
Claim 7 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Eur J Clin Invest (2010) 40:6;1-21) as applied to claims 1, 5-6 and 12 above, and further in view of Hayashi et al (Hepatology (2005) 41:4;1-9) and Ward et al (Gene Therapy (2011) 117:3;799-807).
Claims 1, 5-6 and 12 are anticipated by Wang and thus are also rendered obvious (see above).
Regarding claims 7 and 18: The teachings of Wang are discussed supra. Wang do not teach the ABCB11 promoter sequence is operably linked to a transgene encoding human ABCB11 (BSEP).
Hayashi teach a nucleic acid construct comprising human wild-type ABCB11 cloned into the adenovirus shuttle vector pShuttle (p2 col 1/2 ¶4/1).
Codon optimization of nucleic expression in specific organisms is well known in the art. Ward teach codon optimized constructs achieve a 29- 44-fold increase in expression, and more than 200% yield compared to the expression of normal expression levels (abstract).
The wild type ABCB11 nucleic acid sequence is known in as NM_003742.4. Using a publicly available codon optimization tool provided by Integrated DNA Technologies (https://www.idtdna.com/CodonOpt) biosciences generates a human codon-optimized nucleic acid sequence for ABCB11 which comprises 100% sequence identity with Seq ID NO: 1 (Query is seq ID NO: 8; Sbjct is human codon optimized NM_003742.4).
Query 1 ATGAGCGACTCCGTGATTCTGAGATCAATCAAAAAATTCGGCGAAGAAAATGACGGGTTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 ATGAGCGACTCCGTGATTCTGAGATCAATCAAAAAATTCGGCGAAGAAAATGACGGGTTC 60
Query 61 GAGAGCGATAAATCCTATAATAATGACAAGAAGTCTAGGCTGCAGGACGAGAAGAAGGGC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 61 GAGAGCGATAAATCCTATAATAATGACAAGAAGTCTAGGCTGCAGGACGAGAAGAAGGGC 120
Query 121 GATGGCGTGCGGGTGGGCTTCTTTCAGCTGTTCCGGTTCAGCAGCAGCACCGACATCTGG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 121 GATGGCGTGCGGGTGGGCTTCTTTCAGCTGTTCCGGTTCAGCAGCAGCACCGACATCTGG 180
Query 181 CTGATGTTTGTGGGCAGCCTGTGCGCCTTCCTGCACGGCATCGCACAGCCAGGCGTGCTG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 181 CTGATGTTTGTGGGCAGCCTGTGCGCCTTCCTGCACGGCATCGCACAGCCAGGCGTGCTG 240
Query 241 CTGATCTTTGGCACCATGACAGACGTGTTCATCGACTACGATGTGGAGCTGCAGGAGCTG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 241 CTGATCTTTGGCACCATGACAGACGTGTTCATCGACTACGATGTGGAGCTGCAGGAGCTG 300
Query 301 CAGATCCCTGGCAAAGCCTGCGTGAACAATACCATCGTGTGGACAAACAGCTCCCTGAAC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 301 CAGATCCCTGGCAAAGCCTGCGTGAACAATACCATCGTGTGGACAAACAGCTCCCTGAAC 360
Query 361 CAGAATATGACCAACGGCACACGCTGTGGCCTGCTGAATATCGAGTCTGAGATGATCAAG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 361 CAGAATATGACCAACGGCACACGCTGTGGCCTGCTGAATATCGAGTCTGAGATGATCAAG 420
Query 421 TTTGCCAGCTACTATGCAGGAATCGCAGTGGCCGTGCTGATCACCGGCTACATCCAGATT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 421 TTTGCCAGCTACTATGCAGGAATCGCAGTGGCCGTGCTGATCACCGGCTACATCCAGATT 480
Query 481 TGCTTCTGGGTCATCGCAGCAGCAAGGCAGATCCAGAAGATGAGAAAGTTCTATTTTCGG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 481 TGCTTCTGGGTCATCGCAGCAGCAAGGCAGATCCAGAAGATGAGAAAGTTCTATTTTCGG 540
Query 541 AGAATCATGCGGATGGAGATCGGCTGGTTTGACTGTAACTCTGTGGGCGAGCTGAATACA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 541 AGAATCATGCGGATGGAGATCGGCTGGTTTGACTGTAACTCTGTGGGCGAGCTGAATACA 600
Query 601 AGATTCAGCGACGACATCAACAAGATCAATGACGCCATCGCCGATCAGATGGCCCTGTTT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 601 AGATTCAGCGACGACATCAACAAGATCAATGACGCCATCGCCGATCAGATGGCCCTGTTT 660
Query 661 ATCCAGCGGATGACCAGCACAATCTGTGGCTTCCTGCTGGGCTTCTTTAGAGGCTGGAAG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 661 ATCCAGCGGATGACCAGCACAATCTGTGGCTTCCTGCTGGGCTTCTTTAGAGGCTGGAAG 720
Query 721 CTGACCCTGGTCATCATCAGCGTGTCCCCACTGATCGGAATCGGAGCAGCAACAATCGGC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 721 CTGACCCTGGTCATCATCAGCGTGTCCCCACTGATCGGAATCGGAGCAGCAACAATCGGC 780
Query 781 CTGTCTGTGAGCAAGTTCACCGACTACGAGCTGAAAGCCTACGCCAAGGCAGGAGTGGTG 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 781 CTGTCTGTGAGCAAGTTCACCGACTACGAGCTGAAAGCCTACGCCAAGGCAGGAGTGGTG 840
Query 841 GCAGATGAAGTGATCAGCAGCATGAGGACCGTGGCAGCCTTTGGCGGAGAGAAGAGGGAG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 841 GCAGATGAAGTGATCAGCAGCATGAGGACCGTGGCAGCCTTTGGCGGAGAGAAGAGGGAG 900
Query 901 GTGGAGCGGTACGAGAAGAACCTGGTGTTCGCCCAGCGGTGGGGCATCAGAAAGGGCATC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 901 GTGGAGCGGTACGAGAAGAACCTGGTGTTCGCCCAGCGGTGGGGCATCAGAAAGGGCATC 960
Query 961 GTGATGGGCTTCTTTACAGGCTTCGTGTGGTGCCTGATCTTCCTGTGCTACGCCCTGGCC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 961 GTGATGGGCTTCTTTACAGGCTTCGTGTGGTGCCTGATCTTCCTGTGCTACGCCCTGGCC 1020
Query 1021 TTTTGGTATGGCTCCACCCTGGTGCTGGACGAGGGAGAGTATACCCCTGGCACACTGGTG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1021 TTTTGGTATGGCTCCACCCTGGTGCTGGACGAGGGAGAGTATACCCCTGGCACACTGGTG 1080
Query 1081 CAGATTTTCCTGAGCGTGATCGTGGGCGCCCTGAACCTGGGAAATGCATCCCCATGCCTG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1081 CAGATTTTCCTGAGCGTGATCGTGGGCGCCCTGAACCTGGGAAATGCATCCCCATGCCTG 1140
Query 1141 GAAGCCTTCGCCACAGGAAGGGCAGCAGCCACCTCCATCTTCGAGACAATCGACCGCAAG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1141 GAAGCCTTCGCCACAGGAAGGGCAGCAGCCACCTCCATCTTCGAGACAATCGACCGCAAG 1200
Query 1201 CCTATCATCGACTGTATGTCTGAGGATGGCTACAAGCTGGACAGGATCAAGGGCGAGATC 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1201 CCTATCATCGACTGTATGTCTGAGGATGGCTACAAGCTGGACAGGATCAAGGGCGAGATC 1260
Query 1261 GAGTTTCACAATGTGACCTTCCACTATCCCAGCCGCCCTGAGGTGAAGATCCTGAACGAT 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1261 GAGTTTCACAATGTGACCTTCCACTATCCCAGCCGCCCTGAGGTGAAGATCCTGAACGAT 1320
Query 1321 CTGAATATGGTCATCAAGCCAGGAGAGATGACCGCCCTGGTGGGACCCTCTGGAGCAGGC 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1321 CTGAATATGGTCATCAAGCCAGGAGAGATGACCGCCCTGGTGGGACCCTCTGGAGCAGGC 1380
Query 1381 AAGAGCACCGCCCTGCAGCTGATCCAGCGGTTTTACGACCCTTGCGAGGGAATGGTGACC 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1381 AAGAGCACCGCCCTGCAGCTGATCCAGCGGTTTTACGACCCTTGCGAGGGAATGGTGACC 1440
Query 1441 GTGGACGGACACGACATCAGGTCCCTGAACATCCAGTGGCTGCGCGATCAGATCGGCATC 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1441 GTGGACGGACACGACATCAGGTCCCTGAACATCCAGTGGCTGCGCGATCAGATCGGCATC 1500
Query 1501 GTGGAGCAGGAGCCAGTGCTGTTCTCTACCACAATCGCCGAGAATATCAGATACGGCCGC 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1501 GTGGAGCAGGAGCCAGTGCTGTTCTCTACCACAATCGCCGAGAATATCAGATACGGCCGC 1560
Query 1561 GAGGATGCCACAATGGAGGACATCGTGCAGGCCGCCAAGGAGGCCAACGCCTATAACTTC 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1561 GAGGATGCCACAATGGAGGACATCGTGCAGGCCGCCAAGGAGGCCAACGCCTATAACTTC 1620
Query 1621 ATCATGGATCTGCCCCAGCAGTTCGACACCCTGGTGGGAGAGGGAGGAGGACAGATGTCC 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1621 ATCATGGATCTGCCCCAGCAGTTCGACACCCTGGTGGGAGAGGGAGGAGGACAGATGTCC 1680
Query 1681 GGAGGCCAGAAGCAGAGAGTGGCCATCGCCAGAGCCCTGATCCGCAACCCTAAGATCCTG 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1681 GGAGGCCAGAAGCAGAGAGTGGCCATCGCCAGAGCCCTGATCCGCAACCCTAAGATCCTG 1740
Query 1741 CTGCTGGATATGGCCACAAGCGCCCTGGACAATGAGTCCGAGGCTATGGTGCAGGAGGTG 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1741 CTGCTGGATATGGCCACAAGCGCCCTGGACAATGAGTCCGAGGCTATGGTGCAGGAGGTG 1800
Query 1801 CTGAGCAAGATCCAGCACGGCCACACCATCATCTCTGTGGCACACAGGCTGAGCACAGTG 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1801 CTGAGCAAGATCCAGCACGGCCACACCATCATCTCTGTGGCACACAGGCTGAGCACAGTG 1860
Query 1861 AGAGCAGCCGACACCATCATCGGCTTTGAGCACGGCACAGCAGTGGAGAGGGGCACCCAC 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1861 AGAGCAGCCGACACCATCATCGGCTTTGAGCACGGCACAGCAGTGGAGAGGGGCACCCAC 1920
Query 1921 GAGGAGCTGCTGGAGAGGAAGGGCGTGTACTTCACCCTGGTGACACTGCAGTCCCAGGGC 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1921 GAGGAGCTGCTGGAGAGGAAGGGCGTGTACTTCACCCTGGTGACACTGCAGTCCCAGGGC 1980
Query 1981 AACCAGGCCCTGAATGAGGAGGACATCAAGGATGCCACAGAGGACGATATGCTGGCCCGG 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1981 AACCAGGCCCTGAATGAGGAGGACATCAAGGATGCCACAGAGGACGATATGCTGGCCCGG 2040
Query 2041 ACCTTCAGCAGAGGCTCCTATCAGGATTCTCTGAGGGCCAGCATCAGGCAGCGGAGCAAG 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2041 ACCTTCAGCAGAGGCTCCTATCAGGATTCTCTGAGGGCCAGCATCAGGCAGCGGAGCAAG 2100
Query 2101 TCTCAGCTGAGCTACCTGGTGCACGAGCCACCTCTGGCAGTGGTGGACCACAAGTCCACC 2160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2101 TCTCAGCTGAGCTACCTGGTGCACGAGCCACCTCTGGCAGTGGTGGACCACAAGTCCACC 2160
Query 2161 TATGAGGAGGATCGCAAGGACAAGGACATCCCAGTGCAGGAGGAGGTGGAGCCTGCACCA 2220
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2161 TATGAGGAGGATCGCAAGGACAAGGACATCCCAGTGCAGGAGGAGGTGGAGCCTGCACCA 2220
Query 2221 GTGAGGCGCATCCTGAAGTTTTCCGCCCCAGAGTGGCCCTACATGCTGGTGGGATCTGTG 2280
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2221 GTGAGGCGCATCCTGAAGTTTTCCGCCCCAGAGTGGCCCTACATGCTGGTGGGATCTGTG 2280
Query 2281 GGAGCAGCAGTGAACGGCACCGTGACACCACTGTATGCCTTCCTGTTTTCCCAGATCCTG 2340
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2281 GGAGCAGCAGTGAACGGCACCGTGACACCACTGTATGCCTTCCTGTTTTCCCAGATCCTG 2340
Query 2341 GGCACCTTCTCTATCCCCGACAAGGAGGAGCAGCGGTCCCAGATCAATGGCGTGTGCCTG 2400
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2341 GGCACCTTCTCTATCCCCGACAAGGAGGAGCAGCGGTCCCAGATCAATGGCGTGTGCCTG 2400
Query 2401 CTGTTTGTGGCTATGGGCTGCGTGAGCCTGTTTACACAGTTCCTGCAGGGCTACGCCTTC 2460
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2401 CTGTTTGTGGCTATGGGCTGCGTGAGCCTGTTTACACAGTTCCTGCAGGGCTACGCCTTC 2460
Query 2461 GCCAAGAGCGGCGAGCTGCTGACCAAGCGGCTGAGAAAGTTCGGCTTTAGAGCCATGCTG 2520
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2461 GCCAAGAGCGGCGAGCTGCTGACCAAGCGGCTGAGAAAGTTCGGCTTTAGAGCCATGCTG 2520
Query 2521 GGCCAGGACATCGCCTGGTTTGACGATCTGCGGAACAGCCCAGGCGCCCTGACCACAAGA 2580
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2521 GGCCAGGACATCGCCTGGTTTGACGATCTGCGGAACAGCCCAGGCGCCCTGACCACAAGA 2580
Query 2581 CTGGCCACAGATGCATCTCAGGTGCAGGGAGCAGCAGGCAGCCAGATCGGCATGATCGTG 2640
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2581 CTGGCCACAGATGCATCTCAGGTGCAGGGAGCAGCAGGCAGCCAGATCGGCATGATCGTG 2640
Query 2641 AACTCCTTCACCAATGTGACAGTGGCCATGATCATCGCCTTCAGCTTTTCCTGGAAGCTG 2700
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2641 AACTCCTTCACCAATGTGACAGTGGCCATGATCATCGCCTTCAGCTTTTCCTGGAAGCTG 2700
Query 2701 AGCCTGGTCATCCTGTGCTTCTTCCCCTTTCTGGCCCTGAGCGGAGCAACCCAGACAAGG 2760
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2701 AGCCTGGTCATCCTGTGCTTCTTCCCCTTTCTGGCCCTGAGCGGAGCAACCCAGACAAGG 2760
Query 2761 ATGCTGACCGGCTTCGCCTCCAGAGACAAGCAGGCCCTGGAGATGGTGGGCCAGATCACA 2820
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2761 ATGCTGACCGGCTTCGCCTCCAGAGACAAGCAGGCCCTGGAGATGGTGGGCCAGATCACA 2820
Query 2821 AACGAGGCCCTGAGCAATATCAGGACCGTGGCAGGAATCGGCAAGGAGCGGCGGTTCATC 2880
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2821 AACGAGGCCCTGAGCAATATCAGGACCGTGGCAGGAATCGGCAAGGAGCGGCGGTTCATC 2880
Query 2881 GAGGCCCTGGAGACAGAGCTGGAGAAGCCTTTCAAGACCGCCATCCAGAAGGCCAACATC 2940
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2881 GAGGCCCTGGAGACAGAGCTGGAGAAGCCTTTCAAGACCGCCATCCAGAAGGCCAACATC 2940
Query 2941 TACGGCTTCTGCTTTGCCTTCGCCCAGTGTATCATGTTCATCGCCAACTCTGCCAGCTAC 3000
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2941 TACGGCTTCTGCTTTGCCTTCGCCCAGTGTATCATGTTCATCGCCAACTCTGCCAGCTAC 3000
Query 3001 CGCTATGGCGGCTACCTGATCAGCAATGAGGGCCTGCACTTCAGCTACGTGTTCAGAGTG 3060
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3001 CGCTATGGCGGCTACCTGATCAGCAATGAGGGCCTGCACTTCAGCTACGTGTTCAGAGTG 3060
Query 3061 ATCAGCGCCGTGGTGCTGTCTGCCACAGCCCTGGGAAGGGCCTTCTCCTACACCCCATCT 3120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3061 ATCAGCGCCGTGGTGCTGTCTGCCACAGCCCTGGGAAGGGCCTTCTCCTACACCCCATCT 3120
Query 3121 TATGCCAAGGCCAAGATCAGCGCCGCCAGGTTCTTTCAGCTGCTGGACCGCCAGCCACCC 3180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3121 TATGCCAAGGCCAAGATCAGCGCCGCCAGGTTCTTTCAGCTGCTGGACCGCCAGCCACCC 3180
Query 3181 ATCAGCGTGTACAACACAGCCGGCGAGAAGTGGGATAATTTCCAGGGCAAGATCGACTTT 3240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3181 ATCAGCGTGTACAACACAGCCGGCGAGAAGTGGGATAATTTCCAGGGCAAGATCGACTTT 3240
Query 3241 GTGGATTGCAAGTTCACCTATCCTAGCAGACCAGACTCCCAGGTGCTGAATGGCCTGTCC 3300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3241 GTGGATTGCAAGTTCACCTATCCTAGCAGACCAGACTCCCAGGTGCTGAATGGCCTGTCC 3300
Query 3301 GTGTCTATCAGCCCAGGCCAGACACTGGCCTTTGTGGGCTCCTCTGGCTGTGGCAAGTCC 3360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3301 GTGTCTATCAGCCCAGGCCAGACACTGGCCTTTGTGGGCTCCTCTGGCTGTGGCAAGTCC 3360
Query 3361 ACCTCTATCCAGCTGCTGGAGCGGTTCTATGACCCCGATCAGGGCAAAGTGATGATCGAC 3420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3361 ACCTCTATCCAGCTGCTGGAGCGGTTCTATGACCCCGATCAGGGCAAAGTGATGATCGAC 3420
Query 3421 GGCCACGATAGCAAGAAGGTGAACGTGCAGTTTCTGAGATCCAATATCGGCATCGTGTCT 3480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3421 GGCCACGATAGCAAGAAGGTGAACGTGCAGTTTCTGAGATCCAATATCGGCATCGTGTCT 3480
Query 3481 CAGGAGCCTGTGCTGTTCGCCTGCTCCATCATGGATAACATCAAGTACGGCGACAATACA 3540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3481 CAGGAGCCTGTGCTGTTCGCCTGCTCCATCATGGATAACATCAAGTACGGCGACAATACA 3540
Query 3541 AAGGAGATCCCAATGGAGAGAGTGATCGCAGCAGCAAAGCAGGCACAGCTGCACGATTTC 3600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3541 AAGGAGATCCCAATGGAGAGAGTGATCGCAGCAGCAAAGCAGGCACAGCTGCACGATTTC 3600
Query 3601 GTGATGTCCCTGCCCGAGAAGTATGAGACAAACGTGGGCTCTCAGGGCAGCCAGCTGTCC 3660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3601 GTGATGTCCCTGCCCGAGAAGTATGAGACAAACGTGGGCTCTCAGGGCAGCCAGCTGTCC 3660
Query 3661 AGGGGCGAGAAGCAGAGGATCGCAATCGCCAGGGCCATCGTGCGCGATCCCAAGATCCTG 3720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3661 AGGGGCGAGAAGCAGAGGATCGCAATCGCCAGGGCCATCGTGCGCGATCCCAAGATCCTG 3720
Query 3721 CTGCTGGACGAGGCCACCAGCGCCCTGGATACAGAGTCCGAGAAGACCGTGCAGGTGGCC 3780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3721 CTGCTGGACGAGGCCACCAGCGCCCTGGATACAGAGTCCGAGAAGACCGTGCAGGTGGCC 3780
Query 3781 CTGGACAAGGCCCGGGAGGGAAGAACATGTATCGTGATCGCCCACAGACTGAGCACCATC 3840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3781 CTGGACAAGGCCCGGGAGGGAAGAACATGTATCGTGATCGCCCACAGACTGAGCACCATC 3840
Query 3841 CAGAATGCCGACATCATCGCCGTGATGGCCCAGGGCGTGGTCATCGAGAAGGGCACCCAC 3900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3841 CAGAATGCCGACATCATCGCCGTGATGGCCCAGGGCGTGGTCATCGAGAAGGGCACCCAC 3900
Query 3901 GAGGAACTGATGGCACAGAAAGGGGCTTACTACAAACTGGTCACAACAGGCTCACCTATC 3960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 3901 GAGGAACTGATGGCACAGAAAGGGGCTTACTACAAACTGGTCACAACAGGCTCACCTATC 3960
Query 3961 TCATAG 3966
||||||
Sbjct 3961 TCATAG 3966
It would have been obvious to modify the nucleic acid construct as taught by Wang, drawn to the murine ABCB11 promoter operably linked to murine ABCB11 coding sequence, with the teachings of Hayashi and Ward, to clone the human codon optimized sequence of ABCB11 into the nucleic acid construct.
One would have been motivated to modify the nucleic acid construct of Wang with the teaching of Hayashi and Ward, to use the human codon optimized sequence ABCB11 coding sequence, because Hayashi teach testing the function of the mouse gene does not fully elucidate the function of the human gene (p1/2 col 2/1 ¶3/1) and Ward teach using a codon-optimized sequence can improve protein expression.
One would have had a reasonable expectation of success because exchanging one known transgene for another known transgene in a nucleic acid construct requires standard molecular biology methods which are well known in the art and thus the outcome would be predictable and the sequences and tools needed to generate the codon optimized sequences are well known in the art.
Thus the invention as claimed is rendered obvious by the teachings of Wang, Sauca, Hayashi and Ward.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
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