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 .
Applicant’s amendment filed on 02/13/2026 has been entered.
Claims 1-8, 10-17, 19-20 and 22-23 are pending in the present application.
Applicant’s election without traverse of Group I in the reply filed on 02/13/2026 is acknowledged.
Applicant also elected the following species: (i) SEQ ID NO: 1 as a species of an encoded CDKL5 polypeptide; (ii) SEQ ID NO: 123 as a species of a CDKL5 polynucleotide; (iii) a viral vector as a species of a gene therapy delivery system; (iv) SEQ ID NO: 29 as a species of a promoter; (v) SEQ ID NO: 32 as a species of a cell-penetrating polypeptide; and (vi) SEQ ID NO: 38 as a species of a leader signal polypeptide.
Accordingly, claim 23 was withdrawn from further consideration because it is directed to a non-elected invention. Additionally, claims 4-6 and 8 were also withdrawn from further considerations because they are directed to non-elected species.
Thus, claims 1-3, 7, 10-17, 19-20 and 22 are examined on the merits herein with the above elected species.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 7, 11, 13-14 and 16-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ciani et al (US 9,290,746).
The instant claims encompass a composition comprising: a gene therapy delivery system (e.g., a viral vector; see dependent claim 7); and a CDKL5 polynucleotide encoding a CDKL5 polypeptide, wherein the CDKL5 polypeptide has at least 98% sequence identity to SEQ ID NO: 1 (elected species).
Ciani et al already disclosed at least vectors containing a TATk-CDKL5 cDNA and methods of transducing cells with the vectors containing a TATk-CDKL5 cDNA encoding a TATk-CDKL5 fusion protein, wherein the fusion protein has the polypeptide sequence of SEQ ID NO: 14 that is 99.9% identical to SEQ ID NO: 1 of the present application (the starting Methionine residue in SEQ ID NO: 1 is replaced by a Valine in the CDKL5 fusion protein) and the TATk domain has the amino acid sequence of SEQ ID NO: 4 (encoded by SEQ ID NO: 3) that is 100% identical to SEQ ID NO: 32 of the present application (see at least Abstract; Summary; particularly col. 16, line 56 continues to line 54 at col. 18; and attached sequence searches below). Ciani et al also taught that the CDKL5 fusion protein can optionally contain an Igκ chain leader sequence to direct the polypeptide down the secretory pathway during production by a cell (col. 17, lines 43-59). Ciani et al further taught that the CDKL5 fusion cDNA sequence can be incorporated into a suitable expression vector (a recombinant vector) which is suitable for expressing the CDKL5 fusion protein in a mammalian cell, and the expression vector can contain one or more regulatory sequences or one or more other sequences used to facilitate the expression of the CDKL5 fusion cDNA, with suitable expression vectors are generally known in the art (col. 18, lines 36-54). Ciani et al also stated specifically “As used herein, the term “vector” or is used in reference to a vehicle used to introduce an exogenous nucleic acid sequence into a cell. A vector may include a DNA molecule linear or circular (e.g. plasmids), which includes a segment encoding a polypeptide of interest operatively linked to additional segments that provide for its transcription and translation upon introducing into a host cell or host cell organelles. Such additional segments may include promoter and terminator sequences, and may also include one or more origins of replication, one or more selectable markers, an enhancer, a polyadenylation signal, etc. Expression vectors are generally derived from yeast or bacterial genomic or plasmid DNA, or viral DNA, or may contain elements of both” (col. 14, lines 1-13). Thus, Ciani et al also taught the use of a viral vector to express a TATk-CDKL5 fusion protein in a mammalian cell. Ciani et al further taught that the TATk-CDKL5 fusion protein can increase neurite growth, elongation, branch number, or branch density in a brain; as well as reducing neuron apoptosis in a brain of subject as compared to a control; and a pharmaceutical formulation comprising a therapeutically effective amount of the fusion protein for the treatment of one or more symptoms of a CDKL5 deficiency, Rett syndrome or Rett syndrome variant in a subject in need thereof (Summary; and issued claims 1-20).
Accordingly, at least the above disclosed viral vector containing a TATk-CDKL5 cDNA of Ciani et al meets every limitation of a composition of the present application as claimed. Therefore, the reference anticipates the instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 7, 10-17, 19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ciani et al (US 9,290,746) in view of Stewart et al (WO 2016/115503).
The instant claims encompass a composition comprising: a gene therapy delivery system (e.g., a viral vector; see dependent claim 7); and a CDKL5 polynucleotide encoding a CDKL5 polypeptide, wherein the CDKL5 polypeptide has at least 98% sequence identity to SEQ ID NO: 1 (elected species); and a pharmaceutical formulation comprising the same composition and a pharmaceutically acceptable carrier.
Ciani et al already disclosed at least vectors containing a TATk-CDKL5 cDNA and methods of transducing cells with the vectors containing a TATk-CDKL5 cDNA encoding a TATk-CDKL5 fusion protein, wherein the fusion protein has the polypeptide sequence of SEQ ID NO: 14 that is 99.9% identical to SEQ ID NO: 1 of the present application (the starting Methionine residue in SEQ ID NO: 1 is replaced by a Valine in the CDKL5 fusion protein) and the TATk domain has the amino acid sequence of SEQ ID NO: 4 (encoded by SEQ ID NO: 3) that is 100% identical to SEQ ID NO: 32 of the present application (see at least Abstract; Summary; particularly col. 16, line 56 continues to line 54 at col. 18; and attached sequence searches below). Ciani et al also taught that the CDKL5 fusion protein can optionally contain an Igκ chain leader sequence to direct the polypeptide down the secretory pathway during production by a cell (col. 17, lines 43-59). Ciani et al further taught that the CDKL5 fusion cDNA sequence can be incorporated into a suitable expression vector (a recombinant vector) which is suitable for expressing the CDKL5 fusion protein in a mammalian cell, and the expression vector can contain one or more regulatory sequences or one or more other sequences used to facilitate the expression of the CDKL5 fusion cDNA, with suitable expression vectors are generally known in the art (col. 18, lines 36-54). Ciani et al also stated specifically “As used herein, the term “vector” or is used in reference to a vehicle used to introduce an exogenous nucleic acid sequence into a cell. A vector may include a DNA molecule linear or circular (e.g. plasmids), which includes a segment encoding a polypeptide of interest operatively linked to additional segments that provide for its transcription and translation upon introducing into a host cell or host cell organelles. Such additional segments may include promoter and terminator sequences, and may also include one or more origins of replication, one or more selectable markers, an enhancer, a polyadenylation signal, etc. Expression vectors are generally derived from yeast or bacterial genomic or plasmid DNA, or viral DNA, or may contain elements of both” (col. 14, lines 1-13). Ciani et al further taught that the TATk-CDKL5 fusion protein can increase neurite growth, elongation, branch number, or branch density in a brain; as well as reducing neuron apoptosis in a brain of subject as compared to a control; and a pharmaceutical formulation comprising a therapeutically effective amount of the fusion protein and a pharmaceutically acceptable carrier for the treatment of one or more symptoms of a CDKL5 deficiency, Rett syndrome or Rett syndrome variant in a subject in need thereof (Summary; and issued claims 1-20).
Ciani et al did not explicitly teach a recombinant AAV vector comprising a TATk-CDKL5 cDNA, the use of a promoter having at least 90% sequence identity to SEQ ID NO: 29, and a pharmaceutical formulation comprising the same recombinant AAV vector and a pharmaceutically acceptable carrier.
Before the effective filing date of the present application (10/30/2019), Stewart et al already disclosed at least AAV-based compositions (e.g., AAV1-AAV12 particles) for delivery therapeutic transgenes for the treatment of diseases or disorders of the CNS such as Friedreich’s ataxia, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (Abstract; Summary of the Invention, particularly paragraphs [0021]-[0030], [0034]-[0035]; and Examples). Stewart et al taught an exemplary AAV construct comprising an expression cassette comprising a nucleic acid encoding a frataxin protein that is operably linked to a CB6 promoter (containing a CMV enhancer fused to the chicken β-actin promoter), wherein the expression cassette is flanked by 5’ ITR and 3’ ITR and the AAV construct has the nucleotide sequence of SEQ ID NO: 11 with the nucleotide sequence of nucleotides 238-1099 in SEQ ID NO: 11 exhibits 90% sequence identity to the promoter sequence of SEQ ID NO: 29 of the present application (Example 1, particularly Table 3 at page 82; paragraphs [0051], [0054], [0074]-[0075], [0077]; and attached sequence search below). Stewart et al also disclosed a pharmaceutical composition comprising recombinant AAV particles that are formulated with one or more pharmaceutically acceptable carriers (paragraphs [00222]-[00230]).
Accordingly, it would have been obvious for an ordinary skill in the art to modify the teachings of Ciani et al by also preparing a recombinant AAV vector comprising a TATk-CDKL5 cDNA for the treatment of one or more symptoms of a CDKL5 deficiency in a subject in need thereof, including the use of a CB6 promoter and formulating a pharmaceutical composition comprising the same recombinant AAV vector and a pharmaceutically acceptable carrier; in light of the teachings of Stewart et al as presented above.
An ordinary skill in the art would have been motivated to carry out the above modifications because Stewart et al already disclosed AAV-based pharmaceutical compositions for delivery therapeutic transgenes for the treatment of diseases or disorders of the CNS, including the use of a CB6 promoter having 90% sequence identity to SEQ ID NO: 29 of the present application in an exemplary AAV construct. Moreover, please note that the primary Ciani reference already taught a pharmaceutical formulation comprising a therapeutically effective amount of the TATk-CDKL5 fusion protein and a pharmaceutically acceptable carrier for the treatment of one or more symptoms of a CDKL5 deficiency, Rett syndrome or Rett syndrome variant in a subject in need thereof.
An ordinary skill in the art would have a reasonable expectation of success in light of the teachings of Ciani et al and Stewart et al as set forth above, coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified composition resulting from the combined teachings of Ciani et al and Stewart et al is indistinguishable from the claimed composition of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Ciani et al (US 9,290,746) in view of Stewart et al (WO 2016/115503) as applied to claims 1-2, 7, 10-17, 19 and 22 above, and further in view of Do (US 9,279,007).
The combined teachings of Ciani et al and Stewart et al were presented above. However, none of the cited references teach specifically that the use of a leader signal polypeptide having at least 90% sequence identity to SEQ ID NO: 38 (elected species).
Before the effective filing dated of the present application (10/30/2019), Do et al already disclosed a polypeptide signal sequence of a modified fragment of human immunoglobulin heavy chain binding protein (Bip) that is operably linked to a heterologous polypeptide in a fusion protein; and an expression vector comprising a nucleotide sequence encoding the same fusion protein (Abstract; Summary and Examples). Do constructed an exemplary modified version of the Bip signal sequence in the minigene 2 construct of SEQ ID NO: 14 (modified Bip signal sequence-1-GlcCerase), in which the sequence of nucleotides 16-99 encodes the modified Bip signal sequence that is 100% identical to the leader signal polypeptide of SEQ ID NO: 38 of the present application (Example 2; Tables 2-4 and attached sequence search below). Do et al also demonstrated that the modified Bip signal sequence-1 significantly increases or improves protein expression and secretion of recombinant enzymes and other proteins (Examples 6-8 and Figs. 1-3).
Accordingly, it would have been obvious for an ordinary skill in the art to further modify the combined teachings of Ciani et al and Stewart et al by also selecting the modified Bip signal sequence-1 of SEQ ID NO: 38 of the present application as a leader signal polypeptide to improve expression and secretion of the TATk-CDKL5 fusion protein, in light of the teachings of Do as set forth above.
An ordinary skill in the art would have been motivated to carry out the above modification because Do demonstrated that the modified Bip signal sequence-1 significantly increases or improves protein expression and secretion of recombinant enzymes and other proteins.
An ordinary skill in the art would have a reasonable expectation of success in light of the teachings of Ciani et al, Stewart et al and Do as set forth above, coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified composition resulting from the combined teachings of Ciani et al, Stewart et al and Do is indistinguishable from the claimed composition of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-2, 7, 10-17, 19-20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ciani et al (WO 2020/250081) in view of Ciani et al (US 9,290,746), Stewart et al (WO 2016/115503) and Do (US 9,279,007).
Ciani et al already disclosed a composition comprising a modified gene therapy vector (e.g., AAV-leader-PTD-protein of interest) comprising a first nucleic acid coding for a secretory leader sequence, operatively linked to a second nucleic acid coding for a protein transduction domain (PTD), operatively linked to a third nucleic acid coding for a therapeutic protein, that allows the reduction of viral load and/or number of infections needed in order to achieve the same effectiveness of the same vector carrying the therapeutic protein only (Abstract; and Summary of the Invention). Ciani et al also disclosed that the vector is selected at least among AAV1-AAV13, and that an AAV vector comprises two ITRs (inverted terminal repeats), and within said ITRs at least the following elements: a promoter, a gene of interest and a terminator/polyadenylation signal (lines 30-35 at page 11). Ciani et al also taught that a promoter can be any suitable promoter, including chicken β actin (CBA) and CAG (CMV, chicken β actin, rabbit β globin) promoters and CBh (CMV early enhancer fused to modified chicken β-actin) promoter (lines 6-14 at page 12); a secretory leader sequence can be any one listed in Table 1 (e.g., mouse IgK leader sequence); a suitable PTD can be TATk, MPG, Pep-1 and others (lines 10-15 at page 13; and Table 2); and a therapeutic protein includes CDKL5, MECP2, FOXG1, SCN1A and others (lines 13-17 at page 14; and Table 3). An exemplary recombinant AAV vector is AAVPHP.B_Igk-TATk-CDKL5 vector (lines 23-24 at page 20; and section titled “Effect of gene therapy with AAVPHP.B Igk-TATk-CDKL5 or AAVPHP.B CDKL5 vector in CDKL5 KO mice” at page 25). Ciani et al further taught a pharmaceutical composition comprising the above disclosed viral vector and a pharmaceutically acceptable carrier (lines 4-14 at page 18).
Ciani et al did not teach specifically that the recombinant AAV vector comprising a CDKL5 polynucleotide encoding a CDKL5 polypeptide, wherein the CDKL5 polypeptide has at least 98% sequence identity to SEQ ID NO: 1 of the present application; a promoter having at least 90% sequence identity to SEQ ID NO: 29 of the present application; a cell-penetrating polypeptide such as TAT-k having at least 90% sequence identity to SEQ ID NO: 32 of the present application; and a leader signal polypeptide having at least 90% sequence identity to SEQ ID NO: 38 of the present application.
Before the effective filing date of the present application (10/30/2019), Ciani et al (US 9,290,746) already disclosed at least vectors containing a TATk-CDKL5 cDNA and methods of transducing cells with the vectors containing a TATk-CDKL5 cDNA encoding a TATk-CDKL5 fusion protein, wherein the fusion protein has the polypeptide sequence of SEQ ID NO: 14 that is 99.9% identical to SEQ ID NO: 1 of the present application (the starting Methionine residue in SEQ ID NO: 1 is replaced by a Valine in the CDKL5 fusion protein) and the TATk domain has the amino acid sequence of SEQ ID NO: 4 (encoded by SEQ ID NO: 3) that is 100% identical to SEQ ID NO: 32 of the present application (see at least Abstract; Summary; particularly col. 16, line 56 continues to line 54 at col. 18; and attached sequence searches below). Ciani et al also taught that the TATk-CDKL5 fusion protein can increase neurite growth, elongation, branch number, or branch density in a brain; as well as reducing neuron apoptosis in a brain of subject as compared to a control; and a pharmaceutical formulation comprising a therapeutically effective amount of the fusion protein and a pharmaceutically acceptable carrier for the treatment of one or more symptoms of a CDKL5 deficiency, Rett syndrome or Rett syndrome variant in a subject in need thereof (Summary; and issued claims 1-20).
Additionally, Stewart et al already disclosed at least AAV-based compositions (e.g., AAV1-AAV12 particles) for delivery therapeutic transgenes for the treatment of diseases or disorders of the CNS such as Friedreich’s ataxia, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (Abstract; Summary of the Invention, particularly paragraphs [0021]-[0030], [0034]-[0035]; and Examples). Stewart et al taught an exemplary AAV construct comprising an expression cassette comprising a nucleic acid encoding a frataxin protein that is operably linked to a CB6 promoter (containing a CMV enhancer fused to the chicken β-actin promoter), wherein the expression cassette is flanked by 5’ ITR and 3’ ITR and the AAV construct has the nucleotide sequence of SEQ ID NO: 11 with the nucleotide sequence of nucleotides 238-1099 in SEQ ID NO: 11 exhibits 90% sequence identity to the promoter sequence of SEQ ID NO: 29 of the present application (Example 1, particularly Table 3 at page 82; paragraphs [0051], [0054], [0074]-[0075], [0077]; and attached sequence search below).
Moreover, Do et al already disclosed a polypeptide signal sequence of a modified fragment of human immunoglobulin heavy chain binding protein (Bip) that is operably linked to a heterologous polypeptide in a fusion protein; and an expression vector comprising a nucleotide sequence encoding the same fusion protein (Abstract; Summary and Examples). Do constructed an exemplary modified version of the Bip signal sequence in the minigene 2 construct of SEQ ID NO: 14 (modified Bip signal sequence-1-GlcCerase), in which the sequence of nucleotides 16-99 encodes the modified Bip signal sequence that is 100% identical to the leader signal polypeptide of SEQ ID NO: 38 of the present application (Example 2; Tables 2-4 and attached sequence search below). Do et al also demonstrated that the modified Bip signal sequence-1 significantly increases or improves protein expression and secretion of recombinant enzymes and other proteins (Examples 6-8 and Figs. 1-3).
Accordingly, it would have been obvious for an ordinary skill in the art to modify the teachings of Ciani et al (WO 2020/250081) by also selecting an encoded CDKL5 polypeptide having at least 98% sequence identity to SEQ ID NO: 1 of the present application; a promoter having at least 90% sequence identity to SEQ ID NO: 29 of the present application; a TAT-k having at least 90% sequence identity to SEQ ID NO: 32 of the present application; and the modified Bip signal sequence-1 of SEQ ID NO: 38 of the present application as a leader signal polypeptide to improve expression and secretion of the TATk-CDKL5 fusion protein, in light of the teachings of Ciani et al (US 9,290,746), Stewart et al and Do as set forth above.
An ordinary skill in the art would have been motivated to carry out the above modifications because: (i) Ciani et al (US 9,290,746) already taught successfully a pharmaceutical formulation comprising a therapeutically effective amount of a TATk-CDKL5 fusion protein and a pharmaceutically acceptable carrier for the treatment of one or more symptoms of a CDKL5 deficiency, Rett syndrome or Rett syndrome variant in a subject in need thereof, wherein the TATk-CDKL5 fusion protein has the polypeptide sequence of SEQ ID NO: 14 that is 99.9% identical to SEQ ID NO: 1 of the present application and the TATk domain having the amino acid sequence of SEQ ID NO: 4 (encoded by SEQ ID NO: 3) that is 100% identical to SEQ ID NO: 32 of the present application; (ii) Stewart et al already disclosed AAV-based pharmaceutical compositions for delivery therapeutic transgenes for the treatment of diseases or disorders of the CNS, including the use of a CB6 promoter having 90% sequence identity to SEQ ID NO: 29 of the present application in an exemplary AAV construct; and (iii) Do demonstrated successfully that the modified Bip signal sequence-1 significantly increases or improves protein expression and secretion of recombinant enzymes and other proteins.
An ordinary skill in the art would have a reasonable expectation of success in light of the teachings of Ciani et al (WO 2020/250081), Ciani et al (US 9,290,746), Stewart et al and Do as set forth above, coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified composition resulting from the combined teachings of Ciani et al (WO 2020/250081), Ciani et al (US 9,290,746), Stewart et al and Do is indistinguishable from the claimed composition of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Examiner’s Comment
The prior art did not teach or fairly suggest a CDKL5 polynucleotide having at least 90% sequence identity to SEQ ID NO: 123 (a human codon optimized CDKL5-107 polynucleotide).
Conclusions
No claim is allowed.
Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/
Primary Examiner, Art Unit 1631
Sequence 14,
Patent No. 9290746
TATk-CDKL5 fusion protein polypeptide
Query Match 99.9%; Score 5011; Length 1036;
Best Local Similarity 99.9%;
Matches 959; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MKIPNIGNVMNKFEILGVVGEGAYGVVLKCRHKETHEIVAIKKFKDSEENEEVKETTLRE 60
:|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 49 VKIPNIGNVMNKFEILGVVGEGAYGVVLKCRHKETHEIVAIKKFKDSEENEEVKETTLRE 108
Qy 61 LKMLRTLKQENIVELKEAFRRRGKLYLVFEYVEKNMLELLEEMPNGVPPEKVKSYIYQLI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 109 LKMLRTLKQENIVELKEAFRRRGKLYLVFEYVEKNMLELLEEMPNGVPPEKVKSYIYQLI 168
Qy 121 KAIHWCHKNDIVHRDIKPENLLISHNDVLKLCDFGFARNLSEGNNANYTEYVATRWYRSP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 169 KAIHWCHKNDIVHRDIKPENLLISHNDVLKLCDFGFARNLSEGNNANYTEYVATRWYRSP 228
Qy 181 ELLLGAPYGKSVDMWSVGCILGELSDGQPLFPGESEIDQLFTIQKVLGPLPSEQMKLFYS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 229 ELLLGAPYGKSVDMWSVGCILGELSDGQPLFPGESEIDQLFTIQKVLGPLPSEQMKLFYS 288
Qy 241 NPRFHGLRFPAVNHPQSLERRYLGILNSVLLDLMKNLLKLDPADRYLTEQCLNHPTFQTQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 289 NPRFHGLRFPAVNHPQSLERRYLGILNSVLLDLMKNLLKLDPADRYLTEQCLNHPTFQTQ 348
Qy 301 RLLDRSPSRSAKRKPYHVESSTLSNRNQAGKSTALQSHHRSNSKDIQNLSVGLPRADEGL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 349 RLLDRSPSRSAKRKPYHVESSTLSNRNQAGKSTALQSHHRSNSKDIQNLSVGLPRADEGL 408
Qy 361 PANESFLNGNLAGASLSPLHTKTYQASSQPGSTSKDLTNNNIPHLLSPKEAKSKTEFDFN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 409 PANESFLNGNLAGASLSPLHTKTYQASSQPGSTSKDLTNNNIPHLLSPKEAKSKTEFDFN 468
Qy 421 IDPKPSEGPGTKYLKSNSRSQQNRHSFMESSQSKAGTLQPNEKQSRHSYIDTIPQSSRSP 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 469 IDPKPSEGPGTKYLKSNSRSQQNRHSFMESSQSKAGTLQPNEKQSRHSYIDTIPQSSRSP 528
Qy 481 SYRTKAKSHGALSDSKSVSNLSEARAQIAEPSTSRYFPSSCLDLNSPTSPTPTRHSDTRT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 529 SYRTKAKSHGALSDSKSVSNLSEARAQIAEPSTSRYFPSSCLDLNSPTSPTPTRHSDTRT 588
Qy 541 LLSPSGRNNRNEGTLDSRRTTTRHSKTMEELKLPEHMDSSHSHSLSAPHESFSYGLGYTS 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 589 LLSPSGRNNRNEGTLDSRRTTTRHSKTMEELKLPEHMDSSHSHSLSAPHESFSYGLGYTS 648
Qy 601 PFSSQQRPHRHSMYVTRDKVRAKGLDGSLSIGQGMAARANSLQLLSPQPGEQLPPEMTVA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 649 PFSSQQRPHRHSMYVTRDKVRAKGLDGSLSIGQGMAARANSLQLLSPQPGEQLPPEMTVA 708
Qy 661 RSSVKETSREGTSSFHTRQKSEGGVYHDPHSDDGTAPKENRHLYNDPVPRRVGSFYRVPS 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 709 RSSVKETSREGTSSFHTRQKSEGGVYHDPHSDDGTAPKENRHLYNDPVPRRVGSFYRVPS 768
Qy 721 PRPDNSFHENNVSTRVSSLPSESSSGTNHSKRQPAFDPWKSPENISHSEQLKEKEKQGFF 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 769 PRPDNSFHENNVSTRVSSLPSESSSGTNHSKRQPAFDPWKSPENISHSEQLKEKEKQGFF 828
Qy 781 RSMKKKKKKSQTVPNSDSPDLLTLQKSIHSASTPSSRPKEWRPEKISDLQTQSQPLKSLR 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 829 RSMKKKKKKSQTVPNSDSPDLLTLQKSIHSASTPSSRPKEWRPEKISDLQTQSQPLKSLR 888
Qy 841 KLLHLSSASNHPASSDPRFQPLTAQQTKNSFSEIRIHPLSQASGGSSNIRQEPAPKGRPA 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 889 KLLHLSSASNHPASSDPRFQPLTAQQTKNSFSEIRIHPLSQASGGSSNIRQEPAPKGRPA 948
Qy 901 LQLPGQMDPGWHVSSVTRSATEGPSYSEQLGAKSGPNGHPYNRTNRSRMPNLNDLKETAL 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 949 LQLPGQMDPGWHVSSVTRSATEGPSYSEQLGAKSGPNGHPYNRTNRSRMPNLNDLKETAL 1008
Sequence 13,
Patent No. 9290746
TATk-CDKL5 fusion protein cDNA
Alignment Scores:
Length: 3124
Score: 128.00 Matches: 27
Percent Similarity: 100.0% Conservative: 0
Best Local Similarity: 100.0% Mismatches: 0
Query Match: 100.0% Indels: 0
Gaps: 0
US-17-773-416-32 (1-27) x US-14-633-757A-13 (1-3124)
Qy 1 AspAlaAlaGlnProAlaArgArgAlaArgArgThrLysLeuAlaAlaTyrAlaArgLys 20
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 71 GACGCGGCCCAGCCGGCCAGGCGCGCGCGCCGTACGAAGCTTGCGGCCTACGCCAGAAAG 130
Qy 21 AlaAlaArgGlnAlaArgAla 27
|||||||||||||||||||||
Db 131 GCCGCCAGGCAGGCCAGGGCA 151
Payload AAV construct DNA, SEQ ID 11.
WO2016115503-A1.
Query Match 90.0%; Score 736.4; Length 4945;
Best Local Similarity 94.3%;
Matches 815; Conservative 0; Mismatches 1; Indels 48; Gaps 3;
Qy 1 TTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTAC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 238 TTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTAC 297
Qy 61 ATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 298 ATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTC 357
Qy 121 AATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 358 AATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT 417
Qy 181 GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTAC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 418 GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTAC 477
Qy 241 GCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGAC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 478 GCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGAC 537
Qy 301 CTTACGGGACTTTCCTACTTGGCAGTACATCT---------------------------- 332
|||| |||||||||||||||||||||||||||
Db 538 CTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGTC 597
Qy 333 ----CCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTAT 388
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 598 GAGGCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTAT 657
Qy 389 TTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCC 448
|||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||
Db 658 TTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGC--GGGGGGGGGGGGCGCGCGCC 715
Qy 449 AGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGC 508
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 716 AGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGC 775
Qy 509 CAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCC 568
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 776 CAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCC 835
Qy 569 CTATAAAAAGCGAAGCGCGCGGCGG--------------GGAGTCGCTGCGTTGCCTTCG 614
||||||||||||||||||||||||| |||||||||||||||||||||
Db 836 CTATAAAAAGCGAAGCGCGCGGCGGGCGGGAGCAAGCTTGGAGTCGCTGCGTTGCCTTCG 895
Qy 615 CCCCGTGCCCCGCTCCGCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTA 674
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 896 CCCCGTGCCCCGCTCCGCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTA 955
Qy 675 CTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCAAGAGGTA 734
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 956 CTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCAAGAGGTA 1015
Qy 735 AGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGTTTTACAGGCC 794
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1016 AGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGTTTTACAGGCC 1075
Qy 795 TGAAATCACTTGGTTTTAGGTTGG 818
||||||||||||||||||||||||
Db 1076 TGAAATCACTTGGTTTTAGGTTGG 1099
Sequence 14,
Patent No. 9279007
Minigene 2 (modified Bip signal sequence-1-GlcCerase)
Alignment Scores:
Length: 471
Score: 117.00 Matches: 28
Percent Similarity: 100.0% Conservative: 0
Best Local Similarity: 100.0% Mismatches: 0
Query Match: 100.0% Indels: 0
Gaps: 0
US-17-773-416-38 (1-28) x US-13-988-946-14 (1-471)
Qy 1 MetLysLeuSerLeuValAlaAlaMetLeuLeuLeuLeuSerLeuValAlaAlaMetLeu 20
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 16 ATGAAGCTCTCCCTGGTGGCCGCGATGCTGCTGCTGCTCAGCCTGGTGGCCGCGATGCTG 75
Qy 21 LeuLeuLeuSerAlaAlaArgAla 28
||||||||||||||||||||||||
Db 76 CTGCTGCTCAGCGCGGCGCGGGCC 99