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 .
Claim Status
Claims 1, 3-6, 11-14, 18-20 are amended.
Claims 15-17 are cancelled.
Claims 1-14 and 18-20 are examined on the merits.
Priority
The applicant’s application is a U.S. National Stage application of PCT International Patent Application Serial No. PCT/RU2022/050073, filed March 05, 202, which itself claims the benefit of a Russian Application Serial No. RU2021105703, filed March 05, 2021 is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 5 is objected to because of the following informalities: the recitation of “or the codon-optimized nucleic acid” is redundant and should be deleted. As currently drafted, claim 5 depends from claim 2, which is directed to the codon-optimized nucleic acid of claim 1 without any further elements. It is noted that if claim 2 were amended to include an element in addition to the codon-optimized nucleic acid, then claim 5 should be amended to recite, “the codon-optimized nucleic acid of claim 1, or the expression cassette of claim 2.” Appropriate correction is required.
Claim 6 is objected to because of the following informalities: the recitation of “or the codon-optimized nucleic acid” is redundant and should be deleted. As currently drafted, claim 5 depends from claim 2, which is directed to the codon-optimized nucleic acid of claim 1 without any further elements. It is noted that if claim 2 were amended to include an element in addition to the codon-optimized nucleic acid, then claim 5 should be amended to recite, “the codon-optimized nucleic acid of claim 1, or the expression cassette of claim 2.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 9, 11-12 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.
Claims 9, 11 and 12 requires the provision of a genus of VP1 protein “with one or more point mutations”. The specification defines the phrase "more point mutations" to mean “two, three, four, five, six, seven, eight, nine, or ten point substitutions.” See page 26, 3rd full paragraph. The claims encompass up to 10 point mutations, which are amino acid substitutions, relative to the sequence of SEQ ID NO: 11. The positions of the substitutions within SEQ ID NO: 11 are not limited. Thus, the claims encompasses the provision of a large genus of VP1 capsid protein that must function to target cells.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
The specification envisions an isolated AAV5 (adeno-associated virus serotype 5)-based recombinant virus for increasing the FIX gene expression in target cells, comprising the above codon-optimized nucleic acid or any of the above expression cassettes (e.g., paragraph 4th, page 5). The specification envisions that the AAV5-based recombinant virus has a capsid that includes the AAV5 protein VP1 having the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO: 11 with one or more point mutations (e.g., paragraph 6th, page 5). The specification envisions the AAV5-based recombinant virus has a capsid
that includes an AAV5 protein VP1 having an amino acid sequence that includes amino acid substitutions at positions S2A and T711S of wild-type AAV5 VP1 (SEQ ID NO: 11), and has the amino acid sequence of SEQ ID NO: 14 (e.g., paragraph 7th, page 24). The specification defines the phrase "more point mutations" to refer to two, three, four, five, six, seven, eight, nine, or ten point substitutions (page 26, 3rd full paragraph). Particularly preferred embodiments include substitutions (mutations) that are conservative in nature, i.e. substitutions that take place within a family of amino acids that are joined in their side chains. In particular, amino acids are typically divided into four families: (1) acidic amino acids are aspartate and glutamate; (2) basic amino acids are lysine, arginine, histidine; (3) nonpolar amino acids are alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, and (4) uncharged polar amino acids are glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. Phenylalanine, tryptophan, and tyrosine are sometimes classified as aromatic amino acids. For example, it is reasonably predictable that an isolated substitution of leucine for isoleucine or valine, an aspartate for a glutamate, a threonine for a serine, or a similar conservative substitution of an amino acid for a structurally related amino acid, will not have a major effect on the biological activity. For example, the polypeptide of interest may include up to about 5-10 conservative or non-conservative amino acid substitutions, so long as the desired function of the molecule remains intact (e.g., paragraphs 4th -5th, page 26).
The working examples disclose the construction, transduction, coagulation capacity and in vivo studies of the AAV virus particles comprising the codon-optimized variants of the FIX gene (hFIXco-vl and hFIXco-v2) (plasmids pAAV-hFIXco-v 1 and pAAV-hFIXco-v2).
The examples described in the specification disclose the AAV5 capsid VP1 (SEQ ID NO: 11) and the specification describes the VP1 protein with two point mutations (SEQ ID NO: 14), specifically S2A and T711S. The specification encompass up to 10 point mutations, which are amino acid substitutions, relative to the sequence of SEQ ID NO: 11. The positions of the substitutions within SEQ ID NO: 11 are not limited. Thus, the claims encompasses the provision of a large genus of VP1 capsid protein that must function to target cells.
The state of the art with respect to using AAV5 VP1 protein is under developed and unpredictable. Reid et al. (WO 2020/205889 A1) teaches the AAV5 capsid protein comprises substitutions of residues that are either rationally designed; introduced by mutagenesis; or randomized through generating a library of sequences with random codon usage at one or more sites. Exemplary non-limiting substitutions that change transfection efficiency include, but are not limited to S651A, T578A or T582A. The substituted residues may be incorporated into AAV5 capsid proteins that further comprise insertions at one or more insertion sites, e.g. the GH loop or other loops (e.g., paragraph 0032). The AAV capsid contain 60 copies (in total) of three viral proteins (VPs), VP1, VP2, and VP3, in a predicted ratio of 1: 1: 10, arranged with T= 1 icosahedral symmetry. The three VPs are translated from the same mRNA, with VP1 containing a unique N-terminal domain in addition to the entire VP2 sequence at its C-terminal region. VP2 contains an extra N-terminal sequence in addition to VP3 at its C terminus (e.g., paragraph 0186). The recombinant adeno-associated virus (rAAV) virion disclosed herein comprise an AAV5 capsid protein, wherein the capsid protein comprises one or more substitutions selected from S651G, S651V, S651L, S6511, T578A, T578G, T578V, T578L, T578I, T582A, T582G, T582V, T582L, or T582I compared to a parental AAV5 capsid; and a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product (e.g., paragraph 0098). Reid teaches that one or more amino acid residues are conserved to the residue present in wild-type AAV5 capsid. For example, in some embodiments, T58 l is conserved as a tyrosine (T), or semi-conserved as serine (S) (e.g., paragraph ). By contrast, Shaffer et al (U.S.10,046,016) teaches that infectivity of lung epithelial cells is increased by mutation by a T581A mutation (e.g., paragraph 2nd, column 17). Afione et al. (J. of Virology, 2015) teaches that mutagenesis of amino acids 569 and 585 or 587 within the 3-fold depression resulted in elimination or alteration in sialic acid-dependent transduction by AAV5 (e.g., abstract). Furthermore, Afione teaches that mutation of L587T alters the tropism in vivo by AAV5, the submandibular salivary glands, L587T mutant demonstrated a 3- to 4-fold increase in transduction activity compared to WT AAV5. Similarly, a direct injection of L587T mutant in the hind limb showed a 3- to 4-fold increase in luciferase expression compared with WT AAV5. In contrast, L587T mutant gene transfer to the lung was greatly reduced compared with WT AAV5. M569V and Q359D mutants were also evaluated in the salivary glands and showed no transduction activity (data not shown). These data suggest that alteration in glycan recognition can affect vector activity in vivo (e.g., paragraph 1st, left column, page 8).
As such, the prior art teaches about the unpredictability of the modifying AAV5 VP1 for targeting cells.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 9, 11-12.
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 2 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 2 recites “an expression cassette that includes the codon-optimized nucleic acid of Claim 1”. However, Claim 1 already claims a codon-optimized nucleic acid encoding FIX including the nucleic acid of SEQ ID NO: 2 or SEQ ID NO 4. Claim 2 is merely recasting the same nucleic acid in the context of an “expression cassette” without further limiting the cassette in any manner. Thus, despite the difference in language, these claims have substantially the same scope, claim 2 provides no additional structural or functional narrowing.
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.
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 1-2, 5-7, 14, 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Doering et al. (“Doering”, US 2017/0326256 A1).
Under broadest reasonable interpretation, the scope of the claim is interpreted not to be limited to the sequence of SEQ ID NOs: 2 or 4, but rather to encompass any nucleic acid sequence that encodes SEQ ID NO: 1, wherein at least one codon has been optimized relative to the wild-type sequence. Further, the claim requires “a sequence of that is selected from SEQ ID NO: 2 or SEQ ID NO: 4,” which reads on selection of “a sequence” from either of the recited sequences, where “a sequence” reasonably reads on two or more consecutive nucleotides.
Regarding claim 1, Doering teaches FIX coding sequence variants that are designed for high levels of expression when the transgene is expressed from the liver, which is the target tissue of many FIX-targeted gene therapy strategies (e.g., paragraph 0144). Doering teaches SEQ ID NO 19 that has 100% identity to SEQ ID NO 1 of the instant claims.
PNG
media_image1.png
664
839
media_image1.png
Greyscale
PNG
media_image2.png
324
845
media_image2.png
Greyscale
Doering teaches the nucleotide sequence coding for FIX was optimized by implementing a codon usage bias specific for the human liver cell as compared to naturally occurring nucleotide sequence coding for the corresponding non-codon optimized sequence for a human additional changes were also made to improve translation efficacy, such as optimization of GC content, mRNA secondary structure, premature PolyA sites (e.g., paragraph 0145; Example 1; Table 2A-C; Fig. 7). Doering provides examples of codon-optimization of FIX nucleic acid (SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 124, or SEQ ID NO: 127, or a nucleic acid sequence at least 90% identical SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 124, or SEQ ID NO: 127) (e.g., paragraphs 0012; [0153-0158]). Each of the codon optimized sequences of Doering includes a nucleotide sequence of at least two consecutive nucleotides selected from SEQ ID NO: 2 or SEQ ID NO: 4 of claim 1.
Regarding claims 2, 5, Doering teaches recombinant viral vectors comprising a liver specific promotor in operable combination with a heterologous nucleic acid sequence encoding a protein, such as a clotting factor (e.g., abstract).
Regarding claims 6-7, Doering teaches the vector can be a recombinant AAV vector comprising a genome comprising a nucleic acid molecule encoding any of the liver-specific promoters (e.g., 0013). Doering teaches AAV ITRs, and other selected AAV components described herein, may be readily selected from among any AAV serotype, including AAV5 (e.g., paragraph 0182). Doering teaches the nucleic acids are in vectors contained within a capsid comprising cap proteins, including AAV capsid proteins vp1, vp2, vp3 and hypervariable regions (e.g., paragraph 0164).
Regarding claim 14, Doering teaches the compositions of the disclosure may contain other pharmaceutically acceptable excipients, such
as preservatives, or chemical stabilizers (e.g., paragraph 0233).
Regarding claims 18-20, Doering teaches methods gene transfer for the treatment of hemophilia B using an adeno-associated viral (AAV5) vector encoding human FIX as the gene delivery vehicle. Doering teaches the method comprises administering to the subject a therapeutically effective amount of a vector (such as an AAV vector) encoding a clotting factor as described herein (e.g., paragraph 0015).
Claims 1-2, 5-10, 14, 18-20 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Strelkova et al. (“Strelkova”, US 2022/0306696 A1).
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Regarding claims 1-2, 5-6, Strelkova teaches the vector based on rAAV5 comprises a heterologous nucleic acid sequence encoding a product that is Factor IX or a functional variant thereof (e.g., paragraph 0050; Fig. 5). Strelkova teaches that a heterologous coding sequence is a construct where the coding sequence itself is not found in nature (e.g. synthetic sequences having codons different from the native gene) (e.g., paragraph 0115). (It reads that the Strelkova et al. were in possession of codon-optimized hFIX coding sequence).
PNG
media_image3.png
200
400
media_image3.png
Greyscale
Regarding claims 7-9, Strelkova teaches an isolated altered VP1 protein of adeno-associated virus serotype 5 (AAV5) capsid comprising one or more amino acid substitutions as compared to the VP1 protein of wild-type AAV5 capsid, which increase transduction efficiency, as well as to a capsid and a vector based thereon (e.g., abstract). Strelkova teaches SEQ ID NO 1 with 100% identity with SEQ ID NO 11 of the instant claims (e.g., page 20, see alignment below).
PNG
media_image4.png
974
648
media_image4.png
Greyscale
Regarding claim 10, Strelkova teaches SEQ ID NO 3 (which includes S2A and T711S substitutions) with 100% identity with SEQ ID NO 14 of the instant claim (e.g., pages 23-24; see alignment below).
PNG
media_image5.png
975
656
media_image5.png
Greyscale
Regarding claims 14, 18-20, Strelkova teaches method for the delivery of a gene product to a subject in need thereof, which comprises administering to the subject the above vector based on rAAV5 or the above pharmaceutical composition (e.g., paragraph 0057). Strelkova teaches deliver any foreign nucleic acid with a biological effect to treat or ameliorate the symptoms associated with any disorder related to gene expression, a disease like Hemophilia B (e.g., paragraph 0267). Strelkova teaches that
the rAAV5-based recombinant viral vectors are preferably administered to a cell in a biologically-effective amount. A "biologically-effective" amount of the viral vector is an amount that is sufficient to cause infection ( or
transduction) and expression of the heterologous nucleic acid sequence in the cell (e.g., paragraph 0128). Strelkova teaches that a pharmaceutical composition comprising the rAAV5 viral particle of the invention in a pharmaceutically acceptable carrier or other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents (e.g., paragraph 0233).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 3-4, are rejected under 35 U.S.C. 103 as being unpatentable over Doering et al. (“Doering”, US 2017/0326256 A1) as applied to claims 1-2, 5-7, 14, 18-20 above, and further in view of Chuah et al. (“Chuah”, WO 2016/146757 A1, cited as reference 4 on IDS filed 07/30/2025) and Harding et al. (“Harding”, Gene Therapy, 2004).
The teachings of Doering et al are described above and applied as before. Further, Doering teaches exemplary AAV cassettes from 5’ to 3’: including ITR at the 5’ and 3’ ends, promoter, MVM intron, liver optimized coding sequence, human beta globin polyadenylation sequence or growth hormone (hGH) polyadenylation sequence (e.g., paragraphs 0400-0402; 0208; Table below).
PNG
media_image6.png
200
400
media_image6.png
Greyscale
Under broadest reasonable interpretation, the scope of the claim is interpreted not to be limited to the sequence of SEQ ID NOs: 3 or 5. The claim requires “a sequence of that is selected from SEQ ID NO: 3 or SEQ ID NO: 5,” which reads on selection of “a sequence” from either of the recited sequences, where “a sequence” reasonably reads on two or more consecutive nucleotides.
Doering teaches SEQ ID NO: 8 with 78% identity with SEQ ID NO: 3 of the instant claims.
Doering does not teach the transthyretin promoter and the intron of the hBGH1 gene, as required by the instant claims. However, this is cured by Chuah and Harding.
Chuah teaches to increase the efficiency and safety of liver-directed gene therapy for hemophilia B. By providing a nucleic acid expression cassette and a vector, either a viral vector, comprising specific regulatory elements that enhance liver-directed gene expression (e.g., line 11, page 6). Chuah teaches nucleic acid expression cassettes and vectors containing liver- specific regulatory elements and codon-optimized factor IX or factor VIII transgenes, methods employing these expression cassettes and vectors and uses thereof (e.g., abstract). Chuah teaches to further reduce the vector dose; more potent FIX expression cassettes have been developed. This could be accomplished by using stronger promoter/enhancer elements, codon-optimized FIX or self-complementary, double-stranded AAV vectors (scAAV) that overcome one of the limiting steps in AAV transduction (e.g., line 12, page 3). Chuah teaches the codon optimized padua mutant FIX transgene driven from a minimal liver-specific transthyretin promoter (e.g., line 36, page 6; line 28, page 7).
Harding teaches an optimized the rAAV-LSP-/βgb-hFIX vector with the human B-globin intron inserted between the LSP promoter and the human FIX cDNA (e.g., paragraph first, right column, page 2; Fig. 1). Harding teaches that the addition of the β-globin IVS-II sequence to this vector increased expression approximately 85-fold (430 ng/ml) of FIX in vivo (e.g., paragraph 1st, left column, page 206; Fig. 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the HCB promoter and the MVM intron taught by Doering with the liver-specific transthyretin promoter taught by Chuah and with the intron of the human β-globin gene that increase the expression of FIX gene in vivo taught by Harding; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing an AAV5 vector comprising from 5’ to 3’: ITR at the 5’ and 3’ ends, the liver-specific transthyretin promoter, intron of the human β-globin gene, codon-optimized human FIX coding sequence, the human growth hormone (hGH) polyadenylation signal.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop an AAV5 vector comprising the transthyretin promoter and human β-globin intron to increase expression of a codon-optimized FIX gene in the liver.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Doering et al. (“Doering”, US 2017/0326256 A1), as applied to claims 1-2, 5-7, 14, 18-20 above, and further in view of Chiorini et al. (“Chiorini”, US 6,855,314 B1).
Doering does not teach SEQ ID NO 11, as required by the instant claims. However, this is cured by Chiorini.
Chiorini teaches an isolated AAV5 capsid protein to contain the vector. In particular, the present invention provides not only a polypeptide comprising all three AAV5 coat proteins, i.e., VP1, VP2 and VP3, but also a polypeptide comprising each AAV5 coat protein individually (e.g., line 53, column 11). Chiorini teaches SEQ ID NO 4 that has 100% identity with SEQ ID NO 11 of the instant claims.
PNG
media_image7.png
752
831
media_image7.png
Greyscale
PNG
media_image8.png
753
826
media_image8.png
Greyscale
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the VP1 protein of AAV5 taught by Doering with the VP1 protein (SEQ ID NO 4 that corresponds to SEQ ID NO 11) taught by Chiorini; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing an AAV5 vector with the capsid VP1 (SEQ ID NO 11), for delivering the codon-optimized human FIX coding sequence.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop an AAV5 vector with a capsid VP1 for delivery of a codon-optimized FIX gene.
Claims 9, 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Doering et al. (“Doering”, US 2017/0326256 A1), Chuah et al. (“Chuah”, WO 2016/146757 A1, cited as reference 4 on IDS filed 07/30/2025), Harding et al. (“Harding”, Gene Therapy, 2004) and Chiorini et al. (“Chiorini”, US 6,855,314 B1) as applied to claims 1-8, 14, 18-20 above, and further in view of and Chiorini et al. (US 10,081,659 B2, from now “659”).
Doering, Chuah, Harding, and Chiorini does not teach SEQ ID NO 11 with one or more point mutations. However, this is cured by “659”.
“659” teaches comprising at least one non-native amino acid that confers to the modified AAV particles new properties, such as increased transduction efficiency and reduced immunogenicity (e.g., abstract). “659” teaches SEQ ID NO 35 that has 99.9% identity to SEQ ID 11, comprising one point mutation at amino acid position 350 (E to Q) [see below].
PNG
media_image9.png
751
821
media_image9.png
Greyscale
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the VP1 protein of AAV5 taught by Chiorini (SEQ ID NO 11) with the VP1 protein with one mutation (SEQ ID NO 35) to increase transduction efficiency and reduce immunogenicity of AAV5 taught by “659”; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing an AAV5 vector with the capsid VP1 (SEQ ID NO 11) with one mutation (SEQ VID NO 35), comprising from 5’ to 3’: ITR at the 5’ and 3’ ends, liver-specific transthyretin promoter, intron of the human β-globin gene, codon-optimized human FIX coding sequence, the human growth hormone (hGH) polyadenylation signal.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop an AAV5 vector with a capsid VP1 with one mutation to increase transduction efficiency and reduced immunogenicity of AAV5 for delivery of a codon-optimized FIX gene.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Doering et al. (“Doering”, US 2017/0326256 A1), Chuah et al. (“Chuah”, WO 2016/146757 A1, cited as reference 4 on IDS filed 07/30/2025), Harding et al. (“Harding”, Gene Therapy, 2004), Chiorini et al. (“Chiorini”, US 6,855,314 B1) and Chiorini et al. (US 10,081,659 B2, “659”) as applied to claims 1-9, 11-12, 14, 18-20 above, and further in view of Strelkova et al. (“Strelkova”, US 2022/0306696 A1).
Doering, Chuah, Harding, Chiorini and “659” do not teach SEQ ID NO 14. However, this is cured by Strelkova.
Strelkova teaches an isolated altered VP1 protein of adeno-associated virus serotype 5 (AAV5) capsid comprising one or more amino acid substitutions as compared to the VP1 protein of wild-type AAV5 capsid, which increase transduction efficiency, as well as to a capsid and a vector based thereon (e.g., abstract). Strelkova teaches SEQ ID NO 3 (which includes S2A and T711S substitutions) with 100% identity with SEQ ID NO 14 of the instant claim (e.g., pages 23-24).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the VP1 protein of AAV5 taught by Chiorini (SEQ ID NO 11) with the VP1 protein with two mutations (SEQ ID NO 3) to increase transduction efficiency of AAV5 taught by Strelkova; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing an AAV5 vector with the capsid VP1 (SEQ ID 3), comprising from 5’ to 3’: ITR at the 5’ and 3’ ends, liver-specific transthyretin promoter, intron of the human β-globin gene, codon-optimized human FIX coding sequence, the human growth hormone (hGH) polyadenylation signal.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop an AAV5 vector with a capsid VP1 with two mutations to increase transduction efficiency of AAV5 for delivery of a codon-optimized FIX gene.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 5712722916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637