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 .
Preliminary Amendment
The preliminary amendment dated 05/31/2023 has been entered. Claims 1-12 and 14-19 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest possible effective filing date for the instant claims is December 01, 2020 based on the filing date of the provisional application 63/119,863
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
i) the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference of the material consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (FIG. 2A and 4) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 19 is objected to because of the following informalities:
Claim 19 is drafted as dependent on claim 16 but should be dependent on claim 18 based on the “…..wherein the production cells are….:. The production cells are recited in claim 18 and not in claim 16.
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 1-2, 5-7, 10-12 and 14-19 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming.
Claims 1-2, 5-7, 10-12 and 14-19 are drawn to a rAAV with a capsid comprising cell targeting peptides comprising a motif comprising an amino acid sequence of N-X- (T/I/V/A)-(K/R) (SEQ ID NO: 47) that is inserted into an AAV capsid, which encompasses a genus of agents. Claims 2, 5 and 7 in addition recite that the motif is optionally flanked at the amino terminus and/or the carboxy terminus of the motif by two amino acids to seven amino acids. Claims 2, 5-6 and 14-17 are dependent from claim 1, claims 10-12 are dependent from claim 7 and claim 19 is depended on claim 18. All these claims do not materially limit the genus of agents, especially regarding the sequences of the cell targeting peptide and are therefore included in the rejection. These claims do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. Therefore, the claims are drawn to a genus of “peptides comprising a motif comprising N- X- (T/I/V/A)-(K/R), (X being any amino acid)” for which there is inadequate written description.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
Regarding the genus of the claims the specification describes 7 specific species within the genus claimed (claims 3 and 8; Specification table 1 page 51). From the specification, it is clear that Applicant is in possession of the 7 species of claims 3 and 8. The claims, however are not limited to those species but also includes “peptides comprising a motif comprising N-X- (T/I/V/A)-(K/R), (X being any amino acid)”, and the specification fails to provide a representative number of species within the recited genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus.
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.
3. Claims 1, 2, 5 and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grimm (US 2020/0370039 A1 priority date April 11, 2017)
Grimm teaches Adeno-associated virus (AAV) variants (which reads on recombinant AAV), wherein the viral particles of each AAV variant comprise a specific combination of (i) a strain specific capsid polypeptide and (ii) a peptide inserted into said capsid polypeptide (abstract) as required in instant claims 1-2, 5 and 18. Grimm’s claim 4 recites that their AAV library comprise a motif NXXR in the peptides which reads on motif N-X-(T/I/A/V)-(K/R) of instant claim 1 (X being any amino acid). The peptides are listed in Grimm’s claim 5 and peptides NDVRSAN and NEARVRE are comprised under the motif N-X-(T/I/A/V)-(K/R) of instant claim 1 and are not NDVRAVS (instant claim 1). These two peptides can be inserted after amino acid 588 in the AAV9 capsid polypeptide ([015], [0070] and claim 7) (instant claim 5) Since the insertion site is the same for both Grimm and the instant application, the peptides taught by Grimm are inserted in VP3 as well (instant claims 1-2, 5). Grimm also discloses that the genomes of said AAV variants encode a reporter gene [0084] That is, the AAV variants comprises a vector genome encoding a gene product (AAV vector with an inserted reporter gene) packaged in the AAV capsid, wherein the vector genome comprises a nucleic acid sequence under control of sequences which direct expression thereof (a reporter gene needs to be expressed in order to “report”) as required by instant claim 1. In addition, the amino acid sequence of the peptide is a sequence known to assist or to mediate functional transduction of an AAV variant comprising said amino acid sequence to a target cell of interest, wherein the term "functional transduction" includes all aspects of AAV particle entry having an impact on reporter gene expression. That is, in vitro transduction of the recombinant AAV into cells is mediated/increased and FIG. 7 shows the quantification of results of the method of transduction of the cell lines with the AAV library (instant claims 1 and 18).
Therefore, the reference teachings anticipate the claimed invention.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary.
Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-8, 10-12 and 14-15 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Grimm in view of Varadi (Gene Therapy (2012) 19, 800-809 ), Díaz-Perlas (Peptide Science 2017;108 1-13) and Iwayama (THYROID Volume 26, Number 9, 2016, 1311-1319).
Grimm teachings have been discussed above and incorporated herein. In addition, Grimm teaches polynucleotides that encode a variant AAV capsid polypeptide and further polypeptides, e.g. reporter polypeptides, and/or fusion polypeptides ([0038] and [0039]), (instant claims 7, 11 and 12). Grimm teaches a method for identifying a variant AAV specifically infecting a target cell of interest [0031]. Preferably, a cell of a subject involved in disease, causing disease, or suitable for treating disease, the subject being a human suffering from disease (instant claims 14-15). These AAV vectors were produced by transient triple transfection of HEK293T cells [0158] (instant claim 19).
Grimm does not teach either the peptides listed in instant claim 3 and 8. Grimm does not teach that these peptides (or a fusion polypeptide comprising these peptides) can target endothelial cells (instant claim 7) in the brain (instant claims 11-12 and 14-15).
Varadi teaches peptide libraries displayed on AAV serotype 9 (capsids) for selection of endothelial cell-directed gene transfer vectors (title, entire article) (instant claims 7). Efficiency of endothelial gene transfer using AAV vectors is low but the insertion of peptides significantly increased transduction of endothelial cells with AAV vectors (Discussion, 1st paragraph), (instant claim 18). Transduction efficiencies with mutant AAV displaying the peptides were calculated in several primary and immortalized cells including HEK293T cells (Fig 3), (instant claims 18-19) Some of these peptides (NTVRGTG, NFTRLSA, NNVRGFV) comprise the motif N-X-(T/I/A/V)-(K/R) of instant claims 1-2, 7 and 18 (Fig. 2a).
Varadi does not teach the use of brain endothelial cells (instant claims 14-15) or the peptides of instant claims 3 and 8.
Díaz-Perlas teaches BBB (blood brain barrier) shuttle peptides such as IEINATRAGTNL (Table 2), (SEQ ID NO: 42 of instant claims 3 and 8). BBB shuttle peptides are molecules that have the capacity to carry a cargo across the BBB through either active or passive transport. That is, these peptides can reach endothelial brain cells (Abstract, Blood-brain barrier section, 2nd paragraph) as required by instant claims 14 and 15.
Díaz-Perlas does not teach a method for treating Allan-Herndon-Dudley disease by delivering to a subject rAAV, wherein the encoded gene product is an MCT8 protein (instant claim 15).
Iwayama teaches AAV9–Based Gene Therapy by delivering a functional MCT8 to the Brain of Mct8-Deficient Mice (title, entire article). MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain (Page 1311, Background). These mutations can cause a form of sex-linked mental retardation named the Allan–Herndon–Dudley syndrome (Page 1311, Introduction, 2nd column). These treated mice showed improved TH availability (instant claim 15). The hMCT8 cDNA expression constructs were cloned into the polylinkers of dsAAV CB MCS. The virus was produced in HEK293 cells (instant claim 19) by transient transfection followed by purification and dialyzed against phosphate-buffered saline (PBS) with 0.001% Pluronic-F68 (which reads on the aqueous suspension base of instant claims 6, 10 and 12) to prevent virus aggregation.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Grimm with Varadi to insert peptides such as NTVRGTG, NFTRLSA NNVRGFV, or fusion polypeptides, in AAV capsids to carry a cargo and test these rAAVs for increased transduction of endothelial cells. It would further be obvious to combine Grimm, Varadi with Díaz-Perlas and Iwayama and also insert IEINATRAGTNL in the rAAV capsids for targeting the endothelial cells including brain endothelial cells and thus use these rAAVs carrying a cargo (such as MCT8 gene) for gene targeting therapy, including treatment of Allan–Herndon–Dudley syndrome. One of ordinary skill would have been motivated to do so because all the taught peptides comprise both the motif NXXR of Grimm and the N-X-(T/I/A/V)-(K/R) of the instant application. It would further have been obvious to incorporate a physiological compatible carrier like a PBS buffer to the composition and use HEK293 cells (as taught by Iwayama) for AAV production. One of ordinary skill would have been motivated to do so because these references have used either HEK293 cells or the related HEK293T cells.
There would be a reasonable expectation of success because there are several examples of peptides that will facilitate the targeting into specific cells and the integration of those peptides in AAV capsids using common molecular and cell biology techniques is well described in the art. In addition, improved transduction properties seem to be shared by all peptides comprising the motif NXXR of Grimm and the N-X-(T/I/A/V)-(K/R) of the instant application.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 4, 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Grimm and Varadi in view of Reid (US 2022/0154217 A1 priority date April 1, 2019).
Grimm’s and Varadi’s teachings have been discussed above and incorporated herein.
Grimm and Varadi do not teach the motif being NTVK (instant claims 4 and 9).
Reid teaches AAVs with engineered capsids (title, entire document), wherein an insertion in the capsid comprises the amino acid sequence PLTNTVK (SEQ ID NO: 83) or a sequence comprising at most 1, 2, 3, or 4 amino-acid substitutions relative to PLTNTVK ([0053] and Reid’s claim 52) as required by instant claims 4 and 9. The rAAV virion exhibits increased transduction efficiency in human cardiac fibroblast (hCF) cells compared to an AAV virion comprising the parental sequence [0066] as required by instant claim 18. Packaging cell lines include but are not limited to any easily-transfectable cell line such as 293T cells [0211], (which is related to 293 cells) (instant claim 19). Other non-limiting examples of cardiac cells include endothelial cells [0178], (instant claim 7)
It would have been obvious to one of ordinary skill in the art to combine the teachings of Grimm and Varadi with Reid to insert peptides (PLTNTVK) comprising the NTVK motif in AAV capsids to carry a cargo and test these rAAVs for increased transduction of endothelial cells in cells related to 293 cells. One of ordinary skill would have been motivated to do so because PLTNTVK comprises the NTVK motif which also comprises the motif N-X-(T/I/A/V)-(K/R) of the instant application. There would be a reasonable expectation of success because there are several examples of peptides that will facilitate the targeting into specific cells and the integration of those peptides in AAV capsids using common molecular and cell biology techniques is well described in the art. In addition, improved transduction properties seem to be shared by all peptides comprising the motifs.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Grimm in view of Flotte (Human Gene Therapy 14:1079–1088 (July 20, 2003)).
Grimm teachings have been discussed above and incorporated herein, including a method for identifying a variant AAV specifically infecting a target cell of interest [0031]. Preferably, a cell of a subject involved in disease, causing disease, or suitable for treating disease, the subject being a human suffering from disease.
Grimm does not teach a method for targeting therapy to the lung or treating a disease of the lung (instant claims 16 and 17).
Flotte teaches a Phase I Trial of intranasal and endobronchial administration of a rAAV2-CFTR vector in adult cystic fibrosis patients (title, entire article). An rAAV expressing the full-length human cystic fibrosis transmembrane conductance regulator (CFTR) (instant claim 17) was evaluated for safety in 25 patients with cystic fibrosis with mild to moderate lung disease and there were no obvious adverse events attributable to vector administration (page 1079, Overview summary), (instant claims 16 and 17).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Grimm with Flotte to insert peptides comprising the motif NXXR of Grimm (which comprises the motif N-X-(T/I/A/V)-(K/R) of the instant application) in AAV capsids for gene therapy of the lung and using these rAAV compositions wherein the gen product is CFTR and treat lung diseases. One of ordinary skill would have been motivated to do so because both Grimm and Flotte use rAAV vectors There would be a reasonable expectation of success because the phase I study shows no obvious adverse events attributable to rAAV vector administration
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671