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 1-7,14-17 and 49), and the OTC (ornithine transcarbamylase) transgene as Species A in the reply filed on 07/01/2026 is acknowledged.
Claims 20,27-30,32-34,50,51 and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/01/2026.
Claims 1-7,14-17 and 49 are under examination.
Priority
This application is a 371 of PCT/US22/26483, filed 04/27/2022 which claims benefit of 63/331,385, filed 04/15/2022 and claims benefit of 63/301,933, filed 01/21/2022 and claims benefit of 63/244,205, filed 09/14/2021 and claims benefit of 63/242,474, filed 09/09/2021 and claims benefit of 63/180,603, filed 04/27/2021 as reflected by the most recent filing receipt.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 paragraph, 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 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. See Fig. 12 that includes nucleotide sequences that are not identified by a SEQ ID NO. The Brief Description of the drawings for Fig. 12 on page 9 also does not identify the sequence by a SEQ ID NO.
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See at least pages 13,14,15,27,61 and 66 reciting “www.” or “http://”.
Claim Objections
Claim 1,17 and 49 are objected to because of the following informalities: Claims 1,17 and 49 each recite “PCSK9”. At least the first recitation of a gene name should be fully recited for clarity rather than the acronym of the gene. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: claim 14 recites the transgene is OTC, PKU, CTLN1, or LDLR. At least the first recitation of a gene name should be fully recited for clarity rather than the acronym of the gene. Appropriate correction is required.
Claim 49 is objected to because of the following informalities: lines 6-7 recite “that direct the nuclease to specifically targets the native PCSK9 gene locus” and should recite “that direct the nuclease to specifically target the native PCSK9 gene locus”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 contains the trademark/trade name “ARCUS”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a meganuclease specific for PCSK9 and, accordingly, the identification/description is indefinite. Other than being a meganuclease specific for PCSK9, it does not chemically identify the meganuclease to determine what the scope is.
Claim 49 recites the limitation "the target cell" in line 8. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation in claim 49 of a target cell.
Written Description Rejection
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 1-7,14-17 and 49 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-2,6-7,5-17 and 49 encompass a system for treating a genus of genetic disorders comprising a gene editing vector comprising a nucleic acid sequence encoding a genus of nucleases that targets any portion of a genus of PCSK9 genes (from any species, human, monkey, mouse, etc) and a donor vector comprising a transgene cassette comprising a nucleic acid sequence encoding a genus of transgenes that are not PCSK9, (from any species, human, monkey, mouse, etc) and regulatory sequences that direct expression of the transgene in any target cell. Claim 3 limits the nuclease to targeting PCSK9 exon 7. Claims 4-5 further limit the nuclease to being a meganuclease specific for PCSK9. Claim 14 further limits the transgene to OTC, PKU, CTLN1 or LDLR but still encompasses the recited transgenes being from any species (human, monkey, mouse, etc).
Regarding the state of the art of genetic diseases, Roth et al. (Annu Rev Pathol. 2021 Jan 24; 16: 145-166) taught genetic diseases cause numerous complex and intractable pathologies and DNA sequences encoding each human’s complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome (Abstract). The genetic material in an adult human can be divided into compartments that differ in size, heritability, and diversity. The mitochondrial genome, the smallest (only 16.5 kb) but by far the most abundant, is inherited maternally and varies little among the human population. The traditional human genome contained in the nucleus is significantly larger and harbors mutations that cause the majority of traditional genetic diseases. The nuclear and mitochondrial genomes are determined at conception, although somatic mutations can drive mosaic disorders, cancer, and even aging (page 2). Disruptions in any of these compartments, interacting in many cases with environmental factors, can contribute to different classes of genetic disease (page 3). Roth et al. taught genetic diseases that manifest after birth often affect the nervous, immune, and metabolic systems, which are largely not under selective pressure in the supportive in utero environment. Out of 20,000 protein coding genes, mutations in more than 4,000 have been identified as causative of specific human genetic diseases and approximately 3,000 protein coding genes are essential in human cell lines, and loss-of-function mutations in these genes are likely incompatible with gametogenesis or early embryonic development. Estimates of human population size and genetic diversity predict that all possible single-base-pair changes in the protein coding nuclear genome compatible with life are already present in the global human population (page 8). Roth et al. taught increasingly mutations in noncoding regulatory and functional RNA elements have also been identified as causative for genetic disorders (page 8). Roth et al. taught somatic mutations during early development can cause many of the same genetic disorders as germline mutations, with severity depending on the degree of mosaicism and the end organs affected. For example, in ornithine transcarbamylase deficiency caused by X-linked recessive mutations in the OTC gene, patients with germline mutations rarely survive childhood without a liver transplant, but patients with somatic mutations, even those affecting substantial numbers of the affected cell type, hepatocytes, can live relatively normal lives with dietary modifications (page 10). One of the great continuing challenges to the widespread application of gene therapies lies in generalized platforms for the delivery of customizable gene editing reagents into the cell type and genomic compartment of interest in a patient’s specific genetic disease (page 17).
Therefore, Roth et al. shows the large genus of genetic diseases and genes associated with genetic diseases and challenges associated with gene therapy.
The instant specification discloses a genome editing approach for treating ornithine transcarbamylase deficiency (OTCD) by treating surviving newborns with two AAV vectors: one to deliver a nuclease to create a double-stranded break the PCSK9 gene as a safe-harbor site and the second to deliver an OTC minigene for knock-in into this site (page 72). Example 2, page 73 discloses PSK9 SaCas9 or ARCUS-mediated gene editing and hFIX or OTC mini-gene knock in and refers to FIG. 1 showing the rhPCSK9 locus and donor splice site within exon 7, and a HDR donor vector comprising a donor template of interest, e.g., hFIX, hOTC, and also refers to FIGs. 3A-3C for the dual vector system which show hOTC as the donor template.
Example 2 pages 74-77 disclose using the dual vectors in newborn NHP to examine hFIX mini-gene knock-in in PCSK9 locus mediated by either SaCas9 or ARCUS2.
Example 3, pages 78-80 discloses using M2PCSK9 meganuclease in newborn NHPs and donor vectors containing hOTC gene and results discussed on page 79-80.
Example 4 states that “since the M2PCSK9 targeting sequence in human and macaque PCSK9 is not conserved with the murine PCSK9 gene, we cannot use M2PCSK9 for genome editing in the genomic locus in mouse” (page 80). Therefore, this shows that not all nucleases, including meganucleases can be used for gene editing in all types of species.
Example 5 discusses whether M2PCSK9 meganuclease mediated knock-in of the human OTC gene in newborn PCSK9-hE7-KI.spfASH mice can achieve therapeutic human OTC expression in the target tissue for treatment of OTC deficiency following single co-administration of an M2PCSK9 nuclease expressing vector and human OTC donor vector (page 81). Results showed all mice having reduced mPCSK9 levels, and hOTC levels increased in mice (page 82, Fig. 14F-H).
Example 6 discusses whether M2PCSK9 meganuclease mediated knock-in of the human OTC gene in newborn rhesus macaques can achieve therapeutic human OTC expression in the target tissue for treatment of OTC deficiency following single co-administration of an M2PCSK9 nuclease expressing vector and human OTC donor vector (page 82).
Example 10 pertains to human LDLR gene knock-in in the PCSK9 locus by SaCas9 in mice that are administered a SaCas9 nuclease expressing vector and human LDLR donor vector (page 87). Preliminary results showed mice dosed with saCas9 and donor vectors had significantly reduced serum LDL levels (page 88).
The specification discloses specific vector systems which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claim(s) 1-7,14-17 and 49 are directed to encompass vector systems which only correspond in some undefined way to specifically instantly disclosed vector systems, and the genus of vector systems do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed vector systems comprising a gene editing vector comprising a nucleic acid sequence encoding SaCas9 or ARCUS-mediated gene editing at the donor splice site within exon 7 of the rhPCSK9 locus and the donor vector comprising the transgene hOTC resulting in treatment of OTC deficiency and the vector system comprising a gene editing vector comprising a nucleic acid sequence encoding SaCas9 targeting human PCSK9 exon 7 and human LDLR donor vector that results in treating familial hypercholesterolemia, the skilled artisan cannot envision the detailed chemical structure of the encompassed vector systems comprising a gene editing vector comprising a nucleic acid sequence encoding a genus of nucleases that targets any portion of a genus of PCSK9 genes (from any species, human, monkey, mouse, etc) and a donor vector comprising a transgene cassette comprising a nucleic acid sequence encoding a genus of transgenes that are not PCSK9, (from any species, human, monkey, mouse, etc) and regulatory sequences that direct expression of the transgene in any target cell and that result in treating a genus of genetic disorders. Disclosure of a vector system comprising two species of nucleases in the gene editing vector, and two species of transgenes in the donor vector which result in treating two types of genetic disorders does not provide sufficient written description for the genus encompassed by the claims. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003). The instant specification does not provide a structure-function correlation or core structure of the system that results in the function of treating any genetic disorder.
Therefore, only the above chemically structurally defined vector systems, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
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.
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 1-3,6,7,14-17 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (US 20180110877, Published 26 April 2018), cited on an IDS in view of Conway et al. (US 20180064827, Published 8 March 2018)
Regarding claims 1,2,14,17(c) and (d), and 49, Wilson et al. recites a dual vector system for treating genetic disorders comprising a gene editing AAV vector comprising a Cas9 gene under control of regulatory sequences which direct its expression in a target cell comprising a targeted gene which has one or more mutations resulting in a disorder and a targeting AAV vector comprising one or more sgRNAs and a donor template wherein the sgRNAs comprise at least 20 nucleotides which specifically bind to a selected site in the targeted genes and which is 5′ to a protospacer-adjacent motif (PAM) which is specifically recognized by the Cas9, and wherein the donor template comprises nucleic acid sequences which replaces at least one of the mutations in the targeted gene (claim 1).
Wilson et al. teaches and recites treating a liver metabolic disorder in neonates, the liver metabolic disorder being ornithine transcarbamylase deficiency and the donor template contains sgRNA targeted to a mutation in the OTC gene (paragraph 0009 and claims 24-25). Wilson et al. teach a dual AAV vector system for liver-directed and SaCas9-mediated gene correction. The AAV8.sgRNA1. donor vector contains a 1.8 kb murine OTC donor template sequence (nucleic acid sequence encoding the transgene) as shown in FIG. 1A with the corresponding PAM sequence mutated (paragraph 0013 and Fig. 1B).
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Wilson et al. teach an OTC donor template comprising OTC sgRNA1, SaCas9, and an AgeI restriction site tagged OTC donor plasmid, and in Fig. 4B arrows denote AgeI-sensitive cleavage products resulting from HDR. Wilson et al. teach the AAV donor plasmid in which hFIXco-Padua is flanked by HDR arms (paragraph 0143). Wilson et al. teach a dual vector system in which sgRNAs are cloned into pAAV donor plasmids with the corresponding PAM sequence mutated and AAV8 vectors expressing AsCpf1 and LbCpf1 driven by APB2.TBG-S1 as enhancer/promoter for liver application (OTC and mFIX-KO as first models) (regulatory sequences that direct expression of the transgene in the target cell) have been generated (paragraph 0144). Wilson et al. taught to generate a dual AAV vector system for in vivo OTC gene correction by SaCas9, we constructed two AAV cis-plasmids: 1) the hSaCas9 was subcloned from pX330.hSaCas9 into an AAV backbone plasmid containing the full length TBG promoter (two copies of enhancer elements of the a microglobulin/bikunin gene followed by a liver-specific TBG promoter) and the bovine growth hormone polyadenylation sequence; 2) the 1.8-kb OTC donor template was cloned into the pAAV backbone and the U6-OTC sgRNA sequence was inserted into the AflII site (FIG. 1C), yielding AAV8.sgRNA1 donor. The PAM sequence on the donor template AAV.sgRNA1donor was mutated (Table 1) to prevent re-cleavage by Cas9 after HDR, and an AgeI site was added to facilitate detection of HDR (paragraph 0083).
Wilson et al. teach the compositions described herein are used to reduce expression of a gene having undesirably high expression levels, and such as gene may be a PCSK9 which binds to the receptor for low-density lipoprotein cholesterol, and that reducing PCSK9 expression can be used to increase circulating LDL cholesterol levels (paragraph 0046). Example 7 discloses gene inactivation using AAV SaCas9 and PCSK9 sgRNA that target exons 3,4,7 and 8 of PCSK9 (paragraph 0145-0146).
Wilson does not explicitly teach the specific combination of a gene editing vector comprising a nucleic acid sequence encoding a nuclease that targets the PCSK9 and a donor vector as recited in instant claim 1 wherein the transgene is OTC.
Before the effective filing date, Conway et al. taught methods and compositions for deleting (inactivating) or repressing the PCSK9 gene to produce a PCSK9 null cell, stem cell, tissue or whole organism (paragraph 0008). Conway et al. taught cells in which the expression of a PCSK9, TTR, SERPINA1, KLKB1 and/or HAO1 gene is modulated (e.g., via nuclease-mediated inactivation and/or using one or more engineered TFs) and wherein the cells are further engineered to comprise a least one exogenous transgene or an additional knock out of at least one endogenous gene or combinations thereof. The exogenous transgene may be integrated into a PCSK9, TTR, SERPINA1, KLKB1 or HAO1 gene and/or may be integrated into a safe harbor locus (paragraph 0009). Conway taught compositions, methods and systems for targeted integration of a liver-specific expression cassette. The methods and systems comprise administering one or more expression cassettes as described herein and administering one or more nucleases specific for a target gene (e.g., PCSK9, TTR, SERPINA1, KLKB1 and/or HAO1 and/or safe harbor gene) to a cell (paragraph 0026)
Conway et al. also taught the constructs described herein can be used for hepatic delivery of any transgene (paragraph 0212), the transgene comprises a polynucleotide encoding any polypeptide of which expression in the cell is desired (paragraph 0125), and the transgene can encode functional versions of proteins lacking of deficient in any genetic disease, including metabolic disorders (paragraph 0126), and the proteins that may be expressed include OTC (ornithine transcarbamylase) (paragraph 0128).
Regarding claim 3, Wilson et al. taught gene inactivation using AAV SaCas9 and PCSK9 sgRNA that target exon 7 of PCSK9 (paragraphs 0145-0146).
Regarding claim 6, Wilson et al. taught a gene editing vector, AAV8.SaCas9, comprising a sequence encoding a Cas9 (SaCas9) flanked by nuclear localization signals (Fig. 1B, see above).
Regarding claim 7, Wilson et al. taught (b) a targeting AAV vector comprising one or more of sgRNAs and a donor template, wherein the sgRNAs comprise at least 20 nucleotides which specifically bind to a selected site in the targeted genes and which is 5′ to a protospacer-adjacent motif (PAM) which is specifically recognized by the Cas9, and wherein the donor template comprises nucleic acid sequences which replaces at least one of the mutations in the targeted gene (Claim 1).
Regarding claim 15, Wilson et al. teach both the donor vector and gene editing vector is an AAV vector, and the AAV vector comprising AAV 5’ ITRs and AAV 3’ ITRs as seen in Fig. 1B above.
Regarding claim 16, Wilson et al. teach wherein the ratio of the gene editing vector of (a) to (b) is such that (b) is in excess of (a) (claim 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the dual vector system of Wilson et al. to comprise the specific combination of a gene editing vector comprising a nucleic acid sequence encoding a nuclease that targets the PCSK9 gene and a donor vector comprising an OTC transgene and regulatory sequences that direct expression of the transgene in a target cell, the donor vector further comprising HDR arms 5’ and 3’ to the transgene cassette based on the teachings of Conway et al. with a reasonable expectation of success. There would be a reasonable expectation of success because Conway pertains to modulation of gene expression in the liver including modulation of PCSK9 and genetic diseases including metabolic disorders, and Wilson et al. pertains to a dual vector system and liver metabolic disorders. One of ordinary skill in the art would have been motivated to do so because Conway et al. taught cells in which the expression of a PCSK9, TTR, SERPINA1, KLKB1 and/or HAO1 gene is modulated (e.g., via nuclease-mediated inactivation and/or using one or more engineered TFs) and wherein the cells are further engineered to comprise a least one exogenous transgene or an additional knock out of at least one endogenous gene or combinations thereof and that the exogenous transgene may be integrated into a PCSK9 gene and/or may be integrated into a safe harbor locus (paragraph 0009) and taught systems for targeted integration of a liver-specific expression cassette and the systems comprise one or more expression cassettes as described herein or more nucleases specific for a target gene (e.g., PCSK9, TTR, SERPINA1, KLKB1 and/or HAO1 and/or safe harbor gene) to a cell (paragraph 0026) and the constructs can be used for hepatic delivery of any transgene (paragraph 0212), including transgenes that encode functional versions of proteins lacking of deficient in any genetic disease, including metabolic disorders (paragraph 0126), and the proteins that may be expressed include OTC (ornithine transcarbamylase) (paragraph 0128).
Accordingly, the limitations of claims 1-3,6,7,14-17 and 49 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. in view of Conway et al. as applied to claims 1-3,6,7,14-17 and 49 above, and further in view of Wang et al. Nat Biotechnol 36, 717–725 (2018).
Claim Interpretation: As claim 5 recites the meganuclease is the ARCUS meganuclease which has been rejected as indefinite under 35 U.S.C. 112(b) as reciting a trademark, and the specification does not provide a definition as to the identity of what an ARCUS meganuclease is, art applied to claim 4 will also apply to claim 5.
The teachings of Wilson et al. and Conway et al. as applicable to claims 1-3,6,7,14-17 and 49 have been described above.
Wilson et al. and Conway et al. do not teach wherein the nuclease is a meganuclease specific for PCSK9.
Before the effective filing date, Wang et al. taught gene editing by inactivating PCSK9 in liver through non-homologous end joining following a meganuclease-mediated double-stranded break, using a homing endonuclease from a class of natural, site-specific DNA-cleaving enzymes that recognize unusually long DNA sequences (14–40 bp). Meganucleases are engineered variants of homing endonucleases that can be redirected to different DNA sequences for genome editing applications. Wang et al. taught that pairing an engineered meganuclease with AAV8 is an effective strategy for genome editing in primate liver (Introduction, page 717, left column). Wang et al. taught they developed a first-generation meganuclease, called M1PCSK9, that recognizes a DNA sequence in exon 7 of the human and macaque PCSK9 gene, and developed the M1PCSK9 meganuclease by modifying the I-CreI monomers to specifically recognize each of the two half sites in the PCSK9 target sequence using an in silico protein design and directed evolution, and selected this target site because it is unique in the human genome, conserved between humans and non-human primates, and expected to be amenable to meganuclease design (page 717, right column). Wang et al. taught achieving efficient inactivation of PCSK9 following incubation of iPSC-derived hepatocytes with AAV6.2-M2PCSK9, as shown by a reduction of PCSK9 secreted into the culture media (page 722). Wang et al. taught “We have shown that the combination of an efficient delivery vector in AAV8 and a potent meganuclease results in levels of gene inactivation in non-human primate liver that should be efficacious in certain human diseases (page 723).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the Cas9 nuclease in the gene editing AAV vector in the dual vector system of Wilson et al. in view of Conway et al. with the meganuclease specific for PCSK9 of Wang et al. to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to simple substitution of one known element (Cas9 nuclease) for another (meganuclease) to obtain predictable results and because Wang et al. pertains to gene editing of PCSK9 and therefore is relevant art. One of ordinary skill in the art would have been motivated to do so because Wang et al. taught that pairing an engineered meganuclease with AAV8 is an effective strategy for genome editing in primate liver and that the combination of an efficient delivery vector in AAV8 and a potent meganuclease results in levels of gene inactivation in non-human primate liver that should be efficacious in certain human disease.
Accordingly, the limitations of claims 4 and 5 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-7,14-17 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/726,190 (‘190) (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-8 of ‘190 recite a dual vector system for treating an ornithine transcarbamylase deficiency, the system comprising:(a) a gene editing AAV comprising a first AAV rh79 capsid and a first vector genome comprising a 5' ITR, a sequence encoding a meganuclease having the sequence of SEQ ID NO: 3 that targets PCSK9 under control of regulatory sequences that direct expression of the meganuclease in a target cell comprising a PCSK9 gene, and a 3' ITR; and (b) a donor AAV vector comprising a second AAV rh79 capsid and a second vector genome comprising: a 5'ITR, a 5' homology directed recombination (HDR) arm, a transgene comprising the sequence of SEQ ID NO: 4, or a sequence at least 90% identical to SEQ ID NO: 4 encoding ornithine transcarbamylase (OTC) and regulatory sequences that direct expression of the transgene in the target cell, a 3' HDR arm, and a 3' ITR. Claims 9-16 of ‘190 recite a method of treating an OTC deficiency in humans by co-administering the dual vector system of claim 1.
Instant claims 1-7,14-17 and 49 recite a system for treating a genetic disorder, the system comprising:(a) a gene editing vector comprising a nucleic acid sequence encoding a nuclease that targets the PCSK9 gene; and (b) a donor vector comprising a transgene cassette comprising a nucleic acid sequence encoding a transgene and regulatory sequences that direct expression of the transgene in the target cell, the donor vector further comprising homology-directed recombination (HDR) arms 5' and 3' to the transgene cassette, wherein the transgene is not PCSK9, and instant claim 14 recites wherein the transgene is OTC, PKU, CTLN1, or LDLR.
Therefore, claims 1-16 of ‘190 recite species of the above instant claims, as ‘190 recites a specific meganuclease species of SEQ ID NO: 3 and the donor vector of ‘190 recites a specific species of transgene encoding OTC (comprising the sequence of SEQ ID NO: 4 or a sequence at least 90% identical to SEQ ID NO: 4). Therefore, the entire scope of the claims of ‘190 fall within the scope of the instant claims. The species or sub-genus of meganuclease and the transgene encoding OTC claimed in ‘190 anticipates the claimed genus in the instant claims and, therefore, a patent to the genus would improperly extend the right to exclude granted by a patent to the species or sub-genus should the genus issue as a patent after the species or sub-genus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7,14-17 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3,4,6,14,17-20,22,23,25,26,29-31,33,34 and 60 of copending Application No. 18/994,165 (‘165) in view of Wilson et al. and Conway et al. cited in the 103 rejection above.
Claims 1,3,4,6,14,17-20,22,23,25,26,29-30 and 60 of ‘165 recite a method of treating hemophilia B in an adolescent subject, the method comprising co-administering to the subject having hemophilia B:(a) a gene editing AAV vector comprising a sequence encoding a nuclease and regulatory sequences that direct expression of the nuclease in a target cell comprising a PCSK9 gene; and (b) a donor AAV vector comprising a factor IX (FIX) transgene and regulatory sequences that direct expression of the transgene in the target cell, wherein the donor vector further comprises homology-directed recombination (HDR) arms 5' and 3' to the transgene cassette. Claims 31,33 and 34 of ‘165 recite a dual component system useful for treating hemophilia B in a subject comprising (a) a gene editing AAV vector comprising a sequence encoding a nuclease and regulatory sequences that direct expression of the nuclease in a target cell comprising a PCSK9 gene; and (b) a donor AAV vector comprising a factor IX (FIX) transgene and regulatory sequences that direct expression of the transgene in the target cell, wherein the donor vector further comprises homology-directed recombination (HDR) arms 5’ and 3’ to the transgene cassette.
‘165 recites that the donor AAV vector transgene is factor IX (FIX) and does not recite that the transgene is OTC (ornithine transcarbamylase).
Wilson et al. and Conway et al. cures this deficiency. The teachings of Wilson et al. and Conway et al. have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the dual vector system in the claims of ‘165 by substituting the FIX transgene in the donor AAV vector of ‘165 with a donor OTC transgene for the purpose of treating ornithine transcarbamylase deficiency based on the teachings of Wilson et al. and Conway et al. with a reasonable expectation of success. There would be a reasonable expectation of success because Wilson et al. teach a dual vector system for treating genetic disorders, including OTC deficiency using a donor vector comprising an OTC transgene, and also discloses gene inactivation using AAV SaCas9 and PCSK9 sgRNA that target exons 3,4,7 and 8 of PCSK9, and Conway teaches modulation of PCSK9 and genetic diseases. One of ordinary skill in the art would have been motivated to do so because Wilson taught and recited treating a liver metabolic disorder in neonates, the liver metabolic disorder being ornithine transcarbamylase deficiency and the donor template contains sgRNA targeted to a mutation in the OTC gene and Conway et al. taught cells in which the expression of a PCSK9 gene is modulated (e.g., via nuclease-mediated inactivation and/or using one or more engineered TFs) and wherein the cells are further engineered to comprise a least one exogenous transgene or an additional knock out of at least one endogenous gene or combinations thereof and that the exogenous transgene may be integrated into a PCSK9 gene and/or may be integrated into a safe harbor locus (paragraph 0009) and taught systems for targeted integration of a liver-specific expression cassette and the systems comprise one or more expression cassettes as described herein or more nucleases specific for a target gene (e.g., PCSK9 and/or safe harbor gene) to a cell (paragraph 0026) and the constructs can be used for hepatic delivery of any transgene (paragraph 0212), including transgenes that encode functional versions of proteins lacking of deficient in any genetic disease, including metabolic disorders (paragraph 0126), and the proteins that may be expressed include OTC (ornithine transcarbamylase) (paragraph 0128).
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-7,14-17 and 49 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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