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
Claims 1-4, 13-19, 21, 23, 31, 45-49, 52 are pending.
Applicant’s election of Group 1A, claims 1-4. 13-19, 21, 23, and species of 1q31 as the locus and LAMB3 as the gene of interest in the reply filed on 04/23/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 31, 45-47, 48, 49, 52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 04/23/2026.
Claims 1-4. 13-19, 21, 23, and species of 1q31 as the locus and LAMB3 as the gene of interest are examined here.
Priority
The claims benefit of 63/155,504, filed on 03/02/2021, via its PCT/US2022/01 8246, filed on 03/01/2022, is recognized. All examined claims enjoy the benefit date of ‘504 filing.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/22/2024 was filed before the mailing date of this first Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because for Fig. 7 it is difficult to compare between different chromosome safe harbor sites since each site is designated as a shade of gray. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pg. 60, line 25, https://github. . . ; also on pg. 70, line 5). 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.
Appropriate correction is required.
Improper Markush
Claims 1, 2, 3, and 4 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of a sequence homologous to a sequence in a safe harbor site is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: structurally, each species is a region within different chromosomes and each sequence of the claimed region is unique (e.g., 1q31 is a region of chromosome 1; 3p24 is a region of chromosome 3), thus the sequence of flanking homologous arms complementary to targeted chromosome is not similar. Second, as illustrated in Fig. 2G and H, some targeting vectors with flanking homologous arms to chromosomes (e.g., GSH7 targeting vector [targets chromosome 7 region], GSH8 targeting vector [targets chromosome X region]) do not appear to incorporate within targeted chromosomes depending on cell type, thus each species may not be a safe harbor site due to difficulty in integration of a targeting vector, thus do not have a common use of a safe harbor site.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(a)
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 1-4, 13-19, 21 and 23 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.
Claim 1 recites a “safe harbor site” (SHS) in elected 1q31 site. The 1q31 site is some 13 MB region (in between region ~186-198M region, ~13,000,000 bases; the size is based on Genome Data Viewer on NCBI’s website [www.ncbi.nlm.nih.gov/gdv/browser/genome/?id=GCF_000001405.40, accessed 06/02/2026]). The specification has not delineated 1q31 in terms of nt. positions, although the specification provides location based on distinctive light and dark bands formation following Giemsa staining (pg. 11-12). Regardless, the claimed invention encompasses a vector with flanking homologous arms sequences to any human genome region within 1q31.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the only species whose complete structure is disclosed for the elected region of 1q31, are the flanking sequences within SEQ ID NO: 1 and SEQ ID NO: 3 (pg. 61-65) or SEQ ID NO: 25 (“HA left” or left homology arm) and SEQ ID NO: 45 (“HA right” or right homology arm), both of which are 1000 nt. and can be inserted as homologous arms (pg. 34, line 21-25; pg. 36, line 3-7; pg. 70-71). Both flanking regions of SEQ ID NO: 1/3 are the same sequences for GSH1 engineered nucleic acid and target chromosome 1 (pg. 61-65) and are a subsequence within SEQ ID NO: 25 or 45. While the genus 1q31 encompasses a large number of variants that have the same activity of a safe harbor site (SHS) within 1q31 and have a different sequence, i.e. structure. The specification does not describe the complete structure of a representative number of species of the large genus of SHS within 1q31 or functional equivalents thereof.
Further, it appears these “targeting vectors” based on experiments conducted do not appear to integrate in the chromosome successfully. E.g., Fig. 2G and 2H illustrate that the integration is dependent on various factors, include sequence of the homologous arm, cell-type and chromosome. In Jurkat cells only GSH1 (i.e. chromosome 1 targeting vector) and GSH2 (chromosome 3 targeting vector) are different from untransfected cells in terms of fluorescence levels, while for GSH7, GSH8, and GSH31 the fluorescence levels are not different from untransfected cells (see Fig. 2H). Fig. 2G, tested in HEK293T cells, illustrates increased number of targeting vectors that are more successful (GSH1, GSH2, GSH7, and GSH31, pg. 6, lines 28). Thus, it appears some targeting vectors did not integrate at level to distinguish it from background fluorescent levels; thus, not all flanking homologous arms may be able to function as a “targeting vector” in integrating into the SHS/GHS of a human chromosome. Thus, e.g., for GSH1 only a portion of 1000 nt. sequence length (i.e. length of SEQ ID NO: 25 and 45) was tested that was within the large ~13,000,000 base length of 1q31.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is the criteria used to identify the SHS sites (also called genomic safe harbor (GSH)) in the chromosome, see Fig. 1A-B (e.g., 50 kb away from known genes, 300 kb away from known oncogenes, etc. . . ). Such a functional limitation based on these criteria cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of SHS within 1q31 or functional equivalent thereof, all members of the claimed genus will have that characteristic, see Table 1, pg. 13-14, noting quite a few sites within chromosome 1). It is difficult to envision the structure, i.e. the sequences, based on the criteria noted.
The inventions of Claims (dependent claims 1-4, 13-19, 21, 23) require the use of the inventions of Claim 1 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure of one species of each homologous arm (i.e. SEQ ID NO: 25/45 of elected 1q31) of one site within 1q31 of the claimed broad genus of SHS of 1q31 is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Claim 4 rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling. The disclosure does not enable one of ordinary skill in the art to practice the invention without the nucleic acid sequence between the recited coordinates, which is/are critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
The attempt to incorporate subject matter into this application by reference to GRCH38/hg38 is ineffective because the recited coordinates refer to essential a Genome Reference Consortium Human Build 38 (“GRCh38”) (official name for the current major release of the human genome reference assembly; hg38 is an unofficial name). Here it is an essential material since the sequence pinpoints to the specific location of the chromosome of insertion. “Essential material” may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. Here, the claims are, in effect, incorporating the sequence contained in an electronic database. See MPEP 608.01(p). Accordingly, the reference to the online genomic sequence does not provide the features that are critical or essential to the practice of claimed invention.
One way to obviate the rejection is by reciting specific SEQ ID NOs.
35 U.S.C. 112(b)
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 1-4, 13-19, 21, and 23 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.
Claims 1-4 recite 1q31 or 1q31.3 and are indefinite since they only provide, as the specification points out, “address” on a chromosome, a standardized way for cytogenetic location (pg. 11, lines 19-22). Similar to an “address” it does not indicate the residents (i.e. nucleotide(s) or sequences) of the residence. Second, this address is imprecise at the nucleotide level, since it is uncertain where the flanking regions (i.e. 1q25 or 1q32) begin or end. Thus claims 1-4 are indefinite and the dependent claims (13-19, 21, 23) do not overcome the indefiniteness.
Claim 4 recites coordinates that refers to Genome Reference Consortium Human Build 38 (“GRCh38”) and is the “official name for the current major release of the human reference assembly”; GRCh38 is also referred to as “hg38” in the UCSC Genome Browser, but is not an official assembly name or abbreviation (see Frequently Asked Questions, www.ncbi.nlm.nih.gov/grc/help/faq/, accessed 06/01/2026, pg. 1). Thus the reference assembly can change over time and GRCh38 is the “current” human reference genome assembly. Here, the recitation of specific site based on a version of a genomic build is arbitrary without a point of reference. An “address” only provides a location, but not the residents (i.e. the sequence) of the residence. The claims do not refer to any particular genomic sequence for chromosome 1 and the sequences may have different numbering schemes due to polymorphic nature of chromosome 1 or the improvement in technology in “building” the sequence of chromosome 1. Thus the coordinates associated with current GRCh38/hg38 may change and therefore is indefinite.
Here, claim 17 incorporates by reference to a table or figure, specifically “Table 2”. Since incorporation by reference is a necessity doctrine, not for applicant’s convenience, the claims are indefinite per MPEP 2173.05(s).
MPEP 2173.05 is related to “Specific Topics Related to Issues Under 35 U.S.C.112(b) or Pre-AIA 35 U.S.C. 112, Second Paragraph”
MPEP 2173.05(s) “Reference to Figures or Tables” states:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). (Emphasis added).
The rejection may be overcome by eliminating the incorporation by reference to the table and replacing the reference to the table with a list of gene symbols of the table.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 13-19, 23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Claim 1 recite(s) an “engineered nucleic acid targeting vector comprising a sequence of interest flanked by homology arms, each homology arm comprising a sequence homologous to a sequence in a safe harbor site in a human genome” in elected 1q31 locus. This judicial exception is not integrated into a practical application because the claims do not recite any more elements in addition to the judicial exception, i.e. provide a modified form of the targeting vector that is markedly different from its naturally occurring counterpart. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Here, the claimed subject matter is a composition of matter, but is directed to the judicial exception as a law of nature or a natural phenomenon, i.e. a nature based product. The claimed characteristics are not markedly different from the product’s naturally occurring counterpart in the natural state, i.e. a dsDNA sequence within the 1q31 region of the chromosome.
The claims do not recite additional elements that integrate the judicial exception into a practical application since the homologous arms represent a sequence of the chromosome and “a sequence of interest” can be any sequence of interest within the 1q31 region.
Claims 2-4 do not recite any additional elements that integrate the judicial exception into a practical application since they pinpoint to a specific location within the chromosome.
Regarding instant cl. 13-16, the region of 1q31 has various open reading frames (ORFs), a continuous stretch of codons that begins with ATG start codon and ends with a stop codon and encodes a polypeptide; e.g., the gene ASPM is within the 1q31 region, and its gene is driven by a promoter.
Regarding instant cl. 17, the specification indicates that LAMC2 gene locus is 1q25-q31, pg. 40; thus one of the gene of interest is in the 1q31 region.
Regarding instant cl. 18, the human genome is a dsDNA.
Regarding instant cl. 19, the homology length can be any length within the chromosome.
Regarding instant cl. 23, a delivery system, defined as “any substance or combination of substances that can be used to bring (deliver) a targeting vector a cell” (pg. 48, line 10-11), is broadly interpreted as sterile water or, even, a buffer, which is not an additional element that is sufficient to satisfy the significantly more requirement.
Thus, claims 1-4, 13-19, 23 are rejected under 35 USC 101.
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.
Rejection Based on Magali
Claims 1-4, 13-16, 18, 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Magali (2014, www.ensembl.info/2014/03/11/grch38-assembly-mapping-updating-coordinates-in-the-new-human-genome/#comments), as evidenced by 1q31 or Human_1 186000000-198000000, as an appendix to Magali, (see attachment “Human_1186000000_198000000”).
Here claim 1 recites “engineered nucleic acid targeting vector comprising a sequence of interest flanked by homology arms, each homology arm comprising a sequence homologous to a sequence in a safe harbor site in a human genome” in the elected 1q31 locus. The claim, under BRI, is interpreted to read on the 1q31 locus of the chromosome.
Regarding instant cl. 1-4, Magali discloses that GRCh38 assembly for human was released in December 2013. The Genome Data Viewer provides the assembly of chromosome 1q31. The sequence of position 195338589-195818588 of chromosome 1, which is the range of instant cl. 4, has any sequence of interest, of say 1 Kb, or ENST00000658976.2, and a skilled artisan can define the flanking sequences of the sequence of interest as the homologous arms, which would comprise sequences homologous to 1q31.3 locus.
Regarding instant cl. 13, 15-16, 18, the sequence of 1q31 comprises various open reading frames. E.g. the ASPM gene is within 1q31 (relevant to instant cl. 13, 15, 16). A genome is double stranded (relevant to instant cl. 18). A ~20 nt. sequence of gRNA with a particular endonuclease-specific PAM sequence can be identified within the 1q31 region or a gRNA associated with ASPM gene region (relevant to instant cl. 21).
Rejection Based on Skarnes
Claims 1-3, 13-16, 18-19, 21, 23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Skarnes et al. (US20210079387A1, pub. 03/18/2021, effective date: 08/27/2019), as evidenced by Naseer et al. (2021, Front. Pediatr. 8, pg. 2).
The claim recites “safe harbor site” and, under BRI, it is interpreted as a region within the chromosome where foreign engineered nucleic acid targeting vector can be introduced for “stable expression” of the foreign vector without “detrimental changes to cellular transcriptome” (pg. 1, lines 24-27).
Regarding instant cl. 1-3, Skarnes discloses cleavage-resistant donor nucleic acid (par. 3) intended to minimize or prevent re-cleavage and subsequent damage of a modified target site (single nucleotide variant) by the nuclease (par. 5). Skarnes discloses that a donor nucleic acid comprises a sequence that is partially homologous to a target nucleic acid sequence (par. 27). Skarnes discloses a sequence of interest (i.e. non-homologous portion) with flanking homologous portions that are ranging from 5-200 nt. in length) (par. 27). One of the genomic loci that can be targeted is the ASPM gene that is associated with microcephaly (par. 78, Table 1, pg. 10). It is known that ASPM gene is located at the 1.q31.3 site, as evidenced by Naseer et al. (pg. 2).
Regarding instant cl. 13 and 16, Skarnes broadly discloses that a target site is associated with a disorder and the target site is within or associated with an oncogene or tumor suppressor, which can be understood as a the whole oncogene, i.e. ORF. Further, Skarnes contemplates that an expression vector (e.g. a recombinant expression vector) has a start codon, a termination codon and a transcription termination sequence (par. 81); thus contemplating a vector to express an ORF. Thus, here a skilled artisan can introduce a full length wild-type ASPM gene or other variants to understand the role of ASPM gene on microcephaly.
Regarding instant cl. 14, Skarnes discloses that an expression vector typically includes a promoter (par. 81).
Regarding instant cl. 15, Skarnes discloses the target site is located within a gene of interest (par. 75). Skarnes demonstrates transfecting end-modified single-stranded oligonucleotides (ssODNs) and Cas9 RNP-targeting blue fluorescent protein into culture cells and converting a single codon (H67Y) of blue fluorescent protein sequence to express a green fluorescent (par. 96-98).
Regarding instant cl. 18, Skarnes discloses donor nucleic acid is double stranded (par. 10).
Regarding instant cl. 19, Skarnes discloses that homologous arms can be at least 50 nt. (par. 27).
Regarding instant cl. 21, Skarnes discloses a donor nucleic acid and any one or more of the nucleic acids of a kit may be encoded on the same vector (par. 91); and an additional nucleic acid of the kit further includes site-specific nucleases, including Cas9, ZFN, or TALEN; and/or nucleic acid encoding a gRNA (par. 90).
Regarding instant cl. 23, Skarnes discloses a nucleic acid that is delivered to a cell may be present on a vector (par. 81).
Allowable Subject Matter
No claim allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
KEYUR VYAS
Examiner
Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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