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 claims 268-274 and 288-290 (added in the amended claim set filed 11/26/2025) (Group I) in the reply filed on 11/26/2025 is acknowledged.
Regarding the election of species pertaining to Group III set forth in the restriction requirement dated 09/29/2025, Applicant cancelled claims 285-287 in the amended claim set filed 11/26/2025. Accordingly, the election of species requirement is moot.
Claims 275-284 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/26/2025.
Accordingly, claims 268-274 and 288-290 are pending and under consideration.
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 effective filing date to which the instant application is entitled is 04/07/2020.
Information Disclosure Statement
Receipt of an information disclosure statement on 01/17/2025 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
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). Specifically, Figures 7C, 10C, 12C, 14C, and 16C depict nucleotide sequences that must be identified by sequence identifiers. 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.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification (paragraph [307]) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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 sequence identifiers, 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
Claims 268-273, 288, and 290 are objected to because of the following informalities:
Claims 268, 269, 288, and 290 all recite “site specific recombinase.” While not strictly improper, such recombinases are conventionally referred to as site-specific recombinases (bolded and underlined emphasis added), as evidenced by Olorunniji et al., 2016 (of record). Accordingly, in order to comport with conventional practices in the field, it would be remedial to amend each recitation of “site specific recombinase” to recite “site-specific recombinase” (bolded and underlined emphasis added).
With specific regard to claim 269, the recitation of “the site[-]specific recombinase is a serine recombinase, or a tyrosine recombinase (bolded and underlined emphasis added) does not comport with standard grammatical and/or linguistic conventions. The comma preceding the “or” that separates “serine recombinase” and “tyrosine recombinase” is not grammatically proper. It would be remedial to remove said comma in order to comport with standard grammatical and/or linguistic conventions.
Claim 270 recites “at least two of the plurality of first recognition sequences is a bacterial genomic recombination site (attB) or a phage genomic recombination site (attP)” (bolded emphasis added), which does not comport with standard grammatical and/or linguistic conventions. The bolded “at least two” is a plural subject that requires the plural verb “are” rather than the singular verb “is.” Furthermore, each recombination site is recited in singular form, which is not consistent with the plural recitation of “at least two.” It would be remedial to amend the instant claim language such that the plural subject is consistent with the recited verb and that plurality vs singularity is consistent within each claim, so as to comport with standard grammatical and/or linguistic conventions.
Claim 271 recites, in part, “a second flanking insertion sequence homologous to a second genome sequence downstream of the insertion site, wherein second flanking insertion sequence is located downstream of the GEMS polynucleotide sequence” (bolded emphasis added), which is grammatically improper. The bolded recitation of a second flanking insertion sequence lacks an appropriate article (such as “the”) preceding said recitation. It would be remedial to amend the instant claim to include an appropriate article (such as “the”) preceding the recited “second flanking insertion sequence.”
Claim 272 recites, in part “at least 2 of the plurality of first recognition sequence comprises a sequence…” (bolded emphasis added), which does not comport with standard grammatical and/or linguistic conventions. The bolded “at least 2” is a plural subject that requires the plural verb “are” rather than the singular verb “is.” It would be remedial to amend the instant claim language such that the plural subject is consistent with the recited verb and that plurality vs singularity is consistent within each claim, so as to comport with standard grammatical and/or linguistic conventions. Furthermore, the recitation of “at least 2” is not strictly improper but is nonetheless inconsistent with the earlier recitation of instant claim 270. Claim 270 recites “at least two” (bolded emphasis added), which spells out the instantly claimed number. However, claim 272 recites the instantly claimed number as an Arabic numeral. For purposes of internal consistency, it would be remedial to amend the instant claim set such that numbers are formatted consistently when recited herein. Additionally, the recited SEQ ID NOs of instant claim 272 do not comport with standard grammatical and/or linguistic conventions. It would be remedial to amend the recitation of “selected from the group consisting of sequences SEQ ID NOs: 106, SEQ ID NO: 107 and reverse complements thereof” to read (for example) “selected from the group consisting of SEQ ID NOs: 106 and 107, as well as reverse complements thereof,” thereby comporting with standard grammatical and/or linguistic conventions. This is merely an example set forth by the Examiner and is not intended to be limiting.
Claim 273 recites “the GEMS polynucleotide sequence comprises a sequence that is at least 80% identical to SEQ ID NO: 105, wherein a sequence identity of the GEMS polynucleotide sequence to SEQ ID NO: 105 is calculated by BLASTN,” which does not comport with standard linguistic conventions. It would be remedial to amend the instant claim such that it comports with standard linguistic conventions, for example by reciting “the GEMS polynucleotide sequence comprises a sequence that is at least 80% identical to SEQ ID NO: 105, as calculated by BLASTN.” This is merely an example set forth by the Examiner and is not intended to be limiting.
Claim 290 recites, in part “at least 3 or more recognition sequences” (bolded emphasis added), which is not strictly improper but is nonetheless inconsistent with the earlier recitation of instant claim 270. Claim 270 recites “at least two” (bolded emphasis added), which spells out the instantly claimed number. However, claim 290 recites the instantly claimed number as an Arabic numeral. For purposes of internal consistency, it would be remedial to amend the instant claim set such that numbers are formatted consistently when recited herein.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
Claim 273 is 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 273 is drawn to a GEMS polynucleotide construct comprising a sequence that is at least 80% identical to SEQ ID NO: 105. Per claim 268 (from which instant claim 273 depends), GEMS polynucleotide constructs comprise a plurality of first recognition sequences for a site-specific recombinase. The rejected claim thus comprises a set of polynucleotide sequences, all variants of which must effectively perform the functions of the claimed GEMS polynucleotide construct, meaning all variants must comprise a plurality of functional first recognition sequences for a site-specific recombinase.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes a GEMS polynucleotide construct corresponding to SEQ ID NO: 105, which comprises Bxb1 recognition sites (Table 7). No description is provided of any other GEMS polynucleotide construct with at least 80% identity to SEQ ID NO: 105.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the GEMS polynucleotide construct corresponding to SEQ ID NO: 105. As is known to those of ordinary skill in the art, site-specific recombinases strictly act at specific sequences. While some minor variations of the site sequence may be tolerated by these enzymes, off-site activity is usually very low (reviewed in Olorunniji et al., 2016: page 674, column 2, paragraph 3 (of record)). The instant claim encompasses site-specific recombinase sequences with up to 20% sequence variation, which one of ordinary skill in the art would reasonably expect to disrupt the activity of the associated site-specific recombinase. The instant specification is silent as to the essentiality of these sequences in that the recited 80% identity is not excluded from affecting the sequences recognized by site-specific recombinases. Therefore, results obtained with SEQ ID NO: 105 are not necessarily predictive of any sequence satisfying the instant claim limitations, as the instant claim limitations encompass a set of sequences with a large number of variable residues, including within the specific sequences recognized by site-specific recombinases. Thus, it is impossible for one to extrapolate from the examples described herein those GEMS polynucleotide construct sequences that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of sequences that would meet the structural and functional requirements of the instantly claimed GEMS polynucleotide construct.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claim 273.
Claim Rejections - 35 USC § 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.
Claim 289 is 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 289 recites the limitation "said plurality of first nucleotide recognition sequences" (bolded emphasis added) in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. It would be remedial to amend the instant claim set such that there is sufficient antecedent basis, for example by amending the limitation at issue to recite “said plurality of first recognition sequences” or to recite “a plurality of first nucleotide recognition sequences” (bolded emphasis added). These are merely examples set forth by the Examiner and are not intended to be limiting.
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.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 274 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
With regard to claim 274, which recites “a mammalian cell that comprises the GEMS polynucleotide construct of claim 268,” the broadest reasonable interpretation of the term “mammalian cell” embraces a human having the cell. It is noted that “a cell” is not limited to a single cell and can encompass an organism comprising the cell(s); furthermore, paragraph [0031] of the specification indicates that the cell can be a human cell. Neither the instant claim language nor the disclosure of the instant specification precludes this interpretation. It would be remedial to amend the instant claim to recite “an isolated mammalian cell” to avoid the claim embracing a human organism.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 268-271, 274, and 288-290 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2018/156818 A1 (hereinafter Popma; as cited in the IDS filed 01/17/2025; of record), as evidenced by Yang, 2010 (hereinafter Yang; of record), Hirano et al., 2011 (hereinafter Hirano), and Olorunniji et al., 2016 (hereinafter Olorunniji; of record).
With regard to instant claim 268, which recites “a gene editing multi-site (GEMS) polynucleotide construct for insertion into an insertion site in a genome of a mammalian cell, wherein said GEMS polynucleotide construct comprises: a GEMS polynucleotide sequence that comprises a plurality of first recognition sequences for a site specific recombinase, wherein each of the plurality of first recognition sequences can undergo a site specific recombination with a second recognition sequence of the site specific recombinase, when contacted with the site specific recombinase, wherein the GEMS polynucleotide sequence is heterologous to the genome; and wherein the GEMS polynucleotide sequence is non-coding,” Popma also discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells (abstract; paragraphs [0005] and [0013]). While the GEMS polynucleotide constructs of Popma are disclosed to comprise a plurality of nuclease recognition sequences, recombinases such as the site-specific recombinases of the instant application are known to be a species of nucleases (Yang: abstract). Accordingly, under broadest reasonable interpretation, the plurality of nuclease recognition sequences disclosed in Popma is considered to read on the instantly claimed plurality of recognition sequences that function with site-specific recombinases.
Indeed, Popma does further disclose that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (paragraphs [0005], [0126], 0132], and [0137]-[0140]). Popma explicitly discloses a method for site-specific recombination in which first and second recombination sites (disclosed to be attB or attP) are provided and contacted with a prokaryotic recombinase polypeptide, resulting in recombination between said sites (paragraph [0137]). The attB or attP recombination sites disclosed in Popma are considered to read on the instantly claimed site-specific recombinase recognition sequences, as the instant specification discloses that attP and attB are both exemplary first or second recognition sequences (paragraph [183]), and the instant claim set recites said attB or attP recombination sites at instant claim 270. Thus, Popma discloses a GEMS polynucleotide construct for insertion into a genome at an insertion site, wherein said GEMS construct comprises a GEMS sequence between flanking insertion sequences, wherein said GEMS sequence comprises a plurality of nuclease recognition sequences (which read on the instantly claimed recognition sequences that function with site-specific recombinases), and further that the GEMS vectors taught therein are compatible with site-specific recombination mediated by site-specific recombinases (paragraphs [0005], [0126], 0132], and [0137]-[0140]).
Regarding the recited limitations regarding the heterologous and non-coding nature of the GEMS polynucleotide sequence, these limitations are considered to be inherent properties of the site-specific recombinase recognition sequences of the instantly claimed GEMS polynucleotide sequence. First, Hirano discloses that most site-specific recombinases are found in bacteria and bacteriophages, meaning they are generally heterologous to eukaryotic species, such as the mammals embraced by the instant claim set (page 227, column 2, paragraph 1 of “Introduction") and envisioned by Popma (paragraph [0012]). Additionally, Olorunniji teaches that site-specific recombinase recognition sequences are defined by specific structural motifs, meaning these sequences are non-coding, as is known to those of ordinary skill in the art (Figure 2).
Thus, it is considered that Popma (as evidenced by Yang, Hirano, and Olorunniji) anticipates each and every limitation of instant claim 268.
With regard to instant claim 269, which recites “the site specific recombinase [of the GEMS polynucleotide construct of claim 268] is a serine recombinase…or a tyrosine recombinase,” as set forth above, Popma discloses that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (paragraphs [0005], [0126], 0132], and [0137]-[0140]). Such site-specific recombinases are disclosed to be tyrosine recombinases or serine recombinases (paragraph [0126]), as instantly claimed. Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 269.
With regard to instant claim 270, which recites “at least two of the plurality of first recognition sequences” are “bacterial genomic recombination site[s] (attB) or…phage genomic recombination site[s] (attP),” as set forth above, Popma discloses that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (paragraphs [0005], [0126], 0132], and [0137]-[0140]). Such methods for site-specific recombination are disclosed to comprise providing a first recombination site and a second recombination site, followed by contacting the first and second recombination sites with a recombinase polypeptide, thereby resulting in recombination between the recombination sites (paragraph [0137]). Per Popma, the first and second recombination sites may be attP or attB (paragraph [0137]). Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 270.
With regard to instant claim 271, which recites “the GEMS polynucleotide construct of claim 268 further compris[es]: a first flanking insertion sequence homologous to a first genome sequence upstream of the insertion site, wherein the first flanking insertion sequence is located upstream of the GEMS polynucleotide sequence; and a second flanking insertion sequence homologous to a second genome sequence downstream of the insertion site, wherein [the] second flanking insertion sequence is located downstream of the GEMS polynucleotide sequence,” as set forth above, Popma discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells (abstract; paragraphs [0005] and [0013]). These GEMS constructs are disclosed to comprise flanking insertion sequences, wherein each flanking insertion sequence is homologous to a genome sequence at said insertion site (paragraph [0005]). Furthermore, these flanking insertion sequences flank the GEMS sequence of the GEMS constructs taught therein, said GEMS sequences comprising a plurality of nuclease recognition sequences (paragraph [0005]). This disclosure reads on the instantly claimed structure of a first flanking insertion sequence upstream of the GEMS polynucleotide sequence and a second flanking insertion sequence downstream of the GEMS polynucleotide sequence. Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 271.
With regard to instant claim 274, which recites “a mammalian cell that comprises the GEMS polynucleotide construct of claim 268,” as set forth above, Popma discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells (abstract; paragraphs [0005] and [0013]). Popma specifically discloses a host mammalian cell comprising said GEMS construct (paragraph [0012]). Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 274.
With regard to instant claim 288, which recites “the site specific recombinase [of the GEMS polynucleotide construct of claim 268] is a Bxb1 recombinase,” as set forth above, Popma discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells (abstract; paragraphs [0005] and [0013]). Additionally, as set forth above, Popma further discloses that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (paragraphs [0005], [0126], 0132], and [0137]-[0140]). One such recombinase that is disclosed to be compatible with said methods is the Bxb1 recombinase (paragraph [00136]), as is instantly claimed. Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 288.
With regard to instant claim 289, which recites “said GEMS sequence [of the GEMS polynucleotide construct of claim 268] further comprises a polynucleotide spacer separating said plurality of first nucleotide recognition sequences,” as set forth above, Popma discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells, said GEMS polynucleotide constructs comprising a plurality of nuclease recognition sequences (abstract; paragraphs [0005], [0013], and [0139]). These GEMS polynucleotide constructs are further disclosed to comprise a polynucleotide spacer or a plurality of polynucleotide spacers separating at least one nuclease recognition sequence from an adjacent nuclease recognition sequence (paragraph [0139]), as instantly recited. Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 289.
With regard to instant claim 290, which recites “said plurality of first recognition sequences for the site specific recombinase [of the GEMS polynucleotide construct of claim 268] can comprise at least 3 or more recognition sequences,” as set forth above, Popma discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells, said GEMS polynucleotide constructs comprising a plurality of nuclease recognition sequences (abstract; paragraphs [0005], [0013], and [0139]). Popma further discloses that the plurality of nuclease recognition sequences of the GEMS polynucleotide constructs taught therein comprises at least three nuclease recognition sequences (paragraph [0006]). Thus, it is considered that Popma anticipates each and every additional limitation of instant claim 290.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim 272 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/156818 A1 (hereinafter Popma; as cited in the IDS filed 01/17/2025; of record), as evidenced by Yang, 2010 (hereinafter Yang; of record), Hirano et al., 2011 (hereinafter Hirano), and Olorunniji et al., 2016 (hereinafter Olorunniji; of record) as applied to claim 268 above (see section Claim Rejections - 35 USC § 102), and further in view of US 2006/0172377 A1 (hereinafter Padidam).
The disclosure of Popma (as evidenced by Yang, Hirano, and Olorunniji) is described above and applied as before. However, this disclosure does not teach the first recognition sequence of instant claim 272.
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With regard to instant claim 272, which recites “at least 2 of the plurality of first recognition sequences [of the GEMS polynucleotide construct of claim 268] comprises [sic] a sequence selected from the group consisting of SEQ ID NOs: 106 [and 107],” as set forth above, Popma anticipates the GEMS polynucleotide construct of claim 268. However, Popma does not disclose the instantly claimed sequence of the plurality of first recognition sequences. This deficiency is cured by Padidam, which discloses methods for obtaining site-specific recombination in a eukaryotic cell, said methods utilizing attP and attB recombination sites (abstract). Padidam further discloses that SEQ ID NO: 16 taught therein comprises the attP site of Bxb1 recombinase (paragraph [0211]). As shown in the alignment below, SEQ ID NO: 16 of Padidam is 100% identical to instant SEQ ID NO: 106. Accordingly, it is considered that Padidam discloses each and every additional limitation of instant claim 272.
Given that Popma discloses GEMS polynucleotide constructs for inserting exogenous donor genes into mammalian host cells (said GEMS polynucleotide constructs comprising a plurality of nuclease recognition sequences) as well as that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (for example by using Bxb1 recombinase and/or attP or attB recognition sequences), and that Padidam discloses methods for obtaining site-specific recombination in a eukaryotic cell, said methods utilizing attP and attB recombination sites (wherein SEQ ID NO: 16 comprises the attP site of Bxb1 recombinase and is 100% identical to instant SEQ ID NO: 106), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the plurality of nuclease recognition sites of the GEMS polynucleotide constructs of Popma to specifically comprise a plurality of site-specific recombinase recognition sequences, such as the Bxb1 recombinase attP recognition site corresponding to SEQ ID NO: 16 of Padidam to predictably result in recombination between recognition sites, thereby facilitating insertion of a desired sequence into the genome. One would have been motivated to make such a modification in order to receive the expected benefit of facilitating specific insertion of a desired sequence into the host genome.
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).
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Claims 268, 271, 274, 289, and 290 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 7, and 15 of U.S. Patent No. 10,828,330 (as cited in the IDS filed 01/17/2025), as evidenced by Yang, 2010 (hereinafter Yang; of record), Hirano et al., 2011 (hereinafter Hirano), and Olorunniji et al., 2016 (hereinafter Olorunniji; of record) and in view of WO 2018/156818 A1 (hereinafter Popma; as cited in the IDS filed 01/17/2025; of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patent ‘330 is also drawn to GEMS polynucleotide constructs (abstract; column 1, line 63-column 2, line 8), as in the instant application. Claim 1 of patent ‘330 recites “an isolated gene editing multi-site (GEMS) construct for insertion into a genome at an insertion site, wherein said GEMS construct comprises: a GEMS sequence that comprises a plurality of nuclease recognition sequences.” In comparison, instant claim 268 recites a GEMS polynucleotide construct “for insertion into an insertion site in a genome of a mammalian cell, wherein said GEMS polynucleotide construct comprises: a GEMS polynucleotide sequence that comprises a plurality of first recognition sequences for a site specific recombinase, wherein each of the plurality of first recognition sequences can undergo a site specific recombination with a second recognition sequence of the site specific recombinase, when contacted with the site specific recombinase, wherein the GEMS polynucleotide sequence is heterologous to the genome; and wherein the GEMS polynucleotide sequence is non-coding.” Regarding the recited limitation of insertion into the genome of a mammalian cell, the disclosure of patent ‘330 states that GEMS construct provided therein is intended for use in mammalian systems (column 4, lines 4-7). Furthermore, while the GEMS construct of patent ‘330 comprises a plurality of nuclease recognition sequences, as set forth above regarding instant claim 268 (see section Claim Rejections - 35 USC § 102), recombinases such as the site-specific recombinases of the instant application are known to be a species of nucleases (Yang: abstract). Accordingly, under broadest reasonable interpretation, the plurality of nuclease recognition sequences recited in patent ‘330 is considered to read on the instantly claimed recognition sequences that function with site-specific recombinases. This is supported by the disclosure of Popma, which teaches that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (paragraphs [0005], [0126], 0132], and [0137]-[0140]). Popma explicitly discloses a method for site-specific recombination in which first and second recombination sites (disclosed to be attB or attP) are provided and contacted with a prokaryotic recombinase polypeptide, resulting in recombination between said sites (paragraph [0137]).
Finally, regarding the recited limitations regarding the heterologous and non-coding nature of the GEMS polynucleotide sequence, these limitations are considered to be inherent properties of the site-specific recombinase recognition sequences of the instantly claimed GEMS polynucleotide sequence. First, Hirano discloses that most site-specific recombinases are found in bacteria and bacteriophages, meaning they are generally heterologous to eukaryotic species, such as the mammals embraced by the instant claim set (page 227, column 2, paragraph 1 of “Introduction"). Additionally, Olorunniji teaches that site-specific recombinase recognition sequences are defined by specific structural motifs, meaning these sequences are non-coding, as is known to those of ordinary skill in the art (Figure 2).
Thus, claim 1 of patent ‘330 is not considered to be patentably distinct from instant claim 268 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Claims 2 and 3 of patent ‘330 respectively further limit the claimed GEMS polynucleotide construct such that “said plurality of nuclease recognition sequences comprises at least 3 or more nuclease recognition sequences” and that “said GEMS sequence further comprises one or more polynucleotide spacers separating said plurality of nuclease recognition sequences. As set forth above, recombinases such as the site-specific recombinases of the instant application are known to be a species of nucleases (Yang: abstract). Accordingly, under broadest reasonable interpretation, the plurality of nuclease recognition sequences recited in patent ‘330 is considered to read on the instantly claimed recognition sequences that function with site-specific recombinases. Thus, the limitations recited at claims 2 and 3 of patent ‘330 are identical to those recited at instant claims 290 and 289. To emphasize this, instant claim 290 recites that “said plurality of first recognition sequences for the site specific recombinase can comprise at least 3 or more recognition sequences,” while instant claim 289 recites that “said GEMS sequence further comprises a polynucleotide spacer separating said plurality of first…recognition sequences.” Given that Yang teaches that site-specific recombinases are a species of nucleases, claims 2 and 3 of patent ‘330 are not considered to be patentably distinct from instant claims 289 and 290 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Claim 6 of patent ‘330 recites “an isolated genetically engineered cell that comprises a gene editing multi-site (GEMS) sequence in said cell’s genome, wherein said GEMS sequence comprises a plurality of nuclease recognition sequences,” while claim 7 of patent ‘330 further limits said genetically engineered cell to “a mammalian cell.” In comparison, instant claim 274 recites “a mammalian cell that comprises the GEMS polynucleotide construct of claim 268.” As set forth above, the GEMS polynucleotide construct of claim 268 is not considered to be patentably distinct from the GEMS polynucleotide construct recited in patent ‘330, as Yang teaches that site-specific recombinases are a species of nucleases. Accordingly, claim 6 of patent ‘330 is not considered to be patentably distinct from instant claim 274 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Claim 15 of patent ‘330 recites that “the isolated GEMS construct of claim 1 further compris[es]: a) a first flanking insertion sequence homologous to a first genome sequence upstream of said insertion site, wherein said flanking insertion sequence is located upstream of said GEMS sequence; b) a second flanking insertion sequence homologous to a second genome sequence downstream of said insertion site, wherein said second flanking insertion sequence is located downstream of said GEMS sequence; or c) both.” In comparison, instant claim 271 recites that the GEMS polynucleotide construct claimed therein further comprises “a first flanking insertion sequence homologous to a first genome sequence upstream of the insertion site, wherein the first flanking insertion sequence is located upstream of the GEMS polynucleotide sequence; and a second flanking insertion sequence homologous to a second genome sequence downstream of the insertion site, wherein [the] second flanking insertion sequence is located downstream of the GEMS polynucleotide sequence.” As set forth above, the GEMS polynucleotide construct of claim 268 is not considered to be patentably distinct from the GEMS polynucleotide construct recited in patent ‘330, as Yang teaches that site-specific recombinases are a species of nucleases. Accordingly, claim 15 of patent ‘330 is not considered to be patentably distinct from instant claim 271 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Given that patent ‘330 recites a GEMS polynucleotide construct comprising a plurality of nuclease (which under broadest reasonable interpretation reads on the instantly claimed site-specific recombinases as taught by Yang) recognition sequences for insertion into a mammalian genome, and that Popma discloses the utility of inserting sequences into a host genome via site-specific recombination, wherein first and second recombination sites (disclosed to be attB or attP) are provided and contacted with a prokaryotic recombinase polypeptide, resulting in recombination between said sites, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to build the GEMS polynucleotide construct of patent ‘330 such that the nucleases disclosed therein are site-specific recombinases (as taught by Yang) that facilitate insertion into a mammalian genome by providing first and second recombination sites that are contacted with a prokaryotic recombinase polypeptide, thereby predictably resulting in recombination between said sites and facilitating insertion into a mammalian genome. One would have been motivated to make such a modification in order to receive the expected benefit of facilitating insertion into a mammalian genome.
Claims 268, 271, 274, and 289 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 7, and 8 of U.S. Patent No. 12,440,578, as evidenced by Yang, 2010 (hereinafter Yang; of record), Hirano et al., 2011 (hereinafter Hirano), and Olorunniji et al., 2016 (hereinafter Olorunniji; of record) and in view of WO 2018/156818 A1 (hereinafter Popma; as cited in the IDS filed 01/17/2025; of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patent ‘578 is also drawn to GEMS constructs for insertion into a genome (such as a mammalian genome, as recited at claim 8 of patent ‘578. Claim 1 of patent ‘578 recites “an engineered gene editing multi-site (GEMS) polynucleotide construct for insertion into a genome at an insertion site, wherein said engineered GEMS polynucleotide construct comprises: a GEMS polynucleotide sequence comprising a plurality of nuclease recognition sequences.” In comparison, instant claim 268 recites a GEMS polynucleotide construct “for insertion into an insertion site in a genome of a mammalian cell, wherein said GEMS polynucleotide construct comprises: a GEMS polynucleotide sequence that comprises a plurality of first recognition sequences for a site specific recombinase, wherein each of the plurality of first recognition sequences can undergo a site specific recombination with a second recognition sequence of the site specific recombinase, when contacted with the site specific recombinase, wherein the GEMS polynucleotide sequence is heterologous to the genome; and wherein the GEMS polynucleotide sequence is non-coding.” Regarding the recited limitation of insertion into the genome of a mammalian cell, the disclosure of patent ‘578 states that GEMS construct provided therein is intended for use in mammalian systems (see claim 8 of patent ‘578). Furthermore, while the GEMS construct of patent ‘578 comprises a plurality of nuclease recognition sequences, as set forth above regarding instant claim 268 (see section Claim Rejections - 35 USC § 102), recombinases such as the site-specific recombinases of the instant application are known to be a species of nucleases (Yang: abstract). Accordingly, under broadest reasonable interpretation, the plurality of nuclease recognition sequences recited in patent ‘578 is considered to read on the instantly claimed recognition sequences that function with site-specific recombinases. This is supported by the disclosure of Popma, which teaches that site-specific recombinases are known to be capable of catalyzing insertion of foreign DNA into a host genome and can be introduced into a host cell prior to or concurrently with a GEMS vector to accomplish site-specific recombination that can result in genome integration (paragraphs [0005], [0126], 0132], and [0137]-[0140]). Popma explicitly discloses a method for site-specific recombination in which first and second recombination sites (disclosed to be attB or attP) are provided and contacted with a prokaryotic recombinase polypeptide, resulting in recombination between said sites (paragraph [0137]).
Finally, regarding the recited limitations regarding the heterologous and non-coding nature of the GEMS polynucleotide sequence, these limitations are considered to be inherent properties of the site-specific recombinase recognition sequences of the instantly claimed GEMS polynucleotide sequence. First, Hirano discloses that most site-specific recombinases are found in bacteria and bacteriophages, meaning they are generally heterologous to eukaryotic species, such as the mammals embraced by the instant claim set (page 227, column 2, paragraph 1 of “Introduction"). Additionally, Olorunniji teaches that site-specific recombinase recognition sequences are defined by specific structural motifs, meaning these sequences are non-coding, as is known to those of ordinary skill in the art (Figure 2).
Thus, claim 1 of patent ‘578 is not considered to be patentably distinct from instant claim 268 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Claim 4 of patent ‘578 recites “the engineered GEMS polynucleotide construct of claim 1 further compris[es]: (a) a first flanking insertion sequence homologous to a first genome sequence upstream of said insertion site, said first flanking insertion sequence located upstream of said GEMS polynucleotide sequence; and (b) a second flanking insertion sequence homologous to a second genome sequence downstream of said insertion site, said second flanking insertion sequence located downstream of said GEMS polynucleotide sequence.” In comparison, instant claim 271 recites that the GEMS polynucleotide construct claimed therein further comprises “a first flanking insertion sequence homologous to a first genome sequence upstream of the insertion site, wherein the first flanking insertion sequence is located upstream of the GEMS polynucleotide sequence; and a second flanking insertion sequence homologous to a second genome sequence downstream of the insertion site, wherein [the] second flanking insertion sequence is located downstream of the GEMS polynucleotide sequence.” As set forth above, the GEMS polynucleotide construct of claim 268 is not considered to be patentably distinct from the GEMS polynucleotide construct recited in patent ‘578, as Yang teaches that site-specific recombinases are a species of nucleases. Accordingly, claim 4 of patent ‘578 is not considered to be patentably distinct from instant claim 271 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Claim 5 of patent ‘578 recites “each of said plurality of nuclease recognition sequences [of the GEMS polynucleotide construct of claim 1] is separated from an adjacent nuclease recognition sequence by a polynucleotide spacer.” As set forth above, recombinases such as the site-specific recombinases of the instant application are known to be a species of nucleases (Yang: abstract). Accordingly, under broadest reasonable interpretation, the plurality of nuclease recognition sequences recited in patent ‘578 is considered to read on the instantly claimed recognition sequences that function with site-specific recombinases. Thus, the limitations recited at claims 2 and 3 of patent ‘330 are identical to those recited at instant claims 290 and 289. To emphasize this, instant claim 290 recites that “said plurality of first recognition sequences for the site specific recombinase can comprise at least 3 or more recognition sequences,” while instant claim 289 recites that “said GEMS sequence further comprises a polynucleotide spacer separating said plurality of first…recognition sequences.” Given that Yang teaches that site-specific recombinases are a species of nucleases, claims 2 and 3 of patent ‘330 are not considered to be patentably distinct from instant claims 289 and 290 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Claim 7 of patent ‘578 recites “an isolated host cell comprising a gene editing multi-site (GEMS) polynucleotide sequence in said host cell’s genome, wherein said GEMS polynucleotide sequence comprises a plurality of nuclease recognition sequences,” while claim 8 of patent ‘578 limits the isolated host cell to “a mammalian cell.” In comparison, instant claim 274 recites “a mammalian cell that comprises the GEMS polynucleotide construct of claim 268.” As set forth above, the GEMS polynucleotide construct of claim 268 is not considered to be patentably distinct from the GEMS polynucleotide construct recited in patent ‘578, as Yang teaches that site-specific recombinases are a species of nucleases. Accordingly, claims 7 and 8 of patent ‘578 are not considered to be patentably distinct from instant claim 274 in view of Popma, and as evidenced by Yang, Hirano, and Olorunniji.
Given that patent ‘578 recites a GEMS polynucleotide construct comprising a plurality of nuclease (which under broadest reasonable interpretation reads on the instantly claimed site-specific recombinases as taught by Yang) recognition sequences for insertion into a mammalian genome, and that Popma discloses the utility of inserting sequences into a host genome via site-specific recombination, wherein first and second recombination sites (disclosed to be attB or attP) are provided and contacted with a prokaryotic recombinase polypeptide, resulting in recombination between said sites, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to build the GEMS polynucleotide construct of patent ‘578 such that the nucleases disclosed therein are site-specific recombinases (as taught by Yang) that facilitate insertion into a mammalian genome by providing first and second recombination sites that are contacted with a prokaryotic recombinase polypeptide, thereby predictably resulting in recombination between said sites and facilitating insertion into a mammalian genome. One would have been motivated to make such a modification in order to receive the expected benefit of facilitating insertion into a mammalian genome.
Conclusion
No claims are allowed.
Claims 268-273, 288, and 290 are objected to.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637