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 1-17) and species of “a gene sequence encoding a protein that acts to decrease cell survival rate” and “a suicide gene” in the reply filed on 12/3/2025 is acknowledged.
The species elections for claim 9 and claim 10, as required in the Election/Restriction of 10/23/2025, is withdrawn. Specifically, the species elections for claim 9 “a gene sequence encoding a protein that acts to decrease cell survival rate; or a protein whose intracellular expression is detectable” and claim 10 “a suicide gene, a DNA damage-inducing gene, a DNA repair-inhibiting gene, a luminescent enzyme gene, a fluorescent protein gene, a cell surface antigen gene, a secretory protein gene, or a membrane protein gene” are withdrawn.
Claims 1-29 are pending.
Claims 18-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/3/2025.
Claims 4 and 5 were cancelled in the amended claims submitted on 12/3/2025.
Claims 1-3 and 6-17 are being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (see paragraphs [0038, 0044, and 0071-0072]). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c) (see Figure 22). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended 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 (i.e., “SEQ ID NO:X” or the like) 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 - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing.
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.
Abstract
The abstract of the disclosure is objected to because it contains a grammatical error in the first sentence. The first sentence reads “Disclosed is means which enables simple and rapid detection of the presence or absence of mismatch repair activity, and which is useful for diagnosis and treatment of mismatch repair-deficient cancers.” This should instead read “Disclosed [[is]]are means which enable[[s]] simple and rapid detection of the presence or absence of mismatch repair activity, and which [[is]]are useful for diagnosis and treatment of mismatch repair-deficient cancers.” A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification
The use of the terms “CellTiter-Glo” (paragraph [0072]) and “Nano-Glo” (paragraph [0073]), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
The examples above are not an exhaustive list of unmarked trade names or marks used in commerce throughout the specification. Please carefully read through and properly notate each instance.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112b - Indefinite
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 3 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 3 is directed to a nucleic acid construct comprising a promoter region, a 5’-side region, and a 3’-side region of a gene encoding a protein, with the regions being placed in two different nucleic acid molecules. However, the use of the single “a nucleic acid construct” in the preamble, and “two different nucleic acid molecules” being required in the body of the claim makes the scope of this claim unclear. For purposes of examination, it is being interpreted that the two different nucleic acid molecules are derived from the singular nucleic acid construct after cleavage between the 5’-side region and the 3’-side region, therefore placing the two regions in two different nucleic acid molecules.
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.
Claims 1-3, 7-10, and 13-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kostyrko (Kostyrko et al., 2015; cited on IDS of 10/31/2024).
Regarding claim 1: Kostyrko teaches a nucleic acid construct comprising a promoter region (SV40) and a 5’-side region and a 3’-side region of a gene sequence encoding a protein (GFP; Fig 1, presented below for reference). The 5’-side region has a first homologous region linked downstream thereof and the 3’-side region has a second homologous region linked upstream thereof, wherein the homologous regions are homologous to each other (Fig 1A, represented by the dark blue µ symbol). The 5’ side region and the 3’ side regions are created by dividing the gene sequence encoding the protein (GFP) into two parts and including an overlapping region in each side region (Materials and Methods - Construction of the recombination assays).
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Regarding claim 2: Kostyrko teaches that the nucleic acid construct is within a plasmid (which reads on a circular nucleic acid construct) which can be cleaved between the 5’ side region and the 3’ side region to create a linear nucleic acid construct (see Fig 1A above, the I-SceI site is a restriction enzyme site).
Regarding claim 3: Kostyrko teaches linearized vectors (nucleic acid constructs) comprising a promoter region (SV40) and a 5’-side region and a 3’-side region of a gene sequence encoding a protein (GFP; Fig 1, presented above for reference). The 5’-side region has a first homologous region linked downstream thereof and the 3’-side region has a second homologous region linked upstream thereof, wherein the homologous regions are homologous to each other (Fig 1A, represented by the dark blue µ symbol). The 5’ side region and the 3’ side regions are created by dividing the gene sequence encoding the protein (GFP) into two parts and including an overlapping region in each side region (Materials and Methods - Construction of the recombination assays). Kostyrko teaches cleaving the linearized vector with a restriction enzyme I-SceI between the 5’side region and the 3’ side region. This necessarily creates two different nucleic acid molecules, one containing the 5’ side region and the other containing the 3’ side region. This reads on the regions being placed in two different nucleic acid molecules.
Regarding claims 7 and 8: Kostyrko teaches that the first homologous region and the second homologous region each have a chain length of 9 bp and that the homology between the two sequences is 100% (Fig 1A).
Regarding claims 9 and 10: Kostyrko teaches that the gene sequence encodes a protein whose intracellular expression in detectable and is a fluorescent protein gene (GFP, Fig 1A and Fig 3).
Regarding claim 13: Kostyrko teaches the nucleic acid construct of claim 1. Given that the structure as described by Kostyrko teaches the exact structure as defined in claim 1, the structure of Kostyrko can necessarily act as a diagnostic agent. MPEP 2111.02 II states that
“If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020) (The court found that the preamble in one patent’s claim is limiting but is not in a related patent); Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"); Kropa v. Robie, 187 F.2d at 152, 88 USPQ2d at 480-81 (preamble is not a limitation where claim is directed to a product and the preamble merely recites a property inherent in an old product defined by the remainder of the claim).
In the instant case, the preamble of “A diagnostic agent for mismatch repair-deficient cancer” is not a structural limitation of the nucleic acid construct of claim 1 and therefore this intended use is not further limiting of the nucleic acid construct as taught by Kostyrko.
Regarding claim 14: Kostyrko teaches that the gene sequence encodes a protein whose intracellular expression in detectable (GFP, Fig 1A and Fig 3).
Regarding claim 15 and 16: Kostyrko teaches the nucleic acid construct of claim 1. Given that the structure as described by Kostyrko teaches the exact structure as defined in claim 1, the structure of Kostyrko can necessarily act as a companion diagnostic agent (see citation of MPEP 2111.02 II above). In the instant case, the preamble of “A companion diagnostic agent for predicting an effect of an anticancer drug for mismatch repair-deficient cancer” is not a structural limitation of the nucleic acid construct of claim 1 and therefore this intended use is not further limiting of the nucleic acid construct as taught by Kostyrko. And, because the “anticancer drug” is merely part of an intended use of the construct of claim 1, claim 16 is also rejected.
Regarding claim 17: Kostyrko teaches that the gene sequence encodes a protein whose intracellular expression in detectable (GFP, Fig 1A and Fig 3).
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.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Kostyrko (Kostyrko et al., 2015; cited on IDS of 10/31/2024) as applied to claims 1-2, 7-10, and 13-17, and further in view of Taylor-Parker (AddGene, 2016).
The teachings of Kostyrko are outlined above. Relevant to the instantly rejected claim, Kostyrko teaches a nucleic acid construct that comprises a promoter, a 5’ region and a 3’ region which a composed of a divided gene sequence and each of which contain a first homologous region and a second homologous region, respectively. Kostyrko does not teach that the nucleic acid construct contains a poly-A addition signal downstream of the 3’-side region.
However, use of poly-A addition signals at the 3’ end of nucleic acid constructs was known in the art, as taught by Taylor-Parker.
Taylor-Parker teaches that in many expression plasmids, mammalian terminators are used which “include the sequence motif AAUAAA which promotes both polyadenylation and termination” (Eukaryotic termination and polyadenylation).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the nucleic acid construct of Kostyrko to include the polyA sequence as taught by Taylor-Parker. One would be motivated to do so given the assertion by Taylor-Parker that “The addition of the poly(A) tail is important for stability of the mRNA, protection from degradation, and is integral to the nuclear export and translation processes as well.” (Eukaryotic termination and polyadenylation). One would have a reasonable expectation of success given that Taylor-Parker discusses the successful integration into mammalian expression plasmids to promote translation of genes within said vector.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kostyrko (Kostyrko et al., 2015; cited on IDS of 10/31/2024) in view of Chen (Chen et al., Cell Death & Disease 2018) and Sugawara (Sugawara et al., PNAS 2004).
Kostyrko teaches the nucleic acid construct of claim 1. Kostyrko teaches a nucleic acid construct comprising a promoter region (SV40) and a 5’-side region and a 3’-side region of a gene sequence encoding a protein (GFP; Fig 1, presented below for reference). The 5’-side region has a first homologous region linked downstream thereof and the 3’-side region has a second homologous region linked upstream thereof, wherein the homologous regions are homologous to each other (Fig 1A, represented by the dark blue µ symbol). The 5’ side region and the 3’ side regions are created by dividing the gene sequence encoding the protein (GFP) into two parts and including an overlapping region in each side region (Materials and Methods - Construction of the recombination assays).
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Kostyrko does not teach that the gene sequence encoding a protein is one which acts to decrease cell survival rate. However, usage of reporter genes that induce an easily measurable phenotype, such as cell death, is known in the art, as taught by Chen.
Chen teaches using a nucleic acid construct which comprises a promoter upstream of a reporter construct, which is either luciferase (a gene sequence encoding a protein whose intracellular expression is detectable) or DTA (a gene sequence encoding a protein that acts to decrease cell survival rate, more specifically, a suicide gene; Abstract). Chen teaches using a promoter for the gene XRCC2, which is specifically overexpressed in cancer cells relative to non-cancer cells (Abstract). Chen teaches contacting the nucleic acid construct with cancer cells and decreasing cell survival of cancer cells (Figure 4 and 5).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the nucleic acid construct of Kostyrko to include a gene that acts to decrease cell survival, as taught by Chen. One would be motivated to do so given the assertion by Chen that this allows for high selectivity and efficacy in treating cancer cells. One would have a reasonable expectation of success given that DTA could reasonably be expected to work in the construct of Kostyrko, providing an alternative reporter that would work specifically in a DNA damage repair context.
Kostyrko in view of Chen does not teach using this construct as a therapeutic agent specifically against mismatch repair-deficient cancer. However, suppression of SSA repair products by functional mismatch repair pathways is known in the art, as taught by Sugawara.
Sugawara teaches double strand break repair by single strand annealing using a construct similar to that of Kostyrko in that flanking sequences of homology (with or without sequence divergence) are used to repair a double strand break via single strand annealing. Sugawara teach that sequence divergence in the regions of homology inhibit SSA, but this inhibition is rescued when the cells are deficient in mismatch repair.
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the nucleic acid construct of Kostyrko and Chen to apply them as a therapeutic agent specifically against mismatch repair deficient cells. One would be motivated to do so given the teaching by Sugawara that by inclusion of some mismatches within the overlapping regions, SSA is prevented (and thus no functional DTA would be created) in cells that have a functional mismatch repair system, while SSA would be allowed to occur and create a functional DTA gene to decrease cell survival rate specifically in cells that are deficient for mismatch repair, enabling selective killing of mismatch repair deficient cells. One would have a reasonable expectation of success given that the SSA system construct as taught by Kostyrko, with successful SSA leading to expression of DTA, as taught by Chen for selective killing of cancer cells, could readily be employed to distinguish between mismatch proficient and mismatch deficient cells as taught by Sugawara.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 and 6-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 87-89, 90-93, 95, 107-109, 113, 115-116, 129, 136-137, 140-142, and 146-148 of copending Application No. 19/130,810 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the same limitations. Any additional limitations of the '810 claims are encompassed by the open claim language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/
Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683