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 1-19 (Group I) in the reply filed on 05/12/2026 is acknowledged.
Claims 20, 21, 23, and 48-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 05/12/2026.
Acknowledgment is further made of Applicant’s election of SEQ ID NO: 67 in response to the species election dates 03/13/2026.
Accordingly, claims 1-19 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement filed 06/02/2026 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered, as indicated by line throughs in the attached PTO-1449.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. 63/415,395 (filed 10/12/2022) and 63/531,948 (filed 08/10/2023), fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application, as set forth below.
Neither of the provisional applications disclose that the instantly claimed expression system comprises a catalytic domain of an adenosine deaminase, as recited at instant claim 1. Accordingly, instant claim 1 is not entitled to the priority dates of the provisional applications and has an effective filing date that is the actual filing date of the instant application, which is 10/12/2023.
Neither of the provisional applications disclose the m6A binding domain sequences recited at instant claim 2. Accordingly, instant claim 2 is not entitled to the priority dates of the provisional applications and has an effective filing date that is the actual filing date of the instant application, which is 10/12/2023.
Provisional application ‘395 does not disclose the peptide linker recited at instant claim 3. Accordingly, instant claim 3 is not entitled to the priority date of provisional application ‘395 and has an effective filing date of 08/10/2023, which is the filing date of provisional application ‘948.
Neither of the provisional applications disclose the catalytic domain sequences recited at instant claim 4. Accordingly, instant claim 4 is not entitled to the priority dates of the provisional applications and has an effective filing date that is the actual filing date of the instant application, which is 10/12/2023.
Provisional application ‘395 does not disclose the p53 tumor suppressor protein of instant claim 13, the CRISPR species of instant claim 14, or the host cell of instant claim 17. Accordingly, instant claims 13, 14, and 17 are not entitled to the priority date of provisional application ‘395 and have an effective filing date of 08/10/2023, which is the filing date of provisional application ‘948.
Claims 5-12, 15, 16, 18, and 19 are supported by provisional application ‘395 and are entitled to its filing date of 10/12/2022.
Accordingly, claims 5-12, 15, 16, 18, and 19 are entitled to an effective filing date of 10/12/2022; claims 3, 13, 14, and 17 are entitled to an effective filing date of 08/10/2023; and claims 1, 2, and 4 are entitled to an effective filing date of 10/12/2023.
Drawings
The drawings filed 01/22/2024 are acceptable.
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0012] includes a typographical error, wherein “[[ ]]” is inserted at the penultimate line of the paragraph Similarly, paragraph [0147] includes a typographical error, wherein “[[ ]]” is inserted at the fourth line of the paragraph. It would be remedial to amend the noted paragraphs such that this typographical error is corrected.
Similarly, paragraphs [0026] and [0029] disclose that “FIGs. [5A-5F or 8A-8F] show[[s]] that…”, which also includes a typographical error wherein “[[s]]” is inserted at the first line of the paragraph. It would be remedial to amend paragraphs [0026] and [0029] such that this typographical error is corrected.
The instant specification refers to “SOC2” as suppressor of cytokine signaling 2 at paragraph [0013]. This abbreviation is incorrect. As disclosed at paragraph [0015] and Table 1, the correct abbreviation is “SOCS2.” It would be remedial to amend paragraph [0013] such that suppressor of cytokine signaling 2 is properly abbreviated.
The brief description of the drawings of the instant specification refers to colors that are not present in the black and white drawings (see paragraph [0022]). It would be remedial to either update the brief description of the drawings to remove the reference(s) to color or to file a petition under 37 CFR 1.84(a)(2).
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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). 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. See FIG. 1, FIG. 2K, FIG. 9B, and FIG. 12.
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See paragraph [0066].
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 1, 4, 13, and 15 are objected to because of the following informalities:
Claim 1 is objected to for reciting periods to denote the components of the polynucleotide of the second DNA construct. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. It would be remedial to replace the periods of instant claim 1 with alternative punctuation, such as parentheses.
Claim 4 recites “SEQ ID NO 78”, which lacks a colon separating “SEQ ID NO” and “78.” It is proper when reciting sequence identifiers to include a colon separating the prefix “SEQ ID NO” and the recited number itself. It would be remedial to amend instant claim 4 to recite “SEQ ID NO: 78” (bolded and underlined emphasis added).
Claim 13 recites “suppressor of cytokine signaling 2 (SOC2)” (bolded emphasis added), which is not the proper abbreviation for the disclosed tumor suppressor. As is known to those of ordinary skill in the art and as is disclosed at Table 1 of the instant specification, the proper abbreviation for suppressor of cytokine signaling 2 is “SOCS2” (bolded and underlined emphasis added). It would be remedial to amend instant claim 13 such that it recites the proper abbreviation, SOCS2.
With further regard to claims 1 and 15, which recite “a m6A sensor sequence” (bolded emphasis added), the article “a” is grammatically improper when preceding words articulated with an initial vowel sound. While “m6A sensor sequence” is spelled such that it recites a consonant letter “m”, the pronunciation of the “m” in “m6A sensor sequence” nonetheless begins with a vowel sound. It would be remedial to update the instant claim language to be grammatically proper.
Appropriate correction is required.
Applicant is advised that should claim 16 be found allowable, claim 7 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). In the instant case, both independent claim 16 and dependent claim 7 recite a vector comprising the expression system (i.e. both the first and second DNA constructs) of instant claim 1. They are thus considered to be substantial duplicates of one another.
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 17 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 17, which recites “a host cell comprising the expression system of claim 1 or the vector of claim 16,” the broadest reasonable interpretation of the term “cell” embraces a human having the cell. The instant specification envisions in vivo mammalian host cells comprising the instantly claimed expression system or vector comprising the same (paragraphs [0131] and [0132]). Therefore, under broadest reasonable interpretation of the claim language and in view of the disclosure of the instant specification, the term “cell” in claim 17 embraces a human having the cell. It would be remedial to amend the instant claim to recite “an isolated host cell…” (bolded emphasis added) to avoid the claim embracing a human organism.
Claim Rejections - 35 USC § 112(a) – Written Description
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 4 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 4 is drawn to a set of catalytic domain sequences defined by sequence identifiers or catalytic fragments thereof. The rejected claim thus comprises a set of catalytic domain sequences, wherein said sequences are defined by sequence identifiers or by catalytic fragments of the same sequences.
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 catalytic domain sequences corresponding to those of instant claim 4 at paragraph [0013] (i.e. SEQ ID NOs: 78-81). No description is provided of catalytic fragments of these sequences.
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 catalytic domains comprising the entire length of the claimed sequences. The results are not necessarily predictive of fragments of the claimed sequences, as one of ordinary skill in the art would not reasonably predict that fragments of the claimed sequences would retain their catalytic activity. The specification is silent as to which fragment(s) or residues of the instantly claimed sequences specifically impart catalytic activity. Thus, it is impossible for one to extrapolate from the few examples described herein those catalytic sequence fragments 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 fragments of the instantly claimed sequence identifiers that retain catalytic activity. The prior art teaches that catalytic molecules such as the enzymes of the instant claim set are highly specific due to the shape and charge properties of the active site, which is stabilized by the rest of the protein molecule, meaning the catalytic activity of the active site depends on the rest of the protein molecule, which cannot catalyze reactions on its own (reviewed in Robinson, 2015: see page 4, paragraph 3 and page 5, paragraph 2). The instant specification is silent as to any guidance regarding the structural and sequence requirements of the instantly claimed enzymes for retaining catalytic activity. In the absence of any demonstration or explanation of what fragments of the claimed sequences would retain catalytic activity, it is not clear what sequence fragments would necessarily meet the structural/functional characteristics of the rejected claims.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claim 4.
Claim Rejections - 35 USC § 112(a) - Enablement
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 18 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Instant claim 18 is drawn to a non-human transgenic animal comprising a host cell comprising the expression system of instant claim 1, which itself comprises a first DNA construct comprising a polynucleotide encoding a fusion protein, wherein the fusion protein comprises an N6-methyladenosine (m6A) binding domain of a YT521=B homology (YTH) domain-containing protein fused to a catalytic domain of a cytidine deaminase or a catalytic domain of an adenosine deaminase; and a second DNA construct comprising a polynucleotide encoding a heterologous polypeptide comprising a polynucleotide encoding an effector protein, a polynucleotide encoding an m6A sensor sequence, and a polynucleotide encoding a dihydrofolate reductase (DHFR).
Breadth of the claims: The claim broadly encompasses any transgenic non-human animal, wherein said transgenic non-human animal comprises the expression system comprising a first and second DNA construct, as set forth above. Numerous transgenic non-human animals are known in the art and include, but are not limited to, Drosophila melanogaster (reviewed in Venken et al., 2016), Caenorhabditis elegans (reviewed in Nance and Frøkjær-Jensen, 2019), Mus musculus (reviewed in Gurumurthy and Lloyd, 2019), Rattus norvegicus (reviewed in Meek et al., 2017), Gallus gallus domesticus (reviewed in Bahrami et al., 2019), Danio rerio (reviewed in Lin et al., 2016), and Taeniopygia guttata (reviewed in Heston and White, 2017). The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claim.
Guidance of the specification and existence of working examples: While the specification envisions transgenic animals comprising the instantly claimed expression system (set forth above) at paragraphs [0232] and [0236], the instant specification is entirely silent as to the generation of such transgenic animals and the phenotype(s) of said transgenic animals. In fact, the instant specification is silent as to any in vivo experimentation, disclosing only proof-of-principle assays performed in vitro.
Predictability and state of the art: Regarding the claimed non-human transgenic animal comprising the instantly claimed expression system (set forth above), the phenotype of said non-human transgenic animal is not disclosed in the instant specification (as set forth above) and would not have been predictable at the time of filing. The instantly claimed expression system is broadly drawn to m6A-regulated of an effector protein, which is an extremely broad class of proteins with a wide range of possible phenotypes. The instant specification discloses that the effector protein may be a tumor suppressor protein or a catalytically dead RNA-guided endonuclease. While these are just two examples of possible effector proteins, they both produce entirely separate phenotypes, wherein the tumor suppressor protein (i.e. SOCS2) modulates signaling, for example by inhibiting cytokine-induced signaling pathways (reviewed in Krebs and Hilton, 2001) and wherein the catalytically dead RNA-guided endonuclease binds to a specified target sequence (reviewed in Xue et al., 2015). These are just two examples of effector proteins selected from a vast number of protein species that meet the definition of an “effector protein,” all with different phenotypic effects.
When considering the predictability of this invention, one has to remember that many of the phenotypes examined in transgenic and knockout models are influenced by the genetic background in which they are studied and the effect of allelic variation and the interaction between the allelic variants (reviewed in Chandler et al., 2013; e.g. Figures 1 and 2, Box 1). Further, the state of the art for transgenics is unpredictable because the method of gene transfer typically relies on random integration of the transgene construct. Insertional inactivation of endogenous genes and position effects can dramatically influence the phenotype of the resultant transgenic animal (reviewed in Chandler et al., 2013; e.g. page 351, column 2, paragraph 4-page 362, column 1, paragraph 4).
Further the particular genetic elements required for optimal expression vary from species to species. Therefore, constructs that use heterologous genetic promoter will not always confer the desired phenotype in the resultant transgenic animal. Out lack of understanding of essential genetic control elements makes it difficult to design transgenes with predictable behavior (reviewed in Gama Sosa et al., 2010; e.g. page 65, column 2, paragraph 2).
Finally, different transgenic animal systems all require different considerations regarding methods of generating said transgenic animals and have different rates of success. It is thus accepted in the field that tools for generating transgenic animals must be empirically validated in the model organism of choice and that in vivo results do not always mirror in vitro results (Heston and White, 2017; e.g. page 705, column 1, paragraph 1).
Therefore, in the absence of specific guidance and working examples, the production of any non-human transgenic organism with the breadth of the scope as claimed in claim 18 is unpredictable.
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.
Claims 8-10 and 13 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.
With regard to claim 8, from which claims 9 and 10 depend, the recitation of “a polypeptide encoding dihydrofolate (DHFR)…operably linked to a first promoter” is unclear and indefinite, as polypeptides do not “encode” products as the term is used in the field. As the term is used in the field, polynucleotides encode polypeptide products. This expression is driven from a promoter sequence that is not associated with polypeptides-only with polynucleotides. Thus, the instant claim language is unclear and indefinite. Neither instant claims 9 or 10 resolve this lack of clarity and indefiniteness. It would be remedial to amend instant claim 8 such that the language clearly recites that polynucleotides encode polypeptide products as driven from promoter sequences, as is consistent with the knowledge in the field.
With regard to claim 13, which recites “the tumor suppressor protein [of the expression system of claim 12] is…one of the proteins listed in Table 1,” per MPEP § 2173.05(s), claims are to be complete in themselves-meaning, incorporation by reference to a specific figure or table is only permitted in exceptional circumstances. In the instant application, the claimed tumor suppressor proteins may easily be clearly and definitely recited in the claim language itself. It would be remedial to amend the claim language to recite the claimed tumor suppressor proteins rather than incorporating them by reference, as in the instant claim.
Claim Interpretation
With regard to claim 12, from which claims 13 and 14 depend, the Examiner notes that instant claim 12 recites “the effector protein [of the expression system of claim 1] is a tumor suppressor protein or a catalytically dead RNA-guided endonuclease” (bolded emphasis added), which requires only one/any one of the recited effector protein species to be utilized in the instantly claimed expression system. The recitations of claims 13 and 14 are, respectively, drawn to limitations regarding the tumor suppressor proteins or the catalytically dead RNA-guided endonucleases of instant claim 12, but neither of these recitations requires the instantly claimed expression system to comprise the recited species, as the limitations of instant claim 12 are satisfied by an expression system comprising either a tumor suppressor protein effector or a catalytically dead RNA-guided endonuclease effector. Said another way, the instantly claimed expression system requires either a tumor suppressor protein effector or a catalytically dead RNA-guided endonuclease effector.
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 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14, 18-20, and 22 of copending Application No. 18/709,703 (reference application; corresponds to US 2026/0168988 A1) in view of Lan et al., 2019 (hereinafter Lan; as cited in Applicant IDS).
Copending claim 1 recites “an expression system comprising:
a first DNA construct comprising a polynucleotide encoding a fusion protein, wherein the fusion protein comprises an N6-methyladenosine (m6A) binding domain of a YT521-B homology (YTH) domain-containing protein fused to a catalytic domain of a cytidine deaminase or a catalytic domain of an adenosine deaminase; and
a second DNA construct comprising:
a polynucleotide encoding a heterologous polypeptide;
a[n] m6A sensor sequence; and
a polypeptide encoding a dihydrofolate reductase (DHFR).”
This recitation is identical to that of instant claim 1, with the exception of the heterologous polypeptide, which is recited to be an effector protein in the instant application. However, both the instant and copending applications are drawn to a controllable expression system wherein m6A detection drives expression of the heterologous polypeptide, which may be an effector protein.
As set forth above, those of ordinary skill in the art are aware that m6A RNA modifications are disrupted in oncogenesis such that associated methyltransferases (i.e. METTL3), demethylases, and m6A-binding proteins are frequently upregulated in human cancer tissues (Lan: abstract). This phenomenon has potential therapeutic implications, as targeting m6A modifications with inhibitors is predicted to reduce oncotranscript and oncoprotein expression, cancer cell proliferation, survival, tumor initiation, progression, and metastasis (Lan: abstract; page 1290, column 2, paragraph 1). Importantly, the disclosure of Lan establishes that global m6A hypermethylation is associated with cancer (abstract) and further that this signature is produced via METTL3, which induces SOCS2 m6A modification and reduces its expression (page 1288, column 1, paragraph 1). Per Table 1 of Lan, SOCS2 is a tumor suppressor, which meets the definitions of an effector protein in the instant application. Therefore, one of ordinary skill in the art would be motivated to utilize a tumor suppressor protein such as SOCS2 as the heterologous/effector protein the expression of which is regulated by m6A detection via the systems of the copending and instant applications. This SOCS2 effector protein is recited at instant claims 12 and 13.
Copending claim 2 further limits the claimed m6A sensor sequence, while copending claim 3 further recites that the m6A binding domain is fused to the catalytic domain via a peptide linker, as is also recited at instant claim 3.
Copending claims 4 and 5 further limit the m6A binding domain sequence and the catalytic domain sequence. As shown in the Appendix, instant SEQ ID NO: 67 (recited at instant claim 2) is recited to be an m6A binding domain, which is identical to that recited at copending claim 4 (copending SEQ ID NO: 1). Additionally, instant SEQ ID NO: 78 (recited at instant claim 4) is recited to be a catalytic domain sequence, which is identical to that recited at copending claim 5 (copending SEQ ID NO: 12).
Copending claims 6-8 further recite a vector comprising the first and/or second DNA construct, as recited at instant claims 5-7.
Copending claim 9 further recites that the nucleic acid sequence encoding a fusion protein and/or the nucleic acid sequence encoding a heterologous polypeptide and a polypeptide encoding dihydrofolate reductase (DHFR) are operably linked to a first promoter, as recited at instant claim 8. This promoter is recited to be a constitutive or inducible promoter at copending claim 13 and instant claim 10.
Copending claims 10-12 further recite that the expression system claimed therein further comprises a nucleic acid sequence encoding a selectable marker operably linked to a second promoter, as recited at instant claim 9.
Copending claim 14 recites that the cytidine deaminase claimed therein is APOBEC-1, as recited at instant claim 11.
Copending claim 18 recites “a nucleic acid sequence comprising a nucleic acid sequence encoding a heterologous polypeptide, a[n] m6A sensor sequence, and, a polypeptide encoding dihydrofolate reductase (DHFR),” which is also recited at instant claim 15. However, instant claim 15 recites “an effector protein polypeptide” in place of the “heterologous polypeptide” of the copending application. However, as set forth above, one of ordinary skill in the art would have been motivated based on the disclosure of Lan to utilize an effector protein such as SOCS2 in place of the heterologous polypeptide generically claimed by the copending application.
Copending claims 19, 20, and 22 respectively recite a vector and a host cell comprising the expression system of claim 1, as well as a non-human transgenic animal comprising the claimed host cell. These are also recited at instant claims 16-18.
With regard to instant claims 14, as set forth above (see section Claim Interpretation), instant claim 12 from which instant claim 14 depends requires either a tumor suppressor protein or a catalytically dead RNA-guided endonuclease. Accordingly, the tumor suppressor protein SOCS2 disclosed in Lan and set forth above meets the limitations of claim 12 and claim 14, as claim 14 further limits the catalytically dead RNA-guided endonuclease, which is not required by claim 12.
With regard to instant claim 19, per MPEP § 2111.02(II) the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight. Therefore, while the copending application does not explicitly recite a kit comprising the instantly claimed system, it does recite the instantly claimed system, as set forth above, and therefore is considered to read on the instantly claimed kit.
Given that the copending application recites an identical system to the instantly claimed system, wherein m6A detection drives expression of a protein of interest, with the exception of reciting “a heterologous protein” instead of “an effector protein” such as a tumor suppressor protein, and that Lan discloses that m6A is globally hypermethylated in cancer via METTL3, which also downregulates tumor suppressor protein expression such as SOCS2, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize an effector protein such as tumor suppressor SOCS2 as the heterologous protein of the copending system to predictably express SOCS2 in an m6A-dependent manner. One would have been motivated to make such a modification in order to receive the expected benefit of expressing SOCS2 in an m6A-dependent manner, thereby upregulating SOCS2 expression in cancer cells with global m6A hypermethylation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Claims 1, 4, 13, and 15 are objected to.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 2020/0377617 A1 (hereinafter Meyer; as cited in Applicant IDS) discloses fusion proteins (and polynucleotides encoding the same) that can be used to edit RNA and detect m6A residues, said fusion proteins comprising an N6-methyladenosine (m6A) binding domain of a YT521-B homology (YTH) domain-containing protein fused to a catalytic domain of a cytidine deaminase or a catalytic domain of an adenosine deaminase (paragraphs [0006] and [0010]). The fusion proteins of Meyer facilitate detection of m6A residues in isolated RNA by sequencing the one or more target sequences to identify cytidine to uridine deamination at sites adjacent to m6A residues (paragraph [0011]). Thus, Meyer discloses the first DNA construct of the instant application. However, Meyer is silent as to the second DNA construct.
It is known in the art that m6A RNA modifications are disrupted in oncogenesis such that associated methyltransferases (i.e. METTL3), demethylases, and m6A-binding proteins are frequently upregulated in human cancer tissues (Lan: abstract). This phenomenon has potential therapeutic implications, as targeting m6A modifications with inhibitors is predicted to reduce oncotranscript and oncoprotein expression, cancer cell proliferation, survival, tumor initiation, progression, and metastasis (Lan: abstract; page 1290, column 2, paragraph 1). Importantly, the disclosure of Lan establishes that m6A modifications are associated with oncogenesis, cancer cell proliferation, progression, and metastasis. However, Lan does not disclose the instantly claimed second DNA construct.
The second DNA construct comprises a nucleic acid sequence encoding an effector protein, an m6A sensor sequence, and a polynucleotide encoding a dihydrofolate reductase. Per the instant specification, the instantly claimed m6A sensor sequence comprises two m6A consensus motifs and two tandem convertible stop codon sequences that are in-frame with the claimed effector protein (paragraph [0066]). Meyer discloses m6A consensus sequences (paragraph [0138]) but does not disclose their utility in a sensor sequence construct, as instantly claimed. While the other components of the instantly claimed m6A sensor sequence are generally known in the art, a search of the patent and non-patent literature did not return any prior art that fairly taught, suggested, or motivated combining these known components as in the instant claim set to arrive at the instantly claimed invention without employing hindsight reasoning.
However, the second DNA construct of the instant application is also claimed in copending application 18/709,703, as set forth above.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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