DETAILED ACTION
Receipt of Arguments/Remarks filed on March 30 2026 is acknowledged. Claims 1-20, 22, 28 and 53 were/stand cancelled. Claims 21, 23-24, 26-27, 34, 46 and 54 were amended. Claims 21, 23-27, 29-52 and 54 are pending.
Applicants are reminded that pursuant to MPEP 714 and 37 CFR 1.121, amendments to a claim must be made by rewriting the entire claim with all changes. All claims being currently amended must contain the status of currently amended. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. In the response filed March 30 2026, claims 24-27, 29-30, 32-33, 35, 37, 41 and 43 all contain claim amendments but the changes are not reflected in the claims and the claims do not include a status identifier of currently amended.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 31 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
New and Modified Rejections Necessitated by the Amendments filed March 30 2026
Claim Rejections - 35 USC § 112-Indefiniteness
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 24-27 and 29-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 24 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 24 recites the limitation The system…the R2 retroelement… the D. simulans R2 retroelement in lines 1-2. There is insufficient antecedent basis for these limitation in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 25 as currently written is vague and indefinite. Firstly, the claim depends from claim 224 but this claim is not pending. Secondly, claim 25 recites the limitation The system…the 5’ UTR in line 1. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 26 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 26 recites the limitation The system…the R2 retroelement…the B.mori R2 retroelement in lines 1-2. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 27 as currently written is vague and indefinite. Firstly, the claim depends from claim 226 but this claim is not pending. Secondly, claim 27 recites the limitation The system…the 3’ UTR in line 1. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 29 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 29 recites the limitation the system… the R2 retroelement. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 30 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 30 recites the limitation the system…the second nucleic acid…the R2 retroelement. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 32 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 32 recites the limitation the system…the first nucleic acid. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 33 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 33 recites the limitation The system…the first nucleic acid. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 35 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 35 recites the limitation The system…the first nucleic acid. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 37 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 37 recites the limitation The system…the first nucleic acid…the 3’ UTR. There is insufficient antecedent basis for these limitations in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 41 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 41 recites the limitation The system. There is insufficient antecedent basis for this limitation in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claim 43 as currently written is vague and indefinite. Firstly, the claim depends from claim 221 but this claim is not pending. Secondly, claim 43 recites the limitation The system. There is insufficient antecedent basis for this limitation in the claim. Since the claim depends from a claim that is not pending, there is no antecedent basis for the limitations.
Claims 31, 34, 36, 38-40, 42, 44-45 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Examiner’s Comment
In light of the dependency issues identified above and in the interest of compact prosecution, claims 24, 26, 29, 30, 32-33, 35, 37, 41 and 43 are interpreted as depending from claim 21; claim 25 is interpreted as depending from claim 24; claim 27 is interpreted as depending from claim 26.
Claim Rejections - 35 USC § 112-failure to further limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 23 and 54 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 23 depends from claim 21. Claim 21 recites wherein:(I) the R2 retroelement polypeptide is a Drosophila simulans (D. simulans) R2 retroelement polypeptide, wherein the 5' UTR sequence and the D. simulans R2 retroelement polypeptide are derived from different species, or (II) the R2 retroelement polypeptide is a Bombyx mori (B. mori) R2 retroelement polypeptide, wherein the 3' UTR sequence and the B. mori R2 retroelement polypeptide are derived from different species. However, claim 23 recites the 5' UTR sequence or the 3' UTR sequence is derived from an R2 retroelement selected from the group consisting of: a D. simulans R2 retroelement, an 0. latipes R2 retroelement, and a B. mori R2 retroelement which is broader in scope as this allows for the 5’ UTR to be derived from an R2 retroelement which is D. simulans, for example, but claim 23 requires it to be from a different species. Therefore, claim 23 appears broader in scope as it allows for the 5’ UTR or 3’ UTR to be of the same species as the R2 retroelement.
Claim 54 depends from claim 46. This claim contains the same issues as claim 23 above. Claim 54 broadens the scope of the 5’UTR and the 3’UTR
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21, 23-27, 29-52 and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Rubens et al. (USPGPUB No. 20200109398, cited on PTO Form 1449).
Applicant Claims
The instant application claims a system comprising:
a first nucleic acid comprising (i) a 5’ untranslated region (UTR) sequence and
a 3’ untranslated region (UTR) sequence, and (ii) a template sequence wherein the first nucleic acid is configured to bind to an R2 retroelement polypeptide; and
(b) the R2 retroelement polypeptide or a second nucleic acid encoding the R2
retroelement polypeptide, wherein: (I) the R2 retroelement polypeptide is a Drosophila simulans (D. simulans) R2 retroelement polypeptide,
wherein the 5’ UTR sequence and the D. Simulans R2 retroelement polypeptide are derived
from different species; or (II) the R2 retroelement polypeptide is Bombyx mori (B.mori) R2 retroelement polypeptide,
wherein the 3’ UTR sequence and the B. Mori R2 retroelement polypeptide are derived
from species.
The instant application claims a cell comprising the system.
The instant application claims a method of modifying a target nucleic acid in a cell, the method comprising providing the cell with:
a first nucleic acid comprising (i) a 5’ untranslated region (UTR) sequence and
a 3’ untranslated region (UTR) sequence, and (ii) a template sequence wherein the first nucleic acid is configured to bind to an R2 retroelement polypeptide; and
(b) the R2 retroelement polypeptide or a second nucleic acid encoding the R2
retroelement polypeptide, wherein: (I) the R2 retroelement polypeptide is a Drosophila simulans (D. simulans) R2 retroelement polypeptide,
wherein the 5’ UTR sequence and the D. Simulans R2 retroelement polypeptide are derived
from different species; or (II) the R2 retroelement polypeptide is Bombyx mori (B.mori) R2 retroelement polypeptide,
wherein the 3’ UTR sequence and the B. Mori R2 retroelement polypeptide are derived
from species.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Rubens et al. is directed to methods and compositions for modulating a genome. Claimed is a method of modifying a target DNA strand in a cell, tissue or subject, comprising administering a system for modifying DNA comprising: a polypeptide or a nucleic acid encoding a polypeptide capable of target primed reverse transcription (TPRP), wherein the polypeptide comprises (a) a reverse transcriptase domain and (b) an endonuclease domain, wherein at least one of (a) or (b) is heterologous, and a template RNA comprising (i) a sequence that binds the polypeptide and (ii) a heterologous object sequence.to the cell, tissue or subject, wherein the system reverse transcribes the template RNA sequence into the target DNA strand, thereby modifying the target DNA strand (claim 1; 22). The reverse transcriptase domain is a retrotransposon which includes a RLE-type non-LTR retrotransposon R2 (i.e. a R2 retroelement). The cells are eukaryotic (paragraph 0189). Exemplified is a polypeptide of the system being a R2Bm protein from Bombyx mori and the template RNA component is RNA coding for the GFP protein and flanked at the 5’ end by the 5’ UTR and at the 3’ end by the 3’ UTR of the R2Bm retrotransposase from Bombyx mori. The GFP gene has a polyA tail downstream of its stop codon (i.e. 3’ end) (example 3). Other R2 elements include D. simulans and O. latipes (Table 1). Tables 1-3 provide the sequence of exemplary transposons, including the amino acid sequence, the sequence of the 5’ and 3’ untranslated regions (UTR) and the full transposon nucleic acid sequence (paragraph 0130). Example 4 uses the R2Bm polypeptide of Bombyx mori which is modified by replacing its DNA binding domain in the amino terminus of the polypeptide with a zinc-finger DNA binding domain. The DNA binding domain is attached to the polypeptide at the N-terminal or C-terminal ends (paragraph 0105). The template RNA (e.g. a 5’ untranslated region) comprises a ribozyme which has self-cleavage activity (paragraph 0162). Homology domains of at least 10 bases flanking the 5’ and 3’ end are suggested (paragraph 0048; 0098; 0159; 0250). Exemplified Bombyx mori sequence have 2 A polyA tail. Others such as D. simulans has 23 polyA talk (SEQ ID NO: 1366). It is generally taught that the polyadenylation site may be used to provide other genetic elements required for expression of a heterologous DNA sequence (paragraph 0183). A target locus (e.g. rDNA) in the cell genome is taught (paragraph 0138-0139). Target genes are 28S rDNA (table 4). It is taught the system or components of the system are delivered to cells. Delivery can be with viral-like particles, lipids and exomes (paragraph 0205-0209). Transfection of the polypeptide in cells and template RNA is exemplified (example 3).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Rubens teaches R2 elements from D. simulans, B. mori and O. latipes, Rubens et al. does not exemplify wherein either the 5’UTR or 3’UTR and the R2 retroelement polypeptide are derived from different R2 retroelements.
However, Rubens et al. does teach that swapping of the 5’ and/or 3’ UTR binding module and/or changes to the RNA binding/RT module will lead to better interactions than the wild-type R2 protein or UTR. The increased interaction will lead to an increase in efficacy of retro-transposition and in some cases increases specificity of the R2 protein to interact with the RNA (paragraph 0279). Swapping is taught as increasing protein interactions, changes to protein specificity, stabilizes against nuclease and/or improves cellular tolerance (paragraph 0278). It is taught that the template RNA has a 3’ UTR and/or 5’ UTR homologous to any of the non-LTR retrotransposon in tables 1-3 (paragraph 0159).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 21, exemplified is a polypeptide of the system being a R2Bm protein from Bombyx mori (reading on (b)) and the template RNA component is RNA coding for the GFP protein and flanked at the 5’ end by the 5’ UTR and at the 3’ end by the 3’ UTR of the R2Bm retrotransposase from Bombyx mori (reading on a first nucleic acid).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a 5’ UTR and/or 3’ UTR derived from a different R2 retroelement. One skilled in the art would have been motivated swap the native UTR with other R2 UTR in order to increase the protein binding and/or efficacy of the retrotransposon as taught by Rubens et al.
Regarding claims 23-27 and 54, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize any of the specifically taught R2, 5’ UTR or 3’ UTR. One skilled in the art would have been motivated to try any of the specifically taught UTR as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). Since Rubens et al. recognizes that swapping can lead to advantages there is motivation to try any of the specifically taught UTRs absent a demonstration of an unexpected or unobvious result.
Regarding claims 29-30, Rubens et al. expressly claims either the polypeptide or the nucleic acid encoding the polypeptide.
Regarding claim 31, RNA are expressly taught.
Regarding claim 32-36, the instant specification (paragraph 0036) teaches that the structure is a self-cleaving ribozyme motif or polyadenylation tail. Rubens et al. the GFP gene has a polyA tail downstream of its stop codon (i.e. 3’ end) (example 3). The template RNA (e.g. a 5’ untranslated region) comprises a ribozyme which has self-cleavage activity wherein in some embodiments the ribozyme is similar to an hepatitis delta virus ribozyme (paragraph 0162). Therefore both structures configured to protect the template sequence from degradation are taught by Rubens et al. Regarding the length of the polyA tail, firstly Rubens et al. teaches sequences with lengths falling within the instant scope. Additionally Rubens et al. teaches the polyadenylation site may be used to provide other genetic elements required for expression of a heterologous DNA sequence (paragraph 0183). This provides the motivation to manipulate the length of the polyadenylation tail in order to achieve the desired effect.
Regarding claims 37-40, Rubens et al. teaches homology domains of at least 10 bases flanking the 5’ and 3’ end (paragraph 0048; 0098; 0159; 0250). Rubens et al. teaches flanking the protein interaction domains are 5’ and 3’ homology domains, which have homology to the desired insertion region in the genome (paragraph 0098). Example 12 also teaches experimentation with different homology lengths. Lengths of 2-101 are taught (paragraph 0265). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 41-42 and 47, Rubens et al. teaches rDNA as a target nucleic acid (table 4).
Regarding claims 43-45, Rubens et al. teaches a host cell comprising the system wherein the host cell is a human cell (paragraph 0048). Delivery to cells (e.g. human cells; eukaryotic cells) is taught (paragraph 0189).
Regarding claim 46, Rubens et al. expressly claims and exemplifies a method of modifying a target nucleic acid in a cell (claim 1, example 3, example 4).
Regarding claim 48, Rubens et al. teaches target genes are 28S rDNA (table 4).
Regarding claim 49 and 51, It is taught the system or components of the system are delivered to cells. Delivery can be with viral-like particles, lipids and exomes (paragraph 0205-0209). Transfection of the polypeptide in cells is exemplified (example 3). Since the system or components are delivered, it reads on both the R2 retroelement as well as the first nucleic acid being delivered with a lipid, exosome or virus-like particle.
Regarding claim 50 and 52, transfection of the polypeptide in cells and template RNA is exemplified (example 3).
Response to Arguments
Applicants’ arguments filed March 30 2026 have been fully considered but they are not persuasive.
Applicants argue (page 6-8) that Rubens does not teach or suggest all of the elements of claim 21. Specifically Rubens does not teach the claimed R2 retroelement (D. Simulans) and 5’ UTR which is derived from a different species or the claimed R2 retroelement is B. mori and the 3’UTR is from a different species. The Office references paragraph 0279, does not remedy the deficiency as this general disclosure does not teach, disclose or suggest the claims as amended. Rubens in paragraph 0132 describes the content in a large table of over 1500 sequences. The 5’ UTR and the 3’ UTR of each of these sequences appear to be regions from the same species. A person of ordinary skill in the art would have no reason to select the combination as instantly claimed. It is argued that claim 46 has been amended similarly and is not obvious for the same reasons.
Regarding Applicants arguments, the examiner recognizes that Rubens does not expressly teach a 5’ UTR or 3’UTR from a different species, but that is why the rejection is made under 103. A rejection made under 103 does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. While Applicants argue that there is a large table of over 1500 sequences. Rubens teaches in paragraph 0130 (emphasis added): Tables 1-3 herein provide the sequences of exemplary transposons, including the amino acid sequence of the retrotransposase, and sequences of 5′ and 3′ untranslated regions to allow the retrotransposase to bind the template RNA, and the full transposon nucleic acid sequence. In some embodiments, a 5′ UTR of any of Tables 1-3 allows the retrotransposase to bind the template RNA. In some embodiments, a 3′ UTR of any of Tables 1-3 allows the retrotransposase to bind the template RNA. Thus, in some embodiments, a polypeptide for use in any of the systems described herein can be a polypeptide of any of Tables 1-3 herein, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. In some embodiments, the system further comprises one or both of a 5′ or 3′ untranslated region of any of Tables 1-3 herein (or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto), e.g., from the same transposon as the polypeptide referred to in the preceding sentence, as indicated in the same row of the same table. In some embodiments, the system comprises one or both of a 5′ or 3′ untranslated region of any of Tables 1-3 herein, e.g., a segment of the full transposon sequence that encodes an RNA that is capable of binding a retrotransposase, and/or the sub-sequence provided in the column entitled Predicted 5′ UTR or Predicted 3′ UTR. This paragraph makes it clear that the UTRs can, in one embodiment, be from the same transposon however, the broader teachings are that only one is of the 5’ or 3’ UTR need to be from the same UTR. Paragraph 0132 is the results from a variety of retrotranposases and the examples show the predicted 3’ and 5’ UTR regents that would correspond to the same R2. But the scope of Rubens is not limited to such a scope. As pointed to previously by the examiner, paragraph 0278 states: The RNA molecule binds to the R2 protein via interactions found in the reverse transcriptase module, designated as a sub-module “RNA binding”. The protein recognizes specific structures in the 5′ and/or 3′ UTRs to interact with the RNA. This section again suggests while one of the 5’ or 3’ UTR needs to be of the same species but not both need to be of the same species. This paragraph then goes on to suggest that swapping of the UTR increases protein interactions and changes the protein specificity, etc. which provides the motivation to change either the 3’ or 5’ UTR to a different species. While Rubens might suggest a variety of different species, there is still a finite list of species to choose from. “Disclosure of a multitude of effective combinations does not render any particular formulation less obvious.” Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Nothing in the response filed indicates an unexpected or unobvious effect combining the instant claimed R2 retroelement with a UTR from a different species.
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 21, 23-27, 29-32 and 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-12, 14-20 and 26 of copending Application No. 17257796 (USPGPUB No. 20210285009) in view of Rubens et al. (USPGPUB No. 20200109398, cited on PTO Form 1449). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims a system comprising:
a first nucleic acid comprising (i) a 5’ untranslated region (UTR) sequence and
a 3’ untranslated region (UTR) sequence, and (ii) a template sequence wherein the first nucleic acid is configured to bind to an R2 retroelement polypeptide; and
(b) the R2 retroelement polypeptide or a second nucleic acid encoding the R2
retroelement polypeptide, wherein: (I) the R2 retroelement polypeptide is a Drosophila simulans (D. simulans) R2 retroelement polypeptide,
wherein the 5’ UTR sequence and the D. Simulans R2 retroelement polypeptide are derived
from different species; or (II) the R2 retroelement polypeptide is Bombyx mori (B.mori) R2 retroelement polypeptide,
wherein the 3’ UTR sequence and the B. Mori R2 retroelement polypeptide are derived
from species.
The instant application claims a cell comprising the system.
The instant application claims a method of modifying a target nucleic acid in a cell, the method comprising providing the cell with:
a first nucleic acid comprising (i) a 5’ untranslated region (UTR) sequence and
a 3’ untranslated region (UTR) sequence, and (ii) a template sequence wherein the first nucleic acid is configured to bind to an R2 retroelement polypeptide; and
(b) the R2 retroelement polypeptide or a second nucleic acid encoding the R2
retroelement polypeptide, wherein: (I) the R2 retroelement polypeptide is a Drosophila simulans (D. simulans) R2 retroelement polypeptide,
wherein the 5’ UTR sequence and the D. Simulans R2 retroelement polypeptide are derived
from different species; or (II) the R2 retroelement polypeptide is Bombyx mori (B.mori) R2 retroelement polypeptide,
wherein the 3’ UTR sequence and the B. Mori R2 retroelement polypeptide are derived
from species.
Copending ‘796 claims a gene delivery vehicle system comprising: a) a first nucleic acid and a second nucleic acid, wherein: i) the first nucleic acid comprises a nucleotide sequence encoding an R2 retrotransposon R2 polypeptide, wherein the R2 polypeptide comprises an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence depicted in SEQ ID NO:37 (which the specification teaches is Bombyx mori); and ii) the second nucleic acid comprises a heterologous nucleotide sequence encoding one or more heterologous gene products, wherein the heterologous nucleotide sequence is flanked by an R2 retrotransposon 3' untranslated region (UTR) and an R2 retrotransposon 5' UTR, and wherein the heterologous nucleotide sequence has a length of at least 200 nucleotides, and wherein the R2 polypeptide-encoding nucleotide sequence is codon optimized for expression in a eukaryotic cell; or b) a polypeptide and a nucleic acid, wherein: i) the polypeptide is an R2 retrotransposon R2 polypeptide; and ii) the nucleic acid comprises a heterologous nucleotide sequence encoding one or more heterologous gene products, wherein the heterologous nucleotide sequence is flanked by an R2 retrotransposon 3' UTR and an R2 retrotransposon 5' UTR, and wherein the heterologous nucleotide sequence has a length of at least 200 nucleotides. A method of delivery one or more gene products of interest to a eukaryotic cell is claimed.
The difference between the instant claims and copending ‘796 is that copending ‘796 does not expressly claim that either the 3’ UTR or the 5’ UTR are derived from different R2 retroelements than the R2 retroelement polypeptide. However, this deficiency is cured by Rubens et al.
Rubens et al. does teach that swapping of the 5’ and/or 3’ UTR binding module and/or changes to the RNA binding/RT module will lead to better interactions than the wild-type R2 protein or UTR. The increased interaction will lead to an increase in efficacy of retro-transposition and in some cases increases specificity of the R2 protein to interact with the RNA (paragraph 0279). Swapping is taught as increasing protein interactions, changes to protein specificity, stabilizes against nuclease and/or improves cellular tolerance (paragraph 0278). It is taught that the template RNA has a 3’ UTR and/or 5’ UTR homologous to any of the non-LTR retrotransposon in tables 1-3 (paragraph 0159).
Regarding claim 21-22, copending ‘796 claims the R2 retrotransposon polypeptide exemplified is Bombyx mori (reading on (b)) and the second nucleic acid comprises a heterologous nucleotide sequence flanked at the 5’ end by the 5’ UTR and at the 3’ end by the 3’ UTR.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796 and Rubens et al. and utilize a 5’ UTR and/or 3’ UTR derived from a different R2 retroelement. One skilled in the art would have been motivated swap the native UTR with other R2 UTR in order to increase the protein binding and/or efficacy of the retrotransposon as taught by Rubens et al.
Regarding claims 23-27 and 54, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796 and Rubens et al. and utilize any of the specifically taught R2, 5’ UTR or 3’ UTR. One skilled in the art would have been motivated to try any of the specifically taught UTR as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). Since Rubens et al. recognizes that swapping can lead to advantages there is motivation to try any of the specifically taught UTRs absent a demonstration of an unexpected or unobvious result.
Regarding claim 28, The instant specification teaches that R2 D-clade subgroups contain one N-terminal zinc finger (paragraph 0016). As exemplified by Rubens et al., Example 4 uses the R2Bm polypeptide of Bombyx mori which is modified by replacing its DNA binding domain in the amino terminus of the polypeptide with a zinc-finger DNA binding domain. The DNA binding domain is attached to the polypeptide at the N-terminal or C-terminal ends (paragraph 0105). It is taught that attaching a zinc finger to a DNA binding domain exhibits increased binding to the target DNA sequence without competition with the rDNA (paragraph 0105). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796 and Rubens et al. and utilize a zinc finger with the R2 polypeptide in order to increasing binding as taught by Rubens et al.
Regarding claims 29-30, copending ‘796 expressly claims either the polypeptide or the nucleic acid encoding the polypeptide.
Regarding claim 31, RNA are expressly claimed.
Regarding claim 32-36, the instant specification (paragraph 0036) teaches that the structure is a self-cleaving ribozyme motif or polyadenylation tail. Copending ‘796 claims a nucleotide sequencing encoding a self-cleaving polypeptide (see claim 10). Rubens et al. the GFP gene has a polyA tail downstream of its stop codon (i.e. 3’ end) (example 3). The template RNA (e.g. a 5’ untranslated region) comprises a ribozyme which has self-cleavage activity (paragraph 0162). Therefore both structures configured to protect the template sequence from degradation are taught by Rubens et al. Regarding the length of the polyA tail, firstly Rubens et al. teaches sequences with lengths falling within the instant scope. Additionally Rubens et al. teaches the polyadenylation site may be used to provide other genetic elements required for expression of a heterologous DNA sequence (paragraph 0183). This provides the motivation to manipulate the length of the polyadenylation tail in order to achieve the desired effect. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796 and Rubens et al. and utilize a polyadenylated tail in order to provide for other genetic elements required for expression.
Regarding claims 37-40, Rubens et al. teaches homology domains of at least 10 bases flanking the 5’ and 3’ end are suggested (paragraph 0048; 0098; 0159; 0250). Rubens et al. teaches flanking the protein interaction domains are 5’ and 3’ homology domains, which have homology to the desired insertion region in the genome (paragraph 0098). Example 12 also teaches experimentation with different homology lengths. Lengths of 2-101 are taught (paragraph 0265). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 41-42 and 47, Rubens et al. teaches rDNA as a target nucleic acid (table 4). Copending ‘796 claims insertion into a 28S region (claim 26).
Regarding claims 43-45, Rubens et al. teaches a host cell comprising the system wherein the host cell is a human cell (paragraph 0048). Delivery to cells (e.g. human cells; eukaryotic cells) is taught (paragraph 0189). Copending ‘796 claims a eukaryotic cell.
Regarding claim 46, copending ‘796 expressly claims a method of modifying a target nucleic acid in a cell (claim 26).
Regarding claim 48, Rubens et al. teaches target genes are 28S rDNA (table 4) and copending ‘796 claims 28S region.
Regarding claim 49 and 51, Rubens et al. teaches the system or components of the system are delivered to cells. Delivery can be with viral-like particles, lipids and exomes (paragraph 0205-0209). Transfection of the polypeptide in cells is exemplified (example 3). Since the system or components are delivered, it reads on both the R2 retroelement as well as the first nucleic acid being delivered with a lipid, exosome or virus-like particle. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796 and Rubens et al. and utilize and utilize a lipid, exosome or virus-like particle in order to deliver the gene delivery vehicle system of copending ‘796. One skilled in the art would have been motivated to utilize these delivery vehicles are they are known ways of delivering similar systems as taught by Rubens et al.
Regarding claim 50 and 52, Rubens et al. exemplifies transfection of the polypeptide in cells and template RNA (example 3). Since copending ‘796 claims a similar system, it would have been obvious to transfect the cells with the system (i.e. polypeptide and second nucleic acid) in order to introduce the system into the cell. One skilled in the art would have a reasonable expectation of success as copending ‘796 claims the gene products are delivered to cells.
Response to Arguments
Applicants’ arguments filed March 30 2026 have been fully considered but they are not persuasive.
Applicants argue that copending ‘796 does not recite the required elements in the claims. As indicated in the rejection of the 103, Rubens also does not disclose these elements.
Regarding Applicants’ arguments, firstly while copending ‘796 does not expressly claim the recited elements, copending ‘796 is silent. Specifically, copending ‘796 does not indicate the species of the 3’ UTR or 5’ UTR. However, Rubens does suggest swapping of the 5’ UTR and/or 3’ UTR. Nothing in Applicants arguments establish an unexpected effect of the specifically claimed R2 retroelement and a 3’UTR and/or 5’ UTR from a different species.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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