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 .
Response to Amendment
This action is in response to the papers filed September 12, 2025. Applicant's remarks and amendments have been fully and carefully considered and responded in this office action. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicant's election of Group I (a nucleic acid template) in the response filed May 12, 2025 is reiterated for the record. Claims 11-15 and 20 were withdrawn by the office in the action mailed June 12, 2025, pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 12, 2025.
It is acknowledged that Applicant amended claims 1-10, 18, and 19 and cancelled claims 16 and 17 in the response filed September 12, 2025.
Claims 1-15 and 18-20 are currently pending. Claims 1-10, 18, and 19 are currently under examination.
Priority
This application is a U.S. National Phase of International Application No. PCT/GB2020/051003, filed April 23, 2020, which claims priority to United Kingdom Patent
Application No. GB 1905651.4, filed April 23, 2019.
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119
(a)-(d). The certified copy of GB 1905651.4 has been filed on 10/21/2021.
The priority date is determined to be April 23, 2019, the filing date of GB 1905651.4.
Response to Arguments over 35 U.S.C. 112(b)
In the response filed October 31, 2025, Applicant amended claim 1 to provide antecedent basis for ‘the sequestered end’ in claim 19. This amendment was considered, and the rejection withdrawn.
However, in the response, Applicant substantially amended claims 1, 4, and 6 (with minor amendments to claims 2-10, 18, and 19). It is noted for the record that these amendments introduced language and limitations raised additional considerations and led to new rejections under 25 U.S.C. 112(b). Since the Applicant’s amendments necessitated these new grounds of rejection, this action is considered final.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10, 18, and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-10, 18, and 19 are rejected for the recitation of ‘self-complementary’ in line 9 of claim 1, because it is unclear which processing motif(s) contain(s) sequences which are self-complementary. The claim recites a first and a second processing motif, but describes the ‘self-complementary sequences’ being included in ‘a processing motif.’ If ‘a processing motif’ is meant to describe either of the first or second processing motifs, it is unclear whether the first and second processing motifs are meant to be identical. Therefore, it is unclear whether the self-complementary sequences are intended to be contained within a single processing motif or if the first and second processing motifs may contain sequences which are complementary to each other. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 1-10, 18, and 19 are rejected for the recitation of ‘the single-stranded nucleic acid’ in lines 13-14 of claim 1, because it is unclear which single stranded nucleic acid is being referred to. In the preamble, claim 1 recites a plurality of single-stranded nucleic acids (‘single-stranded nucleic acid constructs with sequestered ends’) as well as the single stranded nucleic acid template for producing those constructs. Therefore, it is unclear whether the conformational motif is required to be capable of forming the sequestered end in the nucleic acid template itself or in the manufactured nucleic acid constructs. It is unclear whether the terminal nucleotide must be present at the end of the template or at the end of each construct. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. Clarification is requested.
Claims 1-10, 18, and 19 are rejected for the recitation of ‘a conformational motif’ in line 12 of claim 1, because it is unclear which conformational motif(s) is/are required to be able to assume a conformation which acts to secure a terminal nucleotide. For example, would the claim’s limitations be satisfied if the first conformational motif was capable of such a conformation and the second one not capable? As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. Clarification is requested.
Claims 4, 18, and 19 are rejected for the recitation of ‘the terminal nucleotide is secured’ in claim 4, as being indefinite. Given that claim 1 is directed to a nucleic acid template which is merely ‘capable of’ assuming a conformation which acts to secure a terminal nucleotide, it is unclear when or under what conditions claim 4 is requiring the securement of the terminal nucleotide. Must it be constitutively secured with an unspecified structure, or merely able to be secured through the recited mechanisms of base-pairing or hydrogen bonding (for example, after a processing step)? As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. Clarification is requested.
Response to Arguments over 35 U.S.C. 102(a)(1)
Arguments concerning Nowak
In the response filed October 31, 2025, Applicant amended several claims, as discussed above. In the response, Applicant stated that they traversed the rejections over Nowak et al., arguing that the ribozyme processing motif of Nowak comprises a conformation which does not include a conformational motif that both (a) includes at least one sequence capable of forming intramolecular hydrogen bonds and (b) assumes a conformation which acts to secure the terminal nucleotide at the end of the single stranded nucleic acid, forming a sequestered end. Applicant argued that if the independent claim is novel over Nowak, the dependent claims must also be novel over Nowak.
Regarding the arguments concerning Nowak, the arguments have been fully considered. It is noted for the record that the amended claims are now being rejected over a new combination of references. Since the Applicant’s amendments necessitated these new grounds of rejection, this action is considered final.
Arguments concerning McCarty
In the response, Applicant amended claims as discussed above. In the response, Applicant stated that they traversed the rejections over McCarty et al. Applicant argued (a) that McCarty does not teach both a processing motif and a separate conformational motif, nor a processing motif with self-complementary sequences, (b) that McCarty doesn’t teach a separate conformational motif that secures the terminal nucleotide, forming a sequestered end and (c) that if the independent claim is novel over McCarty, the dependent claims must also be novel over McCarty.
These arguments have been fully considered, and found persuasive. The rejection of claims 1-10 and 16-19 under 35 U.S.C. 102(a)(1) as being anticipated by Nowak et al. (Nucleic Acids Res; 44(20):9555-9564; 2016) is withdrawn.
It is noted for the record that the amended claims are now being rejected over a new combination of references as documented below. Since the Applicant’s amendments necessitated these new grounds of rejection, this action is considered final.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10, 18, and 19 are rejected under 35 U.S.C. 103 as unpatentable over Kotin et al. (published Mach 14, 2019; International Publication No. WO 2019/051255; Foreign Patent Document #2 in the IDS filed by Applicants on 9/26/22) in view of Kool (published April 9, 2002; US Patent No. 6,368,802).
Regarding claim 1, Kotin teaches nucleic acids suitable for the cell-free, in vitro manufacture of single stranded nucleic acid constructs (par. 101, 331). Although Kotin does not explicitly teach that the generated constructs have sequestered ends, as noted in MPEP 2111.02, “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.” Accordingly, the claim language of “for the cell-free, in vitro manufacture of single stranded nucleic acid constructs with sequestered ends” merely sets forth the intended use of the claimed composition, but does not limit the scope of the claims.
Kotin teaches a sequence encoding the following elements in a single stranded nucleic acid from 5' to 3': a first processing motif, adjacent to a first conformational motif, a sequence of interest, a second conformational motif, adjacent to a second processing motif (Fig. 1C; par. 110-111, 113). In Figure 1C (shown below):
First processing motif = R1
First conformational motif = first Δ ITR
Sequence of interest = ORF
Second conformational motif = second Δ ITR
Second processing motif = R6
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Kotin teaches conformational motifs which include at least one sequence capable of forming intramolecular hydrogen bonds and of assuming a conformation which acts to secure a terminal nucleotide at the end of the single stranded nucleic acid, forming a sequestered end (par. 101; Fig. 1C). In Kotin’s Fig. 1C, the conformational motifs are ITRs, which for example can form intramolecular duplexes (par. 70) that result in closed ends which secure or sequester the terminal nucleotide(s) (par. 75, 101).
Regarding claims 1 and 3, Kotin teaches processing motifs which include recognition sites for an endonuclease and an associated cleavage site (Fig. 1C – R1 and R6; par. 401).
However, Kotin does not teach that the processing motifs include self-complementary sequences capable of forming base-paired sections and does not explicitly teach that the cleavage sites for the endonuclease within the processing motif are at a terminal base pair in the base-paired section.
Regarding claim 1, Kool teaches processing motifs including self-complementary sequences capable of forming base-paired sections (col 10, ln. 33-44). In Kool, the processing motifs are hairpin forming sequences which are cleaved by Type II restriction enzymes.
Regarding claim 3, Kool teaches that the cleavage site for the endonuclease within the processing motif is at a terminal base pair in the base-paired section (col. 22, last par. – col. 23-24: Scheme II). A section of Kool’s Scheme II is shown below, and the terminal base pair/cleavage site is indicated with a circle:
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It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kotin and Kool with a reasonable expectation of success because Kool’s Example 3 demonstrates that hairpin restriction sites can be successfully engineered into closed nucleic acids such as the ceDNA of Kotin (col. 22, ln. 50 – col. 24). One would have been motivated to do so in order to have the entire cleavable group removed and to leave only the desired sequence remaining in a construct (col 10, ln. 40-44).
Regarding claim 2, Kotin teaches cleavage sites within a processing motif which are adjacent to a conformational motif (Fig. 1C). In Figure 1C, R1 and R6 are the processing motifs which contain a cleavage site and which are adjacent to the ITRs (conformational motifs).
Regarding claim 4, Kotin teaches a terminal nucleotide which is secured by inclusion within the conformation assumed and/or by intramolecular base pairing or hydrogen bonding (par. 70, 101). In this case, the terminal nucleotides are secured in a conformation such as an intramolecular duplex formed by two complementary ITRs.
Regarding claim 5, Kotin teaches that the single stranded nucleic acid construct includes aptamers and/or nucleic acid enzymes (par. 63). Here, the nucleic acid enzyme is a ribozyme.
Regarding claims 6 and 7, Kotin teaches conformational motifs wherein intramolecular hydrogen bonds form between the nucleotide bases in the sequence of the conformational motif (par. 65). In this case, the hairpin structures of the ITR are formed through complementary base-pairing, and therefore comprised of intramolecular hydrogen bonds in the form of Watson-Crick base pairs.
Regarding claim 8, Kotin teaches conformational motifs capable of assuming hairpin or stem loop conformations (par. 65). Note that hairpins and stem loops are considered to be synonyms.
Regarding claims 9, 10, 18, and 19, Kotin teaches ITR structures with a double stranded D region having intramolecular base-pairing (Figure 2A, par. 126, 128). Although Kotin does not explicitly teach that the sequestering of the terminal nucleotides of the construct are involved in the base-pairing or included in an ITR structure with a double-stranded D region, such a configuration would follow from the combination of Kotin and Kool. That is, as discussed above, Kool teaches hairpin restriction sites in a circular template molecule which are completely excised from a nucleic acid construct (col. 10, ln. 22-43). The construct of Kotin (Fig. 1C) explicitly touts the benefit of exonuclease resistance (par. 101) and contains processing motifs adjacent to and external to ITR structures (Fig. 1C). These ITR structures sequester a terminal end through base pairing within a double-stranded D region (Fig. 2A, shown below). Here, either the D or D’ segments could be considered the terminal end, depending on which end of the construct the given ITR is attached.
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Therefore, once the processing motifs were excised, the terminal ends would be sequestered through (for example) the circled nucleotide base pairing above.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine M Jones whose telephone number is (571)272-2585. The examiner can normally be reached Monday - Friday, 8AM - 4PM.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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