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 .
Change in Examiner
The examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Stephanie Sullivan, Art Unit 1635.
Response to Amendment/Status of Claims
Claims 12,13,15,19,28,30-33,37,44,54,59 and 61 have been amended. Claims 1-11,16-18,20-26,29,34-36,38-43,45-53,55-58,60,62-83 and 85-102 were previously canceled. Claims 12,13,15,19,27,28,30-33,37,44,54,59,61 and 84 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 27,28,30-33,37,44,54,59,61 and 84) in the reply filed on 12/04/2025 is acknowledged.
Claims 12,13,15 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/04/2025.
Claims 27,28,30-33,37,44,54,59,61 and 84 are under examination.
Priority
This application is a DIV of 16/900,154, filed 06/12/2020 PAT 11,879,145 which claims benefit of 62/861,901, filed 06/14/2019.
Claim Objections
Claim 31 is objected to because of the following informalities: Claim 31 recites “wherein the first unnatural base comprises TPT3, the second unnatural base comprises CNMO or NaM, the third unnatural base comprises TAT1, and the fourth unnatural bases comprises NaM or 5FM. For complete clarity, either the full name of the unnatural base, or the structure should be recited in the claim so there is no ambiguity regarding the identity of what is meant by TPT3, CNMO, NaM, TAT1 and 5FM. In addition, there is a typo in line 3 of claim 31 where “bases” is plural and should be singular as recited in the other instances in the claim. Appropriate correction is required.
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 32 and 44 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 32 is indefinite, as lines 2-3 recite wherein the method comprises “use of a semi-synthetic organism, optionally wherein the organism is a bacterium, optionally wherein the bacterium is Escherichia coli”. The instant specification discloses, “As used herein, a "semi-synthetic organism" is an organism comprising an unnatural component, e.g., an expanded genetic alphabet including one or more unnatural bases” (paragraph 00253), however, claim 32 does not recite that the organism comprises an unnatural component such as an unnatural base, and reciting Escherichia coli doesn’t meet the requirement for this. The step in claim 32 is just “use of a semi-synthetic organism”, and does not refer back to any step or part of the claimed method of claim 27. For these reasons, claim 32 is not clear regarding the “use of” recited in the claim as how this relates to the method steps, as well as how Escherichia coli meets the standard of a semi-synthetic organism.
Claim 44 is indefinite as being both incomplete, by its dependence on a cancelled claim and for lack of antecedent basis for its limitation regarding the first unnatural base, the second unnatural base, the third unnatural base and the fourth unnatural base, which is no longer present due to the cancellation of base claim 34. Amending claim 44 to refer to a claim which recites the first unnatural base, the second unnatural base, the third unnatural base and the fourth unnatural base, or deleting the claim, would obviate the rejection.
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.
The factual inquiries 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 27,28,30,32,33,54,59,61 and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Nature, Vol. 551, 30 Nov 2017, pp. 644-647), cited on an IDS, in view of Romesberg et al. (US 20170029829, Published 2 Feb 2017).
Regarding claims 27,28,32 and 84, Zhang et al. teach a method of transcribing DNA to a tRNA or an mRNA encoding a protein, as Zhang et al. teach in vivo transcription of DNA containing dNaM and dTPT3 (first and second unnatural bases) into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of non-canonical amino acids into superfolder green fluorescent protein, and the results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions (Abstract). Zhang et al. teach a semi-synthetic organism strain with a plasmid encoding superfolder green fluorescent protein (sfGFP) with the native sfGFP codon 151 (TAC) replaced by the unnatural codon AXC (sfGFP(AXC)151; X denotes NaM)), and a transfer RNA comprising an anticodon comprising a second unnatural base (an E. coli tRNASer gene (serT) and the anticodon of serT replaced by the unnatural anticodon GYT (tRNASer(GYT); Y denotes TPT3) (page 644, left column, 2nd paragraph). Therefore, Zhang et al. teach NaM is the first unnatural base, and TPT3 is the second unnatural base, and dNaM and dTPT3 is an unnatural base pair (UBP) (Figure 1a). Zhang et al. teach the data indicate that PtNTT2 is able to import both the deoxy- and ribotriphosphates of both unnatural nucleotides, that T7 RNA polymerase is able to transcribe mRNA and tRNA containing the unnatural nucleotides in vivo, and that the ribosome only efficiently decodes the unnatural codon with an unnatural anticodon (page 2, paragraph 2).
Zhang et al. do not teach the ribonucleoside triphosphates comprising a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and second unnatural base pair are not the same, or wherein the ribonucleotide triphosphates further comprising a fourth unnatural base, wherein the fourth unnatural base is capable of forming a third unnatural base pair with the third unnatural base.
Romesberg et al. cures this deficiency. Romesberg et al. taught the development of a third, unnatural DNA base pair and an expanded genetic alphabet, is a central goal of synthetic and chemical biology and would increase the functional diversity of nucleic acids, providing tools for their site-specific labeling, increase the information potential of DNA, and lay the foundation of a semi-synthetic organism (paragraph 0010). Romesberg et al. taught that the limitation of only having four different base components (nucleotides) in standard nucleic acids restricts their functions and potential as compared to the 20 different amino acids in natural proteins, and that the UBPs and cells stably incorporating the UBPs described herein, offer numerous advantages and can be applied to a broad range of biotechnologies (paragraph 0011). Romesberg et al. taught the discovery that particular unnatural base pairs (UBPs) including but not limited to (d)5SICS-(d)NaM and (d)TPT3-(d)NaM can be amplified with natural base pair-like efficiency and fidelity….Thus, provided herein are methods, compositions, and kits, for increasing the genetic alphabet of cell or an organism (paragraph 00200), and methods of importing or incorporating natural and unnatural nucleotides into nucleic acids of a living cell, and methods of incorporating into a nucleic acid can comprises effecting transcription (paragraph 0201).
Romesberg et al. taught a variety of natural and unnatural nucleotides can be imported into cells, and one example of a pair of unnatural nucleotide triphosphates that can be transported into cells and that can base pair to form an UBP when incorporated into nucleic acids with the cells, includes a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP). One example of a pair of unnatural nucleotide triphosphates that can be transported into cells and that can base pair to form an UBP when incorporated into nucleic acids with the cells, includes a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP), which can be PCR amplified with a natural base pair-like efficiency and fidelity….One example of a pair of unnatural nucleotide triphosphates that can be transported into cells and that can base pair to form an UBP when incorporated into nucleic acids with the cells, includes a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity (paragraph 0226). Romesberg et al. taught other types of unnatural nucleotides can be imported into the cells by the nucleotide triphosphate transporter, such as (d)TPT3, (d)TPT3PA, (d)FTPT3, (d)NaM, (d)5SICS, (d)FEMO, (d)FIMO, (d)MMO2 and combinations thereof (paragraph 0227).
Regarding claim 30, Zhang et al. does not teach a step of before contacting the DNA with the ribonucleoside triphosphates and RNA polymerase, replicating the DNA by contacting the DNA with deoxyribonucleoside triphosphates and a DNA polymerase, wherein the ribonucleoside triphosphates comprise a fifth unnatural base capable of forming a fourth unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the fourth unnatural base pair are not the same.
However, Romesberg et al. taught methods of incorporating an unnatural nucleotide into a nucleic acid can comprise effecting transcription, replication, reverse transcription or translation of unnatural nucleotides into unnatural amino acids (paragraph 0201) and that endogenous or exogenous polymerases, can be utilized to replicate genomic DNA to form a containing a UBP within a cell (paragraph 0203). Romesberg et al. taught the pair of unnatural mutually base-pairing nucleotides as a respective triphosphate, can comprise a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP). The pair of unnatural mutually base-pairing nucleotides as a respective triphosphate, can comprise a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP). The cell can be E. coli, and the (d)5SICSTP and (d)NaMTP or (d)TPT3TP and (d)NaMTP can be efficiently imported into E. coli by, for example, the transporter PtNTT2, wherein an E. coli polymerase, such as Pol I, can efficiently use the unnatural triphosphates to replicate DNA, thereby incorporating unnatural nucleotides and/or UBPs into cellular nucleic acids within the cellular environment (paragraph 0330). Romesberg et al. taught after transport into the cell by the nucleotide triphosphate transporter, the unnatural base-pairing nucleotides are incorporated into nucleic acids within the cell by cellular machinery, e.g., the cell's own DNA and/or RNA polymerases, a heterologous polymerase, or a polymerase that has been evolved using directed evolution (paragraph 0332). Romesberg et al. taught examples of pairs of unnatural nucleotide triphosphates that can be transported into cells and that can base pair to form an UBP when incorporated into nucleic acids with the cells, including a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity and that such unnatural nucleotides can have a ribose or deoxyribose sugar moiety (paragraph 0226).
Regarding claim 33, as Zhang et al. taught the unnatural bases, dNaM and dTPT3 and having the structures shown in Fig 1A below, Zhang et al. teaches the limitations of claim 33.
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Regarding claim 54, Zhang et al. teach in vivo transcription of DNA containing dNaM and dTPT3 (first and second unnatural bases) into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons (Abstract), and taught in vivo translation of the sfGFP protein (When cultures reached an OD600 ≈ 0.4–0.6, they were supplemented with NaMTP (250 μM) and TPT3TP (30 μM) (unless otherwise indicated e.g. Extended data Fig. 4) and the appropriate ncAA (or ddH2O for cultures without PrK or 0.2 M NaOH for cultures without pAzF) at the concentrations indicated in the respective figure captions. Cultures were then grown for 20 min before adding 1 mM IPTG to induce T7 RNA polymerase and transcription of tRNASer, tRNAPyl, or tRNApAzF, and PylRS or pAzFRS, if present, and subsequently monitored for growth and fluorescence. Following a period of T7 RNA polymerase and tRNA induction (0.5 h for Ser incorporation and pAzFRS experiments, 1 h for PylRS experiments), sfGFP was induced with 100 ng/mL of anhydrotetracycline. After induction, cell cultures were rapidly cooled by shaking in a shallow ice water bath and collected at the time points indicated (see respective figures). Cultures were aliquoted (50 μL for plasmid isolation to determine UBP retention, 50 μL for crude cell lysates, and 150 μL (Ser incorporation samples), 150 or 230 μL (PrK incorporation samples from cells expressing fully natural or unnatural codon-containing sfGFP, respectively), or 100 μL (pAzF incorporation samples) for affinity purification of sfGFP) (page 7).
Regarding claims 59 and 61, Zhang et al. also teach to demonstrate the encoding of non-canonical amino acids with UBPs, plasmids were constructed with the Methanosarcina mazei tRNAPyl (GYT) gene. tRNAPyl can be selectively charged by the Methanosarcina bakeri pyrrolysyl-tRNA synthetase with the ncAA N6-[(2-propynyloxy)carbonyl]L-lysine (PrK) (page 644, right column). Zhang et al. teach seryl-tRNA synthetase does not rely on anticodon recognition for tRNA aminoacylation, thus eliminating the potential complications of inefficient charging (Page 644, left column). Zhang et al. teach that PrK (the unnatural amino acid which is a lysine analogue) is specifically incorporated into sfGFP through decoding of the unnatural codons by tRNAs with an unnatural anticodon (page 645, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the DNA transcription method of Zhang et al. with the teachings of Romesberg et al. regarding unnatural nucleotides and unnatural base pairs and combinations thereof to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success, because Romesberg et al. also pertains to unnatural bases and unnatural base pairs (UBPs) including but not limited to TPT3-(d)NaM as well as additional unnatural bases and UBPs, and increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to modify the DNA transcription method of Zhang et al. with the teachings of Romesberg et al. to provide ribonucleoside triphosphates comprising a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, as well as the ribonucleoside triphosphates comprising a fourth unnatural base that is capable of forming a third unnatural base pair with the third unnatural base, because Romesberg et al. teach that the UBPs and cells stably incorporating the UBPs described herein, offer numerous advantages and can be applied to a broad range of biotechnologies (paragraph 0011), the discovery that particular unnatural base pairs (UBPs) including TPT3-(d)NaM can be amplified with natural base pair-like efficiency and fidelity and provide methods and compositions for increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to provide additional unnatural bases and base pairs beyond a first and second unnatural base pair because Romesberg et al. taught different types and combinations of UBPs (a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity (paragraph 0226), and that Romesberg et al. taught other types of unnatural nucleotides can be imported into the cells by the nucleotide triphosphate transporter, such as (d)TPT3, (d)TPT3PA, (d)FTPT3, (d)NaM, (d)5SICS, (d)FEMO, (d)FIMO, (d)MMO2 and combinations thereof (paragraph 0227), and the teaching that an expanded genetic alphabet, is a central goal of synthetic and chemical biology and would increase the functional diversity of nucleic acids, providing tools for their site-specific labeling, increase the information potential of DNA, and lay the foundation of a semi-synthetic organism.
Accordingly, the limitations of claims 27,28,32,33,54,59,61 and 84 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the DNA transcription method of Zhang et al. with a step of replicating DNA by contacting DNA with deoxyribonucleoside triphosphates and DNA polymerase, wherein the ribonucleoside triphosphates comprise a fifth unnatural base capable of forming a fourth unnatural base pair with the first unnatural base, before contacting the DNA with ribonucleotide triphosphates and RNA polymerase, based on the teachings of Romesberg et al. to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success, because Romesberg et al. also pertains to unnatural bases and unnatural base pairs (UBPs) including but not limited to TPT3-(d)NaM as well as additional unnatural bases and UBPs, and increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to do so because Romesberg et al. taught methods of incorporating an unnatural nucleotide into a nucleic acid can comprise effecting replication of unnatural nucleotides into unnatural amino acids (paragraph 0201) and that endogenous or exogenous polymerases, can be utilized to replicate genomic DNA to form a containing a UBP within a cell (paragraph 0203) and taught using E. coli polymerase, such as Pol I, can efficiently use the unnatural triphosphates to replicate DNA, thereby incorporating unnatural nucleotides and/or UBPs into cellular nucleic acids within the cellular environment (paragraph 0330), and that such unnatural nucleotides can have a ribose or deoxyribose sugar moiety (paragraph 0226).
Accordingly, the limitations of claim 30 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 31,37 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. in view of Romesberg et al. as applied to claims 27,28,30,32,33,
54,59,61 and 84 above, and further in view of US 20160168187 (hereinafter ‘187, Published 16 June 2016).
The teachings of Zhang et al. and Romesberg et al. as applicable to claims 27,28,30,32,33,54,59,61 and 84 have been described above.
While Zhang et al. and Romesberg et al. taught the unnatural base pair TPT3-NaM, Zhang et al. and Romesberg et al. do not teach wherein the third unnatural bases comprises TAT1 and the fourth unnatural base comprises NaM or 5FM. Zhang et al. and Romesberg et al. do not teach wherein at least one of the first, second, third or fourth unnatural base is
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, or the specific combinations of unnatural bases recited in claim 44.
Before the effective filing date, ‘187 taught analogs of unnatural nucleotides bearing predominantly hydrophobic nucleobase analogs that form unnatural base pairs during DNA polymerase-mediated replication of DNA or RNA polymerase-mediated transcription of RNA (Abstract). ‘187 taught compositions and methods described herein are based on the expansion of the genetic alphabet in vitro, and provide site-specific incorporation of unnatural nucleotides (paragraph 0006).
‘187 taught nucleobase pairs comprising a first nucleobase analog having any of the formulas B9a or B9b and a second nucleobase having any of the formulas alpha15a or alpha15b, in which B9b has this formula (paragraph 0030).
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Therefore, regarding the compound of formula B9b above, as X is taught as independently carbon or nitrogen, and therefore when the two X’s in the six membered ring are C, and the X in the 5 membered ring is N, and the other X beside it is C, Y is S, E is S, and R2 is optional, the structure of TAT1 of the instant claims, which is
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is taught and an ordinary artisan could arrive at this compound with a reasonable expectation of success because regarding X, there are only two choices, either C or N. In addition, the structure of dTPT3 is explicitly taught (shown below), and is very similar to the structure of TAT1, and one of ordinary skill in the art would only have to substituted one C for N in the TPT3 compound to arrive at the structure of TAT1.
‘187 also taught the unnatural base pair, dTPT3PA-dNaM (i.e., the pair formed between dTPT3PA and dNaM) and the unnatural base pair dTPT3-CNMO (paragraphs 0041,0107). ‘187 taught nucleobase analogs including beta nucleoside analogs having any of formulas from FIGS. 9,12,13 and 16, and X may be 5FM (paragraph 0114). The structure of dTPT3 is shown in Fig. 9 below:
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It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the transcribing method of Zhang et al. in view of Romesberg et al. using TPT3 as the first unnatural base, and NaM or CNMO as the second unnatural base, and to use the compound of formula B9b above (X is taught as independently carbon or nitrogen, and therefore when the two X’s in the six membered ring are C, and the X in the 5 membered ring is N, and the other X beside it is C, Y is S, E is S, and R2 is optional) as the third unnatural base, and the fourth unnatural base NaM or 5FM based on the teachings of ‘187, and use the teachings of ‘187 regarding unnatural bases and unnatural base pairs and specific combinations thereof with a reasonable expectation of success. There would be a reasonable expectation of success, because ‘187 also pertains to expansion of the genetic alphabet in vitro, and this would amount to simple substitution of one known unnatural base with another known unnatural base to obtain predictable results. An ordinary artisan could arrive at the instant structure of
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as the third unnatural base because regarding X, there are only two choices, either C or N. In addition, the structure of dTPT3 is explicitly taught and is very similar to the structure of TAT1, and one of ordinary skill in the art would only have to substitute one C for N in the TPT3 compound to arrive at the structure of TAT1. Regarding instant claim 44 (ii), regarding the first unnatural base being TPT3, the second unnatural base being CNMO, the third unnatural base being TAT1 and the fourth unnatural base being NaM, an ordinary artisan could arrive at this combination based on the combined teachings of Zhang et al., Romesberg et al. and ‘187.
Accordingly, the limitations of claims 31,37 and 44 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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 27,28,30,32,33,54,59,61 and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,513,706, Issued 24 Dec 2019, in view of Zhang et al. and Romesberg et al., cited above.
Instant claims 27,28,30,32,54,59,61 and 84 recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same. Instant claim 28 recites a fourth unnatural base capable of forming a third unnatural base pair with the third unnatural base, and claim 33 recites specific species of unnatural bases.
Claims 1-12 of U.S. Pat. 10,513,706 recite an isolated cell comprising DNA comprising at least one unnatural base pair (UBP) the at least one UBP comprising a first unnatural nucleotide and a second unnatural nucleotide; and a heterologous nucleic acid encoding a nucleoside triphosphate transporter that is at least 85% identical to SEQ ID NO: 1, wherein the isolated cell is an Escherichia coli cell, and recites options for the first and second unnatural nucleotide, including many of the same unnatural bases as in instant claim 33.
U.S. Pat. 10,513,706 does not recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same.
Zhang et al. and Romesberg et al. cure these deficiencies, the teachings of which have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art to have modified claims 1-12 of U.S. Pat. 10,513,706 with the teachings of Zhang et al. and Romesberg et al. to arrive at the instant claims with a reasonable expectation of success because both Zhang et al. and Romesberg et al. pertain to unnatural base pairs formed by unnatural nucleotides and teach the same unnatural nucleotides as those recited in claims 1-12 of U.S. Pat. 10,513,706. One of ordinary skill in the art would have been motivated modify the claims of U.S. Pat. 10,513,706 to provide a transcribing method as instantly claimed because Zhang et al. teach in vivo transcription of DNA containing dNaM and dTPT3 (first and second unnatural bases) into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of non-canonical amino acids into superfolder green fluorescent protein, and the results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions, and Romesberg et al. taught that the UBPs and cells stably incorporating the UBPs described herein, offer numerous advantages and can be applied to a broad range of biotechnologies (paragraph 0011), the discovery that particular unnatural base pairs (UBPs) including TPT3-(d)NaM can be amplified with natural base pair-like efficiency and fidelity and provide methods and compositions for increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to provide additional unnatural bases and base pairs beyond a first and second unnatural base pair because Romesberg et al. taught different types and combinations of UBPs (a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity (paragraph 0226), and that Romesberg et al. taught other types of unnatural nucleotides can be imported into the cells by the nucleotide triphosphate transporter, such as (d)TPT3, (d)TPT3PA, (d)FTPT3, (d)NaM, (d)5SICS, (d)FEMO, (d)FIMO, (d)MMO2 and combinations thereof (paragraph 0227), and the teaching that an expanded genetic alphabet, is a central goal of synthetic and chemical biology and would increase the functional diversity of nucleic acids, providing tools for their site-specific labeling, increase the information potential of DNA, and lay the foundation of a semi-synthetic organism.
Claims 31,37 and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,513,706, Issued 24 Dec 2019, in view of Zhang et al. and Romesberg et al., cited above and further in view of US 20160168187 (hereinafter ‘187, Published 16 June 2016).
The teachings of ‘706, Zhang et al. and Romesberg et al. as applicable to claims 27,28,30,32,33,54,59,61 and 84 have been described above.
‘706, Zhang et al. and Romesberg et al. do not teach do not teach wherein the third unnatural bases comprises TAT1 and the fourth unnatural base comprises NaM or 5FM. Zhang et al. and Romesberg et al. do not teach wherein at least one of the first, second, third or fourth unnatural base is
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, or the specific combinations of unnatural bases recited in claim 44.
The teachings of ‘187 have been described above in the 103 rejection.
It would have been obvious to one of ordinary skill in the art to have modified claims 1-12 of U.S. Pat. 10,513,706 with the teachings of Zhang et al. and Romesberg et al. in view of ‘187 to arrive at the instant claims with a reasonable expectation of success. An ordinary artisan would be motivated to use TPT3 as the first unnatural base, and NaM or CNMO as the second unnatural base, and to use the compound of formula B9b above of ‘187 (X is taught as independently carbon or nitrogen, and therefore when the two X’s in the six membered ring are C, and the X in the 5 membered ring is N, and the other X beside it is C, Y is S, E is S, and R2 is optional) as the third unnatural base, and the fourth unnatural base NaM or 5FM based on the teachings of ‘187, and use the teachings of ‘187 regarding unnatural bases and unnatural base pairs and specific combinations thereof with a reasonable expectation of success. There would be a reasonable expectation of success, because ‘187 also pertains to expansion of the genetic alphabet in vitro, and this would amount to simple substitution of one known unnatural base with another known unnatural base to obtain predictable results. An ordinary artisan could arrive at the instant structure of
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as the third unnatural base because regarding X, there are only two choices, either C or N. In addition, the structure of dTPT3 is explicitly taught and is very similar to the structure of TAT1, and one of ordinary skill in the art would only have to substitute one C for N in the TPT3 compound to arrive at the structure of TAT1. Regarding instant claim 44 (ii), regarding the first unnatural base being TPT3, the second unnatural base being CNMO, the third unnatural base being TAT1 and the fourth unnatural base being NaM, an ordinary artisan could arrive at this combination based on the combined teachings of ‘706,Zhang et al., Romesberg et al. and ‘187.
Claims 27,28,30,32,33,54,59,61 and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,834,689 (‘689), Issued 5 Dec 2023, in view of Zhang et al. and Romesberg et al., or over claims 1-28 of U.S. Patent No. 12,319,944 (‘944) Issued 3 June 2025, in view of Zhang et al. and Romesberg et al.
Instant claims 27,28,30,32,54,59,61 and 84 recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same. Instant claim 28 recites a fourth unnatural base capable of forming a third unnatural base pair with the third unnatural base, and claim 33 recites specific species of unnatural bases.
Claims 1-25 of ‘689 recite a cell comprising a nucleoside triphosphate transporter, a tRNA from Methanosarcina mazei or Methanococcous jannaschii comprising an anticodon and recites specific anticodon sequences and comprising a first unnatural nucleobase which are the same unnatural nucleobases recited in the instant claims; an aminoacyl tRNA synthetase, and an mRNA encoding the protein comprising the unnatural amino acid and comprising a codon and recites specific codon sequences and wherein the codon comprises an unnatural nucleotide comprising a second unnatural nucleobase and which are the same unnatural nucleobases recited in the instant claim 33.
Claims 1-28 of ‘944 recite a method of producing a protein comprising an unnatural amino acid in a cell comprising contacting the cell with an unnatural amino acid, the cell comprising: a nucleoside triphosphate transporter; a tRNA from Methanosarcina mazei or Methanococcous jannaschii comprising an anticodon comprising a first unnatural nucleobase which are the same unnatural nucleobases recited in the instant claim 33; an aminoacyl tRNA synthetase that aminoacylates the tRNA with the unnatural amino acid; an mRNA encoding the protein comprising the unnatural amino acid and comprising a codon, the codon comprising an unnatural nucleotide comprising a second unnatural nucleobase and which are the same unnatural nucleobases recited in the instant claims.
‘689 and ‘944 do not recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same.
Zhang et al. and Romesberg et al. cure these deficiencies, the teachings of which have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art to have modified claims 1-25 of ’689 or claims 1-28 of ‘944 with the teachings of Zhang et al. and Romesberg et al. to arrive at the instant claims with a reasonable expectation of success because both Zhang et al. and Romesberg et al. pertain to unnatural base pairs formed by unnatural nucleotides and teach the same unnatural nucleotides as those recited in claims 1-25 of ’689 or claims 1-28 of ‘944. One of ordinary skill in the art would have been motivated modify the claims of ’689 or ‘944 to provide a transcribing method as instantly claimed because Zhang et al. teach in vivo transcription of DNA containing dNaM and dTPT3 (first and second unnatural bases) into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of non-canonical amino acids into superfolder green fluorescent protein, and the results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions, and Romesberg et al. taught that the UBPs and cells stably incorporating the UBPs described herein, offer numerous advantages and can be applied to a broad range of biotechnologies (paragraph 0011), the discovery that particular unnatural base pairs (UBPs) including TPT3-(d)NaM can be amplified with natural base pair-like efficiency and fidelity and provide methods and compositions for increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to provide additional unnatural bases and base pairs beyond a first and second unnatural base pair because Romesberg et al. taught different types and combinations of UBPs (a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity (paragraph 0226), and that Romesberg et al. taught other types of unnatural nucleotides can be imported into the cells by the nucleotide triphosphate transporter, such as (d)TPT3, (d)TPT3PA, (d)FTPT3, (d)NaM, (d)5SICS, (d)FEMO, (d)FIMO, (d)MMO2 and combinations thereof (paragraph 0227), and the teaching that an expanded genetic alphabet, is a central goal of synthetic and chemical biology and would increase the functional diversity of nucleic acids, providing tools for their site-specific labeling, increase the information potential of DNA, and lay the foundation of a semi-synthetic organism.
Claims 31,37 and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,834,689 (‘689), Issued 5 Dec 2023, in view of Zhang et al. and Romesberg et al. and further in view of US 20160168187 (hereinafter ‘187, Published 16 June 2016), or over claims 1-28 of U.S. Patent No. 12,319,944 (‘944) Issued 3 June 2025, in view of Zhang et al. and Romesberg et al. and further in view of US 20160168187 (hereinafter ‘187, Published 16 June 2016).
The teachings of ‘689,’944, Zhang et al. and Romesberg et al. as applicable to claims 27,28,30,32,33,54,59,61 and 84 have been described above.
‘689,’944, Zhang et al. and Romesberg et al. do not teach do not teach wherein the third unnatural bases comprises TAT1 and the fourth unnatural base comprises NaM or 5FM. Zhang et al. and Romesberg et al. do not teach wherein at least one of the first, second, third or fourth unnatural base is
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, or the specific combinations of unnatural bases recited in claim 44.
The teachings of ‘187 have been described above in the 103 rejection.
It would have been obvious to one of ordinary skill in the art to have modified the claims of ‘689 or ‘944 with the teachings of Zhang et al. and Romesberg et al. further in view of ‘187 to arrive at the instant claims with a reasonable expectation of success. An ordinary artisan would be motivated to use TPT3 as the first unnatural base, and NaM or CNMO as the second unnatural base, and to use the compound of formula B9b above of ‘187 (X is taught as independently carbon or nitrogen, and therefore when the two X’s in the six membered ring are C, and the X in the 5 membered ring is N, and the other X beside it is C, Y is S, E is S, and R2 is optional) as the third unnatural base, and the fourth unnatural base NaM or 5FM based on the teachings of ‘187, and use the teachings of ‘187 regarding unnatural bases and unnatural base pairs and specific combinations thereof with a reasonable expectation of success. There would be a reasonable expectation of success, because ‘187 also pertains to expansion of the genetic alphabet in vitro, and this would amount to simple substitution of one known unnatural base with another known unnatural base to obtain predictable results. An ordinary artisan could arrive at the instant structure of
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as the third unnatural base because regarding X, there are only two choices, either C or N. In addition, the structure of dTPT3 is explicitly taught and is very similar to the structure of TAT1, and one of ordinary skill in the art would only have to substitute one C for N in the TPT3 compound to arrive at the structure of TAT1. Regarding instant claim 44 (ii), regarding the first unnatural base being TPT3, the second unnatural base being CNMO, the third unnatural base being TAT1 and the fourth unnatural base being NaM, an ordinary artisan could arrive at this combination based on the combined teachings of Zhang et al., Romesberg et al. and ‘187.
Claims 27,28,30,31-33,37,44,54,59,61 and 84 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4,6-8,15,17,18,20,125-152 of copending Application No. 17/709,041 (‘041) in view of Zhang et al. and Romesberg et al., cited previously.
Instant claims 27,28,30,32,54,59,61 and 84 recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same. Instant claim 28 recites a fourth unnatural base capable of forming a third unnatural base pair with the third unnatural base, and claims 31,33,37 and 44 recite specific species of unnatural bases.
Claims 1-4,7,143-146 of ‘041 recite a eukaryotic cell comprising a mRNA comprising a codon comprising a first unnatural base, wherein the mRNA encodes a polypeptide comprising at least one unnatural amino acid encoded by the codon; and a transfer RNA comprising an anticodon comprising a second unnatural base, wherein the first and second unnatural bases are capable of forming an unnatural base pair in the eukaryotic cell. Claim 8 recites first and second unnatural bases including NaM, CNMO, MMO2, 5FM, 2OME, 5F2OMe, C1MO, BrMO, PTMO, MTMO, TPT3, SICS, FSICS, 5SICs and TAT1 and claim 136 recites the first unnatural base is TPT3 and the second unnatural base is NaM or CNMO; and therefore claims the same unnatural bases of instant claims 31,33,37 and 44. Claims 15,17 and 137 recite the unnatural amino acid, Azk. Claims 18,20,138-140 recite specific eukaryotic cells, including human, mammalian, HEK293T, hamster, CHO cells. Claims 125-129 recite specific codons and anticodons; claims 130-133 recite specific tRNA synthetases and tRNA (pyrrolysyl or tyrosyl) derived from specific cells.
Claims of ‘041 do not recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same.
Zhang et al. and Romesberg et al. cure these deficiencies, the teachings of which have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art to have modified claims 1-4,6-8,15,17,18,20,125-152 of ‘041 with the teachings of Zhang et al. and Romesberg et al. to arrive at the instant claims with a reasonable expectation of success because both Zhang et al. and Romesberg et al. pertain to unnatural base pairs formed by unnatural nucleotides and teach many of the same unnatural nucleotides as those recited in claim 8 of ‘041. One of ordinary skill in the art would have been motivated modify the claims of ‘041 to provide a transcribing method as instantly claimed because Zhang et al. teach in vivo transcription of DNA containing dNaM and dTPT3 (first and second unnatural bases) into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of non-canonical amino acids into superfolder green fluorescent protein, and the results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions, and Romesberg et al. taught that the UBPs and cells stably incorporating the UBPs described herein, offer numerous advantages and can be applied to a broad range of biotechnologies (paragraph 0011), the discovery that particular unnatural base pairs (UBPs) including TPT3-(d)NaM can be amplified with natural base pair-like efficiency and fidelity and provide methods and compositions for increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to provide additional unnatural bases and base pairs beyond a first and second unnatural base pair because Romesberg et al. taught different types and combinations of UBPs (a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity (paragraph 0226), and that Romesberg et al. taught other types of unnatural nucleotides can be imported into the cells by the nucleotide triphosphate transporter, such as (d)TPT3, (d)TPT3PA, (d)FTPT3, (d)NaM, (d)5SICS, (d)FEMO, (d)FIMO, (d)MMO2 and combinations thereof (paragraph 0227), and the teaching that an expanded genetic alphabet, is a central goal of synthetic and chemical biology and would increase the functional diversity of nucleic acids, providing tools for their site-specific labeling, increase the information potential of DNA, and lay the foundation of a semi-synthetic organism.
This is a provisional nonstatutory double patenting rejection.
Claims 27,28,30,32,33,54,59,61 and 84 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55-77 of copending Application No. 19/196,915 (‘915) in view of Zhang et al. and Romesberg et al., cited previously.
Instant claims 27,28,30,32,54,59,61 and 84 recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same. Instant claim 28 recites a fourth unnatural base capable of forming a third unnatural base pair with the third unnatural base, and claim 33 recites specific species of unnatural bases.
Claims 55-74 of ‘915 recite a kit for producing a protein comprising an unnatural amino acid comprising a plasmid comprising a sequence that encodes a mutant tRNA comprising a mutant anticodon sequence and wherein Y is an unnatural nucleobase, and a cell, and lists many of the same unnatural nucleobases as those in instant claim 33. Claims 75-76 of ‘915 recite a method of producing a protein using the kit of claim 58 wherein the protein comprises an unnatural amino acid comprising contacting the cell with an unnatural ammino acid that is encoded by the mutant codon sequence of the mRNA wherein the mutant mRNA and mutant tRNA are generated in the cell and is translated in the cell thereby producing the protein and claim 77 of ‘915 reciting a method of producing a protein comprising an unnatural amino acid using a cell-free translation system.
Claims of ‘915 do not recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same, or third and four unnatural bases forming a third unnatural base pair.
Zhang et al. and Romesberg et al. cure these deficiencies, the teachings of which have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art to have modified the claims of ‘915 with the teachings of Zhang et al. and Romesberg et al. to arrive at the instant claims with a reasonable expectation of success because both Zhang et al. and Romesberg et al. pertain to unnatural base pairs formed by unnatural nucleotides and teach many of the same unnatural nucleotides as those recited in claims 55,57,64,65,66,77 of ‘915. One of ordinary skill in the art would have been motivated modify the claims of ‘915 to provide a transcribing method as instantly claimed because Zhang et al. teach in vivo transcription of DNA containing dNaM and dTPT3 (first and second unnatural bases) into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of non-canonical amino acids into superfolder green fluorescent protein, and the results demonstrate that interactions other than hydrogen bonding can contribute to every step of information storage and retrieval. The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions, and Romesberg et al. taught that the UBPs and cells stably incorporating the UBPs described herein, offer numerous advantages and can be applied to a broad range of biotechnologies (paragraph 0011), the discovery that particular unnatural base pairs (UBPs) including TPT3-(d)NaM can be amplified with natural base pair-like efficiency and fidelity and provide methods and compositions for increasing the genetic alphabet of cell or an organism. One of ordinary skill in the art would have been motivated to provide additional unnatural bases and base pairs beyond a first and second unnatural base pair because Romesberg et al. taught different types and combinations of UBPs (a triphosphate of (d)5SICS ((d)5SICSTP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3 ((d)TPT3TP) and a triphosphate of (d)NaM ((d)NaMTP), a triphosphate of (d)TPT3PA and a triphosphate of NaMA-dNaM pair which can be PCR amplified with a natural base pair-like efficiency and fidelity (paragraph 0226), and that Romesberg et al. taught other types of unnatural nucleotides can be imported into the cells by the nucleotide triphosphate transporter, such as (d)TPT3, (d)TPT3PA, (d)FTPT3, (d)NaM, (d)5SICS, (d)FEMO, (d)FIMO, (d)MMO2 and combinations thereof (paragraph 0227), and the teaching that an expanded genetic alphabet, is a central goal of synthetic and chemical biology and would increase the functional diversity of nucleic acids, providing tools for their site-specific labeling, increase the information potential of DNA, and lay the foundation of a semi-synthetic organism.
This is a provisional nonstatutory double patenting rejection.
Claims 31,37 and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55-77 of copending Application No. 19/196,915 (‘915) in view of Zhang et al. and Romesberg et al. as applied to claims 27,28,30,32,33,54,59,61 and 84 above, and further in view of US 20160168187 (hereinafter ‘187, Published 16 June 2016).
The teachings of ‘915, Zhang et al. and Romesberg et al. as applicable to claims 27,28,30,32,33,54,59,61 and 84 have been described above.
‘915, Zhang et al. and Romesberg et al. do not teach do not teach wherein the third unnatural bases comprises TAT1 and the fourth unnatural base comprises NaM or 5FM. Zhang et al. and Romesberg et al. do not teach wherein at least one of the first, second, third or fourth unnatural base is
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, or the specific combinations of unnatural bases recited in claim 44.
The teachings of ‘187 have been described above in the 103 rejection.
It would have been obvious to one of ordinary skill in the art to have modified the claims of ‘915 with the teachings of Zhang et al. and Romesberg et al. in view of ‘187 to arrive at the instant claims with a reasonable expectation of success. An ordinary artisan would be motivated to use TPT3 as the first unnatural base, and NaM or CNMO as the second unnatural base, and to use the compound of formula B9b above of ‘187 (X is taught as independently carbon or nitrogen, and therefore when the two X’s in the six membered ring are C, and the X in the 5 membered ring is N, and the other X beside it is C, Y is S, E is S, and R2 is optional) as the third unnatural base, and the fourth unnatural base NaM or 5FM based on the teachings of ‘187, and use the teachings of ‘187 regarding unnatural bases and unnatural base pairs and specific combinations thereof with a reasonable expectation of success. There would be a reasonable expectation of success, because ‘187 also pertains to expansion of the genetic alphabet in vitro, and this would amount to simple substitution of one known unnatural base with another known unnatural base to obtain predictable results. An ordinary artisan could arrive at the instant structure of
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as the third unnatural base because regarding X, there are only two choices, either C or N. In addition, the structure of dTPT3 is explicitly taught and is very similar to the structure of TAT1, and one of ordinary skill in the art would only have to substitute one C for N in the TPT3 compound to arrive at the structure of TAT1. Regarding instant claim 44 (ii), regarding the first unnatural base being TPT3, the second unnatural base being CNMO, the third unnatural base being TAT1 and the fourth unnatural base being NaM, an ordinary artisan could arrive at this combination based on the combined teachings of Zhang et al., Romesberg et al. and ‘187.
Claims 27,28,30,31-33,37,44,54,59,61 and 84 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3,4,6,9,11,12,14,16,18,21,24,25,27-30,32,34,35,42,45,54,61,71-75 of copending Application No. 17/716,848 (‘848).
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 27,28,30,32,59,61 and 84 recite a method of transcribing a DNA to a tRNA or an mRNA encoding a protein comprising contacting DNA comprising a gene encoding the tRNA or protein with ribonucleoside triphosphates and an RNA polymerase, wherein the gene encoding the tRNA or protein comprises a first unnatural base paired to and forming a first unnatural base pair with a second unnatural base, and wherein the ribonucleoside triphosphates comprise a third unnatural base capable of forming a second unnatural base pair with the first unnatural base, wherein the first unnatural base pair and the second unnatural base pair are not the same. Instant claim 28 recites a fourth unnatural base capable of forming a third unnatural base pair with the third unnatural base, and claims 31,33,37 and 44 recite specific species of unnatural bases. Instant claim 54 recites a step of translating the mRNA into protein wherein the protein comprises an unnatural amino acid at a position corresponding to a codon of the mRNA that comprises the third unnatural base.
Claims 1,3,4,6,9,11,12,14,16,18,21,24,25,27-30,32,34,35 and 42 of ‘848 recite a method of synthesizing an unnatural polypeptide comprising providing at least one unnatural DNA molecule comprising at least four unnatural base pairs wherein the unnatural DNA molecule encodes a mRNA molecule encoding an unnatural polypeptide and at least first and second tRNA molecules containing first and second unnatural anticodons, transcribing the at least one unnatural DNA molecule to afford the mRNA molecule and at least first and second tRNA molecules and synthesizing an unnatural polypeptide encoded by the mRNA molecule by translating the mRNA molecule. Claims 45,54,61,71,72-75 recite a cell comprising at least one unnatural DNA molecule comprising at least four unnatural base pairs and wherein the unnatural DNA molecule encodes the mRNA molecule and at least a first and second tRNA molecules as recited in claim 45. Claims 6 and 71 recite unnatural bases including NaM, CNMO, MMO2, 5FM, 2OME, 5F2OMe, C1MO, BrMO, PTMO, MTMO, TPT3, SICS, FSICS, 5SICs and TAT1 and therefore claims the same unnatural bases of instant claims 31,33,37 and 44. Claim 21 recites the same unnatural amino acids as instant claims 59 and 61.
Therefore, the instant claimed transcribing method is comprised within the method of ‘848 which recites a transcribing step and the same unnatural bases and base pairs, and the claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 27,28,30-33,37,44,54,59,61 and 84 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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