DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I, claims 27-53 and 56-58, drawn to an engineered organism comprising a recoded genome in the reply filed on 08/04/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 54-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 08/04/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Status of Claims
Claims 1-26 are canceled, claims 27-58 are pending, and claims 54-55 are withdrawn.
Accordingly, claims 27-53 and 56-58 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
This application is a continuation application which claims priority to U.S. application Ser. No. No. 16/309,645, now U.S. Pat. No. 11,361,845, and filed Dec. 13, 2018; which is a National Stage Application under 35 U.S.C. 371 of co-pending PCT application PCT/US17/37596 designating the United States and filed Jun. 15, 2017; which claims the benefit of U.S. provisional application No. 62/350,468 filed on Jun. 15, 2016.
Due to the limitation of “substantially all” in instant independent claims 27 and 57 not being supported by the aforementioned applications, the examiner is considering the effective filing date of claims 27-55 and 57 in the instant claim set to be 12/13/2018.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 04/13/2022, 11/15/2022, 05/22/2023, and 08/22/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Figures 5 and 17 each recite nucleic acid sequence longer than 10 bases without an accompanying SEQ ID NO either in the drawing or description of the drawing. Applicant is advised to double check and identify each and every occurrence of this non-compliance and remedy according to the instruction above.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See page 47 second to last paragraph. There are two instances.
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 27-53 and 57 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.
The term “Substantially all” in claims 27 and 57 is a relative term which renders the claim indefinite. The term “substantially all” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, the term “substantially all” render indefinite the exact proportion, percentage, or specific genomic loci of UAG codons that must be replaced versus those that may remain un-recoded in the template genome and achieving the claimed engineered organism.
Claims 28-53 either directly or ultimately depend from independent claim 27 and do not further define the relative term, and thus inherit the rejection of claim 27.
Claim 34 recites the limitation "XXX1" in line 2. There is insufficient antecedent basis for this limitation in the claim. Note, the examiner is unable to determine what is being claimed and therefore claim 34 cannot be examined with respect to the prior art.
Claim 35 recites the limitation "XXX2" in line 2. There is insufficient antecedent basis for this limitation in the claim. Note, the examiner is unable to determine what is being claimed and therefore claim 35 cannot be examined with respect to the prior art.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27-53 and 57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
Claim 27 recites “wherein the recoded genome comprises at least one trinucleotide sequence corresponding to a particular codon at all or substantially all instances in a corresponding template genome that is replaced with a trinucleotide sequence corresponding to an alternative codon.” The limitation “substantially all instances” encompasses an engineered organism whose recoded genome retains some fraction of un-recoded instances of the particular codon (UAG) as a permanent structural feature of the engineered organism. The specification does not describe embodiments that are partially recoded; rather, the specification only describes the recoded engineered organism in terms of complete replacement of UAG stop codons, see [0006]-[0016], [0164], and [0120]. Nor does the specification provide any standard for (e.g., numerical percentage, a defined exception category, or a specific working example) by which such a partial-recoded organism would be distinguishable from the fully-recoded organism that the specification does describe. Although Fig. 13 description refers to “partially recoded strains” in the context of Fig. 13A-B, the specification describes these as intermediate construction stages during the step-wise assembly of recoded segments on plasmids (e.g., steps 4-7 of Fig. 10A) prior to complete genome assembly. The specification lacks a representative number of species of a fully assembled engineered organism whose genome permanently retains a partial subset of non-recoded target UAG codons across the template genome while maintaining viability without RF1. Similarly, claim 57 recites “substantially all instances within the corresponding template genome.”
Furthermore, the state of the art at the time of filing shows the field treating “complete” or “genome wide” removal of UAG codons as the acceptable success criterion, see page 820 second column and abstract of Ostrov et al., (Science353,819-822(2016), in IDS).
Therefore, the specification fails to reasonably convey to one skilled in the art that the inventors possessed a genus of engineered organisms comprising a partially or “substantially” recoded genome at the time of filing. Claims 28-53 either directly or ultimately depend from independent claim 27 and do not further define the relative term, and thus inherit the rejection of claim 27.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 27, 46-48, 51, and 53, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Issacs (WO2016073079A2, In IDS).
Regarding claims 27, Isaacs discloses an engineered organism comprising a recoded genome, wherein the organism is E. coli (claim 9: “a genomically recoded organism (GRO) variant of E. coli strain C321.ΔA (GenBank accession CP006698) wherein TAG is substituted for at least one codon in at least one essential gene of interest.”). Isaacs further discloses that the recoded genome comprises at least one trinucleotide sequence corresponding to a particular codon at all instances in a corresponding template genome that is replaced with a trinucleotide sequence corresponding to an alternative codon (claim 2: “all genomic iterations of a first stop codon sequence have been reassigned to a second stop codon sequence”). Isaacs further teaches wherein the at least one trinucleotide sequence corresponding to the particular codon is reassigned to a non-standard amino acid (claim 1: “at least one codon is reassigned creating an available sense codon for a recombinant tRNA… wherein the recombinant tRNA can be charged by a paired recombinant aminoacyl-tRNA synthetase (aaRS) to permit site-specific incorporation of a synthetic amino acid (sAA) or non-standard amino acid (nsAA)…”). Isaacs further discloses that the prfB gene comprises a mutation relative to the corresponding template genome (claim 5: “the gene encoding release factor 1 (RF1), release factor 2 (RF2), or a combination thereof is interrupted or deleted,” and it is well established in the art and by instant claim 46 that RF2 is encoded by the prfB gene; a gene interruption or deletion constitutes a mutation relative to the corresponding template genome). Isaacs’ claim 1 recites that the recoded genome comprises “at least one iteration of the available sense codon…present in at least one essential gene of interest” and “wherein the recombinant tRNA can be charged by a paired recombinant aminoacyl-tRNA synthetase (aaRS) to permit site-specific incorporation of a synthetic amino acid (sAA) or non-standard amino acid (nsAA) into a nascent peptide chain during translation of the essential gene,” disclosing that the at least one trinucleotide sequence corresponding to the particular codon is reassigned to a non-standard amino acid. Claims 1-5 and 9 of Isaacs, read together in light of the specification’s consistent identification of the E. coli C321.ΔA-derived GRO as the disclosed embodiment throughout, describe an engineered E. coli organism meeting each and every limitation of instant claim 27.
Regarding claim 46, Issacs teaches wherein translation of a release factor 2 (RF2) encoded by the prfB gene is altered or disrupted in the engineered organism compared to translation of RF2 in an engineered E. coli comprising the recoded genome without the mutation in the prfB gene (claim 5: “the gene encoding release factor 1 (RF1), release factor 2 (RF2), or a combination thereof is interrupted or deleted.”)
Regarding claim 47, Isaacs teaches the recoded genome further comprises an UAG codon at all or substantially all instances within the corresponding template genome that is changed to an alternative codon (claim 2: “all genomic iterations of a first stop codon sequence have been reassigned to a second stop codon sequence,” and claim 3: “wherein the first stop codon sequence is TAG”).
Regarding claim 48, Isaacs teaches the alternative codon is a synonymous codon (claim 2: “endogenous sense codon sequence have been reassigned to a synonymous codon sequence”).
Regarding claim 51, Isaacs’ claim 5, discussed above, discloses that a gene encoding release factor 1 (RF1) is removed from the recoded genome and that the expression or function of RF1 is impaired, reciting that the gene encoding RF1 “is interrupted or deleted.” This disclosure is further supported by the instant specification, which states that “release factor 1 is deleted or interrupted in the GRO.” Isaacs further teaches “the cognate translation machinery can be removed/mutated/deleted to remove natural codon function (UAG - RF1, UGA - RF2),” see pg. 29 lines 20-23.
Regarding claim 53, Isaacs WO discloses that the engineered organism is viable, the specification stating that “the GRO are typically viable when cultured under permissive conditions including the synthetic amino acid or non-standard amino acid,” pg. 5 line 13.
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 27-32, 43-48, 50-51, 53, and 56-58 are rejected under 35 U.S.C. 103 as being unpatentable over Lajoie MJ, et al., (Science., 18;342(6156):357-60, in IDS, herein “Lajoie 1”) in view of Curran JF. (Analysis of effects of tRNA: message stability on frameshift frequency at the Escherichia coli RF2 programmed frameshift site. Nucleic Acids Res. 1993 Apr 25;21(8):1837-43) and Lajoie MJ, et al., (Science, 342, 361-363, in IDS, herein “Lajoie 2”).
Regarding claims 27 and 47-48, Lajoie 1 teaches an engineered organism comprising a recoded genome, wherein the organism is E. coli (abstract and pg. 358 column 1: strain C321.ΔA, derived from E. coli MG1655), wherein the recoded genome comprises at least one trinucleotide sequence corresponding to a particular codon at all instances in a corresponding template genome that is replaced with a trinucleotide sequence corresponding to an alternative codon, wherein the at least one trinucleotide sequence corresponding to the particular codon is reassigned to a non-standard amino acid, wherein the recoded genome further comprises an UAG codon at all or substantially all instances within the corresponding template genome that is changed to an alternative codon, wherein the alternative codon is a synonymous codon (abstract: “We replaced all known UAG stop codons in Escherichia coli MG1655 with synonymous UAA codons”; pg. 358 column 1: genome sequencing “confirmed that all 321 known UAGs were removed from its genome” (Table 1, strain C321.ΔA). Lajoie 1 further teaches the UAG codon, once removed genome-wide, is reassigned to encode a non-standard amino acid (abstract: “this GRO exhibited improved properties for incorporation of nonstandard amino acids that expand the chemical diversity of proteins in vivo;” pg. 358 column 1: the engineered strain permits “the complete reassignment of UAG from a stop codon to a sense codon capable of incorporating NSAAs into proteins,” and pg. 358 column 2: “these results indicate that only the complete removal of all instances of the UAG codon overcomes these deleterious effects; therefore, it may be the only scalable strategy for sustained NSAA translation and for complete reassignment of additional codons”).
Regarding claims 27-28, in a separate mutated E. Coli genome, Lajoie 1 teaches prfB mutant, prfB#, which “is an RF2 variant (T246A, A293E, and removed frameshift) exhibiting enhanced UAA termination … and weak UAG termination…,” see pg. 3 paragraph 2. Therefore, each of the T246A, A293E, and removed frameshift read on a mutation in prfB that results in a mutated codon that is not reassigned to the non-standard amino acid. Note: the removed frameshift is of particular relevance.
Regarding claim 46, Lajoie 1 teaches an RF2 variant by way of mutating the prfb gene and reports that the RF2 variant “exhibits enhanced UAA termination and weak UAG termination,” see pg. 3 paragraph 2.
Regarding claim 50, Lajoie 1’s teaching replacing all known UAG stop codons in Escherichia coli MG1655 with synonymous UAA codons, covers both coding and non-coding motifs.
Regarding claim 51, Lajoie 1 teaches wherein a gene encoding release factor 1 (RF1) is removed from the recoded genome (pg. 2 third paragraph: “we constructed a GRO in which all instances of the UAG codon have been removed, permitting the deletion of release factor 1,” and pg. 3 first paragraph: “The GRO [C321.ΔA, named for 321 UAG→UAA conversions and deletion of prfA (encodes RF1, Table 1)]). Thus, Lajoie 1 teaches that a gene encoding release factor 1 (prfA) is removed from the recoded genome, necessarily impairing RF1 expression/function (strain C321.ΔA carries a clean ΔprfA deletion (Table 1), described as “the deletion of release factor 1,” abstract). Lajoie 1 teaches using CoS-MAGE to replace 40 UAGs per strain, see supplemental materials page 32.
Regarding claim 53: Lajoie 1 teaches that the engineered organism is viable (pg. 358 column 1: C321.ΔA “exhibits normal prototrophy and morphology” and demonstrated fitness equivalent to its RF1+ precursor).
Overall, Lajoie 1 teaches that the resulting GRO possesses a devoted UAG sense codon for robust NSAA incorporation that is suitable for industrial protein production. GROs also establish the basis for genetic isolation and virus resistance, and additional recoding will help fully realize these goals—additional triplets could be reassigned, unnatural nucleotides could be used to produce new codons, and individual triplet codons could be split into several unique quadruplets that each encode their own NSAA.
Lajoie 1 does not teach that the prfB gene comprises a mutation relative to a corresponding template genome in the same organism in which a particular codon, namely UAG, is replaced. Lajoie 1 therefore does not teach that the following occur in the same engineered microorganism genome: 1) the particular codon is replaced with the trinucleotide sequence corresponding to the alternative codon at an instance within the prfB gene as in claim 29; 2) wherein the particular codon is a forbidden sense codon as in claim 30; 3) wherein the forbidden sense codon is AGG or AGC as in claim 31, and 4) the prfB gene further comprises a downstream frameshift mutation.
Curran teaches a nucleotide sequence with 100% identity to SEQ ID NO: 2351 (5'-CTTAGGGGGTATCTTTGAC-3') corresponding to the prfB gene template sequence, see Figure 1 (reproduced below for convenience), table 1 which defines XYZ in Figure 1 as CUU, and pg. 1842 first column last paragraph. Curran’s figure 1 details the location and codons involved in the frameshift Also illustrated in Curran’s Figure 1, is the ribosome binding like motif which positions over the forbidden sense codon AGG in the prfB gene template sequence.
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Lajoie 2 teaches that prfB is among a panel of 42 highly expressed essential E. coli genes independently selected for individual recoding, pg. 362 column 1: "we attempted to individually recode 42 essential genes, including all 41 essential ribosomal protein-coding genes and prfB, which relies on a programmed frameshift for proper translation." Lajoie 2 teaches that the prfB gene was mutated by (i) removing its genetically encoded internal frameshift via a single-nucleotide deletion (Supplementary Materials: "Genetically encoded frameshifts were removed (prfB CUUU→CUU)"), and (ii) recoding an upstream AGG codon within prfB (pg. 362 column 2: "removing the frameshift and recoding an upstream AGG codon that may be involved in pausing translation and enhancing frameshifting"), wherein AGG is confirmed as one of the 13 "forbidden codons" targeted across the 42-gene panel (Supplementary Materials: UAG, AGA, AGG, CUU, CUC, CCC, ACC, AUA, GUC, GCC, UCC, CGG, UGA). Lajoie 2 thereby teaches a first mutation in a trinucleotide sequence corresponding to a forbidden sense codon (the AGG recoding) and a second mutation (the frameshift-removing single-nucleotide deletion). Neither the mutated codon resulting from the AGG recoding nor the mutated sequence resulting from the frameshift-removing deletion is reassigned to a non-standard amino acid at either position. Lajoie 2 teaches CoS-MAGE strains in which only forbid-den codons were changed (table S5).
Lajoie 2 further teaches targeted, forbidden-codon-only edits, as opposed to wholesale synonymous-codon reshuffling across a gene, which produced an average 15-20% fitness defect and which the authors caution “could lead to unacceptable fitness impairment” if combined genome-wide, see pg. 363 columns 2-3. Lajoie 2 further teaches that this recoded prfB strain exhibited no significant fitness defect relative to control (pg. 362 column 2: "did not significantly affect fitness (t test, P = 0.86)"). Lajoie 2 further teaches that their “future strategies for genome-wide codon reassignment will only change codons of interest while selecting for variants with normal growth,” see pg. 363 column 3.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to combine Lajoie 1’s genomically recoded E. coli strain in which all instances of the UAG codon are replaced and RF1 is deleted to permit UAG reassignment with Lajoie 2’s teaching of a prfB gene mutation comprising removal of the gene’s internal programmed frameshift via a single-nucleotide deletion together with recoding of the upstream forbidden AGG codon in the prfB gene template sequence taught by Curran, to arrive at an engineered E. coli organism having both a UAG-replaced recoded genome and a mutated prfB gene, wherein the mutation in prfB comprises a first mutation in a trinucleotide sequence corresponding to the forbidden sense codon AGG and a second downstream mutation (the frameshift-removing mutation), neither of which results in a codon reassigned to the non-standard amino acid.
A PHOSITA would have been motivated to combine these teachings because doing so extends the genetic code reduction achieved by Lajoie 1’s UAG-recoded strain by an additional forbidden codon, consistent with the shared research program’s stated goal of progressively eliminating redundant codon/anticodon pairs for biocontainment and genetic isolation purposes, while avoiding the fitness costs associate with more extensive genome recoding.
A PHOSITA would have had a reasonable expectation of success because Lajoie 2’s data demonstrates that the specific prfB mutation at issue was already reduced to practice and shown not to significantly impair fitness in a E. coli strain common to both studies, using genome-engineering techniques (MAGE/Cos-MAGE) shared across both references. Combining this pre-validated, fitness neutral prfB modification with Lajoie 1’s UAG-recoded strain represents the application of a known technique to a known gene yielding a predictable result.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Lajoie MJ, et al., (Science., 18;342(6156):357-60, in IDS, herein “Lajoie 1”) in view of Curran JF. (Analysis of effects of tRNA: message stability on frameshift frequency at the Escherichia coli RF2 programmed frameshift site. Nucleic Acids Res. 1993 Apr 25;21(8):1837-43) and Lajoie MJ, et al., (Science, 342, 361-363, in IDS, herein “Lajoie 2”) as applied to claims 27 above, and further in view of Lee DH, et al., (Adaptive evolution of Escherichia coli K-12 MG1655 during growth on a Nonnative carbon source, L-1,2-propanediol. Appl Environ Microbiol. 2010 Jul;76(13):4158-68).
The teachings of Lajoie 1, Lajoie 2 and Curran are incorporated herein by reference to the 103 rejections above.
Lajoie 1, Lajoie 2, and Curran do not teach wherein the engineered organism has been passaged for more than 600 generations.
Regarding claim 49, Lajoie 1 teaches culturing the engineered organisms for over ~7340 doublings, see pg. 3 first paragraph.
Lee teaches “In this study, we evolved Escherichia coli K-12 MG1655 with a nonnative carbon source, l-1,2-propanediol (l-1,2-PDO), for ∼700 generations. We found that (i) experimental evolution of E. coli for ∼700 generations in 1,2-PDO-supplemented minimal medium resulted in acquisition of the ability to use l-1,2-PDO as a sole carbon and energy source so that the organism changed from an organism that did not grow at all initially to an organism that had a growth rate of 0.35 h−1; (ii) six mutations detected by whole-genome resequencing accumulated in the evolved E. coli mutant over the course of adaptive evolution on l-1,2-PDO; (iii) five of the six mutations were within coding regions, and IS5 was inserted between two fuc regulons; (iv) two major mutations (mutations in fucO and its promoter) involved in l-1,2-PDO catabolism appeared early during adaptive evolution; and (v) multiple defined knock-in mutant strains with all of the mutations had growth rates essentially matching that of the evolved strain. These results provide insight into the genetic basis underlying microbial evolution for growth on a nonnative substrate.” See abstract, Fig. 3,
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to passage the recoded E. Coli organism for more than 600 generations. A PHOSITA would have been motivated to allow the engineered microorganism to adapt and improve fitness after the pressure of recoding the genome. A PHOSITA would have had a reasonable expectation of success because passaging engineered microorganisms for this duration was already standard practice in the field, representing routine laboratory technique.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Lajoie MJ, et al., (Science., 18;342(6156):357-60, in IDS, herein “Lajoie 1”) in view of Curran JF. (Analysis of effects of tRNA: message stability on frameshift frequency at the Escherichia coli RF2 programmed frameshift site. Nucleic Acids Res. 1993 Apr 25;21(8):1837-43) and Lajoie MJ, et al., (Science, 342, 361-363, in IDS, herein “Lajoie 2”) as applied to claims 27 above, and further in view of Krishnakumar R, et al., (Experimental challenges of sense codon reassignment: an innovative approach to genetic code expansion. FEBS Lett. 2014 Jan 31;588(3):383).
The teachings of Lajoie 1, Lajoie 2, and Curran are incorporated herein by reference to the 103 rejections above.
Lajoie 1, Lajoie 2, and Curran do not teach wherein a gene encoding a cognate tRNA to the at least one particular codon is removed from the recoded genome.
Krishnakumar teaches: “Sense codon recoding requires an unused or rarely used sense codon and an orthogonal tRNA-synthetase pair where the tRNA anticodon reads the “blank” sense codon and inserts the 21st amino acid in response to the sense codon. However, unlike stop codons, every sense codon in the genetic code (although redundant) has a cognate tRNA and encodes for one of the 20 standard amino acids. Therefore, removing a sense codon does not necessarily create “blank” codons unless the cognate tRNA is missing as well.” See pg. 382 first column.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to remove the gene encoding a cognate tRNA to the at least one particular codon from the recoded genome of Lajoie 1. A PHOSITA would have been motivated to do so in order to fully create a blank codon that can be reassigned to an alternative codon (i.e., 21st amino acid). A PHOSITA would have had a reasonable expectation of success because the artisan could employ the same methodologies, which are standard in the art and that were already being employed to remove the gene encoding release factor 1 from the recoded genome.
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.
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Claims 27, 30–31, 38, 46-47, 50, 52-53, and 56–57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,361,845 B2 in view of Curran JF. (Analysis of effects of tRNA: message stability on frameshift frequency at the Escherichia coli RF2 programmed frameshift site. Nucleic Acids Res. 1993 Apr 25;21(8):1837-43) and Lajoie MJ, et al., (Science, 342, 361-363, in IDS, herein “Lajoie 2”).
Regarding claim 27, ’845 claims 1 and 15 recite viable bacterial cells comprising a recoded genome in which at least one particular sense codon is changed to an alternative codon at all instances within an essential gene in a corresponding template genome. ’845 claims 1(i) and 15(i) further require that the recoded genome comprises at least one instance in which the particular sense codon is reassigned to at least one non-standard amino acid. ’845 claims 1(ii) and 15(ii) further require the recoded genome comprises at least one instance where a trinucleotide sequence corresponding to the sequence of the at least one particular sense codon that is changed to an alternative codon.
Regarding instant claims 30 and 31, ’845 claims 1 and 15 expressly identify AGG and AGC among the recited particular sense codons. Therefore, instant claim 30’s recitation that the particular codon is a forbidden sense codon, and instant claim 31’s narrowing of the forbidden sense codon to AGG or AGC, are not patentably distinct from the claimed and disclosed sense-codon species of ’845.
Regarding instant claim 38, ’845 claims 1(ii) and 15(ii) expressly encompass a recoded trinucleotide within an internal ribosome pausing site motif or ribosome binding site motif, provided that the recoding preserves a structure or function of the motif.
Regarding instant claim 47, ’845 claims 4 and 16 expressly recite that all UAG codons are removed from the recoded genome.
Regarding instant claim 50, ’845 claims 1(ii) and 15(ii) expressly recite that a trinucleotide sequence corresponding to the particular sense codon within a non-coding motif is changed to a trinucleotide sequence corresponding to the alternative codon. ’845 claims 2, 3, and 16 further recite genome-wide recoding of one or more particular sense codons.
Regarding instant claims 46 and 51, ’845 claim 5 recites that a gene encoding a release factor is removed from the recoded genome.
Regarding instant claim 52, ’845 claims 1(i) and 15(i) expressly require removal from the recoded genome of a gene encoding a cognate tRNA to the particular sense codon.
Regarding instant claim 53, ’845 claim 15 expressly recites viable bacterial cells, and ’845 claim 1 recites providing viable bacterial cells.
Regarding instant claim 56, ’845 claims 1 and 15 recite viable bacterial cells having a recoded genome in which a particular sense codon is changed to an alternative codon within an essential gene, reassigned to a non-standard amino acid, and recoded at a non-coding motif that includes an internal ribosome pausing site motif or ribosome binding site motif.
Regarding instant claim 57, ’845 claims 2, 3, and 16 expressly recite genome-wide changing of particular sense codons to alternative codons, and ’845 claims 4 and 16 additionally recite removal of all UAG codons from the recoded genome.
‘845 claims do not explicitly recite that the viable bacterial cells are E. Coli; that the essential gene is prfB, that prfB comprises a mutation either upstream or downstream of the instance of the at least one trinucleotide sequence corresponding to the particular codon, or that the mutation in prfB results in a mutated codon that is not reassigned to the non-standard amino acid.
The teachings of Lajoie 2 and Curran are incorporated herein by reference to the 103 rejections above. Briefly, Lajoie 2 teaches that prfB is an essential E. coli gene that relies on a programmed frameshift for proper translation and teaches recoding an upstream AGG codon while removing the internal programmed frameshift by a single-nucleotide deletion. Curran describes the RF2/prfB programmed frameshift site and the associated Shine–Dalgarno-like/RBS-like sequence context. These teachings confirm that use of the specifically disclosed prfB embodiment within the broader essential-gene/non-coding-motif framework of the ’845 patent, including routine selection of a recoding and frameshift-associated mutation configuration, would have been obvious to a person of ordinary skill in the art.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to select E. Coli as the viable bacterial cell and prfB as the essential gene to arrive at an engineered E. coli organism having both a UAG-replaced recoded genome and a mutated prfB gene, wherein the mutation in prfB comprises a first mutation in a trinucleotide sequence corresponding to the forbidden sense codon AGG and a second downstream mutation (the frameshift-removing mutation), neither of which results in a codon reassigned to the non-standard amino acid. A PHOSITA would have been motivated to combine these teachings because doing so extends the genetic code reduction achieved by 845’s UAG-recoded strain by an additional forbidden codon, consistent with the shared research program’s stated goal of progressively eliminating redundant codon/anticodon pairs for genetic isolation purposes and protein production, while avoiding the fitness costs associate with more extensive genome recoding. A PHOSITA would have had a reasonable expectation of success because Lajoie 2’s data demonstrates that the specific prfB mutation at issue was already reduced to practice and shown not to significantly impair fitness in a E. coli strain.
Claims 27–48, 51, 53, and 56–58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-53 of copending Application No. 18/901,470 (reference application) in view of Curran JF. (Analysis of effects of tRNA: message stability on frameshift frequency at the Escherichia coli RF2 programmed frameshift site. Nucleic Acids Res. 1993 Apr 25;21(8):1837-43) and Lajoie MJ, et al., (Science, 342, 361-363, in IDS, herein “Lajoie 2”).
Reference claims 32–35 claim the same 19-nucleotide prfB template sequence as the instant claims and generically claim mutations at identified variable positions, including the XXX₁ wobble-mutation species, XXX2 forbidden codon reassignment species, and XXX3 frameshift-mutation species. The instant claims select and characterize particular sequence-defined species and upstream/downstream positional relationships within that same claimed mutation framework. Lajoie 2 and Curran further confirm that the prfB locus contains an upstream RBS-like/pausing element and a programmed frameshift region, and that mutation of these positions was a known recoding strategy. Therefore, the instant species and positional formulations would have been encompassed by, or obvious variants of, the reference application’s claimed prfB mutation genus.
Regarding instant claim 27, reference claim 27 recites an engineered E. coli organism comprising a recoded genome in which UAG is replaced with an alternative codon at all or substantially all instances in a corresponding template genome and in which prfB comprises a mutation relative to the corresponding template genome. Reference claim 46 further requires reassignment of the particular codon to a non-standard amino acid. The combination of reference claims 27 and 46 recites each limitation of instant claim 27, except that reference claim 27 identifies UAG as the particular codon while instant claim 27 recites a broader particular-codon genus.
Regarding instant claim 28, reference claim 39 recites that the prfB mutation results in a mutated codon that is not reassigned to the non-standard amino acid. Reference claim 46 recites reassignment of the particular codon to a non-standard amino acid. Thus, reference claims 27, 39, and 46 recite the same relationship as instant claim 28: a recoded particular codon reassigned to a non-standard amino acid and a separate mutated prfB codon that is not reassigned to the non-standard amino acid.
Regarding instant claims 29–31, reference claims 28–30 recite a mutation in a trinucleotide sequence corresponding to a forbidden sense codon in prfB, including AGG or AGC, and reference claim 31 recites that the mutation comprises a frameshift mutation. Instant claims 29–31 characterize the relevant recoding event as replacement of a particular codon at an instance within prfB, then specify the species in which the particular codon is a forbidden sense codon and, more narrowly, AGG or AGC.
Lajoie 2 teaches the relevant prfB configuration: recoding an upstream AGG codon and removing a downstream programmed frameshift. Curran identifies the RF2/prfB programmed-frameshift and RBS-like sequence context. Therefore, reciting the forbidden-codon prfB mutation of reference claims 28–31 as replacement of a particular codon at an instance within prfB, including the AGG or AGC species, would have been an obvious recharacterization of the same prfB recoding and frameshift system.
Regarding instant claim 32, reference claim 32 recites the identical prfB template sequence, 5’-CTTAGGGGGTATCTTTGAC-3’. The absence or presence of a SEQ ID NO designation does not create a structural distinction.
Regarding instant claims 33, 36, and 37, the instant claims select defined mutant sequence species derived from the template sequence of instant claim 32: 5’-CTACGGGGGTATCTTTGAC-3’ (SEQ ID NO: 2352), 5’-CTTCGTGGGTATCTTGAC-3’ (SEQ ID NO: 2353), and 5’-CTTCGTGGGTATCTTTGAC-3’ (SEQ ID NO: 2354). Reference claims 33–37 generically claim mutations at the corresponding variable positions in the identical prfB template sequence, including wobble and frameshift mutation types, nucleotide deletion, and nucleotide substitution alternatives.
The generic variable positions in the reference claims correspond to the positions at which the instant claims identify the nucleotide outcomes of SEQ ID NOs: 2352–2354. The reference claimed genus therefore encompasses the instant sequence-defined species or, at minimum, renders selection of the specifically recited nucleotide outcomes an obvious variant. The reference and instant claims address the same prfB template sequence, mutation positions, and RBS/frameshift-related mutation scheme.
Regarding instant claims 34 and 35, reference claims 34 and 35 expressly recite, respectively, a wobble mutation and a frameshift mutation in the corresponding variable-position trinucleotide sequences.
Regarding instant claim 38, reference claim 47 recites that ribosome binding site strength is modulated by the prfB mutation. Reference claims 31 and 34–35 further recite frameshift and wobble mutation types in the disclosed prfB sequence context. Curran describes the RBS-like/Shine–Dalgarno-like motif associated with the RF2 programmed frameshift, and Lajoie 2 teaches removal of the programmed frameshift in conjunction with recoding of the upstream AGG codon. Thus, a frameshift mutation together with one or more-point mutations in the prfB RBS-like motif, as recited in instant claim 38, is an obvious structural expression of the RBS-modulation and prfB frameshift-mutation subject matter claimed in the reference application.
Regarding instant claims 39–42, reference claims 32–35 recite the identical prfB template sequence, 5’-CTTAGGGGGTATCTTTGAC-3’, and claim mutations at defined variable positions within that sequence. In particular, reference claim 33 recites a mutation in one or more of the trinucleotide sequences corresponding to XXX₁, XXX₂, and XXX₃, and reference claim 34 recites a wobble mutation in the trinucleotide sequence corresponding to XXX₁. Reference claim 35 separately recites a frameshift mutation in the trinucleotide sequence corresponding to XXX3.
As shown by the shared template-sequence context, the XXX₁ trinucleotide of reference claims 33–34 corresponds to the upstream prfB mutation position relative to the particular-codon instance in prfB that is recoded in the instant claims. The generic variable-position genus of reference claims 33–35 therefore encompasses the structural arrangement of instant claim 39, in which the prfB mutation is upstream of the recoded particular-codon instance within prfB.
Reference claim 39 further recites that the prfB mutation results in a mutated codon that is not reassigned to the non-standard amino acid. Reference claim 46 recites reassignment of the particular codon to a non-standard amino acid. Thus, reference claims 27, 33–35, 39, and 46 collectively recite the same relationship required by instant claim 40: an upstream prfB mutation yielding a codon that is not reassigned to the non-standard amino acid, in an organism having a separately recoded particular codon reassigned to a non-standard amino acid.
Regarding instant claims 43–45, reference claims 31, 33–35, and 40–45 recite the same prfB template sequence, a forbidden-sense-codon mutation scheme, and frameshift mutation alternatives. In particular, reference claims 40–43 recite a first mutation in a trinucleotide corresponding to a forbidden sense codon and a second mutation in the same prfB sequence, and reference claims 44–45 recite a forbidden-codon mutation including the AGG or AGC species.
Instant claims 43–45 characterize the relevant prfB mutation as downstream of the separately recoded particular-codon instance. Lajoie 2 teaches the same relevant directional architecture: recoding an upstream AGG codon in prfB and removing a downstream programmed frameshift by a single-nucleotide deletion. Curran confirms the programmed-frameshift sequence context. Therefore, the downstream frameshift-mutation architecture of instant claims 43–45 is encompassed by, or at least would have been an obvious positional expression of, the reference application’s claimed two-mutation prfB system.
Regarding instant claim 47, reference claim 27 expressly recites that UAG is replaced with an alternative codon at all or substantially all instances in the corresponding template genome.
Regarding instant claim 48, reference claim 27 recites replacement of UAG with an alternative codon. Replacing UAG with UAA or UGA is a synonymous change with respect to the translational termination function.
Regarding instant claim 51, reference claim 48 recites that a gene encoding release factor 1, RF1, is removed from the recoded genome.
Regarding instant claim 53, reference claim 51 recites that the engineered organism is viable.
Instant claim 56 expressly requires replacement and non-standard-amino-acid reassignment of a particular codon at an instance within prfB. Lajoie 2 teaches recoding an upstream AGG codon within prfB, while Curran identifies the relevant prfB sequence and frameshift-site context. Therefore, locating the reference application’s recoded particular codon at an instance within the already claimed prfB mutation locus would have been an obvious combination of the reference application’s UAG/nsAA-reassignment and prfB-mutation subject matter.
Regarding instant claim 57, reference claim 27 expressly recites replacement of UAG at all or substantially all instances in the corresponding template genome. Applying that same all-or-substantially-all-instances recoding scope to the prfB-instance embodiment of instant claim 56 does not render instant claim 57 patentably distinct.
Regarding instant claim 58, reference claims 31–38 and 40–45 recite multiple prfB mutations at defined positions within the common prfB template sequence. Lajoie 2 further teaches an upstream AGG recoding event and a separate downstream frameshift-removing deletion in prfB. Thus, the recitation that prfB comprises a mutation upstream or downstream of the recoded particular-codon instance is an obvious positional expression of the same multi-edit prfB recoding architecture
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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