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 27-51 in the reply filed on 07/08/2026 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Claims 52-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 07/08/2026.
Status of claims
Claims 1-26 are canceled.
Claims 27-53 are pending.
Claims 52-53 are withdrawn.
Claims 27-51 are under examination at this time.
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. 17/719,431 and filed Apr. 13, 2022; which is a continuation application which claims priority to U.S. application Ser. 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 claim 27 not being supported by the aforementioned applications, the examiner is considering the effective filing date of all claims in the instant claim set to be 09/30/2024.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 0/30/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is 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.
Claim Objections
Claims 32-33, 36-38, and 42-44 are objected to because of the following informalities: each claim recites nucleic acid sequence comprising stretches of at least 10 contiguous bases without the required accompanying SEQ ID NO identifier. 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 27-51 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 claim 27 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 28-51 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 39 recites the limitation "the non-standard amino acid” in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 40 recites the limitation " the non-standard amino acid " in line 4. There is insufficient antecedent basis for this limitation in the claim.
In claims 38 and 44 the template sequence “5'- CTTAGGGGGTATCTTX1X2-3'” recite the variable X1. However, the variable X1 is undefined in the claims. Because X1 is undefined, it is unclear what nucleotide, modification, or sequence position X1 represents within the claimed prfB template sequence causing the claims to be ambiguous to one of ordinary skill in the 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 27-51 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.
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.
Claim Interpretation
Claims 32-38 and 42-45 recites a nucleotide sequence corresponding to SEQ ID NO: 2317 of the sequence listing, which is a template sequence of the prfB gene. Claims 33-38 and 43-44 recite this template sequence using variables in place of certain trinucleotide sequences or individual nucleotides. For purposes of examination, these claims are interpreted as reciting the nucleotide sequence of SEQ ID NO: 2317, with the variables serving only to identify the nucleotide position(s) or trinucleotide sequence(s) within SEQ ID NO: 2317 to which the separately recited mutation limitations apply. The variables are not interpreted as altering or expanding the underlying template sequence recited in the claims 32 and 42.
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, and 48-51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Issacs (WO2016073079A2, In IDS).
Regarding claim 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, wherein the particular codon is UAG (claim 2: “all genomic iterations of a first stop codon sequence have been reassigned to a second stop codon sequence,” claim 3: “the first stop codon sequence is TAG,” and claim 4: “the second stop codon sequence is TAA or TGA.”). 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 that RF2 is encoded by the prfB gene; a gene interruption or deletion constitutes a mutation relative to the corresponding template genome). Claims 2-5 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 claim 27.
Regarding claim 46, 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.
Regarding claims 48 and 49, 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 specification, which states that “release factor 1 is deleted or interrupted in the GRO.”
Regarding claim 50, Isaacs’ claim 8 discloses an organism further comprising an orthogonal aminoacyl-tRNA synthetase and/or tRNA, reciting “a nucleic acid encoding an expression control sequence operably linked a sequence encoding the recombinant aminoacyl-tRNA synthetase (aaRS), the recombinant tRNA, or the combination thereof.”
Regarding claim 51, 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 27-31, 39-41, 46, and 48-51 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 Lajoie MJ, et al., (Science, 342, 361-363, in IDS, herein “Lajoie 2”).
Regarding claim 27, 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, and wherein the particular codon is UAG (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).
Regarding claims 27 and 46, Lajoie 1 teaches that the UAG codon, once removed genome-wide, is reassigned to encode a non-standard amino acid (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 48 and 49: 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).
Regarding claim 50: Lajoie 1 teaches an organism further comprising an orthogonal aminoacyl-tRNA synthetase and tRNA (pg. 358 Fig. 1 legend: the strategy “introduced an orthogonal aminoacyl–tRNA synthetase (aaRS) and tRNA to reassign UAG as a dedicated sense codon capable of incorporating nonstandard amino acids”).
Regarding claim 51: 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).
Lajoie 1 does not teach that the prfB gene comprises a mutation relative to the corresponding template genome in the same organism in which UAG is replaced. Table 1 of Lajoie 1 shows the opposite, the flagship strain C321.ΔA, in which all 321 UAG codons are replaced, carries a wild-type, unmutated prfB gene. The only strain in Lajoie 1 carrying a mutated prfB (the “prfB#” variant) is strains C0.B ¶ and C0.B ¶ .DA::S, which have zero codon changes. Lajoie 1 therefore does not teach the prfB-mutation limitation of claim 27, nor the further limitations of claims 28 (mutation in a trinucleotide sequence corresponding to a forbidden sense codon), 29 (forbidden sense codon selected from the recited group), 30 (forbidden codon is AGG or AGC), 31 (mutation comprises a frameshift mutation), 39 (mutation in prfB results in a mutated codon that is not reassigned to the non-standard amino acid), 40 (mutation in prfB comprises a first mutation in a trinucleotide sequence corresponding to a forbidden sense codon and a second mutation, wherein the second mutation results in a mutated codon that is not reassigned to the non-standard amino acid), or 41 (forbidden sense codon is AGG or AGC), each of which depends from and further limits the prfB-mutation limitation of claim 27.
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 further teaches that 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 II 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, to arrive at an engineered E. coli organism having both a UAG-replaced recoded genome and a mutated prfB gene, with the mutation further targeting a forbidden sense codon (AGG) via a frameshift mutation, and wherein the mutation in prfB comprises a first mutation in a trinucleotide sequence corresponding to the forbidden sense codon AGG and a second 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.
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 27-31 and 46-51 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. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claim 27, ‘845 claims 1 and 15 broadly claims viable bacterial cells comprising a recoded genome wherein a particular sense codon is changed to an alternative codon at all instances within an essential gene, wherein at least one instance of that change is within a non-coding motif, including a ribosome binding site motif or an internal ribosome pausing site motif such that the alternative codon preserves the structure or function of that motif. ‘845 claims 4and 16 further requires that all UAG codons are removed from the recoded genome. The term “essential gene” in ‘845 claims 1 & 15 is not limited to any particular gene, and the scope of that term is properly defined by reference to the ‘845 specification. The ‘845 specification’s only disclosed example of a mutation within an essential gene’s internal ribosome-binding-site-like motif meeting this description is the prfB gene. The specification discloses that “gene prfB has an internal RBS-like motif,” that “this RBS motif is involved in a downstream planned frameshift in prfB (Curran, 1993),” that “to maintain the frameshift, AGG→CGG mutation and additional wobble was required and that preserving this frameshift required a specific mutation at the AGG64 codon within the recited template sequence, see Fig. 27 description. Because ‘845 claims 1 & 15 do not exclude prfB, or the specifically disclosed AGG64 mutation, from the scope of “essential gene” and “non-coding motif,” and because the specification provides no basis for excluding this disclosed example from the claimed genus, ‘845 claims 1 & 15, encompass an organism having a mutation at this prfB site. Combined with ‘845 claims 4 & 16 (all UAG codons removed genome-wide), the ‘845 claims as broadly drafted encompass an E. coli organism having both UAG codons removed genome-wide and a mutation within the prfB gene’s disclosed non-coding motif, which is the entirety of instant claim 27.
Regarding claims 28-30, ‘845 claims 1 & 15 recite AGG and AGC as members of the claimed particular-sense-codon genus subject to the non-coding-motif-preserving mutation. This is not patentably distinct from instant claims 28-30’s recitation of a forbidden sense codon, narrowed to AGG or AGC, as the target of the prfB mutation.
Regarding claim 31, ‘845 claims 1 & 15’s “non-coding motif” genus expressly includes an “internal ribosome pausing site motif,” and the specification’s disclosed prfB frameshift site is an example within an essential gene meeting this description, and by the specification’s own definition (citing Craigen 1985 and Curran 1993), a translational frameshift signal, see Fig. 27 description. A mutation disrupting or preserving that motif is inherently a frameshift-type mutation as disclosed. Instant claim 31’s general recitation of a frameshift mutation is not patentably distinct.
Regarding claim 46, ‘845 claims 1(i) & 15(i) recite, verbatim, that the recoded genome comprises at least one instance where the particular sense codon is reassigned to at least one non-standard amino acid. This is not patentably distinct from instant claim 46.
Regarding claim 47, ‘845 claims 1(ii) & 15(ii) recite that the alternative codon within the non-coding motif “preserves a structure or function of the non-coding motif,” i.e., that the motif’s strength or function is maintained, rather than disrupted, by the recited mutation. Instant claim 47’s recitation that RBS strength “is modulated by the mutation” describes the same underlying phenomenon (a change in RBS motif strength resulting from the recited mutation) in broader, unqualified terms, and is not patentably distinct.
Regarding claim 48, ‘845 claim 5 recites that a gene encoding a release factor is removed from the recoded genome. The specification’s defined example of release factor gene removal is the prfA (RF1), disclosed throughout in the context of enabling UAG codon reassignment, see column 29. ‘845 claim 5, construed in light of the specification, is not patentably distinct from instant claim 48’s recitation that the RF1-encoding gene is removed.
Regarding claim 49, Instant claim 49 broadens ‘845 claim 5’s specifically disclosed species (gene removal) into a genus (impairment of expression or function generally). Gene removal is the only disclosed means of impairing gene function in both specifications. Broadening a disclosed species into its genus in this manner is not patentably distinct subject matter.
Regarding claim 50, ‘845 claims 1(i) & 15(i) require reassignment of a particular sense codon to a non-standard amino acid, which is achieved through introduction of an orthogonal aminoacyl-tRNA synthetase/tRNA pair. Instant claim 50’s express recitation of this machinery is not patentably distinct from the machinery used to practice ‘845 claims 1 & 15.
Regarding claim 51, ‘845 claim 15 recites “viable bacterial cells,” and ‘845 claim 1 recites “providing viable bacterial cells.” This is not patentably distinct from instant claim 51’s recitation that the engineered organism is viable.
Claims 27-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-35, 38, 41, 45, 48, 51, 55, and 56 of copending Application No. 17/719,431 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claim 27, reference claim 27 recites an engineered E. coli organism comprising a recoded genome wherein a particular codon is replaced at all or substantially all instances with an alternative codon, wherein the particular codon is reassigned to a non-standard amino acid, and wherein the prfB gene comprises a mutation relative to the corresponding template genome; reference claim 47 further recites that the particular codon is UAG. The combination of reference claims 27 and 47 discloses every element of instant claim 27 except that reference claim 27 additionally requires reassignment of the particular codon to a non-standard amino acid, a limitation instant claim 27 does not require. Omitting a limitation already disclosed as optional (see reference claim 48, reciting the alternative codon as a synonymous codon) from an independent claim to broaden its scope is not patentably distinct subject matter; a skilled artisan would have found it obvious to draft an independent claim reciting the combination of reference claims 27 and 47 without the mandatory nsAA-reassignment limitation, since that limitation is disclosed elsewhere in the reference claim set as a separately claimed, non-essential feature (reference claims 27/56 in the reference application).
Regarding claims 28-30, reference claims 29-31 recite that the particular codon replaced within the prfB gene is a forbidden sense codon, and that the forbidden sense codon is AGG or AGC. Instant claims 28-30 recite substantially the same subject matter (a prfB mutation site corresponding to a forbidden sense codon) differing only in claim dependency structure.
Regarding claim 31, reference claim 45 recites that the mutation in the prfB gene is a frameshift mutation. Instant claim 31 recites the same limitation without the positional qualifier, “downstream of the instance…”, found in the reference claim’s dependency chain. Broadening a claimed frameshift-mutation limitation by dropping an already disclosed positional qualifier is not patentably distinct subject matter.
Regarding claim 32, reference claim 32 recites that the mutation is in the prfB gene template sequence 5’-CTTAGGGGGTATCTTTGAC-3’ (SEQ ID NO: 2351), which is the identical nineteen-nucleotide sequence recited in instant claim 32, differing only in the presence of a SEQ ID NO designation in the reference claim.
Regarding claims 33-35, reference claims 33-35 recite specific resulting mutant sequences (SEQ ID NOs: 2352-2354) reflecting wobble and frameshift mutations at defined positions within the same prfB template sequence recited in claim 32 of both applications, while instant claims 33-35 recite the same mutation positions generically (as XXX¹, XXX², XXX³) without specifying the resulting mutant nucleotide identity. The reference claims’ specific mutant sequences fall entirely within the scope of the instant claims’ generic positional recitation; claiming a genus that fully encompasses previously and separately claimed species, using the same mutation-type language (wobble mutation, frameshift mutation) at the same sequence positions, is not patentably distinct subject matter.
Regarding claims 36-38, reference claims 33-35 disclose specific point mutations, including a nucleotide deletion-consistent frameshift, at defined positions within the shared prfB template sequence. Instant claims 36-38 recite a deletion of, or point mutation at, a single nucleotide position within the same template sequence; a nucleotide deletion or single-nucleotide substitution at a position already disclosed as subject to mutation in the reference claims, for the purpose of achieving the same frameshift or wobble effect, would have been an obvious variant to a skilled artisan.
Regarding claim 39-40, reference claim 28 recites that the mutation in prfB results in a mutated codon that is not reassigned to the non-standard amino acid. Instant claims 39 and 40 recite the same limitation, with instant claim 40 additionally combining it with a forbidden-sense-codon mutation already separately claimed in the reference application (reference claims 30-31). Combining two limitations that are each independently claimed in the reference application, with no unexpected result from the same combination, is not patentably distinct subject matter.
Regarding claims 41-45, reference claims 30-31 disclose a forbidden sense codon (AGG or AGC) as the target of a claimed prfB mutation, and reference claims 33-35 disclose specific mutations at defined positions within the shared prfB template sequence. Instant claims 41-45 recite the same forbidden-codon identity (AGG or AGC) and the same template-sequence mutation positions, applied to a “second mutation” limitation that is itself not patentably distinct from reference claim 28 as discussed above.
Regarding claim 46, reference claims 27 and 56 each recite an engineered organism in which the particular trinucleotide sequence is reassigned to a non-standard amino acid, as a mandatory limitation of an independent claim. Instant claim 46 recites the identical reassignment limitation, applied as a dependent claim to instant independent claim 27.
Regarding claim 47, reference claims 38 and 41 recite a frameshift mutation combined with point mutations in an RBS-like motif, and a mutation within a ribosome binding site motif within the prfB gene, respectively. Instant claim 47’s recitation that RBS strength is modulated by the mutation describes the same underlying phenomenon in functional rather than structural terms. A claim reciting the functional consequence (modulated RBS strength) of a structural feature already claimed (a mutation within an RBS-like motif) is not patentably distinct.
Regarding claim 48, reference claim 51 recites that a gene encoding release factor 1 (RF1) is removed from the recoded genome, which is the identical limitation.
Regarding claim 49, reference claim 51 recites removal of the RF1-encoding gene, which is one species of the broader genus “expression or function of RF1 is impaired” recited in instant claim 49. Broadening a previously and specifically claimed species (gene removal) into an undisclosed-but-obvious genus (impairment generally) is not patentably distinct subject matter.
Regarding claim 50, reference claim 55 recites a polypeptide comprising a non-standard amino acid made using the engineered organism of reference claim 27, which by definition requires machinery (an orthogonal aminoacyl-tRNA synthetase and/or tRNA) capable of incorporating the non-standard amino acid via the reassigned codon. Instant claim 50’s express recitation of an orthogonal aminoacyl-tRNA synthetase and/or tRNA is not patentably distinct from the machinery necessarily employed, and defined in the reference specification, to practice reference claim 55.
Regarding claim 51, reference claim 53 recites that the engineered organism is viable.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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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