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
1. Applicant’s election without traverse of the invention of Group I (drawn to a eukaryotic cell comprising a leucyl-tRNA synthetase) and the species of SEQ ID NOs: 2 and 19, in the reply filed on 03/12/2026 is acknowledged.
Claims 2, 5-8, 11, 13-35, 37, 38, 41-82, 84-86, and 92 have been cancelled. Claims 1, 12, 39, and 87 have been amended. Claims 93-97 are new.
Claims 1, 2, 4, 9, 10, 12, 36, 39, 40, 83, 87-91, and 93-97 are pending and under examination.
Claim Objections
2. Claims 1, 39, and 87 are objected to because of the recitation “wherein the tRNA synthase mutein comprises an amino acid sequence that has at least 98% sequence identity to”. The tRNA synthase mutein cannot comprise more than its amino acid sequence.
Correction to “wherein the amino acid sequence of the leucyl-tRNA synthase mutein has at least 98% sequence identity to” is required.
3. Claim 4 is objected to because of the recitation “a premature stop codon” (last two lines”. Correction to “the premature stop codon” is required.
4. Claim 12 is objected to because of the recitation “the nucleic acid sequence encoding the tRNA synthase mutein comprises a nucleotide sequence set forth by sequence set forth by SEQ ID NO: 55”. The encoding nucleic acid cannot comprise more than the encoding nucleic acid sequence.
Correction to “the nucleic acid sequence encoding the tRNA synthase mutein is set forth by SEQ ID NO: 55” is required.
5. For the reasons above claims 36 and 93 -97 should be amended to recite:
Claim 36: “wherein the nucleic acid sequence of the suppressor leucyl-tRNA is selected from SEQ ID NOs: 16-42 and 67”.
Claims 93 and 94: “wherein the nucleic acid sequence of the suppressor leucyl-tRNA is set forth by SEQ ID NO: 19”.
Claims 95-97: “wherein the amino acid sequence of the tRNA synthase mutein is set forth by SEQ ID NO: 2”.
6. Claims 83 and 89 are objected to because the claims do not provide a basis for the recited ratios. It is clear from the specification that the ratios are copy number ratios (see [0132]; [0187]). Appropriate correction is required.
Double Patenting
7. 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.
8. Claims 1, 3, 4, 9, 10, 12, 36, 39, 40, 83, 87-91, and 93-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 21-27, 29, 30, 32-34, 36, 41, and 45-47 of copending Application No. 17/633,672 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are drawn to (1) the same genetically engineered cell stably expressing the same leucyl-tRNA synthetase mutein/suppressor leucyl-tRNA pair, where the cell is capable of expressing a target protein containing an unnatural leucine analog; and (2) to the same method for expressing the target protein containing the unnatural leucine analog by using the stably transfected cell. Although not specifically recited in the instant claims, one of skill in the art would have understood that obtaining the genetically engineered cell entails using a transfer vector encoding the leucyl-tRNA synthetase mutein. The instant specification discloses that the unnatural leucine analog comprises alkyne, azide, cyclopropene, alkene, ketone, aldehyde, diazirine, or tetrazine functional groups (see p. 29, lines 7-10).
As evidenced by the attached Sequence Alignments, SEQ ID NO: 1 recited in the application claim 1 is 99% identical to the instant SEQ ID NO: 2, while SEQ ID NOs: 2, 19, and 55 recited in the application claims are identical to SEQ ID NOs: 2, 19, and 55 recited in the instant claims.
Thus, the instant claims and the application claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112(d)
9. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
10. Claims 3, 40, and 88 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
By reciting that the protein containing the unnatural amino acid is expressed for at least 60 days, claims 3, 40, and 88 fail to further limit the subject matter of the parent claims 1, 39, and 87, respectively, which are limited to a cell stably expressing the leucyl-tRNA synthase mutein and the suppressor leucyl-tRNA, i.e., limited to continuous expression.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
11. 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.
12. Claims 1, 2, 4, 9, 10, 12, 39, 40, 83, 87-91, and 95-97 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (U.S. Patent No. 9,624,485), in view of Roy et al. (MABS, online 11/27/2019, 27: 1-17; cited on the IDS filed on 02/12/2026).
Liu et al. teach: (1) a eukaryotic cell capable of expressing a target protein comprising an unnatural amino acid and (2) a method for expression the target protein by culturing the cell in the presence of the unnatural amino acid; the cell comprises an orthogonal E. coli leucyl-tRNA synthetase mutein and an orthogonal E. coli amber suppressor leucyl-tRNA; the unnatural amino acid is introduced at a position corresponding to a selector stop codon introduced into the nucleic acid encoding the target protein, where the stop codon is recognized by the suppressor leucyl-tRNA; the leucyl-tRNA synthetase mutein is set forth by SEQ ID NO: 96 (claims 1, 39, and 87) (see Abstract; column 4, lines 10-56; column 2, lines 35-60; column 5; column 6, lines 12-18; column 8, lines 14-42; column 9, lines 34-51; column 15, lines 20-64; column 20, lines 16-20; column 22, lines 1-28; column 30, lines 19-35; column 39, lines 23-42; column 49, lines 31-43; Example 8; Fig. 15, see the description of SEQ ID NO: 96).
As evidenced by the attached Sequence Alignment, SEQ ID NO: 96 is 99.2% identical to the claimed SEQ ID NO: 2 (claims 1, 39, and 87).
Liu et al. do not teach cell lines stably expressing the tRNA synthetase mutein and suppressor tRNA (claims 1, 39, and 87). However, Liu et al. teach the need for obtaining stable cell lines for efficient production of the target protein comprising the unnatural amino acid (see column 61, lines 55-59 and 63-67). Obtaining cell lines stably expressing the leucyl-tRNA synthetase mutein and suppressor leucyl-tRNA would have been obvious to one of skill in the art, with the reasonable expectation that doing so would afford efficient production of the target protein. By obtaining cel lines stably expressing leucyl-tRNA synthetase mutein and suppressor leucyl-tRNA in their genome, one of skill in the art would have also obtained cell lines capable of expressing the target protein for at least 60 days (claims 3, 40, and 88).
With respect to claims 4 and 90, Liu et al. teach that the orthogonal suppressor tRNA specifically recognizes the selector stop codon and do not cross-react with any of the endogenous tRNAs and synthetases (see column 2, lines 36-50; column 4, lines 33-49). One of skill in the art would have reasonably concluded that the cell of Liu et al. is capable of expressing at least 60% of the level of expression by a corresponding control cell line where the gene lacks the selector stop codon (claim 4) and also that the cell has a higher unnatural amino acid incorporation even at low genomic copy numbers compared to a cell line expressing the wild type tRNA (claim 90).
With respect to claims 9, 10, 83, 87, 89, and 91, there is no evidence of record indicating that the recited copy ranges and ratios are associated with unexpected results. Furthermore, the prior art teaches that the expression level of the target protein comprising the unnatural amino acid is dependent on the copy numbers. For example, Roy et al. teach that expression increases with increasing the ratio between the suppressor tRNA and aminoacyl-tRNA synthetase (see paragraph bridging p. 5 and 6; p. 6, Table 2). One of skill in the art would have found obvious to use routine experimentation and vary the ratio (and thus, copy number) with the reasonable expectation that doing so would identify the optimal ratios for the production of the target protein. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed ranges/ratios was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
With respect to claims 12 and 95-97, it is noted that there is no evidence of record indicating that specifically using SEQ ID NO: 2 or SEQ ID NO: 55 (encoding SEQ ID NO: 2) leads to unexpected results compared to the sequences taught by Liu et al. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
13. Claims 1, 2, 4, 9, 10, 12, 36, 39, 40, 83, 87-91, and 93-97 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. taken with Roy et al., in further view of Chatterjee et al. (WO 20/257668; cited on the IDS filed on 02/12/2026).
The teachings of Liu et al. and Roy et al. are applied as above for claims 1, 2, 4, 9, 10, 12, 39, 40, 83, 87-91, and 95-97. Liu et al. and Roy et al. do not specifically teach the suppressor leucyl-tRNA set forth by SEQ ID NO: 19 (claims 36, 93, and 94). Chatterjee et al. teach the E. coli amber suppressor leucyl-tRNA set forth by SEQ ID NO: 30 with increased recognition for the selector stop codon, which enhances the incorporation efficiency of any unnatural amino acid which uses an engineered E. coli leucyl-synthetase (see Abstract; [0009]; [0012]-[0013]; [0028]; [0036]; [0056]; [0095]-[0096]; Fig. 17A). Modifying Liu et al. and Roy et al. by using the suppressor leucyl-t-RNA set forth by SEQ ID NO: 30 would have been obvious to one of skill in the art, with the reasonable expectation that doing so would result in efficient incorporation of unnatural lysine analogs into the target protein. As evidenced by the attached Sequence Alignment, SEQ ID NO: 30 is identical to the claimed SEQ ID NO: 19.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
14. No claim is allowed. No claim is free of prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ILEANA POPA/Primary Examiner, Art Unit 1633
Prosecution Insights