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 .
Examiner of Record
The Examiner of record has changed.
Election/Restrictions
Restriction:
Applicant’s election of Group I (claims 1-12) drawn to an eukaryotic cell comprising various orthogonal components, in the reply filed on Nov 25th 2025 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Claims 13-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim.
B. Species Election:
Applicant’s election without traverse of:
A. as the ribozyme, a hammerhead ribozyme (claims 1-2 and 4-12);
B. as the means of controlling transcriptional synthesis of the ptRNA-ribozyme, a tetracycline responsive promoter element (TRE) (claims 1-12);
C. as the means of controlling transcriptional synthesis of the pRS-ribozyme, a tetracycline responsive promoter element (TRE) (claims 1-12);
D. as the tetO-binding protein, a tetracycline repressor (tetR) (claims 1-12); and
E. as the characteristics of the ptRNA, option b) from claim 11 (claims 1-12);
in the same reply is also acknowledged.
Claim 3 is being withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Status of Claims
Claims 1-2 and 4-12 are present for examination.
Priority
Acknowledgment is made for this Application filed on 04/09/2019 which is a national stage application of PCT/EP2017/076140 filed on 10/13/2017 and claims priority from foreign application EP16194038.2 filed on 10/14/2016.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/13/2023 and 06/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because:
i) the labels for Figures 1 - 5 are preceded by the word "Figure" instead of the abbreviation "FIG." MPEP §608.02.V states that according to 37 C.F.R. 1.84(u)(1) “View numbers must be preceded by the abbreviation "FIG.".
AND
ii) the partial views for Figure 5, which appears on several sheets, are followed by "Continued" instead of the same number followed by a capital letter such as FIG. 5A, FIG. 5B, etc. C.F.R. 1.84(u)(1) requires that “partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” See MPEP 608.02.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Objection - 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. For example page 9 of the specification comprises embedded hyperlink and/or other form of browser-executable code.
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 11 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 recites exemplary language (“in particular”). Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim (see MPEP 2173.05(d)).
By nature of claim 23’s ultimate dependency on claim 11, claim 23 is also rejected for not clarifying the issue.
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.
Claims 11 and 12 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. Claims 11 and 12 depend from claim 1, which is a cell, but these claims refer only to polynucleotides. Thus they do not include the eukaryotic cell, and also do not require the polynucleotide encoding the tRNA synthetase. Claim 12 does not require element (ii) (recites the limitation as an alternative by use of or). Thus, both claims 11 and 12 don’t require the tRNA synthase. Thus, the claims fail to further limit the subject matter of the claim upon which it depends, as well as fail to include all the limitations of the claim upon which it depends. 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 § 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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Murray (WO 2017/124034, IDS).
Murray discloses compositions and methods for producing aminoacyl-tRNA analogues (summary, 0011). The method comprises: in vitro transcription of a cis-acting ribozyme fusion for the production of an optimized 75 nucleotide Methanococcus jannaschii (Mj) tRNA using the DNA template, and T7 RNA polymerase [00245]. Fig. 4 shows that a transcript with Mj tRNA and HDV ribozyme is obtained. Once transcription is complete, autocatalytic cleavage by the HDV ribozyme results in a tRNA (last lines of same para). Similarly, Murray prepare engineered aminoacyl tRNA synthetase (aaRS) enzyme corresponding to a polyspecific aaRS enzyme from Methanococcus jannaschii (Mj) [00248]. Murray test the ability of the prepared synthetase to acylate the prepared tRNA (Example 10, [00259]). Murray further teach the composition functions in a cell. See recitation from [00167] and [00207] regarding transcription and translation respectively below:
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Other references to the composition being comprised in a cell are found at: [00222] - [00223]. Thus, Murray’s recitation of aaRS enzyme from Methanococcus jannaschii (Mj), a transcript with Mj tRNA and HDV ribozyme, and transcription and translation of these two components in a eukaryotic cell read on instant pRS and ptRNA-ribozyme comprised in a eukaryotic cell.
Thus, Murray anticipates instant claim 1.
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 1, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Yokoyama (US 2010/0267087 A1) in view of Rossi (EP 0596901 B1).
Regarding claims 1 and 11, Yokoyama had taught DNA sequences encoding mutant pyrrolysyl-tRNA synthetases and tRNAs pairs such that the expressed enzyme can acylate the tRNA in a eukaryotic host cell (A method for incorporating a tyrosine analog into a desired position of a protein using TyrRS/tRNAtyr system, [0009]; mammalian cell [0064]; M. mazei-derived wild-type tRNA [0053]; M. mazei derived wild-type PylRS [0064]). The tRNA synthetases and tRNAs pairs are encoded in expression vectors comprising the corresponding DNA ([0054]-[0006]). See also claims 12 and 18.
Thus Yokoyama’s teachings of a mammalian cell transformed with a mutant pyrrolysyl-tRNA synthetase and tRNA pair from M. mazei read on instant eukaryotic cell comprising: (a) a polynucleotide encoding a prokaryotic aminoacyl tRNA synthetase (pRS), (b) a polynucleotide encoding a prokaryotic tRNA (ptRNA), wherein the pRS is capable of acylating the ptRNA, wherein the ptRNA is a pyrrolysyl tRNA of M.mazei.
Regarding claim 7, Yokoyama had further taught:
i) for expressing mutant PylRS in mammalian cells, the following may be performed: DNA sequence of M. mazei derived wild-type PylRS gene with Histidine-tag etc. at N terminus region thereof is amplified using PCR; this DNA sequence is integrated into an expression vector such as commercially available pcDNA3.1 (Invitrogen) [0064].
ii) tRNA may be coexpressed together with iii) T7 RNA polymerase in animal cells by linking T7 phage-derived T7 promoter [0065].
Yokoyama had not taught wherein the ptRNA is linked to a ribozyme (claim 1).
However, before the effective filing date of instant invention, Rossi had taught a novel chimeric tRNA - ribozyme (title, [0005]) i.e., a transcript comprising tRNA and ribozyme. See also Fig. 1. Rossi had taught that such a transcript is encoded in a vector [0007]. Thus, Rossi’s invention reads on instant polynucleotide encoding a tRNA and one ribozyme. Rossi further taught that such a chimera i) competes with the native tRNA ([0005], Fig. 2); ii) is transcribed by T7 RNA polymerase [0007]; iii) binds RNA and possesses RNAse activity (middle of para on column 2); and iv) binds an RNA-binding protein (HIV-1 RT; top of para on column 2).
It would have been obvious to one of ordinary skill in the art before the time of the invention to have incorporated a ribozyme sequence into the polynucleotide encoding the ptRNA of Yokoyama to obtain a single transcript of the ptRNA with the ribozyme as taught by Rossi. One would be motivated to do so for the advantage of obtaining a single transcript of ptRNA with ribozyme which was demonstrated by Rossi to have unique properties such as binding RNA-binding proteins, functioning as an RNAse, while simultaneously releasing the tRNA (Rossi Fig. 2). One would have further been motivated to make such a combination when an RNA-binding protein was part of the mix, as Rossi had taught that such a mix was effective. One of ordinary skill in the art would have a reasonable expectation of success in doing so since both Yokoyama and Rossi teach encoding (and subsequent) expression of the tRNA from a plasmid wherein expression is driven by a T7 promoter. See MPEP 2144 II and 2143 I.(A).
Thus, Yokoyama in view of Rossi make obvious instant claims 1, 7, and 11.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Yokoyama (US 2010/0267087 A1) and Rossi and as applied to claims 1, 7, and 11 above, and further in view of Taira (US 5,500,357).
Yokoyama and Rossi make obvious a eukaryotic cell comprising a pyrrolysyl-tRNA synthetase and ptRNA pair from M. mazei linked to a ribozyme; i.e., pRS and ptRNA-ribozyme.
Neither Yokoyama nor Rossi teach wherein the ribozyme is a hammerhead ribozyme (claim 2).
However, before the effective filing date of instant invention, Taira had taught a polynucleotide encoding a tRNA linked to one or more ribozymes wherein the ribozyme is a hammerhead ribozyme. Taira had taught an embodiment wherein the ribozyme is linked in cis with the tRNA and the ensuing transcript comprising a tRNA and a ribozyme as a means to improve recombinant DNA technology, specifically an improved method for a recombinant DNA to be produced in vivo (title, column 2, lines 20-25) and recitation below from column 3, lines 10-25:
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As seen in the recitation, more than one ribozyme is linked to the tRNA and the tRNA is encoded in a plasmid. See also Fig. 7B showing a tRNA with several linked ribozymes. Taira had taught that such a plasmid has many advantages, one advantage is being amplifiable in vivo while the host cell harboring the recombinant DNA encoding the ribozyme is kept growing (column 2, lines 15-17). The recombinant DNA is in a plasmid vector pGENE8459, thus reads on a polynucleotide under the control of a T7 promoter (Fig. 8). Tiara further show that the ribozymes are released (autocatalysis) from the transcript. Thus, the tRNA is expected to be free of the ribozymes after transcription. Thus, Taira’s invention reads on a polynucleotide encoding a tRNA linked to one or more ribozymes wherein the ribozyme is a hammerhead ribozyme as recited in instant claim 2.
It would have been obvious to one of ordinary skill in the art before the time of the invention to have substituted sequences encoding hammerhead ribozymes as taught by Taira in to the polynucleotide encoding the ptRNA-ribozyme of Yokoyama and Rossi to obtain a single transcript of the ptRNA with the hammerhead ribozyme. One would be motivated to do so for the advantage of obtaining a continuous source of such a transcript in vivo. One of ordinary skill in the art would have a reasonable expectation of success in doing so since all of Yokoyama, Rossi, and Taira teach expression of the tRNA by a T7 promoter-driven polymerase. See MPEP 2144 II and 2143 I.(B).
Thus, Yokoyama and Rossi in view of Taira make obvious instant claim 2.
Claims 4 – 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Yokoyama (US 2010/0267087 A1) and Rossi and as applied to claims 1, 7, and 11 above, and further in view of Ren (US 20090293148 A1) and Jackson (Jackson Laboratory, Retrieved from the Internet: <URL: https://www.jax.org/news-and-insights/2015/april/introduction-to-tet-expression-systems on 2/6/2025, 4 pgs.).
Yokoyama and Rossi make obvious a eukaryotic cell comprising a tRNA synthetase and ptRNA pair from M. mazei linked to a ribozyme; i.e., pRS and ptRNA-ribozyme.
Neither Yokoyama nor Rossi had taught inducible control of the ptRNA or pRS with TRE containing tetO or a tetO binding protein such as tetR.
However, before the effective filing date of instant invention, Ren had taught inducible control of any gene of interest with TRE, as an improved method of controlling gene expression. For e.g., in [0222] Ren taught a DNA template comprising a promoter (preferably a T7 promoter,…) operably linked to a nucleotide sequence encoding a chimeric RNA of the invention. Also see title.
Regarding claims 4-5 and 8, Ren provided various options for control of the promoter. For e.g., in [0506] Ren taught that the promoter may be a chemically inducible promoter acting on a fusion protein with a tetracycline-responsive element (TRE). The chimeric gene of Ren’s invention could be a tRNA or an enzyme (tRNA, [0096] and enzyme, [0108]).
Ren did not teach all the components that make up a TRE system such as tetO sequence is bound by tetO-binding protein such as tetR (claim 6).
However, before the effective filing date of instant invention, Jackson had taught the basic requirements of a Tet expression system (title).
Regarding claim 6, Jackson had taught that TRE is made up of Tet operator (tetO) sequence concatemers fused to a promoter. In the Tet-On system, the TetR repressor protein recognizes the tetO sequences in the TRE of the target transgene in the presence of Dox. Thus, transcription of the TRE-regulated target gene is stimulated by TetR only in the presence of Dox.
It would have been obvious to one of ordinary skill in the art before the time of the invention to have incorporated TRE sequences upstream of the T7 promoter that drives the expression of the ptRNA and pRS of Yokoyama and Taira, as taught by Ren and obtain a TRE controlled T7 promoter-driven ptRNA/pRS expression. One would be motivated to do so for the advantage of having high-level, tight, inducible control of the expression of the ptRNA/pRS in vivo. One would additionally be motivated to do so for both the ptRNA and pRS because Yokoyama had taught that the ptRNA/pRS work as a pair. Therefore, it would be important to induce expression of both genes simultaneously. One of ordinary skill in the art would have a reasonable expectation of success in doing so since all of Yokoyama, Taira, and Ren taught expression of the gene of interest from a T7-promoter driven plasmid. See MPEP 2144 II and 2143 I.(A).
Thus, Yokoyama and Rossi in view of Ren and Jackson make obvious instant claims 4-6 and 8.
Regarding claim 12, the teachings of Yokoyama, Rossi, Taira, and Ren and Jackson discussed above as applied to claims 1, 2, and 4-6 are similarly applied to claim 12.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Yokoyama (US 2010/0267087 A1) and Rossi and as applied to claims 1, 7, and 11 above, and further in view of Dunn (Gene, Volume 68, Issue 2, 7 September 1988, Pages 259-266).
Yokoyama and Rossi make obvious a eukaryotic cell comprising a pyrrolysyl-tRNA synthetase and ptRNA pair from M. mazei linked to a ribozyme; i.e., pRS and ptRNA-ribozyme; wherein the genes are under the control of a T7 promoter, and further comprise a polynucleotide encoding a T7 RNAP.
Neither Yokoyama nor Rossi teach wherein the T7 RNAP carries a nuclear localization signal.
However, before the effective filing date of instant invention, Dunn had taught a means to direct T7 RNAP to the nucleus in a mammalian cell by insertion of a specific sequence of nucleotides into the sequence of T7 RNAP. Dunn had taught a 36-bp synthetic nucleotide sequence encoding the SV40 T antigen nuclear location signal would achieve the goal of targeting the T7 RNAP to the nucleus (title, abstract, whole paper).
It would have been obvious to one of ordinary skill in the art before the time of the invention to have included a nuclear location signal as taught by Dunn in to the polynucleotide encoding the T7 RNAP of Yokoyama to achieve expression of the T7 RNAP in the nucleus. One would be motivated to do so for the advantage of directing T7 RNA polymerase to the nucleus so as to make this enzyme useful for selective transcription in eukaryotic cells and thus overcome the drawback faced by T7 RNAP localizing to the cytoplasm. One of ordinary skill in the art would have a reasonable expectation of success in doing so since all of Yokoyama, Rossi, and Dunn teach expression of the T7 RNAP in eukaryotic cells. See MPEP 2144 II and 2143 I.(B).
Thus, Yokoyama and Rossi in view of Dunn make obvious instant claim 9.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim Objections
Claim 10 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635