DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 25 June 2026 have been entered. Claims 1-3, 5-18, 21-30, 32-38, 40-41, and 93-94 were previously pending in the application. Claim 40 has been cancelled, and no new claims have been added by Applicant. Claims 1-3, 5-18, 21-30, 32-38, 41, and 93-94 are currently pending in the application. Claim 1 is an independent claim.
The following election of species remains in effect in the instant application:
Kozak sequences: a. SEQ ID NO: 125 (RNNATG) or SEQ ID NO: 28 (RVVATG)
Overlapping Kozak sequence and/or start codon and TRAP binding site sequences: a. SEQ ID NO: 29;
Nucleic acid sequences according to claim 17-18: f. SEQ ID NO: 70;
Sequence elements proximal to the TRAP binding site: Promoter: i. Leader sequences: 2. SEQ ID NO: 26.
Claims 18 and 25-30 remain withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 5-17, 21-24, 32-38, 41, and 93-94 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/GB2020/052873, filed 11 November 2020, which claims priority to United Kingdom 1916452.4, filed 12 November 2019, and United Kingdom 2001998.0, filed 13 February 2020. Filing of a certified copy of the United Kingdom 1916452.4, filed 12 November 2019, and the United Kingdom 2001998.0, filed 13 February 2020 is acknowledged.
Thus, the earliest possible priority for the instant application is 12 November 2019.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and cancelled claims 1-3, 5-17, 21-24, 32-38, 40-41, and 93-94 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn in view of Applicant’s amendments to the claims.
Amended claims 17 and 37 are newly 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.
Amended claim 17 recites, “The ribonucleic acid sequence of claim 1, wherein said ribonucleic acid sequence is encoded by the nucleotide sequence set forth in any one of SEQ ID NOs: 34-37, 69-92 or 108-112”, wherein the sequence of SEQ ID NO:70 is the elected sequence. As such, amended claim 17 now requires that the recited sequences encode the full claimed ribonucleic acid sequence according to claim 1 rather than merely being comprised within the nucleic acid sequence previously recited in claim 1.
The sequence of SEQ ID NO: 70 is GAGCATG. The ribonucleic acid sequence of claim 1 is required to comprise i) a nucleotide of interest comprising an AUG start codon, ii) a Kozak sequence comprising the start codon, and iii) a tryptophan RNA-binding attenuation protein (TRAP) binding site; wherein the TRAP binding site overlaps the Kozak sequence; and wherein the TRAP binding site is capable of interacting with TRAP such that translation of the nucleotide of interest is repressed in a viral vector production cell. As such, the limitations of claim 17 conflict with the limitations of claim 1 in that the sequence of elected SEQ ID NO: 70 (GAGCATG) cannot meet all the limitation of claim 1.
The instant specification teaches that “A consensus TRPA binding site sequence that is capable of binding TRAP is [KAGNN] repeated multiple times (e.g. 6, 7, 8, 9, 10, 11, 12 or more times)”. Therefore, the sequence of elected SEQ ID NO: 70 (GAGCATG) does not comprise a TRAP binding site capable of interacting with TRAP such that translation of the nucleotide of interest is repressed in a viral vector production cell in that the sequence of elected SEQ ID NO: 70 (GAGCATG) comprises only a single KAGN2-3 repeat.
As such, the metes and bounds of the claim cannot be determined.
Amended claim 37 has multiple issues of indefiniteness.
Amended claim 37 recites, “The ribonucleic acid sequence of claim 34, wherein the nucleic acid sequence is encoded by the sequence as defined in SEQ ID NO: 114 [KAGATG] or SEQ ID NO: 116 [KAGNATG]”. Claim 34 depends on claim 1.
Firstly, recitation of “the nucleic acid sequence” has insufficient antecedent basis in the claim. None of claims 37, 34, nor 1 have any prior recitation of “a nucleic acid sequence”.
Secondly, amended claim 37 now requires that the recited sequences encode the full claimed ribonucleic acid sequence according to independent claim 1 rather than merely being comprised within the nucleic acid sequence previously recited in independent claim 1.
The ribonucleic acid sequence of claim 1 is required to comprise i) a nucleotide of interest comprising an AUG start codon, ii) a Kozak sequence comprising the start codon, and iii) a tryptophan RNA-binding attenuation protein (TRAP) binding site; wherein the TRAP binding site overlaps the Kozak sequence; and wherein the TRAP binding site is capable of interacting with TRAP such that translation of the nucleotide of interest is repressed in a viral vector production cell.
As such, the limitations of claim 37 conflict with the limitations of independent claim 1 in that the sequence of SEQ ID NO: 114 [KAGATG] or SEQ ID NO: 116 [KAGNATG] cannot meet all the limitation of claim 1.
The instant specification teaches that “A consensus TRPA binding site sequence that is capable of binding TRAP is [KAGNN] repeated multiple times (e.g. 6, 7, 8, 9, 10, 11, 12 or more times)”. Therefore, the sequences of SEQ ID NO: 114 [KAGATG] or SEQ ID NO: 116 [KAGNATG] do not comprise a TRAP binding site capable of interacting with TRAP such that translation of the nucleotide of interest is repressed in a viral vector production cell in that the sequence of SEQ ID NO: 114 [KAGATG] or SEQ ID NO: 116 [KAGNATG] comprises only a single KAGN2-3 repeat.
As such, the metes and bounds of the claim cannot be determined.
Claim Interpretation
As discussed in the prior action, amended independent claim 1 recites, “wherein the TRAP binding site is capable of interacting with tryptophan RNA-binding attenuation protein such that translation of the nucleotide of interest is repressed in a viral vector production cell”, has been interpreted to encompass an inherent functional attribute of the claimed nucleic acid sequence without requiring that the claimed nucleic acid be present in a viral vector production cell. Additionally, “such that translation of the nucleotide of interest is repressed in a viral vector production cell” has been interpreted such that the interaction of the RNA tbs with TRAP in a viral vector production cell results in the translational repression.
Claim 21 has been recites, “wherein the TRAP binding site does not comprise a type II restriction enzyme site”, which has been afforded its broadest reasonable interpretation to encompass wherein the TRAP binding site does not comprise any single individual type II restriction enzyme, such that at least one type II restriction enzyme site is not found within the sequence. Specifically, the TRAP binding site may comprise any number of type II restriction enzyme recognition sites as long as at least one type II restriction site is not present in the sequence.
Claim Rejections - 35 USC § 103
The rejection of amended and cancelled claims 1-3, 5-17, 21-24, 32-38, 40-41, and 93-94 under 35 U.S.C. 103 as being unpatentable over Farley [US20160333373A1, published 17 November 2016]; in view of Babitzke [2004, Current Opinion in Microbiology, 7, 132-139]; REBASE [1999, BamHI, retrieved on 9 August 2025 from the Internet: <https://web.archive.org/web/19991111001358/http://rebase.neb.com/rebase/enz/BamHI.html>, archived on 11 November 1999]; Zhu et al. [2001, Biochimica & Biophysica Acta, 1521, 19-29]; and Schlatter et al. [2003, Biotechnology & Bioengineering, 81(1), 1-12]; is withdrawn over cancelled claim 40 and maintained over amended claims 1-3, 5-17, 21-24, 32-38, 41, and 93-94. Applicant's amendments to the claims, arguments, and declaration filed 28 December 2025 have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant has amended the claims to recite a ribonucleic acid, and updated the corresponding dependent claims reciting DNA sequences such that the RNA/elements of the RNA are encoded by the recited sequences, to address issues of indefiniteness identified in the prior action. However, given the direct relationship between RNA and DNA sequences, merely reciting that the previously claimed “nucleic acid” is a “ribonucleic acid” does not render the claimed invention nonobvious over the cited prior art.
The amendments to claims 16-17, 24, and 37 have altered the scope of the claims to require that each of the recited RNA elements is encoded by the sequence according to the recited SEQ ID NOs, thereby requiring the full-length sequence of the claimed SEQ ID NOs rather than encompassing fragments of the sequences according to the claimed SEQ ID NOs.
Regarding claim 16 and 37, Babitzke was cited for teaching the elected species of an overlapping Kozak and/or start codon and tbs comprising the full length sequence of SEQ ID NO: 29 (GAGATG) [column 11 ¶ 1-2, Figure 2], which then also comprises the full length sequence of SEQ ID NO: 114 (KAGATG).
Regarding claims 17 and 37, as discussed in the prior action, Farley and Babitzke teach the motivation to assemble the tbs and start codon to overlap the first nucleotide (e.g., A) of the start codon ATG using the tbs taught by Farley to arrive at the tbs-start codon junction of GAGCATG (SEQ ID NO: 70) by replacing the 3’ terminal N from the 3’ terminal KAGNN repeat of the tbs taught by Farley, with the first nucleotide of the ATG start codon to arrive at a sequence comprising the full length sequence of SEQ ID NO: 70 (GAGCATG), which then also comprises the full length sequence of SEQ ID NO: 116 (KAGNATG).
Regarding claim 24, as discussed in the prior action, Zhu abstract, column 2 ¶ 1, column 16 ¶ 2, Figure 1A] and Schlatter [column 18 ¶ 2] were cited for teaching the motivation include the EF1α TOP leader sequence having 100% identity to the full-length sequence of SEQ ID NO: 26 (CTTTTTCGCAAC) within the 5’ UTR (e.g., between a promoter and a start codon) of transgene to allow translational control of the transgene expression, including increasing the repression of the gene by blocking ribosomal binding to the transcript.
Therefore, Applicant’s amendments do not overcome a finding of obviousness over Farley, Babitzke, REBASE, Zhu, and Schlatter under 35 USC 103.
Applicant argues that:
the Office assumes that the +0 construct of Farley disclosed an overlapping tbs/Kozak architecture, notwithstanding the unrebutted Declaration testimony that the tbs and start codon merely abut and do not overlap;
the Office assumes that overlap of a bacterial TRAP binding site with a bacterial translation initiation region, as described in Babitzke, is equivalent to the claimed overlap with a eukaryotic Kozak sequence;
the Office assumes that a mammalian TOP-mediated translational control element could be incorporated into the bacterial TRAP/tbs system while preserving or improving TRAP-mediated repression, despite the absence of any teaching or reasonable expectation of success in the cited references;
Farley itself provides no suggestion that moving the tbs closer to the initiation codon would improve repression, and, in fact, the data presented in Farley did not demonstrate progressively improved repression as the tbs approached the start codon, wherein Farley further teaches that the +0 construct did not demonstrate improved repression relative to the spaced variants and further exhibited reduced transgene expression “likely due to deletion of optimal Kozak consensus sequence" [Farley 0598], such that Farley teaches away from altering the Kozak sequence; and
A person of ordinary skill in the art would not have had a reasonable expectation that a mammalian TOP leader sequence could simply be incorporated into the engineered TRAP/tbs structure while preserving, much less improving, TRAP-mediated repression, and as such the inventor’s discovery that EF1a-derived leader sequences enhanced TRAP-mediated repression while maintaining robust non-repressed expression was therefore unexpected and surprising, as addressed in the instant specification at 4:25-27, 5:5-20, 13:32-14:3; 31:23-27; and 38:27-30.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), note that the declaration by Dr. Farley was not disregarded nor unrebutted in the prior Office Action. The response found on pages 10-13 of the prior Office Action (OA) fully rebuts the declaration provided by Dr. Farley by contesting the assertions presented therein, including that Farley only discloses adjacent (tbs-ATG) and not overlapping (tbs-Kozak) sequence elements (see OA pages 10-11), that the data presented by Farley shows that moving the tbs closer to the start codon did not achieve increased translation repression (see 11-12), and that one skilled in the art would not consider the native TRAP binding site disclosed in Babitzke to be relevant to the present invention (see OA page 12). The Dr. Farley declaration assertion that bacteria have Shine Dalgarno sequences and not Kozak sequences is not contested.
As discussed in the prior action, the claims recite a nucleic acid sequence, and as such, are drawn to a product wherein the structure of the nucleic acid sequence determines the patentability of the present invention. Determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). Similarly, patentability of a product does not depend on the intent of its production if the resulting structure is the same.
As discussed in the prior actions, Farley created a nucleic acid sequence comprising i) a nucleotide of interest comprising an ATG/AUG start codon, ii) a Kozak sequence comprising the start codon, and iii) a tryptophan RNA-binding attenuation protein (TRAP) binding site (tbs) [Figure 4, 6, 13]; wherein the TRAP binding site overlaps the Kozak sequence (e.g., “+0” spacer between the tbs and ATG, wherein the 3’ terminal tbs repeat KAGNN overlaps the core Kozak RNNATG (SEQ ID NO: 125 of the instant application) at a junction sequence of GGAGTCATGG) [Figure 6, 13A]. The overlapping sequence taught by Farley, GGAGTCATGG, is such that the Kozak sequence (GTCATG) comprises a portion of the tbs (e.g., the GTC) and the tbs comprises a portion of the Kozak sequence, (e.g., the same GTC overlapping sequence).
The declaration by Dr. Farley expressly stating that the variant “+0” spacer construct utilized a truncated Kozak sequence, “such that the tbs and start codon abut; however, they do not overlap” (emphasis added) does not change the fact that the junction sequence of GAGCTATG comprises an overlapping tbs and Kozak sequence according to the consensus Kozak sequence of RNNATG, which is an elected Kozak sequence according to SEQ ID NO: 125. Within the junction sequence of GGAGTCATGG, the tbs and start codon abut, as attested by Dr. Farley. However, in truncating the Kozak to generate the abutted junction sequence of GGAGTCATGG, whether intentional or not, Dr. Farley generated and disclosed an overlapping tbs-Kozak sequence. Although Farley did not teach that the overlapping sequence was designed to be an overlapping tbs-Kozak sequence, the effect of the truncation performed by Farley was to generate an overlapping tbs-Kozak sequence. Therefore, Farley does in fact disclose an overlapping TRAP binding site (tbs) and Kozak sequence. Farley’s lack of explicit description of the construct as comprising an overlapping architecture does not preclude the construct from having an overlapping architecture.
The claims do not require that the tbs overlap with the AUG start codon, but only with a Kozak sequence which comprises the AUG start codon. Accordingly, the Farley reference teaches all of the structural limitations of the product recited in independent claim 1, wherein the Farley reference is lacking only the specific elected junction/overlapping sequences of SEQ ID NO: 29 (GAGATG) or SEQ ID NO: 70 (GAGCATG), which deficiency is cured by the teachings of Babitzke, as discussed in the prior actions.
Applicant asserts that Examiner’s assertion that Farley’s junction sequence of GGAGTCATGG necessarily teaches overlap is unsupported by evidence in the prior action, and that the Office’s position relies on “reconstructing a putative Kozak sequence across the junction between two adjacent sequence elements using Applicant’s own disclosure as a roadmap.
However, this is not consistent with the prior action. Firstly, Farley teaches the junction in Figures 6 and 13, such that “reconstruction” merely requires looking at the sequences taught by Farley within those two figures. Secondly, the prior action explicitly addresses the suitability of the sequence of GGAGTCATGG to function as a legitimate Kozak sequence. Specifically, as discussed in the prior action, the GGAGTCATGG Kozak sequence comprised in the +0 spacer construct of Farley comprises the elected RNNATG core Kozak sequence, is similar to the consensus Kozak sequence of GCCRCCATGG, and comprises the critical purine (having a G) at position -3 and G at position +4. Additionally, as further evidence of the suitability of this sequence as a bona fide Kozak sequence, Coppola specifically teaches that the exact same sequence, GGAGTCATGG, agrees reasonably well with the consensus sequence for translation initiation in eukaryotes (i.e., mice) and is present as the functional, native initiator sequence in the murine N-type calcium channel α1 subunit mRNA [Coppola et al. 1994, FEBS Letters, 338, 1-5, column 3 ¶ 7, Figure 1].
Accordingly, the sequence disclosed by Farley is a functional Kozak sequence which overlaps with the tbs sequence as taught by Farley [Figure 6, 13].
Regarding Applicant’s argument 2), Applicant asserts that because a TRAP binding site is a bacterial sequence, and a Kozak sequence is a eukaryotic sequence recognized by a eukaryotic ribosome, that the teachings of Babitzke are not relevant to the present invention.
However, as discussed in the prior actions, Babitzke was cited for teaching that the B. subtilis ycbK gene, which comprises a natural tbs, comprises the sequence of GAGATG [Figure 2]. Babitzke also teaches that, for the trpP gene, extending the tbs into the coding region results in more effective inhibition of ribosome binding (and thus more effective inhibition of translation), that the tbs of the ycbK gene overlaps the translation initiation region and extends into the coding sequence, and that one might predict that the repeats in the coding sequence may increase the effectiveness of bound TRAP in blocking ribosome binding [column 11 ¶ 1-2, Figure 2]. As such, given the teachings of the increased effectiveness of translational attenuation for TRAP bindings sites which overlap with the start codon and extend into the coding sequence and the teaching that the natural ycbK gene comprises an overlap configuration wherein the KAGNN repeat overlaps with the start codon with a junction sequence of GAGATG, Babitzke teaches motivation for an ordinarily skilled artisan to arrange a TRAP binding site relative to the start codon such that the tbs extends into the coding sequence and such that the KAGNN repeats of the tbs overlap with the start codon to produce a junction sequence of GAGATG, as elected, for increased effectiveness of translational attenuation of the nucleotide of interest.
Steric blocking of ribosomal binding to reduce translation is a well-known regulatory mechanisms which is not exclusive to bacterial systems nor exclusive to bacterial ribosomes. In fact, Farley teaches the inclusion of the same bacterial TRAP binding site for attenuation of translation in eukaryotic systems, such that TRAP binding to the tbs represses translation initiation in eukaryotic cells by physically blocking the 40S scanning ribosome complex before it can reach the initiation codon, where-upon the more stable and higher-affinity translation machinery would otherwise form [0042-0043]. Therefore, the Farley reference teaches that the mechanism of translational inhibition by TRAP binding to a tbs in eukaryotes is by physical blocking of the eukaryotic ribosome. Additionally, Farley teaches that the physical blocking of ribosome access to the trpF and yhaG ribosome binding sites is one of the mechanisms for TRAP regulation of tryptophan biosynthesis and transport in its natural context [0150-0155], thereby equating the physical blocking of eukaryotic ribosomes by TRAP bound to tbs to the physical blocking of bacterial ribosomes by TRAP bound to tbs that occurs naturally in bacteria.
Therefore, the Farley reference itself provides the evidence of record that one of ordinary skill in the art would have considered the bacterial TRAP-tbs ribosome blocking mechanism to be equivalent to the claimed eukaryotic TRAP-tbs ribosome blocking mechanism. Application of the teachings of Babitzke to the teachings of Farley does not require an ordinarily skilled artisan to equate the bacterial Shine-Dalgarno sequence to the eukaryotic Kozak sequence, but merely to understand that a physical blockage mechanism to prevent ribosomal access to the start codon, and thereby prevent nucleation of a translation initiation complex at the start codon, would be equivalent across domains, which understanding is taught by Farley, as discussed above.
Regarding Applicant’s argument 3), the Office has not made any assumption that a mammalian TOP-mediated translational control element could be incorporated into the bacterial TRAP/tbs system while preserving or improving TRAP-mediated repression. The system taught by Farley is a eukaryotic system, which includes mammals, such that Farley has incorporated a bacterial TRAP/tbs system into a eukaryotic system, codon optimized the tbs for mammalian expression, used the system for gene expression regulation in mammalian cells, and taught wherein mammalian targets are particularly preferred [0045, 0251, 0303, 0354, 0526, 0579, 0586, 0639-0640]. Therefore, in modifying the teachings of Farley to include a mammalian TOP-mediated translational control element, the mammalian TOP-mediated translational control element is being incorporated into a mammalian expression system.
Farley was cited for teaching the inclusion of either a 34 nt 5’ leader sequence or a 41 nt 5’ leader sequence upstream of the tbs [0123, 0576].
Additionally, Zhu was cited for teaching that the sequence of instant SEQ ID NO: 26 (CTTTTTCGCAAC) is the terminal oligopyrimidine tract (TOP) from the EF1α mRNA 5’UTR which is required for translational control of EF1a transcripts, such that it facilitates the translational repression of the transcript following rapamycin treatment and binding of a repressor protein to the TOP sequence [abstract, column 2 ¶ 1, column 16 ¶ 2, Figure 1A].
Further, Schlatter was cited for teaching that TOP elements adopt a specific secondary structure that prevents ribosome binding and translation initiation of mRNAs, and the use of a TOP sequence for the conditional control of transgene expression from a vector in mammalian cells, wherein a TOP sequence is inserted between a promoter and a transgene coding region [abstract]. Schlatter also teaches that this system has proved to provide unprecedented precision in controlling translation in stable transgenic mammalian cell lines [column 18 ¶ 2].
Therefore, given the teachings of Zhu that the EF1α TOP comprises the sequence of instant SEQ ID NO: 26 and the teachings of Schlatter to use TOP sequences as translation control elements to control the expression of transgenes, Zhu and Schlatter together teach the motivation for an ordinarily skilled artisan to include the EF1α TOP leader sequence within the 5’ UTR (e.g., between a promoter and a start codon) of a transgene to allow translational control of the transgene expression in mammalian cells, including increasing the repression of the gene by blocking ribosomal binding to the transcript following treatment with rapamycin.
Regarding Applicant’s argument 4), note that the motivations provided by the prior art references are not required to be the same motivations taught by the instant disclosure. Additionally, Farley teaches an overlapping tbs-Kozak sequence, and as such does not need to teach a motivation to alter the structure explicitly taught. Additionally, Babitzke was cited for teaching the motivation to move the tbs to overlap the start codon. Specifically, Babitzke was cited for teaching that the B. subtilis ycbK gene, which comprises a natural tbs, comprises the sequence of GAGATG [Figure 2]. Babitzke also teaches that, for the trpP gene, extending the tbs into the coding region results in more effective inhibition of ribosome binding (and thus more effective inhibition of translation), that the tbs of the ycbK gene overlaps the translation initiation region and extends into the coding sequence, and that one might predict that the repeats in the coding sequence may increase the effectiveness of bound TRAP in blocking ribosome binding [column 11 ¶ 1-2, Figure 2]. As such, given the teachings of the increased effectiveness of translational attenuation for TRAP bindings sites which overlap with the start codon and extend into the coding sequence and the teaching that the natural ycbK gene comprises an overlap configuration wherein the KAGNN repeat overlaps with the start codon with a junction sequence of GAGATG, Babitzke teaches the motivation to arrange a TRAP binding site relative to the start codon such that the tbs extends into the coding sequence and such that the KAGNN repeats of the tbs overlap with the start codon to produce a junction sequence of GAGATG, as elected, for increased effectiveness of translational attenuation of the nucleotide of interest by inhibiting ribosomal access to the initiation codon.
Regarding Applicant’s argument 5), as discussed above, with respect to Applicant’s assertion that a person of ordinary skill in the art would have had a reasonable expectation that a mammalian TOP leader sequence could simply be incorporated into the engineered TRAP/tbs structure while preserving, much less improving, TRAP-mediated repression, note that the leader sequence is claimed to be present upstream of the tbs sequence, not incorporated into the tbs structure. Additionally, the EF1a leader sequence is not a requirement of the broadest independent claim, claim 1.
As discussed above and in the prior action, Zhu was cited for teaching that the sequence of instant SEQ ID NO: 26 (CTTTTTCGCAAC) is the terminal oligopyrimidine tract (TOP) from the EF1α mRNA 5’UTR which is required for translational control of EF1a transcripts, such that it facilitates the translational repression of the transcript following rapamycin treatment and subsequent binding of a repressor protein La to the TOP sequence [abstract, column 2 ¶ 1, column 16 ¶ 2, Figure 1A].
Additionally, Schlatter was cited for teaching that TOP elements adopt a specific secondary structure that prevents ribosome binding and translation initiation of mRNAs, and the use of a TOP sequence for the conditional control of transgene expression from a vector in mammalian cells, wherein a TOP sequence is inserted between a promoter and a transgene coding region [abstract]. Schlatter also teaches that this system has proved to provide unprecedented precision in controlling translation in stable transgenic mammalian cell lines [column 18 ¶ 2].
Therefore, given the teachings of Zhu that the EF1α TOP element comprises the sequence of instant SEQ ID NO: 26 and the teachings of Schlatter to use TOP sequences as translation control elements to control the expression of transgenes, Zhu and Schlatter teach the motivation for an ordinarily skilled artisan at the time of filing the instant application to include the EF1α TOP leader sequence within the 5’ UTR (e.g., between a promoter and a start codon) of a transgene RNA to allow translational control of the transgene expression, including increasing the repression of the gene by blocking ribosomal binding to the transcript subsequent to rapamycin treatment and/or La protein expression/activation. As such, an ordinarily skilled artisan would have had a reasonable expectation of success in achieving translational control of an mRNA comprising a TOP sequence by controlling the addition of rapamycin and/or expression of La protein. Additionally, an ordinarily skilled artisan would have had reasonable expectation that in the absence of rapamycin and/or La protein binding, that the EF1a TOP element would allow expression of the transgene, as taught by Zhu, for example in Figure 1 wherein an EF1a TOP-containing hGh transgene is enriched in polysome fractions in untreated cells compared to rapamycin treated cells and in Figure 5 wherein in vitro translation of the EF1a TOP-containing hGh transgene occurs in the absence of La protein but is inhibited in the presence of La protein [Figure 1, 5].
With respect to Applicant’s assertion that the present inventors surprisingly found that EF1a-derived leader sequences enhanced TRAP-mediated repression while maintaining robust non-repressed expression, Applicant has referenced instant specification at 4:25-27, 5:5-20, 13:32-14:3; 31:23-27; and 38:27-30 for teaching the unexpected nature of Applicant’s findings from combining an EF1a-derived leader sequence and TRAP-mediated repression.
Specification 4:25-27 teaches:
“Surprising, the use of this system does not impede the production of packageable vector genome molecules nor the activity of vector virions, and does not interfere with the long-term expression of the NOI in the target cell” (with no reference to any supporting data).
Specification 5:5-20 teaches:
“1. Improved 5'UTR leader sequences (upstream of tbs) composed of nucleotides derived from the first (non-coding) exon of the EF1a gene are surprisingly shown to be able to allow consistently lower 'repressed' levels of transgene expression mediated by the TRAP-tbs complex compared to 5'UTR leader sequences from a variety of constitutive promoters.
2. Improved UTR or 'spacer' sequences inserted between an internal ribosome entry site (IRES) and the tbs are surprisingly shown to improve both fold-repression and non-repressed levels (i.e. without TRAP). [Note that this is not a claimed feature.]
3. Variant Kozak sequences that overlap with the 3' end of the tbs are surprisingly shown to lead to improved occlusion of the transgene initiation codon by the TRAP- tbs complex.
4. Sequences comprising compressed, overlapping multi-cloning sites between the tbs and the transgene Kozak sequence (transgene start codon (ATG)) are surprisingly shown to enable ease of cloning whilst retaining low levels of transgene expression when repressed by TRAP. [Note that this is not a claimed feature.]
5. Overlap of the 3' end of the tbs with the transgene start codon ATG is surprisingly shown to lead to improved occlusion of the transgene initiation codon by the TRAP- tbs complex” (with no reference to any supporting data).
Specification 13:32-14:3 teaches, within the brief description of Figure 1, which is a schematic of the construct without any supporting data:
“Surprisingly, it is found that when compared to leader sequences from other promoters, use of such a leader sequence leads to improved levels of repression of the transgene by TRAP-tbs (TRAP denoted by doughnut shape).”
Specification 31:23-29 teaches:
“The present inventors have surprisingly found that improved levels of repression can be achieved by ‘hiding’ the Kozak sequence within the 3’ terminus of the tbs or portion thereof (using overlapping tbs and Kozak sequences; see Figure 2B and 2C), compared to the use of non-overlapping tbs and Kozak sequences. In addition, all of the tested overlapping Kozak and tbs sequences unexpectedly directed efficient levels of translation initiation, i.e. the tested overlapping sequences provided similar levels of transgene expression to the non-overlapping Kozak and tbs sequences in the absence of TRAP.” Note that Figures 2B and 2C are schematics of the construct (B) and a depiction of the Kozak sequence overlap with one repeat of the tbs with no reference to any supporting data.
Specification 38:27-30 teaches:
“Surprisingly, it was found that the first exon of the EF1a promoter (SEQ ID NO: 25) provides consistently good levels of transgene repression by TRAP compared to 5’UTR leaders comprising native leader sequences, and this leader also provides good levels of transgene expression in the absence of TRAP” (with no reference to any supporting data).
All of the cited passages assert a surprising finding related to the inclusion of the TOP leader sequence and/or the overlap of the tbs and the Kozak sequence within the claimed ribonucleic acid construct. However, none of the passages provide any data supporting the assertions of surprising effects.
As discussed above, Farley teaches an overlapping tbs-Kozak sequence and that TRAP-tbs binding provides a physical block to prevent ribosome binding to the start codon. Additionally, Babitzke teaches the motivation to arrange a TRAP binding site relative to the start codon such that the tbs extends into the coding sequence and such that the KAGNN repeats of the tbs overlap with the start codon to produce a junction sequence of GAGATG, as elected, for increased effectiveness of translational attenuation of the nucleotide of interest by inhibiting ribosomal access to the initiation codon. Therefore, given the teachings of Farley and Babitzke, it would not have been surprising to an ordinarily skilled artisan that overlapping the tbs with the Kozak sequence and/or start codon would result in improved repression of the transcript operably linked to the Kozak and/or start codon.
As discussed above, Zhu teaches wherein TOP-mediated repression is secondary to rapamycin treatment and subsequent binding of a repressor protein La to the TOP sequence [abstract, column 2 ¶ 1, column 16 ¶ 2, Figure 1A]. Further, Zhu teaches that La protein binding to the TOP element in the EF1A 5’ UTR RNA correlates with TOP mRNA translational repression following rapamycin treatment of cells [abstract, column 3 ¶ 2, column 17 ¶ 4].
Therefore, the expression and activity levels of TOP element binding proteins and specific conditions within the cells will determine the level to which a TOP element is able to facilitate repression of a given transcript. Applicant has not shown any data to indicate that the particular cellular conditions under which transgene expression was assessed were conditions for which TOP element-mediated repression would be expected.
As discussed in the prior action, the data provided by the instant disclosure does not provide support for the assertion that the present inventors surprisingly found that the sequence encoding the terminal oligopyrimidine tract (TOP) element did not reduce transgene expression in the absence of TRAP.
In particular, Figure 3 shows repression by TRAP-tbs for full native promoters (including the EF1alpha promoter according to instant SEQ ID NO: 134) with their native 5’UTR leader sequences as well as truncated promoters with the “Improved Leader L33” [page 15 line 1-13, Figure 3]. The “Improved Leader L33” corresponds to the sequence of instant SEQ ID NO: 25 (identical to SEQ ID NO: 139), which comprises the sequence of SEQ ID NO: 26 (also identical to SEQ ID NO: 140) and therefore encodes the EF1alpha TOP element [Table 1]. Applicant has compared the presence of the full native EF1alpha promoter + 5’UTR sequence to a truncated EF1alpha promoter + the “Improved Leader L33” and shown that the construct having the “Improved Leader L33” exhibited a slightly higher expression level than the construct comprising the native sequence. However, the data presented in Figure 3 does not provide a control lacking a leader sequence, having only the elected leader of SEQ ID NO: 26, nor otherwise differing by only the presence of the “Improved Leader L33” or elected leader sequence.
Applicant suggests in the former response that the presence of the intron in the native promoters is insignificant since it is spliced out of the mRNA, and does not address the potential impact of the intron on expression levels. The data presented in Figure 3 was generated by transfecting the constructs comprising the indicated promoters and leader sequences upstream of the tbs-Kozak sequence operably linked to a GFP coding sequence in HEK293T cells [page 149 lines 8-17]. The GFP expression was then measured by flow cytometry as a GFP Expression Score (%GFP positive cells x mean fluorescence intensity), without normalization for the transcription levels of the construct. Therefore, Applicant’s assumption that the presence of an intron is not impacting the data has not been validated.
Note also that for the other promoters tested, the data in Figure 3 show that the “Improved Leader L33” has similar- sometimes slightly higher and sometimes slightly lower- GFP expression levels compared to the respective native promoters.
As such, Applicant has not shown that the “Improved Leader L33” nor the elected leader sequence “surprisingly” do not repress expression, particularly given that the TOP element is present in both the native EF1alpha leader sequence and the “Improved Leader L33” and that transcriptional levels have not been accounted for.
Figure 8 is a comparison of the “Improved Leader L33” (“L33”) and the elected leader sequence (referred to as “L12”). Figure 8 does not compare constructs comprising the elected L12 with any constructs lacking the elected leader sequence. Therefore, Figure 8 does not provide any data regarding a lack of repression for the elected leader sequence in the absence of TRAP.
Further, data presented for additional promoters have mixed results, wherein the L33-comprising construct is only very slightly increased or even reduced relative to the respective native promoter, and wherein the variance between the L33-comprising construct and the native construct is comparable to the variance observed between the L33- and L12-comrpising constructs, suggesting that the differences observed are not likely attributable to substantial alterations in the repressibility of the constructs [Figure 3, 8].
Regarding the assertion in specification 4:25-27 that “the use of this system does not impede the production of packageable vector genome molecules nor the activity of vector virions” is surprising, note that these statements are not accompanied by references to any data. Note that the specific lines cited by Applicant in the remarks filed 25 June 2026 do not indicate which elements comprise “this system” as references in line 25. However, the cited lines fall within the context of the following paragraph:
“WO2015/092440 (incorporated herein by reference) discloses the use of a heterologous translation control system in eukaryotic cell cultures to repress the translation of the NOI (repress transgene expression) during viral vector production and thus repress or prevent expression of the protein encoded by the NOI. This system is referred to as the Transgene Repression In vector Production cell system or TRIP system. In one form, the TRIP system utilises the bacterial trp operon regulation protein, tryptophan RNA-binding attenuation protein (TRAP), and the TRAP binding site/sequence (tbs) to mediate transgene repression. Surprisingly, the use of this system does not impede the production of packageable vector genome molecules nor the activity of vector virions, and does not interfere with the long-term expression of the NOI in the target cell.” [lines 19-27] (emphasis added). Therefore, the statement cited by Applicant is referencing the system found in WO2015/09244, which is the publication of International Application No. PCT/GB2014/053813, which is the International Application of which Farley is a 35 U.S.C. 371 national stage filing. Accordingly, the surprising results to which instant specification 4:25-27 are referring are in fact the surprising results already disclosed by Farley and do not constitute a new surprise of the instant invention nor a result of the particular EF1a TOP leader sequence incorporation.
Further, Farley teaches the identical statement: “We have surprisingly found that use of this system does not impede the production of packageable vector genome molecules nor the activity of vector virions, and does not interfere with the long-term expression of the NOI in the target cell.” [0021]. Accordingly, the cited statement is not indicative of a surprising or unexpected result arising out of any unique features of the instantly claimed invention.
Regarding the assertion in specification 5:5-20, 13:32-14:3, and 28:27-30 that improved 5'UTR leader sequences (upstream of tbs) composed of nucleotides derived from the first (non-coding) exon of the EF1a gene are surprisingly shown to be able to allow consistently lower 'repressed' levels of transgene expression mediated by the TRAP-tbs complex compared to 5'UTR leader sequences from a variety of constitutive promoters, note that these statements are not accompanied by references to any data.
Additionally, Applicant presents data in Figure 3 which demonstrates that leader sequences from EF1a result in lower expression in the presence of TRAP compared to the absence of TRAP, wherein the improved leader L33 (“Impr Lrd L33”) exhibits identical activity to the 34 nt leader of CMV with or without TRAP. Note that the “Improved Leader L33” corresponds to the 33 nt sequence of instant SEQ ID NO: 25 (identical to SEQ ID NO: 139), which comprises the sequence of SEQ ID NO: 26 (also identical to SEQ ID NO: 140) and therefore encodes the EF1alpha TOP element [Table 1]. Note also that the “Improved Leader L33” is the same length as and identical to the sequence taught by Zhu as the EF1A 5’UTR sequence used in the EF1A-hGH construct [Figure 1A], and as such is a well-known leader sequence for promoting translational repression and does not comprise any “improvements” imparted by Applicants.
As discussed above, the instant specification does not teach whether or not the experiments generating the data presented in Figure 3 were performed under conditions which would promote TOP-mediated repression.
Importantly, note again that the Improved Leader L33 does not show any improvement compared to the CMV 34nt leader. The CMV 34nt leader is the same leader taught by Farley [0123, 0599, Figure 24i, see also instant specification pg 149 ln 11-12, which teaches that the CMV 34nt leader is the original 34 nt leader used in WO2015/092440, which is the publication of International Application No. PCT/GB2014/053813, which is the International Application of which Farley is a 35 U.S.C. 371 national stage filing]. Therefore, the substitution of the claimed Improved Leader L33 for the CMV 34nt leader does not constitute an unexpected improvement in TRAP-mediated repression compared to the leader sequence taught by Farley.
Note also that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Specifically, Applicant has merely shown that altering a construct from having the full native intron-containing EF1alpha promoter with the native 5’ UTR leader sequence (comprising the elected sequence of SEQ ID NO: 26) to having a truncated EF1alpha promoter with a shorter leader sequence L33 (also comprising the elected leader sequence of SEQ ID NO: 26) slightly increased the GFP expression levels in the absence of co-transfected TRAP in a single cell type under a single set of culture conditions [page 149 lines 8-17, Table 1, Figure 3]. Applicant as also shown that altering a construct from having the CMV 34nt leader sequence to having a truncated EF1alpha promoter with a shorter leader sequence L33 (also comprising the elected leader sequence of SEQ ID NO: 26) does not alter the GFP expression levels in the absence or present of co-transfected TRAP [Figure 3]. Applicant also showed that a construct comprising the elected L12 leader sequence has a similar expression level to the L33-comprising construct when transfected in the absence of co-transfected TRAP in a single cell type under a single set of culture conditions [Figure 8].
Therefore, Applicant’s evidence is not commensurate in scope with the claimed invention, which recites a nucleic acid sequence not limited to any particular leader sequence in the broadest independent claim. With respect to claim 24 specifically, the invention requires the elected leader sequence, but is not limited to any function of the leader sequence nor to inclusion of the nucleic acid within any particular cells, nor to the expression of the nucleic acid under any particular cellular conditions. Additionally, the claim as written requires the sequence of SEQ ID NO: 26 but does not exclude additional sequences, such as the full EF1alpha 5’ UTR or any other sequences.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Farley, Babitzke, Zhu, and Schlatter under 35 USC 103, and the rejection is maintained.
Double Patenting
The rejection of amended and cancelled claims 1-3, 5-17, 21-24, 32-38, 40-41, and 93-94 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,544,429, hereafter referred to as the ‘429 patent, in view of Babitzke [2004, Current Opinion in Microbiology, 7, 132-139] is withdrawn over cancelled claim 40 and maintained over amended claims 1-3, 5-17, 21-24, 32-38, 41, and 93-94. Applicant's amendments to the claims, arguments, and declaration filed 28 December 2025 have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to address issues of indefiniteness which do not alter the scope sufficiently to render the application patentably distinct from the ‘429 patent, and as such do not overcome this nonstatutory double patenting rejection.
Applicant argues that:
The Farley Declaration establishes that the +0 construct of Farley utilized a truncated Kozak sequence, such that the tbs and start codon merely abut one another and do not overlap, and the Office has not provided evidence rebutting this factual testimony; and
The Babitzke reference concerns bacterial translation initiation system that does not comprise a eukaryotic Kozak sequence and so does not disclose or suggest the claimed overlap between a TRAP binding site and a eukaryotic Kozak sequence.
However, this is not agreed.
Regarding Applicant’s argument 1), as discussed in the prior actions, the ‘429 patent claims recite all the limitations of the instant independent claim 1 other than the overlap with the Kozak sequence and/or start codon. Although the ‘429 patent claims do not recite the instantly claimed overlap with the Kozak sequence and/or start codon, the ‘429 patent claims encompass the instantly claimed invention. This rejection does not rely upon unclaimed teachings of Farley which disclose a construct having an overlapping tbs-Kozak, but merely that the overlapping tbs-Kozak is an obvious variant of the invention claimed by the ‘429 patent claims, as described in more detail below. As such, the alleged establishment of the +0 construct of Farley utilizing a truncated Kozak sequence, such that the tbs and start codon merely abut one another and do not overlap, is not a relevant allegation with respect to this rejection on the ground of nonstatutory double patenting.
Regarding Applicant’s argument 2), Babitzke was cited for teaching that the B. subtilis ycbK gene, which comprises a natural tbs, comprises the sequence of GAGATG [Figure 2]. Babitzke also teaches that, for the trpP gene, extending the tbs into the coding region results in more effective inhibition of ribosome binding (and thus more effective inhibition of translation), that the tbs of the ycbK gene overlaps the translation initiation region and extends into the coding sequence, and that one might predict that the repeats in the coding sequence may increase the effectiveness of bound TRAP in blocking ribosome binding [abstract, column 11 ¶ 1-2, Figure 2].
As such, given the teachings of the increased effectiveness of translational attenuation for TRAP bindings sites which overlap with the start codon and extend into the coding sequence and the teaching that the natural ycbK gene comprises an overlap configuration wherein the KAGNN repeat overlaps with the start codon with a junction sequence of GAGATG, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to arrange a TRAP binding site relative to the start codon such that the tbs extends into the coding sequence and such that the KAGNN repeats of the tbs overlap with the start codon to produce a junction sequence of GAGATG or GAGCATG, as elected, for increased effectiveness of translational attenuation of the nucleotide of interest.
Babitzke is not relied on for teaching overlap with a Kozak sequence, but merely for teaching overlap with a start codon for more effective physical blockage of ribosomal binding to facilitate translational repression [abstract, column 2 ¶ 2, column 11 ¶ 1-2, Figure 2] . Translational attenuation mechanisms wherein a protein binds to block ribosome binding is not unique to bacterial systems, in that both bacterial ribosomes and eukaryotic ribosomes must be able to bind to the translation initiation site of their respective transcripts.
Therefore, given the motivation taught by Babitzke to have the tbs site overlap with the start codon for more efficient repression, the ‘429 patent claims encompass and render obvious claims 1-17, 19-24, 32-38, 41, and 93-94 of the instant application.
Accordingly, Applicant’s amendments and arguments do not overcome this rejection on the ground of nonstatutory double patenting, and the rejection is maintained.
The rejection of amended and cancelled claims 1-3, 5-17, 21-24, 32-38, 40-41, and 93-94 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12,054,735, hereafter referred to as the ‘735 patent, in view of Babitzke [2004, Current Opinion in Microbiology, 7, 132-139] is withdrawn over cancelled claim 40 and maintained over amended claims 1-3, 5-17, 21-24, 32-38, 41, and 93-94. Applicant's amendments to the claims, arguments, and declaration filed 28 December 2025 have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to address issues of indefiniteness which do not alter the scope sufficiently to render the application patentably distinct from the ‘735 patent, and as such do not overcome this nonstatutory double patenting rejection.
Applicant argues that:
The Farley Declaration establishes that the +0 construct of Farley utilized a truncated Kozak sequence, such that the tbs and start codon merely abut one another and do not overlap, and the Office has not provided evidence rebutting this factual testimony; and
The Babitzke reference concerns bacterial translation initiation system that does not comprise a eukaryotic Kozak sequence and so does not disclose or suggest the claimed overlap between a TRAP binding site and a eukaryotic Kozak sequence.
However, this is not agreed.
Regarding Applicant’s argument 1), as discussed in the prior actions, the ‘735 patent claims recite all the limitations of the instant independent claim 1 other than the overlap with the Kozak sequence and/or start codon. Although the ‘735 patent claims do not recite the instantly claimed overlap with the Kozak sequence and/or start codon, the ‘735 patent claims encompass the instantly claimed invention. This rejection does not rely upon unclaimed teachings of Farley which disclose a construct having an overlapping tbs-Kozak, but merely that the overlapping tbs-Kozak is an obvious variant of the invention claimed by the ‘735 patent claims, as described in more detail below. As such, the alleged establishment of the +0 construct of Farley utilizing a truncated Kozak sequence, such that the tbs and start codon merely abut one another and do not overlap, is not a relevant allegation with respect to this rejection on the ground of nonstatutory double patenting.
Regarding Applicant’s argument 2), Babitzke was cited for teaching that the B. subtilis ycbK gene, which comprises a natural tbs, comprises the sequence of GAGATG [Figure 2]. Babitzke also teaches that, for the trpP gene, extending the tbs into the coding region results in more effective inhibition of ribosome binding (and thus more effective inhibition of translation), that the tbs of the ycbK gene overlaps the translation initiation region and extends into the coding sequence, and that one might predict that the repeats in the coding sequence may increase the effectiveness of bound TRAP in blocking ribosome binding [abstract, column 11 ¶ 1-2, Figure 2].
As such, given the teachings of the increased effectiveness of translational attenuation for TRAP bindings sites which overlap with the start codon and extend into the coding sequence and the teaching that the natural ycbK gene comprises an overlap configuration wherein the KAGNN repeat overlaps with the start codon with a junction sequence of GAGATG, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to arrange a TRAP binding site relative to the start codon such that the tbs extends into the coding sequence and such that the KAGNN repeats of the tbs overlap with the start codon to produce a junction sequence of GAGATG or GAGCATG, as elected, for increased effectiveness of translational attenuation of the nucleotide of interest.
Babitzke is not relied on for teaching overlap with a Kozak sequence, but merely for teaching overlap with a start codon for more effective physical blockage of ribosomal binding to facilitate translational repression [abstract, column 2 ¶ 2, column 11 ¶ 1-2, Figure 2] . Translational attenuation mechanisms wherein a protein binds to block ribosome binding is not unique to bacterial systems, in that both bacterial ribosomes and eukaryotic ribosomes must be able to bind to the translation initiation site of their respective transcripts.
Therefore, given the motivation taught by Babitzke to have the tbs site overlap with the start codon for more efficient repression, the ‘735 patent claims encompass and render obvious claims 1-17, 19-24, 32-38, 41, and 93-94 of the instant application.
Accordingly, Applicant’s amendments and arguments do not overcome this rejection on the ground of nonstatutory double patenting, and the rejection is maintained.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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