DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (claims 1-9, 11, 20, 22, 25-28, 32, and 37) in the reply filed on March 06, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 39 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 06, 2026.
It is noted that claim 9 directed to Hepacivirus IRES, which is a nonelected Species type 2 of Species Group A: “internal ribosome entry site (IRES)”. Therefore, claim 9 is also withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 06, 2026.
Accordingly, claims 1-8, 11, 20, 22, 25-28, 32, and 37 are examined herein.
Priority
The instant application claims priority based on a US Provisional Application No. 63/038,536 filed on June 12, 2020. The provisional application describes instant claim 1 (claim 1), instant claim 6 (claim 2), instant claim 7 (claim 3), instant claim 11 (claim 5), instant claim 25 (claim 9), instant claim 26 (claim 10), instant claim 27 (claim 11), instant claim 28 (FIG. 5), instant claim 32 (claim 17), and instant claim 37 (claim 15). Accordingly, the effective filling date of instant claims 1, 6, 7, 11, 25-28, 32, and 37 is June 12, 2020.
Support for the recitation of “cricket paralysis virus, Kashmir bee virus, an acute bee paralysis virus” is found in [8]; however, support for the recitation remaining species of Group I Discistroviridae IRES recited in instant claim 8 could not be found in ‘536. Support for the recitation of “wherein the target virus is Zika virus” is found in [17]; however, support for the recitation of wherein the target virus if a coronavirus in instant claim 22 could not be found in ‘536. In addition, support for instant claims 2-5, 9, and 20 could not be found in ‘536. Therefore, instant claims 2-5, 8, 9, 20, and 22 are not afforded the effective filling date of June 12, 2020.
The instant application also claims priority based on a PCT/US2021/037,030 filed on June 11, 2021. However, support for instant claims 2-5, 8, 9, 20, and 22 could not be found in ‘030. Therefore, instant claims 2-5, 8, 9, 20, and 22 are not afforded the effective filling date of June 11, 2021.
Accordingly, instant claims 2-5, 8, 9, 20, and 22 are afforded the effective filling date of instant application 18/009,534, which is December 09, 2022, and instant claims 1, 6, 7, 11, 25-28, 32, and 37 are afforded the effective filling date of US Provisional Application No. 63/038,536, which is June 12, 2020.
Specification
The disclosure is objected to because of the following informalities: the term “Plauta” ([66], [134], [135]) for “a Plauta Stali Intestine Virus” is inconsistent with the state of the art. Kanamori et al (A tertiary structure model of the internal ribosome entry site (IRES) for methionine-independent initiation of translation; RNA, 2001, 7:266-274) teaches a Plautia Stali Intestine Virus (emphasis added on misspelling).
Appropriate correction is required.
Drawings
The drawings are objected for the following reasons: 37 CFR 1.84 (u)(1) states “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.” In the current case, the view numbers for the partial views for Figures 7 FIG. 14E, FIG. 14F, and FIG. 15E) that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
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.
Claim Objections
Claims 2-3, 8, 26, and 32 are objected to because of the following informalities:
In claim 2, line 2, and claim 32, line 4, the acronym “IRES” is defined as being “internal ribosome entry site”. However, the acronym has previously been defined in claim 1. An acronym should only be defined the first time it appears in an independent claim or in the group of claims under an independent claim.
In claim 3, line 2, the term “Discistroviridae IRES” (emphasis added) is misspelled and it is recommended to correct the term to “Dicistroviridae IRES” without an “s” between “i” and “c”.
In claim 8, line 3, the term “Plauta” for “a Plauta Stali Intestine Virus” is inconsistent with the state of the art. Kanamori et al (A tertiary structure model of the internal ribosome entry site (IRES) for methionine-independent initiation of translation; RNA, 2001, 7:266-274) teaches a Plautia Stali Intestine Virus (emphasis added on misspelling).
In claim 26, line 3, the term “compliment” is misspelled and it is recommended to be correct the term to “complement”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1,3-8, 11, 20, 22, 25-27, and 32 is 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.
Claims 1, 3, 8, and 32 recite the term Group I Dicistroviridae IRES (emphasis added), which renders the determination of the exact scope of the claim difficult. The specification teaches “the IRES sequence can be a Group 1, Group 2, Group 3, or Group 4” ([65] and “Group I IRES elements used by members of the Dicistroviridae family of viruses” ([66]). It is unclear whether Group I Dicistroviridae IRES encompass only IRES known in the art to be classified in the Dicistroviridae family or additional IRES classified in other virus family. Martinez-Salas et al (Insights into Structural and Mechanistic Features of Viral IRES Elements; Frontiers in Microbiology, 2018, 8:1-15) teach “viral IRES elements have been classified into different types, which are related to their structural organization and, in turn, to their mechanism of initiation.” (pg. 3, col. 1, para. 2). Accordingly, the state of the art does not recognize classification of viral IRES elements into Groups and one of ordinary skill in the art cannot determine which IRES are included in the recited Group I Dicistroviridae.
The term “substantially” in claim 7 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how many nucleotides the second nucleotide sequence is reverse complementary to the first nucleotide sequence.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 – Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 4 and 5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a recombinant nucleic acid molecule comprising a Group I Dicistroviridae IRES, does not reasonably provide enablement for a recombinant nucleic acid molecule comprising a Group I Dicistroviridae IRES, specifically from a mammalian pathogenic virus or mammalian commensal virus (claim 4) or from a human pathogenic virus or human commensal virus (claim 5). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
Claim 4 is drawn to the recombinant nucleic acid molecule of claim 1 wherein the IRES of Group I Dicistroviridae (recited in claim 1 which claim 4 depends from) is modified and is an IRES from a mammalian pathogenic virus or mammalian commensal virus. The breadth of claim 4 is drawn to possession of a genus of mammalian pathogenic virus or mammalian commensal virus within Group I Dicistroviridae. Further, claim 5 depends on claim 4 and the breath of claim 5 is drawn to possession of a subgenus of human pathogenic virus or human commensal virus.
Guidance of the Specification
The specification discloses “IRES riboswitches described herein can be derived from any IRES sequence obtained or naturally-occurring in a mammalian (e.g., human) pathogenic or mammalian (e.g., human) commensal viral genome or sequence. Such viruses and their sequences are known in the art.” ([65]). The teachings of the specification regarding to mammalian (e.g., human) pathogenic or commensal virus are not specifically directed to the Group I Dicistroviridae family. The specification fails to provide an actual reduction to practice of an embodiment comprising the claimed IRES, any relevant identifying characteristics including complete structure or common conserved motifs of claimed IRES, any correlation between structure and function, or representative number of species.
State of the Art
At the time of the filling, the state of the art relating to Group I Dicistroviridae IRES demonstrated that viruses in this family are not from a mammalian pathogenic or commensal virus, or a human pathogenic or commensal virus as required in claims 4 and 5. Christian et al (Dicistroviruses; Encyclopedia of Virology, 2008:37-44) teach “the family Dicistroviridae currently comprises 12 species” (pg. 37, col. 2, para. 3) and “[t]o date, all members of the Dicistroviridae have been isolated from invertebrates” (pg. 40, col. 2, para. 1). In addition, Christian et al disclose that the hosts for dicistroviruses are not mammalian or human (pg. 40, col. 2, para. 2), and “studies on the experimental host range of dicistroviruses are limited and those that have been carried out have not substantially extended the known host ranges” (pg. 41, col. 2, para. 2). Therefore, the state of the art does not teach one of ordinary skill in the art to make and use claimed IRES because no mammalian pathogenic or commensal virus, or human pathogenic or commensal virus exist in the Group I Dicistroviridae family. One of ordinary skill in the art would need to conduct substantial and unpredictable experimentation to determine virus in the Group I Dicistroviridae family meet the claimed limitations.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to screen mammalian pathogenic or commensal viruses and human pathogenic or commensal viruses to identify which specific virus could also be classified under Group I Dicistroviridae family.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed. Therefore, claims 4 and 5 are not considered to be enabled by the instant disclosure.
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.
Claims 1-3, 6-7, 11, 28, 32, and 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shinichi et al (JP 2017-209030 A; Published Date: Nov 30, 2017). The rejection of claim 32 is evidenced by Alberts et al (From DNA to RNA; Molecular Biology of the Cell, 2002, pages 1-29).
Regarding claims 1-3, and 7, Shinichi et al teach a recombinant nucleic acid molecule comprising (a) a first segment encoding a recombinant Group I Dicistroviridae internal ribosome entry site (IRES), (e.g., a Plauta Stali Intestine Virus IRES), that has been modified to incorporate exogenous nucleotide sequences at a first site and a second site (see annotated illustration below) (FIG. 1 and 12, [0015], Claims 1-6, and Claim 8). Shinichi et al disclose an artificial IRES consists of, from 5’ to 3’ end, site A with sequence a for internal ribosome entry, site B with sequence b that is not essential for internal ribosome entry contained in the natural IRES sequence , and site C with sequence c also for internal ribosome entry (claim 1). Shinichi et al further disclose that site B is a binding structure connecting site A and site C, and the binding structure is is composed of (α) a single-stranded RNA having a sequence different from sequence b in site B and having a stem-loop structure as illustrated in FIG. 1, or (β) a hybridized double-stranded RNA (claim 1). The binding structure in Shinichi et al artificial IRES positively anticipates the instantly recited limitations of a IRES that have been modified to incorporate exogenous nucleotide (e.g., site B binding structures) sequences at a first and second site.
Shinichi et al disclose wherein the first site comprises a first nucleotide sequence (e.g., 5’ end of stem loop in site B’s binding structure (α) or one of the hybridized double-stranded RNA of site B’s binding structure (β)), and the second site comprises a second nucleotide sequence which is the reverse complement of at least a portion of the first nucleotide sequence (e.g., 3’ end of stem loop in site B’s binding structure or one of the hybridized double-stranded RNA of site B’s binding structure (β)) (FIG. 1 and claim 1).
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The recombinant nucleic acid taught by Shinichi et al also comprises (b) a second segment encoding a protein (e.g., luciferase), downstream and operably linked to the first segment such that translation of the protein is repressed when the IRES is in an inactivated state (FIG. 1 and FIG. 12). Shinichi et al teach “the stability of the binding structure site particularly affects the stability of the three-dimensional structure of the IRES”, and “it is possible to switch ON and OFF of the gene expression by adjusting the stability of the binding structure site” ([0052]). In one embodiment, Shinichi et al disclose an ON-to-OFF reporter in which upon introduction of an antisense RNA, referred as the dual switch, allows translation of gene of interest 1 (FIG. 12, top, left) because the 5’ end of the dual switch is complementary to the stem loop and disrupts the artificial IRES secondary structure, thereby inhibiting translation (FIG. 12, bottom, left; [0103], [0052]-[0053], and [0056]-[0059]). It is noted that Shinichi et al also disclose the dual switch also allows simultaneous OFF-to-ON translation of gene of interest 2 (FIG. 12, top, right). In this reporter, the artificial IRES is split into two fragments, joinable by a binding structure (i.e., first site and second site) comprising of complementary nucleotide sequences. One fragment is present in the reporter and is in inactivated state alone. Translation is activated only upon introduction of the second fragment which hybridizes with the first fragment to reconstitute a functional IRES (FIG. 12, bottom, right; [0103], [0052]-[0053], and [0056]-[0059]).
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Regarding claim 6, Shinichi et al teach wherein the nucleic acid molecule or artificial IRES is an mRNA (brief description of the drawings: FIG. 1 and FIG. 5) and the mRNA consists of sequences for internal ribosome entry at 5’ and 3’ ends (claim 1) as well as a sequence that “does not prevent the ribosome from entering the inside of the mRNA” ([0016]).
Regarding claim 11, Shinichi et al teach the binding structure or sequence b (i.e., first and second site) is “not set at a site where the stem-loop structure of the IRES is disrupted”, instead it “is set between sites where the respective stem-loop structures of the natural IRES sequence are formed” ([0020]). Further, Shinichi et al teach “the PSI-IRES has seven stem-loop structures…the sequence b is preferably present between stem-loop sequences 1 and 2, between stem-loop sequences 2 and 3…”, and “it is known that stem-loop sequences 1 and 2 are not essential for ribosome entry into mRNA for translation, [t]herefore, when PSIV-IRES is used as a natural IRES, stem-loop sequences 1 and 2 may be modified” ([0021]). However, “if the sequence b is set between stem-loop sequences 3 and 4”, to its 5’ end may be stem-loop sequences 1, 2, and 3, and to its 3’ end may be stem-loop sequences 4 to 7 ([0021]). Accordingly, Shinichi et al teach wherein the first and second sites are each independently selected from any of Sites 1 to 8, depending on the selection of natural IRES sequence to modify.
Regarding claim 28, Shinichi et al teach an expression construct (FIG. 12) comprising the recombinant nucleic acid molecule of claim 1, and further comprising 5’ and 3’ of the following as matches to instant claim 28:
(a) an IRES pseudoknot sequence annotated with “PK” at specific locations on the artificial IRES (FIG. 12, top);
(b) and IRES pseudoknot sequence found in the wild-type sequence of a virus in which the IRES naturally occurs, specifically sequence a and c that are stem-loop structures derived from natural IRES sequences ([0020]);
(c) a promoter in the gene sequence along with an initiation codon ([0049]);
(d) a stop codon (FIG. 12, [0049]);
(e) a stem-loop that is a “non-natural IRES stem-loop structure enables suppression of expression leakage (i.e., suppression of ribosome entry and initiation of translation when an IRES three-dimensional structure is not formed due to the presence of a promoter or the like)” ([0022]); and
(g) a reporter gene (e.g., luciferase) (FIG. 1).
Regarding claim 37, the teachings of Shinichi et al on ON-to-OFF and OFF-to-ON reporters via a dual switch (i.e., a trigger RNA comprising a third nucleotide sequence) are discussed above as applied to claim 1, component (b). As illustrated in FIG. 12, the 5’ end of the dual switch is complementary and hybridizes to the first and second site comprising a first and second nucleotide sequence (e.g., stem-loop). Further, the 3’ end of the dual switch is complementary and hybridizes to the first nucleotide sequence (e.g., a single-stranded RNA to form a hybridized double-stranded RNA as the binding structure of the artificial IRES).
Regarding claim 32, the teachings of Shinichi et al on ON-to-OFF and OFF-to-ON reporters via a dual switch is discussed above as applied to claim 1, component (b), and claim 6. As illustrated in FIG. 12, the recombinant mRNA comprises the following:
(a) a first segment encoding a first protein (e.g., gene of interest 1);
(b) a second segment, downstream of the first segment, encoding a recombinant Group I Dicistroviridae IRES that has been modified to incorporate exogenous nucleotide sequences at a first and a second site, specifically Shinichi et al teach the reporter comprises a second artificial IRES without an annotated stem-loop as the binding structure (i.e., first and second site) because hybridization of first and second site yields a double-stranded RNA (FIG. 12, bottom, right);
(c) a third segment encoding a second protein (e.g., gene of interest 2), downstream from and operably linked to the second segment such that translation of the second protein is repressed when the IRES is in an inactivated state (e.g., “translation OFF”);
wherein the first site comprises a first nucleotide sequence (e.g., a single-stranded RNA), and the second site comprises a second nucleotide sequence (e.g., reverse complement of the single-stranded RNA) that hybridizes to activate the IRES and turn on translation (FIG. 12, bottom, right);
wherein transcription of the recombinant mRNA molecule is dependent on a polymerase as this inherent property is evidenced by Alberts et al that teach DNA transcriptions to RNA are performed by RNA polymerases (pg. 3, para. 1; Figure 6-8) and “the RNA molecules that are copied from these genes” carried in a cell’s DNA “are called messenger RNA (mRNA)” (pg. 4, para. 2).
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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Shinichi et al (JP 2017-209030 A; Published Date: Nov 30, 2017) as applied to claim 1 above, and further in view of Kanamori et al (A tertiary structure model of the internal ribosome entry site (IRES) for methionine-independent initiation of translation; RNA, 2001, 7:266-274).
Regarding claim 8, the teachings of Shinichi et al on the artificial IRES (i.e., recombinant nucleic acid molecule) is discussed above as applied to claim 1. Shinichi et al teach wherein the IRES that is modifies is a Plautia Stali Intestine Virus (PSIV) IRES in Group I Dicistroviridae ([0015] and [0021]).
However, Shinichi et al do not teach wherein the Group I Dicistroviridae IRES is a cricket paralysis virus (CrPV), as the elected species for examination.
Kanamori et al teach a tertiary structure model for PSIV IRES that is also applicable to CrPV (pg. 267, col. 1, para. 3; and Figure 7B). Further, Kanamori et al teach sequence alignment of the intercistronic regions of PSIV and CrPV IRES indicate that they “use an essentially identical mechanism for translation initiation of viral capsid proteins” (pg. 272, col. 1, para. 3; Figure 7A). In addition, Kanamori et al teach this tertiary structure can be divided intro three domains (Figure 1C, illustrated below).
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“Domain 1 consists of pseudoknot II and the largest stem-loop III. This stem-loop has an internal bulge with conserved sequences…Domain 2 contains pseudoknot III and two stem-loops IV and V. This is the most conserved domain in the IRES elements of CrPV-like viruses. A mismatch pair with adenine in Domain 2a and the loop sequence of Domain 2b are absolutely conserved in these viruses…conserved UAC motif suggesting possible importance…such as binding to ribosomes. Domain 3 contains pseudoknot I. The structure of the stem-loop in Domain 3 is almost identical in CrPV-like viruses” (pg. 272, col. 2, para. 1). Further, Kanamori et al highlights that “the single-stranded region of Domain 3…is unlikely to interact with another part of the IRES. This implies that Domain 3 would be located externally in the IRES, whereas Domains 1 and 2 seem to form a packed core structure that would interact with ribosomes” (pg. 273, col. 1, para.2). Lastly, Kanamori et al disclose “stem-loops I and II are not necessary for activity of the PSIV-IRES element” (pg. 269, col. 1) and “the 5’ boundary of the PSIV IRES is located about 180 nt upstream from the 5’ border of the capsid-coding region” (pg. 270, col. 1, para. 1).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the artificial IRES of Shinichi et al to comprise a CrPV IRES as taught by Kanamori et al because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results given that the substituted component (CrPV IRES), its structure (comprising domains 1 and 2 that interact with ribosomes and stem-loops I and II not essential for IRES activity) and its function (initiation translation of downstream genes) were known in the art. One would have been motivated to have done so for the advantage of developing expression constructs with translational control based on different viral IRES. One would have had a reasonable expectation of success in doing so because Kanamori et al teach conserved motifs in both PSIV and CrPV IRES and these teachings are consistent with Shinichi et al working example of a recombinant nucleic acid molecule wherein the PSIV IRES is modified to incorporate a first and second site nucleotide sequences into stem-loop sequences I and II as these two stem-loops are not essential for ribosome entry into mRNA translation ([0021]).
Claims 20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Shinichi et al (JP 2017-209030 A; Published Date: Nov 30, 2017) as applied to claim 1 above, and further in view of Pardee et al (Rapid, Low-Cost Detection of Zika Virus Using Programmable Biomolecular Components; Cell, 2016, 165:1255-1266).
Regarding claims 20 and 22, the teachings of Shinichi et al on the artificial IRES (i.e., recombinant nucleic acid molecule) is discussed above as applied to claim 1. Shinichi et al also teach wherein the first nucleotide sequence is random nucleotide sequence of preferably about 2 to 100 bases and forms a toehold stem loop sequence which structure is modified in the presence of a trigger RNA oligo, illustrated below ([0054] and FIG. 11).
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However, Shinichi et al do not teach wherein the first nucleotide sequence (e.g., toehold stem loop) is the reverse complement of a sequence found in a target eukaryotic organism, target prokaryotic organism, or target virus, wherein the target virus is Zika virus.
Pardee et al teach a toehold stem loop containing nucleotide sequences that is reverse complement of a trigger RNA that is a fragment of Zika virus genome (pg. 1256, col. 2, para. 2; pg. 1257, col. 1, para. 1) for the purpose of using toehold switch sensors for sequence-based detection of Zika virus (pg. 1256, col. 2, para. 2).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the toehold stem loop of Shinichi et al to the toehold stem loop to comprise nucleotide sequences reverse complement of genome sequence of Zika virus as taught by Pardee et al because it would have merely amounted to a simple substitution. The substituted component (toehold stem loop), its structure (containing a region for hybridization with a trigger RNA, a RBS and a start codon) and its function (change folding structure in the presence of the trigger RNA to regulate translation of downstream genes) were known in the art. One would have been motivated to have done so for the advantage of modifying the artificial IRES of Shinichi et al to enable detection of Zika virus as taught by Pardee et al. One would have had a reasonable expectation of success in doing so because Shinichi et al already teach a recombinant nucleic acid molecule comprising an IRES that is modified with a first and second site to contain a toehold stem loop wherein the IRES is configured to fold and modulate translation through RNA structural rearrangements induced by complementary antisense interactions to the toehold stem loop (FIG. 11 and FIG. 12), and Pardee et al teach a toehold stem loop that also changes structure and modulate translation by complementary antisense interactions, specifically a sequence from the Zika virus genome, to the toehold stem loop.
Claims 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Shinichi et al (JP 2017-209030 A; Published Date: Nov 30, 2017) as applied to claim 1 above, and further in view of Green et al (Toehold Switches: De-Novo-Designed Regulators of Gene Expression; Cell, 2014, 159:925-939).
Regarding claims 25-27, the teachings of Shinichi et al on the artificial IRES (i.e., recombinant nucleic acid molecule) is discussed above as applied to claim 1. Shinichi et al teach wherein the first and second nucleotide sequences are capable of hybridizing when expressed in a eukaryotic cell under in vivo and in vitro conditions, causing the IRES to fold into an activated state, wherein the eukaryotic cell is preferably a cell derived from a mammal (i.e., not a plant cell) (claim 10, FIG. 6D, FIG. 8, [0044], [0050]). Shinichi et al also teach wherein the IRES is configured to fold into an inactivated state in the presence of a trigger RNA molecule comprising a third nucleotide sequence, wherein the third nucleotide sequence is the reverse compliment of the first nucleotide sequence of the recombinant nucleic acid molecule of claim 1 (FIG. 12). In particular, Shinichi et al teach the IRES is configured to fold into an inactivate state and suppressed protein expression in the presence of an antisense RNA comprising a nucleotide sequence complementary to a toehold stem-loop in the IRES, illustrated above (FIG. 11, Brief description of drawings for FIG. 11).
However, Shinichi et al do not teach wherein hybridization of the first and second nucleotide sequences cause the IRES to fold into an inactivated state as required by instant claim 25, and wherein the IRES is configured to fold into an activated state in the presence of a trigger RNA as required by instant claims 26 and 27.
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Green et al teach a recombinant nucleic acid molecule (e.g., a toehold switch) that sequestered the region around the start codon and protein translation is repressed until the presence of a trigger RNA with an arbitrary sequence (pg. 927, col. 2, para 1 and 4; Fig. 1B), as illustrated below. Green et al further teach the structure of the toehold switch contains an extended single-stranded region for hybridization with a trigger RNA, followed by a hairpin-based processing module containing both a strong ribosome binding site (RBS) and a start codon AUG that is followed by a 21-nucleotide linker coding for low-molecular-weight amino acids added to the N terminus of the gene of interest (pg. 928, col. 1, para. 2). Green et al further teach “the trigger RNA contains a 30 nt single-stranded RNA sequence” (pg. 928, col. 1, para. 3).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the artificial IRES of Shinichi et al to comprise the toehold switch taught by Green et al because it would have merely amounted to a simple substitution given that the substituted component (toehold switch), its structure (containing a region for hybridization with a trigger RNA, a RBS and a start codon) and its function (repress translation of downstream genes or activate translation in response to the trigger RNA) were known in the art. Further, this modification would have also merely amounted to a simple combination where each element (artificial IRES of Shinichi et al and toehold switch of Green et al) merely performs the same function as it does separately (artificial IRES contains natural IRES sequences for internal ribosome entry and toehold switch contains sequestered RBS and star codon to repress translation). One would have been motivated to have done so for the advantage of developing a different translation-control module comprising a toehold switch that turns on translation in response to a trigger RNA as opposed to turning off translation as demonstrated by Shinichi et al (FIG. 11). In addition, Shinichi et al do teach a translation-control module comprising a binding structure that turns on translation in response to a trigger RNA containing a fragment of the IRES (FIG. 12, OFF-to-ON translation). Therefore, one would have been motivated to have done this modification for the advantage of developing a OFF-to-ON translation control module using a shorter trigger RNA (about 30 nucleotides) as demonstrated by Shinichi et al and Green et al. One would have had a reasonable expectation of success in doing so because Shinichi et al already teach a recombinant nucleic acid molecule comprising an IRES that is modified with a first and second site to contain a toehold stem loop wherein the IRES is configured to fold and modulate translation through RNA structural rearrangements induced by complementary antisense interactions to the toehold stem loop when expressed in a eukaryotic cell under in vivo and in vitro conditions (FIG. 11 and FIG. 12), and Green et al teach a toehold switch comprising same elements in the recombinant nucleic acid molecule of Shinichi et al (RBS, start codon, linker, coding gene) (Fig. 1B).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6-8, 11, 26-27, and 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, 16, 24-26, and 29 of copending Application No. 18/008,935 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other the recombinant plant, vector or plasmid, and recombinant nucleic acid molecule of ‘935 recites the same instant limitations in the same combination that are recited in the instant recombinant nucleic acid. For compact prosecution, the following table outlines the instant claims that corresponds to claims of ‘935.
Instant claims
Claims of ‘935
1
1, 16, 24
6
1, 16 “DNA encoding an mRNA”
7
6
8
7
11
8
26
25
27
26
37
29
Regarding instant claim 26, ‘935 discloses a recombinant nucleic acid “wherein the Group I Dicistroviridae IRES is configured to activate expression of the protein in response to the presence of an mRNA which comprises a segment that is the reverse complement of the first nucleotide sequence” (claim 1, lines 13-15) which anticipates instant claim reciting “wherein the IRES is configured to fold into an activated state in the presence of a trigger RNA molecule comprising a third nucleotide sequence, wherein the third nucleotide sequence is the reverse complement of the first nucleotide sequence”, specifically mRNA of ‘935 anticipates a trigger RNA in instant claim. Similarly, instant claim 26 is anticipated by ‘935 claim 16, lines 13-15.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights