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 .
Amendments and Status of the Claims
This action is in response to papers filed 6/18/2025 in response to NFOA dated 12/18/2024, in which claims 1 and 17 were amended, claims 18, 20, 22, 24, 26-29, and 31-65 were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Applicant has amended:
Drawings. However, the amendment is not fully responsive. Therefore, the objection to the Drawings is maintained.
claims 1 and 17 to overcome the 112(a) rejection; the 112(a) rejection has not been overcome; the 112(a) rejection is maintained. Applicants arguments pertaining to the 112(a) rejection have been addressed at the end of the 112(a) rejection in this Office Action.
claims 1 and 17 to overcome the 102 and 103 rejections and argue that the rejections should be withdrawn; the rejections have not been overcome; the 102 and 103 rejections are maintained. Applicants arguments pertaining to the 102 and 103 rejection have been addressed at the end of the 103 rejection in this Office Action.
Arguments that are no longer relevant are not addressed.
Objections and Rejections not reiterated here are withdrawn.
Claims 16-17, 19, 21, 23, 25, and 30 are under consideration.
Election/Restrictions
With the cancellation of withdrawn claims, the restriction and species election requirement of 8/27/2024 is moot.
Priority
The priority date for this application is: 2/14/2019.
Objection to Drawings Maintained
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because:
i) the view numbers for Figures 1 - 7 are preceded by the word "Fig" instead of the abbreviation "FIG."
i.e., the required period after the word FIG is missing.
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 Rejections - 35 USC § 112(a)
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.
Written Description
Claims 16-17, 19, 21, 23, 25, and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Species Encompassed
The claimed invention encompasses: a composition of a fusion protein (AFP) wherein the fusion protein is made up of two parts: (a) an assembler polypeptide (AP) and (b) an effector polypeptide (EP). Further, (a) is selected from: (a1) a polypeptide segment of an intracellular targeting polypeptide (ICTP segment), and (a2) a polypeptide segment of a phase separation polypeptide (PSP segment), such that the AP segment targets (associates with) an intracellular structural element within or directly adjacent to the cytoplasm, and phase separation polypeptide has the ability to undergo self-association in the cytoplasm of a cell, respectively;
(b) is selected from: (b1) an RNA-targeting polypeptide (RNA-TP) segment, and (b2) an orthogonal aminoacyl tRNA synthetase (O-RS) segment;
wherein said polypeptide segments (a) and (b) are functionally linked in said AFP.
Species Disclosed in the Specification
When claim 16 is analyzed in light of the specification, instant composition is used in a method of preparing a polypeptide of interest (POI) comprising a non-canonical amino acid (ncAA). The specification defines the assembler polypeptide (AP) part of the fusion protein as comprising two broad genera of polypeptides, i.e., (a1) a polypeptide segment of an intracellular targeting polypeptide (ICTP segment), and (a2) a polypeptide segment of a phase separation polypeptide (PSP segment), and the composition comprising the effector polypeptide as also comprising two broad genera of different polypeptides, i.e., (b1) an RNA-targeting polypeptide (RNA-TP) segment, and (b2) an orthogonal aminoacyl tRNA synthetase (O-RS) segment. In the analyses, it is found that the genus of (a1) a polypeptide segment of an intracellular targeting polypeptide (ICTP segment), (a2) a polypeptide segment of a phase separation polypeptide (PSP segment), (b1) an RNA-targeting polypeptide (RNA-TP) segment, and (b2) an orthogonal aminoacyl tRNA synthetase (O-RS) segment are four different broad genera that do not fulfil the written description requirement as discussed below:
(a1) a polypeptide segment derived from an intracellular targeting polypeptide (ICTP segment)
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, KIF16B, KIF13A, LCK, TOM20-, MCP, FRB-CD28, EBAG91-29, CG1, CMP, P450, EB1, and SLP3, are the only species whose complete structure is disclosed (identified by SEQ ID Nos, Table 3; pgs. 18 -20 for EB1 and SLP3) and corresponding function of the species when present in a fusion protein, is evaluated though not all data is shown in instant disclosure. But the claims also encompass structurally diverse IC-TPS such as dyneins, and functional fragments and mutants thereof (pg. 17, line 30). The claims are not limited to the 12 species disclosed rather to any isoforms that would function to enrich the fusion protein at a specified site within the cytoplasm as claimed. While the genus encompasses a large number of variants and molecules that function as recited, the specification does not describe the complete structure of a representative number of species of the large genus of ICTP segments or functional isoforms thereof.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is to enrich the fusion protein at a specified site within the cytoplasm. Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of IC-TP segment or functional equivalent thereof (functional isoform) all members of the claimed genus will have that characteristic.
(a2) a phase separation polypeptide (PSP segment)
In the instant case, FUS, MCP, EWSR1, LAF-1, and SPD5, are the only species whose complete structure is disclosed (identified by SEQ ID Nos, Table 3) and corresponding function of the species when present in a fusion protein is evaluated, though not all data is shown in instant disclosure. But the claims also encompass structurally diverse PSP segments such as functional fragments and mutants thereof (pg. 21, line 16). The claims are not limited to the 5 species disclosed rather to any isoforms that would function to concentrate the fusion protein at a specified site within the cytoplasm as claimed. While the genus encompasses a large number of variants and molecules that function as recited, the specification does not describe the complete structure of a representative number of species of the large genus of PSP segments or functional isoforms thereof.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is to concentrate the fusion protein at a specified site within the cytoplasm. Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of PSP segment or functional equivalent thereof (functional isoform) all members of the claimed genus will have that characteristic.
(b1) an RNA-targeting polypeptide (RNA-TP) segment
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, MCP, λN22, and PCP, are the only species whose complete structure is disclosed (identified by SEQ ID Nos, Table 3) and corresponding function of the species when present in a fusion protein, is evaluated though not all data is shown in instant disclosure. But the claims also encompass structurally diverse RNA-TP such as functional fragments and mutants thereof (pg. 24, lines 13-16). The claims are not limited to the 3 species disclosed rather to any isoforms that would function to selectively interact with the mRNA of the POI (Summary of the Invention, pg. 3). While the genus encompasses a large number of variants and molecules that function as recited, the specification does not describe the complete structure of a representative number of species of the large genus of RNATP segments or functional isoforms thereof.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is to function to selectively interact with the mRNA of the POI. Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of RNA-TP segment or functional equivalent thereof (functional isoform) all members of the claimed genus will have that characteristic.
(b2) an orthogonal aminoacyl tRNA synthetase (O-RS) segment
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, PylRSAF, PylRSAA, PylRSAAAF, IFRS1, CbzRS, CpkRS, and OMeRS are the only species whose complete structure is disclosed (identified by SEQ ID Nos, pg. 57) and corresponding function of the species when present in a fusion protein, is evaluated though not all data is shown in instant disclosure. But the claims also encompass structurally diverse O-RS segments such as tyrosyl-tRNA synthetases from different species, and functional fragments and mutants thereof (pg. 25, line 25). The claims are not limited to the 7 species disclosed rather to any isoforms, that would function to introduce ncAAs into a POI (pg. 1, lines 5-10). While the genus encompasses a large number of variants and molecules that function as recited, the specification does not describe the complete structure of a representative number of species of the large genus of O-RS segments or functional isoforms thereof.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is to be the essential member of the OT system to catalyze incorporation of ncAA in to the POI. Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of IC-TP segment or functional equivalent thereof (functional isoform) all members of the claimed genus will have that characteristic.
Guidance Provided by the Art
Patel (Patel A. et al., Cell, Volume 162, Issue 5, 1066 – 1077, IDS) teaches FUS is a PSP capable of undergoing phase transitions and aggregation (abstract). In agreement with previous reports, Patel teaches in unstressed HeLa cells, FUS predominately localizes to the nucleus (Figure 1B). Patel further teaches in unstressed HeLa cells and mouse ES cells, FUS forms small foci in the nucleoplasm (Figure 1B, Figure S1C). Based on these teachings, it is not evident that an AFP made with a PSP like FUS will localize to the cytoplasm in order to create sites of high local concentration in the cytoplasm.
Further, it is not clear from the art if a fusion protein made from different polypeptides fused together will retain the functions of the individual polypeptides. A search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, Reidhaar-Olson JF, Lim WA, Sauer RT. Deciphering the message in protein sequences: tolerance to amino acid substitutions. Science. 1990 Mar16;247(4948):1306-10; See page 1306).
With respect to use of PSPs to cause self-association, Boeynaems (Boeynaems S. et al., Trends Cell Biol. 2018 Jun;28(6):420-435) cast doubt on the ability to regulate self-aggregation. Outstanding questions in the field are: it is not understood what the essential and nonessential components of different membraneless organelles are, it is not understood what the sequence and structural properties of such organelles are, the tools to pursue this question in living cells are not well-worked out, how the specificity of membraneless organelle composition are generated is currently completely lacking, and finally we know little about how cells spatiotemporally regulate phase separation. See Boeynaems, Outstanding Questions on pg. 24. Based on these teachings, it is not evident that an AFP made with a PSP will allow for self-association to the extent that will still allow the AFP to be functional but not pathological.
Thus the art is unable to remedy the lack of written description for any combination of segments could be used to achieve the claimed function of targeting/enriching any AFP to the cytoplasm.
Dependent Claims
The inventions of claims 17, 19, 21, 23, 25, and 30 require the use of the inventions of claim 16 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Conclusion
In conclusion, Applicant’s disclosure of 12 species of IC-TP segments, 5 species of PSP segments, 3 species of RNA-TP segments, and 7 species of O-RS segments in the composition of the AFP is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus of each of the categories (segments that make up the AFP) at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genera.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP 2163).
Response to Arguments
Applicant's arguments filed 6-18-2025 to claim rejections under 35 USC § 112a.
Applicants essentially assert that: 1) the claimed subject matter is adequately described; 2) what is known in the art need not be described; 3) provide a reference authored by inventors that describes the invention under consideration; and 4) reserve comment on the subsection "Guidance provided by the art" of the NFOA.
Applicant's arguments have been fully considered but they are not persuasive:
In response to 1), Applicant is right with respect to the description disclosing a large number of individual species, however, what the description is lacking is a correlation of the broad genera claimed to a structure of the genera that encompasses the disclosed species that in combination make up the AFP claimed, when the vast number of species disclosed are recited in the claims by a desired function; i.e., a clear and specific description of the structure of particular claimed combination of genera, even though each element is listed or described in the specification. For e.g., the only orthogonal aminoacyl tRNA synthetase (b2) tested as part of the AFP is PylRS, yet the claims broadly recite orthogonal aminoacyl tRNA synthetase, which phrase covers the gamut of enzymes from any conceivable domain; 2) the field is new. There is an inverse correlation between what is known in a new field and what is required of the disclosure; 3) the provided reference is an excellent rendition of an enabled method. However, the written description requirement is distinct from the enablement requirement; and 4) It is noted that Applicants wish to reserve comment on the various documents cited for a future date.
See 2163 II.A.3.(a) ii for a description of § 112a with respect to genus claims. Therefore, Applicant’s arguments are not persuasive.
Claim Interpretation
It is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
Considering the wherein clauses and the recitation of one polypeptide to be picked from given alternatives, claim 16 is being given the Broadest Reasonable Interpretation to mean:
A fusion protein (AFP) comprising:
(a) one assembler (AP) polypeptide segment which is either: (a1) a polypeptide segment derived from an intracellular targeting polypeptide (IC-TP segment), or (a2) a polypeptide segment derived from a phase separation polypeptide (PSP segment), and
(b) at least one effector (EP) polypeptide segment that is selected from: (b1) an RNA-targeting polypeptide (RNA-TP) segment, or (b2) an orthogonal aminoacyl tRNA synthetase (O-RS) segment; wherein the AP segment functions to enrich the AFP at specified sites within the cytoplasm and wherein said polypeptide segments are functionally linked in said AFP.
The term “orthogonal” in “orthogonal aminoacyl tRNA synthetase” is given the Broadest Reasonable Interpretation with respect to the description on pg. 34, lines 15-30 to mean a tRNA synthetase that does not perform its canonical function.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 16-17, 19, 21, 23, and 25 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Adams (US 20100310576).
Claim 16 is being given the Broadest Reasonable Interpretation as per Claim Interpretation section above to mean the claimed fusion comprises segments (a1) or (a2) and (b1) or (b2).
Regarding claim 16, Adams teaches fusion proteins comprising at least one aspartyl-tRNA synthetase (AspRS polypeptide) and a heterologous fusion partner [0016]. Aspartyl-tRNA synthetases have non-canonical biological activities (title). The fusion polypeptides are covalently linked, either directly or indirectly via an amino acid linker, to one or more heterologous polypeptide sequences (fusion partners). The polypeptides forming the fusion protein are typically linked C-terminus to N-terminus, although they can also be linked C-terminus to C-terminus, N-terminus to N-terminus, or N-terminus to C-terminus. The polypeptides of the fusion protein can be in any order [0124]. The fusion partners may be selected so as to increase the solubility of the protein or to enable the protein to be targeted to desired intracellular compartments [0125]. Thus, Adams teaches a fusion protein (AFP) comprising:
(a) at least one assembler (AP) polypeptide segment that (a1) targets to an intracellular structural element and
(b) at least one effector (EP) polypeptide segment that is selected from: (b2) an orthogonal aminoacyl tRNA synthetase (O-RS) segment; wherein the AP segment functions to enrich the AFP at specified sites within the cytoplasm and wherein said polypeptide segments are functionally linked in said AFP.
Regarding claim 17, Adams teaches an embodiment wherein the AspRS polypeptide of the invention may be part of a dimer. Further, dimers may include, for example, homodimers between two identical AspRS polypeptides, heterodimers between two different AspRS polypeptides (e.g., a full-length AspRS polypeptide and a truncated AspRS polypeptide or two different truncated AspRS polypeptides), and/or heterodimers between an AspRS polypeptide and a heterologous polypeptide. Certain heterodimers, such as those between an AspRS polypeptide and a heterologous polypeptide, may be bi-functional.[0132]. Adams teaches other embodiments wherein an AspRS polypeptide of the invention may be part of a multi-unit complex with 2, 3, 4, or 5 or more monomers. Monomer units of a multi-unit complex may be different, homologous, substantially homologous, or identical to one another. However, a multi-unit complex of the invention includes at least one monomer comprising an AspRS polypeptide or at least two or more AspRS polypeptides as described herein [0134]. Thus, Adams teaches an assembler fusion protein (AFP) combination comprising at least two AFPs of claim 16 wherein at least a first AFP comprises an EP selected from an RNA- TP segment, wherein at least a second AFP comprises an EP selected from an O-RS segment, and wherein said polypeptide segments are functionally linked in each of said AFP polypeptide chains.
Regarding claims 19, 21, 23, and 25, Adams teaches expression vectors comprising the polynucleotides that encode the fusion proteins discussed above, and a host cell comprising such expression vectors [0017]. See recitation from [0128]: Fusion proteins may generally be prepared using standard techniques. For example, DNA sequences encoding the polypeptide components of a desired fusion may be assembled separately, and ligated into an appropriate expression vector. The 3' end of the DNA sequence encoding one polypeptide component is ligated, with or without a peptide linker, to the 5' end of a DNA sequence encoding the second polypeptide component so that the reading frames of the sequences are in phase. This permits translation into a single fusion protein that retains the biological activity of both component polypeptides; and recitation from [0138]: The AspRS polypeptides described herein may be prepared by any suitable procedure known to those of skill in the art, such as by recombinant techniques. For example, AspRS polypeptides may be prepared by a procedure including the steps of: (a) preparing a construct comprising a polynucleotide sequence that encodes an AspRS polypeptide and that is operably linked to a regulatory element; (b) introducing the construct into a host cell; (c) culturing the host cell to express the AspRS polypeptide; and (d) isolating the AspRS polypeptide from the host cell.
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(s) 16-17, 19, 21, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Adams (US 20100310576) as applied to claims 16 -17, 19, 21, 23, and 25, in the 102(a1)(a2) rejection above, and further in view of in view of Roberts (US 20150024442 A1), Shuster (Shuster, B.S. et al., Nat Commun 9, 2985 (2018), IDS), and Seong (WO/2017/160118) as evidenced by its English translation.
This rejection is being made for an embodiment where the AFP comprises (a1) and (a2) and (b1) and (b2).
The teachings of Adams with respect to the AFP of claims 16-17, 19, 21, 23, and 25, are discussed above and apply.
Adams does not teach wherein the AP consists of both of IC-TP (a1) and PSP (a2) and the EP consists of both an RNA-TP segment (b1) together with the required tRNA synthetase (b2) (claim 16), or a combination of two AFPs wherein each AFP comprises all 4 segments of claim 16 (claim 17), or a nucleic acid molecule that encodes all 4 segments of claim 16 (claim 19), or an expression cassette comprising the nucleotide molecule encoding all 4 segments of claim 16 (claim 21), or an expression vector comprising the expression cassette encoding all 4 segments of claim 16 (claim 23), or a cell that comprises the above nucleotides that encode all 4 segments of claim 16 (claim 25).
Roberts (US 20150024442 A1), Shuster (Shuster, B.S. et al., Nat Commun 9, 2985 (2018), IDS, and Seong (WO/2017/160118) as evidenced by its English translation, resolve the deficiency of Adams (US 20100310576), wherein Roberts teaches fusion proteins with IC-TP segments (abstract) and Shuster teaches fusion proteins with PSP (title and abstract) and Seong describes maximizing soluble recombinant protein production by making a fusion protein comprising tRNA synthetase and an RNA-TP segment (hRBD) (abstract, [1]), as further discussed below.
Roberts teaches fusion proteins of an acyltransferase polypeptide with at least one heterologous intracellular localization domain (abstract). Roberts teaches the heterologous intracellular localization domain may be fused to the N-terminus of the polypeptide or to an internal region of the polypeptide wherein the internal region is within about 2-100 amino acids of the N-terminus of the polypeptide or within about 2-5 amino acids of the N-terminus of the polypeptide [0012]. Roberts teaches the heterologous intracellular localization domain selectively localizes the polypeptide to the cytoplasmic side of various intracellular organelles [0013]. Roberts teaches the heterologous intracellular localization domain comprises an amino acid sequence of at least one transmembrane domain (TMD) from a bacterial plasma membrane protein [0015]. Roberts teaches the inclusion of TMD as a heterologous fusion partner resulted in the polypeptide maintaining its enzymatic activity [0460].
Shuster teaches the intrinsically disordered arginine/glycine-rich RGG domain from the P granule protein LAF-1 is a means to recruit soluble proteins in order to concentrate and localize the latter to specific sites within the cell (whole paper). Shuster teaches RGG domains can be engineered to selectively recruit proteins of interest (2nd paragraph, l. column, pg. 10). Shuster reduce to practice creation of plasmids comprising RGG domains and proteins of interest (RGG-GFP, methods section, 4th paragraph, l. column, pg. 11) and demonstrate its ability to phase separate and form stable compartments in model cell cytoplasm (Fig. 6).
Seong teaches a novel peptide and a fusion protein including the same for improving the expression efficiency of a target protein composed of four amino acids derived from LysRS (Lysyl tRNA synthetase), and a fusion protein comprising the peptide and hRBD (human LysRS RNA binding domain) (abstract, technical field). hRBD is an RNA-TP segment (As per pg. 23 of instant specification, the RNA-TP segments of the fusion proteins of the invention are preferably mRNA-targeting polypeptide segments).
Thus, the limitations of an AFP comprising all of (a1) and (a2) and (b1) and (b2) have been met in the combination of references discussed above.
Regarding claims 17, 19, 21, 23, and 25, the teachings of Adams as discussed in the 102 rejection above as applied to claims 17, 19, 21, 23, and 25, are similarly applied to the 103 rejections of claims 17, 19, 21, 23, and 25.
In view of the teachings of Roberts, Shuster, and Seong, it would have been obvious to one of ordinary skill in the art before the time of the invention to have incorporated the specific examples of IC-TP, PSP, and RNA-TP in the AFP of Adams in order to produce a functional AFP, since all of Roberts, Shuster, and Seong provide one in the art evidence of reduction to practice of enriching the fusion protein at specified sites within the cytoplasm (Roberts, Shuster) and improving the expression efficiency of a target protein (Seong). One of ordinary skill in the art would have a reasonable expectation of success since all references teach expression of fusion proteins, wherein the fusion partners retain their original functions. See MPEP 2143 I.(A) and (G).
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Adams (US 20100310576) as applied to claim 16 above, and further in view of Chin (WO 2012/038706 A1).
Regarding claim 30, the preamble of this claim recites a “kit”. The specification, however, does not define this term, and so it is being interpreted to encompass any collection of reagents that includes all of the elements of the claims. Any further interpretation of the word is considered an “intended use” and does not impart any further structural limitation of on the claimed subject matter.
The teachings of Adams have been discussed above and apply. Specifically, Adams teaches the at least one expression vector of claim 23 as discussed above, but Adams does not teach at least one non-canonical amino acid (ncAA) residue, or salt thereof, corresponding to the at least one ncAA residue of the POI.
Chin teaches the incorporation of several unnatural amino acids (Fig. 1A) using variants of pyrrolysyl-tRNA synthetase/tRNAPyl pairs in yeast (Summary of Invention). Chin teaches the steps involved in a method to incorporate such unnatural amino acids into a protein (pg. 9, lines 14 till end of page). See recitation from Chin pg. 9, lines 29-32: wherein the unnatural amino acid to be incorporated is an alkyne-containing amino acid or a posttranslationally modified amino acid or an amino acid containing bio-orthogonal chemical handles or a photo-caged amino acid or a photo-crosslinking amino acid. Further, Chin teaches nucleic acid sequences encoding a tRNA and encoding tRNA synthetase orthogonal to the yeast cell, said nucleotide sequence operably linked to a promoter capable of directing transcription by eukaryotic RNA polymerase III (pg. 19, 1st 3 lines). Thus, Chin teaches at least one ncAA, corresponding to the at least one ncAA residue of the POI, and at least one expression vector of claim 23.
It would have been obvious to one of ordinary skill in the art before the time of the invention to have incorporated a ncAA into a POI and simultaneously substituting a pyrrolysyl-tRNA synthetase in the AFP of Adams for the advantage of incorporating a wide variety of unnatural amino acids into proteins made in a eukaryote such as yeast with site specificity. One of ordinary skill in the art would have a reasonable expectation of success in doing so since both Adams and Chin teach orthogonal tRNA synthetases for non-canonical biological activities. See MPEP 2144 II and 2143 I.(A).
Response to Arguments
I. Applicant's arguments filed 6-18-2025 to claim rejections under 35 USC § 102.
Applicants essentially assert that: 1) Anticipation requires the disclosure in a single prior art reference of each element of the claim under consideration and cite case law; 2) in view of amendments, rejection should be withdrawn; and 3) the reference of Adams applied, concerns Aspartyl-t RNA synthases (AspRS), which is not within the scope of current claims, specifically, any concrete technical teaching of how functional fusion proteins can be produced is lacking.
Applicant's arguments have been fully considered but they are not persuasive:
In response to 1), MPEP 2131 states: To reject a claim as anticipated by a reference, the disclosure must teach every element required by the claim under its broadest reasonable interpretation; 2) the amendments have not changed the claim interpretation, and so the applied reference still sands; and 3) MPEP 2131.02 I states “A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus.”. Adams disclosure of a fusion protein comprising an Aspartyl-t RNA synthases is a species which falls within the claim interpretation used in the NFOA rejection (and reiterated here). Further, MPEP 2120 I states: (B) a claim is met by a prior art disclosure which does not disclose the inventive concept involved. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, Applicant’s argument regarding the applied art of Adams, “any concrete technical teaching of how functional fusion proteins can be produced is lacking” is not persuasive.
Applicant may consider amending claims such that a narrower claim interpretation may be made.
II. Applicant's arguments filed 6-18-2025 to claim rejections under 35 USC § 103.
Applicants essentially assert that: 1) A prima facie case of obviousness has not been made and cite case law; 2) Adams does not teach or suggest a fusion protein as claimed. Further, Adams does not contain any teachings related to genetic code expansion (GCE), a key concept related to the currently pending claims; and 3) secondary documents do not remedy the deficiencies of Adams, because, neither alone nor in any combination, fairly teach or suggest the fusion protein or kit as currently claimed. Further, none of the secondary documents contain any teachings related to genetic code expansion (GCE), a key concept related to the currently pending claims.
Applicant's arguments have been fully considered but they are not persuasive:
In response to 1), in view of the broad claim interpretation an obviousness rationale was presented in the rejection; the amendments have not changed the claim interpretation, and so the applied references still stand; 2) Applicant is correct to the extent that Adams does not teach the fusion protein as per the second claim interpretation. However, Applicant has not provided any reasoning for why one of skill would not consider combining the reference of Adams with secondary references; and 3) In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., GCE) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As in the case of the 102 rejection, Applicant may consider amending claims such that a narrower claim interpretation may be made.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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