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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on September 23, 2025.
Currently, claims 1, 11, 14, 17, 40-42, and 58-74 are pending and under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
New Rejections Necessitated by Amendment
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 58-60 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 58-60 recite that the “mRNA” of claim 1 comprises the nucleic acid sequence of SEQ ID NO:3, 4, or 5, respectively.
It is noted that each of SEQ ID NOs:3-5 is a “DNA” sequence. See for instance the sequence information for SEQ ID NO:5 as reproduced below.
PNG
media_image1.png
202
296
media_image1.png
Greyscale
Hence, claims 58-60 recite structurally conflicting, inconsistent limitations (mRNA vs. DNA), thereby rendering the claims indefinite.
Claim Rejections - 35 USC § 112
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 61-62 and 64-73 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) contains 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.
The instant claims require that each of the claimed target protein “version” is bound by the “binding peptide” that replaced the substrate recognition domain of the CHIP protein, wherein the “version” includes a “lapidated version”, “acylated version”, “s-nitrosylated version”, and “an ATP or ADP bound version”.
It is noted that the instant specification at best describes the binding peptide being an anti-GFP nanobody (vHHGFP4) that binds target GFP (green fluorescent protein) or the binding peptide being “scFv4B12” that binds “A1AT” in an unmodified form or version, which is fused to a modified CHIP (SEQ ID NO:8)-encoding sequence and is degraded by the construct encoding vHHGFP4 or scFv4B12 fused to SEQ ID NO:8. Now, it is noted that the most relevant prior art, see Delisa et al. (US 2014/0112922 A1, of record), at best taught a target protein of “glycosylated forms” or “phosphorylated forms” as being bound by a fusion nucleic acid construct comprising the instantly claimed SEQ ID NO:8 except the GGGS linker. That is, the relevant prior art knowledge pertaining to the required function of the claimed fusion mRNA construct in binding each of the recited “version” of the target protein recited in claims 61-62 and 64-73 was non-existent before the effective filing date sought in the instant case, and the instant specification fails to provide adequate written description in sufficient detail for the structure-function correlation required for claims 61-62 and 64-73.
Accordingly, the specification fails to reasonably convey that the instant co-inventors had possession of the subject matter of claims 61-62 and 64-73 as of the filing date sought in the instant application.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 11, 14, 17, 40-42, 63, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Claims 1-3, 11, 14, 17, 40-42, and 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Delisa et al. (US 2014/0112922 A1, of record) in view of in view of Fontin-Mleczek et al. (US 2019/0040378 A1, of record), Meacham et al. (Nature Cell Biology, 2001, 3:100-105, of record), Peng et al. (BBRC, 2007, 354:864-871, of record), and Gómez-Gonzalo et al. (Virology, 2004, 328:120-130, of record).
Delisa discloses a fusion DNA construct encoding a chimeric protein comprising 1) “a targeting domain” comprising a single chain Fv antibody fragment (scFv) and 2) “a degradation domain” comprising a “human C-terminus of Hsc70-interacting protein (“CHIP”) without the N-terminal TRP domain”, wherein the human CHIP and scFv amino acid sequences are linked via a “GSGSG” linker-encoding sequence, wherein Delisa’s SEQ ID NO:5 encoded by the fusion DNA construct comprises an amino acid sequence that is 100% identical to positions 1-181 of SEQ ID NO:8 claimed in the instant case. See Delisa’s SEQ ID NO:5 below, wherein box has been added for the amino acid sequence at positions 1-5 of SEQ ID NO:8 and underline has been added for the amino acid sequence corresponding to positions 6-181 of SEQ ID NO:8.
PNG
media_image2.png
254
526
media_image2.png
Greyscale
It is noted that amino acids 182-185 of SEQ ID NO:8 that is 185 amino acids long are GGGS (Gly Gly Gly Ser) linker.
Delisa teaches that the (scFv) encoded by the DNA fusion construct is the “targeting domain” that binds the target substrate and the “degradation domain” of the above-underlined C-terminus human CHIP amino acid sequence encoded by the DNA fusion construct “lacks an endogenous substrate recognition region” and is the “degradation domain E3 ligase” of CHIP, which interacts with a target protein of “glycosylated forms” or “phosphorylated forms” or bound to a substrate including “receptors”, wherein the target protein includes “enzymes”, “metabolic proteins”, or “pathogenic proteins” that are “aberrantly expressed”. See paragraphs 001, 0014-0016, 0019, 0032, 0044, 0076, and 0082-0083; claims 1-16.
Delisa does not teach formulating the fusion DNA construct as an mRNA in an LNP. Delisa also does not teach including an ER signal (SEQ ID NO:9) sequence and the ER retention sequence (SEQ ID NO:10).
Fontin-Mleczek teaches making an artificial mRNA comprising “at least one coding sequence” that encodes “a fusion protein” comprising two proteins linked via a GS linker including “GGGS”, wherein said at least one coding region further encodes “at least one signal peptide” such as “signal sequence” and “localization sequence”, wherein the mRNA is encapsulated in “a lipid nanoparticle (LNP)” comprising a cationic lipid (e.g., “ckk-E12”), a neutral lipid, a sterol. (e.g., cholesterol), and a PEGylated lipid. See claims 1, 4, 18; paragraphs 0051, 0098, 0126, 0132-0136, 0404-0409, 0415.
Fontin-Mleczek teaches that the fusion protein encoded by the mRNA is routed or translocate to “MHC class I and MHC class I processing compartments”, wherein “the MHC class I and II processing and loading take place, like the endoplasmic reticulum, endosomes or the lysosome.” See paragraph 0045.
Meachasm teaches that “CHIP has the potential to interact with CFTR in the ER” and that “CFTR degradation initiates in the ER” thus “CHIP probably functions at the ER to influence GFP-CFTR localization”, wherein CHIP overexpression “did not cause the accumulation of the immaturely glycosylated, ER-localized B form” of CFTR and was able to “reduce the accumulation of the CFTRΔF508 B form” and “caused almost all of the B form to be degraded” thus, “CHIP regulates CFTR ubiquitination.” See page 100.
Meachasm reports that “CHIP and Hsc70 function at the level of the ER to regulate the fate of immature CFTR.” See page 101.
Meachasm teaches that “the Hsc70/CHIP complex may function in ER quality control to sense the folded state of membrane proteins that have large cytosolic domains.” See page 103.
Peng teaches, “To exert their function, intrabodies have to be directed to the subcellular compartment, where the antigen is located. This can be achieved by the incorporation of signal sequences into the antibody molecules”. See page 865.
Peng teaches “endoplasmic reticulum (ER) retention signal SEKDEL sequence”, which “allows the retention of recombinant antibodies within the endoplasmic reticulum (ER) and, hence, can be used to block the expression of receptors on the cell surface.” See page 865.
It is noted that Peng’s SEKDEL sequence is 100% identical to SEQ ID NO:10 claimed in claim 55.
Gómez-Gonzalo discloses “the endoplasmic reticulum signal peptide GWSCIILFLVATATGAHS”. See page 127.
It is noted that Gómez-Gonzalo’s ER signal peptide sequence of GWSCIILFLVATATGAHS is 100% identical to SEQ ID NO:9 claimed in claim 54.
It would have been obvious to one of ordinary skill in the art before the effective filing date to formulate Delisa’s fusion DNA construct encoding a fusion protein comprising CHIP that “lacks an endogenous substrate recognition region” that is linked via “GSGSG” linker to the antibody fragment (scFv) as an LNP formulation encapsulating a fusion mRNA encoding Delisa’s chimeric protein. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because one of ordinary skill in the art would have reasonably deemed Fontin-Mleczek’s mRNA formulation encapsulated in an LNP would provide the same intended purpose/effect as Delisa’s DNA construct in encoding the chimeric protein comprising CHIP lacking its endogenous substrate recognition region linked via “GSGSG” linker to a desired substrate-binding antibody fragment, and because one of ordinary skill in the art would have readily and reasonably considered that a chimeric protein-encoding DNA construct and a chimeric protein-encoding mRNA in an LNP as mere alternative forms of nucleic acid molecules that encode the desired chimeric protein.
One of ordinary skill in the art would have been further motivated to include RNA sequences encoding the “endoplasmic reticulum (ER) retention signal SEKDEL sequence” disclosed in Peng and “the endoplasmic reticulum signal peptide GWSCIILFLVATATGAHS” disclosed in Gómez-Gonzalo when making an LNP formulation encapsulating a fusion mRNA encoding a substrate-targeting antibody fragment that interacts with CHIP in the ER in view of the teachings of Meachasm demonstrating that CHIP “may function in ER quality control to sense the folded state of membrane proteins that have large cytosolic domains”, further in view of the fact that it was an art-recognized goal to make an LNP-encapsulated mRNA encoding a fusion protein that is designed to be routed or translocate to “the endoplasmic reticulum, endosomes or the lysosome” by including “at least one signal peptide” such as “signal sequence” and “localization sequence” in the fusion protein-encoding sequence as taught by Fontin-Mleczek, wherein one of ordinary skill in the art would have reasonably expected that incorporation of ER retention and signal sequences known in the art as disclosed by Peng and Gómez-Gonzalo would improve the likelihood of delivering the fusion mRNA encoding CHIP whose substrate recognition domain is replaced with a target substrate-binding antibody fragment to the target substrates (e.g., “phosphorylated substrates” or “glycosylated forms” of “enzymes”) that are “aberrantly expressed” in the ER, thereby obtaining enhanced activity/function of the chimeric protein at the cellular compartment (ER) known as the site of interaction between CHIP and the substrate protein targeted by the antibody fragment. Now, when linking the ER retention signal of Peng and/or the ER signal peptide of Gómez-Gonzalo to the C-terminus of the CHIP protein lacking the endogenous substrate recognition region, one of ordinary skill in the art would have reasonably incorporated an art-recognized GS linker such as “GGGS” linker at the C-terminus of the CHIP protein sequence, thereby arriving at SEQ ID NO:8 claimed in the instant case with a reasonable expectation of success, wherein SEQ ID NO:8 is a mere art-recognized amino acid sequence of the C-terminus of the human CHIP protein, wherein the first 5 amino acid residues are the art-recognized “GSGSG” linker and the last 4 amino acid resides are the art-recognized “GGGS” linker, wherein the first 181 amino acid residues including the “GSGSG” linker of SEQ ID NO:8 were known to be encoded by Delisa’s nucleic acid.
In view of the foregoing, claims 1, 11, 14, 17, 40-42, 63, and 74 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on September 23, 2025 have been fully considered but they are not persuasive. Applicant argues that the claims are not obvious because of “the surprising and unexpected results” in providing “the efficacy of the claimed mRNA constructs” by pointing out Examples 6 and 11, Figures 14-15 and 23C, and Table 1 of the instant application. In response, it is noted that “evidence of unexpected results must compare the claimed invention with the closest prior art.” See MPEP §716.02. In the instant case, the closest prior art product is Delisa’s fusion nucleic acid comprising a sequence encoding SEQ ID NO:8 (CHIP lacking the N-terminus) claimed in the instant case except the last four amino acid residues. As such, applicant’s comparison of the construct comprising a sequence encoding SEQ ID NO:8 in Figure 14 to that comprising a sequence encoding SPOP (SEQ ID NO:6) in Figure 15 or that comprising a sequence encoding anti-Cereblon in Figure 23C cannot support the asserted unexpected and surprising results.
In addition, the rejected claims do not recite any mRNA sequence; rather, the claims merely recite any mRNA that “encodes” the recited amino acid sequences of SEQ ID NOs:8-10. That is, the rejected claims in the instant rejection are broadly drawn to any mRNA sequence encoding SEQ ID NOs:8-10, whereas the mRNA having the alleged “efficacy” with of “the surprising and unexpected results” is specifically directed to a single mRNA sequence encoding amino acid elements in a specific order (SEQ ID NO:9, antibody, SEQ ID NO:8, and SEQ ID NO:10), which is not claimed in the rejected claims. Hence, even if the results provided by the disclosed mRNA should be deemed truly unexpected and surprising, they are not commensurate in scope with the rejected claims, which are not directed to the disclosed, specific mRNA sequence encoding SEQ ID NOs:8-10. Note that the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” See MPEP §716.02. Further, unexpected results must also be “commensurate in scope with the degree of protection sought by the claimed subject matter.” In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
In view of the foregoing, applicant’s arguments are not found persuasive to support the asserted nonobviousness of the rejected claims.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RAM SHUKLA can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANA H SHIN/Primary Examiner, Art Unit 1635