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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/05/2026 has been entered.
Application status
In response to the previous Office action, a Final rejection (mailed on 03/05/2026), Applicants filed a response on 12/15/2025. Said amendment canceled Claims 1-55, 66, 71, 73, 77 and 79, and amended Claim 56. Thus, Claims 56-65, 67-70, 72 and 80 are at issue and present for examination.
It is noted by the Examiner that Claims 74-76 and 78 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention in the previous Office actions, a non-Final rejection (mailed on 09/15/2025).
Specification Objection – MAINTAINED
The attempt to incorporate subject matter into this instant specification is ineffective because the specification makes a general statement about ‘incorporation by reference’ but there was no suggestion of a clear intent to ‘incorporate by reference’ of this particular reference because the applicant has not identified what is the “essential material” in this reference (see MPEP 608.01(p)(2)) As such, the reference of Vogelstein et al. is not clearly identified as “required” in accordance with 37 CFR 1.57(c)(2). Therefore, the amendment to specification is “NOT ENTERED”.
Applicants’ arguments:
For clarity, 37 C.F.R. 1.57(c)(2) does not reference "required" material as implied by the rejection, but simply states that the specification must "[c]learly identify the referenced patent, application, or publication." 37 C.F.R. 1.57(c)(2).
For additional clarity, 37 C.F.R. 1.57(d), which relates to incorporation by reference of "essential material," addresses scenarios wherein an applicant attempts to amend language from an external document (patent or patent publication) directly into the claims without amending the specification. Because Applicant is amending the specification, and because Vogelstein is not a patent or patent publication, 37 C.F.R. 1.57(d) does not apply here. This is further illustrated by Example 1 of M.P.E.P. 608.01(p)(2).
Applicable statutory guidance can be found in 37 C.F.R. 1.57(c)
Incorporation by reference of a patent, application, or publication is proper where the specification expresses a "clear intent to incorporate by reference by using the root words 'incorporate' and 'reference"' and clearly identifies the referenced patent, application, or publication.
Applicant asserts that amendment of the specification to incorporate the passage of Vogelstein is proper under 37 C.F.R. 1.57(c) because the specification expresses a clear intent to "incorporate by reference" references disclosed with respect to the subject matter for which each is cited, and Vogelstein is referenced for the subject matter of oncogenes, which subject matter is clearly described in the passage amended into the specification herewith.
The specification states that "[a]ll references, patents and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited. .." Specification as filed, page 38, lines 10-11. This statement clearly expresses intent to incorporate by reference all references disclosed with respect to the subject matter for which each is cited. Notably, this statement is compliant with 37 C.F.R. 1.57(c)(1) because it uses the term "incorporate by reference."
The specification states that "[i]n some embodiments, the [protein of interest (POI)] is an oncoprotein," reciting a non-limiting list of potential oncoproteins. Specification as filed, page 12, lines 14-22. The specification goes on to state that "[o]ther exemplary oncogenes are well known in the art and several such examples are described in, for example, The Genetic Basis of Human Cancer (Vogelstein, B. and Kinzler, K.W. eds McGraw-Hill, New York, N.Y., 1998" Specification as filed, page 12, lines 22-24. These statements clearly cite Vogelstein et al. for the subject matter of "other exemplary oncogenes."
The passage of Vogelstein amended into the specification is from Chapter 11, entitled "Oncogenes." Vogelstein, page 177. The incorporated passage begins by stating "[t]he identification of new oncogenes and tumor-suppressor genes can lead to the delineation of new signaling pathways involved in cancer." Vogelstein, page 189, column 2, paragraph 2. Therefore, the passage of Vogelstein amended into the specification clearly describes "other exemplary oncogenes" in addition to those listed on page 12 of the specification as filed.
Therefore, amendment of the specification to incorporate this passage of Vogelstein is proper under 37 C.F.R. 1.57(c) because the specification expresses a clear intent to "incorporate by reference" references disclosed with respect to the subject matter for which each is cited, and Vogelstein is referenced for the subject matter of oncogenes, which subject matter is clearly described in the passage amended into the specification herewith.
Examiner’s explanation:
In accordance with 37 CFR 1.57(c), while applicants have met the first part of the above requirement i.e., “Incorporation by reference of a patent, application, or publication is proper where the specification expresses a "clear intent to incorporate by reference by using the root words 'incorporate' and 'reference''’, Applicants have failed to meet the second requirement i.e., “clearly identifies the referenced patent, application, or publication”. 37 C.F.R. 1.57(c). A sweeping, broad, or blanket claim in the amendment filed on 04/20/22 that the PCT application and the provisional patent application are incorporated by reference fails to clearly identify the specific reference of Vogelstein et al. as being incorporated by reference. For the reasons provided herein, the previous objection of the specification is maintained, and the amendment to specification filed on 06/05/2026 is NOT ENTERED.
Claim Rejections - 35 USC § 112 – MAINTAINED
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.
Claim 80 is rejected under 35 U.S.C. 112(a), 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.
Claim 80 was newly added on 12/15/2025, however, there is not a single mention of “β-catenin” in the specification, drawings or claims as originally filed (italicized for added emphasis). The Applicants point out that support can be found in lines 22-33 of page 39. However, this section seems to be what Applicants are trying to incorporate into specification that is “NOT ENTERED” by the Examiner due to the issues with the ‘incorporation by reference’ as explained above (see under Specification). Taken together, claim 80 is rejected as being drawn to a ‘new matter’.
Applicants’ argument:
Applicants argue that in view of the amendment to the specification presented herewith, this rejection is rendered moot.
Examiner’s explanation:
In view of the same issue present with the “incorporation by reference” in the instant specification as noted above, the previous rejection under the written description requirement of 35 U.S.C. 112(a) is maintained.
Claim Rejections - 35 U.S.C. § 103 - MAINTAINED
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.
Claim 56-65, 67-68 and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Buscail et al. (First-in-man Phase 1 Clinical Trial of Gene
Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings, Molecular Therapy vol. 23 no. 4, 779–789 apr. 2015) in view of Kronke et al. (Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells, Science. 2014 January 17; 343(6168): 301–305), Goding et al. (WO 2007062474 A1) and Stevis et al. (US 20140275489 A1).
The instant claims are drawn to a DNA vector comprising in operable linkage: from 5’ to 3’:
(a) a promoter;
(b) a nucleotide sequence encoding a fusion protein comprising a protein of interest fused to a cytotoxic element selected from the group consisting of deoxycytidine kinase, thymidylate kinase, thymidine kinase-guanylate kinase fusion, and FKBP-Caspase9 fusion;
(c) an internal ribosomal entry site (IRES); and
(d) a nucleotide sequence encoding a reporter protein.
Buscail et al. teach a DNA vector (CYL-02) comprising in operable linkage: (a) a glucose-responsive promoter (GRP78 or GRP94); (b) a nucleotide sequence encoding a fusion protein comprising a protein of interest (UMK) fused to a cytotoxic element, deoxycytidine kinase (dCK), which is used for a Phase 1 clinical trial for human patients (which encompasses isolated host cell). The Examiner notes that eukaryotic promoters, like GRP78 and GRP94 which work in human cells, are considered an inducible promoter because they are activated or "turned on" by a specific stimulus, i.e., glucose deprivation. Buscail et al. further teach that said fusion protein is separated by a peptide linker, “FMDV 2A peptide” (see page 786, right column, 4th para under “Treatment plan”).
Buscail et al. do not teach a peptide linker comprising one or more iterations of GGS, a reporter protein which is fluorescent, CMV promoter, a protein of interest which is IKZF3.
Kronke et al. teach that an oncoprotein, IKZF3, is one of the essential transcription factors in proliferation of multiple myeloma. Kronke et al. further teach that Lenalidomide is a drug with clinical efficacy in multiple myeloma which causes selective ubiquitination and degradation of IKZF3 (see abstract).
Goding et al. teach that an expression construct, i.e., polycistronic DNV vector, comprising a CMV promoter operably linked to a nucleotide sequence encoding multiple proteins of interest with an IRES inserted in between said proteins or a fluorescent reporter protein, i.e., a green or red fluorescent reporter protein (see pg. 40, line 20; pg. 31, line 1; and claims 10, 11, 13, 23 and 26).
Stevis et al. teach that a fusion protein comprising a reporter protein, which can be Renilla luciferase or green fluorescent protein (see para [0100]), wherein said fusion protein is linked by a peptide linker comprising one or more iterations of Gly-Gly-Ser (see para [0122]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make and use the DNA vector taught by Buscail et al. and substitute with the following: a peptide linker comprising one or more iterations of GGS, a reporter protein which is fluorescent, CMV promoter, a protein of interest which is IKZF3 as taught by Kronke et al. Goding et al. and Stevis et al. A person of ordinary skill in the art (POSITA) would have been motivated to make and use such DNA vector because [1] suicide gene such as dCK is routinely fused a gene (UMK) associated with pancreatic cancer for cell survival as taught by Buscail et al., and since IKZF3 is also a known oncogene for multiple myeloma, a POSITA would have been motivated to swap UMK with IKZF3 and express such fusion protein with a reporter protein for cell survival assays; and [2] an IRES allows expressing two or more proteins in a single mRNA transcript, i.e., a fusion protein and a reporter protein as taught by Goding et al.. Furthermore, it would have been a routine experimentation for a POSITA to swap between different but obvious variants of promoters, peptide linkers, and reporter proteins that are present in such DNA vector by using the CMV promoter, a peptide linker comprising GGS, and a reporter protein which is Renilla luciferase or GFP. As discussed in KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007), it is considered obvious to combine prior art elements which are obvious variants known to be used in equivalent fields of endeavor together into a single combination.
Regarding the newly added limitation of “from 5’ to 3’:” of claim 56, changing the order of components from 5’ to 3’ in a DNA vector is a routine optimization for a POSITA. The references of Buscail et al., Kronke et al. Goding et al. and Stevis et al. clearly show that the claimed promoters, peptide linkers, and reporter proteins were known to be used in equivalent fields of endeavor; thus, it is considered obvious to combine them together and further perform a routine optimization the order in which they are arranged from 5’ to 3’ in a DNA vector.
A POSITA would have had a reasonable expectation of success to make and use such DNA vectors because all of the required biochemical reagents and techniques were rampantly used as evidenced by Buscail et al., Kronke et al. Goding et al. and Stevis et al. prior to the filing of the instant application. For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Applicants’ Arguments:
The Supreme Court has recognized that, in an obviousness rejection, there should be a determination of "whether there was an apparent reason to combine the known elements in the fashion claimed by the patent at issue." Emphasis Added. KSR International Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Similarly, the Federal Circuit has distinguished the mere feasibility of a combination with desirability of the combination, and has indicated that motivation to combine requires the latter. Winner Int'l Royalty Corp. v. Wang, 202 F.3d 1340, 1349 (Fed. Cir. 2000) (finding the district court did not err when ruling there was no motivation to combine a second reference with a first reference when such a combination would render the first reference more convenient but less secure).
A person having ordinary skill in the art would have no motivation to modify the DNA vector of Buscail to include an IRES and a reporter protein 3' of the promoter and fusion protein of Buscail because the resulting DNA vector would have no added function.
The Examiner cites Buscail as teaching, in relevant part "a DNA vector (CYL-02)
comprising in operable linkage: (a) a glucose-responsive promoter (GRP78 or GRP94); (b) a nucleotide sequence encoding a fusion protein comprising a protein of interest (UMK) fused to a cytotoxic element, deoxycytidine kinase (dCK)." Final Office Action, page 4. The Examiner acknowledges that Buscail fails to teach "a peptide linker comprising one or more iterations of GGS, a reporter protein which is fluorescent, CMV promoter, a protein of interest which is IKZF3." Final Office Action, page 5.
To remedy these deficiencies, the Examiner cites Kronke as teaching the oncoprotein IKZF3, an expression construct comprising "a CMV promoter operably linked to a nucleotide sequence encoding multiple proteins of interest with an IRES inserted in between said proteins," and Stevis as teaching a fusion protein comprising a reporter protein. Final Office Action, page 5.
Applicant has previously asserted that a person having ordinary skill in the art would not be motivated to modify the DNA vector of Buscail to include an IRES and a reporter protein 3' of the promoter and fusion protein because the fusion protein of Buscail is cytotoxic, and it would not be logical to add a reporter protein to a DNA vector that kills a cell upon expression. See Amendment and Response filed December 15, 2025.
In response, the Examiner stated that "in the context of the DNA vector of Buscail et al. cells do not immediately die just because the cells comprise the DNA vector of Buscail et al." and that "by having an additional fluorescent reporter protein, a POSITA would be able to determine if the inducible promoters for expression of cytotoxic protein is working properly as a 'switch' mechanism in a 'cell survival assay' since a POSITA can now monitor the living cells comprising the DNA vectors with fluorescence and determine if cell death occurs when the 'switch' is turned on." Final Office Action, page 13.
The Examiner's response appears to rely upon the idea that the claimed DNA vector encompasses a DNA vector wherein the reporter protein is expressed from a different expression cassette than the fusion protein. At least in view of the amendments to independent claim 56 presented herein, Applicant asserts that the Examiner's argument is no longer applicable to the claimed DNA vector. Rather, a person having ordinary skill in the art would not be motivated to modify the DNA vector of Buscail to reach the claimed DNA vector in view of Kronke, Goding, and Stevis, because the resultant vector would provide no function over the unmodified DNA vector of Buscail.
Independent claim 56 is amended herein to recite "[a] DNA vector comprising in
operable linkage, from 5' to 3':" a promoter, a nucleotide sequence encoding a fusion protein, an IRES, and a nucleotide sequence encoding a reporter protein. Applicant submits that independent claim 56 is not obvious over Buscail in view of Kronke, Goding, and Stevis because a person having ordinary skill in the art would have no reason to combine in a DNA vector in operable linkage from 5' to 3' a promoter, a nucleotide sequence encoding a fusion protein comprising a protein of interest fused to a cytotoxic element, an IRES, and a nucleotide sequence encoding a reporter protein. In particular, a person having ordinary skill in the art would have no reason to combine the elements of independent claim 56 in operable linkage and arranged from 5' to 3' as recited because the resulting DNA vector would provide no additional function because the nucleotide sequence encoding the reporter protein and the nucleotide sequence encoding the fusion protein would be expressed from the same promoter. A cell comprising the DNA vector would die upon expression of the cytotoxic element of the fusion protein, rendering the reporter protein useless for the purposes of the cited documents.
For at least this reason, reconsideration and withdrawal of the rejection are respectfully requested.
Examiner’s Explanation:
Applicants’ arguments have been fully considered but are not deemed persuasive for the following reasons. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Applicants argue that a POSITA would not have been motivated to modify the DNA vector of Buscail et al. because it would not add any meaningful functionality.
Contrary to Applicants’ allegations, the Examiner notes that the combined teachings of the prior art would provide a meaningful functionally and motivation to make and use the invention as claimed. Especially in the context of the DNA vector of Buscail et al. cells do not immediately die just because the cells comprise the DNA vector of Buscail et al. As explained previously, the DNA vector of Buscail et al. comprise eukaryotic promoters, GRP78 and GRP94, which are an inducible promoter because they are activated or "turned on" by a specific stimulus, i.e., glucose deprivation (see the body of the instant rejection). As such, by having an additional fluorescent reporter protein, a POSITA would be able to determine if the inducible promoters for expression of cytotoxic protein is working properly as a ‘switch’ mechanism in a ‘cell survival assay’ since a POSITA now can monitor the living cells comprising the DNA vectors with fluorescence and determine if the cell death occurs when the ‘switch’ is turned on.
Furthermore, arranging a promoter, a nucleotide sequence encoding a fusion protein, an IRES, and a nucleotide sequence encoding a reporter protein in 5’ to 3’ order in a DNA vector falls under ‘routine optimization’ for a POSITA as explained above.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Claim 56-65, 69-70 and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Buscail et al. (First-in-man Phase 1 Clinical Trial of Gene
Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings, Molecular Therapy vol. 23 no. 4, 779–789 apr. 2015) in view of Ochiishi et al. (Development of new fusion proteins for visualizing amyloid-β
oligomers in vivo, Scientific Reports volume 6, Article number: 22712, published 03/16/2016), Goding et al. (WO 2007062474 A1) and Stevis et al. (US 20140275489 A1).
The instant claims are drawn to a DNA vector comprising in operable linkage: from 5’ to 3’:
(a) a promoter;
(b) a nucleotide sequence encoding a fusion protein comprising a protein of interest fused to a cytotoxic element selected from the group consisting of deoxycytidine kinase, thymidylate kinase, thymidine kinase-guanylate kinase fusion, and FKBP-Caspase9 fusion;
(c) an internal ribosomal entry site (IRES); and
(d) a nucleotide sequence encoding a reporter protein.
Buscail et al. teach a DNA vector (CYL-02) comprising in operable linkage: (a) a glucose-responsive promoter (GRP78 or GRP94); (b) a nucleotide sequence encoding a fusion protein comprising a protein of interest (UMK) fused to a cytotoxic element, deoxycytidine kinase (dCK), which is used for a Phase 1 clinical trial for human patients (which encompasses isolated host cell). The Examiner notes that eukaryotic promoters, like GRP78 and GRP94 which work in human cells, are considered an inducible promoter because they are activated or "turned on" by a specific stimulus, i.e., glucose deprivation. Buscail et al. further teach that said fusion protein is separated by a peptide linker, “FMDV 2A peptide” (see page 786, right column, 4th para under “Treatment plan”).
Buscail et al. do not teach a peptide linker comprising one or more iterations of GGS, a reporter protein which is fluorescent, CMV promoter, a protein of interest which is amyloid protein.
Ochiishi et al. teach that the intracellular accumulation of amyloid-β (Aβ) oligomers critically contributes to disease progression in Alzheimer’s disease (AD) and can be the potential target of AD therapy. Ochiishi et al. further teach Aβ-GFP fusion protein for in vivo imaging.
Goding et al. teach that an expression construct, i.e., polycistronic DNV vector, comprising a CMV promoter operably linked to a nucleotide sequence encoding multiple proteins of interest with an IRES inserted in between said proteins or a fluorescent reporter protein, i.e., a green or red fluorescent reporter protein (see pg. 40, line 20; pg. 31, line 1; and claims 10, 11, 13, 23 and 26).
Stevis et al. teach that a fusion protein comprising a reporter protein, which can be Renilla luciferase or green fluorescent protein (see para [0100]), wherein said fusion protein is linked by a peptide linker comprising one or more iterations of Gly-Gly-Ser (see para [0122]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make and use the DNA vector taught by Buscail et al. and substitute with the following: a peptide linker comprising one or more iterations of GGS, a reporter protein which is fluorescent, CMV promoter, a protein of interest which is Aβ as taught by Ochiishi et al. Goding et al. and Stevis et al. A person of ordinary skill in the art (POSITA) would have been motivated to make and use such DNA vector because [1] suicide gene such as dCK are routinely fused a gene (UMK) associated with pancreatic cancer for cell survival as taught by Buscail et al., and since Aβ is also a known protein which accumulates intracellularly in Alzheimer’s disease, a POSITA would have been motivated to swap UMK with Aβ and express such fusion protein with a reporter protein for cell survival assays; and [2] an IRES allows expressing two or more proteins in a single mRNA transcript, i.e., a fusion protein and a reporter protein as taught by Goding et al. Furthermore, it would have been a routine experimentation for a POSITA to swap between different but obvious variants of promoters, peptide linkers, and reporter proteins that are present in such DNA vector by using the CMV promoter, a peptide linker comprising GGS, and a reporter protein which is Renilla luciferase or GFP. As discussed in KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007), it is considered obvious to combine prior art elements which are obvious variants known to be used in equivalent fields of endeavor together into a single combination.
Regarding the newly added limitation of “from 5’ to 3’:” of claim 56, changing the order of components from 5’ to 3’ in a DNA vector is a routine optimization for a POSITA. The references of Buscail et al., Kronke et al. Goding et al. and Stevis et al. clearly show that the claimed promoters, peptide linkers, and reporter proteins were known to be used in equivalent fields of endeavor; thus, it is considered obvious to combine them together and further perform a routine optimization the order in which they are arranged from 5’ to 3’ in a DNA vector.
A POSITA would have had a reasonable expectation of success to make and use such DNA vectors because all of the required biochemical reagents and techniques were rampantly used as evidenced by Buscail et al., Ochiishi et al. Goding et al. and Stevis et al. prior to the filing of the instant application. For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Applicants’ Arguments:
Claims 56-65, 69, 70, and 72 are rejected under 35 U.S.C. § 103 as being obvious over Buscail in view of Ochiishi et al. (Sci Reports, 2016, "Ochiishi"), Goding and Stevis. Applicant respectfully traverses this rejection and each assertion made in support thereof.
As described above regarding the rejection of claims 56-65, 67, 68, and 72 under 35 U.S.C. § 103 as being obvious over Buscail in view of Kronke, Goding, and Stevis, a person having ordinary skill in the art would have no motivation to modify the DNA vector of Buscail to include an IRES and a reporter protein 3' of the promoter and fusion protein of Buscail because the resulting construct would have no added function. Ochiishi fails to provide any teaching or suggestion that would motivate a person having ordinary skill in the art to make such a modification of the DNA vector of Buscail.
The Examiner cites Ochiishi as teaching that "intracellular accumulation of amyloid-3 (A3) oligomers critically contributes to disease progression in Alzheimer's disease (AD) and can be the potential target of AD therapy" and an "Aj3-GFP fusion protein for in vivo imaging." Final Office Action, page 15.
Previously, Applicant argued that a person having ordinary skill in the art would not be motivated to modify the DNA vector of Buscail to include an IRES and a reporter protein because the fusion protein of Buscail is cytotoxic, and it would not be logical to add a reporter protein to a DNA vector that kills a cell upon expression. See Amendment and Response filed December 15, 2025.
Here, like in the rejection of claims 56-65, 67, 68, and 72 under 35 U.S.C. § 103 as being obvious over Buscail in view of Kronke, Goding, and Stevis, the Examiner's response appears to rely upon the idea that the claimed DNA vector encompasses a DNA vector wherein the reporter protein is expressed from a different expression cassette than the fusion protein. At least in view of the amendments to independent claim 56 presented herein, Applicant asserts that the Examiner's argument is no longer applicable to the claimed DNA vector.
Ochiishi fails to provide any additional teaching or suggestion that would motivate a person having ordinary skill in the art to modify the DNA vector of Buscail to include an IRES and a reporter protein 3' of the promoter and fusions protein. Even in view of Ochiishi, a person having ordinary skill in the art would have no motivation to make such a modification because the resulting DNA vector would provide no function over the unmodified DNA vector of Buscail because the nucleotide sequence encoding the reporter protein and the nucleotide sequence encoding the fusion protein would be expressed from the same promoter. Because the fusion protein of Buscail is cytotoxic, the cell would die before the reporter protein could be detected. Therefore, a person having ordinary skill in the art would have no motivation to modify Buscail as alleged by the Examiner in view of Ochiishi, Goding, and Stevis.
Examiner’s Explanation:
Applicant's arguments filed 06/05/2026 have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Applicants argue that a POSITA would not have been motivated to modify the DNA vector of Buscail et al. because [1] Buscail already provides a method of detecting presence of the DNA vector directly in patient samples, and [2] would likely decrease the sensitivity of a detection assay at least because the DNA vector of Buscail et al. is cytotoxic, and cells treated with the DNA vector would die upon administration of the DNA vector.
Contrary to Applicants’ allegations, the Examiner notes that the combined teachings of the prior art would provide a motivation to make and use the invention as claimed. Especially in the context of the DNA vector of Buscail et al. cells do not immediately die just because the cells are treated with the DNA vector of Buscail et al. As explained previously, the DNA vector of Buscail et al. comprise eukaryotic promoters, GRP78 and GRP94, which are an inducible promoter because they are activated or "turned on" by a specific stimulus, i.e., glucose deprivation (see the body of the instant rejection). As such, by having an additional fluorescent reporter protein, a POSITA would be able to determine if the inducible promoters for expression of cytotoxic protein is working properly as a ‘switch’ mechanism in a ‘cell survival assay’ since a POSITA now can monitor the living cells comprising the DNA vectors with fluorescence and determine if the cell death occurs when the ‘switch’ is turned on.
Furthermore, arranging a promoter, a nucleotide sequence encoding a fusion protein, an IRES, and a nucleotide sequence encoding a reporter protein in 5’ to 3’ order in a DNA vector falls under ‘routine optimization’ for a POSITA as explained above.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 56-65, 67-70, 72 and 80 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
Prosecution Insights