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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 8, 2026 has been entered.
DETAILED ACTION
The amendment filed April 8, 2026 in response to the Office Action of October 8, 2025 is acknowledged and has been entered.
Claim 1 has been amended.
Claim 12 has been added.
Claims 1-3 and 7-12 are pending and under consideration.
Priority
Acknowledgement has been made that this application claims priority to foreign applications: JP 2017-127973, filed 2017-06-29.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more amended claims of this application. Examiner has established a priority date of July 24, 2023 for amended claims 1-3 and 7-11 because the amended claims as currently constituted recite: “a method for removing suppression of anti-tumor immunity caused by a tumor cell, comprising suppressing expression of Slug gene in the tumor cell with a nucleic acid hybridizing to the Slug gene to remove suppression of anti-tumor immunity by cytotoxic T cells, wherein in the tumor cell, a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated; and/or an aryl hydrocarbon receptor (AhR) is activated, and wherein the nucleic acid hybridizing the Slug gene is a short hairpin RNA (shRNA) or a small interfering RNA (siRNA)” and a review of the parent applications does not reveal the broadly claimed methods (also see 112(a) rejection below). Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
MAINTAINED/MODIFIED REJECTION
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 1-3 and 7-12 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.
Claim 1 was amended after the filing date. The limitation of “a method for removing suppression of anti-tumor immunity caused by a tumor cell, comprising suppressing expression of Slug gene in the tumor cell with a nucleic acid hybridizing to the Slug gene to remove suppression of anti-tumor immunity by cytotoxic T cells, wherein in the tumor cell, a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated; and/or an aryl hydrocarbon receptor (AhR) is activated, and wherein the nucleic acid hybridizing the Slug gene is a short hairpin RNA (shRNA) or a small interfering RNA (siRNA)” in claim 1 has no clear support in the specification as originally filed. Applicants argue in the Remarks filed April 8 2026 that support for the limitation can be found throughout the original specification and claims, for example in paragraphs [0049]-[0052] of the specification.
Paragraphs [0049]-[0052] of the specification (filed 07/24/2023) describe Example 5, in which a specific shRNA (SEQ ID NO: 14) for Slug was inserted into to a lentiviral vector. The prepared lentiviral vector was infected to MCA25 in which a constitutively active mouse AhR gene was transfected and constitutively expressed, named MCA205 actAhR shSlug (page 42, lines 14-27). Fig. 12 shows that MCA205 actAhR shSlug, in which Slug gene expression was stably knocked down, form smaller tumor than MCA205 actAhR NonTarget (without shSlug) (also see the bottom paragraph on page 43).
The original specification discloses suppressing expression of Slug gene using one specific slug shRNA in a lentiviral vector in one specific tumor model: MCA205 over-expressing AhR (Figs. 11-13, and Example 5). However, the specification as originally filed, does not support the amended claim 1 which encompass removing suppression caused by a broad genus of tumor cells and with a broad genus of siRNAs. As evidenced by Malesu (downloaded from: siRNA vs shRNA: Key Differences in Gene Knockdown Methods; Publication Date: 01/19/2026), although both siRNA and shRNA are RNAi-based strategies, they are different in many aspects. siRNA and shRNA rely on the same cellular RNAi machinery but differ in their experimental behavior and applications. siRNA is delivered as a preformed RNA duplex and produces an immediate reduction in target mRNA levels that diminishes over time due to degradation and cell division. This transient effect makes siRNA suitable for short-duration experiments. In contrast, shRNA is expressed continuously from plasmids or viral vectors, resulting in stable, sustained knockdown that can persist for weeks or longer (§ Key difference between siRNA and shRNA). Given the differences (stable vs transient), the effects of the specific shRNA may not be achieved by siRNAs. In addition, as evidenced by Rao (Rao et al., Advanced Drug Delivery Reviews, 61 (2009) 746-759, Publication Year: 2009), siRNA and shRNA go through different processing steps; different structures (see Fig. 3 and Fig. 4).
Furthermore, although the specification has support for anti-tumor activity of shRNA to Slug gene to a specific tumor cell (MCA205 over-expressing AhR), the specification lacks support for the claimed method on broadly claimed tumor cells: “removing suppression of anti-tumor immunity caused by a tumor cell, … wherein in the tumor cell, a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated; and/or an aryl hydrocarbon receptor (AhR) is activated”.
Thus, the subject matter claimed in the amended claim 1 broadens the scope of the invention as originally disclosed in the specification and claims.
Claims 2, 3, and 7-12 are also rejected because these claims encompass new matters: a broad genus of tumor cells and/or a broad genus of siRNAs or shRNAs. encompassed by the rejected claim above.
Response to Arguments
For the 112(a) New Matter rejection, Applicant argues:
It was well known in the art at the time of filing this application that an shRNA produces a double-stranded RNA molecule having short hairpin structure that generates siRNAs specifically hybridizing with the subject mRNA to suppress or knock down the gene expression thereof. See, e.g., Moffat J et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell. 2006 Mar 24;124(6):1283-98; Kim D et al. RNAi mechanisms and applications. Biotechniques. 2008 Apr;44 (5):613-6. Moreover, it was also well known that inhibition of gene expression is achieved by hybridization of the subject gene with an inhibitory RNA molecule. A person of ordinary skill in the art ("POSITA") would have understood that inhibitory RNA molecules having a sequence complementary to the target gene would hybridize to and inhibit the expression of such target gene. A POSITA would have also understood that variations to the complementary sequence can also be introduced that could affect the hybridization affinity to-and therefore extent of inhibition of-the target gene. See, e.g., pmc.ncbi.nlm.nih.gov/articles/PMC1069010; cellecta.com/pages/principles-of-rnai-and-shrna-design; pmc.ncbi.nlm.nih.gov/articles/PMC1484447.
Applicant’s arguments have been fully considered but they are not persuasive. MPEP 608.04(a) states: Matter not present on the filing date of the application in the specification, claims, or drawings that is added after the application filing is usually new matter.
In addition, although both shRNA and siRNA are based on RNAi machinery (as argued by Applicant), they have key differences which may impact the outcomes, as evidenced by Malesu and Rao. In addition, the amended claims encompass chemically synthesized double stranded siRNAs which are intrinsically different from shRNAs. The originally filed application does not have support for the broadly claimed siRNAs specific for Slug.
In addition, the specification only has support for specific tumor cell: MCA205 with a constitutively active mouse AhR (Example 5). The specification lacks support for broadly claimed: “removing suppression of anti-tumor immunity caused by a tumor cell, …, wherein in the tumor cell, a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated; and/or an aryl hydrocarbon receptor (AhR) is activated”. Thus, the subject matter claimed in the amended claims broadens the scope of the invention as originally disclosed in the specification and claims from what was originally.
Thus, the 112(a) rejection is maintained for the reasons of record.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tsukamoto (Tsukamoto et al., US 2020/0383981 A1, Publication Date: 12/10/2020, of record).
Since the specification does not define the term “removing suppression of anti-tumor immunity caused by a tumor cell”, given BRI, any anti-tumor activity would be considered as removing suppression of anti-tumor immunity caused by a tumor cell.
Tsukamoto teaches knockdown of Slug gene expression by shRNA, by introducing shRNA into MCA205 actAhR (Example 5, [0205]).
Tsukamoto teaches that Slug shRNA down-regulated Slug gene expression in mouse with activated AhR (Fig. 11 and [0207]).
Tsukamoto teaches that MCA205 actAhR NonTarget formed a tumor that was significantly larger than the mock. On the other hand, MCA205 actAhR shSlug, in which Slug gene expression was stably knocked down, formed small tumors equivalent to the mock. This indicates that tumor growth can be inhibited by suppressing the Slug gene. See Fig. 12 and [0213].
Tsukamoto teaches that MCA205 actAhR shSlug in which Slug gene expression was stably knocked down, IFN-γ production by cytotoxic T cells was significantly increased, indicating that anti-tumor immunity was enhanced (See Fig. 13 and [0215]). IFN-γ production is an indicator of anti-tumor immune activity by cytotoxic T cells (see [0177]).
Response to Arguments
For the 102 rejection, Applicant argues:
In rejecting claims 1 and 3, the office action alleges that the priority date of the present application is July 24, 2023 due to lack of adequate support or enablement in the prior-filed applications. For the reasons explained above, pending claim 1 and its dependent claim 3 are sufficiently supported by the foreign priority application filed on June 29, 2017. As such, Tsukamoto, the publication date of which is December 10, 2020, is not prior art to the pending claims and cannot be an anticipatory reference.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, the specification and claims as originally filed do not has support for the amended claims and broaden the scope of the invention as originally disclosed. Accordingly, the Priority date for the amended claims has been established as July 24, 2023. As such, Tsukamoto is still qualified as prior art for the pending claims and still anticipate amended claims 1, 3 and 12.
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.
Claims 2, and 7-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsukamoto (Tsukamoto et al., US 2020/0383981 A1, Publication Date: 12/10/2020, of record), as applied to claims 1 and 3 above.
Regarding claims 2 and 8-11, Tsukamoto teaches as set forth above. However, Tsukamoto does not explicitly teach that wherein in the tumor cell a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated.
Tsukamoto teaches human IDO1 YYFF mutants which has Y111F and Y249F mutations in MCA205 and SW837 tumor cells ([0189], [0217]).
Tsukamoto teaches that human wild-type IDO1 induced high Slug gene expression but IDO1 YYFF mutant could not (Fig. 8, [0195] of Example 4; Fig. 14, [0223] of Example 6).
Tsukamoto teaches mouse IDO1 YYFF mutant which has Y115F and Y253F mutations. Wild-type IDO1 induced high Slug gene expression but IDO1 YYFF mutant could not ([0045] and Fig. 6).
As shown below with an alignment of mouse and human IDO1, tyrosine-115 and tyrosine-253 residues of mouse IDO1 correspond to the 111-th position and/or the 249-th position of human IDO1:
indoleamine 2,3-dioxygenase 1 [Homo sapiens]
Sequence ID: NP_002155.1Length: 403Number of Matches: 1
Query 10 EGSRRILEDHHIDEDVGFALPHPLVELPDAYSPWVLVARNLPVLIENGQLREEVEKLPTL 69
E S I +++HIDE+VGFALP+P LPD Y+ W+ +A++LP LIE+GQLRE VEKL L
Sbjct 6 ENSWTISKEYHIDEEVGFALPNPQENLPDFYNDWMFIAKHLPDLIESGQLRERVEKLNML 65
Query 70 STDGLRGHRLQRLAHLALGYITMAYVWNRGDDDVRKVLPRNIAVPYCELSEKLGLPPILS 129
S D L H+ QRLA L LG ITMAYVW +G DVRKVLPRNIAVPYC+LS+KL LPPIL
Sbjct 66 SIDHLTDHKSQRLARLVLGCITMAYVWGKGHGDVRKVLPRNIAVPYCQLSKKLELPPILV 125
Query 130 YADCVLANWKKKDPNGPMTYENMDILFSFPGGDCDKGFFLVSLLVEIAASPAIKAIPTVS 189
YADCVLANWKKKDPN P+TYENMD+LFSF GDC KGFFLVSLLVEIAA+ AIK IPTV
Sbjct 126 YADCVLANWKKKDPNKPLTYENMDVLFSFRDGDCSKGFFLVSLLVEIAAASAIKVIPTVF 185
Query 190 SAVERQDLKALEKALHDIATSLEKAKEIFKRMRDFVDPDTFFHVLRIYLSGWKCSSKLPE 249
A++ Q+ L KAL +IA+ LEKA ++F ++ D V+P FF VLRIYLSGWK + +L +
Sbjct 186 KAMQMQERDTLLKALLEIASCLEKALQVFHQIHDHVNPKAFFSVLRIYLSGWKGNPQLSD 245
Query 250 GLLYEGVWDTPKMFSGGSAGQSSIFQSLDVLLGIKHEAGKESPAEFLQEMREYMPPAHRN 309
GL+YEG W+ PK F+GGSAGQSS+FQ DVLLGI+ AG A+FLQ+MR YMPPAHRN
Sbjct 246 GLVYEGFWEDPKEFAGGSAGQSSVFQCFDVLLGIQQTAGGGHAAQFLQDMRRYMPPAHRN 305
Query 310 FLFFLESAPPVREFVISRHNEDLTKAYNECVNGLVSVRKFHLAIVDTYIMKPSKKKPTDG 369
FL LES P VREFV+S+ + L +AY+ CV LVS+R +HL IV YI+ P+ ++P +
Sbjct 306 FLCSLESNPSVREFVLSKGDAGLREAYDACVKALVSLRSYHLQIVTKYILIPASQQPKEN 365
Query 370 DKSEEPSNVESRGTGGTNPMTFLRSVKDTTEKALL 404
SE+PS +E++GTGGT+ M FL++V+ TTEK+LL
Sbjct 366 KTSEDPSKLEAKGTGGTDLMNFLKTVRSTTEKSLL 400
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use an shRNA to down-regulate Slug gene expression to treat cancer (e.g. removing suppression of anti-tumor immunity caused by a tumor cell), as taught by Tsukamoto, and to treat tumor, wherein in the tumor cell a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated, because Tsukamoto also teaches that phosphorylation at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 are required for induction of Slug gene expression. Thus, one of ordinary skill in the art would have recognized that a tumor with IDO1 phosphorylation at claimed position(s) would be more likely have higher Slug expression and be suitable for treatment by shRNA to Slug gene. Since the treatment is well known in the art as evidenced by Tsukamoto, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to identify a suitable population for the claimed method.
Regarding claim 7, Tsukamoto teaches as set forth above. Additionally, , Tsukamoto teaches at paragraphs [0035-0037]: A method for screening a candidate substance for inhibiting expression of Slug gene or inhibiting synthesis of Slug, wherein the method includes: ex vivo measuring Slug inhibition activity by a test substance, inhibition activity against a factor which activates Slug by a test substance, expression of Slug gene by a test substance, or synthesis of Slug by a test substance, in a cell in which a tyrosine residue(s) at the 111-th position and/or the 249-th position of human IDO1, or a tyrosine residue(s) of non-human IDO1 at a position(s) corresponding to the 111-th position and/or the 249-th position of human IDO1 is/are phosphorylated, and/or in a cell in which AhR is activated; and selecting the candidate substance based on the measured Slug inhibition activity by the test substance, the inhibition activity against a factor which activates Slug by the test substance, measured expression inhibition of Slug gene by the test substance, or measured synthesis inhibition of Slug by the test substance.
Thus, it would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to target Slug gene for treating tumors, to use shRNA to suppress Slug gene expression as taught by Tsukamoto, and to further screen a more effective substance as claimed, because searching for a more effective substance that suppresses tumor invasion and metastasis was a well-known problem for an ordinary skill in the art. In order to obtain an inhibitory substance for Slug that is more effective than shRNA, a person skilled in the art would have easily conceived of screening for a substance that inhibits the expression and function of AhR and Slug by allowing a new candidate substance different from shRNA to act on the tumor cells in which the expression of AhR and Slug described in Tsukamoto. Given that Tsukamoto teaches the method of measuring Slug, one of ordinary skill would have had a reasonable expectation of success to reach the claimed invention. The motivation would have been to expand the options and to develop a more effective treatment.
Response to Arguments
For the 103 rejection, Applicant argues:
For the reasons explained above, Tsukamoto is not prior art and therefore cannot render obvious any of the pending claims.
Applicant is reiterating the arguments set forth above. Thus for the reasons set forth above the rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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