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 Claims
Claims 1-19 are pending.
Priority
Claims 1-19 are a 371 of PCT/JP 2022/035626 filed on September 26, 2022, which has priority to JAPAN 2021-157187 filed on September 27, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on March 26, 2024, and on October 1, 2025, and on April 3, 2026, were filed before the mailing of the First Office Action on July 11, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Applicant is advised that should claim 1 be found allowable, claim 6 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 6 is substantially the same as claim 1 because claim 1 already requires differentiating cells into the recited expression construct has been introduced. Claim 6 is merely reciting the introduction of the same expression construct into the same cells. Thus, despite a slight difference in wording, these claims have substantially the same scope.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 18 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because:
Claim 18 is directed at an intended use where the “use of regulatory T cells” in the production of a pharmaceutical composition. The “use” limitation is not one of the four statutory categories of patent-eligible subject matter, i.e. process, machine, manufacture, or composition of matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 8, 9, and 18 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.
Claim 1 recites “(1) differentiating cells that can differentiate into regulatory T cells, into which an expression construct is introduced, into regulatory T cells”. As drafted, the phrase “into which an expression construct is introduced” is not clear whether this phrase is defining a characteristic of the starting cells or a method step of introducing the expression construct prior to differentiation.
Claim 8 recites “wherein the cells that can differentiate into regulatory T cells or cells differentiated therefrom”. As written, claim 8 is unclear. Is the claim limitation referring to precursor cells capable of differentiating into regulatory T cells, , regulatory T cells themselves, or both precursor and differentiated cell populations as alternative subjects of the limitation. A person of ordinary skill would have difficulty in determining what the metes and bounds of the claimed limitation are.
Claim 9 recites “wherein the cells that can differentiate into regulatory T cells or cells differentiated therefrom”. As written, claim 8 is unclear. Is the claim limitation referring to precursor cells capable of differentiating into regulatory T cells, , regulatory T cells themselves, or both precursor and differentiated cell populations as alternative subjects of the limitation. A person of ordinary skill would have difficulty in determining what the metes and bounds of the claimed limitation are.
Claim 18 recites “use of the regulatory T cells”. As written, the claim language is directed an intended use and not one of the four statutory categories for patents. Because of this, a person of ordinary skill would not be able to determine the metes and bounds of the claim with reasonable certainty.
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.
Claims 1-19 are rejected under 35 U.S.C. §103 as being unpatentable over Haque et al. [Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity, Scientific Reports, 2016], in view of Kohn et al. [WO 2019 040655 A1], in view of Maruyama et al. [The molecular mechanisms of Foxp3 gene regulation, Seminars in Immunology, 2011], in view of Iriguchi et al. [A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy, Nature Communications, January 2021], in view of Zhang et al. [US 2018 104278 A1], in view of Torrey et al. [A novel TNFR2 agonist antibody expands highly potent regulatory T cells, Science Signaling, 2020].
For claim 1 a method of producing regulatory T cells, Haque et al. teaches a method for differentiating pluripotent stem cells, including induced pluripotent stem cells, into regulatory T cells. However, Haque et al. does not teach an expression construct being introduced into a cell capable of differentiating into a regulatory T cell where the construct comprises conserved non-coding sequences 1, 2, and 3, a promoter, and a nucleic acid sequence that encodes the FOXP3 protein.
However, Kohn et al. discloses an expression construct comprising an expression cassette including the conserved non-coding sequences CNS1, CNS2, and CNS3 of the Foxp3 gene [¶ 00012], as well as a nucleic acid encoding the human Foxp3 protein that is operably linked to a constitutive promoter [¶ 0003, 0009]. Additionally, Maruyama et al. teaches that Foxp3 is the master regulator of regulatory T cell development and that CNS1, CNS2, and CNS3 function in cooperation to regulate Foxp3 expression, lineage commitment, and regulatory T cell stability [2. Foxp3 gene conserved regions]. Based on this, it would have been prima facie obvious to a person of ordinary skill in the art to modify the systems and methods of Haque et al. where a method of differentiating pluripotent stem cells into regulatory T cells with the teachings of Kohn et al. that teaches an expression construct containing the conserved non-coding sequences of CNS1, 2, and 3 along with a nucleic acid sequence that encodes a Foxp3 protein, and lastly a promoter with the further teachings of Maruyama et al. that teaches the importance of the conserved non-coding sequences 1, 2, and 3 and their role regulating Foxp3 expression, lineage commitment, and regulatory T cell stability. Therefore, there is a reasonable expectation of success that a person of ordinary skill, combining the teachings of Haque et al. with the teachings of Kohn et al. and Maruyama et al., that they would be able to develop a regulatory T cell that is derived from pluripotent stem cells, including iPSCs, where an expression vector containing conserved non-coding sequences, a promoter, and the nucleic sequence for Foxp3 protein, could be combined allowing the differentiated regulatory T cells to maintain identity and suppressive functions.
For claims 2 and 3 where the cells that can differentiate into regulatory T cells are pluripotent stem cells, Haque et al. teaches the use of both pluripotent stem cells and induced pluripotent stem cells can be used as the base cell for differentiating into regulatory T cells [Abstract].
For claim 4 where the CNS1, 2, and 3 are located upstream of the promoter, Kohn et al. teaches CNS1, CNS2, and CNS3 are upstream of the promoter [Figure 6 and Figure 7].
For claim 5 where the regulatory T cells are CD25+/Foxp3+, Haque et al. teaches that iPSCs have the ability to differentiate into CD4+CD25+FoxP3+ regulatory T cells by the approach of gene transduction of Ag-specific TCR and FoxP3, followed by stimulation with Notch signaling [Results: Generation of Ag-specific iPSC-Tregs].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Haque et al. where the authors disclosed differentiating pluripotent stem cells into regulatory T cells with the teachings of Kohn et al. that teaches the conserved non-coding sequences are located upstream of the promoter in the expression construct with the additional teachings of Haque et al. that it is possible for iPSCs to be differentiated into regulatory T cells capable of being positive for both CD25 and FoxP3. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would be able to develop regulatory T cells derived from pluripotent stem cells, to include induced pluripotent stem cells, using the teachings of Haque et al. combined with Kohn et al. and Maruyama et al. to insert an expression vector that contained conserved non-coding sequences, e.g. CNS1, 2, and 3, along with a promoter, followed by a nucleic acid sequence that encodes the Foxp3 protein where the conserved non-coding sequences are located upstream of the promoter region.
For claim 6, the analysis for claim 1 is applied here.
For claim 7 where a three-dimensional cell aggregate in step (1) contains cells capable of differentiating into regulatory T cells and stromal cells expressing a Notch ligand, Haque et al. teaches differentiating iPSC-Tregs with stromal cell lines expressing Notch ligands DL1, DL4, and I-Ab [Introduction ¶ 4].
For claim 8 and 9 where the cells are cells that can be differentiated into regulatory T cells are cells that are CD34+ cells or hemogenic endothelial cells, Iriguchi et al. teaches that both types of cells can be used in differentiating into regulatory T cells [Figure 1b. and Introduction ¶ 2]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Haque et al. that discloses methods for differentiating pluripotent stem cells into regulatory T cells with the additional teachings of Iriguchi et al. that discloses that both iPSCs positive for CD34 and/or hemogenic endothelial cells can be used to as a starting base cell for differentiating into regulatory T cells when co-cultured with DL-1 or DL-4 expressing stromal cells [Id.]. Therefore, there is a reasonable expectation of success that a person of ordinary skill in the art would recognize the teachings of both Haque et al. and Iriguchi et al. where the base cell for differentiating into a regulatory T cell could include pluripotent stem cells and/or iPSCs that were positive for CD34 or use hemogenic endothelial cells as a starting point for differentiating into regulatory T cells that have been modified in some way to with an expression vector for FoxP3.
For claim 10 where the Notch ligand is selected from the group consisting of DLLR, DLL1, JAG1, or JAG2, both Haque et al. and Iriguchi et al. teach the use of co-culturing the base pluripotent stem cell with stromal cells that express DLL1 or DLL4 [Results: Generation of Ag-specific iPSC-Tregs, Introduction ¶ 2, respectively].
For claim 11, the same analysis for claim 1 and claim 6 are applied here except that the base cell is an iPSC which is also taught by both Haque et al. and Iriguchi et al. [Abstract, respectively]
For claim 12 where the expression construct is organized in the same order as claim 4, please see the analysis for claim 4.
For claim 13 where regulatory T cells are obtained by the method according to claim 1, please see the analysis for claim 1.
For claim 14, Kohn et al. teaches that autologous T cells may be modified with the expression vector [¶ 0003] and that the expression vector can be included in a pharmaceutical composition [¶ 0121].
For claim 15 where the composition is used to treat abnormally enhanced immune responses that include graft vs host disease, Zhang et al., discussing methods for expansion of regulatory T cells, teaches that regulatory T cells are important in controlling various autoimmune diseases including graft vs. host disease [¶ 0003]. Based on this, there is a reasonable expectation of success that a person of ordinary skill in the art developing a regulatory T cell from a pluripotent stem cell that included an expression vector that included conserved non-coding sequences, a promoter, and a nucleic acid sequence for FoxP3, based on the teachings of Haque et al. and Kohn et al. would recognize that these differentiated regulatory T cells could be used to treat abnormally enhanced immune responses such as graft vs. host disease as taught by Zhang et al. Given this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the combination of systems and methods of Haque et al. and Kohn et al. with the additional teachings of Zhang et al. that would allow a person of ordinary skill to recognize the therapeutic potential of the differentiated regulatory T cells taught by the combination of Haque et al. and Kohn et al.
For claim 16 where a subject in need is administered the pharmaceutical composition of claim 15, Zhang et al. discloses administering to a subject a therapeutically effective amount of modified regulatory T cells [¶ 0010].
For claim 17 where the regulatory T cells of claim 13 are used in the prevention of abnormally enhanced immune responses, Zhang et al. further teaches administering the regulatory T cells for the treatment and/or prevention of allograft rejection, graft vs. host disease, or other autoimmune diseases [¶ 0011].
For claim 18 where the regulatory T cells are “used” in the production of a pharmaceutical composition, Zhang et al. discloses the use of regulatory T cells to be included in a pharmaceutical composition [¶ 0054].
For claim 19 where the culturing of regulatory T cells is in the presence of an mTOR inhibitor and a TNFR2 agonist, Torrey et al. teaches that TNFR2 agonist antibody is capable of expanding highly potent regulatory T cells [Abstract]. Additionally, Torrey et al. teaches that regulatory T cell proliferation is also accomplished by the addition of rapamycin, i.e. an mTOR [Discussion ¶ 3].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Haque et al. that discloses a method for differentiating pluripotent stem cells into regulatory T cells with the teachings of Kohn et al. that disclose an expression construct that contains CNS1, 2, and 3, along with a promoter and a nucleic sequence that encodes the FoxP3 protein with the additional teachings of Torrey et al. that discloses the use of both a TNFR2 agonist antibody and rapamycin in culture conditions for expanding regulatory T cells. Based on this, there is a reasonable expectation of success that a person of ordinary skill in the art would have recognized that including a TNFR2 agonist along with a mTOR, here rapamycin, to the culture conditions for the differentiated regulatory T cells that comprised the expression construct of Kohn et al. would lead likely lead to expansion of the differentiated regulatory T cells that contained the engineered expression construct.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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