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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 14-20 and 29-31, in the reply filed on 03/02/2026 is acknowledged. The traversal is on the ground(s) that although Andre discloses the use of TNF-alpha, a known TNFR2 agonist, Andre does not state that TNF-alpha is a TNFR2 agonist, thus Andre does not provide enough evidence to support lack of unity in the claims. This is not found persuasive because TNF-alpha has been a known TNFR2 agonist in the art since the early 1990s and its agonistic behavior on TNFR2 is an intrinsic property of TNF-alpha itself. A statement by Andre that “TNF-alpha acts as an agonist of TNFR2” is not required for TNF-alpha to act as an agonist of TNFR2, and thus Andre teaches the technical feature and supports a lack of unity.
The requirement is still deemed proper and is therefore made FINAL.
Claims 21-28 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 03/02/2026.
Status of the Claims
Claims 14-31 are currently pending.
Claims 23-24 and 27 are amended.
Claims 21-28 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 1-13 are cancelled.
New claims 29-31 have been added.
Claims 14-20 and 29-31 have been considered on the merits.
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.
Claim 29 is 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 29 recites the limitation "the total stromal cells" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 29 recites the phrase “wherein the agonist is presented by stromal cells that constitute about 1% of the total stromal cells in an artificial thymic organoid culture” in lines 1-2 which is indefinite. It is unclear how the artificial thymic organoid culture is present in the method of independent claim 14. It is unclear if Applicant means that an artificial thymic organoid culture containing 1% stromal cells is added to the culture of HSPCs so as to present the agonist in the contacting step of claim 14 or if Applicant means that the artificial thymic organoids contain the HSPCs and the stromal cells and the contacting happens within the artificial thymic organoid itself. Appropriate clarification is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 14-20 and 30 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Andre et al (US205200046767A1).
Regarding claim 14, Andre teaches an in vitro method of generating T-cell precursors from hematopoietic stem and progenitor cells (HSPC) comprising the step of contacting HSPCs with an agonist for tumor necrosis factor receptor 2 (TNFR2) so as to generate T-cell precursors from the HSPCs ([0031]-[0032]).
Regarding claim 15, Andre teaches wherein the T-cell precursors are CD5+ and CD7+ T-cell precursors ([0037, Fig. 9, and [00185]).
Regarding claim 16, Andre teaches wherein the HSPCs are derived from primary cord blood or mobilized peripheral blood HSPCs ([0031]).
Regarding claim 17, Andre teaches wherein the T-cell precursors contain a chimeric antigen receptor (see claim 32 of Andre) and derived from primary HSPCs ([0031]).
Regarding claim 18, Andre teaches wherein the agonist for TNFR2 is transmembrane TNF-alpha ([0032]-[0033]).
Regarding claim 19, Andre teaches wherein a pool of undifferentiated CD34+ HSPCs is maintained within the culture by teaching that CD34+ cells remain within the population of CD34-CD7+ T-cell precursors ([0232]-[0234]).
Regarding claim 20, Andre teaches wherein the agonist improved development potential of the T-cell precursors ([0032]/[0205]).
Regarding claim 30, Andre teaches wherein contacting the HSPCs increases the number of T-cell precursors generated per input HSPC relative to a culture lacking the agonist (Fig. 5, and [0181]).
Therefore, Andre anticipates the claims.
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.
Claims 14 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Andre et al (US205200046767A1) in view of Crooks et al (WO2017075389).
Regarding claim 29, the limitations of the independent claim 14 are taught above.
Andre does not teach that the agonist is presented by stromal cells that constitute about 1% of the total stromal cells in an artificial thymic organoid culture as required by claim 29.
However, Crooks discloses an artificial thymic organoid culture containing about 1% stromal cells ([0021]) which are engineered to express a Notch ligand so as to differentiate a population of T cells from HSPCs within the artificial thymic organoid ([0078]).
Regarding claim 29, Crooks also teaches the inclusion of a TNFR2 signaling agonist, TNF-alpha, in the medium used to differentiate the artificial thymic organoid culture (See claim 6 of Crooks).
Neither Crooks nor Andre teaches that the stromal cells are engineered to express TNF-alpha, however both Andre and Crooks teach treating the cells with a combination of a Notch ligand and TNF-alpha (See Andre [0111]; See Crooks claims 1 and 6). Crooks teaches that the Notch ligand is expressed by stromal cells in the composition (See claim 1 of Crooks). Further, Andre teaches that contacting HSPCs with TNF-alpha increases the number of T-cell precursors generated per starting HSPC relative to a culture lacking the TNF-alpha agonist (fig. 5, and [0181]). The combination of Andre in view of Crooks renders the limitation of contacting HSPCs in an artificial thymic organoid culture with TNF-alpha expressed by stromal cells within the organoid obvious.
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating T-cell precursors from HSPCs taught by Andre with the engineered stromal cells within an artificial thymic organoid taught by Crooks to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because both Andre and Crooks teach treating the cells with a combination of a Notch ligand and TNF-alpha (See Andre [0111]; See Crooks claims 1 and 6) and Andre teaches that contacting HSPCs with TNF-alpha increases the number of T-cell precursors generated per starting HSPC relative to a culture lacking the TNF-alpha agonist (fig. 5, and [0181]). One of ordinary skill in the art would have a reasonable expectation of success when combining Andre with Crooks because Andre teaches the necessary information to generate T-cell precursors using a combination of Notch ligand and TNF-alpha and Crooks teaches the necessary information to generate artificial thymic organoids containing engineered stromal cells expression a Notch ligand.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 14 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Andre et al (US205200046767A1) in view of Inoue et al (J. of Immunology, April 2021, “Characterization of a TNFR2-Selective Agonistic TNF-a Mutant and Its Derivatives as an Optimal Regulatory T Cell Expander”).
Regarding claim 31, the limitations of the independent claim 14 are taught above.
Andre does not teach that the agonist is a TNFR2-selective TNF mutein as required by claim 31.
However, Andre does teach that the agonist is TNF-alpha ([0032]-[0033] of Andre). Additionally, Inoue discloses the relationship between regulatory T cells (Tregs), TNF-alpha, and TNFR2 selective TNF muteins. Inoue discloses that “TNF-a transmits intracellular signaling via two receptor subtypes, TNFR1 and TNFR2. TNFR1 is ubiquitously expressed, but TNFR2 is restricted to specific cell types such as endothelial cells, nerve cells, and immune cells (23 25). Recent studies reported that TNFR2 was highly expressed on mouse and human Tregs (12, 13)… Several other studies reported that oligomeric TNFR2-selective TNF muteins (27), S95C/G148C (TNF07) double-mutated TNF (28) or anti-TNFR2 Ab (22) increased Tregs via TNFR2” (pg. 1741, col. 1, para 1).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating T-cell precursors from HSPCs taught by Andre with the TNFR2-selective TNF muteins taught by Inoue to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Andre teaches the inclusion of TNF-alpha in the method and Inoue discloses that TNF muteins are mutated forms of TNF-alpha which only bind the TNFR2 receptor and cause increased regulatory T cell generation via the TNFR2 pathway. One of ordinary skill in the art would have a reasonable expectation of success when combining Andre with Inoue because Andre teaches the necessary information to generate T-cell precursors using TNF-alpha and Inoue teaches the use of TNFR2-selective TNF muteins in the formation of T cell subsets.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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