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 without traverse of claims 1-5 in the reply filed on 04/22/2025 is acknowledged.
Claims 6-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/22/2025.
Claim Objections
Claims 1-5 are objected to because the numbering of some of the amino acids is not consistent with the amino acid sequences in the sequence listing. For example, there is no K78 in SEQ ID NO:2. There is a K79. K254, however, appears to be correct. SEQ ID NO:2 comprises a K145 and a K146 so it can’t be determined if K145 is the correct amino acid. Figure 1 of Miller (Current Opinion in Endocrine and Metabolic Research 2019, 5:37–44), shows the lysine for activation is K144.
Appropriate correction is required.
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 2 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 2 depends from claim 1 that requires a truncated PGC-1a. The S571 amino acid referenced in claim 2 is not present in the truncated protein. Thus, claim 1 cannot havbe a mutant S571.
Claim Rejections - 35 USC § 103
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 rejection of claim(s) 1-3 under 35 U.S.C. 103 as being unpatentable over Delgoffe (US2019/0350973) taken with Olson (2008, Genes and Development, 22:252-264) is withdrawn in light of the amendment to claim 1 that now requires mutation of K146, K184, K254 or any combination thereof.
The rejection of claim(s) 1-5 under 35 U.S.C. 103 as being unpatentable over Delgoffe (US2019/0350973) taken with Chang (2010, Journal of Biological Chemistry, 285:18039-18050) is withdrawn in light of the amendment to claim 1 that now requires mutation of K146, K184, K254 or any combination thereof.
Claim(s) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Delgoffe (US2019/0350973) taken with Miller (2019, Current Opinion in Endocrine and Metabolic Research, 5:37–44), Jeninga (2010, Oncogene, 29(33): doi:10.1038/onc.2010.206, 15 pages) and Chang (2010, Journal of Biological Chemistry, 285:18039-18050).
Claim 1 is drawn to a CAR-T cells engineered to express a chimeric antigen receptor (CAR) and a PGC-1a that is a mutant NT-PGC-1a. Claim 1 recites numerous potentially altered amino acids and claims any one or combination of those amino acids in combination with an alternatively-spliced variant NT-PGC-1a (that is mainly localized to the mitochondria-containing cytosol as opposed to the nucleus).
Delgoffe teaches that upon entry of T-cells into a tumor, PGC-1a is progressively repressed (para 27), leading to loss of mitochondrial function and metabolic insufficiency (para 8). This repression is carried out by the cell by post-translational phosphorylation, acetylation and methylation at numerous amino acids (para 81). Delgoffe teaches CAR-T cells additionally engineered to express a PGC-1a protein that is resistant to such negative regulation (para 9). Delgoffe teaches one particular option includes mutation of S572A (S571; claim 2), which is not one of the alterations recited in claim 1 (it is recited in claim 2). Delgoffe states, “An examples of a mutation that can be made to PGC-1α to increase its resistance to negative regulation includes but is not limited to S572A” (para 52). Delgoffe does not list other options to alter post-translational modification. **It is noted, SEQ ID NO:9 of Delgoffe is wild-type PGC1a. It is noted that in this sequence, amino acid 572 is not a serine. This sequence (Delgoffe SEQ ID NO:9) 100% aligns with SEQ ID NO:1 of the present application, which is also PGC-1a with a Ser at amino acid 571. For this reason, S572 of Delgoffe is understood as S571 (claim 2). Some amino acid numbers in the claims do not precisely agree with those of SEQ ID NO:2.
Numerous post-translational modification sites within the PGC-1a were known and modification (phosphorylation, methylation, acetylation) of these sites was known to negatively regulate suppression of PGC-1a. For example, Miller depicts over 25 post-translational modification sites in PGC-1a. Miller teaches that the best characterized post-translational modifications of PGC-1a are phosphorylation and acetylation with acetylation being carried out at 13 lysines, including K77 (K78),K144 (K145) and K253 (K254; see Figure 1). Likewise, Jeninga teaches how acetylation of 13 lysine residues is involved in the inhibition of PGC-1a (pages 4-5) and removal of the acetyl groups leads to its activation (Pages 2-3). Miller also teaches the importance of the LXXLL motif at amino acids 29-33 as recited in claim 3. This domain was known to be important for export from the nucleus in the truncated NT-PGC-1a and thus, mutation of the LXXLL motif leads to increased levels in the nucleus where it coactivates transcription, as supported by Chang (page 180043, left col).
Likewise, Chang discusses various pathways that operate to phosphorylate various amino acids in PGC-1a to target it for ubiquitin-mediated proteolysis. Chang teaches mutations that lead to alterations at Thr262 and Ser-265 (Thr263 and Ser266, each recited in claim 4) prevent p38 MAPK-dependent phosphorylation of PGC-1a. Chang also teaches Akt2/protein kinase B-dependent phosphorylation at Ser-570 (S571 of claim 2) and glycogen synthase kinase
3b-dependent phosphorylation at Thr-295. Chang teaches that elimination of the phosphorylation sites prevents phosphorylation and thereby prevent degradation. While these alterations were known previous to the publication of Chang, Chang adds to the repertoire of alterations that lead to cytoplasmic activity of PGC-1a by teaching expression of the alternate splice isoform (NT-PGC-1a) and several mutants at phosphorylation sites. Translocation of NT-PGC-1a to the cytoplasm is higher relative to PGC-1a. NT-PGC-1a is found more in the cytoplasm than the nucleus where it plays a positive metabolic role. Chang teaches that blocking PKA-dependent phosphorylation of NT-PGC-1a at residues 194, 241, and 256 (claimed 195, 242 and 257; claim 4) prevents its nuclear accumulation in response to PKA. Chang also teaches the S294A/S241A/T256A mutant (claimed S295/S242/T257).
Chang teaches:
Whereas PGC-1a is an unstable nuclear protein sensitive to ubiquitin-mediated targeting to the proteasome, NT-PGC-1a is relatively stable and predominantly cytoplasmic, suggesting that its ability to interact with and activate nuclear receptors and transcription factors is dependent upon regulated access to the nucleus…. The nuclear export of NT-PGC-1a is inhibited by protein kinase A-dependent phosphorylation of Ser-194, Ser-241, and Thr-256 on NT-PGC-1a, which effectively increases its nuclear concentration. (Abstract)
It would have been obvious as the time of filing to carry out the method of Delgoffe comprising altering post-translationally processed amino acids to prevent negative regulatory marks on the protein using the alterations as taught by Miller and by Chang to prevent signaling for degradation and favor translocation to the cytoplasm of PGC-1a protein. One would have been motivated to do so as Delgoffe taught that as CAR-T cells enter the tumor, PGC-1a is downregulated, leading to poor metabolic health and ultimately terminal differentiation and death of the T-cell. One would have had a reasonable expectation of success because substitution of addition of the mutations was within the realm of skill of the person of ordinary skill in the art and Olson had already shown that these additional changes led to higher PGC-1a levels.
With regard to claim 3, the specific sequences would have been obvious because Chang taught altering the specific amino acids that are altered relative to the wildtype sequence, which is set forth by Delgoffe in SEQ ID NO:9. For example, altering T295 (T294 in Chang) would lead to SEQ ID NO:3 using the wildtype sequence provided by Delgoffe. Carrying out the truncation taught by Chang using SEQ ID NO:9 of Delgoffe would lead to claimed SEQ ID NO:2 (claim 4) and adding the mutations taught by Chang to prevent phosphorylation would lead to sequences of claim 5.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632 1632