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 .
Status of the Claims
Claims 1-7 and 9-13 are pending.
Claim 1 is newly amended.
Claims 1-7 and 9-13 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 1-7 and 9-13 under 35 U.S.C. 103 as being unpatentable over Karyampudi et al. (US2022/0133795A1) in view of Ni et al. (US2021/0062150A1) and Gibco (Dynabeads Human T-Activator CD3/CD28, 2011) is withdrawn to address the amendment of the claims.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.
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 1-7 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Karyampudi et al. (US2022/0133795A1, previously cited) in view of Ni et al. (US2021/0062150A1, previously cited), Gibco (Dynabeads Human T-Activator CD3/CD28, 2011, previously cited), and Jindasa et al. (Journal of Visualized Experiments, 2011).
In regards to claim 1, Karyampudi teaches methods for expansion and enrichment of peripheral blood lymphocytes (PBLs) including stem memory T cells (TSCMs) specifically (claims 1 and 5, paragraphs [0113, 0274]). Karyampudi teaches that these cells can be transduced to express a CAR (paragraphs [0349-0351]).
In regards to step (1), Karyampudi teaches that the method comprises providing peripheral blood mononuclear cells (PBMCs) (claims 1 and 5).
In regards to step (2), Karyampudi teaches that the method comprises stimulating PBMCs by mixing them with anti-CD3/anti-CD28 antibodies immobilized on magnetic beads which form complexes (claims 1, 5, and 7; paragraph [0006]). Karyampudi teaches that the PBLs can be human (paragraph [0289]).
In regards to steps (3) and (4), Karyampudi teaches that the T cells can be modified to express a CAR by lentiviral expression (paragraphs [0349-0351]).
In the regards to the timing of stimulation, Karyampudi teaches that the PBMCs can be stimulated for about 3 days (paragraph [0132]) which overlaps with the claimed total range of 16 hours to 20 hours (step (3)) and then 40 hours to 48 hours (step (4)).
In regards to the specific timing of transducing a CAR, while Karyampudi is silent as to this timing, the method still results in the same CAR T-cell. Additionally, Applicant should note that according to MPEP 2144(IV)(C), the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); see also In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Indeed, as taught by Ni, steps of transducing T cells to express CARs when those T cells are stimulated with anti-CD3/CD28 can occur at any time before, during or after stimulation (paragraph [0007]). And therefore, a person of ordinary skill in the art could have begun transducing T cells during stimulation with predicable results and a reasonable expectation of success.
Furthermore, during stimulation, Karyampudi teaches that cells may be contacted with IL-2 in a flask (claims 1 and 5; paragraphs [0006, 0140]) at a concentration of about 200 IU/mL (paragraph [0133]) which overlaps with the claimed amount.
In regards to the volume of the medium to a culture area, it is noted that the claim does not require any specific volume or culture area but only states that any volume to culture area between 0.12 to 0.3 ml/cm2 is sufficient. While it is unclear what the ratio of the volume of the media to the culture area of the flask is, a person of ordinary skill in the art could have arrived at a concentration of 0.12 to 0.3 ml/cm2 by routine optimization, and the disclose does not point to a criticality in this ratio.
According to MPEP 2144.05(II)(A), differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
In the instant case, because as taught by Jinadasa, it was known in the art that T cells could be cultured in volumes of 10 mL in T-75 flasks (which have a 75 cm2 surface area) (Protocol, paragraph 3, p1), which results in a surface area of 0.13 ml/ ml/cm2 which overlaps with the claimed range, a person of ordinary skill in the art could have arrived at the claimed range by routine optimization with predicable results and a reasonable expectation of success.
In regards to step (5), Karyampudi teaches that the beads are magnetically removed, (claim 8; Fig. 1), which suggests a dissociation of the complexes of T cells and beads. Additionally, a person of ordinary skill in the art would have been motivated to dissociate complexes in order to maximize T cell yield when removing beads. Furthermore, because Gibco teaches that cells can be dissociated from beads prior to bead removal (General Guidelines, p1), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (6), Karyampudi teaches that the T cells can be further concentrated and enriched for at least 4 days (Fig. 1; paragraph [0131, 0622]), which also overlaps with the claimed range of 92-96 hours.
Additionally, Karyampudi teaches that IL-2 at a concentration of 200 IU/mL can be added to media over multiple steps (claims 19 and 20; paragraphs [0114-0116]).
Finally, Karyampudi teaches that the amount of TSCMs (paragraph [0274]) and be at least 55% of the population, while Ni also teaches that TSCMs can be more than 55% of the population (paragraph [0083]).
In regards to claim 2, Karyampudi teaches that the PBMCs are obtained from whole blood (claims 1 and 5; paragraph [0003]).
In regards to claim 3, Karyampudi teaches that the ratio of beads to T cells is 3:1 (claim 5; paragraph [0113]), which overlaps with the claimed range of 2 to 4-fold.
In regards to claim 4, Karyampudi teaches that cells are incubated at 37°C (claim 21; paragraph [0233]). In regards to the timings, as above, Karyampudi teaches that the PBMCs can be stimulated for about 3 days (paragraph [0132]), which includes the timing of 16-20 hours.
In regards to claim 5, Karyampudi teaches that cells are incubated at 37°C (claim 21; paragraph [0233]). Additionally, Ni teaches that T cells are transduced at about 37°C for about 12 to 20 hours (paragraphs [0095-0097]), which overlaps with the claimed temperate and timing. It would have been predictably obvious to transduce T cells at this temperature and timing because Ni indicates that this is suitable for transducing CARs in T cells [0095-0097]).
In regards to claim 6, Karyampudi teaches that the CAR can be genetically engineered (transduced) to express an anti-CD19 CAR (thus, a gene) (paragraph [0349]).
In regards to claim 7, as above, Karyampudi teaches that cells are incubated at 37°C (claim 21; paragraph [0233]). Karyampudi also that the T cells can be further concentrated and enriched for at least 4 days (Fig. 1; paragraph [0131, 0622]), which also overlaps with the claimed range of 92-96 hours. Additionally, Ni teaches that transduced T cells can be cultured at 37°C (paragraph [0101]).
In regards to claims 9-13, Karyampudi teaches that there can be a 10-fold increase in the amount of TSCMs (paragraph [0274]), while Ni also teaches that TSCMs can expand 10-fold (paragraph [0083]).
Therefore, the combined teaching of Karyampudi, Ni, Gibco, and Jindasa renders the invention unpatentable as claimed.
Response to Arguments
Applicant argues that the present invention can produce huma CAR-T cells exhibiting the greatest expansion rate and enriched with Tscms rapidly (Remarks, p2).
Relatedly, Applicant argues that Ni (referred to as D2) performs T cell activation for at least 3 days and only achieves Tscms at percentages of 45% (citing Fig. 10A) (Remarks, p3).
Applicant’s arguments filed 08/18/2026 have been fully considered but are not found persuasive.
As discussed above, Karyampudi teaches be at least 55% of the population, while Ni also teaches that TSCMs can be more than 55% of the population (paragraph [0083]). Additionally, as above, Karyampudi teaches that there can be a 10-fold increase in the amount of TSCMs (paragraph [0274]), while Ni also teaches that TSCMs can expand 10-fold (paragraph [0083]).
Thus, the claimed results are taught by the prior art.
Applicant argus that short-term activation right after a short-term lentiviral transduction is advantageous because the CAR gene can be transferred before excessive differentiation (Remarks, p3).
Applicant argues that Karyampudi (referred to as D1) does not teach that the time of T ell activation should be controlled between 16 and 20 hours or that lentiviral transduction should be performed right after short-term T cell activation (Remarks, p3).
Applicant’s arguments filed 08/18/2026 have been fully considered but are not found persuasive.
In the regards to the timing of stimulation, as above, Karyampudi teaches that the PBMCs can be stimulated for about 3 days by lentiviral expression (paragraph [0132]) which overlaps with the claimed total range of 16 hours to 20 hours (step (3)) and then 40 hours to 48 hours (step (4)).
In regards to the specific timing of transducing a CAR, while Karyampudi is silent as to this timing, the method still results in the same CAR T-cell. Additionally, Applicant should note that according to MPEP 2144(IV)(C), the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); see also In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
As above, as taught by Ni, steps of transducing T cells to express CARs when those T cells are stimulated with anti-CD3/CD28 can occur at any time before, during or after stimulation (paragraph [0007]). And therefore, a person of ordinary skill in the art could have begun transducing T cells during stimulation with predicable results and a reasonable expectation of success.
Indeed, because the method of Karyampudi achieves the same results (i.e., enrichment of Tscms higher than 55%), the timings do not appear to be critical.
Applicant argues that none of Karyampudi or Ni teaches the feature of claim 1 as amended, and that Gibco (referred to as D3) does not cure these deficiencies (remarks, p4).
Applicant’s arguments filed 08/18/2026 have been fully considered but are not found persuasive because Karyampudi and Ni are not deficient for the reasons discussed above.
Conclusion
No claims are allowed.
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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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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