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 1-11 and 13-21 are currently pending.
Claim 1 is currently amended.
Claims 18-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim 12 remains cancelled.
Claims 1-11, 13-17, and 21 have been considered on the merits.
Withdrawn Rejection/Objections
The 112(b) rejection made onto claims 1-11, 13-17, and 21 is withdrawn in light of the amendments submitted on 11/12/2025.
New and Maintained Rejections Necessitated by Amendment
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.
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 1-11, 13-17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al (Blood, 2014), as evidenced by Abcam (human CD marker chart), Baaten et al (Commun Integr Biol., 2010), and Ren et al (Cell Death and Disease, 2017), in view of Cerwenka et al (Journal of Immunol., 1994) and in view of Jensen et al (US20170015746A1).
With regards to claim 1, Xu teaches a method of generating CD4 and CD8 T cells by isolating T cells from a biological sample (pg. 3751, column 1, para 1). The T cells which have a CD45RAint and CD45ROint phenotype are separated from the biological sample as required by claims 1 and 8-9 (pg. 3752, column 1, para 1, intermediate expression shown in Fig. 3E). The cells are cultured with IL-7 and IL-15 as required by claim 1 (pg. 3751, col. 1, para 2). The concentration of IL-7 is taught to be 10 ng/mL and the concentration of IL-15 is taught to be 5 ng/mL (pg. 3751, col. 1 , para 2). The isolated cells are then genetically modified to express an antigen specific receptor as required by claim 1 (pg. 3751, column 1, para 1). The biological sample is taught to be isolated peripheral blood mononuclear cells (PBMCs) containing T cells from a human having cancer as required by claims 2 and 17 (pg. 3751, column 1, paras 1-2). The T cells are taught to be either CD4+ or CD8+ populations as required by claims 4 and 5 (pg. 3751, column 2, para 5). The T cells express CD95, CD127 (i.e., IL7R), and CD137 (i.e., 4-1BB) as required by claims 5-9 (pg. 3753, column 1, para 2, and pg. 3752, column 2, para 1). Xu teaches that the method further comprises activating the isolated CD4 and CD8 T cells with anti-CD3 and anti-CD28 antibodies as required by claim 10 (pg. 3751, column 1, para 1). Further, Xu teaches contacting the cells with IL7 and IL15 resulting in CD45RAint and CD45ROint phenotype as required by claim 11 (see Fig. 3E and pg. 3753, column 1, para 2). Xu also teaches that the antigen specific receptor is introduced to the T cells by transduction and is a cancer related CAR including a CD19 extracellular binding domain as required by claims 13-16 (pg. 3751, column 1, paras 1-2).
Claim 1 contains a wherein clause that recites the intended result of the method rather than requiring an additional step be performed. MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that a such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Claim 1 states that the result of culturing the cells with IL-7 and IL-15 is that the “IL7 and IL15 maintain the CD45RAintCD45ROint phenotype of the CD4 or CD8 T cells”, which is an intended result of the culture with both IL-7 and IL-15. Therefore since these claims only recite the results of the steps, then art reading on the steps of claim 1 will also read on these results since performing the same steps will inherently lead to the same results in the absence of evidence to the contrary including unexpected results.
Xu meets the limitation of claim 9 where in the T cells express CD44 as evidenced by Baaten. Baaten teaches that CD44 is upregulated after naïve T cells become active and CD44 remains elevated on the surface of T cells as required by claim 9 (abstract).
Xu meets the limitation of claim 9 where in the T cells express SLC38A1 as evidenced by Ren et al. Ren teaches that “current evidence shows that T cells express SNAT1 (SLC38A1)” as required by claim 9 (Fig.2 and description).
Xu meets the limitations of claim 9 where the T cells express IL2RG, CD5, and CD6 as evidenced by Abcam. Abcam teaches that T cells express CD5 (see CD5, expression column). Abcam teaches that at maturity T cells express CD6 (see CD6, expression column). Abcam teaches that IL2RG is expressed by T cells (see CD132, expression and alternative name columns).
Although Xu teaches that the concentration of IL-7 is 10 ng/mL and the concentration of IL-15 is 5 ng/mL (pg. 3751, col. 1 , para 2), Xu does not teach that the combined concentration of IL7 and IL15 is less than 10 ng/ml as required by claim 1.
However, Jensen teaches methods of enriching T cells employing cytokines (abstract/ [0006]). Jensen teaches contacting T cells with at least one cytokine, and more specifically the cytokines can be IL7 and IL15 provided at concentrations of between 0.1 ng/ml and 1 ng/ml and/or up to 10 ng/ml which constitutes the combined concentration of less than 10 ng/ml as required by claim 1. Jensen specifically tested IL7 at a concentration of 5 ng/ml combined with IL15 at a concentration of 0.5 ng/ml which would be a combined 5.5 ng/ml as required by claim 1 ([0288] and Fig. 23). Additionally, Jensen teaches that growing “CD4-enriched cultures in IL-7/IL-15 yielded robust expansion of both cultures and strong expression of memory phenotype” ([0300]). Finally, Jensen states “CD4+ T-cells and CD8+ T-cells grew optimally with different cytokine combinations such that CD4+ T-cells performed best in these studies with IL7 and IL15” ([0301]).
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 CD4 or CD8 T cells taught by Xu with the concentrations of IL7 and IL15 taught by Jensen to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Jensen states “CD4+ T-cells and CD8+ T-cells grew optimally with different cytokine combinations such that CD4+ T-cells performed best in these studies with IL7 and IL15” ([0301]). One of ordinary skill in the art would have a reasonable expectation of success when combining Xu with Jensen because both Jensen and Xu teach the culture of T cells employing low concentration of IL7 and IL15, and the combination would constitute routine optimization of the culture media.
Xu does not teach culturing the CD45RAint and CD45ROint phenotype T cells in TGFß or IL1ß as required by claim 1.
However, Cerwenka teaches that TGFß has pleiotropic regulator effect on many types of immune cells regarding their activation, proliferation, and differentiation (pg. 1, column 1, para 1). Further, Cerwenka teaches that the CD45RA and CD45RO expression patterns are maintained in the presence of TGFß in human T cells (pg. 4371, column 2, last para).
Claim 21 contains a wherein clause that recites the intended result of the method rather than requiring an additional step be performed. MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that a such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Claim 21 states that the result of culturing the cells with TGFß and/or IL-1ß is that the “TGFß and/or IL-1ß maintains the level of one or more glycolytic enzymes”, which is an intended result of the culture with TGFß and/or IL-1ß. Therefore since these claims only recite the results of the steps, then art reading on claim 1 will also read on these results since performing the same steps will inherently lead to the same results in the absence of evidence to the contrary including unexpected results.
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 CD4 or CD8 T cells taught by Xu with the TGFß taught by Cerwenka to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Cerwenka teaches that TGFß has pleiotropic regulator effect on many types of immune cells regarding their activation, proliferation, and differentiation (pg. 1, column 1, para 1). One of ordinary skill in the art would have a reasonable expectation of success when combining Xu with Cerwenka because Cerwenka teaches that TGFß does not increase or decrease the expression pattern of CD45RA and CD45RO in human T cells, i.e. the cells taught by Xu (pg. 4371, column 2, last para).
Therefore, Xu in view of Jensen and Cerwenka render the claims obvious.
Response to Arguments
Applicant’s arguments, see Remarks, pg. 12, last para spanning pg. 13, filed 11/12/2025, with respect to the rejection(s) of claim(s) 1-11, 13-17, and 21 under 35 U.S.C. 103 have been fully considered and are persuasive in part. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Xu, Cerwenka, and Jensen.
Applicant's arguments filed 04/28/2025 have been fully considered but they are not persuasive in part.
Applicant argues (pg. 9-10) against the reference Xu and the reference Cerwenka individually, stating that neither reference teaches the combination of IL7, IL15, and TFGβ or IL1β as well as the specific concentration of IL7/IL15 of less than about 10 ng/ml. This is not found persuasive. in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, the arguments are not found persuasive.
Applicant argues (Remarks, pg. 11, para 2, spanning pg. 12) that Xu does not teach that the CD45RO and CD45RA expression is intermediate and that the cells of the instant invention shown in Fig. 7 support that the cells of Xu are not showing intermediate expression. This is not found persuasive. While Xu does not explicitly state that the expression is "intermediate", this is explicitly taught in the Fig. 3E, which has been cited in the rejection previously and currently presented above, and which is reproduced below. Figure 3E shows cytometry data of the cells and their relative CD45RA and CD45RO expression. When interpreting flow data, the typical understanding is that cells which are in the bottom left most quadrant of each individual chart would have low or no expression of both markers of the x-axis and y-axis. The cells which appear in the bottom right had quadrant would have some or high expression of the marker of the x-axis and low to no expression of the marker of the y-axis. The cells which appear in the top left quadrant would have some or high expression of the marker of the y-axis and low to no expression of the marker of the x-axis. The cells which appear in the top right hard quadrant would have some or high expression of both the markers of the x-axis and y-axis. Applying this information to Fig. 3E of Xu below, this would mean that the bottom left graph shows CD4 positive cells which have been treated with IL-7 and IL-15, which have intermediate expression of both CD45RO and CD45RA expression. This is because the main groupings of cells are found in the relative center of the graph with populations in both top quadrants and the bottom right quadrant. Essentially no cells (1% of cells) are found in the low to no expression quadrant and the cells which are in the top right quadrant are all in the lowest left corner of the quadrant, pointing to intermediate expression in the cell population. This same pattern is seen in the bottom left graph of Fig. 3E, for CD8 positive T cells treated with IL-7 and IL-15. Turning toward Fig. 7 of the instant invention, also reproduced below, the population of cells seen in the top 3rd graph from the left are mostly contained in the bottom left quadrant which signifies that the cell population has little to no expression of either CD45RO and CD45RA. There appears to be additional populations of cells which are either positive for CD45RA and explicitly negative for CD45RO, or positive for CD45RO and explicitly negative for CD45RA. The specification does not appear to explicitly define the term “intermediate expression”. However, the specification states in [0152] that “This subset is primarily characterized by intermediate co-expression of CD45RA and CD45RO (RAintROint). This RAintROint population homogenously expresses CD95 (Fas; a marker that distinguishes Tscm from naive cells), CD127 (IL7R; essential for maintaining homeostatic proliferation) and CD27 (marker of central memory T cells) (Fig. 2)”. Xu also teaches that their population of cells is characterized by the same expression markers (in addition to intermediate co-expression of CD45RA and CD45RO. Xu teaches that the population does express CD95 (pg. 3756, col 2. Para 1), CD27 (Fig. 2E), and CD127 (Fig. 2E, some expression). This additional expression data supports that the cells of Xu are indistinguishable from the cells of the instant invention. Therefore, the expression profile shown in Fig. 3E of Xu constitutes intermediate expression of CD45RA and CD45RO and the argument is not found persuasive.
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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.
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