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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/24/2026 has been entered.
Status of the Claims
Claims 1-5, 7-11 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Claims 18-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 6 and 12 are cancelled.
Claims 1-5, 7-11, 13-17, and 21 have been considered on the merits.
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
Claims 1-5, 7-11, 13-17, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a step/limitation of “wherein the separated CD4 or CD8 T cells intermediately express 4-1BB”. The specification describes “In other embodiments, the CD4/CD8 T cells can intermediately express 4-1BB” ([0010]) and “In other embodiments, the CD4/CD8 T cells having a CD45RAintCD45ROint phenotype can further intermediately express 4-1BB” ([0074]), however the specification does not appear to test or demonstrate that these cells intermediate express 4-1BB.
Claims 2-5, 7-11, 13-17, and 21 are included in this rejection based on dependency from claim 1.
This is a new matter rejection.
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 1-5, 7-11, 13-17, and 21 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.
The term “CD45RAintCD45ROint” and “intermediately express 4-1BB” in claim 1 is a relative term which renders the claim indefinite. The term “intermediate” or “intermediate expression” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define the term “intermediate expression”. Intermediate expression is a term used in the art to describe the fluorescence intensity of cells in flow cytometry. Cells can be negative of a specific CD marker or positive for a specific CD marker. The term “intermediate” implies a comparison of the relative fluorescence intensity to a strongly positive fluorescence signal (i.e., very bright fluorescence intensity). However, the term is a relative term because cell populations which demonstrate intermediate expression and cell populations which demonstrate a very bright or positive expression are both described as having positive expression for the specific CD marker in the art when comparing to a cell population which does not express the specific CD marker at all. Thus, the concept of “intermediate expression” is unclear and indefinite without an explicit definition. Further, the claim terms are being interpreted to be met by any recitation of positive expression in the art with regards to the specific CD markers claimed. Appropriate clarification is required.
Claim Interpretation
The claims generally require that the claimed cells “intermediately” express various factors/CD markers. The claims have been rejected above under 35 U.S.C. 112(b) as containing the relative term “intermediate expression”. The specification does not define the term “intermediate expression”. Intermediate expression is a term used in the art to describe the fluorescence intensity of cells in flow cytometry. Often cell populations which express a factor or CD marker however appear to have a slightly dimmer fluorescence intensity than an extremely “bright” population can be described as having “intermediate expression”. Thus, the concept of intermediate expression is a form of positive expression. Cells in the art which are described as having a positive expression of the claimed CD markers are interpreted to meet the requirement of “intermediate expression”.
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 1-5, 7-11, 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 T cells also intermediately express CD137, also known as 4-1BB as required by claim 1 (pg. 3753, col. 1, para 2; and Supplemental Fig. 3). 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 and 7-9 (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 and less than 2 ng/ml as required by claim 11 ([0006]). 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]). Further, Jensen teaches results demonstrating a population of CD4 T cells and a separate population of CD8 T cells which are intermediately positive for both CD127, also known as 4-1BB, and intermediately positive for CD45Ra/CD45RO phenotype (see Fig. 38A-B).
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, further both Xu and Jensen demonstrate CD4 and CD8 T cell populations which express CD127 (4-1BB), CD45RO, and CD45RA.
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 filed 06/24/2026 have been fully considered but they are not persuasive.
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 (pg. 10, last para spanning pg. 11) that Xu fails to teach the step of culturing isolated CD4 T cells in the presence of IL-7 and IL-15 at a concentration of less than 10 ng/ml and that because of this Xu could not teach the CD45RA and CD45RO intermediate expression.
This argument is not found persuasive. Applicant is arguing against the reference Xu individually although Jensen is now relied upon to teach the combined concentration. 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).
In further response to Applicant’s argument, the term “intermediate” is not defined in the specification and has been rejected above as a term of degree under 35 U.S.C. 112(b). The claim interpretation section present above outlines that any positive expression of the claimed CD markers is interpreted to meet the limitation of “intermediate expression” because intermediate expression is a relative term describing positive expression.
Finally, Both Xu and Jensen teach the treatment CD4 or CD8 cells with IL-7 and IL15. Xu teaches a combined concentration of 15 ng/ml which falls just outside the claimed range of under 10 ng/ml. However, 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 ([0006]). 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). Both Xu and Jensen teach a very close embodiment of the claimed method, and both Xu and Jensen demonstrate that their CD4 and CD8 T cell populations express CD45RA, CD45RO, and 4-1BB/CD137. Xu teaches T cells which have a CD45RAint and CD45ROint phenotype (pg. 3752, column 1, para 1, intermediate expression shown in Fig. 3E) and CD137, also known as 4-1BB (pg. 3753, col. 1, para 2; and Supplemental Fig. 3). Further, Jensen teaches results demonstrating a population of CD4 T cells and a separate population of CD8 T cells which are intermediately positive for both CD127, also known as 4-1BB, and intermediately positive for CD45Ra/CD45RO phenotype (see Fig. 38A-B).
Thus, the combination of Xu and Jensen teach the claimed IL-7 and IL-15 cytokine concentrations and both separately teach the resultant cells have the same expression profiles as claimed. Therefore, the argument is not found persuasive.
Applicant argues (pg. 11, last para spanning pg. 12) that Xu does not teach IL-7 and IL-15 concentrations of about 2 ng/ml or less.
This argument is not found persuasive because Jensen is relied upon to teach the specific concentrations of IL-7 and IL-15 and not Xu. ]). 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 and less than 2 ng/ml as required by claim 11. Therefore, the argument is not found persuasive.
Applicant argues (pg. 12, last para spanning pg. 13) that one of ordinary skill would not be motivated to culture the CD45RA and CD45RO phenotype T cells in TGFB or IL1B.
This argument is not found persuasive. 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). In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues (pg. 13, para 2) that claim 1 has been amended to include that the cell populations express an intermediate level of 4-1BB (CD137) and that Xu only teaches positive expression and not “intermediate expression” of 4-1BB.
This argument is not found persuasive. The term “intermediate” is not defined in the specification and has been rejected above as a term of degree under 35 U.S.C. 112(b). The claim interpretation section present above outlines that any positive expression of the claimed CD markers is interpreted to meet the limitation of “intermediate expression” because intermediate expression is a relative term describing positive expression. Applicant admits that Xu demonstrates positive expression of 4-1BB/CD137. Additionally, Jensen also demonstrates positive expression of 4-1BB/CD137. Both Xu and Jensen demonstrate that their CD4 and CD8 T cell populations express CD45RA, CD45RO, and 4-1BB/CD137. Xu teaches T cells which have a CD45RAint and CD45ROint phenotype (pg. 3752, column 1, para 1, intermediate expression shown in Fig. 3E) and CD137, also known as 4-1BB (pg. 3753, col. 1, para 2; and Supplemental Fig. 3). Further, Jensen teaches results demonstrating a population of CD4 T cells and a separate population of CD8 T cells which are intermediately positive for both CD127, also known as 4-1BB, and intermediately positive for CD45Ra/CD45RO phenotype (see Fig. 38A-B). Therefore, the argument is not found persuasive.
Applicant argues (pg. 13, last para spanning pg. 14) that Jensen only teaches one experimental condition totaling 5.5 ng/ml of IL-7 and IL-15 combined and that the office action failed to provide evidence how the concentration of Jensen would produce the claimed cell populations. Further, Applicant argues that the cells of Jensen are not CD45RA. CD45RO, and 4-1BB/CD137 intermediate.
This is not found persuasive. 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 ([0006]). 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). Both Xu and Jensen teach a very close embodiment of the claimed method, and both Xu and Jensen demonstrate that their CD4 and CD8 T cell populations express CD45RA, CD45RO, and 4-1BB/CD137. Xu teaches T cells which have a CD45RAint and CD45ROint phenotype (pg. 3752, column 1, para 1, intermediate expression shown in Fig. 3E) and CD137, also known as 4-1BB (pg. 3753, col. 1, para 2; and Supplemental Fig. 3). Further, Jensen teaches results demonstrating a population of CD4 T cells and a separate population of CD8 T cells which are intermediately positive for both CD127, also known as 4-1BB, and intermediately positive for CD45Ra/CD45RO phenotype (see Fig. 38A-B). Therefore, the arguments are not found persuasive.
Applicant argues (pg. 15 para 2) that Abcam, Baaten, and Ren fail to remedy the alleged deficiencies of the Xu and Jensen references.
This is not found persuasive for the reasons listed at points 15-21 above.
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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