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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 23 Oct. 2025 has been entered.
Claims 30-57 are currently pending and are considered here.
The claims of an application for which an RCE has been filed may be finally rejected in the action immediately subsequent to the filing of the RCE where all the claims in the application after entry of the response are identical to the claims in the application prior to the entry of the response, and would have been properly finally rejected on the grounds and art of record in the next office action if they had been entered in the earlier application (MPEP 706.07(b)). The instant claims are identical to those examined in the Final Rejection of 24 June 2025 and are being rejected under the same prior art/grounds herein. The current action is thus made FINAL.
Response to Arguments
Applicant's arguments filed 23 Oct. 2025 have been fully considered but they are not persuasive.
Applicant argues that “Fraietta does not teach pre-treatment of refractory patients as claimed with additional ibrutinib as alleged by the examiner.” This is not persuasive because 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). Turtle teaches a method of treating CLL in patients who have previously received treatment with ibrutinib and are refractory to such treatment by administering autologous CAR T-cells to the patients. Turtle teaches that complete responses to ibrutinib in CLL are rare and associated with short survival, and that treatment with the CAR T-cells showed high effectiveness in patients who had previously failed ibrutinib. Fraietta teaches that CLL is associated with defects in T-cell function which reduce the proliferative capacity of T-cells derived from CLL patients, and that pretreatment of CLL patients with ibrutinib prior to T-cell isolation repairs such defects leading to increased proliferative ability and engraftment of the CAR T-cells. Thus, one of ordinary skill would have sought to treat a patient previously treated with and refractory to ibrutinib with CAR T-cells as taught by Turtle, wherein such patient is pre-treated with additional round(s) of ibrutinib in order to enhance the proliferative ability and engraftment of CAR T-cells derived from the patient, as taught by Fraietta.
Applicant further argues that the pretreatment effect on T-cells taught by Fraietta has a BTK-dependent mechanism, and that the refractory patient population in the instant claims would have resistance-conferring BTK mutations such that one of ordinary skill would not expect pretreatment according to Fraietta to be effective. In support, Applicant cites Woyach (cited in IDS of 23 Oct. 2025) as evidence that ibrutinib refractory patients have one or more mutations (a C481S mutation in BTK and/or mutations in downstream BTK target PLCγ2) that inhibit ibrutinib’s inhibitory effect on BTK and that would also interfere with the ibrutinib-mediated effect on T-cells taught by Fraietta, which depend on BTK inhibition. This is not persuasive because Woyach relates to a different patient population than that recited in the instant claims. The claims are directed to a patient population that is “refractory to a first course of treatment with ibrutinib” and is then re-treated with a second course of ibrutinib. The term “refractory” means non-responsive to treatment (see e.g., definition at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/refractory). In contrast, the patient population in Woyach comprises patients who were responsive to treatment with ibrutinib but then acquired resistance during the course of treatment (Woyach, p. 2287, right col., 1st ¶; p. 2288-2289, under Mutations in BTK and PLCγ2 Revealed By Whole-Genome Sequencing). Woyach evidences that patients at baseline prior to treatment did not exhibit the BTK/PLCγ2 mutations and developed the mutations only after resistance to ibrutinib was acquired (p. 2288-2289, under Mutations in BTK and PLCγ2 Revealed By Whole-Genome Sequencing). A more extensive study of ibrutinib-naive CLL patients also showed that the C481S mutation is non-detectable prior to ibrutinib treatment (Famà et al., Blood, The Journal of the American Society of Hematology 124.25 (2014): 3831-3833, at p. 3831, last ¶ to p. 3832, 1st full ¶). Woyach further teaches that the mutations may result from continuous drug pressure on the target enzyme (p. 2292, last ¶ to p. 2293, 1st ¶). Thus, Woyach relates to a distinct patient population relative to the instant claims - responsive patients who later acquire resistance due to BTK/PLCγ2 mutations in Woyach vs. non-responsive patients in the instant claims. Since Woyach and Fama teach that the BTK/PLCγ2 mutations are absent in the ibrutinib-naïve CLL patient population, one would not expect the ibrutinib refractory patient population of the instant claims to harbor the mutations (patients having treatment resistance due to the mutations would be expected to show initial responsiveness followed by acquired resistance as in Woyach, whereas the claimed patient population includes totally non-responsive patients). Consistent with this, Wu et al., Journal of hematology & oncology 9.1 (2016): 80, teaches that other mechanisms for ibrutinib resistance unrelated to the BTK/PLCγ2 mutations are known (p. 2, right col., 1st full ¶).
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119e and/or 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, App. No. 17812148 (filed 12 July 2022) fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In particular, the disclosure of the prior-filed application, Application No. 62504337 (filed 10 May 2017), fails to describe the instantly claimed method of expanding PBLs from a subject who has been pre-treated with an ITK inhibitor and is refractory to such treatment. The effective filing date is at least 10 July 2017.
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.
Claims 30-34, 38, 39, 41-50 and 54-57 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Turtle et al., Blood 128.22 (2016): 56 in view of each of Fraietta et al., Blood, The Journal of the American Society of Hematology 127.9 (2016): 1117-1127 (cited in IDS of 24 May 2024) and US Patent 8916381 to June.
Turtle teaches a method of treating chronic lymphocytic leukemia (CLL; a hematologic malignancy and liquid tumor) in patients who have previously received treatment with the ITK inhibitor ibrutinib and are refractory to treatment (i.e. did not respond) with ibrutinib, comprising administering autologous CAR T-cells to the patients (entire doc, including under METHODS AND RESULTS). Turtle teaches that complete responses to ibrutinib in CLL are rare and associated with short survival, and that treatment with the CAR T-cells showed high response rates and durable CRs in poor prognosis patients who have previously failed ibrutinib (under BACKGROUND and CONCLUSION). Turtle does not detail the methods used for manufacturing the CAR T-cells.
Claims 30-34, 38, 39, 41-50 and 54-57 differ from Turtle in that: the CAR T-cells are made by a method comprising obtaining PBMCs from the patient, culturing the cells in the presence of IL-2 and CD3/CD28 antibodies for 9-14 days and harvesting the cells (claims 30 and 46); the patient is re-treated with a second course of ibrutinib (claims 30 and 46); the patient is re-treated with ibrutinib for at least 3 months (claims 31, 33, 47, 49) and with at least 3 rounds (claims 32 and 48); the CD3/CD28 antibodies are on magnetic beads and the beads are at a 3:1 ratio to cells in the culture (claims 34 and 50); the culturing is at 37C and 5% CO2 (claim 41); the culturing is for 9 days (claim 42) or 11 days (claim 43); and the patient has not undergone treatment with ibrutinib for at least one month prior to being re-treated (claims 45, 54).
Fraietta teaches that CLL is associated with defects in T-cell function which reduce the proliferative capacity of T-cells derived from CLL patients, and that pretreatment of CLL patients with ibrutinib prior to T-cell isolation repairs such defects leading to increased proliferative ability and engraftment of CAR T-cells derived CLL patients pretreated with ibrutinib (p. 1118, 1st ¶ under Results to p. 1119, last full ¶; Figs. 1-2). Fraietta teaches that the positive effects on T-cells require prolonged pretreatment with ibrutinib for at least 5 months over at least 5 cycles of treatment prior to T-cell isolation (p. 1118, 1st ¶ under Results to p. 1119, last full ¶; Figs. 1-2). Fraietta further teaches that a cohort of patients pretreated with ibrutinib for at least one year had particularly robust CAR T-cell expansion and function (p. 1122, 1st ¶ under Discussion; Table 1). Fraietta also teaches that concurrent administration of ibrutinib with therapeutic CAR T-cells leads to increased T-cell expansion and engraftment in vivo along with improved survival in an animal CLL model (p. 1121-1122, under Continuous ibrutinib treatment enhances CTL019 efficacy in drug-resistant ALL and CLL mouse models).
June teaches methods for treating a cancer (such as CLL) by administering autologous CAR-T-cells to a patient (entire doc, including Abstract; claims). Turtle teaches that the CAR T-cells can be made by a general method comprising: obtaining PBMCs from the patient via apharesis; incubating the PBMCs with CD3/CD28 magnetic beads and culturing the cells for 8-12 days; and harvesting the CAR 19 T-cells (col. 4, lines 30-49; col. 30, line 25 to col. 33, line 22). June teaches that the culturing can be for in the presence of IL-2 and that the culturing time can be any time between several hours and 14 days or any hourly integer in between (which would include 9 days and 11 days, as recited in claims 11 and 12) (col. 30, line 25 to col. 33, line 22). June also teaches that the CD3-CD28 magnetic beads can be Dynabeads (col. 22, lines 25-32) and that the beads can be provided in a beads to cells ratio of 3:1 (col. 31, lines 54-60). The culturing is carried out in an environment appropriate for cell growth, including 37C and 5% CO2 (col. 33, lines 19-21).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to carry out the method of Turtle for treating a patient with CLL who is refractory to ibrutinib by administering CAR T-cells wherein the patient is further re-treated with ibrutinib (as a pretreatment prior to harvesting T-cells from the patient and/or as a concurrent treatment with the CAR T-cells) as taught by Fraietta because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to subject a patient being treated with CAR T-cells according to Turtle to a re-treatment with ibrutinib as taught by Fraietta because Fraietta teaches that prolonged pretreatment with ibrutinib enhances CAR T-cell expansion in vitro and that concurrent administration of ibrutinib with CAR T-cells leads to increased T-cell expansion and engraftment in vivo along with improved survival. Subjecting a patient being treated with CAR T-cells according to Turtle to a re-treatment with ibrutinib as taught by Fraietta would have led to predictable results with a reasonable expectation of success because Fraietta teaches ibrutinib administration as a pretreatment and/or concurrent therapy with the same type of CAR T-cell therapy for the same condition (CLL) as taught by Turtle.
It would have further been obvious to one of ordinary skill in the art at the time the invention was made to carry out the method of Turtle in view of Fraietta for treating a patient with CLL by administering CAR T-cells and/or ibrutinib wherein the CAR T-cells are made by a method taught by June because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Carrying out the method of Turtle in view of Fraietta wherein the CAR T-cells are made by the method of June would have led to predictable results with a reasonable expectation of success because June provides a general methodology for making CAR T-cells for the same general purpose of treating cancer as in the methods of Turtle and Fraietta. One of ordinary skill would have been motivated to use the method of June to make CAR T-cells for use in the treatment of Turtle in view of Fraietta because June teaches that the method can be used to make CAR T-cells for treating the same type of CLL cancer treated in Turtle and Fraietta (June, col. 34, lines 46-58; Examples 1-2).
Regarding claims 31, 33, 47 and 49, wherein the patient is re-treated with ibrutinib for at least 3 months, Fraietta teaches that the pretreatment with ibrutinib prior to T-cell harvesting must be prolonged for a period of at least 5 months and that patients pretreated for at least one year showed even better results. Thus, it would have been obvious that a patient found to be refractory to ibrutinib in an initial treatment (e.g., lasting less than one year) could be subjected to re-treatment with ibrutinib for an additional period (e.g., at least 3 months) to achieve the beneficial effects taught by Fraietta. Moreover, Fraietta further teaches that concurrent administration of ibrutinib with CAR T-cells can further enhance T-cell expansion and engraftment in vivo and improve survival, and it would have thus also been obvious to re-treat a patient found to be refractory to ibrutinib in an initial treatment with ibrutinib concurrently with CAR T-cell therapy. Fraietta teaches administering ibrutinib as part of the concurrent therapy for a period of 100 days (Fraietta, Fig. 6) and further teaches that ibrutinib therapy for CLL generally requires continuous treatment for life (p. 1126, 1st full ¶). Thus, it would have been obvious to administer ibrutinib as part of a concurrent therapy for a prolonged period of at least 3 months (e.g., for the life of the patient).
Regarding claims 32 and 48, Fraietta teaches that the ibrutinib therapy was administered in cycles (rounds) of about one month (e.g., p. 1122, under Discussion stating that ibrutinib pretreatment required at least 5 months/5 cycles). Thus, it would have been obvious that the re-treatment of ibrutinib for at least 3 months noted above could be in at least 3 cycles. Moreover, it is noted that neither the claims nor the specification defines the duration or other features of a “round” of treatment, and any portion of a larger treatment schedule can be considered a “round”.
Regarding claims 45 and 54, wherein the patient has not undergone treatment with ibrutinib for at least one month prior to re-treatment, Fraietta shows that pretreatment with ibrutinib was effective at enhancing T-cell expansion characteristics when treatment was discontinued up to 2 months prior to T-cell harvesting/isolation (Table 1, subject UPN18). Thus, it would have been obvious that the patient in the method of the cited combination could discontinue ibrutinib treatment for at least one month prior to retreatment, e.g. wherein the patient has undergone an initial prolonged treatment with ibrutinib and is found to be refractory to treatment and then subsequently undergoes concurrent CAR T-cell and ibrutinib therapy.
Claims 35-37 and 51-53 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Turtle in view of June and Fraietta, as applied to claims 30-34, 38, 39, 41-50 and 54-57, further in view of Perera et al., American journal of hematology 92.9 (2017): 892-901 (cited in IDS of 24 May 2024).
Claims 35-37 and 51-53 differ from Turtle in view of June and Fraietta, as applied to claims 30-34, 38, 39, 41-50 and 54-57, in that: during day 4 of the culturing additional IL-2 is added and the first culture medium is changed (claims 35 and 51); the first medium is changed with a second medium (claims 36 and 52); and the first and second mediums are different (claims 37 and 53).
Perera teaches a method for making CAR T-cells from PBMCs that is substantially similar to that of June, comprising: a) obtaining a sample of PBMCs from peripheral blood; b) isolating PBLs from said sample; c) stimulating the PBLs in a first cell culture medium (AIM-V) with IL-2 (30 IU/ml) and anti-CD3/anti-CD28 beads (with a ratio of 3 beads/cell) for 2 days; d) culturing the cells in the AIM-V culture medium with 300 IU/ml IL-2 (i.e. a different medium) and anti-CD3/anti-CD28 beads for up to several weeks with exchange of fresh culture medium every two days (i.e. with a second, third, etc. culture medium to which IL-2 has been added); and e) isolating/harvesting the PBLs from the culture for further use (while Perera does not expressly teach separating the cells from the CD3/CD28 beads, it would have been obvious that the cell isolation would include such a step as the CAR T cells yielded by the method are intended for therapeutic use and/or related testing) (Perera, under 2.3 T-cell transduction; p. 895, right col., 1st full ¶).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to carry out the method of Turtle in view of June and Fraietta wherein the culturing step is carried out as taught by Perera with changes of fresh medium with additional IL-2 every two days because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Carrying out the method of Turtle in view of June and Fraietta wherein the CAR T-cells are made by the method which includes changes of fresh medium with additional IL-2 every two days as taught by Perera would have led to predictable results with a reasonable expectation of success because Perera teaches making CAR T-cells for the same general purpose of treating a hematologic malignancy as in the method of Turtle in view of June and Fraietta and one of ordinary skill would recognize that the details of the culturing step (including medium changes and the like) could be taken from any similar method for making CAR T-cells.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Turtle in view of June and Fraietta, as applied to claims 30-34, 38, 39, 41-50 and 54-57, further in view of Beavis et al., The Journal of clinical investigation 127.3 (2017): 929-941 (cited in IDS of 24 May 2024).
Claim 40 differs from the combination of Turtle in view of June and Fraietta, as applied to claims 30-34, 38, 39, 41-50 and 54-57, in that: the IL-2 is at a concentration of about 3000 IU/ml during the culturing step.
Beavis teaches a method of making human CAR T-cells substantially similar to that of June, in which the stimulating step is carried out in media containing IL-2 at a concentration of 3000 IU/ml (p. 939, under Generation of human CAR T cells).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to carry out the method of Turtle in view of June and Fraietta for making CAR T cells wherein the IL-2 concentration is about 3000 IU/ml (as in Beavis) because Beavis teaches a method of making human CAR T-cells substantially similar to that of June in which the IL-2 concentration is 3000 IU/ml. Differences in concentration generally do 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."; see MPEP 2144.05, II.). There is no evidence of such criticality here with respect to the range/value recited in claim 40.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached on 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
Prosecution Insights