DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s reply filed on 7/28/2026 is acknowledged. Claims 1, 3-9, 11-12 and 15-26 are pending. Claims 2, 10 and 13-14 are canceled. Claims 4 and 15 are withdrawn. Claims 1, 3, 7-8, 11, 17-22 and 24-26 are amended.
3. Claims 1, 3, 5-9, 11-12 and 16-26 are under examination.
Priority
4. 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. 119(e) 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)
None of the provisional applications 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 claims 1, 3, 5-9, 11-12 and 16-26. Specifically, none of the provisional applications discloses “obtaining a sample of PBMCs from peripheral blood of a patient, wherein said patient is refractory to treatment with an ILK inhibitor and is pretreated with an ITK inhibitor”. The provisional applications do not disclose that the patient is refractory to an ILK inhibitor such as ibrutinib. Furthermore, none of the provisional applications except Application No. 62647367 disclose removing CD19+ B cells and co-culturing PBLs with the CD19+ B cells.
Accordingly, the effective filing date for the instant claims is the filing date of PCT/US2018/032109, i.e. 5/10/2018.
Specification
5. The amendment to the specification filed on 7/28/206 is acknowledged and entered.
Objections and Rejections Withdrawn
6. All objections and rejections in the office action mailed on 4/28/2026 are withdrawn in view of applicant’s amendments.
New Grounds of Objection and Rejection
Claim Objections
7. Claims 1 and 25 are objected to because of the following informalities:
Claim 1 is objected to for a grammatical error. Claim 1 recites ““(e) Exchanging the first cell culture medium with a second cell culture medium and additional IL-2 at a concentration of about 3000 IU/ml”. It appears that the term “adding” is missing before “additional IL-2”. Furthermore, the meaning of “additional IL-2” in step (e) and (g) is unclear as the claim does not mention a prior IL-2 in the second or third cell culture medium.
Claim 25 recites “wherein the PBLs are administered in an amount of from about 0.1x109 to about 15x109 PBLs”. Claim 25 is objected to because it does not specify a subject to whom the PBLs are administered. Claim 25 has been amended to depend from claim 1. Claim 1 does not mention administering to the patient the PBLs harvested from step (i).
Claim Rejections - 35 USC § 112
8. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
9. Claims 11-12 and 19-23 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 11-12 and 19-23 have been amended to depend from claim 1.
(A) Claim 11 is drawn to the method of claim 1, wherein after step (d), additional IL-2 is added and the cell culture medium is exchanged with a second cell culture medium.
Claim 1 recites after step (d) “(e) Exchanging the first cell culture medium with a second cell culture medium and additional IL-2 at a concentration of about 3000 IU/ml”. Claim 11 does not further limit claim 1 as the limitations in claim 11 are present in claim 1.
(B) Claim 12 is drawn to the method of claim 11 wherein after step (e), additional IL-2 is added and the second cell culture medium is exchanged with a third cell culture medium. Claim 1 recites after step (e) “g. Exchanging the second cell culture medium with a third cell culture medium and adding additional IL-2 at a concentration of 3000 IU/mL”. Claim 12 does not further limit claim 1 as the limitations in claim 12 are present in claim 1.
(C) Claim 19 is drawn to the method of claim 1, wherein there are from about 1x105 to about 10x105 PBLs in the gas permeable container at the beginning of step (d).
Claim 20 is drawn to the method of claim 1, wherein there are from about 2.5x105 to about 10x105 PBLs in the gas permeable container at the beginning of step (d).
Claim 21 is drawn to the method of claim 1, wherein there are at least 5x105 PBLs in the gas permeable container at the beginning of step (d).
Claim 1 recites “adding from about 5x105 to about 5x105 of the co-cultured cells from step (c) to a gas-permeable container in a first cell culture medium”. The range “about 1x105 to about 10x105 in claim 19, “about 2.5x105 to about 10x105 in claim 20 and “at least 5x10” in clam 21 do not further limit the range of about 5x105 to about 5x105 required by claim 1.
(D) Claim 22 is drawn to the method of claim 1, wherein the IL-2 is present in a concentration of between 1000 IU/ml and 6000 IU/ml in steps (d) and (e).
Claim 23 is drawn to the method of claim 22, wherein the IL-2 is present in a concentration of about 3000 IU/ml.
Claim 1 specifically recites “3000 IU/ml IL-2” in steps (d) and (e). Therefore, claims 22-23 do not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
10. 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.
11. Claims 1, 5-9, 11, 12 and 16-25 are rejected under 35 U.S.C. 103 as being unpatentable over June et al. (WO2012/079000A1, pub. date: 6/14/2012), in view of Turtle et al. (Blood, 2016, 128(22): 56), Deola et al. (J Immunology, 2008, 180:1362-1372), and Somerville et al. (J Translational Medicine, 2012, 10:69: 1-11).
Regarding claim 1, June teaches a method of treating CLL (chronic lymphocytic leukemia) using CAR-modified T cells, the method comprising:
collecting autologous PBMCs from a patient in need of treatment (instant step a),
activating and expanding T cells using the method described and/or known in the art,
genetic modifying the T cells
and then infusing the modified T cells back into the patient (page 14, page 53, lines 8-11).
June et al. teaches that the CAR comprises an scFv that binds to CD19, a human CD8 hinge, a transmembrane domain, a CD3 zeta signaling domain, and a costimulatory signaling region (page 2 and 34).
June et al. teaches prior to expansion and genetic modification of the T cells, T cells can be obtained from a number of resources including PBMC (page 39), and a specific subpopulation of T cells, such as CD3+, CD8+ can be further isolated by positive or negative selection techniques (which would remove CD19+ B cells) (instant step b) (page 40), unselected cells can be used in the activation and expansion process (page 41, line 4-5). June et al. teaches that T cells may be obtained from a patient directly following treatment because the quality of T cells obtained may be optimal or improved for their ability to expand ex vivo (page 43, last para).
June et al. teaches a method of activation and expansion of T cells, the method comprises contacting T cells with anti-CD3 antibody and anti-CD28 antibody, under conditions appropriate for stimulating proliferation of T cells (instant steps d and e) wherein the ratio of anti-CD3:CD28 antibodies bound to the beads is 1:1, for up to 10 days (page 45, lines 18), and culturing the T cells for about 2-3 days in gas permeable bags (instant step d and e) or WAVE bioreactor in culture medium (instant claim 10), in the presence of IL-2, and in another embodiment, the beads and T cells are cultured together for 2-3 days (page 47, last para). Several cycles of stimulation may also be desired, after about 10±2 days, the beads are removed, the cells are harvested and washed (step f-h) (page 47, last para and Fig. 1B, page 48, lines 5, 9).
Regarding claims 19-21, June et al. teaches that at the beginning of initial stimulation, there are at least 104 to 109 T cells, 1x106 cells (page 47, lines 5-28).
Regarding claim 24, June et al. teaches that the ratio of anti-CD3:CD28 coupled beads to T cells is 1:1 (page 46, lines 15).
Regarding claim 25, June et al. teaches that CAR-T cells are administered in an amount of 3x108, 1.25x109, or 2-5x109 (page 71 Table).
Regarding claims 1 and 5-9, June et al. does not teach the method is for treating a patent who is refractory to ibrutinib (an ITK inhibitor) and who has previously been treated with at least one round of ibrutinib prior to obtaining a sample of PBMCs. However, these deficiencies are made up for in the teachings of Turtle et al.
Regarding claims 1 and 5-9, Turtle teaches a method of treating ibrutinib-refractory chronic lymphocytic leukemia (CCL) with CD19 CAR-T cells, the method comprising:
obtaining CD4+ and CD8+ T cells from patients with CLL who had previously received ibrutinib by immunomagnetic selection. Turtle teaches that all patients had previously received ibrutinib, and 11 were ibrutinib-refractor (page 2, line 4)
Regarding claim 25, Turtle teaches administering 2x105, 2x106 or 2x107 CAR-T cells/kg to the patents, which corresponding to 1.4x107, 1.4x108 or 1.4x109 CAR-T cells for patients having an average body weight of 70 kg.
Turtle et al. teaches that CD19 CAR-T cells of defined CD4:CD8 ratio are highly active in CLL and can induce high response rates and durable CRs in poor prognosis pts who have previously failed ibrutinib
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of June et al. to treat ibrutinib-refractory CLL with CD19 CAR T cells, wherein the CD19 CAR T cells were prepared from T cells isolated from PBMCs of the patient having ibrutinib-refractory CLL in view of Turtle. One of ordinary skill in the art would have been motivated to do so because Turtle et al. teaches that CD19 CAR-T cells are highly active in CLL and can induce high response rates and durable CRs in poor prognosis pts who have previously failed ibrutinib. One of ordinary skill in the art would have had
a reasonable expectation of success because June teaches a method of treating CLL using CD19 CAR-T cells, the method comprising: collecting autologous PBMCs from a patient in need of treatment (instant step a), activating and expanding T cells using the method described and/or known in the art, genetic modifying the T cells with CD19 CAR and then infusing the modified T cells back into the patient (page 14, page 53, lines 8-11), and Turtle teaches a method of treating patents having ibrutinib-refractory CLL with CD19 CAR-T cells, the method comprising: obtaining CD4+ and CD8+ T cells from patients who have previously failed ibrutinib by immunomagnetic selection, and modifying the T cells with CD19 CAR, and further administering CD19 CAR T cells to patients having ibrutinib-refractory CCL.
Regarding claims 1, 17 and 18, June and Turtle do not teach co-culturing T cells with B cells for 2 to 5 days, wherein the ratio of B cells to PBLs is from about 0.1:1 to about 10:1, 0.1:1, 1:1 or 10:1. However, these deficiencies are made up for in the teachings of Deola et al.
Regarding claim 1, Deola et al. teaches that B cells promote cytotoxic T cell survival and proliferation/expansion (Title and page 1370, last para). Deola et al. teaches a method of stimulating and expanding T cells, the method comprising obtaining PBMC from a subject, magnetic cell sorting of CD8, CD19 and CD4 subpopulations by negative selection on autoMACS separator (page 1362, last para, 1363, para 2), co-culturing CTL and freshly isolated CD19+ B cells (page 1363, column 1) (instant step b and c). Deola et al. teaches that CTL/B cell interactions contribute to CTL proliferation (page 1369, column 1).
Regarding claims 17 and 18, Deola et al teaches co-culturing CTL and freshly isolated CD19+ B cells with a ratio of CD8+ T cells to CD19 B cells being 1:1 for 4 days (page 1363, column 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have obtained CD19+ B cells from the PBMCs of the patient and further co-cultured the T cells with CD19+ B cells at a ratio of 1:1 for 4 days in view of Deola. One of ordinary skill in the art would have been motivated to do so because Deola et al. teaches that B cells promote cytotoxic T cell survival and proliferation/expansion (Title and page 1370, last para). One of ordinary skill in the art would have had a reasonable expectation of success because June et al. teaches prior to expansion and genetic modification of the T cells, T cells can be obtained from a number of resources including PBMC (page 39), and a specific subpopulation of T cells, such as CD3+, CD8+ can be further isolated by positive or negative selection techniques (which would remove CD19+ B cells) (instant step b) (page 40), unselected cells can be used in the activation and expansion process (page 41, line 4-5), and Deola et al. teaches that B cells promote cytotoxic T cell survival and proliferation/expansion (Title and page 1370, last para).
Regarding claims 1, 11-12, 16 and 22-23, June, Turtle and Deola do not teach culturing T cells in the presence of 3000 IU/ml IL-2. June, Turtle and Deola do not specifically teach after step (d), the cell culture medium is exchanged with a second cell culture medium and additional IL-2 is added (i.e. step e), and after step (e), the second cell culture medium is exchanged with a third cell culture medium and additional IL-2 is added (i.e. step g), wherein the first and second cell culture medium is same as the first cell culture medium. However, these deficiencies are made up for in the teachings of Somerville et al.
Regarding claims 1, 11-12, 16 and 22-23, Somerville et al. discloses a method of expansion of lymphocytes for adoptive cell transfer therapy, the method comprising:
a. obtaining PBL from peripheral blood of a patient and genetically modifying patient’s PBL to express a TCR that targets NY-ESO-1, MART-1 or gp100 (page 2, column 1, para 3 and column 2);
b. stimulating the PBL (T cells) with anti-CD3 antibody and 3000 IU/ml IL-2;
c. five days later, about 2/3 of the media was removed and replaced with fresh media containing 3000 IU/ml IL-2;
d. two days later, cells were transferred from flask to an alternate growth chamber (gas permeable static bags or WAVE bioreactor);
e. an equal volume of media (AIM V supplemented with 5% human serum plus 3000 IU/ml IL-2) was added.
when using gas permeable static bags, each patient’s cells were initially fed with up to 10 liters AIM V supplemented with 5% human AB serum and 3000 IU/ml IL-2, subsequently AIM-V (without serum) supplemented with 3000 IU/ml of IL-2 was used to feed cells.
when using the WAVE bioreactor, each patient’s cells were initially perused with AIM V supplemented with 5% human AB serum, 0.02% pluronic and 3000 IU/ml IL-2, subsequently AIM-V (without serum) supplemented with 0.02% pluronic and 3000 IU/ml of IL-2 was used to feed cells (pages 2-3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used 3000 IU/ml IL-2 for T cell activation and expansion in view of Somerville. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Somerville has used IL-2 at a concentration of 3000 IU/ml to stimulate and expand T cells.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have exchanged culture medium with fresh culture medium supplemented with 3000 IU/ml IL-2 every 2 or 5 days during the entire culture period in view of Somerville. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because June teaches that several cycles of stimulation may also be desired, after about 10±2 days, the beads are removed, the cells are harvested and washed (step f-h) (page 47, last para and Fig. 1B, page 48, lines 5, 9), and Somerville teaches exchange culture medium with fresh culture medium supplemented with 3000 IU/ml IL-2 every 2 or 5 days during the entire culture period.
All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
12. Claims 1, 3, 5-9, 11, 12 and 16-25 are rejected under 35 U.S.C. 103 as being unpatentable over June et al. (WO2012/079000A1, pub. date: 6/14/2012), in view of Turtle et al. (Blood, 2016, 128(22): 56), Deola et al. (J Immunology, 2008, 180:1362-1372), and Somerville et al. (J Translational Medicine, 2012, 10:69: 1-11), further in view of Fraietta et al. (Blood, 2016, Mar 3, 127(9): 1117-1127).
The teachings of June, Turtle, Deola and Somerville have been set forth above as they apply to claims 1, 5-9, 11, 12 and 16-25.
Regarding claim 3, June, Turtle, Deola and Somerville do not teach the patient is pre-treated with an ITK inhibitor prior to obtaining a PBMC sample.
Fraietta et al. teaches that anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells, and ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019) (abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have pre-treated CCL patients with ibrutinib prior to obtaining a PBMC sample in view of Fraietta. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Fraietta et al. teaches that a T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells, and ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019) (abstract and page).
All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
13. Claim(s) 1, 5-9, 11, 12 and 16-26 are rejected under 35 U.S.C. 103 as being unpatentable over June et al. (WO2012/079000A1, pub. date: 6/14/2012), in view of Turtle et al. (Blood, 2016, 128(22): 56), Deola et al. (J Immunology, 2008, 180:1362-1372), and Somerville et al. (J Translational Medicine, 2012, 10:69: 1-11), further in view of Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
The teachings of June, Turtle, Deola and Somerville have been set forth above as they apply to claims 1, 5-9, 11, 12 and 16-25.
Regarding claim 26, June, Turtle, Deola and Somerville do not teach treating CLL with Richter Syndrome.
Xia et al. teaches treating patients with Richter Syndrome using CD19-directed CAR T cells.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the CD19 CAR T cells prepared according to the method of June, Turtle, Deola and Somerville to treat patients with Richter Syndrome. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Xia et al. teaches that patients with Richter Syndrome can be treated with CD19-directed CAR T cells.
All the claimed elements were known in the art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary kill in the art at the time of the invention.
Double Patenting
14. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
15. Claim 1, 3, 5-9, 11-12 and 16-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 127-146 of copending Application No. 19/557,089 (reference application), in view of Deola et al. (J Immunology, 2008, 180:1362-1372), and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
This is a provisional nonstatutory double patenting rejection.
The claims of copending application disclose a method for expanding peripheral blood lymphocytes (PBLs) from peripheral blood, and a method for treating a hematological malignancy, the method comprising the steps of:
a. Obtaining a sample of peripheral blood mononuclear cells (PBMCs) from peripheral blood of a patient who is pre-treated with ibrutinib or another insulin-like tyrosine kinase (ITK) inhibitor and who is refractory to treatment with ibrutinib or such other ITK inhibitor,
b. Culturing said PBMCs in a culture comprising a first culture medium with IL-2 and anti-CD3/anti-CD28 antibodies, for a period of time selected from the group consisting of: about 9 days, about 10 days, about 11 days, about 12 days, about 13 days and about 14 days, thereby effecting expansion of peripheral blood lymphocytes (PBLs) from said PBMCs; and
c. Harvesting the PBLs from the culture in step b,
d. Administering the PBLs to the patient in a therapeutically effective amount to treat said hematological malignancy.
wherein in step (b) the anti-CD3/anti-CD28 antibodies are bound to magnetic beads, and wherein the beads to cells ratio is 3:1 in the culture,
wherein in step (b), on day 4 of culturing said PBMCs additional IL-2 is added to the culture and the first culture medium is changed in the culture,
wherein the first cell culture medium contains about 3000 IU/mL of IL-2.
the first culture medium is exchanged with a second culture medium in the culture,
the peripheral blood is from a patient suffering from a hematologic malignancy,
wherein the patient is pretreated with ibrutinib and is refractory to treatment with ibrutinib, wherein the patient has not undergone treatment with ibrutinib or another ITK inhibitor for at least 1 month prior to being pre-treated with ibrutinib or such other ITK inhibitor, wherein the patient is pre-treated with ibrutinib or another ITK inhibitor for at least 3 months,
wherein the patient is pre-treated with at least three rounds of an ibrutinib regimen,
wherein the hematological malignancy is CLL
The claims of copending application do not teach co-culturing T cells with B cells for 2 to 5 days, wherein the ratio of B cells to PBLs is from about 0.1:1 to about 10:1, 0.1:1, 1:1 or 10:1, and do not disclose treating a patent who has CLL with Richer’s transformation.
The teachings of Deola and Xia have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have obtained CD19+ B cells from the PBMCs of the patient and further co-cultured the T cells with CD19+ B cells at a ratio of 1:1 for 4 days in view of Deola. One of ordinary skill in the art would have been motivated to do so because Deola et al. teaches that B cells promote cytotoxic T cell survival and proliferation/expansion (Title and page 1370, last para). One of ordinary skill in the art would have had a reasonable expectation of success because Deola et al. teaches that B cells promote cytotoxic T cell survival and proliferation/expansion (Title and page 1370, last para).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of the copending application to treat CLL with Richter’s transformation with CD19 CAR T cells, wherein the CD19 CAR T cells were prepared from T cells isolated from PBMCs of the patient in view of Xia. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Xia et al. teaches that patients with Richter Syndrome can be treated with CD19-directed CAR T cells.
16. Claim 1, 3, 5-9, 11-12 and 16-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 38-84 copending Application No. 19/554,595. (reference application), in view of Turtle et al. (Blood, 2016, 128(22): 56), and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
This is a provisional nonstatutory double patenting rejection.
The claims of copending Application disclose a method for expanding peripheral blood lymphocytes (PBLs) from peripheral blood, and a method for treating a hematological malignancy comprising:
a. Obtaining a sample of peripheral blood mononuclear cells (PBMCs) from peripheral blood, wherein said sample is optionally cryopreserved;
b. Isolating PBLs from said sample by selecting and removing CD19+ B cells;
c. Optionally co-culturing said PBLs with said CD19+ B cells;
d. Stimulating said PBLs in a first cell culture medium with IL-2 and anti-CD3/anti-CD28 antibodies for a period of from about 2 to about 6 days in a gas permeable container;
e. Culturing the PBLs from step (d) for a period of from about 2 to about 6 days with IL-2 and anti-CD3/anti-CD28 antibodies;
f. Isolating the antibody-bound PBLs from the culture in step (e);
g. Removing the antibodies from the PBLs isolated in step (e); and
h. Harvesting the PBLs, and
i. Administering the PBLs to the patient in a therapeutically effective amount to treat said hematological malignancy,
wherein the patient is pre-treated with an ITK inhibitor prior to obtaining a PBMC sample, and the ITK inhibitor is ibrutinib,
wherein after step (d), additional IL-2 is added and the first cell culture medium is exchanged with a second cell culture medium,
wherein after step (e), additional IL-2 is added and the second culture medium is exchanged with a third cell culture medium.
wherein the first cell culture medium and the second cell culture medium are the same,
wherein the ratio of B-cells to PBLs in step (c) is selected from the group consisting of 0.1:1, 1:1, and 10:1 (B-cells:PBLs),
wherein there are at least from about 2.5x105 to 10x105 PBLs in the gas permeable container at the beginning of step (d),
wherein the IL-2 is present in a concentration of about 3000 IU/ml,
the anti-CD3/anti-CD28 antibodies are coated onto beads and the PBLs:beads ratio is about 1:1 in each of steps (c) and (d),
wherein the patient is pre-treated with at least three rounds of an ibrutinib regimen,
wherein the hematological malignancy is CLL,
wherein the PBLs are administered in an amount of from about 0.1x109 to about 15x109 PBLs.
The claims of copending application do not disclose treating a patent who is refractory to ibrutinib (an ITK inhibitor) or who has CLL with Richer’s transformation.
The teachings of Turtle and Xia have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of the copending application to treat ibrutinib-refractory CLL and CLL with Richter’s transformation with CD19 CAR T cells, wherein the CD19 CAR T cells were prepared from T cells isolated from PBMCs of the patient in view of Turtle and Xia. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Turtle et al. teaches that CD19 CAR-T cells are highly active in CLL and can induce high response rates and durable CRs in poor prognosis pts who have previously failed ibrutinib and Xia et al. teaches that patients with Richter Syndrome can be treated with CD19-directed CAR T cells.
17. Claims 1, 3, 5-9, 11-12 and 16-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-9, 14, 19, 24-25, 37-38, 41, 45, 100, 104, 107 and 112 of copending Application No. 19/121,778 (reference application), in view of Turtle et al. (Blood, 2016, 128(22): 56), Deola et al. (J Immunology, 2008, 180:1362-1372), and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
This is a provisional nonstatutory double patenting rejection.
The claims of copending application disclose a method of treating a hematological malignancy in a patient, the method comprising administering, to a patient, a therapeutically effective population of peripheral blood lymphocytes (PBLs) obtained from the patient, wherein the patient has been pre-treated with an ITK inhibitor,
wherein the patient is suffering from CCL, wherein the therapeutically effective population of PBLs comprises from about 2.3x 1010 to about 13.7x 1010 PBLs, the method further comprising:
(a) obtaining peripheral blood mononuclear cells (PBMCs) from less than or equal to about 50 mL of whole blood from a patient suffering from the hematological malignancy, wherein the patient is optionally pretreated with an ITK inhibitor, a BTK inhibitor and/or a BCL2 inhibitor; (b) admixing beads selective for CD3 and CD28 with the PBMCs, wherein the beads are added at a ratio of 3 beads: 1 cell, to form an admixture of PBMCs and beads; (c) culturing the admixture of PBMCs and beads at a density of about 25,000 cells per cm2 to about 50,000 cells per cm2 on a gas-permeable surface of one or more containers containing a first cell culture medium and IL-2 for a period of about 4 days; (d) adding to each container of step (c) IL- 2 and a second cell culture medium that is the same as or different from the first cell culture medium and culturing for a period of about 5 days to about 7 days to form an expanded population of peripheral blood lymphocytes (PBLs); and (e) harvesting from each container the expanded population of PBLs; and (f) administering a therapeutically effective portion of the expanded population of PBLs to the patient,
wherein before step (b) the method further comprises the step of removing B-cells from the PBMCs by admixing magnetic beads selective for CD 19 with the PBMCs to form complexes of the magnetic beads and CD 19+ cells in an admixture and using a magnet to remove the complexes from the admixture to provide PBMCs depleted of B-cells,
wherein the first cell culture medium contains about 3000 IU/mL of IL-2 and the second cell culture medium contains about 3000 IU/mL of IL-2,
wherein the method is performed over about 9 days, wherein the patient is suffering from a leukemia or a chronic lymphocytic leukemia and is pretreated with ibrutinib.
The claims of copending application do not teach culturing the T cells with CD19+ B cell isolated from the patient, and do not teach treating patients with CLL that is refractory to ibrutinib or CLL with Richter’s transformation. However, these deficiencies are made up for in the teachings of Deola, Turtle and Xia.
The teachings of Deola, Turtle and Xia have been set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of copending application to culture the T cells with CD19+ B cell in view of Deola. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because the prior art teaches that T cells can be cultured and then expanded in the presence of B cells and CD19+ B cell isolated from the patient, can improve T cell expansion and proliferation.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of the copending application to treat ibrutinib-refractory CLL and CLL with Richter’s transformation with CD19 CAR T cells, wherein the CD19 CAR T cells were prepared from T cells isolated from PBMCs of the patient in view of Turtle and Xia. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Turtle et al. teaches that CD19 CAR-T cells are highly active in CLL and can induce high response rates and durable CRs in poor prognosis pts who have previously failed ibrutinib and Xia et al. teaches that patients with Richter Syndrome can be treated with CD19-directed CAR T cells.
18. Claims 1, 3, 5-9, 11-12 and 16-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over clams 5, 6, 8-22 and 24-26 of copending Application No. 17/812,146, in view of Turtle et al. (Blood, 2016, 128(22): 56), Deola et al. (J Immunology, 2008, 180:1362-1372), and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
This is a provisional nonstatutory double patenting rejection.
The claims of copending Application No. 17/812,148 disclose a process for the preparation of peripheral blood lymphocytes (PBLs) from a whole blood sample, the process comprising the steps of:
a. obtaining peripheral blood mononuclear cells (PBMCs) from less than or equal to about 50 mL of whole blood from a patient having a liquid tumor, wherein the patient is optionally pretreated with an ITK inhibitor;
b. admixing beads selective for CD3 and CD28 with the PBMCs obtained from the patient, wherein the beads are added at a ratio of 3 beads:1 cell, to form an admixture of PBMCs and beads;
c.(i) culturing the admixture of PBMCs obtained from the patient and on a gas-permeable surface of one or more containers containing a first cell culture medium and IL-2 for a period of about 4 days; or
(ii) wherein in step (b) the admixture of beads and PBMCs forms complexes of PBMCs and beads, wherein before step (c) the process comprises the step of separating the complexes from the admixture, and wherein step (c) is replaced by the step of culturing the complexes of PBMCs and beads at a density of about 12,500 cells (+/- 20%) per cm2 to about 50,000 cells (+/- 20%) per cm2 on a gas- permeable surface in one or more containers containing a first cell culture medium and IL-2 for a period of about 4 days: d. adding to each container of step (c) IL-2 and a second cell culture medium that is the same as or different from the first cell culture medium and culturing for a period of about 5 days to form an expanded population of PBLs; and
e. harvesting from each container the expanded population of PBLs,
wherein the total number of cells harvested is from about 8 billion to about 22 billion.,
wherein in step (b) magnetic beads selective for CD3 and CD28 are admixed to the PBMCs, and wherein the step of separating the complexes from the admixture is performed by using a magnet to remove the complexes from the admixture, the beads selective for CD3 and CD28 are beads conjugated to anti-CD3 antibodies and anti-CD28 antibodies,
wherein after step (d) the process comprises the step of:
(f) performing a selection to remove any remnant B-cells from the expanded population of PBLs,
wherein in step (f) the selection is performed by using beads selective for CD19 to remove the remnant B-cells,
wherein in step (f) the selection is performed by admixing the beads selective for CD19 with the expanded population of PBLs to form complexes of beads and any remnant B-cells and removing the complexes from the admixture.
wherein in step (f) the selection is performed by admixing magnetic beads selective for CD19 with the expanded population of PBLs to form complexes of magnetic beads and any remnant B-cells and using a magnet to remove the complexes from the admixture,
wherein the beads selective for CD19 are beads conjugated to anti-CD19 antibody,
wherein before step (b) the process further comprises the step of removing B-cells from the PBMCs by selecting against CD19 to provide PBMCs depleted of B-cells.,
before step (b) the process further comprises the step of removing B-cells from the PBMCs by admixing magnetic beads selective for CD19 with the PBMCs to form complexes of the magnetic beads and CD19+ cells in an admixture and using a magnet to remove the complexes from the admixture to provide PBMCs depleted of B-cells.
wherein the first cell culture medium contains about 3000 IU/mL of IL-2,
wherein the second cell culture medium contains about 3000 IU/mL of IL-2,
wherein the patient is pretreated with an ITK inhibitor, the patient is pretreated with ibrutinib, wherein the patient is suffering from a leukemia or a chronic lymphocytic leukemia.
The claims of copending application do not teach culturing the T cells with CD19+ B cell isolated from the patient, and do not teach treating patients with CLL that is refractory to ibrutinib or CLL with Richter’s transformation. However, these deficiencies are made up for in the teachings of Deola, Turtle and Xia.
The teachings of Deola, Turtle and Xia have been set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of copending application to culture the T cells with CD19+ B cell in view of Deola. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because the prior art teaches that T cells can be cultured and then expanded in the presence of B cells and CD19+ B cell isolated from the patient, can improve T cell expansion and proliferation.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of the copending application to treat ibrutinib-refractory CLL and CLL with Richter’s transformation with CD19 CAR T cells, wherein the CD19 CAR T cells were prepared from T cells isolated from PBMCs of the patient in view of Turtle and Xia. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Turtle et al. teaches that CD19 CAR-T cells are highly active in CLL and can induce high response rates and durable CRs in poor prognosis pts who have previously failed ibrutinib and Xia et al. teaches that patients with Richter Syndrome can be treated with CD19-directed CAR T cells.
Conclusion
19. 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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/HONG SANG/Primary Examiner, Art Unit 1643
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