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 species election without traverse of (a) Ibrutinib, (ii) chronic lymphocytic leukemia (CLL) and (iii) CM-2 as the cell culture medium for each of claims 10, 13 and 14 in the reply filed on 3/30/2026 is acknowledged.
3. Claims 1-26 are pending. Claims 4 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/30/2026.
4. Claims 1-3, 5-14 and 16-26 are under examination.
Information Disclosure Statement
5. The information disclosure statement filed 3/13/2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to JP 2014-507118A1, JP2017-518052A and JP2002-516562A.
The information disclosure statement filed on 3/13/2023 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the date for item A65 is not provided. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to item A65.
37 C.F.R. 1.98 (b)(5) Each publication listed in an information disclosure statement must be identified by publisher, author (if any), title, relevant pages of the publication, date, and place of publication.
Priority
6. 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, 5-14 and 16-26. Specifically none of the provisional applications except Application No. 62647367 discloses removing CD19+ B cells and co-culturing PBLs with the CD19+ B cells. Application No. 62647367 does not disclose pretreating said PBLs with an ITK inhibitor.
Accordingly, the effectively filing date for the instant claims is the filing date of PCT/US2018/032109, i.e. 5/10/2018.
Specification
7. The amendment to the specification filed on 7/11/2023 is acknowledged and entered. However, applicant failed to incorporate the amendment filed on 3/13/2023 (see paragraph [0001]).
Claim Objections
8. Claims 1-3, 5-14 and 16-26 are objected to because of the following informalities:
Claim 1 is objected to for reciting the term “ITK”. For clarity, the full terminology of ITK should be included at first mention.
Claim 1 is objected to for reciting “adding from 2.5x105 to about 5x105 cells to a gas-permeable container” in step d. Prior to step d, the claim mentions multiple cells, thus it is unclear which cells the term is in reference to. For clarity, the claim may be amended to recite “adding from 2.5x105 to about 5x105 co-cultured cells from step c”.
Claim 1 is objected to for a typographical error, see “and and” in line 3 of step d.
Claim 2 is objected to for reciting “stimulating said PBLs” in step d. It is unclear if “said PBLs” refers to co-cultured cells from step c or PBLs from step b.
Claims 8 and 26 are objected to for reciting “(or Richter’s syndrome)”. The term “or” should be deleted if Richter’s syndrome is identical to Richter’s transformation.
Claim 19 recites “there are at least from about 1 x 105 to about 10x105 PBLs”. Similarly, claim 20 recites “there are at least from about 2.5 x 105 to about 10x105 PBLs”. The recitation of “at least” in conjunction with the recited range makes it unclear whether the claims are reciting that there are at least x number of cells where x can be within the claimed range (i.e. an unbounded range with the lower bound within the claimed range), or whether the number of cells must be within the claimed range (i.e. a closed range).
Claim 22 is objected to for a typographical error. The term “6000 IL/ml” should be 6000 IU/ml.
Claims 1-3, 5-14 and 16-26 are objected to for reciting multiple “optionally” in one claim which render the claims ambiguous and scope of the claims unclear.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
9. 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.
10. Claims 1-3, 5-14 and 16-26 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.
Claim 1 recites “the antibody-bound PBLs” in step h. There is insufficient antecedent basis for this limitation in the claim. Claim 1 only mentions anti-CD3/anti-CD28 antibodies.
Claim 2 recites “isolating the antibody-bound PBLs” in step f. There is insufficient antecedent basis for this limitation in the claim. Claim 2 only mentions anti-CD3/anti-CD28 antibodies. Claim 3, 5-14 and 16-26 are indefinite because they depend from claim 2 and fail to correct the issue.
Claims 10, 13 and 14 are rejected as vague and indefinite for reciting the term “CM-2” and “CM-4” as the sole means of identifying a particular culture medium. The use of laboratory designations only to identify a particular substance renders the claims indefinite because different laboratories may use the same laboratory designations to define completely distinct substance. The terms CM-2 and CM-4 do not appear to have a known/established meaning in the relevant art. The specification does not expressly define the terms CM-2 or CM-4. The specification discloses “CM-2 cell culture medium (comprised of RPMI-1640, human AB serum, 1-glutamine, 2-mercaptoethanol, gentamicin sulfate, AIM-V media)” (page 52, [00187]). The specification further discloses “CM-4 (comprised of AIM-V media, 2mM Glutamax, and 3000IU/ml IL2)” (page 52, [00185]). It is unclear whether the CM-2 and CM-4 media contain additional ingredients beyond the above-listed ingredients and/or whether they require specific amounts of said ingredients.
Claims 10, 13 and 14 also contain the trademark/trade name AIM-V®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular cell culture medium and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
11. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
12. Claims 2, 8-10, 19-21 and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by June et al. (WO2012/079000A1, pub. date: 6/14/2012).
Note: the limitation following the term “optionally” in step c of claim 2 is not considered.
Regarding claims 2 and 8-10, June teaches a method of treating CLL (chronic lymphocytic leukemia) (instant preamble) using CAR-modified T cells (instant step j), 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 (instant step i), and then infusing the modified T cells back into the patient (instant step j)(page 14, page 53, lines 8-11). 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+, CD28+ 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 such as AIM-V with or without serum (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). 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).
Regarding claim 24, June et al. teaches that the ratio of anti-CD3:CD28 antibodies bound to the beads is 1:1 (page 45, lines 18).
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).
Claim Rejections - 35 USC § 103
13. 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.
14. Claims 2, 8-14, 16 and 19-25 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 Somerville et al. (J Translational Medicine, 2012, 10:69: 1-11).
The teachings of June have been set forth above as they apply to claims 2, 8-10, 19-21 and 24-25.
Regarding claims 22-23, June et al. does not teach culturing T cells in the presence of 3000 IU/ml IL-2.
Regarding claims 11-14, June does not specifically teach after step (d), additional IL-2 is added and the cell culture medium is exchanged with a second cell culture medium, and after step (e), additional IL-2 is added and the second cell culture medium is exchanged with a third cell culture medium, and the second and third cell culture medium is same as the first cell culture medium.
However, these deficiencies are made up for in the teachings of Somerville.
Somerville et al. discloses a method of expansion of lymphocytes for adoptive cell transfer therapy, the method comprising:
a. obtaining PBL (a sample of PBMCs) 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 in the method of June 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 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.
15. Claim(s) 1, 2, 8-14 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), Somerville et al. (J Translational Medicine, 2012, 10:69: 1-11), further in view of Deola et al. (J Immunology, 2008, 180:1362-1372).
The teachings of June and Somerville have been set forth above as they apply to claims 2, 8-14, 16 and 19-25.
Regarding claims 1, 17 and 18, June and Somerville 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..
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 cell with a ratio of CD8+ T cells to CD19 B cells being 1:1 for 4 days (page 1363, column 1). Deola et al. teaches that CTL/B cell interactions contribute to CTL proliferation (page 1369, 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 cell from 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 with 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).
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.
16. Claims 2, 3, 5-14, 16 and 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over June et al. (WO2012/079000A1, pub. date: 6/14/2012), 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 and Somerville have been set forth above as they apply to claims 2, 8-14, 16 and 19-25.
Regarding claims 3, and 5-7, June and Somerville do not teach the patient has been pre-treated with ibrutinib.
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 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.
17. Claims 2, 8-14, 16 and 19-25 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 Somerville et al. (J Translational Medicine, 2012, 10:69: 1-11), further in view of Ports et al. (US20190328786A1, pub. date: 10/31/2019, effectively filed date: 12/3/2016).
The teachings of June and Somerville have been set forth above as they apply to claims 2, 8-14, 16 and 19-25.
June and Somerville do not teach culturing T cells in the presence of ibrutinib recited in the optional steps.
Ports teaches methods of making therapeutic CAR T-cells wherein the CAR T-cells are incubated with ibrutinib during and/or after manufacture (entire doc, including [0153]; [0498]; [0782]-[0787]). Ports teaches that ibrutinib can improve T cell function, including functions related to the expansion, proliferation and persistence of T cells ([0153]; [0498]; [0782]-[0787]). The ibrutinib can be added during stimulation/expansion of the cells ([0498]; [0782]-[0787]).
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 June to add ibrutinib during the stimulating and/or culturing steps in view of Ports. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Ports teaches that ibrutinib can improve T cell function, including functions related to the expansion, proliferation and persistence of T cells ([0153]; [0498]; [0782]-[0787]), and ibrutinib can be added during stimulation/expansion of the cells ([0498]; [0782]-[0787]).
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.
18. Claim(s) 2, 8-14, 16 and 19-26 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 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 and Somerville have been set forth above as they apply to claims 2, 8-14, 16 and 19-25.
Regarding claim 26, June 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 method of June 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
19. 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.
20. Claim 1-3, 5-14 and 16-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
(i) claims 1-126 of copending Application No. 19/557,089 (reference application), and
(ii) claims 1-126 copending Application No. 19/554,595.
Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims, in particular claims 38-60 of each copending Application disclose a method for expanding peripheral blood lymphocytes (PBLs) from peripheral blood 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, wherein the first cell culture medium is selected from the group consisting of CM-2, CM-4, and AIM-V, 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 second cell culture medium is selected from the group consisting of CM-2, CM-4, and AIM-V, wherein the third cell culture medium is selected from the group consisting of CM-2, CM-4, and AIM-V, wherein the first cell culture medium and the second cell culture medium are different or the same, the ratio of B-cells to PBLs in step (c) is from about 0.1:1 to about 10:1 (B-cells:PBLs), 0.1:1, 1:1, and 10:1 (B-cells:PBLs), there are at least from about 1x105 to about 10x105 PBLs in the gas permeable container at the beginning of step (d), there are at least from about 2.5x105 to 10x105 PBLs in the gas permeable container at the beginning of step (d), wherein there are at least 5x105 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, wherein 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), the method further comprising addition of an ITK inhibitor during at least one of step (c), (d) and (e), an ITK is ibrutinib.
The claims in particular claims 61-83 of each copending application disclose a method for treating a hematological malignancy, the method comprising: a. Obtaining a sample of PBMCs from peripheral blood of a patient suffering from a hematological malignancy; 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 (f); and h. Harvesting the PBLs; and i. Administering the PBLs to the patient in a therapeutically effective amount to treat said hematological malignancy.
The claims of each copending application disclose all the limitations of instant claims, as such anticipate instant invention
21. Claims 1-3, 5-14 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 Deola et al. (J Immunology, 2008, 180:1362-1372), Ports et al. (US20190328786A1, pub. date: 10/31/2019, effectively filed date: 12/3/2016),
and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
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, or with ibrutinib, and do not teach treating patients with Richter’s transformation. However, these deficiencies are made up for in the teachings of Deola, Ports and Xia.
The teachings of Deola, Ports and Xia have been set forth above (see 103 rejections).
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, and/or with ibrutinib in view of Deola and Ports. 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/or ibrutinib and CD19+ B cell isolated from the patient, and/or ibrutinib can improve T cell expansion and proliferation.
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 method of copending application 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.
22. Claims 1-3, 5-14 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 Deola et al. (J Immunology, 2008, 180:1362-1372), Ports et al. (US20190328786A1, pub. date: 10/31/2019, effectively filed date: 12/3/2016), and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
This is a provisional nonstatutory double patenting rejection.
Clams 5, 6, 8-22 and 24-26 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 to provide PBMCs depleted of B-cells,
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.,
wherein before step (b) the process further comprises the step of removing B-cells from the PBMCs by admixing beads selective for CD19 with the PBMCs to form complexes of the beads and CD19+ cells in an admixture and removing the complexes from the admixture 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, or with ibrutinib, and do not teach treating patients with Richter’s transformation. However, these deficiencies are made up for in the teachings of Deola, Ports and Xia.
The teachings of Deola, Ports and Xia have been set forth above (see 103 rejections).
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, and/or with ibrutinib in view of Deola and Ports. 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/or ibrutinib and CD19+ B cell isolated from the patient, and/or ibrutinib can improve T cell expansion and proliferation.
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 method of copending application 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.
23. Claims 1-3, 5-14 and 16-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-57 of copending Application No.18/674,418 (reference application), in view of Deola et al. (J Immunology, 2008, 180:1362-1372), Ports et al. (US20190328786A1, pub. date: 10/31/2019, effectively filed date: 12/3/2016), and Xia et al. (Cancer Research, 2017, April, 77 (13_supplement): Abstract CT041).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of copending application disclose a method for expanding peripheral blood lymphocytes (PBLs) from peripheral blood of a patient who is refractory to a first course of treatment with ibrutinib or another insulin-like tyrosine kinase (ITK) inhibitor, the method comprising the steps of:(a) re-treating the patient with a second course of ibrutinib or such other ITK inhibitor;(b) obtaining a sample of peripheral blood mononuclear cells (PBMCs) from peripheral blood of the patient;(c) 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 PBLs from said PBMCs; and(d) harvesting the PBLs from the culture in step (c),
wherein the patient is re-treated with ibrutinib or such other ITK inhibitor for at least 3 months, wherein in step (c) the anti-CD3/anti-CD28 antibodies are bound to magnetic beads, and wherein the beads to cells ratio is 3:1 in the culture, in step (c) 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 culture medium is exchanged with a second culture medium in the culture, wherein the first culture medium is different from the second culture medium or the same, wherein the first cell culture medium and the second culture medium contains about 3000 IU/mL of IL-2.
The claims of copending application do not teach culturing the T cells with CD19+ B cell isolated from the patient, or with ibrutinib, and do not teach treating patients with Richter’s transformation. However, these deficiencies are made up for in the teachings of Deola, Ports and Xia.
The teachings of Deola, Ports and Xia have been set forth above (see 103 rejections).
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, and/or with ibrutinib in view of Deola and Ports. 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/or ibrutinib and CD19+ B cell isolated from the patient, and/or ibrutinib can improve T cell expansion and proliferation.
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 method of copending application 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.
Conclusion
24. No claims are allowed.
25. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1643
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