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 .
Application Status
The amended claims filed on July 12, 2023 are acknowledged. Claims 8-11, 13-15, 20-21, 24, 28-31, 34-55, 57-61, 66-68, and 70-73 are canceled. Claims 4-7, 12, 16, 18, 27, 32, and 56 are amended.
Claims 1-7, 12, 16-19, 22-23, 25-27, 32-33, 56, 62-65, and 69 are pending and under examination herein.
Priority
The earliest support for the subject matter of claims 1-5, 12, 16-19, 22-23, 25-27, 32-33, 56, and 62-65 is found in U.S. Provisional Patent Application No. 63/136,217, filed January 12, 2021.
The earliest support for the subject matter of claims 6-7 and 69 is found in the PCT Patent Application No. PCT/IL2022/050038, filed on January 11, 2022.
Information Disclosure Statement
It is noted for Applicant that an updated version of the Information Disclosure Statement (IDS) form is available at https://www.uspto.gov/patents/apply/forms. The version(s) presently submitted are approved for use through July 31, 2006.
Claim Objections
Claims 19 and 25 are objected to because of the following informalities. Appropriate correction is required.
For clarity, the recitation of “expresses” in line 2 of claim 19 should be amended to recite “express”.
For clarity/consistency, the recitation of “provided” in line 3 of claim 25 should be amended to recite “providing”.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-3 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 2 recites the limitation “wherein 7-12% of the cells are CD3+CD4+ cells, 20-28% are CD3+CD56+ cells, and 10-14% are CD3+CD8+CD56+ cells” in lines 1-3. There is insufficient antecedent basis for this limitation (“the cells”) in the claim. Claim 2 depends from claim 1, which recites a cell composition comprising “in vitro-expanded peripheral blood mononuclear cells (PBMC)”, said PBMCs comprising subpopulations of “CD3+CD8+ cells expressing NKG2D and granzyme B”, “CD56- cells”, and “CD3- cells”. Claim 2 is indefinite because it is unclear whether the limitations set forth in the wherein clause of the claim refer to one or more of the subpopulations of PBMCs, or to all of the PBMCs comprised in the cell composition of claim 1.
Claim 3, which depends from claim 2, does not remedy this deficiency and is similarly rejected.
Claim Rejections - 35 USC § 102 and 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(1)
Claims 1-7, 12, and 16-17 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Martkamchan (Advances in Clinical and Experimental Medicine (2016) 25(5): 821-828; cited in IDS).
Martkamchan discloses the preparation of a population of cells intended for use in adoptive therapy. Martkamchan notes that a previous report found that unfractionated cells in culture are more useful for cell proliferation compared to purified T cells because autocrine and paracrine actions in the unfractionated cells stimulate T cell proliferation (e.g., Discussion, pages 825-826). Martkamchan expanded PBMCs derived from whole blood samples with anti-CD3/CD28 monoclonal antibodies immobilized on magnetic beads in the presence of IL-2 (e.g., Methods). Martkamchan teaches that the expanded cell cultures were restimulated on day 7 and maintained by the addition of fresh media on days 4, 7, 11, 14, 17, and 21 (e.g., Methods), relevant to claims 16-171. Regarding claims 1-4, Table 2 shows that at Day 21, for PBMCs incubated with 20 U/mL or 100 U/mL IL-2, between 76.5 ± 15.4% to 87.2 ± 6.1% of cells were CD3+CD8+ cells, more than 70% are CD56- cells, and less than 5% are CD3- cells. The amount of CD3+CD8+ cells at Day 21 is 6-7 times the amount of CD3+CD4+ cells in the composition in the 20 U/mL IL-2 group.
Regarding claims 1-7 and 12, although Martkamchan is silent with respect to whether the expanded PBMCs express markers including NKG2D, granzyme B, DNAM-1, CXCR3, and/or CXCR6, it is noted that MPEP § 2112.01 states, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).” Thus, the instantly claimed composition, comprising materially the same proportions of cells as that described in the prior art and produced from the same starting population of cells, would inherently be expected to express the biomarkers set forth in the instant claims.
Claim Rejections - 35 USC § 103
(2)
Claims 1, 18-19, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Martkamchan (Advances in Clinical and Experimental Medicine (2016) 25(5): 821-828; cited in IDS) as applied to claims 1-7, 12, and 16-17 above, further in view of Balabanian (WO 2021/069593 A1; PCT filing date: October 8, 2020; earliest priority date: October 9, 2019).
The teachings of Martkamchan are recited in the 35 U.S.C. § 102/103 rejection above.
However, Martkamchan does not expressly teach that the cell composition produced by the method of the disclosure is genetically modified to express a modified CXCR4 receptor comprising a mutation or truncation at the C-terminal tail domain or to express a chimeric antigen receptor (CAR).
Balabanian describes modified T cells (e.g., CD8+ or CD4+ T cells) expressing CXCR4 with the deletion of the C-terminal domain between 10-20 amino acid residues and use thereof in the treatment of cancers such as leukemia (e.g., Abstract; pages 1 and 3-5; claims 1-5, 8, and 14-15). Balabanian teaches that the CXCR4 C-terminal truncation serves to increase the long-term maintenance and magnitude of the T cell response (in particular CD8+ T cell responses) and increases the activity of T cells by increasing the quantity of antigen-specific T cells (e.g., page 3), relevant to claims 18 and 22. Pertinent to claim 19, Balabanian states, “Moreover, in cell therapy and in adoptive cell therapy, especially with CarT cells, an issue to be solved concern the activity of T cells, and in particular CD8 T cells, in the long term, and the present invention represents a solution to this problem” (page 3). Balabanian further discloses CAR-T cells for use in adoptive cell therapy which express a CXCR4 C-terminal domain truncation (e.g., claims 1-3 and 6-10).
Balabanian teaches that mutated CXCR4 may be cloned into an expression vector and expressed following a lentiviral-based strategy in activated PBMCs from healthy individuals (e.g., page 7).
In view of the further teachings of Balabanian, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify cells generated in the method of production taught by Martkamchan to further express a CAR and/or a CXCR4 C-terminal domain truncation. The skilled artisan would have been motivated to incorporate the CXCR4 mutation because Balabanian teaches that this mutation increases the long-term maintenance and activity of T cells, which Balabanian notes is advantageous for adoptive cell therapies, especially CAR-T cell therapy. The skilled artisan would further have been motivated to express a CAR in the cells, in particular one against a tumor-associated antigen, because the CAR would target the cells to tumor cells expressing the antigen to better exert a therapeutic effect. There would have been a reasonable expectation of success because a significant proportion of the cells produced in the expansion method of Martkamchan are CD3+CD8+ T cells, which are suited for the manipulations described by Balabanian.
(3)
Claims 1, 18-19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Martkamchan (Advances in Clinical and Experimental Medicine (2016) 25(5): 821-828; cited in IDS) as applied to claims 1-7, 12, and 16-17 above, further in view of Sourdive (WO 2019/106163 A1).
The teachings of Martkamchan are recited in the 35 U.S.C. § 102/103 rejection above.
However, Martkamchan does not expressly teach that the cell composition produced by the method of the disclosure is genetically modified to express exogenous IL-15 and/or IL-21 or to express a chimeric antigen receptor (CAR).
Sourdive discloses methods of genetic engineering that can be used to confer additional therapeutic properties to immune cells, including exogenously expressing a chimeric antigen receptor against a tumor-associated antigen (e.g., CD22) and/or cytokines such as IL-15 into PBMCs (e.g., Figures 2, 4, and 17 and captions at pages 8-11; see also pages 19-22, Examples at pages 32-36), relevant to claims 18-19 and 23. Sourdive discloses that the integration of IL-15 coding sequences at the PD1 or CD25 locus “dramatically helps the elimination of the tumor cells by the CAR positive cells” (page 11; Figure 17). Sourdive states that the method of the invention “aims to reduce the potential side effects of IL15/IL15rα systemic secretion while maintaining its capacity to reduced activation induced T-cell death (AICD), promote T-cell survival, enhance T-cell antitumor activity and to reverse T-cell anergy” (page 35).
In view of the further teachings of Sourdive, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify cells generated in the method of production taught by Martkamchan to further express a CAR and an exogenous IL-15 cytokine. The skilled artisan would have been motivated to express exogenous IL-15 in the cells of the ACT cell composition because Sourdive teaches that the exogenous cytokine enhances the antitumor activity of the co-expressed CAR construct and also confers several other advantages such as increased T cell survival. The skilled artisan would further have been motivated to express a CAR in the cells, in particular one against a tumor-associated antigen, because the CAR would target the cells to tumor cells expressing the antigen to better exert a therapeutic effect. There would have been a reasonable expectation of success because Sourdive provides a proof-of-concept that PBMCs may be genetically engineered to express exogenous IL-15 and a CAR as illustrated, e.g., in Example 1.
(4)
Claims 25-27, 56, and 62-65 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (Blood (1992) 80(7): 1846-1853; cited in IDS) in view of Langer (US 2023/0032934 A1; PCT filing date: November 25, 2020; earliest priority date: November 27, 2019), as evidenced by Sconocchia (Blood (2005) 106(10): 3666-3672).
Anderson compares the proliferation and cytotoxicity of the combination of anti-CD3 (OKT3; i.e., a CD3 activator) and interleukin-2 (IL-2) stimulation in marrow mononuclear cells (MMC) and peripheral blood mononuclear cells (PBMCs) derived from 8 normal donors, 15 patients with acute lymphoblastic leukemia (ALL), and 7 patients with non-Hodgkin lymphoma (NHL) in remission (e.g., Abstract). Relevant to claims 25-27, Anderson discloses a method in which PBMCs were diluted in media containing anti-CD3 (OKT3, at a concentration of 0-100 ng/mL or otherwise 10 ng/mL) and recombinant IL-2 (at a concentration of 0-1000 U/mL or otherwise 100 U/mL) (e.g., Methods). Anderson discloses that cell numbers for normal control PBMCs incubated with both OKT3 and IL-2 increased 83-fold after 14 days and that the most rapid proliferation was observed between days 7 and 14 (e.g., Results, page 1848-1849; Table 1).
Relevant to claims 56 and 62-65, Anderson investigated the cytotoxicity of PBMC IL-2+anti-CD3-activated cultures at days 12 and 19 against hematological tumor cell lines (e.g., Results, page 1849; Table 3). Anderson reports that the PBMC IL-2+anti-CD3-activated cultures showed greater tumor-killing activity in the K562 cell line (i.e., chronic myelogenous leukemia (CML)2, NK-sensitive) and the Daudi cell line (NK-resistant, LAK-sensitive) than similarly stimulated MMCs (e.g., Table 3). Anderson notes that “the number of cells resulting from anti-CD3+IL-2 activation is 50- to 200-fold more than IL-2 activation”, and that “the total cytolytic potential of this scheme is greater than using IL-2 alone” (page 1849).
Regarding functional differences between IL-2 only versus anti-CD3+IL-2 stimulated cultures, Anderson performed a cytolytic assay against hematologic tumor targets and observed that “when anti-CD3 was added to the cytolytic assay, increases in the cytotoxicity of the cultures were not only dose- and target-dependent, but also related to the method of activation (Fig 5)”, with the addition of anti-CD3 in the assays increasing the cytolytic activity of combination-stimulated effectors but not IL-2-only-activated effectors (e.g., Results, page 1849; Figure 5).
However, Anderson does not expressly teach supplementing effective amounts of the IL-2 and anti-CD3 (OKT3) every 48-96 hours in the recited method, nor the specific markers expressed by the proliferated cells produced in said method.
Langer discloses methods for ex vivo expansion of tumor-reactive T cells and compositions containing the same (e.g., Abstract). Langer recites that the methods of the invention produce or expand T cells for use in adoptive cell therapy methods for treating a disease in which cells or tissues associated with the disease express a target antigen recognized by the T cells (e.g., ¶ 0156). Langer teaches that the biological sample containing a population of T cells to be used for the methods of the invention may be sourced from a blood sample containing PBMCs (e.g., ¶ 0163, 0228-0235). Exemplary methods of the invention comprise expansion of populations of T cells with one or more T cell stimulatory agents (e.g., claims 1 and 8; ¶ 0005-0087). Further relevant to the method of claims 25-26, Langer discloses embodiments in which the expansion steps include incubation of the T cell populations with IL-2 and an anti-CD3 (OKT3) antibody, which provides a co-stimulatory signal to the cells (e.g., ¶ 0026, 0159-0160, 0169-0170). Langer further provides that the incubation with T cell stimulatory agent(s) is carried out for 7-14 days, e.g., about 9 or 10 days, and that the media (including the stimulatory agents such as cytokines and anti-CD3) can be exchanged every other day or every third day (e.g., ¶ 0317, 0395-0411, 0437). Further relevant to claim 27, the concentration of recombinant IL-2 for the incubation may be chosen to facilitate T cell expansion and sustain T cell viability, e.g., a concentration from about 300 IU/mL to about 100 IU/mL (e.g., ¶ 0246, 0407-0409), and the concentration of the anti-CD3 antibody may be added in a range between about 1 ng/mL to about 50 ng/mL (e.g., ¶ 0401).
In view of the teachings above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a method of producing a cell composition for adoptive cell transfer (ACT) that comprises expanding a PBMC sample in the constant presence of IL-2 and anti-CD3 antibody for at least nine days, wherein the IL-2 and anti-CD3 antibody are replenished every 2-3 days and the number of viable cells is enhanced by at least 20-fold, through the process of routine optimization, and to administer the resulting cell population in a method of treatment for a tumor. The skilled artisan would have been motivated to incubate the PBMCs in both IL-2 and anti-CD3 because Anderson teaches that PBMCs stimulated with the combination of both reagents show significantly enhanced proliferation compared to IL-2 stimulation alone and because the resulting PBMCs have cytolytic activity against hematological cancer cells. There would have been a reasonable expectation of success in modifying the expansion protocol parameters because it was within the routine skill of one of ordinary skill in the art at the time of filing to co-culture PBMCs in IL-2 and anti-CD3 and to adjust cell culture incubation conditions as needed to optimize output.
In regards to the specific reagent dosages and time intervals recited in the instant claims, it is noted that "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 (II)(A). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
(5)
Claims 25 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (Blood (1992) 80(7): 1846-1853; supra) in view of Langer (US 2023/0032934 A1; supra), as evidenced by Sconocchia (Blood (2005) 106(10): 3666-3672; supra), as applied to claims 25-27, 56, and 62-65 above, and further in view of Balabanian (WO 2021/069593 A1; supra).
The teachings of Anderson are recited in the 35 U.S.C. § 103 rejection above.
However, Anderson does not expressly teach that the cell composition produced by the method of the disclosure is genetically modified to express a chimeric antigen receptor (CAR).
The teachings of Langer, Sconocchia, and Balabanian are recited in the 35 U.S.C. § 103 rejections above.
In view of the further teachings of Balabanian, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify cells generated in the method of production collectively taught by Anderson and Langer to further express a CAR. The skilled artisan would have been motivated to express a CAR in the cells, in particular one against a tumor-associated antigen, because the CAR would target the cells to tumor cells expressing the antigen to better exert a therapeutic effect. There would have been a reasonable expectation of success because Langer teaches that the methods of the invention are used to produce or expand T cells for use in adoptive cell therapy methods for treating a disease in which cells or tissues associated with the disease express a target antigen recognized by the T cells.
(6)
Claims 25 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (Blood (1992) 80(7): 1846-1853; supra) in view of Langer (US 2023/0032934 A1; supra), as evidenced by Sconocchia (Blood (2005) 106(10): 3666-3672; supra), as applied to claims 1-7, 12, 16-17, 25-27, 56, and 62-65 above, and further in view of Sourdive (WO 2019/106163 A1; supra).
The teachings of Anderson are recited in the 35 U.S.C. § 103 rejection above.
However, Anderson does not expressly teach that the cell composition produced by the method of the disclosure is genetically modified to express exogenous IL-15 and/or IL-21 or to express a chimeric antigen receptor (CAR).
The teachings of Langer, Sconocchia, and Sourdive are recited in the 35 U.S.C. § 103 rejections above.
In view of the further teachings of Sourdive, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify cells generated in the method of production collectively taught by Anderson and Langer to further express a CAR and an exogenous IL-15 cytokine. The skilled artisan would have been motivated to express exogenous IL-15 in the cells of the ACT cell composition because Sourdive teaches that the exogenous cytokine enhances the antitumor activity of the co-expressed CAR construct and also confers several other advantages such as increased T cell survival. The skilled artisan would further have been motivated to express a CAR in the cells, in particular one against a tumor-associated antigen, because the CAR would target the cells to tumor cells expressing the antigen to better exert a therapeutic effect. There would have been a reasonable expectation of success because Sourdive provides a proof-of-concept that PBMCs may be genetically engineered to express exogenous IL-15 and a CAR as illustrated, e.g., in Example 1.
(7)
Claims 56 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (Blood (1992) 80(7): 1846-1853; supra) in view of Langer (US 2023/0032934 A1; supra), as evidenced by Sconocchia (Blood (2005) 106(10): 3666-3672; supra), as applied to claims 1-7, 12, 16-17, 25-27, 56, and 62-65 above, and further in view of Wang (Journal of Hematology and Oncology (2019) 12: 59).
The teachings of Anderson are recited in the 35 U.S.C. § 103 rejection above.
However, Anderson does not expressly teach that the tumors treated in a method of the disclosure are resistant to treatment by at least one checkpoint molecule inhibitor.
The teachings of Langer and Sconocchia are recited in the 35 U.S.C. § 103 rejection above.
Wang summarizes preclinical and clinical advances in the use of immune checkpoint blockade (ICB) and CAR-T cell therapies for hematologic malignancies. Wang teaches that while ICB and CAR-T therapy have shown considerable success in the treatment of these conditions, only a subset of patients see clinical benefit (e.g., Abstract; Table 1).
In view of the further teachings of Wang, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer a cell composition generated in the method of production collectively taught by Anderson and Langer to a patient whose tumor was resistant to treatment with at least one ICB. The skilled artisan would have been motivated to do so because Wang teaches that a subset of hematological cancer patients does not respond to or relapses after treatment with ICBs, and these patients have a clear need to be treated. There would have been a reasonable expectation of success because it was within the skill of those in the art at the time of filing to administer ACT compositions for the purpose of treating cancer, and because PBMCs expanded according to the conditions set forth by Anderson and Langer demonstrate cytotoxic activity against tumor cells.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
1 It is noted that “…wherein the incubation is performed in the absence of other cytokines or antibodies” as recited in claim 17 is being interpreted to mean “in the absence of other cytokines” or, in the alternative, “in the absence of other antibodies”, due to the recitation of “or”. In the case of Martkamchan, the expansion takes place in the absence of other cytokines.
2 As evidenced by Sconocchia, CML is characterized by aberrant expression of MICA and MICB (e.g., Abstract).
Prosecution Insights