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 .
1. Original claims 1-21 are pending and under examination.
Claim Objections
2. Claim 5 is objected to because of the recitation that the polypeptide conferring
resistance is AGT or MGMT. Since AGT and MGMT are the same (see the attached
NSJ Bioreagents, p. 2; of record in the parent application 16/715,692), correction to remove the recitation of either AGT or MGMT from the claim is required.
3. Claims 17 and 18 are objected to because of the recitation “The method of claim 15”. Since claim 15 is drawn to a composition, correction to “The composition of claim 15” is required.
Double Patenting
4. 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.
5. Claims 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,322,145, in view of both Reardon et al. (ASCO Annual Meeting, 2015, Abstract TPS2077) and Lamb et al. (PLOS One, 2013, 8: 1-9). Reardon and Lamb are of record in the parent application 16/715,692.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to a method for treating glioma or glioblastoma (GBM) by administering a population of cytotoxic immune cells comprising [Symbol font/0x67][Symbol font/0x64] T-cells genetically-modified to express AGT or P140KMGMT and L22YDHFR and a combination of temozolomide and methotrexate.
The patent claims do not recite administering an inhibitor targeting PD-L1 (such as the monoclonal antibody MEDI4736) as required by the instant claims 1 and 7-9. Reardon et al. teach that the PD1/PD-L1 signaling is a significantly contributes to immunosuppression in GBM; Reardon et al. teach that GBM tumors express PD-L1 and that targeting PD-L1 is a promising anti-tumor therapy; Reardon discloses ongoing clinical trials using the anti-PD-L1 monoclonal antibody MEDI4736 to treat GBM in human patients (see Abstract). Modifying the patent claims by further using MEDI4736 would have been obvious to one of skill with the reasonable expectation that doing so would overcome immunosuppression and result in enhanced therapy.
The patent claims do not specifically recite that the population of cytotoxic immune cells comprises NK cells, as required by the instant claim 4. Lamb et al. teach obtaining a population of cytostatic immune cells from the peripheral blood and genetically modifying this population to express P140KMGMT; the genetically-modified population comprises ≥ 80% [Symbol font/0x67][Symbol font/0x64] T-cells, ≤ 5% αβ T-cells, and ≤15% NK cells, where the P140KMGMT-expressing [Symbol font/0x67][Symbol font/0x64] T-cells are temozolomide (TMZ)-resistant and suitable for treating glioma and GBM via combination therapy with TMZ (see Abstract; p. 1, column 2, last paragraph; p. 2, column 1, second paragraph and paragraph bridging columns 1 and 2). One of skill in the art would have found obvious to isolate [Symbol font/0x67][Symbol font/0x64] T-cells as taught by Lamb et al. and further use them to generate genetically modified [Symbol font/0x67][Symbol font/0x64] T-cells recited in the patent claims with the reasonable expectation of obtaining a composition suitable for treating glioma or GBM.
Thus, the patent claims and the instant claims are obvious variants.
6. Claims 1-3, 7-14, 19, and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,322,145, in view both Reardon et al. and Nishimura et al. (Cell Stem Cell 2013, 12: 114-126; of record in the parent application 16/715,692).
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to a method for treating glioma or glioblastoma (GBM) by administering a population of cytotoxic immune cells comprising [Symbol font/0x67][Symbol font/0x64] T-cells genetically-modified to express AGT or P140KMGMT and L22YDHFR and a combination of temozolomide and methotrexate.
The patent claims do not recite administering an inhibitor targeting PD-L1 (such as the monoclonal antibody MEDI4736) as required by the instant claims 1 and 7-9. Reardon et al. teach that the PD1/PD-L1 signaling is a significantly contributes to immunosuppression in GBM; Reardon et al. teach that GBM tumors express PD-L1 and that targeting PD-L1 is a promising anti-tumor therapy; Reardon discloses ongoing clinical trials using the anti-PD-L1 monoclonal antibody MEDI4736 to treat GBM in human patients (see Abstract). Modifying the patent claims by further using MEDI4736 would have been obvious to one of skill with the reasonable expectation that doing so would overcome immunosuppression and result in enhanced therapy.
The patent claims do not recite that the [Symbol font/0x67][Symbol font/0x64] T-cells are derived from hiPSCs, as recited in the instant claim 19 and 20. Nishimura et al. teach that reprogramming T-cells to iPSCs and redifferentiating the resulting iPSCs back to T-cells rejuvenates the T-cells and enhances their therapeutic potential (see Abstract; p. 114; p. 115, column 1, first full paragraph; column 2, second full paragraph). Although Nishimura et al. do not specifically teach [Symbol font/0x67][Symbol font/0x64] T-cells, one of skill in the art would have reasonably concluded that Nishimura’s teachings could be also applied to other immune cells. Thus, one of skill in the art would have found obvious to modify the patent claims by obtaining human [Symbol font/0x67][Symbol font/0x64] T-cells from hiPSCs, with the reasonable expectation that doing so would result in enhanced therapy.
Thus, the patent claims and the instant claims are obvious variants.
7. Claims 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, and 11 of U.S. Patent No. 10,543,233, in view of both Reardon et al. and Lamb et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim encompass a population of cytotoxic immune cells comprising [Symbol font/0x67][Symbol font/0x64] T-cells genetically-modified to express MGMT, L22YDHFR, or MDR1, where MGMT confers resistance to temozolomide, and where the composition is suitable to treat cancer. The patent specification defines that MGMT could be P104KMGMT (see column 18, lines 49-63; Example 3).
Since the patent claims disclose that the composition is suitable to treat any cancer, one of skill in the art would have found obvious to modify the patent claims by further claiming a method for treating cancer by administering the cytotoxic immune cells together with temozolomide to a subject, to achieve the predictable result of treating the cancer in the subject. One of skill in the art would have reasonably concluded that the method could be used to treat any type of cancer, including GBM. One of skill in the art would have considered treating GBM as an obvious variant.
The patent claims do not recite an inhibitor targeting PD-L1, where the inhibitor is the monoclonal antibody MEDI4736. Reardon et al. teach that GBM tumors express PD-L1 and that targeting PD-L1 is a promising anti-tumor therapy; Reardon discloses ongoing clinical trials using the anti-PD-L1 monoclonal antibody MEDI4736 to treat GBM in human patients (see Abstract). Thus, modifying the patent claims by further using MEDI4736 would have been obvious to one of skill with the reasonable expectation that doing so would result in a composition capable of overcoming immunosuppression and providing enhanced therapy.
The patent claims do not specifically recite that the population of cytotoxic immune cells comprises 50-95% [Symbol font/0x67][Symbol font/0x64] T-cells and 5-25% NK cells, where more than 50% of the [Symbol font/0x67][Symbol font/0x64] T-cells are genetically-modified as required by the instant claims 15-18. Lamb et al. teach obtaining a population of cytostatic immune cells from the peripheral blood and genetically modifying this population to express P140KMGMT; the genetically-modified population comprises ≥ 80% [Symbol font/0x67][Symbol font/0x64] T-cells, ≤ 5% αβ T-cells, and ≤15% NK cells, where at least 50% of the [Symbol font/0x67][Symbol font/0x64] T-cells express P140KMGMT and where the P140KMGMT-expressing [Symbol font/0x67][Symbol font/0x64] T-cells are temozolomide (TMZ)-resistant and suitable for treating glioma and glioblastoma via combination therapy with TMZ (see Abstract; p. 1, column 2, last paragraph; p. 2, column 1, second paragraph and paragraph bridging columns 1 and 2). While not specifically taught by Lamb et al., one of skill in the art would have reasonably expected that at least 50% of the ≥ 80% [Symbol font/0x67][Symbol font/0x64] T-cells would express P140KMGMT. One of skill in the art would have found obvious to isolate [Symbol font/0x67][Symbol font/0x64] T-cells as taught by Lamb et al. and further use them to generate genetically modified [Symbol font/0x67][Symbol font/0x64] T-cells recited in the patent claims with the reasonable expectation of obtaining a population comprising ≥ 80% [Symbol font/0x67][Symbol font/0x64] T-cells out of which at least 50% would express MGMT or P140KMGMT.
Since the patent claims recite that either MGMT or DHFR could be used to confer drug resistance, one of skill in the art would have found obvious modify the cells with both MGMT and DHFR as recited in the instant claims 11-13, with the reasonable expectation that doing so would enable confer resistance for multiple drugs and would enable therapy with a combination of drugs.
Thus, the patent claims and the instant claims are obvious variants.
8. Claims 1-3, 7-14, 19, and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,543,233, in view both Reardon et al. and Nishimura et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim encompass a population of cytotoxic immune cells comprising [Symbol font/0x67][Symbol font/0x64] T-cells genetically-modified to express MGMT, L22YDHFR, or MDR1, where MGMT confers resistance to temozolomide, and where the composition is suitable to treat cancer. The patent specification defines that MGMT could be P104KMGMT (see column 18, lines 49-63; Example 3).
Since the patent claims disclose that the composition is suitable to treat any cancer, one of skill in the art would have found obvious to modify the patent claims by further claiming a method for treating cancer by administering the cytotoxic immune cells together with temozolomide to a subject, to achieve the predictable result of treating the cancer in the subject. One of skill in the art would have reasonably concluded that the method could be used to treat any type of cancer, including GBM. One of skill in the art would have considered treating GBM as an obvious variant.
Since the patent claims recite that either MGMT or DHFR could be used to confer drug resistance, one of skill in the art would have found obvious modify the cells with both MGMT and DHFR as recited in the instant claims 11-13, with the reasonable expectation that doing so would enable confer resistance for multiple drugs and would enable therapy with a combination of drugs.
The patent claims do not recite an inhibitor targeting PD-L1 (such as the monoclonal antibody MEDI4736) as required by the instant claims 7-9. Reardon et al. teach that the PD1/PD-L1 signaling is a significantly contributes to immunosuppression in GBM; Reardon et al. teach that GBM tumors express PD-L1 and that targeting PD-L1 is a promising anti-tumor therapy; Reardon discloses ongoing clinical trials using the anti-PD-L1 monoclonal antibody MEDI4736 to treat GBM in human patients (see Abstract). Modifying the patent claims by further using MEDI4736 would have been obvious to one of skill with the reasonable expectation that doing so would overcome immunosuppression and result in enhanced therapy.
The patent claims do not recite that the [Symbol font/0x67][Symbol font/0x64] T-cells are derived from hiPSCs, as recited in the instant claim 19 and 20. Nishimura et al. teach that reprogramming T-cells to iPSCs and redifferentiating the resulting iPSCs back to T-cells rejuvenates the T-cells and enhances their therapeutic potential (see Abstract; p. 114; p. 115, column 1, first full paragraph; column 2, second full paragraph). Although Nishimura et al. do not specifically teach [Symbol font/0x67][Symbol font/0x64] T-cells, one of skill in the art would have reasonably concluded that Nishimura’s teachings could be also applied to other immune cells. Thus, one of skill in the art would have found obvious to modify the patent claims by obtaining human [Symbol font/0x67][Symbol font/0x64] T-cells from hiPSCs, with the reasonable expectation that doing so would result in enhanced therapy.
Thus, the patent claims and the instant claims are obvious variants.
Claim Rejections - 35 USC § 112(b)
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 4, 9, and 14 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.
Regarding claim 4, the term "other" renders the claim indefinite because the claim includes elements not actually disclosed (those encompassed by "other"), thereby rendering the scope of the claim unascertainable. See MPEP § 2173.05(d).
Claim 9 recites "PD-L1 monoclonal antibody (MEDI4736)”. This
recitation renders the claim indefinite because it is not clear whether the genus of anti-
PD-L1 monoclonal antibodies or the preferred species MEDI4736 recited in parenthesis
is a claim limitation. Preferences may be set forth in another dependent claim; when stated in a single claim, preferences lead to confusion over the intended scope of the
claim.
The term “substantially” in claim 14 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim or specification. Neither the specification nor the art provides a standard for ascertaining the intended degree, and thus, one of skill in the art would not be reasonably apprised of the scope of the invention.
Thus, the metes and bounds of the claims cannot be determined and the claims
are indefinite.
Claim Rejections - 35 USC § 103
11. 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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
12. Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Spencer et al. (PGPUB 2015/0017137, published on 1/15/2015), in view of both Lopez et al. (Blood, 2012, 120: 839; Abstract) and Lamb et al. (PLOS One, 2013, 8: 1-9).
Spencer et al. teach a method for treating glioblastoma (GBM) by administering to a human subject temozolomide (TMZ) and isolated human [Symbol font/0x67][Symbol font/0x64] T-cells genetically modified to express MGMT (same as AGT) or P140KMGMT, where at least 50% of the isolated [Symbol font/0x67][Symbol font/0x64] T-cells are genetically modified; the genetically-modified [Symbol font/0x67][Symbol font/0x64] T-cells are TMZ-resistant (claims 1-3, 5, 6, 10, and 15) (see [0015]; [0066]; [0090]; [0100]; [0108]-[0110]; [0115]-[0122]; [0127]-[0128]; [0131]; [0134]-[0137]; [0140]; [0142]-[0143]; claims 1-3 and 9).
Spencer et al. do not teach administering an inhibitor targeting PD-L1, where the inhibitor is the monoclonal antibody B7-H1 (claims 1 and 7-9). Lopez et al. teach that [Symbol font/0x67][Symbol font/0x64] T-cells undergo apoptosis in tumor-bearing subjects due to upregulated PD-1 expression upon contact with the tumor cells and that disrupting the PD-1 pathway by the addition of an anti-PD-L1 monoclonal antibody inhibits apoptosis and restores proliferation. Lopez et al. suggest disrupting the PD-1 pathway in vivo by using an anti-PD-L1 monoclonal antibody to revive the [Symbol font/0x67][Symbol font/0x64] T-cells in tumor-bearing subjects (see Abstract). Thus, one of skill in the art would have found obvious to further administer an anti-PD-L1 monoclonal antibody with the reasonable expectation that doing so would lead to enhanced therapy via reviving the [Symbol font/0x67][Symbol font/0x64] T-cells.
With respect to claims 11-13, Spencer et al. teach that [Symbol font/0x67][Symbol font/0x64] T-cells could also be modified to express dihydrofolate reductase (DHFR) and that the human subject is treated with a combination of temozolomide and methotrexate (see [0100]; claims 1 and 4-7).
With respect to claim 14, one of skill in the art would have found obvious to administer B7-H1 and the MGMT or P140KMGMT-expressing [Symbol font/0x67][Symbol font/0x64] T-cells either simultaneously or sequentially with the reasonable expectation that doing so would identify the regimen resulting in optimal therapy.
Spencer et al. do not specifically teach NK cells (claims 4 and 16-18). Lamb et al. teach a population of cells genetically-modified to express P140KMGMT suitable to treat GBM; the population comprises ≥ 80% [Symbol font/0x67][Symbol font/0x64] T-cells, ≤ 5% αβ T-cells, and ≤15% NK cells (see Abstract; p. 1, column 2, last paragraph; p. 2, column 1, first, second, and fourth paragraphs, paragraph bridging columns 1 and 2; p. 5, column 2). Using this population in the method of Spencer et al., Lopez et al., and Reardon et al. would have been obvious to one of skill in the art with the reasonable expectation that doing so would treat GM in the human subjects. While not specifically taught, one of skill in the art would have reasonably expected that at least 50% of the ≥ 80% [Symbol font/0x67][Symbol font/0x64] T-cells would express P140KMGMT.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
13. Claims 1-6, 10, 15, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Spencer et al., in view of Nishimura et al. (Cell Stem Cell 2013, 12: 114-126; of record in the parent application 16/715,692).
Spencer et al. teach a method for treating GBM by administering to a human subject temozolomide (TMZ) and isolated human [Symbol font/0x67][Symbol font/0x64] T-cells or NK cells genetically modified to express P140KMGMT or MGMT, where at least 50% of the isolated [Symbol font/0x67][Symbol font/0x64] T-cells or NK cells are genetically modified; the genetically-modified [Symbol font/0x67][Symbol font/0x64] T-cells or NK cells are TMZ-resistant (claims 1-3, 10, and 15) (see [0015]; [0066]; [0090]-[0091]; [0100]; [0108]-[0110]; [0115]-[0122]; [0127]-[0128]; [0131]; [0134]-[0137]; [0140]; [0142]-[0143]).
Spencer et al. do not teach that the human [Symbol font/0x67][Symbol font/0x64] T-cells or NK cells are derived from
hiPSCs (claims 19 and 20). Nishimura et al. teach that reprogramming T-cells to iPSCs and redifferentiating the resulting iPSCs back to T-cells rejuvenates the T-cells and enhances their therapeutic potential (see Abstract; p. 114; p. 115, column 1, first full
paragraph; p. 123, column 2, second full paragraph). Although Nishimura et al. do not specifically teach [Symbol font/0x67][Symbol font/0x64] T-cells and NK cells, one of skill in the art would have reasonably concluded that Nishimura’s teachings could be also applied to other immune cells. One of skill in the art would have found obvious to obtain human [Symbol font/0x67][Symbol font/0x64] T-cells and NK cells from hiPSCs and further use the resultant human [Symbol font/0x67][Symbol font/0x64] T-cells or NK cells in the method of Spencer et al., with the reasonable expectation that doing so would result in enhanced therapy. Furthermore, since Spencer et al. teach that both [Symbol font/0x67][Symbol font/0x64] T-cells and NK cells could be used to treat GBM, one of skill in the art would have found obvious to combine the genetically modified [Symbol font/0x67][Symbol font/0x64] T-cells and NK cells, to achieve the predictable result of obtaining a composition suitable for treating GBM (claims 4-6 and 21). MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
14. No claim is allowed. No claim is free or prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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