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 .
Status of the Claims
1. Claims 1-47 are the original claims filed 6/7/2019. In the Response of 9/10/2019, claims 5, 6, 10, 20, 22, 24, 28, and 29 are amended and claims 2, 7-8, 11-19, 21, 25-26, 30, 32, 35, 39, 41, 43, and 45 are cancelled. In the Response of 4/21/2022, Claims 1, 3, 10, 28, and 31 are amended, and claims 42, 44, 46, and 47 are canceled. In the Response of 11/14/2022, claims 1, 3-6, 10, 20, 27-29, 31, 33, 36-38, and 48 are amended. In the Response of 4/10/2023, claims 1, 4, 9, 10, 20, 24, 29, 34, 36, 37, and 48 are amended and new Claims 50-55 are added. In the Response of 7/25/2023, claims 1, 6, 9, 20, 28, 31, 37, 50-52, and 55 are amended, claim 54 is cancelled, and new claims 56-58 are added. In the Response of 12/19/2023, claims 6, 9, 23, 36, 40, 48, 56, and 57 are amended, claims 3, 4, 37, 38, and 49 are cancelled, and new claims 59-61 are added. In the Response of 4/3/2024, Claims 1, 5, 6, 27, 31, 55, and 59 are amended, and Claim 29 is cancelled. In the Response of 11/1/2024, Claims 1, 5-6, 9, 31, 36, and 58-59 are amended and Claims 48 and 55 are canceled. In the Response of 8/12/2025, no amendments are made to the claims. In the Response of 4/14/2026, no amendments are made to the claims.
Applicant’s election without traverse of BTK inhibitor and ibrutinib in the reply filed on 4/21/2022 is acknowledged. Claims 6, 34 and 59 are withdrawn.
Claims 1, 5-6, 9-10, 20, 22-24, 27-28, 31, 33-34, 36, 40, 50-53, and 56-61 are pending.
Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are the claims under examination.
This Office Action contains new grounds for rejection.
Priority
2. USAN 16/435,257, filed 06/07/2019, and having 4 RCE-type filing therein, is a Divisional of 14/680,860, filed 04/07/2015, now U.S. Patent # 10357514 and having 2 RCE-type filing therein, 14/680,860 Claims Priority from Provisional Application 62/097,278, filed 12/29/2014, 14/680,860 Claims Priority from Provisional Application 62/087,888, filed 12/05/2014, 14/680,860 Claims Priority from Provisional Application 62/076,238, filed 11/06/2014, 14/680,860 Claims Priority from Provisional Application 62/036,493, filed 08/12/2014, 14/680,860 Claims Priority from Provisional Application 62/007,309, filed 06/03/2014, 14/680,860 Claims Priority from Provisional Application 61/976,396, filed 04/07/2014.
Information Disclosure Statement
3. As of 5/24/2026, a total of sixteen (16) IDS are filed: 9/10/2019; 9/10/2019; 9/10/2019; 9/10/2019; 9/10/2019; 4/21/2022; 11/14/2022; 4/10/2023; 7/25/2023; 12/19/2023; 4/3/2024; 7/2/2024; 11/1/2024; 1/16/2025; 8/12/2025; and 4/14/2026. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Rejections
Claim Rejections - 35 USC § 103
4. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 is/are rejected under 35 U.S.C. 103 as being obvious over Porter et al (IDS 1/16/2025; ref #3; Porter 1) or Porter et al (N Engl J Med. 2011 August 25; 365(8): 725–733; Porter 2) as evidenced by the specification and in view of NCT01029366 (12/9/2009), U.S. Patent No. 10221245 (USAN 14/214,728) and WO 2014/018567 (filing date 7/23/202013) is maintained and as evidenced by Rada et al (Oncotarget, 2017, Vol. 8, (No. 63), pp: 106639-106647) is withdrawn.
Double Patenting
5. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11975026 is withdrawn.
The claims 20-23 of 11975026 do not recite the hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR. The specification of 11975026 supports a CD19 CAR-expressing cell used in combination with a kinase inhibitor:
(493) In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., a CDK4 inhibitor described herein, e.g., a CD4/6 inhibitor, such as, e.g., 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (also referred to as palbociclib or PD0332991). In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., a BTK inhibitor described herein, such as, e.g., ibrutinib. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., an mTOR inhibitor described herein, such as, e.g., rapamycin, a rapamycin analog, OSI-027. The mTOR inhibitor can be, e.g., an mTORC1 inhibitor and/or an mTORC2 inhibitor, e.g., an mTORC1 inhibitor and/or mTORC2 inhibitor described herein. In one embodiment, the kinase inhibitor is a MNK inhibitor, e.g., a MNK inhibitor described herein, such as, e.g., 4-amino-5-(4-fluoroanilino)-pyrazolo[3,4-d] pyrimidine. The MNK inhibitor can be, e.g., a MNK1a, MNK1b, MNK2a and/or MNK2b inhibitor. In one embodiment, the kinase inhibitor is a DGK inhibitor, e.g., a DGK inhibitor described herein, such as, e.g., DGKinh1 (D5919) or DGKinh2 (D5794). In one embodiment, the kinase inhibitor is a CDK4 inhibitor selected from aloisine A; flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone; crizotinib (PF-02341066; 2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF265); indisulam (E7070); roscovitine (CYC202); palbociclib (PD0332991); dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS 387032); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438); and XL281 (BMS908662).
(494) In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., palbociclib (PD0332991), and the palbociclib is administered at a dose of about 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg (e.g., 75 mg, 100 mg or 125 mg) daily for a period of time, e.g., daily for 14-21 days of a 28 day cycle, or daily for 7-12 days of a 21 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of palbociclib are administered.
(495) In one embodiment, the kinase inhibitor is a BTK inhibitor selected from ibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13.
(496) In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., ibrutinib (PCI-32765), and the ibrutinib is administered at a dose of about 250 mg, 300 mg, 350 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg (e.g., 250 mg, 420 mg or 560 mg) daily for a period of time, e.g., daily for 21 day cycle cycle, or daily for 28 day cycle.
(497) In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of ibrutinib are administered.
6. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 on the ground of nonstatutory double patenting as being unpatentable over claims claims 1-12 U.S. Patent No. 12344651 (formerly claims 33-49 of copending Application No. 18/617912 (reference application US 20240390492)) is withdrawn.
The claims of 12344651 do not recite a hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR. The specification of 12344651 supports a CD19 CAR-expressing cell used in combination with a kinase inhibitor:
(493) In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., a CDK4 inhibitor described herein, e.g., a CD4/6 inhibitor, such as, e.g., 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (also referred to as palbociclib or PD0332991). In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., a BTK inhibitor described herein, such as, e.g., ibrutinib. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., an mTOR inhibitor described herein, such as, e.g., rapamycin, a rapamycin analog, OSI-027. The mTOR inhibitor can be, e.g., an mTORC1 inhibitor and/or an mTORC2 inhibitor, e.g., an mTORC1 inhibitor and/or mTORC2 inhibitor described herein. In one embodiment, the kinase inhibitor is a MNK inhibitor, e.g., a MNK inhibitor described herein, such as, e.g., 4-amino-5-(4-fluoroanilino)-pyrazolo[3,4-d] pyrimidine. The MNK inhibitor can be, e.g., a MNK1a, MNK1b, MNK2a and/or MNK2b inhibitor. In one embodiment, the kinase inhibitor is a DGK inhibitor, e.g., a DGK inhibitor described herein, such as, e.g., DGKinh1 (D5919) or DGKinh2 (D5794). In one embodiment, the kinase inhibitor is a CDK4 inhibitor selected from aloisine A; flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone; crizotinib (PF-02341066; 2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF265); indisulam (E7070); roscovitine (CYC202); palbociclib (PD0332991); dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS 387032); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438); and XL281 (BMS908662).
(494) In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., palbociclib (PD0332991), and the palbociclib is administered at a dose of about 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg (e.g., 75 mg, 100 mg or 125 mg) daily for a period of time, e.g., daily for 14-21 days of a 28 day cycle, or daily for 7-12 days of a 21 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of palbociclib are administered.
(495) In one embodiment, the kinase inhibitor is a BTK inhibitor selected from ibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13.
(496) In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., ibrutinib (PCI-32765), and the ibrutinib is administered at a dose of about 250 mg, 300 mg, 350 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg (e.g., 250 mg, 420 mg or 560 mg) daily for a period of time, e.g., daily for 21 day cycle cycle, or daily for 28 day cycle.
(497) In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of ibrutinib are administered.
7. The provisional rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 30, 33, 42-43, 49, 53, 59, 61, 63, 65-66, 84, 140, 149-153, and 160-161 of copending Application No. 17/104,983 (reference application US 20210220404, now USAN 12383601) is withdrawn.
The claims of 12383601 do not recite a hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
8. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10221245 (USAN 14/214,728); 10253086 (USAN 15/094,674); 10273300 (USAN 14/981,142); 10525083 (USAN 15/727,402); 10774388 (USAN 15/517,597); 10829735 (USAN 15/216,036); 10927184 (USAN 16/192,375); 11026976 (USAN 16/664,223); 11149076 (USAN 16/256,731);
The claims of 12383601, 10273300, 10525083, 10829735, 10927184, 11026976, 11149076 do not recite a hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
The claims of 10253086 do recite a hematological cancer being treated by a cell-associated CD19CAR but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
The claims of 10774388 do recite a hematological cancer being treated by a cell-associated CD22 CAR (that may include a CD19CAR) but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
9. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10711282 is withdrawn.
The claims of 10711282 do not recite a hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
10. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-94 of U.S. Patent No. 9573988 is withdrawn.
The claims of 9573988 do not recite a hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
11. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of U.S. Patent No. 11028177 is withdrawn.
The claims of 11028177 do not recite a hematological cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
12. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11273219 is maintained.
The claims of 11273219 do recite a hematological cancer being treated by a cell-associated CD19CAR but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
13. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10603378 is withdrawn.
The claims of 10603378 do recite a hematological cancer being treated by a cell-associated CD19CAR but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
14. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of 154-55, 57-81 of U.S. Patent No. 12344657 (formerly copending Application No. 17/464,528 (reference application US 20220195010)) is withdrawn.
The claims of 12344657 do recite a hematological cancer being treated by a cell-associated CD19CAR but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
15. The provisional rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of copending Application No. 18/339,565 (reference application US 20230374105) is withdrawn.
The claims of 18/339,565 do recite a cancer being treated by a cell-associated CD19CAR but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
16. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No. 11872249 is withdrawn.
The claims of 11872249 do recite a hematological cancer being treated by a cell-associated CD20 CAR (that may include a CD19CAR) but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
17. The rejection of Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18/529,915 (reference application US 20240252538; now USPN 12594321) is withdrawn.
The claims of 12594321 do recite a hematological cancer being treated by a cell-associated CD19 CAR but there is no proviso of the patient cancer being resistant, relapsed or partially responsive to a BTK inhibitor such as ibrutinib as a qualification to receive a cell-associated CD19CAR.
New Grounds for Rejection
Claim Rejections – 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection I, a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
19. Claim 24(ii) is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 24(ii) recites “a sequence of CD27, a functional signaling domain of CD3 zeta, or both.”
Claim 24 is drawn to the intracellular signaling domain of claim 10. Claim 24 (i) and (iii)-(vi) are clear in reciting the component is a signaling domain, whereas Claim 24(ii) is drawn to any sequence of CD27, and is therefore a broadening limitation within its own claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
20. Claims 1, 5, 9-10, 20, 22-24, 27-28, 31, 33, 36, 40, 50-53, 56-58 and 60-61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for CAR19-transfected normal CD4/CD8 cells or PBMC (T cells) in treating an ibrutinib-resistant cancer model (Jeko-1 cell line) in a clinically relevant single dose, does not reasonably provide enablement for any population of cells expressing a CD19 binding CAR molecule at just any dosage regimen. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
“population of cells” the specification teaches limiting examples of the cell type for expression of the CAR from human immune effector cell to T cells bearing inherent deficiencies:
[0030] In certain embodiments of the compositions and methods disclosed herein, the cell expressing the CAR molecule (also referred to herein as a “CAR-expressing cell”) is a cell or population of cells as described herein, e.g., a human immune effector cell or population of cells (e.g., a human T cell or a human NK cell, e.g., a human T cell described herein or a human NK cell described herein). In one embodiment, the human T cell is a CD8+ T cell. In one embodiment, the cell is an autologous T cell. In one embodiment, the cell is an allogeneic T cell. In one embodiment, the cell is a T cell and the T cell is diaglycerol kinase (DGK) deficient. In one embodiment, the cell is a T cell and the T cell is Ikaros deficient. In one embodiment, the cell is a T cell and the T cell is both DGK and Ikaros deficient. It shall be understood that the compositions and methods disclosed herein reciting the term “cell” encompass compositions and methods comprising one or more cells, e.g., a population of cells.
None of the claims are limited to the nature and kind of population of cells that are suitable for transfection with the CD19-CAR vector and that perform the operation of broadly treating any BKT-resistant or preferably an ibrutinib-resistant hematological cancer in vitro and/or in vivo.
None of the claims are drawn to a dosage amount for the monotherapy of just any cell expressing the CD19CAR to effectuate therapeutic treatment effect on any any BKT-resistant or preferably an ibrutinib-resistant hematological cancer in vitro and/or in vivo.
Disclosure in the Specification
To paraphrase Applicants comments from the Response of 4/14/2026:
“Surprisingly, Applicants demonstrated the technical benefits of the presently claimed methods. For instance, Example 8 describes experiments in which cancer cell lines, including an ibrutinib-resistant cancer cell line, JEKO-1, were treated with CART19 cells.12 Applicants demonstrated through a series of in vitro experiments that treatment of JEKO-1 cells with CART-19 led to degranulation (as measured by percentage of CD107a+ cells), cytokine production (e.g., production of IL-2 and TNF-alpha), cancer cell killing, and CART proliferation.13 Moreover, Applicants performed in vivo experiments in which mice were injected with MCL cell lines, including the ibrutinib-resistant JEKO-1.14 As shown in FIG. 19A, treatment with cells expressing CD19 CAR led to decreased tumor burden in the JEKO-1 MCL mouse model. In summary, Applicants demonstrated that CAR therapy is effective as a monotherapy in ibrutinib-resistant cells, indicating the benefits of a CD 19 CAR treatment in treating a mammal that has a hematological cancer and is a partial responder, refractory, or relapsed to a kinase inhibitor.”
Notably in Example 8, the population of CAR cells is preferential
Generation of CAR Constructs and CAR T Cells.
[0941] The murine anti-CD19 Chimeric antigen receptor (containing a CD8 hinge, 41BB costimulatory domain and CD3 zeta signaling domain) was generated as previously described. See, e.g., Milone et al. Molecular Therapy: the Journal of the American Society of Gene Therapy. 17.8(2009):1453-64. Production of CAR-expressing T cells was performed as previously described. See, e.g., Gill et al. Blood. 123.15(2014):2343-54. Normal donor CD4 and CD8 T cells or PB mononuclear cells (PBMC) were obtained from the Human Immunology Core of the University of Pennsylvania. T cells were plated at 1×10.sup.6/ml, with a CD4:CD8 ratio of 1:1 and expanded in X-vivo 15 media (Lonza, 04-418Q), human serum AB 5% (Gemini, 100-512), penicillin/streptomycin (Gibco, 15070063) and Glutamax (Gibco, 35050061) using anti-CD3/CD28 Dynabeads (Life Technologies, 11161D) added on the day 1 of culture and removed on day 6. T cells were transduced with lentivirus on day 2. T cells were expanded in culture for 8-15 days and harvested when the median cell volume was below 300 fl. T cells were then cryopreserved in FBS 10% DMSO for future experiments. Prior to all experiments, T cells were thawed and rested overnight at 37° C.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19, 24 (CCPA 1970). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
Notably in Example 8 and the conclusions are drawn that at least for in vitro studies, a single dose of the CART was analyzed:
[0978] Different MCL cell lines with variable sensitivities to ibrutinib (IC50 ranging from 10 nM to 10 pM) were used for in vitro experiments. These different cell lines were used to model both ibrutinib-sensitive and ibrutinib-resistant MCL. At all but the highest doses of ibrutinib, CART19 cell function was unimpaired, with intact T cell expansion kinetics, tumor recognition and killing, and cytokine production. Furthermore, the results did not reveal a T helper polarization upon ibrutinib exposure. This finding may be due to a combination of factors, including the use of a mixed culture of CD4 and CD8 cells, in contrast to the model of CD4-only experimentation performed by Dubovksy et al. Blood 122.15(2013):2539-49. Both ibrutinib-sensitive and ibrutinib-resistant cell lines strongly activated CART19 cells and induced killing, cytokine production and proliferation. Combination of CART19 and ibrutinib in vitro led to at least additive tumor killing. The results in this example show a superiority of CART19 over ibrutinib when each was used as monotherapy at clinically relevant doses and schedules of administration (single dose for CART19, continuous administration for ibrutinib).
Notably in Example 8 and the conclusions that are drawn that at least for in vivo studies, a differential dosing of the CART was analyzed:
[0979] A systemic xenograft MCL model was also generated in this example, using the MCL-RL cell line generated in a laboratory. Treatment of these mice with different doses of allogeneic CAR19 T cells led to a dose dependent anti-tumor effect. A similar dose response to CART-19 was also observed in the ibrutinib resistant JEKO-1 cell line. MCL-RL was treated in vivo with different doses (e.g., 0, 25 and 125 mg/kg/day) of Ibrutinib, leading to a median overall survival respectively of 70, 81 and 100 days (p<0.001). A direct in vivo comparison of the ibrutinib 125 mg/kg and CART19 showed a significantly improved tumor control for CART19 treated mice. Also, MCL-RL engrafted mice were treated with vehicle, ibrutinib, CART19 or the combination of CART19 and ibrutinib (iCART19). At clinically relevant doses, monotherapy of MCL with CART19 was superior over monotherapy with ibrutinib, and the combination of ibrutinib with CART19 led to an augmented anti-tumor effect. In particular, the iCART19 combination in vivo led to initially higher circulating levels of CART19 cells, followed by deep tumor responses, and relapses were significantly delayed when ibrutinib was added to CART19. The iCART19 combination resulted in an improved tumor control with 80% of mice reaching complete remission and long-term disease-free survival. Mechanistically, mice treated with ibrutinib had higher numbers of circulating CART19 cells without changes in Th1/Th2 or memory phenotype. Thus, the results herein show that ibrutinib can be combined with CART19 in a rational manner and suggest that the properties of each of these therapies may compensate for deficiencies of the other, thus leading to enhanced long-term anti-tumor effect. The experiments and results of combining BCR signaling inhibition with anti-CD19 directed T cell therapy pave the way to rational combinations of non-cross resistant therapies for B cell malignancies.
The instant specification defines "effective amounts" for a CD19 CART monotherapy in treating BTK- or ibrutinib-resistant hematological cancers, in vitro and in vivo, as discussed in the record prosecution history above. However, the scope of the instant claimed hematological cancers; the nature and kind of “population of cells”, and the “effective amount” is not commensurate in scope with those data relied upon by Applicants in Example 8 that enable the practice (making and use) of the method invention. (See In Alza Corp. v. Andrx Pharmaceuticals LLC, where the court held that claims construed to cover both osmotic and non-osmotic dosages were invalid for lack of enablement.[25] In this case, the court found that "the quantity of experimentation, lack of guidance in the specification, absence of working embodiments, and breadth of the claims demonstrates that. ... [the] patent specification fails to enable a person of ordinary skill to make and use nonosmotic oral dosage.).
Conclusion
21. No claims are allowed.
22. The reference pertinent to the claimed invention is WO 2012079000A1 (published 2012-06-14) that teaches a CD19-CAR (SEQ ID NO: 12 (scfv) having identical VHCDR1-3 and VLCDR1-3 to instant claimed SEQ ID NOS: 19-20-24 and 25-26-27, respectively) used to treat CCL patients with partial response to alemtuzumab, alemtuzumab with bendamustine with rituximab, or rifoximab with fludarabine.
23. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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