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. Claims 1-3, 8, 10-17, 19, 22-35 are pending and being examined.
Priority
2. The instant application claims priority as:
a CIP of PCT/US23/79221 11/09/2023, wherein:
PCT/US23/79221 has PRO 63/589,659 10/12/2023
PCT/US23/79221 has PRO 63/503,977 05/24/2023
PCT/US23/79221 has PRO 63/503,481 05/21/2023
PCT/US23/79221 has PRO 63/383,086 11/10/2022
A review of the priority applications reveals there is no support in any of the provisional applications for the upper range of IL-2 administered at 500,000 IU/kg. The provisional applications disclose administering IL-2 at a dose range of 10x103 IU/kg – 300 x 103 IU/kg, in other words, 10,000 – 300,000 IU/kg at:
PRO 63/589,659 on p. 50-54, [0185-0195];
PRO 63/503,977 on p. 38, [0171];
PRO 63/503,481 on p. 36, [0139]; and
PRO 63/383,086 on p. 33, [0131].
Instant claim 1 comprises a range of IL-2 administered at 15,000 IU/kg – 500,000 IU/kg that encompasses values greater than the upper limit of 300,000 IU/kg disclosed in the provisional applications. PCT/US23/79221 does disclose a range of IL-2 encompassing 15,000 IU/kg – 500,000 IU/kg at claim 3 and paragraph [0197]. Therefore, claims 1-3, 8, 10-17, 19, 22-25, 29, 33-35 encompassing the range of IL-2 15,000 IU/kg – 500,000 IU/kg receive the earliest effective filing date of PCT/US23/79221 November 9, 2023.
Claims 26-28, 30-32, limited to IL-2 doses within the range of 10,000 – 300,000 IU/kg, receive the earliest effective filing date of PRO 63/383,086 November 10, 2022.
Claim Objections
3. Claim 30 is objected to because of the following informalities: Claim 30 references the antibody as “anti-IL-2 antibody” then “IL-2 antibody”. Examiner suggests amending the latter to recite “anti-IL-2 antibody” in order to remain consistent in terminology.
Further, claim 30 recites: The method of claim 30, wherein … (b) the low dose IL-2 comprises administering at least a single loading low dose of IL-2 or multiple low doses of IL-2.
The claim should be amended to recite “(b) wherein administering the low dose of IL-2 comprises administering at least a single loading low dose of IL-2 or multiple low doses of IL-2…” to be grammatically correct because the low dose IL-2 itself cannot comprise any administering steps. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
4. Claims 1-3, 8, 10-17, 19, 22-35 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: “A method of treating a solid cancer in a subject comprising a step of administering to the subject…wherein the low dose of IL-2 comprises between about 15,000 IU/kg of a subject’s body weight – 500,000 IU/kg of a subject’s body weight…”
Claim 30 recites: “A method of treating a solid cancer in a subject comprising a step of administering to the subject…wherein the low dose of IL-2 comprises 135,000 IU/kg of a subject’s body weight…”
Claims 23-28 also recite doses in reference to “a subject’s body weight”.
The claims are unclear with regard to what “subject” the claims are referencing with regard to “a subject’s body weight”. Whose body weight? The subject treated or someone else? Given it is unclear what subject’s weight is being used to determine the IU/kg dose of IL-2 and mg/kg dose of anti-IL-2 antibody, the scope or amount of IU/kg and mg/kg dose administered to the treated subject is unclear. The metes and bounds of the claimed inventions cannot be determined.
Examiner Suggestion: Amend each phrase of “a subject’s body weight” to recite “the subject’s body weight”.
5. Claims 14 and 19 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 14 recites “the tumor” and “said tumor”. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites “the full length heavy chain” and “the full length light chain”. There is insufficient antecedent basis for these limitations in the claim.
6. Claim 31 is 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 31 recites:
The method of claim 30, wherein (a) multiple doses of said anti-IL-2 antibody are administered, wherein optionally the multiple dose administration comprises bi-weekly administration; and (b) the low dose IL-2 comprises administering at least a single loading low dose of IL-2 or multiple low doses of IL-2, said administration is prior to, concurrent with, or following the administration of said anti-IL-2 antibody.
It is unclear which “said administration” the claim is referencing because there are several administrations recited in the claim. It is unclear which “the administration of said anti-IL-2 antibody” the claim is referencing because claim 31 and 30 recite different administrations of anti-IL-2 antibody.
Claim Rejections - 35 USC § 103
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.
7. Claim(s) 1-3, 8, 10-17, 19, 22-35 are rejected under 35 U.S.C. 103 as being unpatentable over Amit et al (Journal of ImmunoTherapy of Cancer, November 10, 2021, 9(Suppl 2):A1-A1054; Abstract 704); in view of WO 2021/161287, Amit et al, published August 19, 2021; and US Patent Application Publication 2018/0094053, Roell et al, published April 2018.
Amit (Journal of ImmunoTherapy of Cancer) teaches successfully treating a solid tumor (B16F10 metastatic melanoma or MC38 colorectal tumor) in a subject, comprising administering to the subject first-line treatment of: (a) 25 µg of Au-007 anti-IL-2 antibody (clone 17.069) complexed with low-dose 1.25 µg hIL-2 and administering the complex dose multiple times, or (b) 20 mg/kg of anti-IL-2 antibody multiple times with a separate dose of IL-2 administered both before and after anti-IL-2 antibody administrations; wherein the tumor was successfully reduced in size and treated (Figures 4 and 7, copied below). Amit teaches tumor treatment with the complex was comparable to treatment with anti-PD-1 checkpoint inhibitor antibody (Figure 7).
Figure 4:
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Figure 7:
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Amit does not teach:
the CDR, VH, VL, heavy chain, and light chain sequences of Au-007 anti-IL-2 antibody (clone 17.069) (claims 1, 15, 19);
the low dose of IL-2 is measured in IU/kg and administered in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight (claims 1, 26-28, 30);
Au-007 is an IgG antibody (claim 16);
the antibody comprises a mutation that reduces binding to an Fcγ receptor such as LALA mutation (claim 17);
further administering a PD-1 immune checkpoint inhibitor such as nivolumab (claims 8, 22, 29) and prior to, concurrent with, or following administration of the anti-IL-2 antibody and/or IL-2 (claims 33-35);
the anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight (claims 23-25 and 30).
subcutaneous administration of the IL-2 (claims 1 and 30).
WO 2021/161287, Amit teaches a method of treating cancer in a subject, the method comprising administering to the subject a combination of IL-2 with anti-IL-2 antibody clone 17.069 that comprises VH SEQ ID NO:26, VL SEQ ID NO:27 (Table 6; claim 2; [93-94]), CDR SEQ ID NOs:62-65, DAS, and 67 (Table 7; [19]; claim 1); heavy chain SEQ ID NO:72 and light chain SEQ ID NO:73 (claim 5; [22]; [98]; claim 2) (claim 19-21; [27-32]; [162-175]; [180]; [182]; [223-225]; [234-235]; [237-238]) (see sequence alignment of heavy and light chains below);
wherein the IL-2 and anti-IL-2 antibody can be administered as a complex together or administered separately, and are administered multiple times and in a pharmaceutical composition ([28]; [108-214]);
wherein a dose of IL-2 is administered before the anti-IL-2 antibody ([118]);
wherein the anti-IL-2 antibody is an IgG, IgA, IgM, IgE, IgD, a Fv, a scFv, a Fab, or a F(ab')2 ([21]; [94]; [99]; [185]; [187]; claim 3);
wherein the anti-IL-2 antibody clone 17.069 is formatted as an IgG and comprises a heavy chain with a mutation that reduces the Fc-gamma binding and comprises L234A, L235A mutations, also known as LALA mutation ([92]; [255-257]; [311]);
wherein the method further comprises administering an immune checkpoint inhibitor that is an antibody against PD-1, such as nivolumab or pembrolizumab (claims 29, 31; Table 1; [125-143]);
wherein the subject is treated with said immune checkpoint inhibitor concurrently, before, or after treatment with said anti-IL-2 antibody (claim 30; [140]; [202]); and
wherein the cancer treated is melanoma, lung cancer, or renal cell carcinoma ([169]; [180]; [329]).
Amit teaches it is known that IL-2 has been used to treat melanoma and metastatic renal cell carcinoma in the past ([7]), and Amit suggests their method maintains a lack of metastasis or inhibits metastasis of a tumor ([170]).
Amit demonstrates that anti-IL-2 antibody/IL-2 complexes successfully treat a metastatic melanoma (B16F10) model in vivo ([329]; Figure 21).
Amit suggests administering IL-2 subcutaneously as a known delivery route for treatment ([113]).
Roell teaches a method of treating cancer in a subject, the method comprising administering to the subject a complex of IL-2 with anti-IL-2 antibody and wherein the complex of IL-2 with anti-IL-2 antibody can be administered multiple times and in a pharmaceutical composition ([58-62]; [88]; [265-270]; [276-281]; [283-301]);
wherein the cancer is melanoma, NSCLC, colon cancer, and more ([2901-291];
wherein the cancer is metastatic or melanoma metastasis ([290]; [293]);
wherein treatment results in reduced tumor size ([294]);
wherein the anti-IL-2 antibody is IgG, scFv, or diabody ([147-149]; [345]); and
the method further comprising administering an immune checkpoint inhibitor that is an anti-PD-1 antibody ([55]; [57]; [273]; [292]).
Roell teaches the anti-IL-2 antibody can be administered at a dose in the range of 0.3 – 30 mg/kg, including a dose of 5, 6, 7, 8, or 9 mg/kg ([323]).
Roell teaches the IL-2 is administered at a low dose when combined with administration of the anti-IL-2 antibody ([63]; [276]; [279]; [281]).
Roell teaches ([276]):
In some embodiments, the IL-2 antibodies are administered in combination with IL-2 or IL-2 variants. In various embodiments, the antibodies can be complexed with IL-2 prior to administration or the IL-2 and IL-2 antibodies can be administered in combination as described herein (Garcia-Martinez and Leon, Intl. Immunol. 24: 427-446 (2012); Spangler et al., Immunity, 42: 815-825; Arenas-Ramirez et al., Trends in Imunol. 36: 763-777). It is contemplated that when the antibodies are administered in combination with IL-2, the amount of IL-2 is less than the therapeutic dose used, e.g., lower than 700,000 international units (I.U)/kg (0.04 mg/kg). In some embodiments, the IL-2 is administered at a dose of about 300,000 to 6000,000 I.U/kg, about 250,000 to 500,000 I.U./kg, about 100,000 to 250,000 I.U./kg, about 10,000 to 100,000 I.U./kg, or about 1,000 to 10,000 I.U./kg. or about 500 to 5,000 I.U./kg.
Roell exemplifies successfully treating a solid tumor (CT26 tumors), including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2, wherein the combination demonstrated improved therapeutic index compared to IL-2 alone (Example 11; Tables 11 and 12; Figures 17 and 18).
CDR, VH, VL, heavy chain, and light chain sequences of Au-007 anti-IL-2 antibody clone 17.069
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the sequences of anti-Il-2 antibody clone 17.069 in the method of Amit (Journal of ImmunoTherapy of Cancer). One would have been motivated to, and have a reasonable expectation of success to, because: Amit (Journal of ImmunoTherapy of Cancer) teaches administering antibody clone 17.069, and Amit (WO 2021/161287) teaches the sequences of antibody clone 17.069 are known and available.
Low dose of IL-2 is administered in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer low doses of IL-2 within the range of 15,000 – 500,000 IU/kg. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit (Journal of ImmunoTherapy of Cancer) teaches and demonstrates administering a low dose of 1.25 µg hIL-2 in combination with a low dose of anti-IL-2 antibody in a mouse model to successfully treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 encompass those in the range of 15,000 – 500,000 IU/kg.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a low dose of IL-2 at 135,000 IU/kg of a subject’s body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit (Journal of ImmunoTherapy of Cancer) teaches and demonstrates administering a low dose of 1.25 µg hIL-2 in combination with a low dose of anti-IL-2 antibody in a mouse model to successfully treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 are in the range of about 100,000 to 250,000 IU/kg, which encompasses 135,000 IU/kg.
Amit (Journal of ImmunoTherapy of Cancer) and Roell teach or demonstrate the success of administering a low dose of IL-2 with anti-IL-2 antibody for the treatment of cancer, teaching lower doses should be given in combination therapy. Given the recognized need administer low dose Il-2 in combination with anti-IL-2 antibody, and given the known range of low doses in IU/kg, one of skill in the art could have pursued treating cancer with the low IL-2 dose of 135,000 IU/kg within the range taught by Roell, and with a reasonable expectation of success.
Anti-IL-2 antibody is an IgG and comprises a mutation that reduces binding to an Fcγ receptor such as LALA mutation
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize anti-Il-2 antibody clone 17.069 as an IgG and with an Fc LALA (L234A, L235A) mutation in the method of Amit (Journal of ImmunoTherapy of Cancer). One would have been motivated to, and have a reasonable expectation of success to, because Amit (Journal of ImmunoTherapy of Cancer) teaches administering antibody clone 17.069 to treat cancer; and (2) Amit (WO 2021/161287) teaches formatting clone 17.069 as an IgG and with an Fc LALA mutation to reduce binding to an Fcγ receptor for therapeutic administration.
Method further administering a PD-1 immune checkpoint inhibitor such as nivolumab, and prior to, concurrent with, or following administration of the anti-IL-2 antibody and/or IL-2
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further administer immune checkpoint inhibitors that bind PD-1, such as nivolumab or pembrolizumab, in the method of Amit (Journal of ImmunoTherapy of Cancer). One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit (Journal of ImmunoTherapy of Cancer) demonstrates the anti-cancer function of anti-PD-1 antibody is known, successful, and comparable to combined cancer treatment with anti-IL-2 antibody 17.069 and IL-2; (2) Amit (WO 2021/161287) suggests combining immune checkpoint inhibitors, such as anti-PD-1 antibodies nivolumab or pembrolizumab, with administration of the anti-IL-2 antibody + IL-2, and teaches administering the immune checkpoint inhibitors prior to, concurrent with, or following administration of the anti-IL-2 antibody. Given the demonstrated success of each of anti-PD-1 antibody and anti-IL-2/IL-2 complexes treating cancer, and given the suggestion to combine them for the same purpose of treat cancer, it is well within the level of ordinary skill in the art to add administration of anti-PD-1 antibodies to the method of Amit (Journal of ImmunoTherapy of Cancer) and to treat cancer with a reasonable expectation of success.
Anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the anti-IL-2 antibody of Amit (Journal of ImmunoTherapy of Cancer) at a dose in the range of 4.5-12 mg/kg of body weight or at 9 mg/kg of body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit (Journal of ImmunoTherapy of Cancer) teaches and demonstrates administering a low dose of 1.25 µg hIL-2 in combination with a low dose of 25 µg anti-IL-2 antibody in a mouse model to successfully treat cancer; (2) Roell teaches administering IL-2 and anti-IL-2 antibody at a lower dose when combined for the treatment of cancer; and (3) Roell teaches therapeutic doses of anti-IL-2 antibody encompass 0.3 – 30 mg/kg, including a specific dose of 5, 6, 7, 8, or 9 mg/kg.
Subcutaneous administration of IL-2
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the IL-2 subcutaneously. One would have been motivated to, and have a reasonable expectation of success to, because Amit (WO 2021/161287) suggests administering IL-2 subcutaneously as a known delivery route for treatment of cancer in combination with anti-IL-2 antibody.
Instant anti-IL-2 antibody 17.069 heavy chain SEQ ID NO:72 aligned with Amit (WO 2021/161287) SEQ ID NO:72
RESULT 1
BJU46559
ID BJU46559 standard; protein; 451 AA.
XX
AC BJU46559;
XX
DT 30-SEP-2021 (first entry)
XX
DE Anti-IL2 humanized mAb heavy chain region, SEQ ID 72.
XX
KW IL2 protein; Interleukin-2 ligand; antibacterial; antibody therapy;
KW bacterial infection; cancer; chimeric antibody; cytostatic; heavy chain;
KW humanized antibody; immunization; mutein; prophylactic to disease;
KW therapeutic; viral infection; virucide.
XX
OS Rattus sp.
OS Mus sp.
OS Chimeric.
OS Synthetic.
XX
CC PN WO2021161287-A2.
XX
CC PD 19-AUG-2021.
XX
CC PF 15-FEB-2021; 2021WO-IB051267.
XX
PR 16-FEB-2020; 2020US-0977292P.
PR 20-JAN-2021; 2021US-0139315P.
XX
CC PA (AULO-) AULOS BIOSCI INC.
XX
CC PI Amit I, Levin I, Nimrod G, Fischman S, Barak Fuchs R, Strajbl M;
CC PI Wyant T, Zhenin M, Bluvshtein Yermolaev O, Sasson Y, Grossman N;
CC PI Levitin N, Ofran Y;
XX
DR WPI; 2021-966825/074.
XX
CC PT Isolated anti-IL-2 antibody used in composition for treating disease or
CC PT condition and immunizing subject, where disease is viral infection, and
CC PT bacterial infection, comprises heavy chain variable region and light
CC PT chain variable region.
XX
CC PS Claim 5; SEQ ID NO 72; 148pp; English.
XX
CC The present invention relates to a novel isolated antibody which
CC specifically binds to an interleukin-2 (IL-2) protein. The anti-IL2
CC antibody comprises a heavy chain variable (VH) region selected from SEQ
CC ID NO: 10-26 (only even numbers, see BJU46497-BJU46513) and SEQ ID NO: 36
CC (see BJU46523) and a light chain variable (VL) region selected from SEQ
CC ID NO: 11-27 (only odd numbers, see BJU46498-BJU46514) and SEQ ID NO: 37
CC (see BJU46524). The invention further claims: (1) a composition comprises
CC the anti-IL2 antibody and a pharmaceutically acceptable carrier; (2) an
CC isolated polynucleotide sequence encoding the anti-IL2 antibody; (3) a
CC vector comprising the polynucleotide; (4) a host cell comprising the
CC vector; (5) a method for treating a disease or a condition; and (6) a
CC method for immunizing a subject. The anti-IL2 antibody of the present
CC invention is used for preventing and treating viral infection, bacterial
CC infection or cancer.
XX
SQ Sequence 451 AA;
Query Match 100.0%; Score 2409; Length 451;
Best Local Similarity 100.0%;
Matches 451; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGSSVKVSCKASGYSITDDLIHWVRQAPGQGLEWMGWIDPEDGETNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGSSVKVSCKASGYSITDDLIHWVRQAPGQGLEWMGWIDPEDGETNY 60
Qy 61 AQKFQGRVTLTADTSTSTAYMELSSLRSEDTAVYYCARSLDSTWIYPFAYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTLTADTSTSTAYMELSSLRSEDTAVYYCARSLDSTWIYPFAYWGQGTLVTVS 120
Qy 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
Qy 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAG 240
Qy 241 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 300
Qy 301 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 360
Qy 361 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 420
Qy 421 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 451
|||||||||||||||||||||||||||||||
Db 421 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 451
Instant anti-IL-2 antibody 17.069 light chain SEQ ID NO:73 aligned with Amit (WO 2021/161287) SEQ ID NO:73
RESULT 1
BJU46560
ID BJU46560 standard; protein; 220 AA.
XX
AC BJU46560;
XX
DT 30-SEP-2021 (first entry)
XX
DE Anti-IL2 humanized mAb light chain region, SEQ ID 73.
XX
KW IL2 protein; Interleukin-2 ligand; antibacterial; antibody therapy;
KW bacterial infection; cancer; chimeric antibody; cytostatic;
KW humanized antibody; immunization; light chain; mutein;
KW prophylactic to disease; therapeutic; viral infection; virucide.
XX
OS Rattus sp.
OS Mus sp.
OS Chimeric.
OS Synthetic.
XX
CC PN WO2021161287-A2.
XX
CC PD 19-AUG-2021.
XX
CC PF 15-FEB-2021; 2021WO-IB051267.
XX
PR 16-FEB-2020; 2020US-0977292P.
PR 20-JAN-2021; 2021US-0139315P.
XX
CC PA (AULO-) AULOS BIOSCI INC.
XX
CC PI Amit I, Levin I, Nimrod G, Fischman S, Barak Fuchs R, Strajbl M;
CC PI Wyant T, Zhenin M, Bluvshtein Yermolaev O, Sasson Y, Grossman N;
CC PI Levitin N, Ofran Y;
XX
DR WPI; 2021-966825/074.
XX
CC PT Isolated anti-IL-2 antibody used in composition for treating disease or
CC PT condition and immunizing subject, where disease is viral infection, and
CC PT bacterial infection, comprises heavy chain variable region and light
CC PT chain variable region.
XX
CC PS Claim 5; SEQ ID NO 73; 148pp; English.
XX
CC The present invention relates to a novel isolated antibody which
CC specifically binds to an interleukin-2 (IL-2) protein. The anti-IL2
CC antibody comprises a heavy chain variable (VH) region selected from SEQ
CC ID NO: 10-26 (only even numbers, see BJU46497-BJU46513) and SEQ ID NO: 36
CC (see BJU46523) and a light chain variable (VL) region selected from SEQ
CC ID NO: 11-27 (only odd numbers, see BJU46498-BJU46514) and SEQ ID NO: 37
CC (see BJU46524). The invention further claims: (1) a composition comprises
CC the anti-IL2 antibody and a pharmaceutically acceptable carrier; (2) an
CC isolated polynucleotide sequence encoding the anti-IL2 antibody; (3) a
CC vector comprising the polynucleotide; (4) a host cell comprising the
CC vector; (5) a method for treating a disease or a condition; and (6) a
CC method for immunizing a subject. The anti-IL2 antibody of the present
CC invention is used for preventing and treating viral infection, bacterial
CC infection or cancer.
XX
SQ Sequence 220 AA;
Query Match 100.0%; Score 1138; Length 220;
Best Local Similarity 100.0%;
Matches 220; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLRRGNQKNHLAWYQQKPGQPPKLLIYDASTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLRRGNQKNHLAWYQQKPGQPPKLLIYDASTG 60
Qy 61 QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLQSYITPPTFGAGTKVEIKRTVAAPS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLQSYITPPTFGAGTKVEIKRTVAAPS 120
Qy 121 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 180
Qy 181 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 220
||||||||||||||||||||||||||||||||||||||||
Db 181 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 220
8. Claim(s) 1-3, 8, 10-17, 19, 22-35 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/161287, Amit et al, published August 19, 2021; in view of US Patent Application Publication 2018/0094053, Roell et al, published April 2018.
WO 2021/161287, Amit teaches a method of treating cancer in a subject, the method comprising administering to the subject a combination of IL-2 with anti-IL-2 antibody clone 17.069 that comprises VH SEQ ID NO:26, VL SEQ ID NO:27 (Table 6; claim 2; [93-94]), CDR SEQ ID NOs:62-65, DAS, and 67 (Table 7; [19]; claim 1); heavy chain SEQ ID NO:72 and light chain SEQ ID NO:73 (claim 5; [22]; [98]; claim 2) (claim 19-21; [27-32]; [162-175]; [180]; [182]; [223-225]; [234-235]; [237-238]);
wherein the IL-2 and anti-IL-2 antibody can be administered as a complex together or separately, and are administered multiple times and in a pharmaceutical composition; wherein doses of Anti-IL-2 antibody occur before, concurrently, or following administration of IL-2 ([28]; [118]; [178]);
wherein the anti-IL-2 antibody is an IgG, IgA, IgM, IgE, IgD, a Fv, a scFv, a Fab, or a F(ab')2 ([21]; [94]; [99]; [185]; [187]; claim 3);
wherein the anti-IL-2 antibody clone 17.069 further comprises a heavy chain with a mutation that reduces the Fc-gamma binding and comprises L234A, L235A mutations, also known as LALA mutation ([92]; [255]; [311]);
wherein a dose of IL-2 is administered before the anti-IL-2 antibody ([118]);
wherein IL-2 is administered subcutaneously ([113]);
wherein the method further comprises administering an immune checkpoint inhibitor that is an antibody against PD-1, such as nivolumab or pembrolizumab (claim 29, 31; Table 1; [125-143]);
wherein the subject is treated with said immune checkpoint inhibitor concurrently, before, or after treatment with said anti-IL-2 antibody (claim 30; [139-140]; [202]);
wherein the cancer treated is melanoma, lung cancer, or renal cell carcinoma ([169]; [180]; [329]).
Amit teaches it is known that IL-2 has been used to treat melanoma and metastatic renal cell carcinoma in the past ([7]), and Amit suggests their method maintains a lack of metastasis or inhibits metastasis of a tumor ([170]).
Amit demonstrates that anti-IL-2 antibody/IL-2 complexes as a first-line therapy successfully treat a metastatic melanoma (B16F10) model in vivo ([329]; Figure 21).
WO 2021/161287, Amit does not teach:
the IL-2 is administered at a low dose in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight (claims 1, 26-28, 30);
the anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight (claims 23-25 and 30); or
the cancer is metastatic (claims 10 and 32).
Roell teaches a method of treating cancer in a subject, the method comprising administering to the subject a complex of IL-2 with anti-IL-2 antibody and wherein the complex of IL-2 with anti-IL-2 antibody can be administered multiple times and in a pharmaceutical composition ([58-62]; [88]; [265-270]; [276-281]; [283-301]);
wherein the cancer is melanoma, NSCLC, colon cancer, and more ([2901-291];
wherein the cancer is metastatic or melanoma metastasis ([290]; [293]);
wherein treatment results in reduced tumor size ([294]);
wherein the anti-IL-2 antibody is IgG, scFv, or diabody ([147-149]; [345]); and
the method further comprising administering an immune checkpoint inhibitor that is an anti-PD-1 antibody ([55]; [57]; [273]; [292]).
Roell teaches the anti-IL-2 antibody can be administered at a dose in the range of 0.3 – 30 mg/kg, including a dose of 5, 6, 7, 8, or 9 mg/kg ([323]).
Roell teaches the IL-2 is administered at a low dose when combined with administration of the anti-IL-2 antibody ([63]; [276]; [279]; [281]).
Roell teaches ([276]):
In some embodiments, the IL-2 antibodies are administered in combination with IL-2 or IL-2 variants. In various embodiments, the antibodies can be complexed with IL-2 prior to administration or the IL-2 and IL-2 antibodies can be administered in combination as described herein (Garcia-Martinez and Leon, Intl. Immunol. 24: 427-446 (2012); Spangler et al., Immunity, 42: 815-825; Arenas-Ramirez et al., Trends in Imunol. 36: 763-777). It is contemplated that when the antibodies are administered in combination with IL-2, the amount of IL-2 is less than the therapeutic dose used, e.g., lower than 700,000 international units (I.U)/kg (0.04 mg/kg). In some embodiments, the IL-2 is administered at a dose of about 300,000 to 6000,000 I.U/kg, about 250,000 to 500,000 I.U./kg, about 100,000 to 250,000 I.U./kg, about 10,000 to 100,000 I.U./kg, or about 1,000 to 10,000 I.U./kg. or about 500 to 5,000 I.U./kg.
Roell exemplifies successfully treating a solid tumor (CT26 tumors), including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2, wherein the combination demonstrated improved therapeutic index compared to IL-2 alone (Example 11; Tables 11 and 12; Figures 17 and 18).
Low dose of IL-2 is administered in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer low doses of IL-2 within the range of 15,000 – 500,000 IU/kg. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 encompass those in the range of 15,000 – 500,000 IU/kg.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a low dose of IL-2 at 135,000 IU/kg of a subject’s body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 are in the range of about 100,000 to 250,000 IU/kg, which encompasses 135,000 IU/kg.
Amit and Roell teach or demonstrate the success of administering IL-2 with anti-IL-2 antibody for the treatment of cancer, wherein Roell teaches lower IL-2 doses should be given in combination therapy with anti-IL-2 antibody. Given the recognized need administer low dose Il-2 in combination with anti-IL-2 antibody, and given the known range of low doses in IU/kg, one of skill in the art could have pursued treating cancer with the low IL-2 dose of 135,000 IU/kg within the range taught by Roell, and with a reasonable expectation of success.
Anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the anti-IL-2 antibody of Amit at a dose in the range of 4.5-12 mg/kg of body weight or at 9 mg/kg of body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 and anti-IL-2 antibody at a lower dose when combined for the treatment of cancer; and (3) Roell teaches therapeutic doses of anti-IL-2 antibody encompass 0.3 – 30 mg/kg, including a specific dose of 5, 6, 7, 8, or 9 mg/kg.
Cancer treated is metastatic
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat metastatic cancer in the method of Amit. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches it is known that IL-2 has been used to treat metastatic renal cell carcinoma in the past ; (2) Amit suggests their method administering IL-2 and anti-IL-2 antibody maintains a lack of metastasis or inhibits metastasis of a tumor; (3) Amit demonstrates that anti-IL-2 antibody/IL-2 complexes successfully treat a metastatic melanoma (B16F10) model in vivo; and (4) Roell suggests treating cancer that is metastatic or treating melanoma metastasis by administering IL-2 and anti-IL-2 antibody.
9. Claim(s) 1-3, 8, 10-17, 19, 22-35 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 11,851,485, “Amit”, (claiming priority to February 2020) in view of US Patent Application Publication 2018/0094053, Roell et al, published April 2018.
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
U.S. Patent No. 11,851,485 “Amit” comprises the same disclosure as, and claims priority to, WO 2021/161287, Amit et al, as cited above.
US Patent does not disclose:
the IL-2 is administered at a low dose in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight (claims 1, 26-28, 30);
the anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight (claims 23-25 and 30); or
the cancer is metastatic (claims 10 and 32).
Roell discloses as set forth above.
Low dose of IL-2 is administered in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer low doses of IL-2 within the range of 15,000 – 500,000 IU/kg. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 encompass those in the range of 15,000 – 500,000 IU/kg.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a low dose of IL-2 at 135,000 IU/kg of a subject’s body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 are in the range of about 100,000 to 250,000 IU/kg, which encompasses 135,000 IU/kg.
Amit and Roell teach or demonstrate the success of administering IL-2 with anti-IL-2 antibody for the treatment of cancer, wherein Roell teaches lower IL-2 doses should be given in combination therapy with anti-IL-2 antibody. Given the recognized need administer low dose Il-2 in combination with anti-IL-2 antibody, and given the known range of low doses in IU/kg, one of skill in the art could have pursued treating cancer with the low IL-2 dose of 135,000 IU/kg within the range taught by Roell, and with a reasonable expectation of success.
Anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the anti-IL-2 antibody of Amit at a dose in the range of 4.5-12 mg/kg of body weight or at 9 mg/kg of body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 and anti-IL-2 antibody at a lower dose when combined for the treatment of cancer; and (3) Roell teaches therapeutic doses of anti-IL-2 antibody encompass 0.3 – 30 mg/kg, including a specific dose of 5, 6, 7, 8, or 9 mg/kg.
Cancer treated is metastatic
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat metastatic cancer in the method of Amit. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches it is known that IL-2 has been used to treat metastatic renal cell carcinoma in the past ; (2) Amit suggests their method administering IL-2 and anti-IL-2 antibody maintains a lack of metastasis or inhibits metastasis of a tumor; (3) Amit demonstrates that anti-IL-2 antibody/IL-2 complexes successfully treat a metastatic melanoma (B16F10) model in vivo; and (4) Roell suggests treating cancer that is metastatic or treating melanoma metastasis by administering IL-2 and anti-IL-2 antibody.
10. Claim(s) 1-3, 8, 10-17, 19, 22-35 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 12,275,784, “Amit”, (claiming priority to February 2020) in view of US Patent Application Publication 2018/0094053, Roell et al, published April 2018.
U.S. Patent No. 12,275,784 “Amit” comprises the same disclosure as, and claims priority to, WO 2021/161287, Amit et al, as cited above.
US Patent does not disclose:
the IL-2 is administered at a low dose in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight (claims 1, 26-28, 30);
the anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight (claims 23-25 and 30); or
the cancer is metastatic (claims 10 and 32).
Roell discloses as set forth above.
Low dose of IL-2 is administered in the range of 15,000 IU/kg – 500,000 IU/kg, or is 135,000 IU/kg of a subject’s body weight:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer low doses of IL-2 within the range of 15,000 – 500,000 IU/kg. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 encompass those in the range of 15,000 – 500,000 IU/kg.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a low dose of IL-2 at 135,000 IU/kg of a subject’s body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 at a low dose when combined with anti-IL-2 antibody for the treatment of cancer because a lower therapeutic dose is required when the two are combined; (3) Roell demonstrates successfully treating a solid tumor, including reducing tumor growth, in a subject by administering to the subject a combination of anti-IL-2 antibody and low or very low dose of IL-2; and (4) Roell teaches low doses of IL-2 are in the range of about 100,000 to 250,000 IU/kg, which encompasses 135,000 IU/kg.
Amit and Roell teach or demonstrate the success of administering IL-2 with anti-IL-2 antibody for the treatment of cancer, wherein Roell teaches lower IL-2 doses should be given in combination therapy with anti-IL-2 antibody. Given the recognized need administer low dose Il-2 in combination with anti-IL-2 antibody, and given the known range of low doses in IU/kg, one of skill in the art could have pursued treating cancer with the low IL-2 dose of 135,000 IU/kg within the range taught by Roell, and with a reasonable expectation of success.
Anti-IL-2 antibody is administered at a dose of about 0.5 mg/kg-12 mg/kg of the subject’s body weight, or at about 4.5 – 12 mg/kg, at about 9-12 mg/kg of a subject’s body weight or at 9 mg/kg of a subject’s body weight
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the anti-IL-2 antibody of Amit at a dose in the range of 4.5-12 mg/kg of body weight or at 9 mg/kg of body weight. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches administering IL-2 in combination with anti-IL-2 antibody to treat cancer; (2) Roell teaches administering IL-2 and anti-IL-2 antibody at a lower dose when combined for the treatment of cancer; and (3) Roell teaches therapeutic doses of anti-IL-2 antibody encompass 0.3 – 30 mg/kg, including a specific dose of 5, 6, 7, 8, or 9 mg/kg.
Cancer treated is metastatic
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat metastatic cancer in the method of Amit. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Amit teaches it is known that IL-2 has been used to treat metastatic renal cell carcinoma in the past ; (2) Amit suggests their method administering IL-2 and anti-IL-2 antibody maintains a lack of metastasis or inhibits metastasis of a tumor; (3) Amit demonstrates that anti-IL-2 antibody/IL-2 complexes successfully treat a metastatic melanoma (B16F10) model in vivo; and (4) Roell suggests treating cancer that is metastatic or treating melanoma metastasis by administering IL-2 and anti-IL-2 antibody.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
11. Claims 1-3, 8, 10-17, 19, 22-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 8, 10, 12-17, 19, 21-31 of copending Application No. 18/431,983.
The copending application claims a method of treating a solid cancer in a subject comprising administering to the subject a combination therapy comprising anti-IL-2 antibody comprising the same CDR, VH, VL, heavy chain, and light chain sequences instantly claimed, and low dose IL-2, wherein the low dose of IL-2 is between about 15,000 IU/kg – 500,000 IU/kg of a subject’s body weight and is administered subcutaneously;
wherein multiple doses of anti-IL-2 antibody are administered;
wherein the method comprises administering a loading single dose of IL-2 or multiple doses of IL-2 prior to, concurrent with, or following administration of anti-IL-2 antibody;
wherein the method further comprises administering an immune checkpoint inhibitor targeting the same checkpoint proteins instantly claimed, including nivolumab;
wherein the immune checkpoint inhibitor is administered prior to, concurrent with, or following the administration o anti-IL-2 antibody and/or IL-2;
wherein the solid tumor treated is melanoma, metastatic melanoma, RCC, and the same cancers instantly claimed;
wherein the treatment is first, second, or third-line therapy;
wherein treatment reduces the size of the tumor;
wherein the cancer is unresectable locally advanced or metastatic cancer;
wherein the anti-IL-2 antibody is IgG and comprises L234A, L235A Fc mutation;
wherein the dose of IL-2 is 135,000 IU/kg of a subject’s body weight;
wherein the anti-IL-2 antibody is administered at a dose of between about 0.5 mg/kg-12 mg/kg, or 4.5 mg/kg – 12 mg/kg, or 9 mg/kg – 12 mg/kg of a subject’s body weight.
Thus, the copending claims render obvious the limitations of the instantly claimed methods.
This is a provisional nonstatutory double patenting rejection.
12. Claims 1-3, 8, 10-17, 19, 22-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of copending Application No. 19/345,303.
The copending application claims a method of treating unresectable locally advanced or metastatic solid cancer in a subject comprising administering to the subject a combination therapy comprising anti-IL-2 antibody comprising the same CDR, VH, VL, heavy chain, and light chain sequences instantly claimed, and low dose IL-2, wherein the low dose of IL-2 is between about 15,000 IU/kg – 500,000 IU/kg of a subject’s body weight and is administered subcutaneously;
wherein multiple doses of anti-IL-2 antibody are administered;
wherein the method comprises administering a loading dose of IL-2 and a booster dose of IL-2 and the loading dose or booster dose is prior to, concurrent with, or following administration of anti-Il-2 antibody;
wherein the method further comprises administering an immune checkpoint inhibitor targeting the same checkpoint proteins instantly claimed, including nivolumab;
wherein the immune checkpoint inhibitor is administered prior to, concurrent with, or following the administration of anti-IL-2 antibody and/or IL-2;
wherein the solid tumor treated is melanoma, metastatic melanoma, NSCLC, RCC, and the same cancers instantly claimed;
wherein the treatment is first, second, or third-line therapy;
wherein treatment reduces the size of the tumor;
wherein the anti-IL-2 antibody is IgG and comprises L234A, L235A Fc mutation;
wherein the dose of IL-2 is 135,000 IU/kg of a subject’s body weight;
wherein the anti-IL-2 antibody is administered at a dose of between about 0.5 mg/kg-12 mg/kg, or 4.5 mg/kg – 12 mg/kg, or 9 mg/kg – 12 mg/kg of a subject’s body weight.
Thus, the copending claims render obvious the limitations of the instantly claimed methods.
This is a provisional nonstatutory double patenting rejection.
13. Claims 1-3, 8, 10-17, 19, 22-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11,851,485 in view of WO 2021/161287, Amit et al, published August 19, 2021; and US Patent Application Publication 2018/0094053, Roell et al, published April 2018.
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a method comprising administering the same anti-IL-2 antibody comprising the same claimed sequences in combination with IL-2 to a subject to treat a solid cancer. The US Patent claims:
11. A method of treating a disease or a condition in a subject comprising the step of administering to the subject a composition comprising an anti-IL-2 antibody, said anti-TL-2 antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein said VH comprises heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, said VL comprises light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein said CDRs have the amino acid sequences of
(a) the HCDR1 comprises the amino acid sequence of SEQ ID NO:62, the HCDR2 comprises the amino acid sequence of SEQ ID NO:63, the HCDR3 comprises the amino acid sequence of SEQ ID NO:64, the LCDR1 comprises the amino acid sequence of SEQ ID NO:65, the LCDR2 comprises the amino acid sequence DAS, the LCDR3 comprises the amino acid sequence of SEQ ID NO:67, and
wherein said antibody promotes differential growth of subsets of immune cells and decreases undesirable effects caused by IL-2, wherein said disease is cancer and said cancer is selected from melanoma and metastatic renal cell carcinoma, or wherein said disease is a viral infection and said virus is a SARS-CoV-2 virus, and wherein said condition is selected from pulmonary edema or vascular leak syndrome, thereby treating said disease or condition in said subject.
12. The method of claim 11, wherein the VH and VL have the amino acid sequences of
(a) the VH comprises the amino acid sequence of SEQ ID NO:26, the VL comprises the amino acid sequence of SEQ ID NO:27.
13. The method of claim 11, wherein the antibody comprises an IgG, IgA, IgM, IgE, IgD, a Fv, a scFv, a Fab, a F(ab′)2, a minibody, a diabody, or a triabody; or wherein said antibody comprises a heavy chain comprising a mutation that reduces binding to Fcγ receptor; or any combination thereof.
14. The method of claim 13, wherein when said heavy chain comprises a mutation said antibody comprising the heavy chain sequence and the light chain sequence as set forth,
(a) said heavy chain sequence set forth in SEQ ID NO: 72 and said light chain sequence set forth in SEQ ID NO: 73.
15. The method of claim 11, wherein said composition comprises the anti-IL-2 antibody and IL-2, or the anti-IL-2 antibody complexed with IL-2.
16. The method of claim 11, wherein the immune cells comprise one or more of naive T cells, memory T cells, CD8+ T cells, NK cells, or Natural Killer T cells.
17. The method of claim 11, wherein said undesirable effect caused by IL-2 comprises one or more of activation of regulatory T cells, apoptosis of CD25+ T effector cells, IL-2 induced pulmonary edema, IL-2 induced pneumonia, or IL-2-induced vascular leakage.
18. The method of claim 11, wherein said anti-IL-2 antibody inhibits IL-2 binding to CD25.
19. The method of claim 11, wherein said subject is further treated with one or more immune checkpoint inhibitors targeting one or more immune checkpoints, wherein said treatment with said immune checkpoint inhibitors occurs concurrently, before, or after treatment with said anti-IL-2 antibody.
20. The method of claim 19, wherein said immune checkpoint comprises PD-1, PD-L1, CTLA-4, TIGIT, TIM-3, B7-H3, CD73, LAG3, CD27, CD70, 4-1BB, GITR, OX40, SIRP-alpha (CD47), CD39, ILDR2, VISTA, BTLA, or VTCN-1, or a combination thereof.
The US Patent does not claim the IL-2 is administered as a low dose between about 15,000 IU/kg – 500,000 IU/kg of a subject’s body weight, or at 135,000 IU/kg, and is administered subcutaneously; the order of administration of IL-2, anti-IL-2 antibody, and checkpoint inhibitor; and the dose of anti-IL-2 antibody is 0.5 mg/kg-12 mg/kg, or 4.5 mg/kg – 12 mg/kg, or 9 mg/kg – 12 mg/kg of a subject’s body weight.
Amit (WO 2021/161287) and Roell teach the limitations as set forth above, and render obvious the above deficient limitations of the patented method for the same reasons stated in section 9 above.
14. Claims 1-3, 8, 10-17, 19, 22-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,275,784 in view of WO 2021/161287, Amit et al, published August 19, 2021; and US Patent Application Publication 2018/0094053, Roell et al, published April 2018.
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a method comprising administering the same anti-IL-2 antibody comprising the same claimed sequences in combination with IL-2 to a subject to treat a solid cancer. The US Patent claims:
1. A method of treating a disease or a condition in a subject comprising the step of administering to the subject a combination therapy comprising an anti-IL-2 antibody, an IL-2, and an immune checkpoint inhibitor, said anti-IL-2 antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein said VH comprises heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, said VL comprises light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein said CDRs have the amino acid sequences of
(a) the HCDR1 comprises the amino acid sequence of SEQ ID NO:62, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63, the HCDR3 comprises the amino acid sequence of SEQ ID NO:64, the LCDR1 comprises the amino acid sequence of SEQ ID NO:65, the LCDR2 comprises the amino acid sequence DAS, the LCDR3 comprises the amino acid sequence of SEQ ID NO:67;
wherein said antibody promotes differential growth of subsets of immune cells and decreases undesirable effects caused by IL-2, wherein said disease is cancer and said cancer is selected from melanoma and metastatic renal cell carcinoma, or wherein said disease is a viral infection and said virus is a SARS-COV-2 virus, and wherein said condition is selected from pulmonary edema or vascular leak syndrome, thereby treating said disease or condition in said subject.
2. The method according to claim 1, wherein said anti-IL-2 antibody, said IL-2, and said immune checkpoint inhibitor are comprised in the same or different pharmaceutical composition(s), said pharmaceutical composition(s) further comprising a pharmaceutically acceptable carrier.
3. The method according to claim 2, wherein said anti-IL-2 antibody and said IL-2 are in the same composition, and wherein said immune checkpoint inhibitor is in a different composition.
4. The method according to claim 3, wherein said IL-2 is complexed with said anti-IL-2 antibody.
5. The method according to claim 1, wherein the VH and VL have the amino acid sequences of
(a) the VH comprises the amino acid sequence of SEQ ID NO:26, the VL comprises the amino acid sequence of SEQ ID NO:27.
6. The method according to claim 1, wherein said anti-IL-2 antibody comprises an IgG, IgA, IgM, IgE, IgD, a Fv, a scFv, a Fab, a F(ab′)2, a minibody, a diabody, or a triabody or wherein said antibody comprises a heavy chain comprising a mutation that reduces binding to Fcγ receptor; or any combination thereof.
7. The method according to claim 1, wherein said anti-IL-2 antibody comprises a heavy chain sequence and a light chain sequence, as set forth as follows:
(a) said heavy chain sequence set forth in SEQ ID NO: 72 and said light chain sequence set forth in SEQ ID NO: 73.
8. The method according to claim 1, wherein said immune checkpoint inhibitor is targeted to a Programmed death-ligand 1 (PD-L1), a Programmed cell death protein 1 (PD-1), a Cytotoxic T-lymphocyte protein 4 (CTLA-4), a T-cell immunoreceptor with Ig and ITIM domains (TIGIT), a Metalloproteinase inhibitor 3 (TIM-3), B7 homolog 3 (B7-H3), a cluster of differentiation 73 (CD73), a Lymphocyte-activation gene 3 (LAG3), a cluster of differentiation 27 (CD27), a cluster of differentiation 70 (CD70), a Tumor necrosis factor ligand superfamily member 9 (4-1BB), a Glucocorticoid-Induced TNFR-Related (GITR), a Tumor necrosis factor receptor superfamily member 4 (0X40), a cluster of differentiation 47 (SIRP-alpha (CD47)), a cluster of differentiation 39 (CD39), an Immunoglobulin Like Domain Containing Receptor 2 (ILDR2), a V-Domain Ig Suppressor Of T Cell Activation (VISTA), a B and T lymphocyte attenuator (BTLA), or a V-set domain containing T cell activation inhibitor 1 (VTCN-1).
9. The method according to claim 1, wherein said immune checkpoint inhibitor is a Programmed death-ligand 1 (PD-L1) checkpoint inhibitor.
10. The method according to claim 9, wherein said PD-L1 checkpoint inhibitor is selected from avelumab, atezolizumab, durvalumab, sugemalimab, and envafolimab.
11. A combination therapy comprising an anti-IL-2 antibody, IL-2, and an immune checkpoint inhibitor, said anti-IL-2 antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein said VH comprises heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, said VL comprises light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein said CDRs have the amino acid sequences of
(a) the HCDR1 comprises the amino acid sequence of SEQ ID NO:62, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63, the HCDR3 comprises the amino acid sequence of SEQ ID NO:64, the LCDR1 comprises the amino acid sequence of SEQ ID NO:65, the LCDR2 comprises the amino acid sequence DAS, the LCDR3 comprises the amino acid sequence of SEQ ID NO:67;
wherein said anti-IL-2 antibody, said IL-2, and said immune checkpoint inhibitor are comprised in the same or different pharmaceutical composition(s), said pharmaceutical composition(s) further comprising a pharmaceutically acceptable carrier.
12. The combination therapy according to claim 11, wherein said anti-IL2 antibody and said IL-2 are in the same composition, and wherein said immune checkpoint inhibitor is in a different composition.
13. The combination therapy according to claim 11, wherein said immune checkpoint inhibitor is a Programmed death-ligand 1 (PD-L1) checkpoint inhibitor.
14. The combination therapy according to claim 11, wherein the VH and VL have the amino acid sequences of
(a) the VH comprises the amino acid sequence of SEQ ID NO:26, the VL comprises the amino acid sequence of SEQ ID NO:27.
15. The combination therapy according to claim 11, wherein the anti-IL-2 antibody comprises an IgG, IgA, IgM, IgE, IgD, a Fv, a scFv, a Fab, a F(ab′)2, a minibody, a diabody, or a triabody or wherein said antibody comprises a heavy chain comprising a mutation that reduces binding to Fcy receptor, or a combination thereof.
16. The combination therapy according to claim 11, wherein said anti-IL-2 antibody comprises the heavy chain sequence and the light chain sequence as set forth,
(a) said heavy chain sequence set forth in SEQ ID NO: 72 and said light chain sequence set forth in SEQ ID NO: 73.
20. The combination therapy according to claim 12, wherein said IL-2 is complexed with said anti-IL-2 antibody.
21. The combination therapy according to claim 11, wherein said immune checkpoint inhibitor is targeted to a Programmed death-ligand 1 (PD-L1), a Programmed cell death protein 1 (PD-1), a Cytotoxic T-lymphocyte protein 4 (CTLA-4), a T-cell immunoreceptor with Ig and ITIM domains (TIGIT), a Metalloproteinase inhibitor 3 (TIM-3), a B7 homolog 3 (B7-H3), a cluster of differentiation 73 (CD73), a Lymphocyte-activation gene 3 (LAG3), a cluster of differentiation 27 (CD27), a cluster of differentiation 70 (CD70), a Tumor necrosis factor ligand superfamily member 9 (4-1BB), a Glucocorticoid-Induced TNFR-Related (GITR), a Tumor necrosis factor receptor superfamily member 4 (0X40), a cluster of differentiation 47 (SIRP-alpha (CD47)), a cluster of differentiation 39 (CD39), an Immunoglobulin Like Domain Containing Receptor 2 (ILDR2), a V-Domain Ig Suppressor Of T Cell Activation (VISTA), a B and T lymphocyte attenuator (BTLA), or a V-set domain containing T cell activation inhibitor 1 (VTCN-1).
The US Patent does not claim the IL-2 is administered as a low dose between about 15,000 IU/kg – 500,000 IU/kg of a subject’s body weight, or at 135,000 IU/kg, and is administered subcutaneously; the order of administration of IL-2, anti-IL-2 antibody, and checkpoint inhibitor; and the dose of anti-IL-2 antibody is 0.5 mg/kg-12 mg/kg, or 4.5 mg/kg – 12 mg/kg, or 9 mg/kg – 12 mg/kg of a subject’s body weight.
Amit (WO 2021/161287) and Roell teach the limitations as set forth above, and render obvious the above deficient limitations of the patented method for the same reasons stated in section 10 above.
15. Conclusion: No claim is allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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