DETAILED ACTION
Notice of Pre-AIA or AIA Status
The inventor or joint inventor should note that the instant invention, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 82, 87, 90, 93, 95, 98, 106-108, 110-112, 114-116, 130, 155 and 157-159 are pending in the instant invention. According to the Amendments to the Claims, filed March 31, 2025, claims 82, 110 and 112 were amended and claims 1-81, 83-86, 88, 89, 91, 92, 94, 96, 97, 99-105, 109, 113, 117-129, 131-154, 156, 160 and 161 were cancelled.
Status of Priority Objection - Priority Date
This invention is a Continuation (CON) of US Application No. 16/954,878, filed June 17, 2020 and now US 11,793,885, which is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/US2018/067589, filed December 27, 2018.
Similarly, the inventor or joint inventor should further note that this invention’s claim to priority under 35 U.S.C. § 119(e) to US Provisional Application Nos.: a) 62/655,523, filed April 10, 2018; and b) 62/611,056, filed December 28, 2017, respectively, was objected to in the Non-Final Rejection, mailed on August 16, 2024. Consequently, the effective filing date, for examination and prosecution on the merits, is that of International Application No. PCT/US2018/067589, filed December 27, 2018.
Status of Restrictions / Election of Species
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The inventor’s or joint inventor’s provisional election of the following, without traverse, in the reply filed on August 28, 2025, is acknowledged: a) Group III - claims 82, 87, 93, 95, 98, 106, 111, 112, 115, 130, 155 and 157, where
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is a double bond; X = absent; W1 = -(CH2)n1-, wherein n1 = 1; W2 = -(CH2)n2-, wherein n2 = 0; R6 = -OC1-C6 alkyl; A = -O-; L1 = -(CH2)m1-, wherein m1 = 3, 4, or 5; Z1 = -s3-C(O)NR5-s4, -s3-C(S)NR5-s4, or -s3-S(O)2NR5-s4, wherein s3 is the site connected to L1 and s4 is the site connected to Ar1; Ar1 = -s4’-pyrrolylene-s5’-, -s4’-imidazolylene-s5’-, or -s4’-thiazolylene-s5’-, wherein s4’ is the site connected to Z1 and s5’ is the site connected to Z2; Z2 = -s5-C(O)NR5-s6, s5-C(S)NR5-s6, or s5-S(O)2NR5-s6, wherein s5 is the site connected to Ar1 and s6 is the site connected to Ar2; Ar2 = -s6’-(C6-18 arylene)-s7’, wherein s6’ is the site connected to Z2 and s7’ is the site connected to LCB; n3 = 0; and LCB = -formula (L3d’)-, wherein JCB = -C(O)-, where JCB is covalently linked to the cell-binding agent (CBA); and b) cell-binding agent-cytotoxic conjugate represented by the formula (IV) - p. 180, compound #161, shown to the right, and hereafter referred to as conjugate of 2,5-dioxopyrrolidin-1-yl 6-(((S)-1-(((S)-1-((4-(4-(4-(((S)-8-methoxy-6-oxo-12a,13-dihydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)butanamido)-1-methyl-1H-imidazole-2-carbox-amido)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)amino)-6-oxohexanoate, where R1 = -H; R2 = -H; R3 = -H; R4 = -H; W1 = -(CH2)n1-, wherein n1 = 1; W2 = -(CH2)n2-, wherein n2 = 0;
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is a double bond; Y = -H; X = absent; R6 = -OR, wherein R = -CH3; A = -O-; L1 = -(CH2)m1-, wherein m1 = 3; Z1 = -s3-C(O)NR5-s4, wherein R5 = -H, s3 is the site connected to L1 and s4 is the site connected to Ar1; Ar1 = -s4’-1-methylimidazol-2,4-diyl-s5’-, wherein Rd = -CH3, s4’ is the site connected to Z1 and s5’ is the site connected to Z2; Z2 = -s5-C(O)NR5-s6, wherein R5 = -H, s5 is the site connected to Ar1 and s6 is the site connected to Ar2; Ar2 = -s6’-1,4-phenylene-s7’-, wherein s6’ is the site connected to Z2 and s7’ is the site connected to -LCB-; n3 = 0; -LCB- = -NR5a-P2-C(O)-Rx4-JCB- [formula (L3d’)], wherein R5a = -H, P2 =-C(O)CH(CH3)NH-C(O)CH(CH3)NH- (2 residues), Rx4 = -(CH2)4-, and JCB = -C(O)-, where JCB is covalently linked to the cell-binding agent (CBA); and CBA = -NH-CBA’. Claims 82, 87, 93, 95, 98, 106, 111, 112, 115, 130, 155 and 157 read on the elected species. Affirmation of this election must be made by the inventor or joint inventor in replying to this Office action.
Similarly, the inventor or joint inventor should further note that the requirement is still deemed proper and is therefore made FINAL.
Likewise, the inventor or joint inventor should further note that claim 82 is directed to allowable cell-binding agent-cytotoxic conjugates represented by the formula (IV). Pursuant to the procedures set forth in MPEP § 821.04(b), claims 158 and 159, directed to a method of inhibiting abnormal cell growth or treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), and optionally, a chemotherapeutic agent, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Next, the inventor or joint inventor should further note that claims 90, 107, 108, 110, 114 and 116, do not require all the limitations of the allowable cell-binding agent-cytotoxic conjugates represented by the formula (IV), and have NOT been rejoined.
Then, the inventor or joint inventor should further note that since a claimed invention previously withdrawn from consideration under 37 CFR 1.142 has been rejoined, the restriction requirement between Group III and IV, respectively, as set forth in the Office action, mailed on May 1, 2025, is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, the inventor or joint inventor is advised that if any claim presented in a continuation or divisional invention is anticipated by, or includes all the limitations of, a claim that is allowable in the present invention, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant invention.
Moreover, the inventor or joint inventor should further note that once the restriction requirement is withdrawn, the provisions of 35 U.S.C. § 121 are no longer applicable. {See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971); and MPEP § 804.01}.
Furthermore, the inventor or joint inventor should also note that the sections of U.S.C. Title 35 that formed the basis of prior rejections formulated, as well as any references supporting said rejections, that are not included with this Office action, may be found in either the Non-Final Rejection, mailed on August 16, 2024, or the Final Rejection, mailed on January 7, 2025.
Also, the inventor or joint inventor should further note that any rejections and/or objections of record not explicitly addressed herein below, are hereby withdrawn, in light of the inventor’s or joint inventor’s arguments and/or the Amendments to the Claims, filed March 31, 2025.
Thus, a third Office action and prosecution on the merits of claims 82, 87, 93, 95, 98, 106, 111, 112, 115, 130, 155 and 157-159 is contained within.
New Claim Objections
Claim 82 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
A cell-binding agent-cytotoxic agent conjugate represented by formula (IV):
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(IV)
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is H, halogen, CN, NO2, C1-C6 alkyl, C(O)R’, NR’R”, NR’C(O)R”, OR, OC(O)R’, OC(O)NR’R”, OS(O)2OH, SR, S(O)R’, S(O)2R’, S(O)2NR’R”, or S(O)2OH;
R2 is H, halogen, CN, NO2, C1-C6 alkyl, C(O)R’, NR’R”, NR’C(O)R”, OR, OC(O)R’, OC(O)NR’R”, OS(O)2OH, SR, S(O)R’, S(O)2R’, S(O)2NR’R”, or S(O)2OH;
R3 is H, halogen, CN, NO2, C1-C6 alkyl, C(O)R’, NR’R”, NR’C(O)R”, OR, OC(O)R’, OC(O)NR’R”, OS(O)2OH, SR, S(O)R’, S(O)2R’, S(O)2NR’R”, or S(O)2OH;
R4 is H, halogen, CN, NO2, C1-C6 alkyl, C(O)R’, NR’R”, NR’C(O)R”, OR, OC(O)R’, OC(O)NR’R”, OS(O)2OH, SR, S(O)R’, S(O)2R’, S(O)2NR’R”, or S(O)2OH;
each R is independently H or C1-C6 alkyl;
each R’ is independently H, C1-C6 alkyl, C(O)R, N(R)2, or OR;
each R” is independently H, C1-C6 alkyl, C(O)R, N(R)2, or OR;
W1 is -(CH2)n1-;
W2 is -(CH2)n2-;
n1 is 1;
n2 is 0;
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is a double bond;
X is absent;
Y is H or C1-C4 alkyl;
R6 is OC1-C6 alkyl;
A is -O-;
L1 is -(CH2)m1-;
m1 is 3, 4, or 5;
Z1 is s3-C(O)NR5-s4, s3-C(S)NR5-s4, or s3-S(O)2NR5-s4, wherein s3 is the site connected to L1 and s4 is the site connected to Ar1;
Ar1 is s4’-pyrrolylene-s5’, s4’-imidazolylene-s5’, or s4’-thiazolylene-s5’, wherein s4’ is the site connected to Z1 and s5’ is the site connected to Z2;
wherein the pyrrolylene, imidazolylene, or thiazolylene is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb’Rc’, OH, and phenyl; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents;
Rb’ is H, C1-C3 alkyl, C(O)OCH3, C(O)OCF3, C(O)OC(CH3)3, C(O)OCH2-phenyl, C(O)OCH2-fluorenyl, phenyl, or heteroaryl;
Rc’ is H, C1-C3 alkyl, C(O)OCH3, C(O)OCF3, C(O)OC(CH3)3, C(O)OCH2-phenyl, C(O)OCH2-fluorenyl, phenyl, or heteroaryl;
Z2 is s5-C(O)NR5-s6, s5-C(S)NR5-s6, or s5-S(O)2NR5-s6, wherein s5 is the site connected to Ar1 and s6 is the site connected to Ar2;
Ar2 is s6’-C6-C18 arylene-s7’, wherein s6’ is the site connected to Z2 and s7’ is the site connected to LCB;
wherein the C6-C18 arylene is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb”Rc”, and OH; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents;
Rb” is H, C1-C3 alkyl, C(O)OCH3, C(O)OCF3, C(O)OC(CH3)3, C(O)OCH2-phenyl, C(O)OCH2-fluorenyl, phenyl, or heteroaryl;
Rc” is H, C1-C3 alkyl, C(O)OCH3, C(O)OCF3, C(O)OC(CH3)3, C(O)OCH2-phenyl, C(O)OCH2-fluorenyl, phenyl, or heteroaryl;
Z3 is a bond, s7-C(OH)CH2-s8, s7-CR100R101NR5-s8, s7-CH=CH-s8, s7-C(O)NR5-s8, s7-C(O)NR5CH2-s8, s7-C(S)NR5-s8, -NR5-, s7-NR5CR100R101-s8, s7-NR5C(O)-s8, s7-NR5C(O)NR5-s8, s7-NR5C(S)-s8, or s7-S(O)2NR5-s8, wherein s7 is the site connected to Ar2 and s8 is the site connected to Ar3;
R100 is H, halogen, C1-C4 alkyl, or C1-C4 haloalkyl;
R101 is H, halogen, C1-C4 alkyl, or C1-C4 haloalkyl;
Ar3 is C6-C18 aryl, 5- to 18-membered heteroaryl, or -Ar3’-Ar3”-;
wherein the 5- to 18-membered heteroaryl is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb”’Rc”’, and OH; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents;
Ar3’ is C6-C18 aryl or 5- to 18-membered heteroaryl;
wherein the 5- to 18-membered heteroaryl is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb”’Rc”’, and OH; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents;
Ar3” is C6-C18 aryl or 5- to 18-membered heteroaryl;
wherein the 5- to 18-membered heteroaryl is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb”’Rc”’, and OH; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents;
n3 is 0;
Rb”’ is H, C1-C3 alkyl, C(O)OCH3, C(O)OCF3, C(O)OC(CH3)3, C(O)OCH2-phenyl, C(O)OCH2-fluorenyl, phenyl, or heteroaryl;
Rc”’ is H, C1-C3 alkyl, C(O)OCH3, C(O)OCF3, C(O)OC(CH3)3, C(O)OCH2-phenyl, C(O)OCH2-fluorenyl, phenyl, or heteroaryl;
each R5 is independently H or C1-C4 alkyl;
LCB is formula (L3d’):
NR5a-P2-C(O)-Rx4-JCB- (L3d’),
wherein:
R5a is H or C1-C3 alkyl;
P2 is a peptide containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues;
Rx4 is C1-C10 alkylene, C3-C8 cycloalkylene, arylene, or heteroarylene; and
JCB is -C(O)-, where the -C(O)- is covalently linked to the cell-binding agent (CBA);
CBA is -CH2-CBA’, =CH-CBA’, -NH-CBA’, or -S-CBA’, wherein -CH2-CBA’, =CH-CBA’, -NH-CBA’, or -S-CBA’ represents the cell-binding agent (CBA) covalently linked to LCB of the cytotoxic agent via (a) an aldehyde [-C(O)H] group located on the cell-binding agent (CBA); (b) the e-amino (-NH2) group of a lysine located on the cell-binding agent (CBA); or (c) the thiol (-SH) group of a lysine located on the cell-binding agent (CBA); and
w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
with the proviso that if the cell-binding agent-cytotoxic conjugate is represented by the formula (IV), then the cell-binding agent-cytotoxic conjugate is not:
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,
or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 87 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein the conjugate is represented by formula (IVA-1):
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(IVA-1)
or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 93 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein:
L1 is -(CH2)3-;
Z1 is s3-C(O)NR5-s4, wherein s3 is the site connected to L1 and s4 is the site connected to Ar1;
Z2 is s5-C(O)NR5-s6, wherein s5 is the site connected to Ar1 and s6 is the site connected to Ar2; and
each R5 is independently H or CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 95 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein:
Ar1 is s4’-imidazolylene-s5’ or s4’-thiazolylene-s5’, wherein s4’ is the site connected to Z1 and s5’ is the site connected to Z2;
wherein the imidazolylene or thiazolylene is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb’Rc’, OH, and phenyl; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents; and
Ar2 is s6’-phenylene-s7’ or s6’-naphthalenylene-s7’, wherein s6’ is the site connected to Z2 and s7’ is the site connected to LCB;
wherein the phenylene or naphthalenylene is optionally substituted with one substituent selected from the group consisting of C1-C6 alkyl, NRb”Rc”, and OH; and
wherein the C1-C6 alkyl substituent is optionally substituted with one or more independently selected halogen substituents.
Appropriate correction is required. See MPEP § 2173.02.
Claim 98 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 95, wherein:
Ar1 is:
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,
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,
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,
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,
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,
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, or
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,
wherein:
Rd is H, C1-C6 alkyl, NRb’Rc’, or OH, wherein the C1-C6 alkyl is optionally substituted with one or more independently selected halogen substituents; and
s4’ is the site connected to Z1 and s5’ is the site connected to Z2; and
Ar2 is:
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,
wherein:
s6’ is the site connected to Z1 and s7’ is the site connected to LCB.
Appropriate correction is required. See MPEP § 2173.02.
Claim 106 is objected to because of the following informalities: for clarity and precision, the claim is dependent upon and fails to further limit a restricted and/or objected base claim. Appropriate correction is required. See MPEP § 2173.02.
Claim 111 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein the conjugate is represented by formula (IVA-1a):
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(IVA-1a),
or a pharmaceutically acceptable salt thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 112 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 111, wherein:
Ar1 is:
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,
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,
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, or
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,
wherein:
Rd is H, C1-C6 alkyl, NRb’Rc’, or OH, wherein the C1-C6 alkyl is optionally substituted with one or more independently selected halogen substituents; and
s4’ is the site connected to Z1 and s5’ is the site connected to Z2; and
Ar2 is:
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,
wherein:
s6’ is the site connected to Z1 and s7’ is the site connected to LCB.
Appropriate correction is required. See MPEP § 2173.02.
Claim 115 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein:
LCB is formula (L3d’):
NR5a-P2-C(O)-Rx4-JCB (L3d’);
P2 is a peptide containing 2 amino acid residues; and
Rx4 is C1-C6 alkylene.
Appropriate correction is required. See MPEP § 2173.02.
Claim 130 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein the conjugate is:
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,
or a pharmaceutically acceptable salt thereof,
wherein:
w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
Appropriate correction is required. See MPEP § 2173.02.
Claim 155 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b), 35 U.S.C. § 112(d), and/or non-compliance with the Requirement for Restriction/Election of Species, mailed on May 1, 2025, the existing recitation should be replaced with the following recitation:
The conjugate of claim 82, wherein Y is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 157 is objected to because of the following informalities: for clarity and precision, the claim is dependent upon an objected base claim. Appropriate correction is required. See MPEP § 2173.02.
Claim 158 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation(s):
158. A method for inhibiting abnormal cell growth in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a conjugate of claim 82, or a pharmaceutically acceptable salt thereof, and optionally, a chemotherapeutic agent.
162. The method of claim 158, wherein the mammal suffers from a condition, disease, or disorder selected from the group consisting of an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and a viral disease.
Appropriate correction is required. See MPEP § 2173.02.
Claim 159 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation(s):
163. The method of claim 162, wherein the autoimmune disorder, infectious disease, or proliferative disorder is selected from the group consisting of a cancer, graft versus host disease (GVHD), an immune deficiency, an infection, lupus, multiple sclerosis, myositis, rheumatoid arthritis, and transplant rejection,
164. The method of claim 163, wherein the cancer is selected from the group consisting of blastic plasmacytoid dendritic neoplasm (BPDN), breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, myelodysplastic syndrome (MDS), ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, and a sarcoma.
165. The method of claim 164, wherein the breast cancer is triple negative breast cancer (TNBC).
166. The method of claim 164, wherein the head and neck cancer is squamous cell carcinoma of the head and neck.
167. The method of claim 164, wherein the leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), eosinophilic leukemia, and promyelocytic leukemia.
168. The method of claim 167, wherein the acute lymphoblastic leukemia is B-cell acute lymphoblastic leukemia (B-ALL).
169. The method of claim 164, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.
170. The method of claim 164, wherein the lymphoma is non-Hodgkin lymphoma.
Appropriate correction is required. See MPEP § 2173.02.
New Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112:
(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.
Method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV)
Claims 158 and 159 are rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement because the claims contain subject matter, particularly a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), which was not described in the specification in such a way as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use (perform) the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
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(a) Breadth of the claims - the breadth of the claims includes a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), shown to the right;
(b) Nature of the invention - the nature of the invention is performance of a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV)I, shown to the right above;
(c) State of the prior art - Nature Reviews: Drug Discovery offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Similarly, no single drug has been discovered that is effective in treating the myriad of proliferative disorders,… or kidney diseases in a mammal, including, but not limited to, an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and/or a viral disease {See In re Hokum, 226 USPQ 353 (ComrPats 1985)}. Moreover, WO 19/133652 illustrates the synthesis of cell-binding agent conjugates represented by the formula (IV), and/or methods of use thereof {Miller, et al. WO 19/133652, 2019};
(d) Level of one of ordinary skill in the art - the artisans performing the inventor’s or joint inventor’s method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is well established that [T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor {See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)}.
Moreover, the following excerpt is taken from Hackam, et al., with respect to the poor replication of animal research in human clinical trials {Hackam, et al. JAMA, 296(14), 2006, 1731-1732}:
Only about a third of highly cited animal research translated at the level of human randomized trials. This rate of translation is lower than the recently estimated 44% replication rate for highly cited human studies. Nevertheless, we believe these findings have important implications. First, patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease. Second, major opportunities for improving study design and methodological quality are available for preclinical research. Finally, poor replication of even high-quality animal studies should be expected by those who conduct clinical research.
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using (performing) a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV);
(g) Existence of working examples - the disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV).
Similarly, according to the specification, cell-binding agent conjugates represented by the formula (IV) are capable of treating a variety of proliferative disorders,… or kidney diseases in a mammal, including, but not limited to, an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and/or a viral disease; however, the specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in association with any proliferative disorders,… or kidney diseases in a mammal, including, but not limited to, an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and/or a viral disease. There is insufficient disclosure to reasonably conclude that the method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), as recited, would contribute to treatment of any proliferative disorders,… or kidney diseases in a mammal, including, but not limited to, an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and/or a viral disease. Furthermore, the combination of the instant specification and Miller, et al. in WO 19/133652, lacks adequate credible evidence to support the assertion that a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), as recited, would contribute to the prophylaxis of any proliferative disorders,… or kidney diseases in a mammal, including, but not limited to, an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and/or a viral disease, since the inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claims.
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
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(h) Quantity of experimentation needed to make and/or use (perform) the invention based on the content of the disclosure - predicting whether a recited compound is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Furthermore, it is unclear, based on the guidance provided by the specification, whether a cell-binding agent conjugate represented by the formula (IV), such as the cell-binding agent conjugate of 2,5-dioxopyrrolidin-1-yl 6-(((S)-1-(((S)-1-((4-(4-(4-(((S)-8-methoxy-6-oxo-12a,13-dihydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)butanamido)-1-methyl-1H-imidazole-2-carboxamido)phenyl)amino)-1-oxo-propan-2-yl)amino)-1-oxopropan-2-yl)amino)-6-oxohexanoate, shown to the left above, possesses utility as a therapeutic agent, useful in a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV). Thus, one of ordinary skill in the art, at the time this invention was made, would have an unreasonable expectation of success and undue experimentation in transferring the in vitro and/or in vivo method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), wherein the proliferative disorder,… or kidney disease in a mammal, includes, but is not limited to, an autoimmune disorder, destructive bone disorder, a fibrotic disease, an infectious disease, a kidney disease, a neurodegenerative disorder, pancreatitis, a proliferative disorder, and/or a viral disease, to any mammalian population.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using (performing) a method of treating a proliferative disorder,… or kidney disease in a mammal, comprising administering… a cell-binding agent conjugate represented by the formula (IV), is clearly justified.
The examiner suggests amending the claims, particularly as stated in the section above entitled New Claim Objections, to overcome this rejection.
New Claim Rejections - 35 U.S.C. § 112(b)
The following is a quotation of the second paragraph of 35 U.S.C. § 112:
(b) CONCLUSION. The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or joint inventor regards as the invention.
Claim 159 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c), MPEP § 2173.05(h), and/or Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1371, 121 USPQ2d 1277, 1287 (Fed. Cir. 2017).
Similarly, the inventor or joint inventor should further note that claim 159 recites the broad limitations, (1) cancer; (2) breast cancer; (3) head and neck cancer; (4) leukemia; (5) acute lymphoblastic leukemia; (6) lung cancer; and (7) lymphoma, respectively, and the claim also recites (1) blastic plasmacytoid dendritic neoplasm (BPDN), breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, myelodysplastic syndrome (MDS), ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, and a sarcoma; (2) triple negative breast cancer (TNBC); (3) squamous cell carcinoma of the head and neck; (4) acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), eosinophilic leukemia, and promyelocytic leukemia; (5) B-cell acute lymphoblastic leukemia (B-ALL); (6) non-small cell lung cancer and small cell lung cancer; and (7) non-Hodgkin lymphoma, respectively, which are the narrower statements of the limitations.
Likewise, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), pertaining to where broad language is followed by such as and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and consequently, not required, or (b) a required feature of the claim.
Moreover, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
The examiner suggests amending the claims, particularly as stated in the section above entitled New Claim Objections, to overcome this rejection.
Allowable Subject Matter
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The Examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The Examiner is also available on alternate Fridays.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
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/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624