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 .
DETAILED ACTION
The preliminary amendment dated 21 March 2024, in which claims 1, 3, 7, 11, 14, 16, 19, 20, 22, 27, 30, 34, 38, 40, 42 have been amended, and claims 2, 4-6, 8, 12-13, 15, 21, 23-26, 28-29, 31-33, 35-37, 39, 41, 43 have been cancelled, is acknowledged.
Claims 1, 3, 7, 9-11, 14, 16-20, 22, 27, 30, 34, 38, 40 and 42 are pending in the instant application.
Claims 20, 22, 27, 30, 34, 38, 40 and 42 are withdrawn, as being drawn to a non-elected invention or to a non-elected species.
Claims 1, 3, 7, 9-11, 14, 16-19 are examined herein.
Priority
The instant application is a 35 U.S.C. § 371 National Stage entry of International Application No. PCT/US2022/076865, filed on 22 September 2022, which claims priority from U.S. Provisional Patent Applications No. 63/247,645, filed on 23 September 2021; 63/290,630, filed on 16 December 2021; and 63/332,945, filed on 20 April 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 21 March 2024 is acknowledged and considered.
Election/Restrictions
Applicant’s election without traverse of Group (I), claims 1, 3, 7, 9-11, 14, 16-19, drawn to a compound of formula (I), or a pharmaceutical composition comprising said compound, in the reply filed on 1 June 2026, is acknowledged. Claims 20, 22, 27, 30, 34, 38, 40 and 42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Applicants’ election without traverse of the compound below:
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as the species of a compound of formula (I)
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, for initial examination, in the Reply of 1 June 2026, is acknowledged.
The elected species is a compound of formula (I) for which the following definitions apply: R1 = H, R2 = methyl. Claims 1, 3, 7, 9-11, 14, 18-19 read on the elected species. (The examiner considers that the elected species compound I-1 is also a compound of formula (I) where R2 = H and R1 = methyl, thus a compound of instant claims 14, 19).
Since the election was made without traverse, the requirement for restriction/election is herein maintained and is made FINAL.
In the interest of compact prosecution, the examiner has extended the search to a subgenus of compounds of formula (I) beyond the elected species, namely compounds of formula (I) where R1 and R2 are each H, or lower alkyl, or cyclopropyl, or cyclobutyl, or where R1 and R2 combine to form –(CH2)n, claims 1, 3, 7, 9-11, 14, 16-19, and the claims have been examined to the extent they read of this subgenus.
Claims 1, 3, 7, 9-11, 14, 16-19 have been examined and the following objections and rejections are made below.
Claims Objections
Claims 20, 22, 27, 30, 34, 38, 40 and 42, while currently withdrawn, are objected to because of the following informality: The withdrawn claims are objected to for being presented in a non-compliant form. Specifically, the status identifier states the claim is “(Currently amended)”, but the claims are withdrawn because of the election made by the Applicant on 1 June 2026. As such, claims 20, 22, 27, 30, 34, 38, 40 and 42 should be identified as "(Withdrawn)" until such time as examiner rejoins the claims for examination. Appropriate correction is required. See MPEP 714(C).
Claims 1, 7, 14 are objected to because they recite “or optionally”. The word “optionally” is not needed, because the conjunction “or” is used to connect alternatives or choices/options.
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.
Claim 3 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 pre-AIA the applicant regards as the invention.
Claim 3 is drawn to the compound of claim 1, wherein at least one of (i)-(iv) applies. The claim is indefinite because choices (i), (ii) and (iv); or (i), (iii) and (iv); or (i) and (ii); or (i) and (iv) cannot occur at the same time in one compound. Rather, a compound is defined by only one of the possibilities (i), (ii) or (iv). This is why the recitation “at least one applies” renders the claim indefinite.
Further, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation
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, and the claim also recites
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which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate clarification of the claim language is required.
Claims 9, 10, 17 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 pre-AIA the applicant regards as the invention.
In claim 9, the phrase “selected from the group consisting of: […] […] […]
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”, is vague and indefinite because it would mean that the claim is open ended in the closed Markush expression “selected from the group consisting of”. It is suggested that claim 9 recite “selected from the group consisting of […], […], […],
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and
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”.
The same analysis applies to claims 10, 17.
Appropriate clarification is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 7, 9-11, 14, 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Lunt et al. (GB 2,104,522, published 9 March 1983, cited in PTO-892).
Lunt (GB 2,104,522) discloses (Abstract) tetrazine derivatives
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wherein
R1 is, for example, an alkyl group containing up to 6 C atoms, substituted by halogen;
R2 is a carbamoyl group optionally N-substituted by one or two groups selected from alkyl containing up to 4 C atoms, and cycloalkyl containing 3 to 8 C atoms, or salts thereof (page 1, line 72),
and pharmaceutical compositions containing them, as in instant claims 11, 19,
effective as antineoplastic agents (page 2, line 74).
Lunt teaches (page 1, right column, lines 65-67) that preferred R1 is a 2-haloalkyl, namely 2-fluoroethyl, as in instant elected species, or 2-chloroethyl.
Lunt teaches (page 1, right column, lines 69-71) that preferred R2 is a carbamoyl group
-CONH2 or methylcarbamoyl -CONHMe (as in instant elected species).
The genus of tetrazine derivatives taught by Lunt encompasses/overlaps with instant compounds of formula (I)
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of claim 1, wherein R1 and R2 are independently selected from H and alkyl, as in instant claim 1; or R1 and R2 are lower alkyl/methyl, as in instant claim 3, and encompass Applicant’s elected species, as well as compounds (1-9 in order listed) in instant claims 9, 10, compound (first listed) of claim 17, and compounds
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of instant claim 18.
The genus of tetrazine derivatives taught by Lunt, namely a subgenus where R2 is a carbamoyl group N-substituted by one cycloalkyl containing 3 to 8 C atoms encompasses/overlaps with compounds of instant claims 14, 16, 17, 18
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, where R2 is
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.
Lunt specifically teaches (page 2, lines 109-110) the following compound:
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compound D, which differs from the instant elected species
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in that the substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring is 2-chloroethyl (Lunt) vs. 2-fluoroethyl (instant elected species of claims 1, 3, 7, 9, 10, 18).
Lunt teaches (page 2, lines 129-130) that compound D is of particular importance.
Lunt also specifically teaches (page 2, lines 117-118) the following compound:
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compound H, which differs from a compound of instant claims 1, 3, 9, 10, 18
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in that the substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring is 2-chloroethyl (Lunt) vs. 2-fluoroethyl (compound of instant claims).
Lunt does not specifically teach the instant compounds.
It would have been obvious for a person of ordinary skill in the art to prepare a compound from the genus taught by Lunt to arrive at the instant invention.
The person of ordinary skill in the art would have replaced the 2-chloroethyl substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring in compound D taught by Lunt, with 2-fluoroethyl, to arrive at the instant elected species, because Lunt teaches that preferred R1 in the tetrazine derivatives of the invention is a 2-haloalkyl, namely 2-fluoroethyl, or 2-chloroethyl. Thus, the person of ordinary skill in the art would have replaced 2-chloroethyl with 2-fluoroethyl in compound D taught by Lunt, with a reasonable expectation that the resulting tetrazine derivative retains antineoplastic activity.
Further, the person of ordinary skill in the art would have replaced the 2-chloroethyl substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring in compound H taught by Lunt, with 2-fluoroethyl, to arrive at a compound of instant claims 1, 3, 9, 10, 18, because Lunt teaches that preferred R1 in the tetrazine derivatives of the invention is a 2-haloalkyl, namely 2-fluoroethyl, or 2-chloroethyl. Thus, the person of ordinary skill in the art would have replaced 2-chloroethyl with 2-fluoroethyl in compound H taught by Lunt, with a reasonable expectation that the resulting tetrazine derivative retains antineoplastic activity.
Furthermore, the person of ordinary skill in the art would have synthesized a number of compounds from the genus taught by Lunt, namely tetrazine derivatives
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wherein R1 is 2-fluoroethyl, and R2 is a carbamoyl group N-substituted by one or two groups selected from alkyl containing up to 4 C atoms, and cycloalkyl containing 3 to 8 C atoms, with a with a reasonable expectation that the resulting tetrazine derivatives retain antineoplastic activity.
As such, claims 1, 3, 7, 9-11, 14, 16-19 are rejected as prima facie obvious.
Claims 1, 3, 7, 9-11, 14, 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Baig et al. (GB 2,125,402, published 7 March 1984, cited in PTO-892), in view of Lunt et al. (GB 2,104,522, published 9 March 1983, cited in PTO-892).
Baig (GB 2,125,402) discloses (Abstract) tetrazine derivatives
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wherein (page 2, lines 10-22)
Z1, Z2 are, for example, oxygen (page 2, lines 21, 22)
A2 is N (page 1, line 27, page 2, line 20)
A1 is a group -CR3=, where R3 is, for example, H (page 1, lines 11-12)
R1 is, for example, a straight-chain alkyl containing up to 6 carbon atoms, substituted with halogen, preferably chlorine or fluorine (page 1, lines 6-10), and preferably R1 is a 2-haloethyl group, in particular a 2-chloroethyl group (page 2, line 10);
R2 is, for example, -CONR7R8 (page 2, line 12), where R7 and R8 are the same or different, each is, for example, H or a straight-chain alkyl containing up to 4 carbon atoms, or a cycloalkyl group or the group -NR7R8 represents a heterocyclic group (page 1, lines 22-26);
where (page 1, lines 44-45) cycloalkyl groups within the definition of the formula shown above contain 3 to 8 carbon atoms; and
where (page 1, lines 46-50) a heterocyclic group within the definition of the formula above is a 5-, 6- or 7-membered heterocyclic ring which may optionally contain a further heteroatom, i.e. nitrogen, oxygen or sulphur, and which may carry one or two straight- or branched-chain alkyl substituents each containing up to 4 carbon atoms, e.g. a piperidino group or pyrrolidin- 1 -yl, or 4-methyl-piperazin-l -yl,
and pharmaceutical compositions containing them, as in instant claims 11, 19,
effective as antineoplastic agents (page 1, lines 62-63).
Baig teaches (page 1, right column, lines 65-67) that preferred R1 is a 2-haloalkyl, in particular a 2-chloroethyl group (page 2, line 10), and Baig also teaches that R1 is an alkyl substituted with halogen preferably Cl or F. Thus, Baig implicitly teaches R1 = 2-haloalkyl where the halogen substituent is Cl or F.
The genus of tetrazine derivatives taught by Baig, namely a subgenus where R2 is
-CONR7R8 and R7 and R8 are the same or different, and each is a H or a straight-chain alkyl containing up to 4 carbon atoms,
encompasses/overlaps with instant compounds of formula (I)
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of claim 1, wherein R1 and R2 are independently selected from H and alkyl, as in instant claim 1; or R1 and R2 are lower alkyl/methyl, as in instant claim 3, and encompasses Applicant’s elected species, as well as compounds (1-9 in order listed) in instant claims 9, 10, compound (first listed) of claim 17, and compounds
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of instant claim 18.
The genus of tetrazine derivatives taught by Baig, namely a subgenus where R2 is
-CONR7R8, where R7 and R8 are the same or different, each is, for example, H or a cycloalkyl containing 3 to 8 C atoms encompasses/overlaps with compounds of instant claims 14, 16, 17, 18
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, where R2 is
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.
The genus of tetrazine derivatives taught by Baig, namely a subgenus where R2 is
-CONR7R8, where the group -NR7R8 represents a heterocyclic group, including a piperidino group or pyrrolidin- 1 -yl, or 4-methyl-piperazin-l -yl, encompasses/overlaps with
instant compounds of formula (I)
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of claim 1, 3, 14 wherein R1 and R2 combine to form -(CH2)n-; and encompasses compounds (last 3 listed) in instant claims 9, 10, and compound
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of instant claims 14, 16, 17, 18.
Baig also specifically teaches (page 2, lines 54-55) the following compound:
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compound Q, which differs from a compound of formula (I) of instant claims 1, 3, 14, where R1 and R2 combine to form -(CH2)5-, in that the substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring is 2-chloroethyl (Baig) vs. 2-fluoroethyl (compound of instant claims).
Baig also specifically teaches (page 3, lines 15-16) the following compound:
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compound CC, which differs from a compound of instant claims 1, 3, 9, 10, 18
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in that the substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring is 2-chloroethyl (Baig) vs. 2-fluoroethyl (compound of instant claims).
Baig teaches (page 3, lines 29-30) that compounds Q and CC above are of particular importance.
Baig does not specifically teach the instant compounds.
Lunt is as above.
Importantly, Lunt teaches (page 1, right column, lines 65-67) that preferred R1 is a 2-haloalkyl, namely 2-fluoroethyl, as in instant elected species, or 2-chloroethyl. Thus, Lunt teaches that 2-fluoroethyl and 2-chloroethyl can be used interchangeably as R1.
The genus taught by Lunt overlaps with the genus of Baig, and compound H taught by Lunt is the same as compound CC taught by Baig.
It would have been obvious for a person of ordinary skill in the art to combine the teachings of Lunt and Baig to arrive at the instant invention.
The person of ordinary skill in the art would have replaced the 2-chloroethyl substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring in compound Q taught by Baig, with 2-fluoroethyl, to arrive at a compound of instant formula (I) where R1 and R2 combine to form -(CH2)5-, because Baig teaches that R1 in the tetrazine derivatives of the invention is an alkyl substituted with halogen preferably Cl or F and preferred R1 is a 2-haloalkyl, and Lunt teaches that preferred R1 in the tetrazine derivatives is a 2-haloalkyl, namely 2-fluoroethyl, or 2-chloroethyl. Thus, the person of ordinary skill in the art would have replaced 2-chloroethyl with 2-fluoroethyl in compound Q taught by Baig, with a reasonable expectation that the resulting tetrazine derivative retains antineoplastic activity.
Further, the person of ordinary skill in the art would have synthesized other compounds from the subgenus taught by Baig where R2 is -CONR7R8, where the group -NR7R8 represents a heterocyclic group, including a pyrrolidin- 1 -yl, or 4-methyl-piperazin-l -yl, and would have replaced the 2-chloroethyl substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring in said compounds, with 2-fluoroethyl, because Baig teaches that R1 in the tetrazine derivatives of the invention is an alkyl substituted with halogen preferably Cl or F and preferred R1 is a 2-haloalkyl, and Lunt teaches that preferred R1 in the tetrazine derivatives is a 2-haloalkyl, namely 2-fluoroethyl, or 2-chloroethyl. Thus, the person of ordinary skill in the art would have replaced 2-chloroethyl with 2-fluoroethyl in a compound taught by Baig, where R2 is -CONR7R8, and where the group -NR7R8 represents a heterocyclic group, with a reasonable expectation that the resulting tetrazine derivative retains antineoplastic activity.
Furthermore, the person of ordinary skill in the art would have synthesized a number of compounds from the genus taught by Baig and Lunt, namely tetrazine derivatives
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wherein R1 is 2-fluoroethyl, and R2 is -CONR7R8, where R7 and R8 are for example, H or straight-chain alkyl up to 4 carbon atoms, or a cycloalkyl containing 3 to 8 C atoms, with a with a reasonable expectation that the resulting tetrazine derivatives retain antineoplastic activity.
As such, claims 1, 3, 7, 9-11, 14, 16-19 are rejected as prima facie obvious.
Claims 1, 3, 7, 9-11, 14, 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Stevens et al. (US 8,450,479 of 28 May 2013, cited in IDS), in view of Lunt et al. (GB 2,104,522, published 9 March 1983, cited in PTO-892).
Stevens (US 8,450,479) teaches (column 37, lines 1-10) compound RR-004 below
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as a 3-substituted-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amide, and pharmaceutical compositions thereof, effective to treat cancer (Abstract).
Compound RR-004 taught by Stevens is a direct homolog -CONH2 vs. -CONHMe of Applicant’s elected species, compound I-1
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, which is a compound of formula (I)
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of instant claims 1, 3, 7, 9-11, 14, 18-19, for which the following definitions apply: R2 = H and R1 = methyl.
Stevens also teaches the compound below
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(column 34, lines 25-35) as a 3-substituted-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amide, effective to treat cancer.
Stevens does not disclose the instant elected species, compound I-1.
Lunt specifically teaches (page 2, lines 109-110) the following compounds:
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compound C (page 2, lines 107-108),
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compound D (page 2, lines 109-110), as imidazo[5,1-d]-1,2,3,5-tetrazin-4-one derivatives having antineoplastic activity. Lunt teaches that compounds C and D are of particular importance (page 2, lines 129-130).
Lunt broadly teaches (Abstract) tetrazine derivatives
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wherein
R1 is, for example, an alkyl group containing up to 6 C atoms, substituted by halogen;
R2 is a carbamoyl group optionally N-substituted by one or two groups selected from alkyl containing up to 4 C atoms,
and pharmaceutical compositions containing them, as in instant claims 11, 19,
effective as antineoplastic agents (page 2, line 74).
Lunt teaches (page 1, right column, lines 69-71) that preferred R2 is a carbamoyl group
-CONH2 or methylcarbamoyl -CONHMe (as in instant elected species).
Lunt teaches (page 1, right column, lines 65-67) that preferred R1 is a 2-haloalkyl, namely 2-fluoroethyl, as in instant elected species, or 2-chloroethyl.
It would have been obvious for a person of ordinary skill in the art to use the teachings of Stevens and Lunt to arrive at the instant invention.
It would have been obvious to prepare a direct structural homolog -CONHMe vs.
-CONH2 of compound RR-004 taught by Stevens, with the expectation that the resulting homolog possesses similar biological properties.
In the absence of unexpected results, stereoisomers are considered obvious variants of each other. "Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties". In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Furthermore, it would have been obvious to synthesize said direct structural homolog
-CONHMe vs. -CONH2 of compound RR-004 taught by Stevens, because Lunt teaches 3-substituted-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides, in which the preferred R2 is a carbamoyl group -CONH2 or methylcarbamoyl -CONHMe, as antineoplastic agents. Thus, the person of ordinary skill in the art would have synthesized a homolog of compound RR-004 taught by Stevens, in which the -CONH2 is replaced by methylcarbamoyl -CONHMe, with the expectation that the antineoplastic activity is retained.
Furthermore, the person of ordinary skill in the art would have replaced the 2-chloroethyl substituent in position 3 on the imidazo[5,1-d]-1,2,3,5-tetrazin-4-one ring in compound D taught by Lunt, with 2-fluoroethyl, to arrive at the instant elected species, because Lunt teaches that preferred R1 in the tetrazine derivatives of the invention is a 2-haloalkyl, namely 2-fluoroethyl, or 2-chloroethyl. Thus, the person of ordinary skill in the art would have replaced 2-chloroethyl with 2-fluoroethyl in compound D taught by Lunt, with a reasonable expectation that the resulting tetrazine derivative retains antineoplastic activity.
As such, claims 1, 3, 7, 9-11, 14, 18-19 are rejected as prima facie obvious.
Conclusion
Claims 1, 3, 7, 9-11, 14, 16-19 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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