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 .
Claims and Previous Objections/Rejections Status
Claims 1-5,7 and 21-38 are pending in the application.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
New Grounds of Rejection
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.
Claims 1-5,7 and 21-33 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. The instant claims are confusing and unclear as the compounds of Formula (12),(13),(14),(15),(16),(17) and (18) comprise a Markush structure containing so many possible variations, such as the combination of R1,R2 and R3 moieties wherein R1 and R2 may be present or may not be present when the integers n and p are 0. The integer n for the entire linker -((R1)-R2-(R1))n- may be from 0 to 24 which yields a linker of various chain lengths that may form various conformations. The R1 and R2 may be omitted or comprise so many different varieties of substituents and R1 may contain one or more heteroatoms selected from O,S,NR5,P and Si that yields an infinite number of compounds with different structures. The substituent R3 comprises H, -OH, -NH2, -N3, -Cl, -Br, -F, -I and a chelating moiety which have different sizes, reactivities and functions. The compounds of the instant claims comprise numerous different structures so that the scope of the claims cannot be determined. While breadth alone is not indefinite, the instant claims have an almost unlimited number of possible combinations of chemical moieties that it is not possible to determine the metes and bounds of the claims.
The dependent claims fall therewith.
Claims 1-5,7 and 21-33 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte
Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes
species of the claimed invention that do not share both a substantial structural feature and a common
use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush
group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the
same art-recognized class. Members of a Markush group share a common use when they are disclosed
in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No.
27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The claims are directed to the compounds of Formula (12),(13),(14),(15),(16),(17) and (18) comprising a Markush structure containing so many possible variations, such as the combination of R1,R2 and R3 moieties wherein R1 and R2 may be present or may not be present when the integers n and p are 0. The integer n for the entire linker -((R1)-R2-(R1))n- may be from 0 to 24 which yields a linker of various chain lengths that may form various conformations. The R1 and R2 may be omitted or comprise so many different varieties of substituents and R1 may contain one or more heteroatoms selected from O,S,NR5,P and Si that yields an infinite number of compounds. The substituent R3 comprises H, -OH, -NH2, -N3, -Cl, -Br, -F, -I and a chelating moiety which have different sizes, reactivities and functions. The compounds of the instant claims comprise numerous different structures so that the scope of the claim cannot be determined, instant claims have an almost unlimited number of possible combinations of chemical moieties and there is nothing of record to show a common chemical core that is specifically tied to a function in the almost unlimited breadth of the claimed compounds.
Applicant attention is directed to the third paragraph of MPEP 803.02 which discloses: “Since
the decisions in In re Weber, 580 F.2d 455, 198 USPQ 328 (CCPA 1978) and In re Haas, 580 F.2d 461, 198
USPQ 334 (CCPA 1978), it is improper for the Office to refuse to examine that which Applicants regard as
their invention, unless the subject matter in a claim lacks unity of invention. In re Harnisch, 631 F.2d
716, 206 USPQ 300 (CCPA 1980); and Ex parte Hozumi, 3 USPQ2d 1059 (Bd. Pat. App. & Int. 1984). Broadly, unity of invention exists where compounds included within a Markush group (1) share a
common utility, and (2) share a substantial structural feature essential to that utility.”
In the instant case, if it is asserted that the claims share a common utility, it is noted the only
shared structure is a
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bound to different pyridyl, pyrazine or pyrimidyl moieties that does not allow the genus to have an art recognized classification. Hence, the Markush grouping is improper.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual
species or grouping of species that share a substantial structural feature as well as a common use that
flows from the substantial structural feature, or present a sufficient showing that the species recited in
the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that
flows from the substantial structural feature. This is a rejection on the merits and may be appealed to
the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1)
(emphasis provided).
The dependent claims fall therewith.
Response to Arguments
Applicant’s arguments, see REMARKS, filed 7/2/26, with respect to the rejection(s) of claim(s) 1-5,7 and 21-33 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Robillard et al. (US 10,927,139B2) in view of Devaraj et al. (US2018/0244643A1) and Robillard et al. (WO2012/156919).
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.
Claim(s) 1-5,7 and 21-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Robillard et al. (US 10,927,139B2) in view of Devaraj et al. (US2018/0244643A1) and Robillard et al. (WO2012/156919).
Robillard et al. (US 10,927,139B2) discloses tetrazine derivatives comprising the structure
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(column 46, lines 1-10) wherein R1 and R2 are selected from the groups consisting of alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, etc. from a finite list of R1 and R2 substituents (column 46, lines 15+; column 47, lines 5-16).
The 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, etc. encompasses the 2-pyridyl , 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl of Formula (18), Formula (16), Formula (17), Formula (12), Formula (13) and Formula (15) of the instant claims, respectively.
The alkyl is preferably lower alkyl (C-1-4 alkyl), optionally substituted with one or more groups, such as COOR, CONHR, COR, SO2R, SO2OR, etc.; R is H or C1-C6 alkyl, etc. (column 32, lines 13-21; column 47, lines 5-22).
The lower alkyl (C-1-4 alkyl) encompasses the
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of the instant claims wherein y is 1-4 and/or y is not 1 (C-2-4 alkyl) for Formula (18).
The lower alkyl (C-1-4 alkyl) substituted with a combination of COOR, CONHR, COR, SO2R, SO2OR, etc.; R is H or C1-C6 alkyl, etc. encompasses the –(CH2)y-((R1)p-R2)n-(R1)p-R3 that is in a range of from 100 Da to 3000 Da of the instant claims
Robillard et al. ‘139 does not explicitly disclose the pyridyl or pyrimidyl moieties of Formulas (12), (13), (14), (15), (16) and (17).
Robillard et al. ‘139 exemplifies 2-pyridyl compounds, such as
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,
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, etc. (columns 57,58).
The linker
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MW = 144 encompasses a –(CH2)y-((R1)p-R2)n-(R1)p-R3 that is in a range of from 100 Da to 3000 Da of the instant claims.
Devaraj et al. (US2018/0244643A1) discloses
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wherein L1 comprises substituted or unsubstituted alkylene (C1-C8); R1 comprises a detectable moiety and R2 comprises substituted or unsubstituted heteroaryl (p6, [0083]; p9, [0152-0158]).
The heteroaryl comprises 2-pyridyl, 3-pyridyl, 4-pyridyl, etc. (p4, [0062]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to substitute the 2-pyridyl moiety of the tetrazine derivatives
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of
Robillard et al. ‘139 with other analogous 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, moieties, with an expectation of success, to examine and determine the tetrazine derivatives that are most reactive towards the dienophiles for the release of a substance linked to a trans-cyclooctene dienophile for IEDDA as Robillard et al. ‘139 states that the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, etc. substituted tetrazines are more reactive towards dienophiles and Devaraj et al. teaches of tetrazines wherein R2 comprises a variety of pyridyl moieties directly bound to the tetrazine
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.
With regards to Formula (18), Robillard et al. ‘139 does not explicitly disclose that the R1 or R2 comprises an C-2-4 alkyl wherein the C-2-4 alkyl corresponds to
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of the instant claims when y is not 1.
Robillard et al. ‘139 discloses that R1 or R2 lower alkyl includes C-2-4 alkyl optionally substituted
with one or more groups, such as COOR, CONHR, COR, SO2R, SO2OR, etc. as well as that stated above.
Devaraj et al. teaches of tetrazines wherein L1 comprises a substituted or unsubstituted alkylene (C1-C8) directly bound to the tetrazine
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.
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention that one of R1 or R2 moieties of the tetrazine derivative
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comprises 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, etc. and the other R1 or R2 moiety comprises C-2-4 alkyl optionally substituted with one or more groups, such as COOR, CONHR, COR, SO2R, SO2OR, etc., with an expectation of success, as Robillard et al. ‘139 teaches of the different combinations of R1 and R2 substituents wherein the lower alky is not necessarily C1 alkyl but comprises C-2-4 alkyl substituted with one or more groups, such as COOR, CONHR, COR, SO2R, SO2OR, etc. and Devaraj et al. teaches of L1 is substituted or unsubstituted alkylene (C1-C8) that is directly bound to the tetrazine moiety.
Robillard et al. ‘139 does not explicitly disclose the tetrazine derivative
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that are further bound to a DOTA metal chelator moiety.
Robillard et al. ‘139 further discloses that tetrazine derivative, such as
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bound to a DOTA metal chelator via a -C(O)-NH- moiety to chelate 177Lu (columns 61 and 62; column 141, lines 58+).
Robillard et al. (WO2012/156919) discloses tetrazines
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wherein R1 and R2 comprise
alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, etc. optionally substituted with one or more groups, such as COOR, CONHR, COR, SO2R, SO2OR, etc.
(p30, lines 1-5; p31, lines 15+).
The tetrazines may be modified with DOTA complexed to isotopes, such as 177Lu, etc. for use in SPECT, MRI or PET imaging (p38, lines 19+; p62, lines 17-19).
Devaraj et al. further discloses the detectable moieties R1 comprise radio-labeled moieties, magnetic contrast agents, etc. (p9, [0116]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to bind a DOTA metal chelator to the tetrazine derivatives of Robillard et al. ‘139 via a substituted alkylene linker as Devaraj et al. teaches that the detectable moieties comprising radio-labeled moieties or magnetic contrast agents are bound to the tetrazine via a substituted alkylene linker and Robillard et al. ‘919 teaches of predictably binding the 177Lu-DOTA to the tetrazine derivatives via a substituted alkylene linker to yield imaging agents for MRI, PET, SPECT, etc. upon IEDDA reaction with a trans-cyclooctene dienophile.
The tetrazine derivatives of the combined disclosures encompass the tetrazine compounds of the instant claims, have the same properties and are capable of the same functions, such as having a Log P value of at most 3.0 or of at most 2.0.
Applicant asserts that exchanging the ring in the Robillard '139 compounds still would not result in compounds that fall within the scope of the instant claims which require that the –(CH2)y-((R1)p-R2)n-(R1)p-R3 moiety have a molecular weight in a range of from 100 Da to 3000 Da. The compounds resulting from such a substitution retain the same substituent moiety present in the cited Robillard '139 compounds, which, each have a molecular weight well below the recited lower limit of 100 Da.
The reference of Robillard '139 teaches of the linker comprise a lower alkyl (C-1-4 alkyl)
substituted with a combination of COOR, CONHR, COR, SO2R, SO2OR, etc.; R is H or C1-C6 alkyl, etc. that encompasses the –(CH2)y-((R1)p-R2)n-(R1)p-R3 in a range of from 100 Da to 3000 Da of the instant claims.
An example of the linkers of Robillard '139 comprises
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MW = 144 that encompasses a -(CH2)y-((R1)p-R2)n-(R1)p-R3 that is in a range of from 100 Da to 3000 Da of the instant claims.
Applicant assertions with regards to Lappchen are moot as the reference is not used in the instant rejection.
Applicant asserts that The Examiner further asserts that it would have been obvious to provide the pyrazinyl moiety of Formula (14) in view of Devaraj. As with the ring substitution addressed above, selecting a pyrazinyl moiety does not supply the recited requirement that the -(CH2)y-((R1)p-R2)n-(R1)p-R3 moiety have a molecular weight in a range of from 100 Da to 3000 Da, and a compound resulting from such a substitution retains a moiety below the recited lower limit of 100 Da.
The reference of Devaraj teaches that the L1 is substituted or unsubstituted alkylene (C1-C8) that is directly bound to the tetrazine moiety.
The reference of Robillard '139 teaches that one of the R1 or R2 moiety comprises a lower alkyl
(C-1-4 alkyl) or (C-2-4 alkyl) substituted with a combination of COOR, CONHR, COR, SO2R, SO2OR, etc.; R is H or C1-C6 alkyl, etc. encompasses the -(CH2)y-((R1)p-R2)n-(R1)p-R3 that is in a range of from 100 Da to 3000 Da of the instant claims.
Applicant asserts that with respect to claims 29 through 33, the Examiner relies on the Robillard '139 compound in which a single methylene group connects the tetrazine ring to the remainder of the substituent, corresponding to y equal to 1. Claims 29 through 33 each depend from claim 28, which requires that y be an integer in a range of from 2 to 4. The compound relied upon in the rejection therefore lacks a limitation required by claim 28, and by each of claims 29 through 33. Binding a DOTA metal chelator to the terminal carboxylic acid of that compound does not alter the value of y, and the cited combination accordingly cannot result in a compound within the scope of claims 29 through 33.
The reference of Robillard et al. ‘139 teaches of the different combinations of R1 and R2 substituents wherein the lower alky is not necessarily C1 alkyl but comprises C-2-4 alkyl substituted with one or more groups, such as COOR, CONHR, COR, SO2R, SO2OR, etc.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute one lower alky linker for another lower alky linker for the advantage of examining and determining the tetrazine derivatives that are most reactive towards the dienophiles for the release of a substance linked to a trans-cyclooctene dienophile for IEDDA as Robillard et al. ‘139 states that the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,4-pyrimidyl, etc. substituted tetrazines with a lower alkyl linker are more reactive towards dienophiles and Devaraj et al. teaches of tetrazines wherein R2 comprises a variety of pyridyl moieties directly bound to the tetrazine
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and a substituted or unsubstituted alkylene (C1-C8) L1 that is directly bound to the tetrazine moiety.
Conclusion
Claims 34-38 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
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