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 5-20 are pending in the application. Claims 1-4 are cancelled in the amendment filed 6/15/26. Claims 8-20 are withdrawn from consideration.
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 § 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) 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mills (WO97/06829)
in view of Blagbrough et al. (Biochem. Soc. Trans. (2003) Vol 31, part 2, p397-406) and Ksenofontova et al. (J. Mol. LIq. 283 (2019) 695-703) and in further view of Rais et al. (Mol. Pharm. VOL 7, NO.6, 2240-2254) and Yamaguchi et al. (J. Lipid Res. 2006 47: 1196-1202).
Mills (WO97/06829) discloses fluorescent bile acid derivatives (title; p1, first paragraph) based on cholic acid (p4, fourth paragraph) comprising the compound of formula (I)
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wherein A is α-OH or β-OH; B is α-H or β-H; C is -H, α-OH or β-OH; DI is -H, α-OH or β-OH; E is -H, α-OH or β-OH; L is a linking moiety; J is a fluorescent moiety and n is 0 or 1 (p3, last paragraph).
The
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encompasses the
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of the instant claims.
L comprises –(CH2)nNH, where n is 3 or 4 (p4, second paragraph) and when n is 4 encompasses
the
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of lysine of the instant claims.
The amino group of the linker L reacts with the fluorescent active moiety (p5, first two lines).
Mills does not disclose the BODIPY or dansyl fluorescent moieties of the instant claims.
Blagbrough et al. (Biochem. Soc. Trans. (2003) Vol 31, part 2, p397-406) discloses fluorescent molecular probes comprising bile acids that are functionalized with a fluorescent moiety (abstract).
The bile acid compounds comprise compound 4 having a terminal amine moiety
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(Figures 1,5 and 7).
The fluorescent compounds that bind to the terminal amine moiety comprise
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(BODIPY-FL succinimidyl ester) and
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(Dansyl-Cl) (Figure 7; p405, left column).
Ksenofontova et al. (J. Mol. LIq. 283 (2019) 695-703) discloses amino acid-BODIPY conjugates wherein BODIPY succinimidyl ester is reacted with the terminal amino moiety of lysine to yield an amide bond (Scheme 1; p698, 3.2. Synthesis and Characterization of amino acids-BODIPY conjugates). The amino acid-BODIPY conjugates have a unique property of water solubility (abstract; p699, right column, second paragraph; p702, 4. Conclusions).
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 BODIPY moiety to the cholic acid of Mills via the lysine terminal amine moiety for the advantage of providing a probe that visualizes the bile duct of a patient with BODIPY fluorescent probes having good photophysical characteristics and water solubility necessary for in vivo fluorescence imaging as taught by Ksenofontova et al.
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 BODIPY moiety for the dansyl moiety to bind the dansyl moiety
to the
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of Mills via the lysine terminal amine moiety as Blagbrough et al. teaches of the analogous use of BODIPY or dansyl to fluorescently functionalize bile acids via a terminal amine moiety.
It would have been predictable to one of ordinary skill in the art that the BODIPY or dansyl substituted cholic acid
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of Mills yields the compound
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and
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with a reasonable expectation of success wherein the BODIPY and dansyl moieties are bound to the nitrogen of the lysine moiety.
Mills does not disclose ester derivatives, such as
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and
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of the instant claims.
Rais et al. (Mol. Pharm. VOL 7, NO.6, 2240-2254) discloses the bile acids
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wherein the R2 comprises -H or -CH2C6H5 (Figure 1).
Yamaguchi et al. (J. Lipid Res. 2006 47: 1196-1202) discloses chenodeoxycholyl-(NƐ-CBZ)-lysine methyl ester prior to conversion to a carboxyl group (p1197, Synthesis of fluorescent bile salt derivatives.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the fluorescent cholic acid derivatives comprise an intermediate methyl ester
prior to deprotection to a carboxyl group as taught by Yamaguchi et al. and also that Rais et al. teaches
of the esterification of cholic acid derivatives.
It would have been obvious to one of ordinary skill in the art to examine the BODIPY or dansyl methyl ester derivatives of the cholic acid for their ability to visualize the bile duct of a patient while having good photophysical characteristics and water solubility necessary for in vivo fluorescence imaging.
The compounds of the combined disclosures encompass the fluorescent cholic acid derivatives of the instant claims, have the same properties and are capable of the same functions, such as being highly soluble in a large range of solvent and are metabolically stable under storage conditions.
The compounds of the combined disclosures encompass the fluorescent cholic acid derivatives of the instant claims, have the same properties and are capable of the same functions, such as having a very intensive fluorescence and a long half-life of the fluorescent moiety.
Response to Arguments
Applicant’s asserts with regards to Holzinger and Fardel are moot as they are not used in the instant rejection.
Applicant asserts that Yamaguchi only discloses the structure below and does not disclose any methyl esters, or other derivatives including those with a glycine acid or ester and taurine acid or ester added to the lysine side chain
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.
The reference of Yamaguchi was not used to teach of the structure stated but was used to teach
that the methyl ester of chenodeoxycholyl-(NƐ-CBZ)-lysine is a known intermediate prior to conversion to a carboxyl group. The reference of Rais et al. was used to teach of the esterification of cholic acid derivatives.
The reference of Blagbrough et al. was used to teach of BODIPY or dansyl substituted bile acids as well as that stated above.
The reference of Ksenofontova et al. was used to teach of amino acid-BODIPY conjugates wherein BODIPY succinimidyl ester is reacted with the terminal amino moiety of lysine to yield an amide bond as well as that stated above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the fluorescent cholic acid derivatives comprise an intermediate methyl ester prior to deprotection to a carboxyl group as taught by Yamaguchi et al. and also that Rais et al. teaches
of the esterification of cholic acid derivatives.
It would have been obvious to one of ordinary skill in the art to examine the BODIPY or dansyl methyl ester derivatives of the cholic acid for their ability to visualize the bile duct of a patient while having good photophysical characteristics and water solubility necessary for in vivo fluorescence imaging as stated above.
Applicant asserts that Yamaguchi does not disclose the lysine or lysylglycine lateral side chain for
connection of the moieties wherein the direct N-NBD bond is structurally and chemically distinct from the claimed compounds. Yamaguchi itself demonstrates that even minor modifications to the bile acid fluorophore conjugate changes transporter binding parameters.
The reference of Yamaguchi was not used to disclose the lysine or lysylglycine lateral side chain or any modifications but was used to teach that stated above.
The reference of Mills was used to teach of the compound of formula (I)
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that comprise a lysine side chain when L comprises –(CH2)nNH and n 4. The terminal amino moiety of the lysine is used to connect the fluorescent moiety to yield an amide bond.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
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