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 .
Election/Restrictions
Applicant’s election without traverse of group I, claims 1-7 and the species 54 in the reply filed on 12/16/24 is acknowledged.
Claims 8-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/16/24.
The search of the species included
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and was expanded to include the fluorescent moiety
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.
Drawings
The Petition to accept color drawings filed 3/16/22 was granted on 9/29/23.
Claim Objections
Claim 5 is objected to because of the following informalities: the structures of 31, 71 and 73
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of the instant claim 5 comprise a carboxyl moiety and NO2 moieties that are cut off. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7 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 bond formation of the moiety
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of the compound of formula I
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is confusing and unclear. The instant claim 1 does not state that the R3 and R4 may further be taken together to form a ring and therefore, it is unclear if the bond formation is a mistake or is meant to indicate that
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may be further taken together to form a ring.
The dependent claims fall therewith.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The instant
claims 2 and 5 comprise structures
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comprising a ring moiety but the instant claim 1 to which they depend does not indicate that the R3 and R4 moiety may further be taken together to form a ring. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient
showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4,6 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yamaguchi et al. (J. Lipid Res. 2006 47: 1196-1202).
Yamaguchi et al. (J. Lipid Res. 2006 47: 1196-1202) teaches of the fluorescent bile acid chenodeoxycholyl-(NƐ-NBD)-lysine (CDCA-NBD)
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(abstract; Fig.1.) that anticipates the fluorescent cholic acid derivative of the instant claims when m is 0;
R is H; R1 is OH; R2 is OH; R3 and R4 are an amino acid or fragment thereof; R5 is OH; and X is
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.
The CDCA-NBD anticipates the structure
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of the instant claim 2.
The
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anticipates the polyaromatic or polyheterocyclic moiety with a 5- or 6-membered ring and which could be bi- or tricyclic or polycyclic and contain F,N,O,S,B as atoms in the general formula and
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of the instant claims 3 and 4, respectively.
The CDCA-NBD is fluorescent as the fluorescent intensity is determined (p1198, Characterization of CDCA-NBD transport, Visualization of CDCA-NBD uptake; p1199, Discussion; p1200, left column, second paragraph).
With regards to the instant claim 6, the CDCA-NBD anticipates the fluorescent cholic acid derivative of the instant claims, has the same properties and is capable of the same functions, such as being highly soluble in a large range of solvent and medium and metabolically stable under storage
conditions.
With regards to the instant claim 7, the CDCA-NBD anticipates the fluorescent cholic acid
derivative, has the same properties and is capable of the same functions, such as having a very intensive
fluorescence and a long half-life of the fluorescent moiety.
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) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yamaguchi et al. (J. Lipid Res. 2006 47: 1196-1202) in view of Holzinger et al. (Hepatology 1998; 28:510-520) and in further view of Fardel et al. (Expert Opinion on Drug Metabolism & Toxicology, 2015, 11:8, 1233-1251).
Yamaguchi et al. (J. Lipid Res. 2006 47: 1196-1202) discloses the CDCA-NBD fluorescent bile acid
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as well as that stated above.
Yamaguchi et al. does not disclose the stereoisomers, such as
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or their methyl esters.
Holzinger et al. (Hepatology 1998; 28:510-520) discloses fluorescent bile acids, such as
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having variable chirality at the R1 and R2 positions. C-L-NBD (cholyl-[NƐ-NBD]-lysine) and UDC-L-NBD (ursodeoxycholyl-(NƐ-NBD)-lysine) (abstract).
Yamaguchi et al. further discloses that the CDCA-NBD is efficiently transported by OATP1B1 and OATP1B3 with high affinities (abstract; p1197, left column, second paragraph; p1200, left column, second paragraph) and that UDCA-NBD (ursodeoxycholic acid) is also transported via OATP1B1 and OATP1B3 (p1198-1199, Transport of other NBD-labeled bile acids).
Yamaguchi et al. also discloses that the NBD-labeled bile acids are synthesized via a chenodeoxycholyl-NƐ-lysine methyl ester (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 to examine different stereoisomers of CDCA-NBD and/or UDCA-NBD fluorescent bile acids and/or their methyl esters for efficient transport via OATP1B1 and OATP1B3 with high affinities as Holzinger et al. teaches that each of the C-l-NBD or UDC-L-NBD fluorescent bile acid stereoisomers are transported via OATP1B1 and OATP1B3 and the stereoisomers of the fluorescent cholic acid derivatives of the instant claims having analogous structures are probes used for examining the uptake by influx transporters, such as OAT.
Therefore, it would have been obvious to one of ordinary skill in the art that the technology is predictable wherein the stereoisomers of the fluorescent cholyl bile acid derivatives containing various chiral center combinations will predictably provide for fluorescent bile acid probes that are analogously transported via OATP1B1 and OATP1B3.
Yamaguchi et al. does not disclose the fluorescent moiety
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.
Fardel et al. (Expert Opinion on Drug Metabolism & Toxicology, 11:8, 1233-1251) discloses fluorescent bile acid derivatives, such as ursodeoxycholyl-(NƐ-NBD)-lysine and chenodeoxycholyl-(NƐ-NBD)-lysine (CDCA-NBD) (p1236, 2.2. Fluorescent substrates for bile salt export pump (BSEP/ABCB11); p137, 3.2. Fluorescent substrates for organic anion transporting polypeptides (OATPs/SLCOs)).
Fluorescent probes for transporters can be synthesized through the labeling of reference non-fluorescent drug substrates with BODIPY. The examination of fluorescence is illustrated via fluorescein substituted compounds transported by OATP1B1, OATP1B3, etc. (p1243, Expert opinion).
Holzinger et al. further discloses that the fluorescent bile acid cholyl-derivatives may be labelled with fluorescein (Fig. 1) instead of NBD.
It would have obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the fluorescein or NBD of the fluorescent bile acid derivatives and/or methyl ester derivatives for the BODIPY of Fardel et al. to yield fluorescent bile acid derivative, such as
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or
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to examine transport via OATP1B1, OATP1B3 as the number of fluorescent dyes available for transporter studies has grown which predictably provides for fluorescent bile acid derivatives with different dyes having various photostability, quantum yield, signal-to-noise ratios, etc.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor,
Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this
application or proceeding is assigned is 571-273-8300.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618