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 .
Status of Claims
Examined Herein: 143-162
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in PRO 63/070,057 on 8/25/2020 and PCT/US2021/047091 on 8/23/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/25/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings received on 2/22/2023 are accepted.
Withdrawn Rejections
The rejections of claim 158, 160, and 161 under 35 U.S.C. 112(b) are hereby withdrawn in view of Applicant’s amendments to claim 158, 160, and 161, which render the rejections moot.
The rejection of claims 143-149 under 35 U.S.C. 102(a)(1) and (a)(2) over Hutchinson (‘503) is hereby withdrawn in view of Applicant’s amendments to claim 143-149, which introduce limitations not previously claimed or considered.
The rejection of claims 150-156 under 35 U.S.C. 102(a)(1) and (a)(2) over Hutchinson (‘134) is hereby withdrawn in view of Applicant’s amendments to claim 150-156, which introduce limitations not previously claimed or considered.
The rejection of claims 157-159 and 162 under 35 U.S.C. 103 over Duggan and Hutchinson (‘168) is hereby withdrawn in view of Applicant’s amendments to claim 157-159 and 162, which introduce limitations not previously claimed.
The rejection of claims 157-162 under 35 U.S.C. 103 over Duggan, Hutchinson (‘168), and Miyazawa is hereby withdrawn in view of Applicant’s amendments to claim 157-162, which introduce limitations not previously claimed or considered.
Claim Objections
Claims 150 and 157 objected to because of the following informalities:
Claims 150 and 157 recites the limitation “ma substituted cycloalkyl,” which appears to be a typo of “a substituted alkyl.”
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.
Claims 157-162 rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 157 recites the limitation “[a] method for making a compound… (I)-c2.2.2 or (II)-c2.2.2… said method comprising mixing (I)-c2.2.2 or (II)-c2.2.2 with a fluorinating agent.” This limitation is internally inconsistent because (I)-c2.2.2 or (II)-c2.2.2 is used to make (I)-c2.2.2 or (II)-c2.2.2. However, a compound cannot simultaneously serve as both a reactant and a product of the reaction. Claim 157 also recites the limitation “R2 is 18F.” In this embodiment, (I)-c2.2.2 or (II)-c2.2.2 is fluorinated with 18F and then further mixed with a fluorinating agent to prepare 18F-fluorinated (I)-c2.2.2 or (II)-c2.2.2. This limitation is likewise internally inconsistent, as the product already comprises the fluorinated group being introduced by the fluorinating agent. Accordingly, the claim is indefinite because the scope of the claim cannot be determined in view of these internal inconsistencies. For examination purposes, the method is interpreted as a method for making fluorinated (I)-c2.2.2 or (II)-c2.2.2 comprising introducing c2.2.2 with (I) or (II) to yield (I)-c2.2.2 or (II)-c2.2.2. Then, mixing (I)-c2.2.2 or (II)-c2.2.2 with a fluorinating agent to prepare the final fluorinated product. Under this interpretation, (I) and (II) are presumed to be in their stable form, R2 is interpreted as a leaving group in the reactant, and as 18F in the final fluorinated product. [This interpretation is ascertained from the limitations of claim 159 & 161 and from the specification 00619-0640] Applicant is required to provide further clarification or appropriate correction. Dependent claims fall therewith.
Claim 161 recites the limitation “wherein c2.2.2 in (I)-c2.2.2 or (II)-c2.2.2 is introduced…” There is insufficient antecedent basis for this limitation in the claim. Claim 157 does not describe an introduction step.
Claim 162 recites the limitation “thereby obtaining (I)-H and (II)-H.” (I)-H and (II)-H are not defined by the claims or the specification and their structures are not reasonably understood by one of ordinary skill in the art. Since (I)-H and (II)-H are not adequately defined, the scope of the claim cannot be determined. Appropriate correction is required.
Claim 162 also suggests mixing HCl with (I)-c2.2.2 yields (II)-H or mixing (II)-c2.2.2 with HCl yields (I)-H. For a compound of formula (I) to transform to a compound of formula (II), or vice versa, several intermediate steps would need to be performed and recited by the claim. If Applicant intends for mixing HCl with (I)-c2.2.2 to obtain (I)-H and (II)-c2.2.2 to obtain (II)-H, the claim language should be amended to specify this result. Otherwise, the claim omits essential steps for transforming a compound of formula (I) to a compound of formula (II).
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 143 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Bain (US 2010/0173313 A1, Published 7/8/2010).
With respect to claim 143, Bain discloses the compound TM30089. [Bain, 0021, 0024]
TM30089 has the following structure:
PNG
media_image1.png
500
758
media_image1.png
Greyscale
[Structure of TM-30089 retrieved from US 2017/0121773 A1, Paragraph 0050]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (fluorine)
n1 is 1
n2 is 0
n3 is 2; thus, meeting the limitations of claim 143.
With respect to claim 143, Bain discloses the compound TM30642. [Bain, 0021, 0024]
TM30642 has the following structure:
PNG
media_image2.png
196
222
media_image2.png
Greyscale
[Structure of TM30642 retrieved from Pettipher (Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases), Figure 4]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (fluorine)
n1 is 2
n2 is 0
n3 is 2; thus, meeting the limitations of claim 143.
Claims 143, 149, and 150 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Tanimoto (US 2009/0258922 A1, Published 10/15/2009).
With respect to claim 143, Tanimoto discloses the following compound:
PNG
media_image3.png
264
500
media_image3.png
Greyscale
[Structure retrieved from SciFinder Substances and depicts Ib-6 disclosed by Tanimoto]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (fluorine)
n1 is 1
n2 is 0
n3 is 1; thus, meeting the limitations of claim 143. [Tanimoto, Page 21, Table 6, Ib-6]
With respect to claim 143, Tanimoto discloses the following compound:
PNG
media_image4.png
451
975
media_image4.png
Greyscale
[Structure drawn by Examiner using CAS Draw based on the description of Ib-98 disclosed by Tanimoto]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (chlorine)
n1 is 1,
n2 is 1,
n3 is 1; thus, meeting the limitations of claim 143. [Tanimoto, Page 22, Table 9, Ib-98]
With respect to claim 149, Tanimoto discloses the leaving group is -Cl, thus meeting the limitations of claim 149. [Tanimoto, Page 22, Table 9, Ib-98]
With respect to claim 150, Tanimoto discloses the following compound:
PNG
media_image5.png
505
872
media_image5.png
Greyscale
[Structure drawn by Examiner using CAS Draw based on the description of Ia-4 disclosed by Tanimoto]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (fluorine)
R3 is hydrogen
n1 is 1
n2 is 1; thus, meeting the limitations of claim 150. [Tanimoto, Page 18, Table 1, Ia-4]
With respect to claim 150, Tanimoto discloses the following compound:
PNG
media_image6.png
609
769
media_image6.png
Greyscale
[Structure drawn by Examiner using CAS Draw based on the description of Ia-6 disclosed by Tanimoto]
Wherein,
X1 and X2 are each CH,
L1-R1 is a substituted alkyl
L1 is a bond
R1 is a substituted C1 alkyl
Y is a leaving group (fluorine)
R3 is hydrogen
n1 is 1,
n2 is 1; thus, meeting the limitations of claim 150. [Tanimoto, Page 18, Table 1, Ia-6]
Claim 143 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hutchinson (US 2011/0152338 A1, Published 6/23/2011).
With respect to claim 143, Hutchinson discloses the following compound:
PNG
media_image7.png
431
513
media_image7.png
Greyscale
[Hutchinson, Compound 1-6 as an embodiment of Formula I, 0357]
Wherein,
X1 and X2 are each CH
L1-R1 is a substituted alkyl
L1 is a bond
R1 is a substituted C2 alkyl
Y is a leaving group (fluorine)
n1 is 2
n2 is 0
n3 is 2; thus, meeting the limitations of claim 143. [Hutchinson, 0147, Compound 1-6 & 0357]
With respect to claim 143, Hutchinson discloses the following compound:
PNG
media_image8.png
345
439
media_image8.png
Greyscale
[Hutchinson, Compound 1-1 as an embodiment of Formula I, 0349]
Wherein,
X1 and X2 are each CH
L1-R1 is a substituted alkyl
L1 is a bond
R1 is a substituted C2 alkyl
Y is a leaving group (fluorine)
n1 is 1
n2 is 0
n3 is 2; thus, meeting the limitations of claim 143. [Hutchinson, 0147, Compound 1-1 & 0349]
With respect to claim 143, Hutchinson discloses the following compound:
PNG
media_image9.png
480
1005
media_image9.png
Greyscale
[Structure drawn by examiner using CAS Draw based on Compound 1-1 as an embodiment of Formula II disclosed by Hutchinson, 0147]
Wherein,
X1 and X2 are each CH
L1-R1 is a substituted alkyl
L1 is a bond
R1 is a substituted C2 alkyl
Y is a leaving group (fluorine)
n1 is 1
n2 is 0
n3 is 1; thus, meeting the limitations of claim 143. [Hutchinson, 0147, Compound 1-1]
PNG
media_image10.png
540
858
media_image10.png
Greyscale
[Structure drawn by examiner using CAS Draw based on Compound 1-6 as an embodiment of Formula II disclosed by Hutchinson, 0147]
Wherein,
X1 and X2 are each CH
L1-R1 is a substituted alkyl
L1 is a bond
R1 is a substituted C2 alkyl
Y is a leaving group (fluorine)
n1 is 2
n2 is 0
n3 is 1; thus, meeting the limitations of claim 143. [Hutchinson, 0147, Compound 1-6]
Claim Rejections - 35 USC § 103
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.
Claims 143, 144, 146, and 147 are rejected under 35 U.S.C. 103 as being unpatentable over Bain, as applied to claim 143 above.
With respect to claim 143, as described above, Bain discloses TM30089 and TM30642, wherein Y is -F.
Moreover, Bain discloses TM30089 and TM30642 are DP2 antagonists/DP2 ligands. [Bain, 0021, 0024]
Bain does not disclose Y is 18F.
However, with respect to claim 144 and 146, Bain discloses the DP2 ligand may comprise a detectable label, wherein the detectable label is a radioactive label, including 18F. [Bain, 0024-0026, 0249] Bain discloses the incorporation of radioisotopes into the DP2 ligand is accomplished using known techniques, including isotopic labelling. [Bain, 0228, 0249] In a more specific embodiment, Bain discloses 18F is a positron emitting isotope that is detectable by a positron emission tomography (“PET”) scanner and may be attached to the ligand. Moreover, Bain discloses 18F (˜110 min) has the longest half-life among all the other disclosed PET isotopes including 11C (˜20 min), 13N (˜10 min), and 15O (˜2 min). [Bain, 0251]
Modifying the Y substituent of TM30089 by replacing F with 18F, results in the compound of claim 144, wherein:
L1-R1 is -CH3
Y is 18F
n1 is 1
n2 is 0
n3 is 2.
In which case, with respect to claim 147, the compound of claim 144 further comprise triflate if Y is +N(CH3)3. However, in the modified compound disclosed by Bain, Y is not +N(CH3)3. Thus, the compound need not comprise triflate. Therefore, the limitations of claim 147 are met. MPEP 2111.04(II).
Modifying the Y substituent of TM30642 by replacing F with 18F, results in the compound of claim 146, wherein:
• L1-R1 is -CH3
• Y is 18F
• n1 is 2
• n2 is 0
• n3 is 2.
It would be obvious to modify the Y substituent of TM30089 and TM30642 by replacing -F with 18F and have a reasonable expectation of success. Bain discloses DP2 ligands, TM30089 and TM30642, each comprising a fluorine substituent (denoted by Y). Bain further discloses the DP2 ligands may be isotopically labeled with 18F. In view of this express teaching, it is reasonable to expect the fluorine substituent (denoted by Y) may be isotopically labelled, thereby replacing fluorine with 18F. One would have been motivated to do so because it is prima facie obvious to modify a reference when some advantage or expected beneficial result would have been produced by the modification. MPEP 2144(I-II). In the present case, Bain discloses 18F is a positron emitting isotope detectable by positron emission tomography (“PET”) scanner. Moreover, 18F (˜110 min) has the longest half-life among all the other PET isotopes disclosed by Bain including 11C (˜20 min), 13N (˜10 min), and 15O (˜2 min). [Bain, 0251] Therefore, one would have been motivated by the expectation that replacing -F with 18F would enable TM30089 and TM30642 to be detectable by PET and sustain a half-life longer than other PET isotopes.
Claims 143, 148, and 149 are rejected under 35 U.S.C. 103 as being unpatentable over Hutchinson, as applied to claim 143 above.
With respect to claim 143, as described above, Hutchinson discloses compound 1-1 (of Formula I), compound 1-6 (of Formula I), compound 1-1 (of Formula II), and compound 1-6 (of Formula II), wherein Y is -F.
Moreover, Hutchinson discloses Y is a substituent of substituted phenyl. [Hutchinson, 0143, 0147, 0200] Thus, with respect to the aforementioned compounds, Hutchinson discloses the substituent of substituted phenyl is fluorine. [Hutchinson, 0357, 0349, 0147]
Hutchinson does not disclose Y is -NO2, -Br, -Cl, or -I.
However, with respect to claim 148 and 149, Hutchinson discloses the phenyl may be substituted with a -F, -NO2, -Br, -Cl, or -I substituent. [Hutchinson, 0200]
Modifying compound 1-1 (of Formula I), compound 1-6 (of Formula I), compound 1-1 (of Formula II), and/or compound 1-6 (of Formula II) disclosed by Hutchinson by replacing the -F substituent on the substituted phenyl with a -NO2 substituent, results in the compound of claim 148, wherein Y is -NO2.
Modifying the Y substituent of compound 1-1 (of Formula I), compound 1-6 (of Formula I), compound 1-1 (of Formula II), and/or compound 1-6 (of Formula II) disclosed by Hutchinson by replacing the -F substituent on the substituted phenyl with a -Br, -Cl, or -I substituent, results in the compound of claim 149, wherein Y is a -Br, -Cl, or -I.
It would be obvious to one of ordinary skill in the art to modify the Y substituent of compound 1-1 (of Formula I), compound 1-6 (of Formula I), compound 1-1 (of Formula II), and/or compound 1-6 (of Formula II) disclosed by Hutchinson by replacing the -F substituent on the substituted phenyl with a -NO2, -Br, -Cl, or -I substituent and have a reasonable expectation of success. Hutchinson discloses compound 1-1 (of Formula I), compound 1-6 (of Formula I), compound 1-1 (of Formula II), and compound 1-6 (of Formula II), each comprising a substituted phenyl bearing a -F substituent (denoted by Y). Hutchinson additionally discloses the phenyl may be alternatively substituted with a -NO2, -Br, -Cl, or -I substituent. [Hutchinson, 0200] In view of this express teaching, it is reasonable to expect the compounds may be modified by replacing the -F substituent on the substituted phenyl with a -NO2, -Br, -Cl, or -I substituent. One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. MPEP 2144.07. In the present case, Hutchinson discloses the phenyl may be alternatively substituted with a -NO2, -Br, -Cl, or -I substituent. [Hutchinson, 0200] Therefore, the selection of -NO2, -Br, -Cl, or -I based on its suitability as a substituent that may be substituted on the phenyl ring of the compounds disclosed by Hutchinson is prima facie obvious.
Claims 150, 155, and 156 are rejected under 35 U.S.C. 103 as being unpatentable over Tanimoto, as applied to claim 150 above.
With respect to claim 150, as described above, Tanimoto discloses compounds Ia-4 and Ia-6, wherein Y is -F.
Tanimoto further discloses Y is a substituted alkyl substituent of substituted phenyl. [Tanimoto, 0015, 0045, 0076] Thus, with respect to the aforementioned compounds, Tanimoto discloses fluorine is a substituted alkyl and substituent of substituted phenyl. [Tanimoto, Page 18, Table 1, Ia-4 & Ia-6]
Tanimoto does not disclose Y is -NO2, -Br, -Cl, or -I.
However, with respect to claim 155 and 156, Tanimoto discloses the phenyl may be substituted with other substituted alkyl substituents, including -NO2, -Br, -Cl, or -I. [Tanimoto, 0015, 0045, 0062, 0076]
Modifying the Y substituent of compound Ia-4 and Ia-6 by replacing -F with -NO2 results in the compound of claim 155, wherein Y is -NO2.
Modifying the Y substituent of compound Ia-4 and Ia-6 by replacing -F with -Br, -Cl, or -I, results in the compound of claim 156, wherein Y is -Br, -Cl, or -I.
It would be obvious to one of ordinary skill in the art to modify the Y substituent of compound Ia-4 and Ia-6 disclosed by Tanimoto by replacing the -F substituent with -NO2, -Br, -Cl, or -I and have a reasonable expectation of success. Tanimoto discloses compounds Ia-4 and Ia-6, each comprising a substituted phenyl bearing -F substituent (denoted by Y), wherein -F is a substituted alkyl. Tanimoto further discloses the phenyl may be substituted with other substituted alkyl substituents, including -NO2, -Br, -Cl, or -I. In view of this express teaching, it is reasonable to expect the Y substituent of compound Ia-4 and Ia-6 may be modified by replacing the -F substituent with -NO2, -Br, -Cl, or -I. One would have been motivated to do so because it is prima facie obvious to modify a reference by substituting equivalents known for the same purpose. MPEP 2144(I). In the present case, Tanimoto discloses -F, -NO2, -Br, -Cl, and -I are all substituted alkyl substituents that may be present on the substituted phenyl. Therefore, it is prima facie obvious to modify the compounds by replacing one substituted alkyl substituent, -F, with another -NO2, -Br, -Cl, or -I.
Also, with respect to claim 150, Tanimoto discloses the compound below:
PNG
media_image11.png
150
340
media_image11.png
Greyscale
[Structure obtained from SciFinder Substances and depicts Ik-2 disclosed by Tanimoto]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is a C1 alkyl
Y is a leaving group (fluorine)
R3 is -CH3
n1 is 1
n2 is 0. [Tanimoto, Page 37, Table 29, Ik-2]
Tanimoto discloses the N(-CH3) 4-fluoro-phenyl sulphonyl group is at the 5-position on the indole and the compound comprises an acetic acid moiety (wherein n1 = 1).
Tanimoto does not disclose the N(-CH3) 4-fluoro-phenyl sulphonyl group is at the 3-position on the indole, as claimed. Tanimoto does not disclose the compound comprises a propionic acid moiety (wherein n=2).
However, 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. MPEP 2144.09. In the present case, the N(-CH3) 4-fluoro-phenyl sulphonyl group at the 5-position on the indole is a position isomer of a N(-CH3) 4-fluoro-phenyl sulphonyl group at the 3-position on the indole. Moreover, acetic acid is a homolog of propionic acid.
Modifying the compound disclosed by Tanimoto so that the N(-CH3) 4-fluoro-phenyl sulphonyl group is at the 3-position on the indole, results in the compound of claim 150, wherein:
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (fluorine)
R3 is -CH3
n1 is 1
n2 is 0.
Modifying the compound disclosed by Tanimoto so that N(-CH3) 4-fluoro-phenyl sulphonyl group is at the 3-position on the indole and replacing acetic acid with propionic acid results in the compound of claim 150, wherein:
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
Y is a leaving group (fluorine)
R3 is -CH3
n1 is 2
n2 is 0.
It would be obvious to one of ordinary skill in the art to modify the compound Ik-2 disclosed by Tanimoto so that N(-CH3) 4-fluoro-phenyl sulphonyl group is at the 3-position on the indole and/or by replacing acetic acid with propionic acid and have a reasonable expectation of success. Tanimoto discloses an indole (Ik-2) comprising a N(-CH3) 4-fluoro-phenyl sulphonyl group at the 5-position and further comprising an acetic acid moiety (wherein n1 = 1). Generally, compounds which are position isomers or homologs are of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. MPEP 2144.09. Accordingly, an indole comprising a N(-CH3) 4-fluoro-phenyl sulphonyl group at the 3-position is a position isomer of the compound disclosed by Tanimoto. The indole further comprising a propionic acid moiety (wherein n1 = 2) is a homolog of the compound disclosed by Tanimoto. Therefore, it is reasonable to expect the compound disclosed by Tanimoto may be modified to yield a position isomer and/or homolog thereof with similar properties. One would have been motivated to do so because a prima facie case of obviousness may be made when chemical compounds have very close structural similarities. MPEP 2144.09(II). Accordingly, one would have been motivated by the expectation that the modified compounds disclosed by Tanimoto will have similar properties as Ik-2. MPEP 2144.09(I).
Claims 143, 145, and 150-154 are rejected under 35 U.S.C. 103 as being unpatentable over Tanimoto, as applied to claim 143 and 150 above, and further in view of Bain.
With respect to claim 143, as described above, Tanimoto discloses compound Ib-6, wherein Y is -F.
With respect to claim 150, as described above, Tanimoto discloses compounds Ik-2 (n1 = 1, n2 = 0) and Ik-2 (n1 = 2, n2 = 0), wherein Y is -F.
Tanimoto further discloses the compounds are CRTH2 antagonists. [Tanimoto, 0010] CRTH2 is also known in the art as DP2.
Tanimoto does not disclose Y is 18F.
However, with respect to claim 145, 151, 152, and 153, Bain discloses several DP2 antagonist (or ligands) that may comprise a detectable label, wherein the detectable label is a radioactive label, including 18F. [Bain, 0024-0026, 0249] Bain discloses the incorporation of radioisotopes into the DP2 ligand is accomplished using known techniques, including isotopic labelling. [Bain, 0228, 0249] In a more specific embodiment, Bain discloses 18F is a positron emitting isotope that is detectable by a positron emission tomography (“PET”) scanner and may be attached to the ligand. Moreover, Bain discloses 18F (˜110 min) has the longest half-life among all the other disclosed PET isotopes including 11C (˜20 min), 13N (˜10 min), and 15O (˜2 min). [Bain, 0251]
Modifying the Y substituent of Ib-6 by replacing -F with 18F, results in the compound of claim 145, wherein:
L1-R1 is CH3
Y is 18F
n1 is 1
n2 is 0.
Modifying the Y substituent of Ik-2 (n1 = 1, n2 = 0) by replacing -F with 18F, results in the compound of claim 151, 152, and 153, wherein:
L1-R1 CH3
Y is 18F
n1 is 1
n2 is 0.
In which case, with respect to claim 154, the compound of claim 151 further comprise triflate if Y is +N(CH3)3. However, in the modified compounds disclosed by Tanimoto and Bain, Y is not +N(CH3)3. Thus, the compound need not comprise triflate. Therefore, the limitations of claim 154 are met. MPEP 2111.04(II).
Modifying the Y substituent of Ik-2 (n1 = 2, n2 = 0) by replacing -F with 18F, results in the compound of claim 153, wherein:
L1-R1 is CH2Ph
Y is 18F
n1 is 2
n2 is 0.
It would be obvious to modify the Y substituent of Ib-6, Ik-2 (n1 = 1, n2 = 0), and Ik-2 (n1 = 2, n2 =0) by replacing -F with 18F and have a reasonable expectation of success. Tanimoto discloses DP2 antagonists Ib-6, Ik-2 (n1 = 1, n2 = 0) and Ik-2 (n1 = 2, n2 =0), each comprising a fluorine substituent (denoted by Y). Bain discloses several DP2 antagonist (or ligands) that may be isotopically labeled with 18F. Thus, Bain establishes DP2 ligands are amenable to radiolabeling with 18F. Accordingly, the combined teachings of Tanimoto and Bain suggest the DP2 ligands disclosed by Tanimoto are amenable to isotopic labelling with 18F. Therefore, it is reasonable to expect the -F substituent (denoted by Y) of the compounds disclosed by Tanimoto may be isotopically labelled, thereby replacing fluorine with 18F. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(I-II). In the present case, Bain discloses 18F is a positron emitting isotope detectable by positron emission tomography (“PET”) scanner. Moreover, 18F (˜110 min) has the longest half-life among all the other PET isotopes disclosed by Bain including 11C (˜20 min), 13N (˜10 min), and 15O (˜2 min). [Bain, 0251] Therefore, one would have been motivated by the expectation that replacing -F with 18F would enable Ib-6, Ik-2 (n1 = 1, n2 = 0) and Ik-2 (n1 = 2, n2 =0) disclosed by Tanimoto to be detectable by PET and sustain a half-life longer than other PET isotopes.
Claims 157-161 are rejected under 35 U.S.C. 103 as being unpatentable over Bain, in view of Duggan (US 2013/0287686 A1, Published 10/31/2013).
With respect to claim 157, Bain discloses the compound TM30089. [Bain, 0021, 0024]
TM30089 has the following structure:
PNG
media_image1.png
500
758
media_image1.png
Greyscale
[Structure of TM-30089 retrieved from US 2017/0121773 A1 (Published 5/4/2017), Paragraph 0050]
Wherein,
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
R2 is a leaving group (fluorine)
n1 is 1
n2 is 0
n3 is 2.
With respect to claim 160, Bain discloses:
L1-R1 is CH3
R2 is -F
n1 is 1
n2 is 0
n3 is 2. [Bain, 0021, 0024]
Moreover, Bain discloses the DP2 ligand may comprise a detectable label, wherein the detectable label is a radioactive label, including 18F. [Bain, 0024-0026, 0249] Bain discloses the incorporation of radioisotopes into the DP2 ligand is accomplished using known techniques, including isotopic labelling. [Bain, 0228, 0249] In a more specific embodiment, Bain discloses 18F is a positron emitting isotope that is detectable by a positron emission tomography (“PET”) scanner and may be attached to the ligand. Moreover, Bain discloses 18F (˜110 min) has the longest half-life among all the other disclosed PET isotopes including 11C (˜20 min), 13N (˜10 min), and 15O (˜2 min). [Bain, 0251]
Bain does not disclose a method for incorporating 18F into the DP2 ligand.
However, with respect to claim 157, Duggan discloses a method for synthesizing 18F compounds comprised of F-18 substituents on aromatic rings comprising:
introducing c.2.2.2 (Kryptofix) to a precursor compound comprising a leaving group, such as bromo, nitro, or trimethylamine, on an aromatic ring, then mixing the precursor/c2.2.2 solution with a fluorinating agent. [Duggan, 0080, 0082-0085 & Scheme 3A]
With respect to claim 158, Duggan discloses the leaving group may be bromine. [Duggan, 0084]
With respect to claim 159, Duggan discloses the fluorinating agent is K18F. [Duggan, 0080, 0084, 0085, Scheme 3A]
With respect to claim 161, Duggan discloses the c2.2.2. is introduced by K([2.2.2.]-cryptand)2CO3. [Duggan, 0080, 0084, 0085, Scheme 3A]
Combining the compound, TM30089, disclosed by Bain with the method disclosed by Duggan results in the method of claim 157-161.
It would be obvious to combine the TM30089 disclosed by Bain with the method disclosed by Duggan and have a reasonable expectation of success. Bain discloses a DP2 ligand, TM30089, comprising a leaving group, -F, on an aromatic ring. Bain discloses the compound may further comprise a radiolabel, 18F, wherein the incorporation of the radioisotope into the DP2 ligand is accomplished using known techniques. Duggan discloses a known technique for synthesizing 18F compounds comprised of F-18 substituents on aromatic rings via nucleophilic displacement of a leaving group by strongly nucleophilic F-18. Accordingly, the combined teachings of Bain and Duggan suggest 18F may be incorporated into TM30089 using the technique for synthesizing 18F compounds disclosed by Duggan. Therefore, it is reasonable to expect TM30089 disclosed by Bain may be combined with the method disclosed by Duggan. One would have been motivated to do so because the selection of a known technique based on its suitability for its intended use is prima facie obvious. MPEP 2144.07. In the present case, the selection of the technique disclosed by Duggan based on its suitability for synthesizing 18F compounds comprised of F-18 substituents on aromatic rings via nucleophilic displacement, is prima facie obvious.
Claims 157-162 are rejected under 35 U.S.C. 103 as being unpatentable over Bain, in view of Berger (US 2014/0314669 A1, Published 10/23/2014).
With respect to claim 157, Bain discloses the compound TM30089. [Bain, 0021, 0024]
TM30089 has the following structure:
PNG
media_image12.png
417
633
media_image12.png
Greyscale
[Structure of TM-30089 retrieved from US 2017/0121773 A1, Paragraph 0050]
Wherein:
X1 and X2 are each CH
L1-R1 is an unsubstituted alkyl
L1 is a bond
R1 is an unsubstituted C1 alkyl
R2 is a leaving group (fluorine)
n1 is 1
n2 is 0
n3 is 2.
With respect to claim 160, Bain discloses:
• L1-R1 is CH3
• R2 is -F
• n1 is 1
• n2 is 0
• n3 is 2. [Bain, 0021, 0024]
Moreover, Bain discloses the DP2 ligand may comprise a detectable label, wherein the detectable label is a radioactive label, including 18F. [Bain, 0024-0026, 0249] Bain discloses the incorporation of radioisotopes into the DP2 ligand is accomplished using known techniques, including isotopic labelling. [Bain, 0228, 0249] In a more specific embodiment, Bain discloses 18F is a positron emitting isotope that is detectable by a positron emission tomography (“PET”) scanner and may be attached to the ligand. Moreover, Bain discloses 18F (˜110 min) has the longest half-life among all the other disclosed PET isotopes including 11C (˜20 min), 13N (˜10 min), and 15O (˜2 min). [Bain, 0251]
Bain does not disclose a method for incorporating the radioisotopes, specifically 18F, into the DP2 ligand.
However, with respect to claim 157, Berger discloses a method for synthesizing aryl-18F compounds comprising:
introducing c2.2.2 (Kryptofix) to a precursor compound comprising a leaving group (e.g. -halogen, -NO2, trimethyl ammonium compounds, or aryliodonium compounds) on an aryl ring, then mixing the precursor/c2.2.2 solution with a fluorinating agent. [0463, 0606]
With respect to claim 158, Berger discloses the leaving group may be a halogen, including bromine. [Berger, 0463]
With respect to claim 159, Berger discloses the fluorinating agent is [18F]-fluoride but may be K18F. [Berger, 0456, 0459, 0606]
With respect to claim 161, Berger discloses the c2.2.2. is introduced by K([2.2.2.]-cryptand)2CO3. [Berger, 0606]
With respect to claim 162, Berger discloses the method comprises further mixing HCl with the precursor/c2.2.2 solution. [Berger, 0606]
Combining the compound, TM30089, disclosed by Bain with the method disclosed by Berger results in the method of claim 157-162.
It would be obvious to combine TM30089 disclosed by Bain with the method disclosed by Berger and have a reasonable expectation of success. Bain discloses a DP2 ligand, TM30089, comprising a leaving group, -F, on an aromatic ring. Bain discloses the compound may further comprise a radioactive label, 18F, wherein the incorporation of the radioisotope into the DP2 ligand is accomplished using known techniques. Berger discloses a known technique for synthesizing aryl-18F compounds comprising a leaving group (e.g. halogen) on an aryl ring via nucleophilic substitution. Accordingly, the combined teachings of Bain and Berger suggest 18F may be incorporated into TM30089 using the technique for synthesizing aryl-18F compounds disclosed by Berger. Therefore, it is reasonable to expect the compound disclosed by Bain may be combined with the method disclosed by Berger. One would have been motivated to do so because the selection of a known technique based on its suitability for its intended use is prima facie obvious. MPEP 2144.07. In the present case, the selection of the technique disclosed by Berger based on its suitability for synthesizing 18F compounds comprised of F-18 substituents on aromatic rings via nucleophilic displacement, is prima facie obvious.
Response to Arguments
Applicant’s arguments with respect to claims rejected over Hutchinson (‘503, ‘134, ‘168) and Miyazawa have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant's arguments with respect to Duggan are not persuasive.
Applicant asserts “In contrast, Duggan teaches a Palladium-Assisted Electrophilic Aromatic Substitution. Duggan explicitly notes that this method is intended for aromatic structures that are "not amenable to nucleophilic substitution." [Remarks 2/2/2026, Page 12, Paragraph 4 – Page 13, Paragraph 1]
Applicant’s assertion is misleading. The full recitation by Duggan is:
“For some compounds containing aromatic or heterocyclic ring structures that are not amenable to nucleophilic substitution by activated fluoride, an electrophilic fluorination method may be used. These methods include reaction with F-18 fluorine gas (F2) or F-18 N-chloromethyl-N-fluorotriethylenediammonium bis(tetrafluoroborate) (F-18-TEDA). Other methods of electrophilic fluorination include the use of the palladium(IV) complex described in Science, 2011, 334, pp. 639-642; or the diaryliodonium salts described in Organic & Biomolecular Chemistry, 2011, 9, pp. 8346-8355.” [Duggan, 0081]
This teaching by Duggan is not applicable to the instant rejection because all of the cited compounds comprise aromatic or heterocyclic ring structures bearing a leaving group that is amenable to nucleophilic substitution by activated fluoride.
Moreover, Applicant’s assertion is also misleading because Duggan is not limited to Palladium-Assisted Electrophilic Aromatic Substitution. On the contrary, Duggan also teaches nucleophilic substitution. [See, Duggan, 0080-0085 & Scheme 3.] These teachings were cited in the OA of 10/1/2025. Paragraph 0080-0085 and Scheme 3 of Duggan is explicitly drawn to nucleophilic substitution, not palladium-assisted electrophilic aromatic substitution.
Attacking teachings not relied on to support the instant rejection, fails to undermine the instant rejection.
Applicant asserts “In Duggan, Kryptofix [2.2.2] is limited to sequestering potassium to dry the K18F, thereby facilitating the creation of a reactive palladium-fluoride intermediate. It is not used as a phase transfer catalyst for direct nucleophilic displacement on a precursor containing a free carboxymethyl group, as disclosed in the claimed invention.” [Remarks 2/2/2026, Page 13, Paragraph 4]
Applicant’s arguments are not persuasive because they are based on non-cited teachings. The cited teachings do not rely on a reactive palladium-fluoride intermediate. Attacking teachings not relied on to support the instant rejection, fails to undermine the instant rejection.
Moreover, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Kryptofix [2.2.2] being used as “a phase transfer catalyst for direct nucleophilic displacement on a precursor containing a free carboxymethyl group”) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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