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: 20-39
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in PRO 61/904,400 on 11/14/2013, PRO 61/909,822 on 11/27/2013, PCT/US2014/065467 on 11/13/2014, US 15/035,936 on 5/11/2016, US 16/157,024 on 10/10/2018, and US 17/488,810 on 9/29/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/25/2025 (9 total), 7/21/2025, 10/28/2025, and 8/4/2026 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 10/11/2024 are accepted.
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 20, 21, 24, 30, 35, 36, 38, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over McBride (US 2009/0246130 A1, Published 10/1/2009).
With respect to claim 20, McBride discloses a conjugate of the formula B-L-P:
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[McBride, Figure 11]
Wherein,
B is a peptide
L is a divalent linker C(O)-(CH2)2-C(O)-NH
P is a radical comprising the following formula:
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502
619
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With respect to claim 24, McBride discloses that the linker does not include a diradical of the formula *NH-(CH2)2-NH*. [McBride, Figure 11]
With respect to claim 30, McBride discloses that the conjugate comprises the following formula:
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573
834
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With respect to claims 35 and 36, McBride discloses that the conjugate further comprises a radionuclide, Al-18F. [McBride, 0394]
With respect to claim 38, McBride discloses that the conjugate comprises one or more carriers, diluents, or excipients. [McBride, 0070, 0073]
With respect to claim 39, McBride discloses a method of imaging a disease in a host animal, comprising the step of administering to the host animal a diagnostically effective amount of the conjugate and imaging the host animal. [McBride, 0123, 0364, Claim 11]
McBride does not disclose that B is a radical of a folate receptor binding ligand.
However, with respect to claims 20 and 21, McBride discloses that the conjugate is a species of a genus comprising a metal binding moiety (NOTA derivative) attached to a delivery peptide. McBride discloses that in an alternative embodiment, the delivery molecule may be a non-peptide such as folic acid and may be conjugated to NOTA. [McBride, 0011, 0013, 0016]
Modifying the conjugate disclosed by McBride by replacing the peptide with folic acid results in the conjugate of claims 20 and 21.
It would be obvious to one of ordinary skill in the art to modify the compound disclosed by McBride by replacing the peptide with folic acid and have a reasonable expectation of success. McBride discloses a conjugate comprising a peptide targeting molecule conjugated to a NOTA derivative. McBride discloses that in an alternative embodiment the targeting molecule may be a non-peptide targeting molecule such as folic acid. In view of this express teaching, it is reasonable to expect that the targeting molecule in the conjugate disclosed by McBride may be folic acid. One would have been motivated to do so because it is prima facie obvious to modify the prior art when the rationale for doing so is expressly or impliedly contained in the prior art. MPEP 2144(II). In the present case, McBride discloses that an 18F-labeled folate-NOTA conjugate may be used to successfully image the distribution of folate receptors in cancer or inflammatory diseases, when injected into a subject. [McBride, 0475] Therefore, one would have been motivated by the expectation that replacing the peptide with folic acid would enable the conjugate disclosed by McBride to successfully image the distribution of folate receptors in cancer or inflammatory diseases.
Claims 20-24, 29, 34-36, 38, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Low (US 2010/0226967 A1, Published 9/9/2010), in view of Zavarzin (US 2011/0070157 A1, Published 3/24/2011).
With respect to claim 20, Low discloses a conjugate of the formula B-L-P:
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929
1312
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[Low, 0102]
Wherein,
B is a radical of a folate receptor binding ligand (folate)
L is a divalent linker (lysine)
P is a radical of CW800.
With respect to claim 21, Low discloses that the radical of a folate receptor binding ligand is a radical of folic acid.
With respect to claim 22, Low discloses that the linker comprises lysine.
Also, with respect to claim 20, Low discloses a conjugate of the formula B-L-P:
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1808
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[Low, 0094]
Wherein:
B is a radical of a folate receptor binding ligand (folate)
L is a divalent linker (Cys-Asp-Asp-Arg-Asp)
P is a radical of DyLight 600.
With respect to claim 21, Low discloses that the radical of a folate receptor binding ligand is a radical of folic acid. [Low, 0094]
With respect to claim 23, Low discloses that the linker comprises a polypeptide (Cys-Asp-Asp-Arg-Asp) comprising arginine and aspartic acid. [Low, 0094]
With respect to claim 24, Low discloses that the linker does not include a diradical of the formula *NH-(CH2)2-NH*. [Low, 0094]
With respect to claim 38, Low discloses a pharmaceutical composition comprising the conjugate and a carrier. [Low, 0029, 0030, 0054, 0056]
With respect to claim 39, Low discloses a method of imaging a disease in a host animal, comprising the step of administering to the host animal a diagnostically effective amount of the conjugate and imaging the host animal. [Low, 0030-0032]
Low further discloses that the compounds are a species of the general formula Ab-X wherein
“Ab” comprises a vitamin (folic acid) that binds to endothelial progenitor cells and “X” comprises a quantifiable marker (CW800 and DyLight 600). Low discloses that in one embodiment the quantifiable marker comprises a metal chelating moiety that binds a radionuclide. In another embodiment, the quantifiable marker comprises a chromophore. [Low, 0010, 0031]
Low does not disclose that P is a radical comprising a formula selected from the group in claim 20.
However, with respect to claims 20, 29, and 34, Zavarzin discloses chelating agents that bind a radionuclide, including DCTA, DOTA, DTPA, EDTA, NOTA, PCTA, TETA, TE2A, DO2A, p-SCN-Bn-DOTA, and p-SCN-Bn-NOTA. [Zavarzin, 0014]
With respect to claims 35 and 36, Zavarzin discloses that the radionuclide is 68Ga, 177Lu, 90Y, 64Cu, 61Cu, 89Sr, or 153Sm. [Zavarzin, 0014]
Modifying the compound disclosed by Low by replacing CW800 with p-SCN-Bn-NOTA bound to 68Ga, 177Lu, 90Y, 64Cu, 61Cu, 89Sr, or 153Sm results in the conjugate of claims 20, 29, and 34-36, wherein:
P is a radical comprising the following formula:
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The conjugate comprises the following formulas:
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64
763
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326
1845
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Modifying the compound disclosed by Low by replacing DyLight600 with p-SCN-Bn-NOTA or NOTA bound to 68Ga, 177Lu, 90Y, 64Cu, 61Cu, 89Sr, or 153Sm results in the conjugate of claim 20 and 29, 35, and 36 wherein:
P is a radical comprising the following formula:
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2
299
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2
299
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The conjugate comprises the following formulas:
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763
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It would be obvious to one of ordinary skill in the art to modify the compound disclosed by Low by replacing CW800 with p-SCN-Bn-NOTA or DyLight 600 with p-SCN-Bn-NOTA or NOTA bound to 68Ga, 177Lu, 90Y, 64Cu, 61Cu, 89Sr, or 153Sm and have a reasonable expectation of success. Low discloses a conjugate comprising folate and a quantifiable marker comprising a chromophore, CW800 or DyLight 600. However, Low discloses that the quantifiable linker may alternatively comprise a metal chelating moiety that binds a radionuclide. Zavarzin discloses that p-SCN-Bn-NOTA and NOTA are chelating moieties that bind a radionuclide including 68Ga, 177Lu, 90Y, 64Cu, 61Cu, 89Sr, and 153Sm. Accordingly, the combined teachings of Low and Zavarzin suggest that the quantifiable marker in the conjugate disclosed by Low may comprise p-SCN-Bn-NOTA or NOTA. 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(II). In the present case, Low discloses that the quantifiable marker in the conjugate may be useful for diagnosing inflammatory pathologies through imaging. [Low, 0006, 0032] Zavarzin discloses that radiolabeled p-SCN-Bn-NOTA or NOTA may be used as a diagnostic composition and to measure the distribution of the compound by means of PET or SPECT. [Zavarzin, 0006, 0024, 0026] Therefore, one would have been motivated by the expectation that replacing CW800 with p-SCN-Bn-NOTA or DyLight 600 with p-SCN-Bn-NOTA or NOTA would enable the conjugate disclosed by Low to diagnose inflammatory pathologies through imaging means including PET or SPECT.
Claims 20, 21, 25-29, 31, 32, and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over D’Souza (US 2012/0134920 A1, Published 5/31/2012).
With respect to claim 20, D’Souza discloses a conjugate of the formula B-L-P:
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[D’Souza, 0516]
Wherein,
B is a radical of a targeting molecule
L is a divalent linker (NHCH2CH2OCH2CH2OCH2CH2NH)
P is a homolog of a radical of the following formula:
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With respect to claims 25 and 27, D’Souza discloses that the divalent linker comprises *NH[(CH2)2O]2-(CH2)2NH*, wherein n is 2.
With respect to claim 26, D’Souza discloses that the divalent linker comprises *NH[(CH2)2O]n, wherein n is 2.
With respect to claim 29, D’Souza discloses that the conjugate comprises a homolog of the following formula:
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656
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With respect to claim 31, D’Souza discloses that the conjugate comprises a homolog of the following formula:
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883
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With respect to claims 35 and 36, D’Souza discloses that the conjugate further comprises a radionuclide-containing group, Al-18F.
With respect to claim 38, D’Souza discloses a composition comprising the conjugate and one or more carriers, diluents, or excipients. [D’Souza, 0162-0165]
With respect to claim 39, D’Souza discloses a method of imaging a disease in a host animal, comprising the step of administering to the host animal a diagnostically effective amount of the conjugate and imaging the host animal. [D’Souza, 0051]
D’Souza does not disclose that P is a radical comprising a formula selected from the group of claim 20.
However, with respect to claims 20, 21, 28, 32, and 37, D’Souza discloses that the conjugate is a species of a genus comprising a bifunctional chelating agent conjugated to a targeting molecule. D’Souza discloses that the targeting molecule may be folic acid, a folic acid derivative, or analog thereof. [D’Souza, 0002, 0013, Claim 20]
Modifying the conjugate disclosed by D’Souza by substituting the targeting molecule with folic acid results in a homolog of the conjugate of claim 20, 21, 28, 32, and 37.
The radical disclosed by D’Souza (1,4,7-triazacyclononane-1,4-diacetic acid-7-(3-oxopropyl))
comprises 3-oxopropyl, whereas the claimed radical (1,4,7-triazacyclononane-1,4-diacetic acid-7-(2-oxoethyl)) comprises 2-oxoethyl. However, compounds which are 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(II). Therefore, the modified conjugate comprising the radical disclosed by D’Souza, and homologs thereof, are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Accordingly, modifying the compound disclosed by D’Souza by substituting the radical 1,4,7-triazacyclononane-1,4-diacetic acid-7-(3-oxopropyl) with 1,4,7-triazacyclononane-1,4-diacetic acid-7-(2-oxoethyl) results in the conjugate of claims 20, 21, 28, 32, and 37.
It would be obvious to one of ordinary skill in the art to modify the compound disclosed by D’Souza by replacing the targeting molecule with folic acid and have a reasonable expectation of success. D’Souza discloses a conjugate comprising a bifunctional chelate (NOTA homolog) and a targeting molecule. D’Souza further discloses that the targeting molecule may alternatively be folic acid. In view of this express teaching, it is reasonable to expect that folic acid may function as the targeting molecule in the conjugate disclosed by D’Souza. One would have been motivated to do so because it is prima facie obvious to modify the prior art when the rationale for doing so is expressly or impliedly contained in the prior art. MPEP 2144(II). In the present case, D’Souza discloses that an 18F-labeled folate-NOTA conjugate may be used to image the distribution of folate receptors, for example in cancer or inflammatory diseases, when injected into a subject. [D’Souza, 0376] Therefore, one would have been motivated by the expectation that the conjugate disclosed by D’Souza may be used to successfully image the distribution of folate receptors in cancer or inflammatory diseases.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by
D’Souza by replacing the radical 1,4,7-triazacyclononane-1,4-diacetic acid-7-(3-oxopropyl) (“3-oxopropyl”) with 1,4,7-triazacyclononane-1,4-diacetic acid-7-(2-oxoethyl) (“2-oxoethyl”) and have a reasonable expectation of success. D’Souza discloses a conjugate comprising a 3-oxopropyl radical.
Compounds which are homologs are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. Accordingly, a radical that differs from 3-oxopropyl by the successive addition of -CH2- is generally of sufficiently close structural similarity that there is a presumed expectation that it possesses similar properties to the 3-oxopropyl radical. Therefore, it is reasonable to expect that the conjugate comprising the 3-oxopropyl radical disclosed by D’Souza may be replaced with homologs thereof, including a 2-oxoethyl radical, because such conjugates are presumed to possess 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 and similar utilities. MPEP 2144.09(I). In the present case, one would have been motivated by the expectation that, based on the similarity in chemical structure and function between the 3-oxopropyl radical and the 2-oxoethyl radical, they would have similar properties.
Claims 20, 21, 25, 26, 28, 33, 35, 36, 38, and 39 rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (Comparative Analysis of Folate Derived PET Imaging Agents with [18F]-2-Fluoro-2-deoxy‑D‑glucose Using a Rodent Inflammatory Paw Model, Mol. Pharmaceutics, 7/2/2013, 10, 3103−3111), in view of D’Souza.
With respect to claim 20, Kularatne discloses the following conjugate, [68Ga]-DOTA-folate:
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[Kularatne, Page 3107, Scheme 3]
Wherein:
B is a radical of a folate receptor binding ligand (folate)
L is a divalent linker (*NH[(CH2)2O]n-(CH2)2-C(O)NH-(CH2)2NH*)
P is a radical of DOTA.
With respect to claim 21, Kularatne discloses that the radical of a folate receptor binding ligand is folate. [Kularatne, Page 3107, Scheme 3]
With respect to claims 25 and 26, Kularatne discloses that the divalent linker is *NH[(CH2)2O]n-(CH2)2-C(O)NH-(CH2)2NH*, wherein n is 6. [Kularatne, Page 3107, Scheme 3]
With respect to claim 28, Kularatne discloses that the conjugate comprises folate-PEG. [Kularatne, Page 3107, Scheme 3]
With respect to claims 35 and 36, Kularatne discloses that the conjugate further comprises a radionuclide, 68Ga. [Kularatne, Page 3107, Scheme 3]
With respect to claim 38, Kularatne discloses a pharmaceutical composition comprising the conjugate and a pharmaceutically acceptable carrier. [Kularatne, Page 3105, Col. 1, Paragraph 2 and 4]
With respect to claim 39, Kularatne discloses a method of imaging a disease in a host animal, comprising the step of administering to the host animal a diagnostically effective amount of the conjugate and imaging the host animal. [Kularatne, Page 3105, Col. 1, Paragraph 4; Page 3108, Figure 2 and 3]
D’Souza does not disclose that P is a radical comprising a formula selected from the group of claim 20.
However, with respect to claims 20 and 33, D’Souza discloses that NOTA, NODA, NETA, DOTA, and, DTPA are chelating agents that bind a radionuclide (e.g., 68Ga) and may be conjugated to a target molecule including folic acid. [D’Souza, 0002, 0009, 0013]
Modifying the conjugate disclosed by Kularatne by replacing the DOTA radical with a NOTA radical results in the conjugate of claim 20 and 33, wherein:
P is a radical comprising the formula:
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The conjugate is:
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It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Kularatne by replacing the DOTA radical with a NOTA radical and have a reasonable expectation of success. Kularatne discloses a conjugate comprising a chelating agent, a DOTA radical, bound to a radionuclide, 68Ga, and folate. D’Souza discloses that NOTA, NODA, NETA, DOTA, and DTPA are chelating agents that bind a radionuclide (e.g., 68Ga) and may be conjugated to a target molecule including folic acid. Accordingly, the combined teachings of Kularatne and D’Souza suggest that a NOTA radical may function as the chelating agent in the conjugate disclosed by Kularatne. One would have been motivated to do so because substituting equivalents known for the same purpose when their equivalency is recognized in the art is prima facie obvious. MPEP 2144.06(II). Accordingly, substituting one known chelating agent capable of binding 68Ga and forming a conjugate with folate (a DOTA radical) for another (a NOTA radical) is prima facie obvious. Furthermore, one would have been motivated to do so because it is prima facie obvious to modify the prior art when the rationale for doing so is expressly or impliedly contained in the prior art. MPEP 2144(II). In the present case, D’Souza discloses that an 18F-labeled folate-NOTA conjugate may be used to image the distribution of folate receptors, for example in cancer or inflammatory diseases, when injected into a subject. [D’Souza, 0376] Therefore, one would have been motivated by the expectation that replacing the DOTA radical with a NOTA radical would enable the conjugate disclosed by Kularatne to be used to successfully image the distribution of folate receptors in cancer or inflammatory diseases.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILA A CRAIG whose telephone number is (703)756-4540. The examiner can normally be reached Monday-Friday 0800-1600.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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