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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/4/25 has been entered.
Claims Status
Claims 23,26,27,32 and 34-49 are pending in the application. Claims 1-5,7,8,11,13,14,17,18 and 20 are cancelled and claims 37-49 newly added in the amendment filed 9/4/25.
Claim Objections
Claim 23 is objected to because of the following informalities: instant claim 23 depends on cancelled claim 1. The dependent claims are objected therewith. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode
contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 35,36 and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
Claims 35,36 and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The disclosure does not describe a representative number of examples for the imaging agent dyes that provide for the target cell to background ratio to 7.6 four hours after administration. The combination of the dyes, linkers and/or targeting moieties in which tumor types provide the target cell to background ratio to 7.6 four hours after administration is not described.
The disclosure does not describe a representative number of examples for the imaging agent dyes that provide for the target to background ratio is greater than 7.6 five to ten hours after administration and/or the target cell to background ratio is 7.6 to 15 ten to twenty-four hours after administration. The combination of the dyes, linkers and/or targeting moieties in which tumor types provide for the target cell to background ratio is greater than 7.6 five to ten hours after or 7.6 to 15 ten to twenty-four hours after administration is not described.
The disclosure recites “the imaging agent can achieve a TBR of at least target-to-background
ratio about 7.6 2-24 hours after administration.”
For example:
PNG
media_image1.png
400
630
media_image1.png
Greyscale
(p23, lines 9-20).
The Fig. 19 shows
PNG
media_image2.png
382
380
media_image2.png
Greyscale
cRGD-ZW00-1 TBR at 18 hours but does not describe the specific target cell to background ratio to 7.6 four hours after administration.
The disclosure does state that “data generated is expected to show that PSMA-617, KEU, FAP ligand, and octreotide or their dimers, conjugated to ZW700-1 Forte will have further increased stability as compared to cRDG-ZW800-1 or other ZW800-1 or ZW830-1 conjugates. Therefore, one of ordinary skill would not expect the desired stability for any of the targeted ZW800-1 or targeted ZW830-1
imaging agent dyes. The claims are not commensurate in scope.
The dependent claims fall therewith.
Response to Arguments
Applicant's arguments filed 9/4/25 have been fully considered but they are not persuasive.
Applicant asserts that “(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent…” “[T]he Patent Act and this court’s case law requires only sufficient description to show on of skill in the … art that the inventor possessed the claimed invention at the time of filing.”
The Examiner asserts that the disclosure doesn’t provide any examples of the Applicant’s specific target-to-background ratios at specific times points and does not describe the combination of the dyes, linkers and/or targeting moieties in which tumor types provide the specific target-to-background ratios at those specific times points.
The disclosure does state that “data generated is expected to show that PSMA-617, KEU, FAP ligand, and octreotide or their dimers, conjugated to ZW700-1 Forte will have further increased stability as compared to cRDG-ZW800-1 or other ZW800-1 or ZW830-1 conjugates. Therefore, one of ordinary skill would not expect the targeted ZW800-1 or targeted ZW830-1 imaging agent dyes to provide for the specific target-to-background ratios at those specific times points. The claims are not commensurate in scope.
Also, the independent claims 23,34 and 37 do not disclose the structures of the dyes, labile linkers and/or targeting moieties to provide the specific target-to-background ratios at those specific times points.
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 38 and 46-48 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.
Claims 38 and 46-48 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 38 and 46-48 do not comprise a labile linker between the imaging agent and the targeting vector at a position closer to the imaging agent. The instant claims comprise a C-C bond between the imaging agent and the targeting vector at a position closer to the imaging agent. The specification discloses that the labile linking bond can be a labile -O- ether bond, -S- bond or an -NH- bond. 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.
The dependent claims fall therewith.
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) 23,27,34,37-40 and 49 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Choi et al. (Nature Biotechnol. 2013, 31, 148-154).
Choi et al. (Nature Biotechnol. 2013, 31, 148-154) teaches of cRGD-ZW100-1
PNG
media_image3.png
258
192
media_image3.png
Greyscale
zwitterionic near-infrared (NIR) fluorophore imaging agent (Figure 1) that anticipates generating an imaging agent dye of the instant claim 23.
The ZW800-1 anticipates the ZW800-1 of the instant claims 38 and 40.
The phenoxy moiety anticipates the phenoxy moiety of the instant claims, has the same properties and is capable of the same functions, such as configured to stabilize the imaging agent dye in an acidic environment or a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent dye to metabolize in blood external to the target cell rendering the imaging agent non-fluorescent thereby increasing a target cell to background ratio after administration of the imaging agent dye more than a target cell to background ratio of an imaging agent without a labile linker.
The cRGD anticipates the cRGD of the instant claims 39 and 40.
The cRGD-ZW100-1 is used for image-guided surgery upon intravenous administration into mice
(human melanoma cell) tumor model systems (abstract; p150, Tumor targeting and image-guided surgery) that anticipates the administration of the imaging agent for the methods of imaging tumor cells and treating cancer of the instant claims.
The image-guided surgery anticipates administering a surgical treatment of the instant claim 34.
The mice were irradiated and imaged (Figure 3a,b) that anticipates the irradiating and imaging of the methods of imaging tumor cells and treating cancer of the instant claims.
The TBR is examined 4 hours after administration (p150, Tumor targeting and image-guided surgery; Figure 3) that anticipates irradiating and detecting a signal from the imaging agent 2-4 hours after administration of the instant claims.
The first-in-human clinical trials of ZW800-1 are in process and the ZW800-1-targeted small molecules will have reasonable human dosing (p152, right column) and therefore, the use in a human is envisioned and anticipates the human subject of the instant claim 27.
The cRGD-ZW100-1 NIR fluorophore exhibits low background and has a TBR of 17.2 ± 1.2 (mean ± s.d.) 4 hours after administration that anticipates increasing the tumor-to-background ratio of the instant claim 37.
The cRGD-ZW100-1 anticipates the cRGD-ZW100-1 of the instant claims, has the same properties and is capable of the same functions, such as a target cell to background ratio four hours after administration is 7.6.
The instant invention uses the identical compound cRGD-ZW100-1 of Choi et al. for analogous
methods of imaging and treating but does not include any different method steps, any different
conditions or any different imaging techniques to explain the observed results.
Also, products of identical chemical composition can not have mutually exclusive properties. A
chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Claim(s) 23,27,34,37-40,42,43,45,46,48 and 49 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Frangioni et al. (US 10,201,621B2).
Frangioni et al. (US 10,201,621B2) teaches of the charge-balanced imaging agents
PNG
media_image4.png
438
402
media_image4.png
Greyscale
wherein E is absent, O or S; R17-20 are H, etc.; Q is (CH2)q; J is C(O),C(O)O, etc. (abstract; column 3, lines 1-8; column 13; claim 1).
The charge-balanced dyes are particularly advantageous as they provide superior optical imaging properties, good biodistribution and clearance properties (column 3, lines 1-8).
The compounds comprise
PNG
media_image5.png
336
246
media_image5.png
Greyscale
(Figure 7).
The ZW800-1 dye anticipates and/or encompasses the ZW800-1 of the instant claims 38 and 40.
The phenoxy moiety anticipates and/or encompasses the phenoxy moiety of the instant claims, has the same properties and is capable of the same functions, such as configured to stabilize the imaging agent dye in an acidic environment or a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent dye to metabolize in blood external to the target cell rendering the imaging agent non-fluorescent thereby increasing a target cell to background ratio after administration of the imaging agent dye more than a target cell to background ratio of an imaging agent without a labile linker.
The cRGD anticipates and/or encompasses the cRGD of the instant claims 39 and 40.
The cRGD-MM-19 is used in the in vivo rat tumor models (FIG 8) and can be used for methods of imaging and treatment of tumors (column 1, lines 58+; column 23, lines 59+).
The cRGD-MM-19 is used for image-guided surgery in humans (column 4, lines 14-18) that anticipates and/or encompasses administering a surgical treatment of the instant claim 34.
The methods include administering the imaging agent (derivatives), irradiating the tissues or cells and detecting the optical signal (column 4, lines 1-13; claims 1 and 6) that anticipates and/or encompasses the administration of the imaging agent, irradiating and imaging for the methods of imaging tumor cells and treating cancer of the instant claims.
The cRGD-MM-19 has a TBR of 17.2 at 4 h post-injection (column 29, lines 67 to column 30, lines 1-3) that anticipates and/or encompasses increasing the tumor-to-background ratio of the instant claim 37.
The imaging agent derivatives wherein E is absent, O or S anticipate and/or encompass the ZW-700 Forte, ZW-800-1 and ZW-830-1 dyes of the instant claims, respectively.
Also, other targeting ligands may be substituted for the cRGD, such as KUE (column 5, lines 7-10) that anticipates and/or encompasses the KUE targeting ligand of the instant claims.
The cRGD-MM-19 anticipates and/or encompasses the cRGD-ZW100-1 of the instant claims, has the same properties and is capable of the same functions, such as a target cell to background ratio four hours after administration is 7.6.
The instant invention uses the identical compound cRGD-MM-19 for analogous methods of imaging and treating and does not include any different method steps, any different conditions or any different imaging techniques to explain the observed results.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Response to Arguments
Applicant's arguments filed 9/4/25 have been fully considered but they are not persuasive.
Applicant asserts that the rejection has not alleged Frangioni discloses any method at all but instead relies on the structure of the compound “the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer” and that the fact that a certain result or characteristic may occur or be present is not sufficient to establish the inherency of the result or characteristic.
The reference of Frangioni teaches that the cRGD-MM-19 is used in the in vivo rat tumor models and can be used for methods of imaging and treatment of tumors, such as during image-guided surgery in humans.
The methods include administering the imaging agent (derivatives), irradiating the tissues or cells and detecting the optical signal.
The cRGD-MM-19 anticipates and/or encompasses the cRGD-ZW100-1 of the instant claims, has the same properties and is capable of the same functions, such as a target cell to background ratio four hours after administration is 7.6.
The instant invention uses the identical compound cRGD-MM-19 for analogous methods of imaging and treating and does not include any different method steps, any different conditions or any different imaging techniques to explain the observed results.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
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) 23,26,27,34-40,42,43,45,46,48 and 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (Nature Biotechnol. 2013, 31, 148-154) in view of de Valk et al. (Clin. Cancer Res. 2020, 26, 3990-3998) and in further view of Hyun et al. (Mol. Imaging Biol. 2016, 18, 52-61, see pages 1-18), Njiojob et al. (J. Med. Chem. 2015, 58, 2845-2854), Bao et al. (Chem. Commun. 2017, 53, 1611-1614) and Mukkamala et al. (J. Mater. Chem. B, 2022, 10, 2038-2046).
Choi et al. (Nature Biotechnol. 2013, 31, 148-154) discloses the zwitterionic near-infrared (NIR)
fluorophore cRGD-ZW100-1
PNG
media_image3.png
258
192
media_image3.png
Greyscale
imaging agent (Figure 1) as well as that stated
above.
Further, the TBR of cRGD-ZW100-1 is 4.8 by 24 h (abstract; p150, Tumor targeting and image-Guided surgery; Figure 3; p152, last lines of left column to top of right column).
The examination of the TBR up to 24 hours encompasses observing TBR 18-24 hours after
administration of the instant claim 26.
The cRGD-ZW100-1 expressed almost no background in liver and lung metastatic tissues (p150,
right column, second paragraph) that further encompasses increasing tumor-to-background ratio of the instant claim 37.
The authors examined targeting ligands spanning the entire spectrum from small molecules to large proteins (p151, right column).
Choi et al. does not explicitly disclose the peak target-to-background ratio is observed 18-24
hours after administration or the target cell to background ratio four hours after administration is 7.6.
de Valk et al. (Clin. Cancer Res. 2020, 26, 3990-3998) discloses cRGD-ZW800-1 (abstract; p3990,
right column, last paragraph) having the structure
PNG
media_image6.png
404
321
media_image6.png
Greyscale
(Figure 6).
The cRGD-ZW800-1 is used for the intraoperative visualization of colon cancer (abstract; p3991, Translational Relevance) wherein an intravenous bolus of cRGD-ZW800-1 was administered to human patients 2 to 4 hours prior to surgery (title; p3993, cRGD-ZW800-1 injection time window).
The doses 0.005, 0.015 and 0.05 mg/kg 2 to 4 hours prior to surgery showed a mean TBR of 1.4,4.0 and 4.1, respectively (p3993, cRGD-ZW800-1 injection time window; Supplemental Table 1).
The dose 0.05 mg/kg 18 hours prior to surgery displays the highest TBR of 6.2 and the longer intervals between injection and imaging improved the tumor-to-target background ratio (abstract; p3993, cRGD-ZW800-1 injection time window). Background was specifically reduced for cRGD-ZW800-1
and therefore, leading to a much higher TBR (p3335, left column, first paragraph).
Intraoperative colon tumor imaging was performed and images are shown in Figure 1 (p3991,
Intraoperative NIR imaging of colon tumors).
The surgical procedures are stated in Table S1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the cRGD-ZW100-1 may observe a peak target-to-background ratio 18-24 hours after administration as de Valk et al. teaches that administration 18 hours prior to surgery displays the highest TBR and the longer intervals between injection and imaging improved the tumor-to-target background ratio for imaging.
The references of Choi et al. and de Valk et al. disclose the use of cRGD-ZW100-1 for imaging various tumors and therefore, it would have been predictable to one of ordinary skill in the art that imaging cRGD-ZW100-1 for different tumor types will generate various TBRs. Also, TBR of 17.2 ± 1.2 (mean ± s.d.) comprises a range data points higher and lower than 17.2 ± 1.2.
The cRGD-ZW100-1 encompasses the cRGD-ZW100-1 of the instant claims, has the same properties and is capable of the same functions, such as a target cell to background ratio four hours after administration is 7.6.
The instant invention uses the identical compound cRGD-ZW100-1 of Choi et al. for analogous methods of imaging and treating and does not include any different method steps, any different conditions or any different imaging techniques to explain the observed results.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
With regards to the instant claim 46, Choi et al. does not disclose ZW700-1 Forte dye derivative.
Hyun et al. (Mol. Imaging Biol. 2016, 18, 52-61, see pages 1-18) discloses ZW700-1a, ZW700-1b
and ZW700-1c dyes for dual-channel image-guided surgery with a high signal to background ratio (SBR) (abstract; p7, Discussion; p8, Conclusions).
ZW700-1c comprises
PNG
media_image7.png
140
181
media_image7.png
Greyscale
(Figure 1) and encompasses the ZW700-1 Forte of the instant claims.
The class of heptamethine cyanine dyes that fluoresce [Symbol font/0x7E]800 nm only permit single-channel NIR fluorescence imaging wherein most clinical applications require 2 independent targets to be visualized simultaneously. For example, during tumor resection, the malignant cells need to be highlighted to ensure complete resection, but so do normal structures, such as nerves, blood vessels, or internal lumens, so that they can be avoided (p2, second paragraph).
The ZW700-1 dye family can be conjugated to targeting ligands, such as antibodies and small molecules (p8, fourth full paragraph).
ZW700-1 fluorophores were administered intravenously into mice and rats and were detectable
by imaging and were eliminated by 24 h post-injection (p6, In vivo biodistribution and clearance of ZW700-1 fluorophores).
BSA-ZW700-1a is administered in combination with cRGD-ZW800-1 in order to study dual-channel image-guided cancer surgery (p7, Real-time intraoperative imaging using dual-channel NIR fluorescence).
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 ZW800-1 dye of Choi et al. for the ZW700-1c dye of Hyun et al. to allow for imaging at a different wavelength of 700 nm vs 800 nm and/or provide for the advantage of dual-channel NIR during intraoperative cancer resection when desired.
With regards to the instant claim 43, Choi et al. does not disclose ZW830-1 dye derivative.
Njiojob et al. (J. Med. Chem. 2015, 58, 2845-2854) discloses contrast agents for image guided surgery (abstract).
The replacement of the O atom of ZW800-1 with sulfur was examined for biodistribution and
stability in serum (abstract). For example,
PNG
media_image8.png
142
195
media_image8.png
Greyscale
(Scheme 1).
Compound 9 has increased stability in conjugated imaging using various targeting ligands (p2849, right column, second paragraph) and the sulfur increased the overall stability of the fluorophore while allowing excellent optical and clearance properties (p2849, Conclusions).
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 O of the cRGD-ZW800-1 of Choi et al. with a sulfur for the advantage of increasing the overall stability of the fluorophore while allowing excellent optical and clearance properties.
With regards to the instant claim 42,45 and 48, the combined references do not disclose a KUE targeting vector.
Bao et al. (Chem. Commun. 2017, 53, 1611-1614) discloses KUE-PEG4-ZW800-1 PSMA-
targeted contrast agent
PNG
media_image9.png
170
230
media_image9.png
Greyscale
PNG
media_image10.png
168
217
media_image10.png
Greyscale
(Fig.
1) that can be used for in vivo intraoperative imaging of prostate cancer (title, abstract; p1613, left column, first paragraph).
The KUE encompasses the KUE of the instant claims.
The PEG4 encompasses the L, optional linking group of the instant claims.
A KUE-PEGx-ZW800+3C (Fig. 1) derivative was administered intravenously into xenograft mice and images are shown in Fig. 4 (p1613, right column). NIR fluorescence microscopy was done at 4 h post-injection (Fig. 4).
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 cRGD targeting moiety of Choi et al. for the KUE of Bao et al. for the advantage of in vivo site selective intraoperative imaging of prostate cancer.
Also, it would have been predictable to one of ordinary skill in the art to substitute one known
targeting moiety for another known targeting moiety to yield a site specific intraoperative imaging agent for specific detection and/or treatment of the desired target site as Choi et al. examined targeting ligands spanning the entire spectrum from small molecules to large proteins and Hyun et al. teaches that the ZW700-1 dye family can be conjugated to a variety of targeting ligands, including antibodies and small molecules.
With regards to the instant claims 41,44 and 47, the combined references do not disclose a FAP targeting vector.
Mukkamala et al. (J. Mater. Chem. B, 2022, 10, 2038-2046) discloses FTL-S-S0456 NIR dye for intraoperative imaging of most if not all solid tumors (abstract).
FTL-S-S0456 NIR dye comprises
PNG
media_image11.png
292
378
media_image11.png
Greyscale
(Fig. 2).
Fibroblast activation protein (FAP) is upregulated on cancer-associated fibroblasts that infiltrate essentially all solid tumors (abstract).
The attachment of carefully chosen substituents enhance both the binding affinity and specificity of 1 for FAP (p2039, Design and synthesis of a novel FAP-targeting ligand and its fluorescent conjugates).
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 cRGD targeting moiety of Choi et al. for the FAP targeting moiety
of Mukkamala et al. for the advantage of in vivo site selective intraoperative imaging of numerous solid tumors upregulating FAP.
Also, it would have been predictable to one of ordinary skill in the art to substitute one known
targeting moiety for another known targeting moiety to yield a site specific intraoperative imaging agent
for specific detection and/or treatment of the desired target site as Choi et al. examined targeting ligands spanning the entire spectrum from small molecules to large proteins and Hyun et al. teaches that the ZW700-1 dye family can be conjugated to a variety of targeting ligands, including antibodies and small molecules.
Choi et al. does not explicitly disclose a target to background ratio is greater than 7.6 five to ten hours after administration or the target cell to background ratio is 7.6 to 15 ten to twenty-four hours after administration.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the TBR of cRGD-ZW100-1 may observe a target to background ratio is greater than 7.6 five to ten hours after administration as the TBR of 17.2 ± 1.2 (mean ± s.d.) of Choi et al. comprises a range of data points that are higher and lower than 17.2 ± 1.2 4 hours after administration and therefore, it would be predictable that at 5 hours after administration the TBR of 17.2 ± 1.2 (mean ± s.d.) remains greater than 7.6.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the TBR of cRGD-ZW100-1 may observe a target cell to background ratio of 7.6 to 15 ten to twenty-four hours after administration as de Valk et al. teaches that administration 18 hours prior to surgery displays the highest TBR and the longer intervals between injection and imaging
improved the tumor-to-target background ratio for imaging.
The references of Choi et al. and de Valk et al. disclose the use of cRGD-ZW100-1 for imaging various tumors and therefore, it would have been predictable to one of ordinary skill in the art that imaging cRGD-ZW100-1 for different tumor types will generate different TBRs.
The cRGD-ZW100-1 encompasses the cRGD-ZW100-1 of the instant claims, has the same properties and is capable of the same functions, such as a target cell to background ratio greater than 7.6 five to ten hours after administration and/or a target cell to background ratio 7.6 to 15 ten to twenty-four hours after administration.
The instant invention uses the identical compound cRGD-ZW100-1 of Choi et al. for analogous
methods of imaging and treating and does not include any different method steps, any different conditions or any different imaging techniques to explain the observed results.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Claim(s) 23,26,27,32,34 and 37-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mulder et al. (Am. J. Nucl. Med. Mol. Imaging. 2018;8(5):282-291) in view of Frangioni et al. (US 10,201,621B2).
Mulder et al. (Am. J. Nucl. Med. Mol. Imaging. 2018;8(5):282-291) discloses a dual labeled cRGD-based PET/optical tracer for pre-operative and intraoperative treatment of colorectal cancer (title; p289, Conclusion).
The dual labeled tracer comprises cRGD-ZW800-1-Forte-[89Zr]ZrDFO:
PNG
media_image12.png
291
285
media_image12.png
Greyscale
that is injected into mice bearing orthotopic human colorectal tumors for tumor detection with NIRF imaging (abstract; Figures 1-3; p285, Fluorescence Imaging).
PET/CT permitted clear visualization of the colorectal tumors at 4 and 24 h and allows for image-guided treatment intraoperatively (abstract; p286, PET/CT) which encompasses the radioisotope for PET of the instant claim 32.
The cRGD-ZW800-1-Forte-[89Zr]ZrDFO encompasses the imaging agent dye of the instant claims.
The injection of the cRGD-ZW800-1-Forte-[89Zr]ZrDFO and imaging encompasses
the administration and detection in the method of imaging tumor cells of the instant claim 23.
Imaging at 4 hours after administration encompasses administering, irradiating and detecting a signal 4 hours after administration of the instant claim 23.
ZW800-1 Forte is a novel zwitterionic NIR fluorophore that has potential to further improve the tumor-to-background ratio because of its unusually high stability (p283, right column, last paragraph to the top of p284).
The TBRs obtained with cRGD-ZW800-1-Forte-ZrDFO was significantly higher at 24 h post injection (Figure 4; p287, right column, last paragraph; p289, right column, second paragraph) which
encompasses the peak target-to-background ratio is observed 18-24 hours after administration of the
instant claim 26.
Sufficient fluorescent signals were measured in the tumors of mice compared to background (abstract) that encompasses the method of increasing the tumor-to-background ratio of the instant claim 37.
Mulder et al. does not disclose a human subject or the dye comprises a phenoxy group/labile linker between the imaging agent and the targeting vector at a position closer to the imaging agent that is configured to stabilize the imaging agent dye in an acidic environment of a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent to separate from the targeting ligand in an environment external to the target cell rendering the imaging agent non-fluorescent, thereby increasing a target cell to background ratio after administration of the imaging agent dye more than target cell to background ratio of an imaging agent dye without a labile linker.
Frangioni et al. (US 10,201,621B2) discloses charge-balanced imaging agents 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 to substitute the dye of Mulder et al. for a dye comprising a labile linker, such as that of Frangioni et al. as Frangioni et al. teaches of the analogous use of dyes corresponding to ZW800-1, ZW830-1 and/or ZW700-1 Forte for image-guided surgery in humans wherein the dyes impart superior optical imaging, good biodistribution and clearance properties to the agents.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 23,37-40,43,46 and 49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,2,6 and 7 of U.S. Patent No. 10,201,621B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the method of imaging of U.S. Patent No. 10,201,621 encompasses the method of imaging tissue or cells of the instant claims.
The imaging agents of U.S. Patent No. 10,201,621B2 comprise an analogous dye and targeting ligand cGRD of the instant claims.
The methods of imaging of U.S. Patent No. 10,201,621B2 and of the instant claims comprise contacting a tissue or cells with the imaging agent, irradiating and detecting an optical signal.
The imaging agent dyes of U.S. Patent No. 10,201,621B2 encompass the imaging agent dyes of the instant claims, have the same properties and are capable of the same functions, such as a target to cell background ratio four hours after administration is 7.6.
The phenoxy moieties of the imaging agent dyes of U.S. Patent No. 10,201,621B2 and of the imaging agents of the instant claims have the same properties and are capable of the same functions, such as configured to stabilize the imaging agent dye in an acidic environment or a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent dye to metabolize in blood external to the target cell rendering the imaging agent non-fluorescent thereby increasing a target cell to background ratio after administration of the imaging agent dye more than a target cell to background ratio of an imaging agent without a labile linker.
Also, products of identical chemical composition can not have mutually exclusive properties. A
chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Claims 23 and 37-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-7 of U.S. Patent No. 9,023,611B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the method imaging tissue or cells of the U.S. Patent No. 9,023,611B2 encompasses the method of imaging tissue or cells of the instant claims.
The imaging agents of U.S. Patent No. 9,023,611B2 comprise an analogous dye and targeting ligands, not excluding the targeting ligands of the instant claims.
The methods of imaging of U.S. Patent No. 9,023,611B2 and of the instant claims comprise contacting a tissue or cells with the imaging agent, irradiating and detecting an optical signal.
The imaging agent dyes of U.S. Patent No. 9,023,611B2 encompass the imaging agent dyes of the instant claims, have the same properties and are capable of the same functions, such as a target to cell background ratio four hours after administration is 7.6.
The phenoxy moieties of the imaging agent dyes of U.S. Patent No. 9,023,611B2 and of the imaging agents of the instant claims have the same properties and are capable of the same functions, such as configured to stabilize the imaging agent dye in an acidic environment or a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent dye to metabolize in blood external to the target cell rendering the imaging agent non-fluorescent thereby increasing a target cell to background ratio after administration of the imaging agent dye more than a target cell to background ratio of an imaging agent without a labile linker.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Claims 23,27,32,37-39,46 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3,7 and 8-13 of copending Application No. 19/143,603 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the imaging agent dye ZW700-1c comprising a linking group, used for the method of imaging of copending Application No. 19/143,603 encompasses the imaging agent dye ZW700-Forte, optionally comprising a linking moiety L, used for the method of imaging of the instant claims.
The method of imaging of copending Application No. 19/143,603 and the method of imaging of the instant claims comprise administration of the imaging agent dyes to a human, irradiating the cells, detecting a signal.
The imaging agent dye ZW700-1c of copending Application No. 19/143,603 may further comprise a radioisotope for PET or SPECT that encompasses the radioisotope for PET or SPECT of the instant claims.
The imaging agent dyes of copending Application No. 19/143,603 encompass the imaging agent dyes of the instant claims, have the same properties and are capable of the same functions, such as a target to cell background ratio four hours after administration is 7.6.
The phenoxy moieties of the imaging agent dyes of copending Application No. 19/143,603 and of the imaging agents of the instant claims have the same properties and are capable of the same functions, such as configured to stabilize the imaging agent dye in an acidic environment or a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent dye to metabolize in blood external to the target cell rendering the imaging agent non-fluorescent thereby increasing a target cell to background ratio after administration of the imaging agent dye more than a target cell to background ratio of an imaging agent without a labile linker.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 23,27,32,34,37-39,41,42,44,45 and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,6-8,12-14,17,19,20,22-25,30 and 32 of copending Application No. 18/641,149 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the imaging agent dyes of the instant claims, optionally comprising an L linking group, have the same structures as the imaging agent dyes of copending Application No. 18/641,149. The imaging agents of the instant claims and the imaging agents of copending Application No. 18/641,149 are used for the method of imaging and for the method of treating cancer by administration of the imaging agent dyes to a human, irradiating the cells, detecting/diagnosing cancer and/or administering a treatment.
The imaging agent dyes of copending Application No. 18/641,149 encompass the imaging agent
dyes of the instant claims, have the same properties and are capable of the same functions, such as a
target to cell background ratio four hours after administration is 7.6.
The phenoxy moieties of the imaging agent dyes of copending Application No. 18/641,149 and of the imaging agents of the instant claims have the same properties and are capable of the same functions, such as configured to stabilize the imaging agent dye in an acidic environment or a target cell causing the imaging agent to fluoresce and configured to cause the imaging agent dye to metabolize in blood external to the target cell rendering the imaging agent non-fluorescent thereby increasing a target cell to background ratio after administration of the imaging agent dye more than a target cell to background ratio of an imaging agent without a labile linker.
Also, products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 9/4/25 have been fully considered but they are not persuasive.
With regards to the rejection over copending Application No. 18/641,149, Applicant asserts that the claim 23 of the present application have been amended in a manner applicant believes obviates this rejection. Should this rejection be maintained at the time of the claims are otherwise found allowable, Applicant will file a terminal disclaimer to obviate the rejection.
The rejection is stated above and is maintained.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspt