DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of the following species in the reply filed on 10/16/25 is acknowledged:
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Figure 19A is as follows:
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Per this figure and para 225 of the corresponding PGPUB 20240374763, “ZD2” is the peptide TVRTSAD, “We previously developed an oligopeptide, TVRTSAD (ZD2), that binds with high specificity to EDB-FN17.”
From a review of the sequence listing, SEQ ID NO: 1 is TVRTSAD.
The N3 is the linker shown in Figure 19A.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 11 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/16/25.
Claim Status
Claims 1-22 are pending.
Claims 11 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/16/25.
Claims 1-10 and 12-21 are under examination.
Claims 1-10 and 12-21 are rejected.
Priority
The instant application, filed 11/30/2022 is a National Stage entry of PCT/US2021/035852 , International Filing Date: 06/04/2021
PCT/US2021/035852 Claims Priority from Provisional Application 63034520 , filed 06/04/2020
PCT/US2021/035852 Claims Priority from Provisional Application 63170746 , filed 04/05/2021.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 11/30/22, 1/14/25, 3/15/25, and 8/25/25 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Specification
The disclosure is objected to because of the following informalities: in paragraph 210 on page 76 of the specification the oligopeptide sequence TVRTSAD is set forth associated with “(ZD2)” but without the corresponding SEQ ID NO:1.
Appropriate correction is required.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-10 and 12-21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0110886, inventors Lu and Han, (“LH”), published 4/26/18, in view of Saw et al., Nanomedicine NBM 2017; 13, 713-722 (“Saw”).
Independent claim 1 is directed to
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Independent claim 12 is directed to
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The elected species is
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.
This elected species meets the claim 1 and claim 12 limitation of covalently linking the peptide ZD2, which corresponds to SEQ ID NO:1, to the MRI Contrast Agent by “including a carboxylic acid that forms a carboxamide with the amine of the peptide.”
LH broadly teaches a molecular probe includes the following formula: P-L-C wherein P is a EDB-FN targeting peptide, C is a contrast agent; and L is a non-peptide linker that covalently links the peptide to the contrast agent, Abstract
Within this genus, LH particularly teaches synthesis of the elected species, which per its Fig. 35 results in:
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, that is, the elected species, which however per para 56 LH refers to as “ZD2-TA-(Gd-DO3A)”.
LH teaches imaging using ZD2-TA-(Gd-DO3A) in Fig. 36, which per para 244 of Example 7, the last example, produced significant contrast enhancement in PC3 prostate cancer at a dose of 0.1 mmol/kg.
LH also teaches detecting tumors using its P-L-C molecular probes, and comparing imaging signals to signals of controls in order to determine whether the signal indicates presence of tumor, paras 148, 149, 153 (comparing prostate cancer with benign prostatic hyperplasia, BPH), 188.
LH also teaches monitoring growth of tumors, para 160, and use of its P-L-C molecular probes to monitor cancer tumors during cancer therapies, para 129, cited in greater detail below.
Although LH clearly teaches using ZD2-TA-(Gd-DO3A) to detect prostate cancer, this with its EDB-FN targeting peptide, LH does not teach using ZD2-TA-(Gd-DO3A) in a method to detect drug-resistant cancer per instant claim 1, nor to monitor treatment of drug resistant cancer per claim 12.
The level of ordinary skill in the art is high, including based on motivations to improve treatment and diagnosis of cancers including drug resistant cancers.
Saw teaches that multidrug resistance (MDR) is one of the biggest challenges in chemotherapy and a major impediment to current cancer therapy modalities, page 713. While Saw includes a focus on treatment using a “Trojan Horse” approach, to develop a drug-delivery carrier decorated with a targeting ligand for a surface marker protein specific to drug-resistant cancer cells, page 713-714, part of this approach is based on the knowledge that insertion of EDB (extra-domain B) into fibronectin through alternative splicing, and that “EDB is specifically over-expressed around new blood vessels in tumors as well as in tumor-associated extracellular matrix, and is thus considered a promising cancer marker.24,25 It has also been shown that EDB expression is linked to cancer aggressiveness and malignancy.26,” page 714. Saw, based on its and others’ previous findings, “thus hypothesized that drug-resistant breast cancer cells might overexpress the EDB domain as drug-resistant cells are more malignant and aggressive. 32,33 True to our expectation, we observed that EDB was minimally expressed in MCF7 breast cancer cells yet highly expressed when MCF7 cells attain drug resistance,” Id. While Saw focused on treatment therapies for drug-resistant cancers, Saw also utilized EDB-targeting moieties to image tumoral uptake of nanoparticles, page 716 left column.
In concluding on page 721, Saw states, “In conclusion, our results highlight the importance of EDB as a new putative marker of drug-resistant breast cancer” (bold emphasis added). Please note that the title of Saw, “A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin,” indicates that the target is EDB that has inserted into fibronectin, see also page 714 left column.
LH teaches the use of its molecular probes, including the elected species, to detect cancer cells and image cancer tumors, para 2, Fig. 36, Example 7. This is done by targeting what it refers to as EDB-FN. As to monitoring cancer tumors, from para 129, LH teaches, “In certain embodiments, the methods and molecular probes described herein can be used to measure the efficacy of a therapeutic administered to a subject for treating a metastatic or aggressive cancer. In this embodiment, the molecular probe can be administered to the subject prior to, during, or post administration of the therapeutic regimen and the distribution of cancer cells can be imaged to determine the efficacy of the therapeutic regimen. In one example, the therapeutic regimen can include a surgical resection of the metastatic cancer and the molecular probe can be used to define the distribution of the metastatic cancer pre-operative and post-operative to determine the efficacy of the surgical resection. Optionally, the methods and molecular probes can be used in an intra-operative surgical procedure, such as a surgical tumor resection, to more readily define and/or image the cancer cell mass or volume during the surgery,” emphases added.
Given that Saw teaches the importance of EDB as a new putative marker of drug-resistant breast cancer, and that this would be associated with fibronectin in such cancer cells (see Title), and that LH also teaches its constructs, including the elected species, capable of selectively targeting cancer cells and tumors versus non-cancer cells, and detecting and comparing steps and approaches in common with instant claims 1 and 12, one of ordinary skill in the art would have been motivated to employ the evaluated species of LH, including that corresponding with the elected species, to image and monitor cancer cells that are drug resistant. The motivation is to employ an imaging moiety and technique to improve imaging drug resistant cancers, including to track progression or reduction of drug resistant cancer tumors during cancer treatment modalities. Based on the teachings and results of both LH and Saw, there would have been a reasonable expectation of success.
Accordingly, claims 1 and 12 would have been obvious and are rejected under this section.
At least because Saw teaches targeting drug resistant breast cancer, claims 2 and 13 would have been obvious.
Because the ZD2-TA-(Gd-DO3A) of LH comprises Gd-DO3A which is used for magnetic resonance imaging, see paras 163, 237, 240, 242, 244, claims 3 and 14 would have been obvious.
Because LH’s use of ZD2-TA-(Gd-DO3A) and other Gd-DO3A-comprising molecular probes were used to contact a tissue of a subject in vivo, see para 185, claims 4 and 15 would have been obvious.
Because LH administered its Gd-DO3A-comprising molecular probes intravenously before imaging, paras 113, 141, 149, 162, claim 5 would have been obvious.
Because LH clearly teaches and suggests administering its Gd-DO3A-comprising molecular probes and images so generated to control the delivery of a therapeutic agent (e.g., by a micro-electronic machine or micro-machine), para 123, as well as to monitor the efficacy of a cancer therapeutic or cancer therapy administered to a subject, see paras 124-130, claim 16 would have been obvious.
Because the linker in the elected species, which is identical with LH’s ZD2-TA-(Gd-DO3A), is a non-peptide heteroaliphatic linker, see structure above, claims 6 and 17 would have been obvious.
Claims 7 and 18, each stating “wherein the non-peptide linker of the molecular probe includes an alkylene dicarboxamide when covalently linking the peptide and contrast agent”, are interpreted as product by process claims. Per MPEP 2113, it is the resultant product of such covalent linking reaction, including the elected species, which is examined, “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”“. Claims 7 and 18 are rejected on the same bases as claims 1 and 12 above for the elected species product.
Because the Gd-DO3A contrast agent of the elected species includes at least one metal chelating agent, claims 8, 9, 19 and 20 are rejected as obvious.
Because the elected species rejected above conforms to the second formula of claims 10 and 21, and otherwise meet the limitations of these claims, claims 10 and 21 are rejected as obvious.
Regarding the following four 35 USC 103 rejections, the following applies:
Claim 1-10 and 12-21 under examination are directed to an invention not patentably distinct from claims as indicated below of commonly assigned issued patents. Please see each rejection below for specific details of the respective rejection.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned patents, see rejections below, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Claims 1-10 and 12-21 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 10124073 in view of US 2018/0110886, inventors Lu and Han, (“LH”), published 4/26/18, and Saw et al., Nanomedicine NBM 2017; 13, 713-722 (“Saw”).
The instant independent claims 1 and 12 are set forth above.
The 073 claims 18-22 are set forth below:
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These claims administer, to detect cancer cels in a subject having or suspected of having cancer, a molecular probe that comprises TVRTSAD, this being the 073 SEQ ID NO:1, coupled to a detectable moiety, the probe including an MRI contrast agent.
Although the 073 specification teaches synthesis of a molecular probe including a linker, see Fig. 7A, this encompassed by the instant genus of administered molecular probes but differing from the instantly elected species because it has ethylene oxide units as part of the linker, this is not found explicitly in the 073 claims.
Thus, the 073 claims a method of detecting cancer by administering a broad genus of molecular probes, none of which are claimed to be identical with the molecular probes instantly claimed in more specific methods.
The 073 specification discloses evaluating aggressive cancers, and includes the same SEQ ID NO:1 TVRSTAD peptide in its molecular probes, but does not teach its methods directed to detecting drug-resistant cancer in a subject.
The level of ordinary skill in the art is high, including based on motivations to improve treatment and diagnosis of cancers including drug resistant cancers.
LH broadly teaches a molecular probe includes the following formula: P-L-C wherein P is a EDB-FN targeting peptide, C is a contrast agent; and L is a non-peptide linker that covalently links the peptide to the contrast agent, Abstract
Within this genus, LH particularly teaches synthesis of the elected species, which per its Fig. 35 results in:
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, that is, the elected species, which however per para 56 LH refers to as “ZD2-TA-(Gd-DO3A)”.
LH teaches imaging using ZD2-TA-(Gd-DO3A) in Fig. 36, which per para 244 of Example 7, the last example, produced significant contrast enhancement in PC3 prostate cancer at a dose of 0.1 mmol/kg.
LH also teaches detecting tumors using its P-L-C molecular probes, and comparing imaging signals to signals of controls in order to determine whether the signal indicates presence of tumor, paras 148, 149, 153 (comparing prostate cancer with benign prostatic hyperplasia, BPH), 188.
LH also teaches monitoring growth of tumors, para 160, and use of its P-L-C molecular probes to monitor cancer tumors during cancer therapies, para 129, cited in greater detail below.
Although LH clearly teaches using ZD2-TA-(Gd-DO3A) to detect prostate cancer, this with its EDB-FN targeting peptide, neither the 073 claims nor LH claim or teach using ZD2-TA-(Gd-DO3A) in a method to detect drug-resistant cancer per instant claim 1, nor to monitor treatment of drug resistant cancer per instant claim 12.
Saw teaches that multidrug resistance (MDR) is one of the biggest challenges in chemotherapy and a major impediment to current cancer therapy modalities, page 713. While Saw includes a focus on treatment using a “Trojan Horse” approach, to develop a drug-delivery carrier decorated with a targeting ligand for a surface marker protein specific to drug-resistant cancer cells, page 713-714, part of this approach is based on the knowledge that insertion of EDB (extra-domain B) into fibronectin through alternative splicing, and that “EDB is specifically over-expressed around new blood vessels in tumors as well as in tumor-associated extracellular matrix, and is thus considered a promising cancer marker.24,25 It has also been shown that EDB expression is linked to cancer aggressiveness and malignancy.26,” page 714. Saw, based on its and others’ previous findings, “thus hypothesized that drug-resistant breast cancer cells might overexpress the EDB domain as drug-resistant cells are more malignant and aggressive. 32,33 True to our expectation, we observed that EDB was minimally expressed in MCF7 breast cancer cells yet highly expressed when MCF7 cells attain drug resistance,” Id. While Saw focused on treatment therapies for drug-resistant cancers, Saw also utilized EDB-targeting moieties to image tumoral uptake of nanoparticles, page 716 left column.
In concluding on page 721, Saw states, “In conclusion, our results highlight the importance of EDB as a new putative marker of drug-resistant breast cancer.” Please note that the title of Saw, “A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin,” indicates that the target is EDB that has inserted into fibronectin, see also page 714 left column.
LH teaches the use of its molecular probes, including the elected species, to detect cancer cells and image cancer tumors, para 2, Fig. 36, Example 7. This is done by targeting what it refers to as EDB-FN. As to monitoring cancer tumors, from para 129, LH teaches, “In certain embodiments, the methods and molecular probes described herein can be used to measure the efficacy of a therapeutic administered to a subject for treating a metastatic or aggressive cancer. In this embodiment, the molecular probe can be administered to the subject prior to, during, or post administration of the therapeutic regimen and the distribution of cancer cells can be imaged to determine the efficacy of the therapeutic regimen. In one example, the therapeutic regimen can include a surgical resection of the metastatic cancer and the molecular probe can be used to define the distribution of the metastatic cancer pre-operative and post-operative to determine the efficacy of the surgical resection. Optionally, the methods and molecular probes can be used in an intra-operative surgical procedure, such as a surgical tumor resection, to more readily define and/or image the cancer cell mass or volume during the surgery,” emphases added.
Given that Saw teaches the importance of EDB as a new putative marker of drug-resistant breast cancer, and that this would be associated with fibronectin in such cancer cells (see Title), and that the 073 claims molecular probes for detecting cancer but without claiming explicit structure such as in the P-L-C format, however with LH teaching and evaluating such constructs, including the elected species, capable of selectively targeting cancer cells and tumors versus non-cancer cells, and detecting and comparing steps and approaches in common with instant claims 1 and 12, one of ordinary skill in the art would have been motivated to further refine, focus, and/or select the molecular probes of the 073 by choosing the evaluated species of LH, including that corresponding with the elected species, to image and monitor cancer cells that are drug resistant. The motivation is to employ an known and demonstrated imaging moiety and technique to improve imaging drug resistant cancers, including to track progression or reduction of drug resistant cancer tumors during cancer treatment modalities. Based on the teachings and results of both LH and Saw, there would have been a reasonable expectation of success.
Accordingly, claims 1 and 12 would have been obvious and are rejected under this section.
At least because Saw teaches targeting drug resistant breast cancer, claims 2 and 13 would have been obvious and are rejected under this section.
Because the ZD2-TA-(Gd-DO3A) of LH comprises Gd-DO3A which is used for magnetic resonance imaging, see paras 163, 237, 240, 242, 244, claims 3 and 14 would have been obvious and are rejected under this section.
Because LH’s use of ZD2-TA-(Gd-DO3A) and other Gd-DO3A-comprising molecular probes were used to contact a tissue of a subject in vivo, see para 185, claims 4 and 15 would have been obvious and are rejected under this section.
Because LH administered its Gd-DO3A-comprising molecular probes intravenously before imaging, paras 113, 141, 149, 162, claim 5 would have been obvious and is rejected under this section.
Because LH clearly teaches and suggests administering its Gd-DO3A-comprising molecular probes and images so generated to control the delivery of a therapeutic agent (e.g., by a micro-electronic machine or micro-machine), para 123, as well as to monitor the efficacy of a cancer therapeutic or cancer therapy administered to a subject, see paras 124-130, claim 16 would have been obvious.
Because the linker in the elected species, which is identical with LH’s ZD2-TA-(Gd-DO3A), is a non-peptide heteroaliphatic linker, see structure above, claims 6 and 17 would have been obvious and are rejected under this section.
Claims 7 and 18, each stating “wherein the non-peptide linker of the molecular probe includes an alkylene dicarboxamide when covalently linking the peptide and contrast agent”, are interpreted as product by process claims. Per MPEP 2113, it is the resultant product of such covalent linking reaction, including the elected species, which is examined, “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”“. Claims 7 and 18 are rejected on the same bases as claims 1 and 12 above for the elected species product.
Because the Gd-DO3A contrast agent of the elected species includes at least one metal chelating agent, claims 8, 9, 19 and 20 are rejected as obvious and are rejected under this section.
Because the elected species rejected above conforms to the second formula of claims 10 and 21, and otherwise meet the limitations of these claims, claims 10 and 21 are rejected as obvious and are rejected under this section.
Claims 1-10 and 12-21 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 10653801 in view of US 2018/0110886, inventors Lu and Han, (“LH”), published 4/26/18, and Saw et al., Nanomedicine NBM 2017; 13, 713-722 (“Saw”).
The instant independent claims 1 and 12 are set forth above.
The 801 claims are as follows:
1. A method of determining cancer aggressiveness in a subject having or suspected of having cancer, the method comprising: administering to the subject a molecular probe comprising at least one targeting peptide coupled to a detectable moiety, the targeting peptide binding to EDB-FN or EDA-FN and comprising at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30; and detecting the molecular probes in the subject, wherein the amount of the probe detected is indicative of the aggressiveness of the cancer.
2. The method of claim 1, further comprising comparing the amount of probe detected to a control, wherein an increase in the amount of probe detected compared to the control is indicative of the subject having an increased risk of aggressive cancer.
3. The method of claim 1, the detectable moiety comprising an imaging agent and the probe being detectable upon administration to the subject by at least one of gamma imaging, positron emission tomography (PET) imaging, computer tomography (CT) imaging, magnetic resonance imaging, near infrared imaging, or fluorescent imaging.
4. The method of claim 1, detectable moiety including at least one of an optical dye, MRI contrast agent, a PET agent, a SPECT agent, a CT contrast agent, radiolabel, or an ultrasound contrast agent.
5. The method of claim 1, the probe being systemically administered to a subject having or suspected of having cancer.
6. The method of claim 1, the cancer comprising at least one of breast cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, testicular cancer, glioblastoma, sarcoma, bone cancer, brain cancer, head and neck cancers, or skin cancer.
7. A method of measuring the efficacy of a therapeutic agent in treating cancer in a subject, the method comprising: administering the therapeutic agent to the subject; administering a molecular probe to the subject, the molecular probe comprising at least one targeting peptide coupled to a detectable moiety, the targeting peptide binding to EDB-FN or EDA-FN and comprising at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30; and detecting the molecular probe in the subject.
8. The method of claim 7, the molecular probe being administered to the subject in a first administration prior to or after administration of the therapeutic agent to define a first location and/or distribution of the cancer, and the molecular probe being administered to the subject in a second administration after the first administration and the administration of the therapeutic to define a second location and/or distribution of the cancer, the first and second location and/or distribution of the cancer being compared to determine the efficacy of the therapeutic agent.
9. The method of claim 7, the detectable moiety comprising an imaging agent and the probe being detectable upon administration to the subject by at least one of gamma imaging, positron emission tomography (PET) imaging, computer tomography (CT) imaging, magnetic resonance imaging, near infrared imaging, or fluorescent imaging.
10. The method of claim 7, detectable moiety including at least one of an optical dye, MRI contrast agent, a PET agent, a SPECT agent, a CT contrast agent, radiolabel, or an ultrasound contrast agent.
11. The method of claim 7, the probe being systemically administered to a subject having cancer.
12. The method of claim 7, the cancer comprising at least one of breast cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, testicular cancer, glioblastoma, sarcoma, bone cancer, brain cancer, head and neck cancers, or skin cancer.
These claims are directed to determining cancer aggressiveness in a subject having or suspected of having cancer, as well as measuring the efficacy of a therapeutic agent in treating cancer in a subject, by administering a molecular probe that comprises TVRTSAD, this being the 801 SEQ ID NO:1, coupled to a detectable moiety, the probe including an MRI contrast agent (see claims 4 and 10 as to latter).
Although the 801 specification teaches synthesis of a molecular probe including a linker, see Fig. 7A, this encompassed by the instant genus of administered molecular probes but differing from the instantly elected species because it has ethylene oxide units as part of the linker, this is not found explicitly in the 801 claims.
Thus, the 801 claims broader methods with molecular probes that are not explicitly claimed to be identical with the molecular probes instantly claimed in more specific methods.
The 801 specification also discloses evaluating aggressive cancers, and includes the same SEQ ID NO:1 TVRSTAD peptide in its molecular probes, but does not teach its methods directed to detecting drug-resistant cancer in a subject.
The level of ordinary skill in the art is high, including based on motivations to improve treatment and diagnosis of cancers including drug resistant cancers.
LH broadly teaches a molecular probe includes the following formula: P-L-C wherein P is a EDB-FN targeting peptide, C is a contrast agent; and L is a non-peptide linker that covalently links the peptide to the contrast agent, Abstract
Within this genus, LH particularly teaches synthesis of the elected species, which per its Fig. 35 results in:
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, that is, the elected species, which however per para 56 LH refers to as “ZD2-TA-(Gd-DO3A)”.
LH teaches imaging using ZD2-TA-(Gd-DO3A) in Fig. 36, which per para 244 of Example 7, the last example, produced significant contrast enhancement in PC3 prostate cancer at a dose of 0.1 mmol/kg.
LH also teaches detecting tumors using its P-L-C molecular probes, and comparing imaging signals to signals of controls in order to determine whether the signal indicates presence of tumor, paras 148, 149, 153 (comparing prostate cancer with benign prostatic hyperplasia, BPH), 188.
LH also teaches monitoring growth of tumors, para 160, and use of its P-L-C molecular probes to monitor cancer tumors during cancer therapies, para 129, cited in greater detail below.
Although LH clearly teaches using ZD2-TA-(Gd-DO3A) to detect prostate cancer, this with its EDB-FN targeting peptide, neither the 801 claims nor LH claim or teach using ZD2-TA-(Gd-DO3A) in a method to detect drug-resistant cancer per instant claim 1, nor to monitor treatment of drug resistant cancer per instant claim 12.
Saw teaches that multidrug resistance (MDR) is one of the biggest challenges in chemotherapy and a major impediment to current cancer therapy modalities, page 713. While Saw includes a focus on treatment using a “Trojan Horse” approach, to develop a drug-delivery carrier decorated with a targeting ligand for a surface marker protein specific to drug-resistant cancer cells, page 713-714, part of this approach is based on the knowledge that insertion of EDB (extra-domain B) into fibronectin through alternative splicing, and that “EDB is specifically over-expressed around new blood vessels in tumors as well as in tumor-associated extracellular matrix, and is thus considered a promising cancer marker.24,25 It has also been shown that EDB expression is linked to cancer aggressiveness and malignancy.26,” page 714. Saw, based on its and others’ previous findings, “thus hypothesized that drug-resistant breast cancer cells might overexpress the EDB domain as drug-resistant cells are more malignant and aggressive. 32,33 True to our expectation, we observed that EDB was minimally expressed in MCF7 breast cancer cells yet highly expressed when MCF7 cells attain drug resistance,” Id. While Saw focused on treatment therapies for drug-resistant cancers, Saw also utilized EDB-targeting moieties to image tumoral uptake of nanoparticles, page 716 left column.
In concluding on page 721, Saw states, “In conclusion, our results highlight the importance of EDB as a new putative marker of drug-resistant breast cancer.” Please note that the title of Saw, “A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin,” indicates that the target is EDB that has inserted into fibronectin, see also page 714 left column.
LH teaches the use of its molecular probes, including the elected species, to detect cancer cells and image cancer tumors, para 2, Fig. 36, Example 7. This is done by targeting what it refers to as EDB-FN. As to monitoring cancer tumors, from para 129, LH teaches, “In certain embodiments, the methods and molecular probes described herein can be used to measure the efficacy of a therapeutic administered to a subject for treating a metastatic or aggressive cancer. In this embodiment, the molecular probe can be administered to the subject prior to, during, or post administration of the therapeutic regimen and the distribution of cancer cells can be imaged to determine the efficacy of the therapeutic regimen. In one example, the therapeutic regimen can include a surgical resection of the metastatic cancer and the molecular probe can be used to define the distribution of the metastatic cancer pre-operative and post-operative to determine the efficacy of the surgical resection. Optionally, the methods and molecular probes can be used in an intra-operative surgical procedure, such as a surgical tumor resection, to more readily define and/or image the cancer cell mass or volume during the surgery,” emphases added.
Given that Saw teaches the importance of EDB as a new putative marker of drug-resistant breast cancer, and that this would be associated with fibronectin in such cancer cells (see Title), and that the 801 claims molecular probes administered to achieve its methods objectives but without claiming explicit structure such as in the P-L-C format, however with LH teaching and evaluating such constructs, including the elected species, capable of selectively targeting cancer cells and tumors versus non-cancer cells, and detecting and comparing steps and approaches in common with instant claims 1 and 12, one of ordinary skill in the art would have been motivated to further refine, focus, and/or select the molecular probes of the 801 by choosing the evaluated species of LH, including that corresponding with the elected species, to image and monitor cancer cells that are drug resistant. The motivation is to employ an imaging moiety and technique to improve imaging drug resistant cancers, including to track progression or reduction of drug resistant cancer tumors during cancer treatment modalities. Based on the teachings and results of both LH and Saw, there would have been a reasonable expectation of success.
Accordingly, claims 1 and 12 would have been obvious and are rejected under this section. Please note that in this regard detecting drug resistant cancer is a subset of aggressive cancer that per above, see Saw, is recognized to be of particular interest and motivation to improve therapies for.
At least because Saw teaches targeting drug resistant breast cancer, claims 2 and 13 would have been obvious and are rejected under this section.
Because the ZD2-TA-(Gd-DO3A) of LH comprises Gd-DO3A which is used for magnetic resonance imaging, see paras 163, 237, 240, 242, 244, claims 3 and 14 would have been obvious and are rejected under this section.
Because LH’s use of ZD2-TA-(Gd-DO3A) and other Gd-DO3A-comprising molecular probes were used to contact a tissue of a subject in vivo, see para 185, claims 4 and 15 would have been obvious and are rejected under this section.
Because LH administered its Gd-DO3A-comprising molecular probes intravenously before imaging, paras 113, 141, 149, 162, claim 5 would have been obvious and are rejected under this section.
Because LH clearly teaches and suggests administering its Gd-DO3A-comprising molecular probes and images so generated to control the delivery of a therapeutic agent (e.g., by a micro-electronic machine or micro-machine), para 123, as well as to monitor the efficacy of a cancer therapeutic or cancer therapy administered to a subject, see paras 124-130, claim 16 would have been obvious.
Because the linker in the elected species, which is identical with LH’s ZD2-TA-(Gd-DO3A), is a non-peptide heteroaliphatic linker, see structure above, claims 6 and 17 would have been obvious and are rejected under this section.
Claims 7 and 18, each stating “wherein the non-peptide linker of the molecular probe includes an alkylene dicarboxamide when covalently linking the peptide and contrast agent”, are interpreted as product by process claims. Per MPEP 2113, it is the resultant product of such covalent linking reaction, including the elected species, which is examined, “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”“. Claims 7 and 18 are rejected on the same bases as claims 1 and 12 above for the elected species product.
Because the Gd-DO3A contrast agent of the elected species includes at least one metal chelating agent, claims 8, 9, 19 and 20 are rejected as obvious and are rejected under this section.
Because the elected species rejected above conforms to the second formula of claims 10 and 21, and otherwise meet the limitations of these claims, claims 10 and 21 are rejected as obvious and are rejected under this section.
Claims 1-10 and 12-21 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 10925980 in view of US 2018/0110886, inventors Lu and Han, (“LH”), published 4/26/18, and Saw et al., Nanomedicine NBM 2017; 13, 713-722 (“Saw”).
The instant independent claims 1 and 12 are set forth above.
The 980 claims are as follows:
1. A method of detecting the presence, location and/or distribution of cancer cells expressing EDB-FN comprising: contacting a tissue of a subject with a molecular probe, the molecular probe comprising a linear peptide that includes an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9; a contrast agent selected from at least one of a metal chelating agent or a metallofullerene; and a non-peptide linker that covalently links the peptide to the contrast agent, wherein the linker is selected from at least one of a carboxamide and a maleimide, wherein the molecular probe targets and binds to EDB-FN in the tissue; and detecting the molecular probe in the tissue of the subject bound to EDB-FN using an imaging modality, wherein the detected presence, location and/or distribution of the molecular probe bound to EDB-FN in the tissue is correlated with the presence, location and/or distribution of EDB-FN expressing cancer cells in the tissue.
2. The method of claim 1, wherein the contacting step is in vivo, ex vivo, or in vitro.
3. The method of claim 1, wherein the probe is systemically administered to a subject having or suspected of having cancer.
4. The method of claim 1, wherein the cancer is selected from at least one of breast cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, testicular cancer, glioblastoma, sarcoma, bone cancer, brain cancer, head and neck cancers, or skin cancer.
5. The method of claim 1, wherein the subject is administered the probe to determine cancer aggressiveness, and wherein a greater amount of detected and/or distributed probe bound to EDB-FN compared to a control is indicative of an increase in cancer aggressiveness.
6. The method of claim 1, wherein the non-peptide linker is a non-peptide aliphatic or heteroaliphatic linker.
7. The method of claim 1, wherein the non-peptide linker includes an alkylene dicarboxamide when covalently linking the peptide and contrast agent.
8. The method of claim 1, wherein the contrast agent is a magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT) contrast agent.
9. The method of claim 1, wherein the contrast agent is a metal chelating agent selected from at least one of diethylenetriaminepentaacetate (DTPA), 1,4,7,10-tetraazadodecanetetraacetate (DOTA), 1,4,7,10-tetraazadodecane-1,4,7-triacetate (DO3A), ethylenediaminetetraacetate (EDTA), 1,4,7,10-tetraazacyclotridecanetetraacetic acid (TRITA), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7,10-tetraazadodecanetetramethylacetate (DOTMA), 1,4,7,10-tetraazadodecane-1,4,7-trimethylacetate (DO3MA), N,N′,N″,N′″-tetraphosphonatomethyl-1,4,7,10-tetraazacyclododecane (DOTP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene methylphosphonic acid) (DOTMP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phenylphosphonic acid) (DOTPP), or N,N′-ethylenedi-L-cysteine.
10. The method of claim 1, the molecular probe contacted with the tissue of a subject having the formula:
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137
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wherein: P.sub.1 is a linear peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9; L.sub.2 is an amino group of the peptide P.sub.1, and M is a metal selected from the group consisting of Gd.sup.+3, Eu.sup.+3, Tm.sup.+3, Dy.sup.+3, Yb.sup.+3, Mn.sup.+2, Fe.sup.+3, .sup.55Co, .sup.64Cu, .sup.67Cu, .sup.47sc, .sup.66Ga, .sup.68Ga, .sup.90Y, .sup.97Ru, .sup.99mTC, .sup.111In, .sup.109Pd, .sup.153Sm, .sup.177Lu, .sup.186Re, and .sup.188Re, and n is an integer from 0 to 100; or salts thereof.
11. The method of claim 1, wherein the metallofullerene is Gd3N@C80.
12. A method of detecting the presence, location and/or distribution of cancer cells expressing EDB-FN comprising: contacting a tissue of a subject with a molecular probe having the formula: ##STR00007## wherein: P.sub.1 is a linear peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9; L.sub.1 is an optional spacer, L.sub.2 is an amino group of the peptide P.sub.1 or the spacer, and M is a metal selected from the group consisting of Gd.sup.+3, Eu.sup.+3, Tm.sup.+3, Dy.sup.+3, Yb.sup.+3, Mn.sup.+2, Fe.sup.+3, .sup.55Co, .sup.64Cu, .sup.67Cu, .sup.475c, .sup.66Ga, .sup.68Ga, .sup.90Y, .sup.97Ru, .sup.99mTC, .sup.111In, .sup.109 Pd, .sup.153Sm, .sup.177Lu, .sup.186Re, and .sup.188Re; or salts thereof, wherein the molecular probe targets and binds to EDB-FN in the tissue, and detecting the molecular probes in the tissue of the subject bound to EDB-FN using an imaging modality, wherein the detected presence, location and/or distribution of the molecular probe bound to EDB-FN in the tissue is correlated with the presence, location and/or distribution of EDB-FN expressing cancer cells in the tissue.
13. The method of claim 12, the molecular probe contacted with the tissue of a subject wherein L.sub.1 of the probe is selected from at least one of a polyalkyleneoxide, polyvinyl alcohol, polyethylene glycol (PEG), polypropylene glycol (PPG), copolymer of ethylene and propylene glycol, polyoxyethylene (POE), polyurethane, polyphosphazene, polysaccharides, dextran, polyvinylpyrrolidones, polyvinyl ethyl ether, polyacryl amide, polyacrylate, or polycyanoacrylates.
14. The method of claim 12, the probe being detectable upon contacting the tissue of the subject by at least one of positron emission tomography (PET) imaging and magnetic resonance imaging (MRI).
15. A method of detecting the presence, location and/or distribution of cancer cells expressing EDB-FN comprising: contacting a tissue of a subject with a molecular probe having the formula: ##STR00008## wherein: P.sub.1 is a linear peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9; L.sub.2 is an amino group of the peptide P.sub.1, and M is a metal selected from the group consisting of Gd.sup.+3, Eu.sup.+3, Tm.sup.+3, Dy.sup.+3, Yb.sup.+3, Mn.sup.+2, Fe.sup.+3, .sup.55Co, .sup.64Cu, .sup.67Cu, .sup.47Sc, .sup.66Ga, .sup.68Ga, .sup.90Y, .sup.97Ru, .sup.99mTc, .sup.111In, .sup.109Pd, .sup.153Sm, .sup.177Lu, .sup.186Re, and .sup.188Re, and n is an integer from 0 to 100; or salts thereof, wherein the molecular probe targets and binds to EDB-FN in the tissue, and detecting the molecular probes in the tissue of the subject bound to EDB-FN using an imaging modality, wherein the detected presence, location and/or distribution of the molecular probe bound to EDB-FN in the tissue is correlated with the presence, location and/or distribution of EDB-FN expressing cancer cells in the tissue.
16. The method of claim 15, the probe being detectable upon contacting the tissue of the subject by at least one of positron emission tomography (PET) imaging and magnetic resonance imaging (MRI).
These claims are directed to detecting the presence, location and/or distribution of cancer cells expressing EDB-FN, and per claim 5 for determining cancer aggressiveness, by administering a molecular probe that comprises TVRTSAD, this being the 980 SEQ ID NO:1, coupled to a detectable moiety, the probe including an MRI contrast agent, claim 10 explicitly claiming three linking approaches, which encompass linking approaches encompassed by the instant claims.
The 980 specification discloses evaluating aggressive cancers, and includes the same SEQ ID NO:1 TVRSTAD peptide in its molecular probes, but does not teach its methods directed to detecting drug-resis