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 .
Status of Application
Claims 1-38 are under examination.
Claim Objections
Claims 1, 9, 15, and 18 are objected to because of the following informalities: the compounds are blurry and the subscripts are difficult to read. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4, 10, and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: the bounds of “derivatives thereof”. It is unclear if the derivatives thereof are limited by the examples directly after or whether any derivative with any compound, functional group, peptide, etc. known to a person of ordinary skill in the art would fulfill the limitation of “derivative thereof”.
Claim 4, 10, and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 4, 10, and 16, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 23 recites the limitation “the steps” in line 3. There is insufficient antecedent basis for this limitation in the claim. It is unclear to what “the steps” refers to since steps are not in claim 1. The examiner recommends amending “the steps” to “steps”.
Claim 26 recites the limitation “the steps” in line 2. There is insufficient antecedent basis for this limitation in the claim. It is unclear to what “the steps” refers to since steps are not in claim 1. The examiner recommends amending “the steps” to “steps”.
Claim 27 recites the limitation, “the steps” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. It is unclear to what “the steps” refers to since steps are not in claim 1. The examiner recommends amending “the steps” to “steps”.
Claim Interpretation
Claim 4, 10, and 16 recite “such as”. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. See MPEP 2173.05(d). For the purposes of examination, the examiner interprets any prior art containing either linear or macrocyclic polyaminocarboxylates as reading on the radiometal chelator.
Claims 4, 10, and 16 recite “derivatives thereof”. The examiner notes that the specification does not further define the metes and bounds of “derivatives thereof”. Therefore, for the purposes of examination, the examiner interprets any prior art reading on any linear or macrocyclic polyaminocarboxylate as reading on this claim limitation.
Claims 5, 11, 17, and 19 recite “the optionally coordinated radiometal M”. The examiner notes that optional language does not make the feature required in the claim. The examiner notes that “optionally” is maintained in claim 11. While the radiometal M of claim 9 is further limited to the specific metals listed, the metal is still not required in claim 11. Therefore, for the purposes of examining, the examiner interprets “the optionally coordinated radiometal M” as optional in claim 11 and any prior art regardless of whether there is a radiometal or not, reads on this claim.
Claim 21 recites “for use as a diagnostic imaging agent…”. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used for the use in diagnostic imaging agent or as a radiotherapeutic agent or as a theragnostic agent, regardless of whether it was used for any of these uses as reading on this claim limitation.
Claim 22 recites “for use in diagnostic imaging of a cell or population of cells expressing a folate-receptor in vitro or in vivo”. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 23 recites “for use in diagnostic imaging of a cell or population of cells expressing a folate-receptor…” This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation. Additionally, while the claim clearly sets out the boundaries of the steps involved of administering in a diagnostically effective amount and obtaining a diagnostic image of the cell or population of cells expressing a folate-receptor.” This is still claimed as functional language and not a method claim. Therefore, for the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used in these steps as reading on this claim limitation.
Claim 24 recites “for use as a diagnostic imaging agent for therapeutic planning and/or monitoring the effectiveness of an ongoing therapeutic treatment”. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 25 recites “for use in radionuclide therapy of a subject in need thereof”. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 26 recites “for use in radionuclide therapy” and a use of a method. These phrases are functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 27 recites “for use in therapeutic planning and/or monitoring and/or treatment of a tumor” and a method. These phrases are functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 27 recites “administering at least one further compound according to claim 1”. The examiner notes that the compound must be according to claim 1 and that the specification does not define “further compound” as the same or different. The examiner notes that the specification suggests the further compound means it is coordinated to a radiometal (pg 28, lines 5-7) but that it is not clearly defined and it is not required by claim 1. However, for the purposes of examination, the examiner interprets the “further compound” as a radiolabeled compound of claim 1.
Claim 28 recites a compound for use in a method through claim 27. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 29, recites a compound for use in a method through claim 27. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a compound of claim 1 which could be used as such, regardless of whether it was used for this use, as reading on this claim limitation.
Claim 35 recites “theragnostic application”. The examiner notes that the specification defines theragnostic as derived from therapy and diagnostics and refers to the strategy of utilizing the same radioactively labelled drug for diagnostics and for therapy (pg 27, lines 3-5). Therefore, for the purposes of examination, the examiner interprets any prior art containing a radioactively labeled drug which can be used for diagnostics and for therapy as reading on compounds with theragnostic applications.
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.
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) 1-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guzik, P.; et al. Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates-new perspectives for folate receptor-targeted radionuclide therapy, Eur. J. Nucl. Med Mol. Imaging, 2021, 48, 972-983 (as cited in the IDS filed on 08/09/2024) and Siwowska, K.; et al. Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties, Mol. Pharmaceutics, 2017, 14, 523-532 (as cited in the IDS filed on 08/09/2024) and Garrison, J. C.; et al. Evaluation of the Pharmacokinetic Effects of Various Linking Group Using the 111In-DOTA-X-BBN(7-14)NH2 Structural Paradigm in a Prostate Cancer Model, Bioconuagate Chem. 2008, 19, 1803-1812 and Li, M-H; et al. US 2022/0089574 A1.
Guzik, P.; et al. (hereafter referred to as Guzik) is drawn to radioconjugates for folate receptor-targeting (title; abstract). Guzik teaches targeted radionuclide therapy emerged as a promising concept for the palliative treatment of metastasized cancer using radionuclides in combination with a specific tumor-targeting agent (pg 973, col 1 para 1, lines 1-4) and folate receptor (FR) is a membrane-anchored glycoprotein overexpressed in various tumors (pg 973, col 1, para 2, lines 1-3) therapeutic exploitation remains challenging due to low tumor-to-kidney ratio of accumulated folate radioconjugates limiting activity (pg 973, col 1, para 2, lines 5-9) and introducing albumin-binding entity into the structure of radiofolates prolongs blood circulation (pg 973, col 1, para 3, lines 1-6) and better tumor uptake and improved tumor-to-kidney ratios but the kidneys still are the dose-limiting organ (pg 973, col 1, para 3, lines 7-12). Guzik teaches different stereoisomers of the folate receptor and methylation (pg 974, Figure 1) and in vivo studies with biodistribution (pg 974, col 1, para 3-4; pg 974, col 2, para 2) and the accumulation in the tumor, kidneys, and blood (pg 976, Figure 2; pg 977, Table 2).
As to claim 1, Guzik teaches the compound of formula I, where Y is a radiometal chelator, “p” is 3, “n” is 4, and “m” is 4, reproduced below (pg 974, Figure 1).
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Guzik does not teach the hydrophobic AMBA linker adjacent to the albumin-binding moiety.
Siwowska, K.; et al. (hereafter referred to as Siwowska) is drawn to preclinical comparison of albumin-binding radiofolates and areas of modification which can create improvement (title; abstract). Siwowska teaches tumor targeting based on specific tumor-associated markers has been developed for imaging and therapy of many cancer diseases (pg 523, col 1, para 1, lines 1-3) and that folate receptor alpha is one of the tumor targets that has been extensively investigated (pg 523, col 1, para 1, lines 5-7) and has been attached to imaging probes and therapeutics for selective delivery to folate receptor positive tumor cells (pg 523, col 1, para 1, lines 10-11; pg 523, col 2, para 1, lines 1-2) and a large number of folate conjugates have been synthesized for coordination of radionuclides for PET, SPECT, and CT (pg 523, col 2, para 1, lines 7). Siwowska teaches development of folate receptor targeted radionuclide therapy in which folic acid is used for selective delivery of particle emitting radionuclides (pg 5234, col 1, para 2, lines 1-4) and that one of the major concerns of folate radioconjugates is the accumulation in the kidneys (pg 524, col 2, para 1, lines 1-4). Siwowska teaches using serum albumin is effective at enhancing blood circulation time of the radiotherapeutics (pg 524, col 2, para 2, lines 1-8) and that adjusting the chelator for the radionuclide also improved tumor-to-kidney accumulated radioactivity that effectively reduced tumor growth in mice (pg 524, col 1 para 1, lines 1-13). Siwowska teaches that structural features between the albumin-binding entity and folic acid will modulate properties (pg 525, col 1, para 2, lines 1-7). Particularly, there are four regions shown to effect behavior (abstract). Siwowska teaches adjusting the Linker moiety has a strong effect on the properties (pg 524, Figure 1; pg 528, Figure 5; pg 529, Figure 6 and Figure 7; pg 529, Table 2).
Regarding the hydrophobic AMBA linker adjacent to the albumin-binding moiety, Siwowska teaches placing hydrophobic moieties near the albumin-binding moiety (pg 524, Figure 1, structures cm12 and cm13).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Guzik to include hydrophobic linkers as taught by Siwowska because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of adding a hydrophobic moiety near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding a hydrophobic moiety because the prior art of Guzik disclosed a compound known to demonstrate that modifications of the folate can improve tumor-to-kidney ratios (pg 975, Figure 2) and that improving kidney to tumor ratios improves the dose available since the kidney is the dose-limiting organ (pg 973, col 1, para 3, lines 7-12). Additional prior art of Siwowska suggested that adding linkers near the albumin linker has a similar effect of modulating the uptake ratio into tumors vs kidneys (pg 528, Figure 5) and that hydrophobic moieties have the best ratio of tumor-to-kidney (pg 529, Table 2).
The skilled artisan would have been motivated to add hydrophobic moieties to the albumin-binding moiety because it has been shown to improve the ratio of tumor-to-kidney absorbed doses (Siwowska, pg 528, Table 2) and that better ratios enable higher doses for treating cancer. Therefore, it would have been prima facie obvious to combine the teachings of Guzik with Siwowska.
The combined teachings of Guzik and Siwowska do not teach AMBA as the hydrophobic moiety.
The combined teachings of Guzik and Siwowska do not teach AMBA adjacent to the albumin-binding moiety.
Garrison, J. C.; et al. (hereafter referred to as Garrison) is drawn to the development of BB2r-targeted agents for diagnostic imaging, chemotherapy, and radiotherapy (title; abstract). Garrison teaches that bombesin consists of four known receptors subtypes (pg 1803, col 1, lines 1-4) and have been expressed in a variety of human tumors and cell lines (pg 1803, col 1, para 1, lines 4-7). Garrison teaches a wide variety of BB2r-targeted diagnostic imaging, chemotherapy, and radiotherapy agents have been developed (pg 1804, col 1, para 1, lines 1-10) and that a distinctive four component strategy has been used for the development of BB2r-targeted BBN analogues consisting of a targeting vector, a radiometal, a chelation system, and a linking group (pg 1804, col 1, para 2, lines 1-5). Garrison teaches that the targeting vector is varied from peptide sequences to truncated forms (pg 1804, col 1, para 2, lines 5-12) and that radionuclides are useful (pg 1804, col 1, para 2, lines 12-17) and are chosen based on desired application (pg 1804, col 1, para 2, lines 12-24) and chelators similarly can be selected from an assortment (pg 1804, col 1, para 2, lines 27-31). Garrison teaches that a linking group serves several crucial things such as preventing the radiometal-chelation complex from interfering with binding of the targeting vector to the target (pg 1804, col 2, para 3, lines 1-9) that altering the length and hydrophobic nature of the linker can modulate the pharmacokinetics (pg 1804, col 2, para 1, lines 1-12) and that a variety of linkers have been used such as aliphatic hydrocarbons, amino acids, aromatic derivatives, and poly(ethylene glycol) have been used (pg 1804, col 2, para 2, lines 1-10). Garrison teaches 6 linkers including AMBA and AMBA derivatives (pg 1804, Figure 1). Garrison teaches comparable internalization and efflux effect from the linking group (pg 1807, Figures 2 and 3). Garrison teaches that each linker can delivery to the cancer and that AMBA derivative had a pancreatic retention nearly twice that of other linker types in the radioconjugates (pg 1809, col 2, para 2, lines 6-13) and AMBA radioconjugates had the highest accumulation in the tumors at 1 h time point (pg 1810, col 2, para 1, lines 1-5).
Regarding AMBA as the hydrophobic moiety, Garrison teaches AMBA (pg 1804, Figure 1, structure Gly-AM2BA).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the hydrophobic moieties of the combined teaching of Guzik and Siwowska with the AMBA moiety (Gly-AM2BA) as taught by Garrison because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting Gly-AM2BA with the hydrophobic moieties of Guzik and Siwowska near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the hydrophobic moiety near the albumin-binding moiety with Gly-AM2BA because the prior art of Siwowska disclosed linkers could be exchanged near the albumin (pg 524, Figure 1, structures A-C) and that hydrophobic moieties improves tumor-to-kidney ratio (pg 528, Figure 5B and Figure 5C). Additional prior art of Garrison suggested additional hydrophobic moieties, such as Gly-AM2BA, which is equivalent to the instant claim, AMBA, to have superior tumor retention compared to hydrophilic moieties (pg 1810, col 1, para 2, line 13; pg 1810, col 2, para 1, lines 1-7) and that radioconjugates containing aromatic groups clearly demonstrate significantly higher tumor retention compared to hydrophilic or hydrocarbon linking moieties (pg 1810, col 2, para 1, lines 5-13). The overlap between the linkers involves known chemistry.
The skilled artisan would have been motivated to substitute the hydrocarbon moieties of Guzik and Siwowska because the aromatic containing moieties of AMBA derivatives improves tumor retention more, enabling potential for superior tumor-to-kidney ratios for the albumin-binding folate receptor radiotherapeutic of Guzik and Siwowska. Therefore, it would have been prima facie obvious to combine the teachings of Guzik and Siwowska with Garrison.
The combined teachings of Guzik, Siwowska, and Garrison do not explicitly teach AMBA adjacent to the albumin-binding moiety.
Li, M-H; et al. (hereafter referred to as Li) is drawn to molecular structures and methods that physically bind to specific biological molecules or receptors (title; abstract). Li teaches compounds for improving accumulation of existing drugs in tumors (pg 1, para [0001], lines 1-6). Li teaches cell proliferation, angiogenesis, tumor invasion, and migration are important aspects that interact with fibroblasts, endothelial cells and immune cells in the tumor microenvironment (pg 1, para [0002], lines 4-9) and targeting a chemokine ligand can influence development of many types of tumors (pg 1, para [0003], lines 1-8). Li teaches structural difference of iodine molecules in tyrosine and radionuclides to serve as a potential radionuclide inhibitor to kill cells (pg 2, para [0018], lines 1-5) and that the radiopharmaceutical is made of a CXCR4 targeting component, albumin-binding structure, and a radioactive chelator structure (pg 3, para [0018], lines 1-11). Li teaches a variety of structures with these components (pg 8, para [0038], structure D-1; pg 9, para [0038], D-2 and D-3; pg 10, para [0039], D-4 and D-5; pg 11, para [0040], D-6).
Regarding the placement of the AMBA adjacent to the albumin-binding moiety, Li teaches an aromatic moiety next to the albumin-binding moiety (pg 11, para [0038], structure D-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the combined teachings of Guzik, Siwowska, and Garrison to include the AMBA aromatic moiety next to the albumin-binding moiety as taught by Li because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the hydrophobic AMBA next to the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the hydrophobic aromatic AMBA next to the albumin-binding moiety because the prior art of Guzik, Siwowska, and Garrison disclosed hydrophobic moieties such as AMBA improved tumor retention when placed near the albumin moiety. Additional prior art of Li suggested placing the hydrophobic moiety adjacent to the albumin-binding moiety to have similar tumor retention effect because of the overlap of structures between them involves known chemistry of aromatic groups and attached amides.
The skilled artisan would have been motivated to move the hydrophobic aromatic group closer to the albumin-binding moiety because the prior art had demonstrated that tumor retention increased when hydrophobic moieties were placed near the albumin-binding moiety and that placing the aromatic hydrophobic moieties adjacent to albumin-binding moieties still worked. Therefore, it would have been prima facie obvious to combine the teachings of Guzik, Siwowska, and Garrison with Li.
As to claim 2, Guzik teaches “p” is 3 (pg 974, Figure 1).
As to claim 3, Guzik teaches “p” is 3 (pg 974, Figure 1). The difference between the claimed value of 4 and the prior art value of 3 is a -CH2-. In such cases, compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See MPEP 2144.09(II) and prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. See MPEP 2144.09(III).
As to claim 4, Guzik teaches the radiometal chelator is the macrocyclic polyaminocarboxylate DOTA (pg 974, Figure 1).
As to claim 5, Guzik teaches the radiometal is 177Lu (pg 979, Figure 3).
As to claim 6, Guzik teaches “n” is 4 (pg 974, Figure 1).
As to claim 7, Guzik teaches “m” is 4 (pg 974, Figure 1).
As to claim 8, Guzik teaches “n” and “m” are each 4 (pg 974, Figure 1).
As to claim 9, Guzik teaches the compound of formula IIIb, where Y is a radiometal chelator, “p” is 3, “n” is 4, and “m” is 4, reproduced below (pg 974, Figure 1). The prior art value for “Y” is the DOTA chelator (pg 974, Figure 1). The prior art value of “n” is 4 and lies within the claimed range of 1-8. The prior art value of “m” is 4 and lies within the claimed range of 1-8. The claimed range overlaps the prior art value for both “n” and “m”. In the case where the claimed ranges overlap ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
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Guzik does not teach the hydrophobic AMBA linker next to the albumin-binding moiety.
Regarding the hydrophobic AMBA linker adjacent to the albumin-binding moiety, Siwowska teaches placing hydrophobic moieties near the albumin-binding moiety (pg 524, Figure 1, structures cm12 and cm13).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Guzik to include hydrophobic linkers as taught by Siwowska because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of adding a hydrophobic moiety near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding a hydrophobic moiety because the prior art of Guzik disclosed a compound known to demonstrate that modifications of the folate can improve tumor-to-kidney ratios (pg 975, Figure 2) and that improving kidney to tumor ratios improves the dose available since the kidney is the dose-limiting organ (pg 973, col 1, para 3, lines 7-12). Additional prior art of Siwowska suggested that adding linkers near the albumin linker has a similar effect of modulating the uptake ratio into tumors vs kidneys (pg 528, Figure 5) and that hydrophobic moieties have the best ratio of tumor-to-kidney (pg 529, Table 2).
The skilled artisan would have been motivated to add hydrophobic moieties to the albumin-binding moiety because it has been shown to improve the ratio of tumor-to-kidney absorbed doses (Siwowska, pg 528, Table 2) and that better ratios enable higher doses for treating cancer. Therefore, it would have been prima facie obvious to combine the teachings of Guzik with Siwowska.
The combined teachings of Guzik and Siwowska do not teach AMBA as the hydrophobic moiety.
The combined teachings of Guzik and Siwowska do not teach AMBA adjacent to the albumin-binding moiety.
Regarding AMBA as the hydrophobic moiety, Garrison teaches AMBA (pg 1804, Figure 1, structure Gly-AM2BA).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the hydrophobic moieties of the combined teaching of Guzik and Siwowska with the AMBA moiety (Gly-AM2BA) as taught by Garrison because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting Gly-AM2BA with the hydrophobic moieties of Guzik and Siwowska near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the hydrophobic moiety near the albumin-binding moiety with Gly-AM2BA because the prior art of Siwowska disclosed linkers could be exchanged near the albumin (pg 524, Figure 1, structures A-C) and that hydrophobic moieties improves tumor-to-kidney ratio (pg 528, Figure 5B and Figure 5C). Additional prior art of Garrison suggested additional hydrophobic moieties, such as Gly-AM2BA, which is equivalent to the instant claim, AMBA, to have superior tumor retention compared to hydrophilic moieties (pg 1810, col 1, para 2, line 13; pg 1810, col 2, para 1, lines 1-7) and that radioconjugates containing aromatic groups clearly demonstrate significantly higher tumor retention compared to hydrophilic or hydrocarbon linking moieties (pg 1810, col 2, para 1, lines 5-13). The overlap between the linkers involves known chemistry.
The skilled artisan would have been motivated to substitute the hydrocarbon moieties of Guzik and Siwowska because the aromatic containing moieties of AMBA derivatives improves tumor retention more enabling potential for superior tumor-to-kidney ratios for the albumin-binding folate receptor radiotherapeutic of Guzik and Siwowska. Therefore, it would have been prima facie obvious to combine the teachings of Guzik and Siwowska with Garrison.
The combined teachings of Guzik, Siwowska, and Garrison do not explicitly teach AMBA adjacent to the albumin-binding moiety.
Regarding the placement of the AMBA adjacent to the albumin-binding moiety, Li teaches an aromatic moiety next to the albumin-binding moiety (pg 11, para [0038], structure D-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the combined teachings of Guzik, Siwowska, and Garrison to include the aromatic moiety next to the albumin-binding moiety as taught by Li because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the hydrophobic AMBA next to the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the hydrophobic aromatic AMBA next to the albumin-binding moiety because the prior art of Guzik, Siwowska, and Garrison disclosed hydrophobic moieties such as AMBA improved tumor retention when placed near the albumin moiety. Additional prior art of Li suggested placing the hydrophobic moiety adjacent to the albumin-binding moiety to have similar tumor retention effect because of the overlap of structures between them involves known chemistry of aromatic groups and attached amides.
The skilled artisan would have been motivated to move the hydrophobic aromatic group closer to the albumin-binding moiety because the prior art had demonstrated that tumor retention increased when hydrophobic moieties were placed near the albumin-binding moiety and that placing the aromatic hydrophobic moieties adjacent to albumin-binding moieties still worked. Therefore, it would have been prima facie obvious to combine the teachings of Guzik, Siwowska, and Garrison with Li.
As to claim 10, Guzik teaches the radiometal chelator is DOTA ((pg 974, Figure 1).
As to claim 11, Guzik teaches the radiometal is 177Lu (pg 979, Figure 3).
As to claim 12, Guzik teaches “n” is 4 (pg 974, Figure 1).
As to claim 13, Guzik teaches “m” is 4 (pg 974, Figure 1).
As to claim 14, Guzik teaches “n” and “m” are each 4 (pg 974, Figure 1).
As to claim 15, Guzik teaches the compound of formula Vb, where Y is a radiometal chelator, reproduced below (pg 974, Figure 1). The prior art value for “Y” is the DOTA chelator (pg 974, Figure 1).
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Guzik does not teach the hydrophobic AMBA linker next to the albumin-binding moiety.
Regarding the hydrophobic AMBA linker adjacent to the albumin-binding moiety, Siwowska teaches placing hydrophobic moieties near the albumin-binding moiety (pg 524, Figure 1, structures cm12 and cm13).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Guzik to include hydrophobic linkers as taught by Siwowska because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of adding a hydrophobic moiety near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding a hydrophobic moiety because the prior art of Guzik disclosed a compound known to demonstrate that modifications of the folate can improve tumor-to-kidney ratios (pg 975, Figure 2) and that improving kidney to tumor ratios improves the dose available since the kidney is the dose-limiting organ (pg 973, col 1, para 3, lines 7-12). Additional prior art of Siwowska suggested that adding linkers near the albumin linker has a similar effect of modulating the uptake ratio into tumors vs kidneys (pg 528, Figure 5) and that hydrophobic moieties have the best ratio of tumor-to-kidney (pg 529, Table 2).
The skilled artisan would have been motivated to add hydrophobic moieties to the albumin-binding moiety because it has been shown to improve the ratio of tumor-to-kidney absorbed doses (Siwowska, pg 528, Table 2) and that better ratios enable higher doses for treating cancer. Therefore, it would have been prima facie obvious to combine the teachings of Guzik with Siwowska.
The combined teachings of Guzik and Siwowska do not teach AMBA as the hydrophobic moiety.
The combined teachings of Guzik and Siwowska do not teach AMBA adjacent to the albumin-binding moiety.
Regarding AMBA as the hydrophobic moiety, Garrison teaches AMBA (pg 1804, Figure 1, structure Gly-AM2BA).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the hydrophobic moieties of the combined teaching of Guzik and Siwowska with the AMBA moiety (Gly-AM2BA) as taught by Garrison because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting Gly-AM2BA with the hydrophobic moieties of Guzik and Siwowska near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the hydrophobic moiety near the albumin-binding moiety with Gly-AM2BA because the prior art of Siwowska disclosed linkers could be exchanged near the albumin (pg 524, Figure 1, structures A-C) and that hydrophobic moieties improves tumor-to-kidney ratio (pg 528, Figure 5B and Figure 5C). Additional prior art of Garrison suggested additional hydrophobic moieties, such as Gly-AM2BA, which is equivalent to the instant claim, AMBA, to have superior tumor retention compared to hydrophilic moieties (pg 1810, col 1, para 2, line 13; pg 1810, col 2, para 1, lines 1-7) and that radioconjugates containing aromatic groups clearly demonstrate significantly higher tumor retention compared to hydrophilic or hydrocarbon linking moieties (pg 1810, col 2, para 1, lines 5-13). The overlap between the linkers involves known chemistry.
The skilled artisan would have been motivated to substitute the hydrocarbon moieties of Guzik and Siwowska because the aromatic containing moieties of AMBA derivatives improves tumor retention more enabling potential for superior tumor-to-kidney ratios for the albumin-binding folate receptor radiotherapeutic of Guzik and Siwowska. Therefore, it would have been prima facie obvious to combine the teachings of Guzik and Siwowska with Garrison.
The combined teachings of Guzik, Siwowska, and Garrison do not explicitly teach AMBA adjacent to the albumin-binding moiety.
Regarding the placement of the AMBA adjacent to the albumin-binding moiety, Li teaches an aromatic moiety next to the albumin-binding moiety (pg 11, para [0038], structure D-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the combined teachings of Guzik, Siwowska, and Garrison to include the aromatic moiety next to the albumin-binding moiety as taught by Li because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the hydrophobic AMBA next to the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the hydrophobic aromatic AMBA next to the albumin-binding moiety because the prior art of Guzik, Siwowska, and Garrison disclosed hydrophobic moieties such as AMBA improved tumor retention when placed near the albumin moiety. Additional prior art of Li suggested placing the hydrophobic moiety adjacent to the albumin-binding moiety to have similar tumor retention effect because of the overlap of structures between them involves known chemistry of aromatic groups and attached amides.
The skilled artisan would have been motivated to move the hydrophobic aromatic group closer to the albumin-binding moiety because the prior art had demonstrated that tumor retention increased when hydrophobic moieties were placed near the albumin-binding moiety and that placing the aromatic hydrophobic moieties adjacent to albumin-binding moieties still worked. Therefore, it would have been prima facie obvious to combine the teachings of Guzik, Siwowska, and Garrison with Li.
As to claim 16, Guzik teaches the radiometal chelator is DOTA (pg 974, Figure 1).
As to claim 17, Guzik teaches the radiometal is 177Lu (pg 979, Figure 3).
As to claim 18, Guzik teaches the compound of formula VI, reproduced below (pg 974, Figure 1).
PNG
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326
581
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Greyscale
Guzik does not teach the hydrophobic AMBA linker next to the albumin-binding moiety.
Regarding the hydrophobic AMBA linker adjacent to the albumin-binding moiety, Siwowska teaches placing hydrophobic moieties near the albumin-binding moiety (pg 524, Figure 1, structures cm12 and cm13).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Guzik to include hydrophobic linkers as taught by Siwowska because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of adding a hydrophobic moiety near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding a hydrophobic moiety because the prior art of Guzik disclosed a compound known to demonstrate that modifications of the folate can improve tumor-to-kidney ratios (pg 975, Figure 2) and that improving kidney to tumor ratios improves the dose available since the kidney is the dose-limiting organ (pg 973, col 1, para 3, lines 7-12). Additional prior art of Siwowska suggested that adding linkers near the albumin linker has a similar effect of modulating the uptake ratio into tumors vs kidneys (pg 528, Figure 5) and that hydrophobic moieties have the best ratio of tumor-to-kidney (pg 529, Table 2).
The skilled artisan would have been motivated to add hydrophobic moieties to the albumin-binding moiety because it has been shown to improve the ratio of tumor-to-kidney absorbed doses (Siwowska, pg 528, Table 2) and that better ratios enable higher doses for treating cancer. Therefore, it would have been prima facie obvious to combine the teachings of Guzik with Siwowska.
The combined teachings of Guzik and Siwowska do not teach AMBA as the hydrophobic moiety.
The combined teachings of Guzik and Siwowska do not teach AMBA adjacent to the albumin-binding moiety.
Regarding AMBA as the hydrophobic moiety, Garrison teaches AMBA (pg 1804, Figure 1, structure Gly-AM2BA).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the hydrophobic moieties of the combined teaching of Guzik and Siwowska with the AMBA moiety (Gly-AM2BA) as taught by Garrison because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting Gly-AM2BA with the hydrophobic moieties of Guzik and Siwowska near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the hydrophobic moiety near the albumin-binding moiety with Gly-AM2BA because the prior art of Siwowska disclosed linkers could be exchanged near the albumin (pg 524, Figure 1, structures A-C) and that hydrophobic moieties improves tumor-to-kidney ratio (pg 528, Figure 5B and Figure 5C). Additional prior art of Garrison suggested additional hydrophobic moieties, such as Gly-AM2BA, which is equivalent to the instant claim, AMBA, to have superior tumor retention compared to hydrophilic moieties (pg 1810, col 1, para 2, line 13; pg 1810, col 2, para 1, lines 1-7) and that radioconjugates containing aromatic groups clearly demonstrate significantly higher tumor retention compared to hydrophilic or hydrocarbon linking moieties (pg 1810, col 2, para 1, lines 5-13). The overlap between the linkers involves known chemistry.
The skilled artisan would have been motivated to substitute the hydrocarbon moieties of Guzik and Siwowska because the aromatic containing moieties of AMBA derivatives improves tumor retention more enabling potential for superior tumor-to-kidney ratios for the albumin-binding folate receptor radiotherapeutic of Guzik and Siwowska. Therefore, it would have been prima facie obvious to combine the teachings of Guzik and Siwowska with Garrison.
The combined teachings of Guzik, Siwowska, and Garrison do not explicitly teach AMBA adjacent to the albumin-binding moiety.
Regarding the placement of the AMBA adjacent to the albumin-binding moiety, Li teaches an aromatic moiety next to the albumin-binding moiety (pg 11, para [0038], structure D-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the combined teachings of Guzik, Siwowska, and Garrison to include the aromatic moiety next to the albumin-binding moiety as taught by Li because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the hydrophobic AMBA next to the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the hydrophobic aromatic AMBA next to the albumin-binding moiety because the prior art of Guzik, Siwowska, and Garrison disclosed hydrophobic moieties such as AMBA improved tumor retention when placed near the albumin moiety. Additional prior art of Li suggested placing the hydrophobic moiety adjacent to the albumin-binding moiety to have similar tumor retention effect because of the overlap of structures between them involves known chemistry of aromatic groups and attached amides.
The skilled artisan would have been motivated to move the hydrophobic aromatic group closer to the albumin-binding moiety because the prior art had demonstrated that tumor retention increased when hydrophobic moieties were placed near the albumin-binding moiety and that placing the aromatic hydrophobic moieties adjacent to albumin-binding moieties still worked. Therefore, it would have been prima facie obvious to combine the teachings of Guzik, Siwowska, and Garrison with Li.
As to claim 19, Guzik teaches the radiometal is 177Lu (pg 979, Figure 3).
As to claim 20, Guzik teaches pharmaceutical composition (pg 973, col 2, para 2, lines 12-16; pg 974, col 2, para 1, lines 1-3).
As to claim 21, Guzik teaches use of compound as a diagnostic imaging agent (abstract, lines 1-8, pg 975, col 1, para 2, lines 1-11; pg 978, col 1, para 4, lines 1-4; pg 978, col 2, para 1, lines 1-13).
As to claim 22, Guzik teaches use in imaging folate-receptor in vivo (abstract, lines 5-8; pg 977, col 2, para 1, lines 1-11, pg 979, Figure 3).
As to claim 23, Guzik teaches the use of the compound in imaging of a population of cells expressing a folate-receptor (abstract, lines 5-8; pg 975, col 1, para 2, lines 1-11; pg 978, col 1, para 4, lines 1-3; pg 978, col 2, para 1, lines 1-13) with steps of administering the compound in a diagnostically effective amount (pg 974, col 2, para 2, lines 1-12; pg 975, col 1, para 2, lines 1-11) obtaining a diagnostic image of the population of cells expressing a folate-receptor (pg 979, Figure 3).
Claim(s) 24-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guzik, Siwowska, Garrison, and Li as applied to claims 1-23 above, and further in view of Schibli, R.; et al., US 2014/0234216 A1. The teachings of Guzik, Siwowska, Garrison, and Li as applied in the previous rejection are incorporated in this rejection.
As to claim 24, Guzik teaches the use of the compound as a diagnostic imaging agent (pg 974, col 1, para 4, lines 1-8).
The combined teachings of Guzik, Siwowska, Garrison, and Li do not teach monitoring the effectiveness of an ongoing therapeutic treatment.
Schibli, R.; et al. (hereafter referred to as Schibli-2014) is drawn to albumin-binding folate conjugates with radionuclide-based therapeutic or diagnostic moieties and pharmaceutical compositions (title; abstract). Schibli-2014 teaches trifunctional folate conjugates comprising folate, albumin binder, and a radionuclide-based diagnostic or therapeutic moiety as well as pharmaceutical compositions thereof (pg 1, para [0001], lines 1-7). Schibli-2014 teaches cell-specific targeting for delivery of diagnostic or therapeutic agents is a widely researched field and has led to the development of non-invasive diagnostic and/or therapeutic medical applications (pg 1, para [0002], lines 1-6) and the folate receptor (FR) is a high-affinity membrane-associated protein with limited expression on healthy cells (pg 1, para [0003], lines 1-3) and is easily overexpressed in epithelial tumor cells and activated macrophages (pg 1, para [0003], lines 1-13) and that trifunctional folate conjugates have several advantages such as stable complex formation, improved biodistribution, and increased target tissue uptake (pg 1, para [0006], lines 1-9). Schibli teaches a variety of trifunctional folate conjugates (pg 6, Formulae IVa, IVb, and IVc; pg 13, Formulae VIIa, VIIb; pg 14, Formulae VIIc, VIId, and VIIe) and most preferred folate conjugates with a DOTA chelator (pg 22, para [0091], structure; pg 24, para [0091], structures).
Regarding monitoring the effectiveness of an ongoing therapeutic treatment, Schibli teaches monitoring the effectiveness of an ongoing therapeutic treatment (pg 1, para [0002], lines 1-15; claim 32).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Guzik, Siwowska, Garrison, and Li to include the uses as taught by Schibli because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a compound for use as a diagnostic imaging agent for therapeutic planning and/or monitoring the effectiveness of an ongoing therapeutic treatment.
A person of ordinary skill in the art would have had a reasonable expectation of success in the use of the compound because the prior art of Guzik, Siwowska, Garrison, and Li disclosed the compound known to have properties giving it the ability to enable imaging of tumors and kidneys and other diagnostic materials (pg 976, Figure 2; pg 979, Figure 3). Additional prior art of Schibli also suggested trifunctional compounds to have similar folate targeting moiety, a radiometal chelator, and a albumin-binding moiety (Schibli, pg 41, structure 32) because of the overlap of structure between them involves known chemistry. And that this molecule could be used in a method of diagnostic imaging or monitoring a subject (pg 1, para [0002], lines 1-15, claim 32).
The skilled artisan would have been motivated to use the compound for diagnostic imaging for therapeutic planning and/or monitoring the effectiveness of an ongoing therapeutic treatment because imaging tumors can give the medical staff important information as to kidney uptake and tumor uptake and enable a decision to increase, decrease, maintain, or cease the dosing regimen. Therefore, it would have been prima facie obvious to combine the combined teachings of Guzik, Siwowska, Garrison, and Li with teachings of Schibli.
As to claim 25, Schibli teaches use in radionuclide therapy of a subject in need thereof (pg 26, para [0101], lines 1-3).
As to claim 26, Schibli teaches use in a radionuclide therapy comprising the steps of administering to the subject in need thereof the compound in a therapeutically effective amount, localizing the compound in the desired tissue, and subjecting the tissue to radiation to achieve the treatment (pg 26, para [0103], lines 1-9).
As to claim 27, Schibli teaches the use of the compound for monitoring and treatment of a tumor cells (pg 3, para [0032], lines 1-5; pg 26, para [0101], lines 1-3) comprising administering the compound in a diagnostically effective amount to obtain a diagnostic image (pg 26, para [0102], lines 1-8) and administering a compound in therapeutically effective amount for tumor treatment (pg 26, para [0103], lines 1-9).
As to claim 28, Schibli teaches the compound is a diagnostic compound and at least one further compound is a radiotherapeutic compound (pg 26, para [0101], lines 1-3; pg 26, para [0102], lines 1-8; pg 26, para [0103], lines 1-9).
As to claim 29, Schibli teaches the diagnostic image obtained from the at least one compound administered in diagnostically effect amounts in step (i) (pg 26, para [0103], liens 1-9; pg 26, para [0104], col 2, lines 2-6) and is used to determine the therapeutically effective amount of the at least one further compound administered in step (ii) for treatment (pg 26, para [0104], col 2, lines 6-16). The prior art of Schibli teaches that the therapeutically effective amount is whatever amount is necessary for generating a diagnostic image (pg 26, para [0104], col 2, lines 6-16).
As to claim 30, Schibli teaches a method for diagnostic imaging of a cell or population of cells expressing a folate-receptor (pg 26, para [0100], lines 1-3) said method comprising administering at least one compound according to claim 1 in a diagnostically effective amount (pg 26, para [0100], lines 3-7) and obtaining a diagnostic image of said cell or population of cells (pg 26, para [0100], lines 5-7).
As to claim 31, Schibli teaches the method wherein the diagnostic imaging is performed on cells or populations of cells expressing a folate-receptor (pg 26, para [0100], lines 1-7]) in vivo (pg 26, par [0099], lines 1-7) and in vitro (pg 26, para [0109], lines 1-10).
As to claim 32, Schibli teaches a method of for in vitro detection of a cell expressing the folate receptorin a tissue sample (pg 26, para [0109], lines 1-6) in which includes contacting said tissue sample with a compound (pg 26, para [0109], lines 6-8) in a diagnostically effective amount and for sufficient time and conditions to allow binding to occur and detecting such binding by imaging techniques (pg 26, para [0109], lines 8-10) such as PET (pg 26, para [0104], lines 1-8).
As to claim 33, Schibli teaches a method for diagnostic imaging or monitoring a subject comprising steps of (i) administering at least one compound in a diagnostically effective amount (claim 32) and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound (claim 32).
As to claim 34, Schibli teaches a method for therapeutic planning of a treatment in a subject comprising the steps of (i) administering to a subject in need thereof at least one compound according to claim 1 in a diagnostically effective amount to obtain a diagnostic image (pg 26, para [0102], lines 1-8; pg 26, para [0103], lines 1-9; pg 26, para [0104], col 2, lines 2-6) and (ii) determining the therapeutically effective amount of at least one further compound to be administered for treatment (pg 26, para [0102], lines 1-8; pg 26, para [0103], lines 1-9; pg 26, para [0104], col 2, lines 2-16).
As to claim 35, Schibli teaches a method for theragnostic application comprising administering to a subject in need thereof at least one compound in a diagnostically effective amount (pg 26, para [0100], lines 1-6; pg 26, para [0101], lines 1-3; pg 26, para [0102], lines 1-8; pg 26, para [0103], lines 1-9), and administering at least one further compound in a therapeutically effective amount (pg 26, para [0103], lines 1-9), and subjecting the tissue to irradiation to achieve the desired therapeutic effect (pg 26, para [0102], liens 1-8).
As to claim 36, Schibli teaches the method wherein at least one compound of step (i) is a diagnostic imaging compound and at least one further compound of step (ii) is a radiotherapeutic compound (pg 26, para [0102], lines 1-8; pg 26, para [0103], lines 1-9).
As to claim 37, Schibli teaches the method wherein the diagnostic image obtained in step (ii) is used to determine the therapeutically effective amount of the at least one further compound administer in step (iii) for treatment (pg 26, para [0102], lines 1-8; pg 26, para [0103], lines 1-9; pg 26, para [0104], col 2, lines 2-16).
As to claim 38, Schibli teaches the method can be used in combination with any other methods of cancer diagnosis or therapy (pg 27, para [0116], lines 1-8).
Nonstatutory 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 1-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 9,295,739 in view of Guzik, Siwowska, Garrison, Li, and Schibli.
The instant claims are drawn to a trifunctional compound with a folate group, an albumin-binding group, and a radiometal chelating group where AMBA is placed adjacent to the albumin-binding group, where methyl is placed on N5 of the folate group, and where the chelator can have a radiometal. And, methods of using the compound as a diagnostic imaging, radiotherapeutic or theragnostic agent in diagnostic imaging of cells expressing folate-receptor in vitro or in vivo by administering a diagnostically effective amount and obtaining a diagnostic image and monitoring the effectiveness of the treatment; and by administering the therapeutically effective amount of at least one further compound; and, methods where the compounds can be used by localizing the tissue to be treated and subjecting the tissue to radiation
The conflicting claims of U.S. Patent No. 9,295,739 (hereafter referred to as '739) are drawn to a trifunctional compound with a folate group, an albumin-binding group, and a radiometal chelating group and where methyl can be on N5 of the folate group, and where the chelator can have a radiometal. And, methods of using the compound as a diagnostic imaging agent of cells expressing a folate-receptor in vitro or in vivo by administering a diagnostically effective amount and obtaining a diagnostic image and monitoring the effectiveness of the treatment
The conflicting claims of '739 do not teach AMBA adjacent to the albumin-binding group.
The conflicting claims of '739 do not teach the carbonyl on the folate group.
The conflicting claims of '739 do not teach administration of a therapeutically effective amount of at least one further compound.
The conflicting claims of '739 do not teach localizing the tissue to be treated and subjecting the tissue to radiation.
Regarding AMBA adjacent to the albumin-binding group, Siwowska teaches placing hydrophobic moieties near the albumin-binding moiety (pg 524, Figure 1, structures cm12 and cm13).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the conflicting claims of ‘739 to include hydrophobic linkers as taught by Siwowska because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of adding a hydrophobic moiety near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding a hydrophobic moiety because the conflicting claims of ‘739 disclosed a compound known to demonstrate that modifications of the compound are known in the art. Additional prior art of Siwowska suggested that adding linkers near the albumin linker has an effect of modulating the uptake ratio into tumors vs kidneys (pg 528, Figure 5) and that hydrophobic moieties have the best ratio of tumor-to-kidney (pg 529, Table 2).
The skilled artisan would have been motivated to add hydrophobic moieties to the albumin-binding moiety because it has been shown to improve the ratio of tumor-to-kidney absorbed doses (Siwowska, pg 528, Table 2) and that better ratios enable higher doses for treating cancer. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘739 with Siwowska.
The combined teachings of the conflicting claims of ‘739 and Siwowska do not teach AMBA as the hydrophobic moiety.
The combined teachings of the conflicting claims of ‘739 and Siwowska do not teach AMBA adjacent to the albumin-binding moiety.
Regarding AMBA as the hydrophobic moiety, Garrison teaches AMBA (pg 1804, Figure 1, structure Gly-AM2BA).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the hydrophobic moieties of the combined teaching of the conflicting claims of ‘739 and Siwowska with the AMBA moiety (Gly-AM2BA) as taught by Garrison because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting Gly-AM2BA with the hydrophobic moieties of the conflicting claims of ‘739 and Siwowska near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the hydrophobic moiety near the albumin-binding moiety with Gly-AM2BA because the prior art of Siwowska disclosed linkers could be exchanged near the albumin (pg 524, Figure 1, structures A-C) and that hydrophobic moieties improves tumor-to-kidney ratio (pg 528, Figure 5B and Figure 5C). Additional prior art of Garrison suggested additional hydrophobic moieties, such as Gly-AM2BA, which is equivalent to the instant claim, AMBA, to have superior tumor retention compared to hydrophilic moieties (pg 1810, col 1, para 2, line 13; pg 1810, col 2, para 1, lines 1-7) and that radioconjugates containing aromatic groups clearly demonstrate significantly higher tumor retention compared to hydrophilic or hydrocarbon linking moieties (pg 1810, col 2, para 1, lines 5-13). The overlap between the linkers involves known chemistry.
The skilled artisan would have been motivated to substitute the hydrocarbon moieties of the conflicting claims of ‘739 and Siwowska because the aromatic containing moieties of AMBA derivatives improves tumor retention more enabling potential for superior tumor-to-kidney ratios for the albumin-binding folate receptor radiotherapeutic of Guzik and Siwowska. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘739 and Siwowska with Garrison.
The combined teachings of the conflicting claims of ‘739, Siwowska, and Garrison do not explicitly teach AMBA adjacent to the albumin-binding moiety.
Regarding the placement of the AMBA adjacent to the albumin-binding moiety, Li teaches an aromatic moiety next to the albumin-binding moiety (pg 11, para [0038], structure D-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the combined teachings of the conflicting claims of ‘739, Siwowska, and Garrison to include the aromatic moiety next to the albumin-binding moiety as taught by Li because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the hydrophobic AMBA next to the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the hydrophobic aromatic AMBA next to the albumin-binding moiety because the prior art of the conflicting claims of ‘739, Siwowska, and Garrison disclosed hydrophobic moieties such as AMBA improved tumor retention when placed near the albumin moiety. Additional prior art of Li suggested placing the hydrophobic moiety adjacent to the albumin-binding moiety to have similar tumor retention effect because of the overlap of structures between them involves known chemistry of aromatic groups and attached amides.
The skilled artisan would have been motivated to move the hydrophobic aromatic group closer to the albumin-binding moiety because the prior art had demonstrated that tumor retention increased when hydrophobic moieties were placed near the albumin-binding moiety and that placing the aromatic hydrophobic moieties adjacent to albumin-binding moieties still worked. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘739, Siwowska, and Garrison with Li.
Regarding carbonyl on the folate group, Guzik teaches the compound with a carbonyl on the folate group (pg 974, Figure 1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the conflicting claims of ‘739 to include the carbonyl as taught by Guzik because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a carbonyl on the folate group.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the folate group to have a carbonyl group because the conflicting claims of ‘739 disclosed folates known to have a variety of substituents at the same location. Additional prior art of Guzik suggested a carbonyl group at that location would have similar properties of targeting folate receptor moieties because of the overlap of the folate structure.
The skilled artisan would have been motivated to modify the variety of substituents as taught by the conflicting claims of ‘739 with the carbonyl as taught by Guzik because the carbonyl group has been shown to be successful for folate receptor targeting.
Regarding a therapeutically effective amount of at least one further compound, Schibli teaches administering a therapeutically effective amount of at least one further compound (pg 26, para [0103], lines 1-9)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of the conflicting claims of ‘739 to include the administration of a therapeutically effective amount of the compound as taught by Schibli because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method with the administration of a therapeutically effective amount of at least one further compound.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of the conflicting claims of ‘739 with the administration of a therapeutically effective amount of at least one further compound because the conflicting claims of ‘739 disclosed a method known to enable administration of a compound which can be a therapeutic when coordinated to a radiometal. Additional prior art of Schibli suggested that the same compounds can be administered in a therapeutically effective amount of at least one further compound along with diagnostic method because of the specification of Schibli belongs to the claims of the conflicting claims of ‘739.
The skilled artisan would have been motivated to modify the method of the conflicting claims of ‘739 with the administration of a therapeutically effective amount of at least one further compound because this would provide a two-in-one therapy and diagnostic method which could save time and reduce the number of treatments by the patient.
Regarding localizing the tissue to be treated and subjecting the tissue to radiation, Schibli teaches localizing the tissue to be treated and subjecting the tissue to radiation (pg 26, para [0103], lines 1-9).
Claims 1-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-12, 18-20, 22, and 24-28 of copending Application No. 18/834,636 in view of Siwowska, Garrison, and Li.
The instant claims are drawn to a trifunctional compound with a folate group, an albumin-binding group, and a radiometal chelating group where AMBA is placed adjacent to the albumin-binding group, where methyl is place on N5 of the folate group, and where the chelator can have a radiometal. And, methods of using the compound as a diagnostic imaging, radiotherapeutic or theragnostic agent in diagnostic imaging of cells expressing folate-receptor in vitro or in vivo by administering a diagnostically effective amount and obtaining a diagnostic image and monitoring the effectiveness of the treatment; and by administering the therapeutically effective amount of at least one further compound; and, methods where the compounds can be used by localizing the tissue to be treated and subjecting the tissue to radiation
The conflicting claims of U.S. Application No. 18/834,636 (hereafter referred to as '636) are drawn to a trifunctional compound with a folate group, an albumin-binding group, and a radiometal chelating group, and where methyl is placed on N5 of the folate group, and where the chelator can have a radiometal. And, conflicting claims of ‘636 are drawn to methods of using the compound as a diagnostic imaging agent of cells expressing a folate-receptor in vitro or in vivo by administering a diagnostically effective amount and obtaining a diagnostic image and monitoring the effectiveness of the treatment and by administration of a therapeutically effective amount of at least one further compound. And, conflicting claims of ‘636 are drawn to methods where the compounds can be used by localizing the tissue to be treated and subjecting the tissue to radiation.
The conflicting claims of ‘636 do not teach AMBA adjacent to the albumin-binding group.
Regarding AMBA adjacent to the albumin-binding group, Siwowska teaches placing hydrophobic moieties near the albumin-binding moiety (pg 524, Figure 1, structures cm12 and cm13).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the conflicting claims of ‘636 to include hydrophobic linkers as taught by Siwowska because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of adding a hydrophobic moiety near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding a hydrophobic moiety because the conflicting claims of ‘636 disclosed a compound known to demonstrate that modifications of the compound are known in the art. Additional prior art of Siwowska suggested that adding linkers near the albumin linker has an effect of modulating the uptake ratio into tumors vs kidneys (pg 528, Figure 5) and that hydrophobic moieties have the best ratio of tumor-to-kidney (pg 529, Table 2).
The skilled artisan would have been motivated to add hydrophobic moieties to the albumin-binding moiety because it has been shown to improve the ratio of tumor-to-kidney absorbed doses (Siwowska, pg 528, Table 2) and that better ratios enable higher doses for treating cancer. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘636 with Siwowska.
The combined teachings of the conflicting claims of ‘636 and Siwowska do not teach AMBA as the hydrophobic moiety.
The combined teachings of the conflicting claims of ‘636 and Siwowska do not teach AMBA adjacent to the albumin-binding moiety.
Regarding AMBA as the hydrophobic moiety, Garrison teaches AMBA (pg 1804, Figure 1, structure Gly-AM2BA).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the hydrophobic moieties of the combined teaching of the conflicting claims of ‘636 and Siwowska with the AMBA moiety (Gly-AM2BA) as taught by Garrison because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting Gly-AM2BA with the hydrophobic moieties of the conflicting claims of ‘636 and Siwowska near the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the hydrophobic moiety near the albumin-binding moiety with Gly-AM2BA because the prior art of Siwowska disclosed linkers could be exchanged near the albumin (pg 524, Figure 1, structures A-C) and that hydrophobic moieties improves tumor-to-kidney ratio (pg 528, Figure 5B and Figure 5C). Additional prior art of Garrison suggested additional hydrophobic moieties, such as Gly-AM2BA, which is equivalent to the instant claim, AMBA, to have superior tumor retention compared to hydrophilic moieties (pg 1810, col 1, para 2, line 13; pg 1810, col 2, para 1, lines 1-7) and that radioconjugates containing aromatic groups clearly demonstrate significantly higher tumor retention compared to hydrophilic or hydrocarbon linking moieties (pg 1810, col 2, para 1, lines 5-13). The overlap between the linkers involves known chemistry.
The skilled artisan would have been motivated to substitute the hydrocarbon moieties of the conflicting claims of ‘636 and Siwowska because the aromatic containing moieties of AMBA derivatives improve tumor retention more enabling potential for superior tumor-to-kidney ratios for the albumin-binding folate receptor radiotherapeutic of Guzik and Siwowska. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘636 and Siwowska with Garrison.
The combined teachings of the conflicting claims of ‘636, Siwowska, and Garrison do not explicitly teach AMBA adjacent to the albumin-binding moiety.
Regarding the placement of the AMBA adjacent to the albumin-binding moiety, Li teaches an aromatic moiety next to the albumin-binding moiety (pg 11, para [0038], structure D-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of the combined teachings of the conflicting claims of ‘636, Siwowska, and Garrison to include the aromatic moiety next to the albumin-binding moiety as taught by Li because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the hydrophobic AMBA next to the albumin-binding moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the hydrophobic aromatic AMBA next to the albumin-binding moiety because the prior art of the conflicting claims of ‘636, Siwowska, and Garrison disclosed hydrophobic moieties such as AMBA improved tumor retention when placed near the albumin moiety. Additional prior art of Li suggested placing the hydrophobic moiety adjacent to the albumin-binding moiety to have similar tumor retention effect because of the overlap of structures between them involves known chemistry of aromatic groups and attached amides.
The skilled artisan would have been motivated to move the hydrophobic aromatic group closer to the albumin-binding moiety because the prior art had demonstrated that tumor retention increased when hydrophobic moieties were placed near the albumin-binding moiety and that placing the aromatic hydrophobic moieties adjacent to albumin-binding moieties still worked. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘636, Siwowska, and Garrison with Li.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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