Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/10/25 has been entered.
Claims Status
Claims 75,76,78-80,82,83,85-88,91,92,94-121 are pending in the application. Claims 112-121 are newly added in the amendment filed 11/10/25.
Affidavit/Declaration
The declaration under 37 CFR 1.132 filed 11/10/25 is insufficient to overcome the rejection of claims 75,76,78-80,82,83,85-88,91,92,94-111 based upon 35 U.S.C. 103 as set forth in the last Office action because: the Applicant’s unexpected results are due to the use of nickel target material with niobium as the backing material to yield higher purity 61Cu. The Applicant states that it was also surprising that the use of niobium as the backing material lowered the contaminants in the crude [61Cu]CuCl2 solution that was prepared by irradiation.
The instant claims do not recite a nickel target material with niobium as the backing material. Therefore, the claims are not commensurate in scope.
The Applicant further states that following routine purification (e.g., FASTlab) wherein the results indicated a 89.3% and 94% reduction in impurities for natNi or 61Ni on a niobium backing with
respect to silver backing materials.
The reference of Svedjehed et al. (EJNMMI Radiopharm. Chem. 2020, 5, p1-14) was used to teach of the process for preparing high purity [61Cu]CuCl2 and separation from irradiated solid Ni targets. The purification of the dissolved targets was accomplished via an automated FASTlab chemistry module where sequential TBP and TK201 (Triskem) resins isolated [61Cu]CuCl2 and removed Ni, Co, and Fe. The majority of the 58Co impurity was [Symbol font/0x3C]0.0001% relative to 61Cu activity.
Therefore, it would have been predictable to one of ordinary skill in the art that any minor 110mAg, 108mAg, 109Cd, 56Co, 57Co, 60Co, Pb, Al, Fe and Zn impurities will be present in less than that of the major impurity 58Co, such as [Symbol font/0x3C]0.0001% relative to 61Cu activity as the FASTlab resulted in a reduction of the major impurity 58Co to 61Cu ratio by more than a factor of 500 following purification.
The FASTlab of the disclosure uses TBP and TK201 (Triskem) resins that are identical to the TBP and TK201 (Triskem) resins of Svedjehed et al. The resins have the same properties and are capable of the same functions, such as analogously removing the impurities from the irradiated Ni targets and providing the radiochemical purity of the instant claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 75,76,78-80,82,83,85-88,91,92,94-121 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fani et al. (J. Nucl. Med. 2011, 52, 1110-1118) in view of Kim et al. (US 11,497,822B1), and Mansour et al. (Nucl. Med. Biol. 2018, 56, 31-38) and in further view of Greifenstein, L.N, (2019) Synthesis, radiolabeling and in vitro and in vivo evaluation of different chelator systems with 44Sc, 64Cu, 68Ga and 177Lu (Doctoral dissertation, Dissertation, Mainz, Johannes Gutenberg-Universität, 2019) and Goldberg (US 6,306,393B1) and Svedjehed et al. (EJNMMI Radiopharm. Chem. 2020, 5, p1-14).
Fani et al. (J. Nucl. Med. 2011, 52, 1110-1118) discloses 64Cu-NODAGA-LM3 antagonist for in vivo
PET imaging of sst2-positive tumors (abstract; p1111, left column, third and fourth paragraphs; Figure 1).
The NODAGA encompasses the NODAGA of the instant claims. The single NODAGA chelator encompasses n is 1 of the instant claims.
The LM3 (p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)D-Thy-NH2) is a somatostatin-based
antagonist which encompasses the V targeting moiety, such as SST that binds to an SSTR of the instant
claims.
The single LM3 targeting moiety encompasses p is 1 of the instant claims.
The LM3 encompasses the cyclic octapeptide somatostatin receptor targeting moiety of the
instant claim 110 and the LM3 of the instant claim 111.
The LM3
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encompasses the structures of the
instant claims 85 and 86.
The radiopeptide is mixed with PBS/octanol (p1112, Determination of Lipophilicity) wherein the PBS encompasses a pharmaceutically acceptable excipient of the instant claims.
For small animal PET imaging, 64Cu-NODAGA-LM3 (2-3 MBq) was intravenously injected into the tail vein, the animals were scanned at 1,4 and 24 h after injection and PET images obtained (p1112, Small-Animal PET Studies; Figure 5) which encompasses administering an effective amount and generating one or more images of at least a part of a subject’s body of the instant claim 91.
Also, mice were injected with a 100µL 0.15 MBq dose via the tail vein (p1112, In Vivo Biodistribution Studies).
The PET imaging encompasses one or more images is generated using PET of the instant claim 92.
Fani et al. does not disclose 61Cu or the pH of the composition.
Kim et al. (US 11,497,822B1) discloses a radiopharmaceutical composition comprising a NODAGA metal chelator, and an LM3 targeting ligand (column 56, lines 51+; column 58, line 31; column 64, lines 41+, especially line 65; column 95, lines 35-42,47-48; column 96, lines 32-34; column 97, line 38).
The radionuclides comprise copper-64, copper-67, copper-61, copper-62 (column 61, line 64-column 62, line 20). The copper-61 encompasses the 61Cu of the instant claims.
The radiopharmaceutical composition further comprises a pH stabilizing agent and an aqueous
vehicle (column 80, lines 54+; column 95, lines 42-45; column 104, lines 25-33) wherein pH stabilizing
agent and the aqueous vehicle encompass a pharmaceutically acceptable excipient, respectively, of the instant claims.
The pH of the radiopharmaceutical composition is within a range of about 4 to about 8, about 5 to about 7 (column 104, lines 19-24) which encompasses the pH of 4-7 of the instant claim 83.
The pH stabilizing agent prevents or delays chemical decomposition of the radiopharmaceutical conjugate caused by pH changes (column 25, lines 1-4).
The radiopharmaceutical compositions are used for imaging and/or as part of a treatment for diseases. The imaging applications used include PET, SPECT (column 77, lines 26-33).
The method of treating a disease includes an SSR-associated cancer (column 10, lines 49+; column 74, lines 20-25; column 107, lines 61+) which encompasses the method of treating cancer with the effective amount (stated above) of the instant claim 94.
Mansour et al. (Nucl. Med. Biol. 2018, 56, 31-38) discloses that the substitution of 64Cu for a shorter half-life copper isotope 61Cu is very attractive for rendering Cu-radiopharmaceuticals more suitable for human PET scans (p38, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to substitute the 64Cu of Fani et al. for the 61Cu of Kim et al. for PET imaging as Mansour et al. teaches that 61Cu is a more suitable radioisotope for human PET scans due to the advantage of a shorter half-life.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the 64Cu-NODAGA-LM3 antagonist of Fani et al. at a pH within a range of about 4 to about 8 by including a pH stabilizing agent of Kim et al. as the pH stabilizing agent prevents or delays chemical decomposition of the radiopharmaceutical conjugate caused by pH changes.
Therefore, it would have been predictable to one of ordinary skill to substitute one Cu radioisotope, such as 64Cu for another radioisotope, such as 61Cu of Kim et al. according to the desired application, such as diagnosis of diseases via PET, SPECT, etc.
It is obvious to vary and/or optimize the amount of 61Cu provided in the composition, according to the guidance provided by Fani et al., to provide a composition having the desired properties such as the desired activity concentration as Fani et al. teaches of the examination of radiolabeled-NODAGA-LM3 in small animals and mice wherein it would have been predictable to provide an activity concentration for effective PET while causing no harm to the subject. It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Fani et al. does not explicitly disclose the SST structure of the instant claims 86 and 88.
Kim et al. further discloses that the compounds possess one or more chiral centers and each
center exists in the R configuration or the S configuration (column 68, lines 17-49).
It would have been obvious to one or ordinary skill in the art before the effective filing date of the claimed invention that the LM3 targeting moiety of Kim et al. will comprise the SST structure of the instant claims 86 and 88 as the targeting moieties may comprise multiple of chiral centers of either S or R configuration in any combination, including diastereomers.
Fani et al. does not disclose the copper radionuclide 67Cu for treating cancer.
Greifenstein, L.N, (2019) discloses that 64Cu and 67Cu, are available for PET, SPECT and therapeutic approaches. For example, 67Cu decays by emitting β- particle and therefore can be used for therapeutic purpose (p36, 1.3.3 Copper-64).
Goldberg (US 6,306,393B1) discloses that radiolabeled antibody immunoconjugates may be radiolabeled with 67Cu as it is considered one of the more promising radioisotopes for radioimmunotherapy due to its 61.5 hour half-life and abundant supply of beta particles and gamma rays (column 13, lines 32-44).
It would have been obvious to one or ordinary skill in the art before the effective filing date of
the claimed invention to substitute the 64Cu of Fani et al. for the 67Cu as it is considered one of the more
promising radioisotopes for radioimmunotherapy due to its 61.5 hour half-life, abundant supply of beta particles and gamma rays. Therefore, 67Cu is predictably and advantageously used for therapy with a
reasonable expectation of success.
Therefore, it would have been predictable to one of ordinary skill to substitute one Cu radioisotope, such as 64Cu for another radioisotope, such as 67Cu according to the desired application, such as therapeutic treatment of diseases, such as cancer.
Fani et al. does not disclose a theranostic method.
Kim et al. further discloses that the conjugates can be administered as a companion diagnostic (column 77, lines 33-34).
Greifenstein, L.N, (2019) further discloses that the combination of 67Cu with 64Cu offers a perfect pair for theranostic applications (p36, 1.3.3 Copper-64).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a combination of 61Cu and 67Cu-DOTAGA compounds for a theranostic method as Mansour et al. teaches that 61Cu is a better suited radioisotope than 64Cu for PET imaging and therefore, the substitution of the combination of 64Cu-chelated compound/67Cu-chelated compound for the combination of 61Cu-chelated compound/67Cu-chelated compound predictably provides for a significantly more advantageous theranostic application than the typical 64Cu and 67Cu combined theranostic application with a reasonable expectation of success.
Fani et al. does not disclose the end of synthesis radiochemical purity, end of synthesis radiochemical purity for 61Cu, end of synthesis by sum of radionuclide impurities, end of synthesis +12 hour by radionuclidic purity, end of synthesis 56Co activity concentration, radionuclidic purity of the sum
of radiocobalt,
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and the
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.
Svedjehed et al. (EJNMMI Radiopharm. Chem. 2020, 5, p1-14) discloses the process for high
purity [61Cu]CuCl2 and separation from irradiated solid Ni targets (title; abstract).
Several Co radioisotopic contaminants are produced and an efficient method for separating is necessary (p3, last paragraph; p6, [61Cu]CuCl2 separation).
Quality control of the isolated [61Cu]CuCl2 measured 58Co content vs 61Cu by activity, EoB molar activities 85 ± 23 GBq/µmol, NOTA-based EoB apparent molar activities of 31 ± 8 MBq/nmol and 201 MBq/nmol for 30 min and 3.3 h irradiations, respectively (abstract). The 58Co activity content in the purified [61Cu]CuCl2 product EoB is (8.3 ± 0.6) x 10-5% (p10, last paragrph-11, first two lines).
The purification of the dissolved target was accomplished via an automated FASTlab chemistry module where sequential TBP and TK201 (Triskem) resins isolated [61Cu]CuCl2 (abstract; p4, first paragraph; p5-6, Dissolution and [61Cu]CuCl2 separation; Figs. 1 and 2).
The FASTlab technique has a shorter preparation and process time, lower reagent consumption and a more suitable product formulation (p10, third paragraph). The FASTlab resulted in a reduction of the 58Co to 61Cu ratio by more than a factor of 500 following purification (p11, first few sentences; Table 4). The majority of the 58Co impurity (97.87 ± 0.86%) is found in the waste vial (p10, Competing radiocobalt production) and the 58Co radionuclidic impurity of <0.0001% relative to 61Cu activity (p12, Conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to purify the [61Cu]CuCl2 and remove all contaminants, such as 58Co via FASTlab for the highest radiochemically pure [61Cu]CuCl2 starting material to predictably prepare highly pure 61Cu and 67Cu-DOTAGA conjugates.
It would have been obvious to one of ordinary skill in the art to utilize the cassette-based FASTlab purification method of Svedjehed et al. to purify [61Cu]CuCl2 produced from an irradiated Ni-target as it provides for the advantage of a reduction of the major impurity 58Co by more than a factor of 500 compared to 61Cu and therefore, any minor 110mAg, 108mAg, 109Cd, 56Co, 57Co, 60Co, Pb, Al, Fe and Zn impurities will be present in less than that of the major impurity 58Co.
The FASTlab technique is analogous to the cassette-based FASTlab method for purification of 61Cu of the disclosure (specification, [0353],[0357],[0377],[0400]). The cassette-based FASTlab method of the instant disclosure utilizes the same TBP resin and TK201 resin and therefore, the resulting [61Cu]CuCl2 encompasses the [61Cu]CuCl2 of the instant claims and will have EOS, EOS(+12) characterizations, radiochemical purities, radionuclidic purities, sum of radionuclidic impurities, chemical purities and 56Co and 58Co activity concentrations analogous to that of the instant claims.
It would have been obvious to one of ordinary skill in the art before the effective filing date that other minor impurities, such as 110mAg, 108mAg, 109Cd, 56Co, 57Co, 60Co, Al, Fe, Pb, Zn will be removed via the cassette-based FASTlab purification technique as FASTlab removes the main impurity 58Co and the minor impurities will present in less than [Symbol font/0x3C]0.0001% relative to 61Cu of the major impurity 58Co.
Response to Arguments
Applicant's arguments filed 11/10/25 have been fully considered but they are not persuasive.
Applicant asserts an explanation must be provided for the Office’s argument that Svedjeded’s use of FASTlab inherently removes the “other impurities”, 110mAg, 108mAg, 109Cd, 56Co, 57Co, 60Co, Pb, Al, Fe and Zn, because FASTlab removed “the main impurity 58Co.”
The reference of Svedjehed teaches that majority of the 58Co impurity was [Symbol font/0x3C]0.0001% relative to 61Cu activity using FASTlab purification technique as well as that stated above.
Therefore, it would have been predictable to one of ordinary skill in the art that any minor
impurities, such as110mAg, 108mAg, 109Cd, 56Co, 57Co, 60Co, Pb, Al, Fe and Zn will be present in less than the [Symbol font/0x3C]0.0001% relative to 61Cu of the major impurity 58Co as well as that stated above.
Applicant asserts the Office draws the sweeping conclusion that certain impurities can be
removed by a FASTlab cassette without citation to any evidence and without providing any rationale.
The reference of Svedjehed teaches that stated above.
Therefore, it would have been predictable to one of ordinary skill in the art that any minor 110mAg, 108mAg, 109Cd, 56Co, 57Co, 60Co, Pb, Al, Fe and Zn impurities will be present in less than that of the major impurity 58Co, such as [Symbol font/0x3C]0.0001% relative to 61Cu activity as the FASTlab resulted in a reduction of the major impurity 58Co to 61Cu ratio by more than a factor of 500 following purification.
The FASTlab of the disclosure uses TBP and TK201 (Triskem) resins that are identical to the TBP
and TK201 (Triskem) resins of Svedjehed et al., and therefore, the resins have the same properties and are capable of the same functions, such as analogously removing any of the identical impurities of the instant claims from the irradiated Ni targets and providing the radiochemical purity of the instant claims.
Applicant asserts that Svedjehed discloses preparation of a target coin by electrodepositing natural Ni onto silver plating substrates. The purity of the resulting 61Cu prepared by Applicants is far superior to that of Svedjehed as they discovered a novel process for 61Cu production by electrodepositing nickel onto a niobium backing.
The instant claims are not drawn to the process for 61Cu production by electrodepositing nickel onto a niobium backing.
The FASTlab resins of Svedjehed do not rely on the type of metal plating for removal of specific impurities formed after irradiation but will predictably remove the identical impurities formed via irradiation, to that of the instant claims, regardless of the metal plating as the resins are identical, have the same properties and are capable of the same functions.
Also, the instant claims do not recite a nickel target material with niobium as the backing material.
Applicant asserts that nothing in Fani, Kim or Mansour, either alone or in combination, teaches or suggests any of purity elements (a) to (e).
The references of Fani, Kim or Mansour were not used to teach of any of purity elements (a) to
(e).
The reference of Svedjehed is stated above.
Applicant asserts that nothing in Svedjehed, Fani, Kim, Mansour, Greifenstein, or Goldberg either alone or in combination, teaches or suggests any of purity elements (a) to (e).
The references of Fani, Kim, Mansour, Greifenstein, or Goldberg were not used to teach of any of purity elements (a) to (e).
The reference of Svedjehed is stated above.
Conclusion
No claims are allowed at this time.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618