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 .
Claims Status
Claims 64-67 are pending in the application.
Claim Objections
Claim 65 is objected to because of the following informalities: the instant claim 65 includes a period within the body of the claim text and is located after 30°C. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 64-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vyas (ANZSNM-
2019) and/or Sørensen et al. (J. Label. Compd. Radiopharm. 2020, 1-11) in view of de Palo et al. (US 2020/0030464A1) and evidenced by Kraihammer et al. (EJNMMI Radiopharm. Chem. (2023) 8:7, p1-13).
Vyas (ANZSNM-2019) discloses a labelling method for the synthesis of Lu-177 based therapeutic
radiopharmaceuticals, such as PSMA or DOTA TATE (p22).
The method includes mixing various ligands PSMA or DOTA TATE with Lu-177 in a buffer solution
comprising sodium ascorbate and ascorbic acid (p22).
The Lu-177 encompasses the Lu-177 of the instant claims.
The various ligands include DOTA, PSMA-617, PSMA-I&T (p2; p19; p25; p28).
The PSMA-I&T ligand encompasses the EuK-Sub-kf-iodo-y-DOTAGA ligand of the instant claims.
The amount of ascorbic acid comprises 300 mg (p19; p25) and encompasses the ascorbic acid during the complexation of the instant claims.
The ascorbic acid helps to minimize the process of radiolysis to increase the stability of the final product (p20).
The solution is heated for 30 minutes at 90 degrees, cooled for 10 minutes and subsequently purified via HPLC (p22) that encompasses heating the admixed Lu-177 and EuK-Sub-kf-iodo-y-DOTAGA in the absence of gentisate compound at a temperature not exceeding 94°C and cooling the complex formed of the instant claims.
The synthesis of Vyas does not comprise gentisic acid during the complexation reaction.
The amount of buffer (sodium ascorbate and ascorbic acid can be calculated based on the amount of number of Lu-177 mole available and the amount of ligand for labelling is also calculated based on the number of Lu-177 moles available for labelling and atomic mass of available ligands (p20 and p21).
Sørensen et al. (J. Label. Compd. Radiopharm. 2020, 1-11) discloses the synthesis of [177Lu]PSMA-I&T comprises mixing PSMA-I&T and 177LuCl3 with aqueous ascorbic acid at pH 4.5. The labelling reaction was carried out at 120°C for 100 s and then 105°C for 800 s. The reaction mixture was diluted with isotonic saline and eluted twice through a sterilizing filter (scheme 2; p4, 2.4 Synthesis of [177Lu]PSMA-I&T).
The 177LuCl3 encompasses the Lu-177 of the instant claims.
The PSMA-I&T ligand encompasses the EuK-Sub-kf-iodo-y-DOTAGA ligand of the instant claims.
The ascorbic acid encompasses the ascorbic acid during the complexation of the instant claims.
The synthesis of Sørensen et al. does not comprise gentisic acid during the complexation reaction.
Vyas and/or Sørensen et al. do not explicitly disclose that the ascorbic acid is present in an amount between 55 mg/mL to 75 mg/mL while heating the mixture of PSMA-I&T and Lu-177 and does not disclose the addition of 10 mg/mL to 100 mg/mL ascorbate and 5 mg/mL to 100 mg/mL gentisate after cooling the complex formed.
de Palo et al. (US 2020/0030464A1) discloses the synthesis of radionuclide complexes, such as 177Lu DOTA-TATE having high chemical stability that are used for diagnostic and/or therapeutic purposes (abstract; p4-5, [0076],[0079]; claim 17).
The stability of the radionuclide complexes are achieved by adding at least one stabilizer against radiolytic degradation during complexation of 177Lu and DOTA-TATE and adding at least one second stabilizer during dilution (p2, [0028-0035]; p10, [0313-0315]; p, 17, [0451-0452]).
The stabilizer(s) added during complexation comprises ascorbic acid, etc. and the second stabilizer comprises gentisic acid and/or ascorbic acid (p3, [0072-0074]).
The stabilizer(s) added during complexation is/are present during complex formation in a total concentration of from 15 to 50 mg/mL (p7, [0219-0220]; p10, [0330]).
The second stabilizer(s) can be added in an amount of 0.5 to 10 mg/mL (p3, [0071]; p4, [0101]).
The use of two stabilizers introduced during the manufacturing process at different stages was
found to be of particular suitability in stabilizing sensitive radiopharmaceutical solutions. The first stabilizer added during complexation protects against radiolysis and the other stabilizer enhances the protecting effects for the shelf-life period (p2, [0040-0042]).
The complexation of 177Lu and DOTA-TATE is accomplished at a temperature of 70 to 99°C, such as between 90-95°C (p10, [0335]).
The second stabilizer(s) are added after the reaction solution is cooled down to an ambient temperature (p17, [0453]).
The synthesis of de Palo et al. does not necessarily comprise gentisic acid during the complexation reaction.
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to include an amount of 55 mg/mL to 75 mg/mL of ascorbic acid stabilizer as the only stabilizer present during complexation as Vyas teaches that the amount of buffer (sodium ascorbate and ascorbic acid can be calculated based on the amount of number of Lu-177 mole available and provides the advantage of enhanced protection against radiolytic degradation as taught by de Palo et al. wherein ascorbic acid is chosen from the finite list of preferred first stabilizers of gentisic acid and ascorbic acid for the synthesis of 177Lu therapeutic radiopharmaceuticals.
The references of Vyas and de Palo et al. are drawn to analogous methods of synthesis of 177Lu based therapeutic radiopharmaceuticals and therefore, it would have been predictable to one of ordinary skill in the art to utilize the sequential stabilizer(s) addition method of de Palo et al. for the synthesis of [177Lu]PSMA-I&T of Vyas and/or Sørensen et al. to yield [177Lu]PSMA-I&T with reduced radiolytic degradation, reduced thermal stress and enhanced protection during product storage.
Furthermore, it is obvious to vary and/or optimize the amount of the ascorbic acid provided during the complexation reaction, according to the guidance provided by Vyas and de Palo et al., to provide a composition having the desired properties such as protection against radiolytic degradation. 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).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add a combination of the second stabilizer(s) gentisic acid and ascorbic acid in a concentration of at least 0.5 to 10 mg/mL after cooling the formed complex of Vyas and/or Sørensen et al. as taught by de Palo et al. for the advantage of the reduction of the overall thermal stress of the stabilizers and strengthening of the protective power of the stabilizers following drug product storage time period.
Furthermore, it is obvious to vary and/or optimize the amount of the gentisic acid and ascorbic acid provided after cooling the complex formed, according to the guidance provided by de Palo et al., to provide a composition having the desired properties such as the reduction of the overall thermal stress of the stabilizers and strengthening of the protective power of the stabilizers following drug product storage time period. 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).
Vyas and/or Sørensen et al. do not disclose free unchelated lutetium-177 in an amount of 1 weight % or less; and/or free of radiochemical impurities in an amount of 3 weight % or less and/or free of chemical impurities in an amount of 5 weight % or less.
Sørensen et al. further discloses that the radiochemical yield was more than 98%. The radioactivity-detected HPLC analysis of [177Lu]PSMA-I&T evidenced a complete chelation of the 177Lu3+ ion, thus a radiochemical purity of more than 99%. The stability over a period of 7 days yielded a radiochemical purity of more than 95% (p9, 3.3. Development of the automated GMP production of
[177Lu]PSMA-I&T).
de Palo et al. further discloses the addition of DTPA sequestering agent to remove any
uncomplexed Lu (p4, [0102]).
Also, the suitable stabilizer(s) ensures high stability of at least 95%, 96%,97%,98%,99% or 100% chemical stability with respect to the chemical purity after 72 hours at 25°C (p2, [0038-0039]).
The high stability allows for sufficient time for the 177Lu-DOTATATE pharmaceutical aqueous
solution to be shipped from a centralized pharmaceutical production site to remote clinical centers
(p2, [0046]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to remove any uncomplexed lutetium-177 and/or utilize the sequential addition of the combination of stabilizers as taught de Palo et al. to prepare the 177Lu based therapeutic radiopharmaceutical, such as [177Lu]PSMA-I&T with the highest purity and stability for the advantage enhanced protection against radiolytic degradation and increased drug product storage time period during transportation to remote clinical centers.
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention that the sequential addition of the combination of stabilizers as taught de Palo et al. predictably yields a 177Lu pharmaceutical aqueous solution having the highest stability (e.g. 100%) with respect to the chemical purity, such as maintained at ≥ 95% for at least 72h when stored at 25°C will maintain the chemical purity at ≥ 95% for at least 5 days.
Vyas and/or Sørensen et al. do not disclose the retention time of approximately 9 to 12 minutes by HPLC.
Vyas discloses the HPLC purification of the Lu-177 based therapeutic PSMA radiopharmaceuticals as well as that stated above.
It is evidenced by Kraihammer et al. (EJNMMI Radiopharm. Chem. (2023) 8:7, p1-13) that [177Lu]PSMA-I&T elutes with a retention time of about 9.5 minutes via HPLC method A (p5, HPLC Method
A).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention that the that [177Lu]PSMA-I&T of Vyas and/or Sørensen et al. elutes with a retention time of about 9.5 minutes via HPLC as evidenced by Kraihammer et al. as the [177Lu]PSMA-I&T of Vyas and/or Sørensen et al. is identical to the [177Lu]PSMA-I&T of Kraihammer et al.
Therefore, the [177Lu]PSMA-I&T of Vyas and/or Sørensen et al. is analogous to the [177Lu]PSMA-I&T of the instant claims, has the same properties and is capable of the same functions, such as a retention time of approximately 9 to 12 minutes via HPLC.
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 64-66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of U.S. Patent No. 11,129,912C1. Although the claims at issue are not identical, they are not patentably distinct from each other because the method for preparing a complex of lutetium-177 and EuK-Sub-kf-iodo-y-DOTAGA of U.S. Patent No. 11,129,912C1 comprises admixing lutetium-177, EuK-Sub-kf-iodo-y-DOTAGA and one or more ascorbate in an amount between 55 mg/mL to 75 mg/mL, heating in the absence of gentisate at a temperature not exceeding 94°C and cooling the complex formed. The resulting complex is further admixed with one or more ascorbate compounds between 10 mg/mL to 100 mg/mL and one or more gentisate compounds between 5 mg/mL to 100 mg/mL. The method of U.S. Patent No. 11,129,912C1 encompasses the complex produced by the method of the instant claims comprising admixing lutetium-177, EuK-Sub-kf-iodo-y-DOTAGA and one or more ascorbate in an amount between 55 mg/mL to 75 mg/mL, heating in the absence of gentisate at a temperature not exceeding 94°C and cooling the complex formed. The resulting complex is further admixed with one or more ascorbate compounds between 10 mg/mL to 100 mg/mL and one or more gentisate compounds between 5 mg/mL to 100 mg/mL.
The complex prepared by the method of U.S. Patent No. 11,129,912C1 yields a complex that
maintains a radiochemical purity of at least 95% for 3 days that encompasses the complex prepared by the method of the instant claims that maintains a radiochemical purity of at least 95% for 3 days.
The complex prepared by the method of U.S. Patent No. 11,129,912C1 yields a complex that is free of unchelated lutetium-177 in an amount of 1 weight % or less; and/or free of radiochemical impurities in an amount of 3 weight % or less and/or free of chemical impurities in an amount of 5 weight % or less that encompasses the complex prepared by the method of the instant claims that is free of unchelated lutetium-177 in an amount of 1 weight % or less; and/or free of radiochemical impurities in an amount of 3 weight % or less and/or free of chemical impurities in an amount of 5 weight % or less.
The complex prepared by the method of U.S. Patent No. 11,129,912C1 yields a complex that maintained at 30°C or less with purity levels that exhibited for 3 days or more following formation of the complex that encompasses the complex prepared by the method of the instant claims that maintained at 30°C or less with purity levels that exhibited for 3 days or more following formation of the complex.
The complex of U.S. Patent No. 11,129,912C1 encompasses the complex of the instant claims, has the same properties and is capable of the same functions, such as having a retention time of approximately 9 to 12 minutes by HPLC.
Claims 64 and 66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-12 of U.S. Patent No. 11,491,246B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the 177Lu-PSMA I&T of U.S. Patent No. 11,491,246B2 prepared via combining lutetium-177, EuK-Sub-kf-iodo-y-DOTAGA and one or more ascorbate in an amount between 55 mg/mL or greater (e.g. 55 mg/mL to 75 mg/mL), heating in the absence of gentisate at a temperature no greater than 90°C and cooling the complex formed. The resulting complex is further admixed with one or more ascorbate compounds between 50 mg/mL to 100 mg/mL and one or more gentisate compounds from 15 mg/mL. The method of U.S. Patent No. 11,491,246B2 encompasses the complex produced by the method of the instant claims comprising admixing lutetium-177, EuK-Sub-kf-iodo-y-DOTA and one or more ascorbate in an amount between 55 mg/mL to 75 mg/mL, heating in the absence of gentisate at a temperature not exceeding 94°C and cooling the complex formed. The resulting complex is further admixed with one or more ascorbate compounds between 10 mg/mL to 100 mg/mL and one or more gentisate compounds between 5 mg/mL to 100 mg/mL.
The complex prepared by the method of U.S. Patent No. 11,491,246B2 yields a complex that
maintains a radiochemical purity of at least 95% for 3 days that encompasses the complex prepared by the method of the instant claims that maintains a radiochemical purity of at least 95% for 3 days.
The complex of U.S. Patent No. 11,491,246B2 encompasses the complex of the instant claims, has the same properties and is capable of the same functions, such as having a retention time of approximately 9 to 12 minutes by HPLC.
Claims 64,66 and 67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 12,558,440B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the complex of U.S. Patent No. 12,558,440B2 prepared via combining lutetium-177, EuK-Sub-kf-iodo-y-DOTAGA and one or more ascorbate in an amount between 55 mg/mL or greater (e.g. 55 mg/mL to 75 mg/mL), heating in the absence of gentisate at a temperature no greater than 90°C and cooling the complex formed. The resulting complex is further admixed with one or more ascorbate compounds between 50 mg/mL to 100 mg/mL and one or more gentisate compounds from 15 mg/mL. The method of U.S. Patent No. 12,558,440B2 encompasses the complex produced by the method of the instant claims comprising admixing lutetium-177, EuK-Sub-kf-iodo-y-DOTA and one or more ascorbate in an amount between 55 mg/mL to 75 mg/mL, heating in the absence of gentisate at a temperature not exceeding 94°C and cooling the complex formed. The resulting complex is further admixed with one or more ascorbate compounds between 10 mg/mL to 100 mg/mL and one or more gentisate compounds between 5 mg/mL to 100 mg/mL.
The complex prepared by the method of U.S. Patent No. 12,558,440B2 yields a complex that
maintains a radiochemical purity of at least 95% for 3 days that encompasses the complex prepared by the method of the instant claims that maintains a radiochemical purity of at least 95% for 3 days.
The complex has 99% or greater lutetium-177 incorporation of U.S. Patent No. 12,558,440B2 encompasses the incorporation of lutetium-177 and EuK-Sub-kf-iodo-y-DOTAGA is greater than 98 mole percent of the instant claims.
The complex of U.S. Patent No. 12,558,440B2 encompasses the complex of the instant claims, has the same properties and is capable of the same functions, such as having a retention time of approximately 9 to 12 minutes by HPLC.
Conclusion
No claims are allowed at this time.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
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