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 and Previous Objections/Rejections Status
Claims 22-28 and 37-59 are pending in the application. Claims 37-56 are withdrawn from consideration. Claims 52-59 are newly added in the amendment filed 3/17/26.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Affidavit/Declaration
The declaration under 37 CFR 1.132 filed 3/17/26 is sufficient to overcome the rejection of claims 22-28 based upon the statement that the Applicant’s study of the 177Lu-DOTATATE formulation of Mathur et al. predicts a concentration of 0.15 mg/mL (1.5 mg/10 mL) of gentisic acid in the final volume of 10 ml which results from the first gentisic acid solution after cartridge purification with the C18 Sep-Pak column. The C18 Sep-Pak cartridges retained the vast majority of genetic acid, with only about 4.4-4.7% (an average of 4.55%) detected in the final eluted solution. The 0.15 mg/mL is outside of the recited range of “0.2 to 50 mg/mL.”
Terminal Disclaimer
The terminal disclaimers filed 3/17/26 were approved on 3/17/26.
Response to Arguments
Applicant’s arguments, see REMARKS, filed 3/17/26, with respect to the rejection(s) of claim(s)
22-28 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Strosberg et al. (N. Engl. J. Med. 2017; 376: 125-135 and Protocol N° AAA-III-01) in view of Iori et al. (Contrast Media Mol. Imaging Volume 2017, Article ID 8160134, 2017, pp 1-12) and Mathur et al. (Cancer Biother. Radiopharm. 2017, 32, 266-273).
New Grounds of Rejection
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) 22-28 and 57-59 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Strosberg et al. (N. Engl. J. Med. 2017; 376: 125-135 and Protocol N° AAA-III-01) in view of Iori et al. (Contrast Media Mol. Imaging Volume 2017, Article ID 8160134, 2017, pp 1-12) and Mathur et al. (Cancer Biother. Radiopharm. 2017, 32, 266-273).
Strosberg et al. (N. Engl. J. Med. 2017; 376: 125-135 and Protocol) discloses the method of manufacturing a 7.4 GBq 177Lu-DOTATATE pharmaceutical aqueous solution supplied in monodose vials (abstract; Protocol N° AAA-III-01: [version 11/14/11: p4, treatment; p7, Duration of treatment; p25, 1.33; p41, 5.1.1.; p160, Instructions for the use of Lutathera 7400 MBq]; [version 6/5/14: p5, treatment; p11, Duration of treatment; p30, 1.3.3; p49, 5.1.1; p191, Instructions for the use of Lutathera 7400 MBq]; [version 11/28/14, p18, 2.4.2]; [version 6/29/15, p20, 3.4.2])
PNG
media_image1.png
432
628
media_image1.png
Greyscale
([version 11/14/11: p41, Table 3]; [version 6/5/14: p49, Table 3]).
The 7.4 GBq 177Lu-DOTATATE encompasses the pharmaceutical aqueous solution of 7.4 GBq 177Lu-DOTATATE of the instant claims.
The 7.4 GBq 177Lu-DOTATATE manufactured and supplied monodose vials encompasses the method of manufacturing a pharmaceutical solution of the instant claims.
The pharmaceutical aqueous solution is provided in a formulation solution of 22 to 25 mL and a radioconcentration of 370 MBq/mL at end of production (Protocol N° AAA-III-01: [version 11/14/11 p41, 5.1.1.; Table 3; p158, Qualitative and Quantitative Composition; p159, Nature and Contents of Container]; [version 6/5/14, p49, 5.1.1; Table 3; p188, Qualitative and Quantitative Composition; p189, Nature and Contents of Container]; [version 11/28/14, p18, 2.4.2]; [version 6/29/15, p20, 3.4.2]) that encompasses a volumetric radioactivity of 250 MBq/mL to 500 MBq/mL of the instant claims.
The pharmaceutical aqueous solution comprises 0.63 mg/mL of gentisic acid and 2.8 mg/mL of
ascorbic acid for a total of 3.43 mg/mL of stabilizers (Protocol N° AAA-III-01: [version 11/14/11 Table 3]; [version 6/4/14 Table 3]) that encompasses the first stabilizer(s) gentisic acid and/or ascorbic acid in a total amount to result in a concentration of 0.2 to 5 mg/mL of the instant claims.
The 0.63 mg/mL of gentisic acid and 2.8 mg/mL of ascorbic acid encompasses the ratio of the concentration of the first stabilizer to the concentration of the second stabilizer is from 1:3 to 1:5 of the instant claims.
The ascorbic acid encompasses the second stabilizer consists of ascorbic acid of the instant claims.
The pharmaceutical aqueous solution does not comprise any ethanol (Protocol N° AAA-III-01: [version 11/14/11 p158, Pharmaceutical Components]; [version 6/5/14 p188, Pharmaceutical Components]) and therefore, encompasses less than 5% ethanol less, than 2% ethanol, less than 1% ethanol and is free of ethanol of the instant claims.
The pharmaceutical aqueous solution has a radiochemical purity of ≥97% and a shelf life of 72 hours at a temperature below 25°C (Protocol N° AAA-III-01: ([version 11/14/11 p42, Table 3; p162, Lutathera storage requirements]; [version 6/4/14 p50, Table 3]).
The 7.4 GBq 177Lu-DOTATATE pharmaceutical aqueous solution of Strosberg et al. comprises
analogous composition components in analogous concentrations that yields an analogous volumetric radioactivity to that of the instant claims. Therefore, the 7.4 GBq 177Lu-DOTATATE pharmaceutical aqueous solution of Strosberg et al. has the same properties and is capable of the same functions, such
as a radiochemical purity as determined by HPLC of ≥95% for at least 72 hours when stored at 25°C.
Strosberg et al. does not explicitly disclose a.) adding the first stabilizer during complexation and
the second stabilizer in the aqueous dilution solution or b.) a radiochemical purity as determined by HPLC of ≥95% for at least 72 hours when stored at 25°C.
Iori et al. (Contrast Media Mol. Imaging Volume 2017, Article ID 8160134, 2017, pp 1-12) discloses the method for manufacturing 177Lu-DOTATOC comprising the addition of sodium ascorbate solution during complexation of 177LuCl3 with DOTATOC and a second addition of ascorbic acid/ascorbate buffer in the bulk vials used to prepare patient doses. The ascorbic/ascorbate buffer solution decreases radiolysis phenomena enhancing stability of the products (abstract; 2.3 Manual Labeling).
Mathur et al. (Cancer Biother. Radiopharm. 2017, 32, 266-273) discloses a bulk scale “ready-to-use” 177Lu-DOTA-TATE formulation that is safe for human use for more than 1 week (radiochemical purity [Symbol font/0x3E]98%) (abstract).
The protocol for synthesis comprises direct heating of 177LuCl3 with DOTA-TATE solution (0.25 mL) in ammonium acetate buffer (2.2 mL) containing gentisic acid (33 mg) (p267, Synthesis) for complexation.
The 177Lu-DOTA-TATE product was diluted with acetate buffer containing gentisic acid (1.5% w/v ≈ 15 mg/mL) to final radioactive concentration of 740 MBq/mL (ethanol content <10%)(abstract; p267, Synthesis).
The radiochemical purity was [Symbol font/0x3E]97.0 ± 0.5% 3 days post formulation at room temperature (Table 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add the two radiation stability enhancers gentisic acid and ascorbic acid of Strosberg et al. sequentially for manufacturing the 177Lu-DOTA-TATE pharmaceutical aqueous solution wherein one is added during complexation and one is added for storage and transport to provide the advantage of decreasing the radiolysis phenomena and enhancing stability of the radiolabeled product, as taught by Iori et al. The two separate additions of stabilizers during complexation and for storage/transportation as taught by Iori et al. and/or Mathur et al. predictably provides an improvement over Strosberg’s teaching that the pharmaceutical aqueous solution has a radiochemical purity of ≥97% and a shelf life of 72 hours at a temperature below 25°C and yields a radiochemical purity of ≥ 95% for at least 72 h when stored at 25[Symbol font/0xB0]C.
Applicant’s assertions with regards to the references of Chen et al. and De Jong et al. are moot as they are not used in the instant rejection.
Applicant asserts that the initial complex of Mathur et al. is loaded on a C-18 column, washed with several volumes of solvent then the 177Lu-DOTA-TATE complex is eluted with 1 mL ethanol. This procedure removes most, if not all, of the corresponding first stabilizer gentisic acid in the C-18 washing step, such that very little first stabilizer would remain in the final pharmaceutical aqueous solution. After the C-18 column purification, the amount of gentisic acid in the final pharmaceutical aqueous solution was measured by HPLC to be an average of only 4.55% of the initial amount, which means only about 1.5 mg of the original 33 mg of gentisic acid ends up in the final solution. The 0.15 mg/mL is outside of the recited range of “0.2 to 50 mg/mL.” Also, if one assumes the activity of Mathur et al. final solution is 9.25 GBq, i.e., unchanged from the starting material as described in the “Synthesis” section of Mathur et al., a radioactive concentration of 740 MBq/mL would require a volume of 12.5 mL. Accordingly, the concentration of the remaining 1.5 mg gentisic acid would be 0.12 mg/mL, still outside the recited range of the first stabilizer of the instant claim 22.
Further, Applicant asserts that based on a 10 mL final derived from Mathur et al., to reach the final volume, the 1 mL ethanol solution needs to be diluted with 9 mL of buffer solution, wherein the buffer solution contains 1.5% w/v gentisic acid. The addition of buffer solution include 135 mg of gentisic acid (i.e., 15 mg/mL x 9 mL), resulting in a concentration of 13.5 mg/mL for the corresponding second stabilizer. This gives a ratio of first to second stabilizers of 0.15:13.5 or 1:90, which is very different from the ration of “1:3 to 1:5”, the corresponding second stabilizer would have a concentration
of 13.8 mg/mL and thus the ratio of first to second stabilizers works out to be 0.12:13.8 or 1:115, even
more different from the ratio of “1:3 to 1:5.”
The reference of Mathur et al. was not used to teach of the recited range of the first stabilizer 0.2 to 50 mg/mL or ratios of first to second stabilizers but was used to teach that the addition of two stabilizers, such as the first stabilizer during complexation and a second stabilizer during storage to provide a radiochemical purity of ≥ 95% for at least 72 h when stored at 25[Symbol font/0xB0]C.
The reference of Strosberg et al. was used to teach that the pharmaceutical aqueous solution comprises 0.63 mg/mL of gentisic acid and 2.8 mg/mL of ascorbic acid for a total of 3.43 mg/mL of stabilizers that encompasses the first stabilizer(s) gentisic acid and/or ascorbic acid in a total amount to result in a concentration of 0.2 to 5 mg/mL of the instant claims and a second stabilizer.
The 0.63 mg/mL of gentisic acid and 2.8 mg/mL of ascorbic acid encompasses the ratio of the concentration of the first stabilizer to the concentration of the second stabilizer is from 1:3 to 1:5 of the instant claims.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this
application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MELISSA J PERREIRA/ Examiner, Art Unit 1618
Prosecution Insights