DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of group I, 225Ac and the combination of gentisic acid (GA) and ascorbic acid (AA) in the reply filed on May 16, 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 – 6 and 10 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Miederer et al. (Clin Cancer Res, 2008; cited on IDS filed 11/13/2023) in view of de Blois et al. (Appl Rad Isotopes, 2014) and Poty et al. (Chem Commun, 2018).
Miederer et al. discloses peptide receptor radionuclide therapy (PRRT) uses ß-particle radiolabeled somatostatin analogs as a treatment strategy for neuroendocrine tumors but a high percentage of tumors do not respond to this treatment so α-emitting isotopes such as the 10 day half-life actinium-225 with extremely high cytotoxicity on the cellular level were investigated (whole document, e.g., abstract). 225Ac-DOTA (2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) conjugates have shown sufficient stability to serve as a linking moiety for 225Ac-targeted therapy (p 3556, col 1, ¶ 1). Either due to the physical recoil energy or the different chemical properties of the first daughter nuclide 221Fr, after 225Ac disintegration, retention of the daughter isotopes in the chelate is highly unlikely (p 3556, col 1, ¶ 1). The somatostatin analog DOTATOC ((DOTA0-Phe1-Tyr3) octreotide) labeled with 225Ac accumulated in neuroendocrine xenograft tumors and lead to a growth delay in the tumors, leading to the conclusion that α-particle-emitting isotopes may led to future improvements in PRRT of neuroendocrine tumors (p 3556, col 1, ¶ 2). To prepare the labeled somatostatin analog, typically 1 – 3 MBq of 225Ac in HCl buffered with sodium acetate, the stabilizer against radiolytic degradation gentisic acid and DOTATOC in ultrapure water was incubated at 70°C for 60 minutes (p 3556, col 2, ¶ 1). Radiochemical purity (RCP) was determined by instant thin layer chromatography (ITLC) with silica gel-impregnated glass fiber sheets that after secular equilibrium was reached, were analyzed using a TLC scanner (p 3556, col 2, ¶ 1).
The labeling of the claimed DOTATATE with 225Ac is not disclosed. A combination of gentisic acid and ascorbic acid as stabilizers against radiolytic degradation is not disclosed.
de Blois et al. discloses the presence of quenchers in single vial pharmaceutical formulations of a radiolabeled peptide in a quantity sufficient to prevent radiolysis of the formulation (p 28, col 1). Somatostatin analogs (SS-analogs) are exposed to radicals produced by the 177Lu or 111In radionuclides during labeling, storage and transport (p 28, col 2, ¶ 1). The preservation of high levels of RCP with the use of quenchers is reported, with compounds such as gentisic acid and ascorbic acid being reported in the literature as quenches in various combinations and concentrations in the reaction mixture prior to radiolabeling to prevent radiolysis (p 28, col 2, ¶ 1). The effect of quenches on stability of radiolabeled SS-analogs was studied (¶ bridging p 28 and 29). During optimization, the typical radiolabeling reaction mixture consisted of 60 MBq of 177Lu or 111InCl3 in HCl, peptide dissolved in MilliQ® water, sodium acetate buffer and various combinations and concentrations of quenchers (p 29, col 1, ¶ 2). Final concentrations of 1 – 20 mM for each of gentisic acid and ascorbic acid were investigated time dependently to determine the maximal protection (section 2.4). Radiolabeling of DOTA-TATE requires heating for 15 minutes at 80°C and after cooling room temperature, generally recognized in the art as about 25°C, quality control including RCP was measured ITLC-SG and HPLC with RCP being determined as a function of time post radiolabeling at room temperature at regular time intervals (p 29, col 1, ¶ 2). The optimal quenching concentrations for gentisic acid (MW = 154 g/mol) and ascorbic acid (MW = 176 g/mol) were 3.5 mM (section 3.2), which both exceed the limitation of claim 13 as 0.2 mg/mL GA is 1.3 mM and 0.2 mg/mL is 1.1 mM. The combination of 3.5 mM gentisic acid and ascorbic acid with ethanol was optimal, enabling the storage and transport of the radiolabeled analogs in single vial, ready-for-use liquid formulations up to 7 days after radiolabeling (section 3.3 and conclusion section).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a combination of gentisic acid and ascorbic acid when radiolabeling DOTATATE with 225Ac and to optimize the time at elevated temperature for the chelation reaction. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Miederer et al. discloses 225Ac labeling of a DOTA containing SS analog for 60 minutes at 70°C while de Blois et al. discloses a shorter time of 15 minutes at 80°C for DOTATATE but with different isotopes. Stabilizers such as the combination of gentisic acid and ascorbic acid were optimal for stabilization as taught by de Blois et al. against the reactive species that can react with the peptide. One of ordinary skill in the art would recognize that time and temperature would affect the rate and extent of chelate formation and possibly the amount of reactive species generated. There is no evidence of record as to the criticality of the claimed parameters.
While de Blois et al. discloses cooling to room temperature, doing so until secular equilibrium is established is not disclosed.
Poty et al. discloses actinium-225 labeling of immunoglobulins (whole document, e.g., title). The DOTA portion of the DOTA-PEG7-Tz molecule was labeled with 225Ac (0.7 – 33.0 MBq) at 37°C in ammonium acetate for 1 hour (p 2600, col 1, ¶ 4). Instant thin layer chromatography (iTLC) indicated the presence of free non-equilibrium daughters at low level and at secular equilibrium, the radioligands obtained had an RCP of >98% (p 2600, col 2, ¶ 1). Page 4, ¶ 1 of the supplemental information indicates that secular equilibrium was reached 20 hours after elution. Depending on the RCP observed, either no further purification or purification using a C18-light cartridge was carried out (SI, p 4, ¶ 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to allow sufficient time at room temperature for secular equilibrium to be achieved before further steps are taken with the 225Ac-labled DOTATATE. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because daughter ion formation can affect chelate formation as disclosed by Miederer et al. and waiting until secular equilibrium has been established, which is taught by Poty et al. to take 20 hours, before characterization steps such as assessment of the RCP will provide information on a solution that has reached this equilibrium state. Allowing the secular equilibrium step to take place at room temperature of about 25°C after the initial step at higher temperature for a faster rate of chelate formation to limit any further degradation of the peptide portion that might occur at elevated temperature and also does not require the use of external equipment to maintain the elevated temperature as secular equilibrium is established.
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over Miederer et al., de Blois et al. and Poty et al. as applied to claims 1 – 6 and 10 – 13 above, and further in view of Petrik et al. (Nucl Med Commun, 2011).
Miederer et al., de Blois et al. and Poty et al. are discussed above.
A filtration step is not disclosed by any of Miederer et al., de Blois et al. and Poty et al.
Petrik et al. discloses radiolabeling of DOTA-derivatized peptides with various radioisotopes (whole document, e.g., abstract). Protocols for the preparation of DOTA-peptides labeled with a variety of radiometals to meet GMP (good manufacturing practice) standards is disclosed (p 888, col 1, ¶ 1). After reaction under the specific conditions for each radionuclide, the reaction solution was immediately transferred onto the C18 cartridge, washed with saline and eluted with 50% (v/v) ethanol through the low-protein-binding sterile filter into the product vial (p 889). The parts of the system such as the sterile filter for product purification and sterile filtration are the same for all cassette types (p 893, col 2, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a filtration step into the method rendered obvious by Miederer et al., de Blois et al. and Poty et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because such a step is part of GMP and will provide a purified and sterile 225Ac-DOTATATE product that is suitable for administration to a subject. One of ordinary skill in the art would be aware that pharmaceutical compositions are most often sterilized and such a step will also remove any residual solid components present in the reaction mixture and forms part of GMP as taught by Petrik et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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