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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/30/2026 has been entered.
Response to Amendment
The amendment filed on 06/30/2026 has been entered. Claims 1-12 are pending in the application. Applicant’s amendments to the claims have not introduced new matter and are supported in the specification in at least Pg. 8-10 of the instant specification. The term “substantially” is indefinite however because a skilled artisan would not know exactly how free of water the solvent is and the specification does not provide a measure of the term to define its scope. See the 112(b) rejection below. Examiner notes the instant specification, while not explicitly using the term “substantially free” describes the solvent as “preferably being free from water” which is interpreted to be a solvent with minimal water content, as understood by a skilled artisan.
Response to Arguments
Applicant’s arguments, see Pg. 7-9, filed 06/30/2026, with respect to claim 1, have been fully considered and are persuasive. Specifically, Arguments regarding Shirakami not teaching alcohol solutions that are free of water and halogens are convincing. Further, arguments regarding Wilbur not teaching using inert gas to remove solvent are convincing. However, upon further consideration, a new grounds of rejection is made in view of Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1), Pozzi et al. (J Nucl. Med. 2005, 46, 4), and Guerard et al. (Bioorganic and Med. Chem. 2017, 25, 5975-5980).
Claim Rejections - 35 USC § 112
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 1-12 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.
The term “substantially” in claim 1 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Examiner notes the instant specification, while not explicitly using the term “substantially free” describes the solvent as “preferably being free from water” which is interpreted to be a solvent with minimal water content, as understood by a skilled artisan.
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 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.
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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1), Pozzi et al. (J Nucl. Med. 2005, 46, 4), and Guerard et al. (Bioorganic and Med. Chem. 2017, 25, 5975-5980), with evidentiary support provided by Maxtite (Methanol ACS Reagent Grade).
Regarding claim 1, Shirakami teaches a method of preparing an astaine-211 solution that begins with alpha-particle irradiation of bismuth-209 in a cyclotron to provide astaine-211 prior to heating the substance to evaporate astatine-211, and dissolving the evaporated astatine-211 in a liquid in the presence of a pH modifier including sodium hydrogen carbonate (i.e. sodium bicarbonate (Pg. 3, par. 5-7; Pg. 3, Test Example 1, Examples 2-5). Shirakami further teaches the liquid used to dissolve the astaine-211 can be an alcoholic solution comprised of ethanol (Pg. 3, par. 7-11). Shirakami teaches the astantine-211 dissolving step is conducted at room temperature, specifically at 0 to 40 °C (Pg. 3, par. 3).
Shirakami teaching sodium bicarbonate meets the limitation “weak acid,” as outlined in the instant specification on Pg. 9 and in instant claims 2-4. Shirakami teaching ethanol as a solvent meets the limitation “volatile and polar solvent…free of halogen atoms,” as outlined in the instant specification on Pg. 8 and in instant claim 5. Shirakami teaching the sodium bicarbonate alcoholic solution being added at room temperature requires cooling the evaporated astastine-211, meeting the limitation of step (3).
The claim further requires “a step of removing the solvent from the astatine-211 solution containing weak acid salt obtained in step (4),” to which Shirakami does not explicitly discuss.
Wilbur teaches a process for isolation and purification of astatine-211 where following
irradiation of a bismuth sample to produce astatine-211 and dissolution in acid to prepare a solution comprising astatine-211, the acid solution is removed from the astatine-211 residue ([0017]; [0027]; [0042]).
Advantageously, removing the acid solution provides astatine -211 residues, which can be further processed to provide purified astatine-211 in larger quantities and greater yields than known methods ([0042]; [0054]; [0064]).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to remove the acid solution from the astatine-211 in the process of Shirakami in order to provide an astatine-211 residue that can be further purified in large quantities and with improved yield, as taught by Wilbur.
The claim further requires the polar solvent is “substantially free of water” to which Shirakami and Wilbur do not teach a solvent that is “substantially free of water”.
Pozzi teaches a method of preparing an At-211 solution from bombarded bismuth where the At-211 is dissolved in regent grade solvents, including methanol (Abstract; Pg. 701, left and right col.). As evidenced by Maxtite, reagent grade methanol contains less than 0.1% water content and is interpreted to be consistent with solvent “substantially free of water.” Examiner notes the instant specification does not explicitly describe the term “substantially” and instead describes the solvent as “preferably free from water.” See Pg. 8. Accordingly, a solvent with less than 0.1% water, as taught by Pozzi, is considered to meet the limitation required by the claim.
Advantageously, methanol is a much better choice for solvent than chloroform or benzene as a solvent for the synthesis of high activity levels of At-211 labeled radiopharmaceuticals (Pg. 706, left col.).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to use a reagent grade methanol solvent in the process of Shirakami in order to provide an astatine-211 solution with a high activity level, as taught by Pozzi.
The claim further requires the solvent is removed under a stream of inert gas. Shirakami and Pozzi do not explicitly discuss solvent removal, while Wilbur teaches removing solvent but does not state the solvent is removed “under a stream of inert gas.” Guerard teaches a method of labeling compounds with At-211 where after generating At-211 by bombardment of bismuth, the At-211 solution recovered is reduced to dryness under a stream of nitrogen (Pg. 5979, right col.).
Advantageously, the method taught by Guerard provides astatinated molecules without an HPLC step, thus allowing easy transfer to a fully automated synthesis (Pg. 5979, left col).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to remove solvent from the At-211 solution with a stream of nitrogen in the process of Shirakami in order to avoid HPLC and allow easy transfer to a fully automated synthesis as taught by Guerard.
Regarding claim 2-4, Shirakami teaches sodium bicarbonate (NaHCO3) is added to the astatine-211 solution (Pg. 3, par. 4-6; Pg. 4, Example 1).
Regarding claim 5, Shirakami further teaches the liquid used to dissolve the astaine-211 can be an alcoholic solution comprised of ethanol (Pg. 3, par. 7-11). Shirakami teaching ethanol as a solvent meets the limitation “volatile and polar solvent,” as outlined in the instant specification on Pg. 8 and in instant claim 5.
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1), Pozzi et al. (J Nucl. Med. 2005, 46, 4), and Guerard et al. (Bioorganic and Med. Chem. 2017, 25, 5975-5980) and further in view of Goodman et al. (US20060292073A1).
Regarding claims 6-8, modified Shirakami teaches the method of preparing astaine-211 of claim 1 and the claims further require limitations to which Shirakami, Wilbur, Pozzi, and Guerard are silent.
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Goodman teaches a method of radiolabeling compounds (Abstract), where the radioactive labeling element is incorporated by exchange of trifluoromethanesulfonyloxy groups with alkali metal salts of halogen isotopes, including astaine-211 ([0014]; [0041]; Pg. 6, Scheme 2, step h; Scheme 5, step j).
It is noted Goodman depicts substitution of the trifluoromethanesulfonyloxy group with fluoride-18, however as noted above, Goodman describes the method as being effective with a variety of halogen isotopes, including astatine-211 ([0014]). The trifluoromethanesulfonyloxy meets the limitation “haloalkylsulfonyloxy” in claim 7 and “trifluoromethanesulfonyloxy” in claim 8. Further, the process of Goodman is understood to be a nucleophilic substitution reaction, where trifluoromethanesulfonyloxy is a leaving group being displaced by the incoming halogen isotope nucleophile. Further, this process is analogous to that disclosed in the instant invention in at least Pg. 10-14 of the instant specification, meeting the limitation “nucleophilic substitution reaction.”
Advantageously, the method disclosed by Goodman is reliable, efficient, and allows gram scale preparations of key precursors for radiolabeling ([0011]).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to incorporate a halogen isotope into a compound by nucleophilic substitution of a trifluoromethanesulfonyloxy in the process of Shirakami in order to incorporate halogen isotopes in a reliable and efficient manner that allows gram scale preparation of radiolabeled compounds, as taught by Goodman.
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Shirakami et al. (WO2019131998A1; English) in view of Wilbur et al. (US20160053345A1), Pozzi et al. (J Nucl. Med. 2005, 46, 4), and Guerard et al. (Bioorganic and Med. Chem. 2017, 25, 5975-5980) and further in view of Ogawa et al. (Nuclear Medicine and Biology, 2015, 42, 875-879).
Regarding claims 9-12, modified Shirakami teaches the method of preparing astaine-211 of claim 1 and the claims further require limitations to which Shirakami, Wilbur, Pozzi, and Guerard are silent.
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Ogama teaches a process to prepare astatine-211 labeled compounds by standard electrophilic halogenation of aromatic rings substituted with tributylstannyl moieties with astatine-211 reagents (Abstract; Title; Fig. 1, Pg. 877, 3. Results).
The moiety Sn(nBu)3 taught by Ogawa meets the limitation “trialkylstannyl group” of claim 11, and “tributylstannyl group” of claim 12. Further, Ogawa describing the reaction as electrophilic halogenation of an aromatic ring substituted with tributylstannyl groups meets the limitation of “electrophilic substitution reaction” in claim 9 and “aromatic electrophilic substitution reaction” in claim 10.
Advantageously, electrophilic halogenation of corresponding tributylstannyl precursors with astatine-211 provides a very high radiochemical yield in the resulting products (Pg. 877, 3.1. Preparation of (+)-[211At]pAtV).
Thus, prior to the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to incorporate astatine-211 into an aromatic ring by electrophilic halogenation of corresponding tributylstannyl precursors in the process of Shirakami in order provide compounds with a very high radiochemical yield, as taught by Ogawa.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jordan Wayne Taylor whose telephone number is (571)272-9895. The examiner can normally be reached Monday - Friday, 7:30 AM - 5 PM EST; Second Fridays Off.
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/JORDAN W TAYLOR/Examiner, Art Unit 1738
