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 .
Acknowledgement of Receipt
Applicant’s Response, filed 10/8/2025, in reply to the Office Action mailed 7/28/2025, is acknowledged and has been entered. Claim 1 has been amended. Claim 1 is pending and is examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds for rejection are set forth herein, necessitated by claim amendment.
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.
Claim(s) 1 is rejected under 35 U.S.C. 103 as being unpatentable over Purohit et al. (J. Med. Chem., 2008, 51, 10, p. 2954-2970) in view of Yu et al. (Semin Nucl Med, 2011, 41, p. 305-313).
Purohit discloses synthesis and biological evaluation of pyridazinone analogues as potential cardiac positron emission tomography tracers, including compound 27 corresponding to flurpiridaz.
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Compounds 22–28 within this series were radiolabeled with the PET isotope 18F. Nucleophilic radiofluorination methods require activated leaving groups such as sulfonates (e.g., tosylates, mesylate) in order to generate alkylfluoride containing radioligands.35 Primary sulfonates are often the preferred leaving group because of their ease of displacement with nucleophilic 18F, compared with secondary sulfonate leaving groups, which often eliminate under fluorination conditions to yield olefinic byproducts. With this in mind, the [18F]22–28 were prepared with chemical yields ranging from 8.2 to 35% (Table 6) by the reaction of their corresponding tosylate precursors with kryptofix222/K18F complex and potassium carbonate in acetonitrile at 90 °C for 30 min followed by preparative HPLC separation of the reaction mixture (Scheme 7). The appropriate fractions were concentrated and analyzed for radiochemical yield and purity. The radioactivity of the final product was ∼25 mCi with radiochemical purity >99% when prepared with 500 mCi [18F]fluoride, with a total time of synthesis of 90 min (page 2958).
18F solution with the remaining constituents (K, CO3 2-, K222) was transferred to a conical bottomed 5 mL Wheaton vial containing 3.0 mg of the desired tosylate precursor 55, 64, 66, 69, 71, 73, or 74 (3.0 mg) dissolved in ACN (0.5 mL). The vial and contents were heated at 90 °C for 30 min. The reaction solution was transferred to a 25 mL pear-shaped flask and diluted with water (18.5 mL). The resultant mixture was passed through a Sep Pak C18 cartridge, then rinsed with water (5 mL). The Sep Pak C18 cartridge was then eluted with ACN (3 mL) and the column dried with N2(g). The collected acetonitrile fraction was purified via HPLC (Phenomenex LUNA C-18 column 250 mm × 10 mm, 5 µm particle size, 100 Å pore, mobile phases A: 90/10 H2O/CH3CN; B: CH3CN, both containing 0.1%TFA as stabilizer; gradient: 0–100/15 sustained at 100% B to 20 min, flow rate 2.5 mL/min) 18F analogues 22–28 eluted from the column and were collected as single fractions (Table 6). The solvent was then removed via rotary evaporation. Upon drying, the contents of the flask were reconstituted with a 10% ethanol solution (page 2968).
Purohit does not specifically recite a composition comprising flurpiridaz and a flurpiridaz hydroxy analog at an amount greater than 0 µg/mL, and 5 µg/mL.
Yu teaches that the hydroxylated analog of flurpiridaz is separated from flurpiridaz by HPLC upon synthesis from the tosylate precursor. See scheme showing a simplified schematic representation of flurpiridaz F-18 radiosynthesis process. It is 1-step direct radiolabeling. 18F eluted from the column reacts with tosylate precursor to replace the leaving group to generate flurpiridaz F-18 and other impurities. The products are separated by using high-performance liquid chromatography (HPLC), and flurpiridaz F-18 is collected. The final product is formulated in water with 50 mg/mL ascorbic acid for unit dose delivery (page 312).
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It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a composition comprising flurpiridaz and having a very small amount of hydroxy derivative of flurpiridaz as a minor impurity when the teaching of Purohit is taken in view of Yu. One would have been motivated to do so, with a reasonable expectation of success, because Purohit teaches that compound 27 (flurpiridaz) is prepared upon fluorination of a toluene sulfonate ester precursor and was purified by high-performance liquid chromatography using acetonitrile-based mobile phase to give a radiochemical purity of greater than 99%, and Yu teaches that the hydroxy derivative of flurpiridaz is an impurity that is separated from flurpiridaz by HPLC. While Purohit does not specifically recite an absolute amount of hydroxy impurity which accounts for 99% RCP, one of ordinary skill would desired to optimize the amount of impurity in order to obtain a product with high purity for in vivo studies, such as by optimization of HPLC parameters using routine techniques known in the art. Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Yalamanchili et al. (J. Nuclear Cardiol., 2007, 14, p. 782–788) in view of Yu et al. (Semin Nucl Med, 2011, 41, p. 305-313).
Yalamanchili teaches that BMS-747158-02 is a novel fluorine 18-labeled pyridazinone derivative designed for cardiac imaging.
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Synthesis of F-18 BMS-747158-02 was performed at Bristol-Myers Squibb Medical Imaging. Radiolabeling involved the fluorination of a toluene sulfonate ester precursor and F-18 BMS-747158-02 was purified by high-performance liquid chromatography to give a radiochemical purity of greater than 95%. Purified F-18 BMS-747158-02 was reconstituted in 98% saline solution/2% ethanol. Fluorine 19 BMS-747158-01 was synthesized at Bristol Myers Squibb Medical Imaging. The chemical structure of F-18 BMS-747158-02 and F-19 BMS-747158-01 is shown in Figure 1 (page 783).
Yalamanchili does not specifically recite a composition comprising flurpiridaz and a flurpiridaz hydroxy analog at an amount greater than 0 µg/mL, and 5 µg/mL.
Yu teaches a simplified schematic representation of flurpiridaz F-18 radiosynthesis process. It is 1-step direct radiolabeling. 18F eluted from the column reacts with tosylate precursor to replace the leaving group to generate flurpiridaz F-18 and other impurities. The products are separated by using high-performance liquid chromatography (HPLC), and flurpiridaz F-18 is collected. The final product is formulated in water with 50 mg/mL ascorbic acid for unit dose delivery (page ).
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It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a composition comprising flurpiridaz and having a very small amount of hydroxy derivative of flurpiridaz as a minor impurity when the teaching of Yalamanchili is taken in view of Yu. One would have been motivated to do so, with a reasonable expectation of success, because Yalamanchili teaches that BMS-747158-02 is prepared upon fluorination of a toluene sulfonate ester precursor and F-18 BMS-747158-02 (flurpiridaz) and was purified by high-performance liquid chromatography to give a radiochemical purity of greater than 95%, and Yu teaches that the hydroxy derivative of flurpiridaz is an impurity that is separated from flurpiridaz by HPLC. While Yalamanchili does not specifically recite an absolute amount of hydroxy impurity which accounts for 95% RCP, one of ordinary skill would have desired to optimize the amount of impurity in order to obtain a product with high purity for in vivo studies, such as by optimization of HPLC parameters using routine techniques known in the art. Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Cesati (US 2013/0064769) in view of Yu et al. (Semin Nucl Med, 2011, 41, p. 305-313).
Cesati teaches methods and system for the synthesis of imaging agents, and precursors thereof. The methods may exhibit improved yields and may allow for the large-scale synthesis of imaging agents, including imaging agents comprising a radioisotope (18F). Various embodiments of the invention may be useful as sensors, diagnostic tools, and the like. In some cases, methods for evaluating perfusion, including myocardial perfusion, are provided. Synthetic methods of the invention have also been incorporated into an automated synthesis unit to prepare and purify imaging agents that comprise a radioisotope. In some embodiments, the present invention provides a novel methods and systems comprising imaging agent 1, including methods of imaging in a subject comprising administering a composition comprising imaging agent 1 to a subject by injection, infusion, or any other known method, and imaging the area of the subject wherein the event of interest is located (abstract).
In one set of embodiments, the imaging agent precursor comprises the formula
herein referred to as imaging agent precursor 1 (see FIG. 1), i.e. corresponding to flurpiridaz.
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Upon reaction, the resulting imaging agent product is transferred from the reaction module to the purification module for further processing, treatment, and/or purification. The purification module may include, for example, a column (e.g., an HPLC column) fluidly connected to one or more sources of solvents to be used as eluents. The purification module may further comprise a source of a stabilizing agent (e.g., ascorbic acid or a salt thereof), which may be added to the imaging agent upon purification (e.g., by HPLC). The purified imaging agent is then transferred to the formulation module, where further purification and formulation may be performed. The formulation module may include a filter for aseptic filtration and/or a C-18 column for solvent exchange (paragraph 0370).
In another embodiment, a cassette comprises a reaction module and a formulation module. A reaction module of the invention may include a source of 18F, a filter to remove unreacted [18O]H2O, a source of an ammonium salt, a source for a diluent for the 18F, a source for an imaging agent precursor, (e.g., imaging agent precursor 1 shown in FIG. 1, or other imaging agent precursor), a source for an H2O diluent for the imaging agent precursor, a reaction vessel for reacting the 18F and the imaging agent precursor, a solid phase extraction column (e.g., a C18 column, or other suitable column) in fluid communication with the reaction vessel. The solid phase extraction column includes a solid sorbent to adsorb the radiolabeled imaging agent product on the sorbent. At least a portion of the residual reaction impurities pass through solid phase extraction column without adsorbing on the sorbent. The reaction module also includes a source of wash solutions in fluid communication with the solid phase extraction column for providing wash solutions to elute the remaining impurities on the sorbent, and includes a source of an eluent (e.g., as H2O/MeCN, or other suitable eluent) in fluid communication with the solid phase extraction column for eluting the radiolabeled imaging agent product off the sorbent. The reaction module may also include a source of a diluent for the eluted radiolabeled imaging agent (paragraph 0371).
A formulation module of an apparatus of the invention may be in fluid communication with a reaction module and may include a solid phase extraction cartridge that includes a solid sorbent (e.g., C-18, or other suitable sorbent) to adsorb the diluted radiolabeled imaging agent, a source of wash solutions (e.g., comprising ascorbic acid, a salt thereof, or other suitable wash solution) in fluid communication with the solid phase extraction cartridge for providing wash solutions to wash off any remaining impurities on the sorbent, and a source of eluting fluid (e.g., ethanol, or other suitable eluting fluid) in fluid communication with the solid phase extraction cartridge for eluting the radiolabeled imaging agent product off the sorbent. The formulation module may also include a source of a diluent (e.g., comprising ascorbic acid, a salt thereof, or other suitable diluent), for diluting the eluted radiolabeled imaging agent. The formulation module may also be in fluid communication with a sterilizing filter (e.g., a Millipore Millex GV PVDF sterilizing filter, or other suitable sterilizing filter) (paragraph 0372).
Cesati does not specifically recite a composition comprising flurpiridaz and a flurpiridaz hydroxy analog at an amount greater than 0 µg/mL, and 5 µg/mL.
Yu teaches a simplified schematic representation of flurpiridaz F-18 radiosynthesis process. It is 1-step direct radiolabeling. 18F eluted from the column reacts with tosylate precursor to replace the leaving group to generate flurpiridaz F-18 and other impurities. The products are separated by using high-performance liquid chromatography (HPLC), and flurpiridaz F-18 is collected. The final product is formulated in water with 50 mg/mL ascorbic acid for unit dose delivery (page ).
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It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a composition comprising flurpiridaz and a very small amount of hydroxy derivative of flurpiridaz as a minor impurity when the teaching of Cesati is taken in view of Yu. One would have been motivated to do so, with a reasonable expectation of success, because Cesati teaches that the compound corresponding to flurpiridaz is prepared upon fluorination of a toluene sulfonate ester precursor and may be purified by high-performance liquid chromatography or solid phase extraction using H2O/MeCN as eluting fluid, and Yu teaches that the hydroxy derivative of flurpiridaz is an impurity that is produced upon reaction of fluorine-18 and the toslyate precursor of flurpiridaz. While Cesati does not specifically recite an absolute amount of residual hydroxy impurity, one of ordinary skill would desired to optimize the amount of residual impurity in order to obtain a product with high purity for in vivo studies, such as by optimization of HPLC or SPE parameters using routine techniques known in the art. For example, Cesati states that the solid phase extraction column includes a solid sorbent to adsorb the radiolabeled imaging agent product on the sorbent. At least a portion of the residual reaction impurities pass through solid phase extraction column without adsorbing on the sorbent. The reaction module also includes a source of wash solutions in fluid communication with the solid phase extraction column for providing wash solutions to elute the remaining impurities on the sorbent, and includes a source of an eluent (e.g., as H2O/MeCN, or other suitable eluent) in fluid communication with the solid phase extraction column for eluting the radiolabeled imaging agent product off the sorbent (paragraph 0371).
Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Conclusion
No claims are allowed at this time.
The following reference is made of record as being relevant to the instant invention: Mistry et al., SOT 2008 ANNUAL MEETING, 2008, p. 476.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618