DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims. 1-4, 6-7, 9-10, and 12-23 are pending in this application.
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 .
Status of Claims
Claims 1-2, 7, 9, 12, 17, and 19 are amended. Claims 5, 8, and 11 are cancelled.
Response to Amendment
The amendments filed on 7 Nov. 2025 have been entered.
Response to Arguments
In view of Applicants amendments, the objection to claims 1, 17, and 19 because of minor informalities is withdrawn.
In view of Applicants amendments, the objection to the specification as failing to provide proper antecedent basis for the claimed subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 1-4, 6-7,9-10 and 12-23 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 1-4, 6-7, 9-10, 12, and 16 under 35 USC 103 as being unpatentable over Chudakov et al. (Radiochem.; published 2014), in view of Evers et al. (WO 2010/132043 A1; published 18 Nov. 2010) and Aardaneh et al. (J. Nucl. Chem.; published 2006), in further view of Biosafety (http://blink.uscd.edu/safety/research-lab/biosafety/decontamination/index/html; published 29 Sep. 2009) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-4, 6-7, 9-10, and 12-23 under 35 USC 103\ as being unpatentable over Chudakov et al. (Radiochem.; published 2014), in view of Evers et al. (WO 2010/132043 A1; published 18 Nov. 2010) and Aardaneh et al. (J. Nucl. Chem.; published 2006), and Biosafety (http://blink.uscd.edu/safety/research-lab/biosafety/decontamination/index/html; published 29 Sep. 2009), in further view of Verma et al. (WO 2017/192189 A1; published 9 Nov. 2017) is withdrawn.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6-7, 9-10, and 12-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. In this case, the Examiner is unable to find support in the specification for the amended instant steps a) and b) as recited instant claims 1, 17, and 19. In addition, the Examiner is unable to find support in the specification as originally filed for the recitation of “wherein the generator column is subject to only two sterilization steps and the generator column loaded with the particulate ion exchange matrix is subject to only a single sterilization step.” The response filed on 7 Nov. 2025 does not point to any sections of the specification supporting those claim amendments. Regarding amended a) and b), the specification at pg. 7 discloses that after the ion exchange matrix is filled in the generator column, the matrix is preferably conditioned. The flow rate during the conditioning is preferably of about 0.02-1.0 mL/hr. After conditioning is performed. The rinsing step can be performed by the elution of 0.9% sodium chloride at a flow rate of 10 mL/min. Thus, the specification as filed make it clear that steps a) and b) are conducted using a column filed with ion exchange matrix. The Examiner is unable to find any mention of only two sterilization steps or that the column loaded with the ion exchange matrix is subject to only a single sterilization step. Claims 2-4, 6-7, 9-10, 12-16, 18, and 20-23 depend to one of claims 1, 17, and 19 and fall therewith.
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 1-4, 6-7, 9-10, and 12-23 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.
Claim 1, 17, and 19 recite the limitation "the empty generator column" at steps a) and/or b). There is insufficient antecedent basis for this limitation in the claim. Claims 2-4, 6-7, 9-10, 12-16, 18, and 20-23 depend to one of claims 1, 17, and 19 and fall therewith.
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.
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) 1-4, 6-7, 9-10, 12, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chudakov et al. (Radiochem.; published 2014), in view of Evers et al. (WO 2010/132043 A1; published 18 Nov. 2010) and Aardaneh et al. (J Radioanal. Nuc. Chem.; published 2006), in further view of Biosafety (http://blink.uscd.edu/safety/research-lab/biosafety/decontamination/index/html; published 29 Sep. 2009).
Chudakov et al. teach characterization of an 82Rb generator for positron emission tomography (see title). Chudakov et al. teach a draft of a GR-02 generator
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that includes a generator column, internal steel vessel, and shielding lead contain in a steel shell (see Fig. 2). Such design of the plug facilitated the generator assembling and its disassembling after the end of service for subsequent utilization (pg. 536). Chudakov et al. teach sterilization. All metal parts of the generator column where preliminarily sterilized in an autoclave at 120oC for 20 min. The solution and the sorbent in the hermetically sealed generator column were thermally sterilized before loading the generator (pg. 537). The sorbent powder fraction of 80-160 µm was separated by sieving kept for 10-12 h in a 0.1 M NH4OH solution and repeatedly elutriated. The sorbent in the column was saturation with sodium ions by passing a 2 M NaCl solution through the column. After such treatment sorbent was transferred into the generator column in the form of a suspension. The excess sodium ions were removed by passing a 0.9% NaCl solution through the column. The column was hermetically sealed with standard Luer plastic plugs, wrapped into aluminum foil and thermally sterilized in an autoclave at 120-130oC for 30-60 min after which it was ready for 82Sr sorption, i.e., for generator loading (pg. 538). The hydrodynamic resistance depends on the flow rate of the liquid fed into it (pg. 538). The length of the column packed with sorbent by the described procedure of 27, 40, and 60 mm, the inlet pressure is ~40, ~60, and ~90 kPa and without sorbent it is 20 kPa (pg. 539). The generator should be sterilized prior to starting its medical use. The sterilization performed with the hermetically sealed column does not lead to appreciable increase in breakthrough (pg. 529). Hydrous tin(IV) oxide in the α-form was used as sorbent (pg. 537). Chudakov et al. teach the main characteristics of the 82Sr/82Rb generator including a height of 275 mm and external diameter of 95 mm (table 2). The generator column can be fabricated at a large distance from a clinic and transported to any distance in the transport package (pg. 541).
Chudakov et al. do not teach conditioning the empty generator column at a flow rate of about 0.02 mL/h to about 1.0 mL/h, rinsing the empty generator column by elution of 0.9% sodium chloride at a flow rate of 10 mL/min, sterilizing the empty generator column by dry heat prior to loading, or that after installing the generator column loaded with particulate ion exchange matrix into a generator compartment, sterilizing the generator compartment with the generator column installed within the generator compartment with steam to allow the column preparation steps in a non-sterile environment. Although Chudakov et al. teach the generator column passes all kinds of tests required for registration of a medical item, Chudakov et al. do not teach that the generator column is compliant to periodic quality tests optionally at least once per day prior to use. Chudakov et al. do not expressly teach that the generator column is subject to only two sterilization steps and the generator column loaded with the particulate ion exchange matrix is subject to only a single sterilization step.
Evers et al. teach a radionuclide generator and method of sterilization (see title). Evers et al. teach that sterilization may be performed by exposing a column assembly of a radionuclide generator, having a column loaded with parent radionuclide to saturated steam environment. Liquid that resides into the column assembly may be heated to vapor form (e.g. steam) to kill and/or inactivate contaminants. Providing a vented cover at the outlet port of the column assembly during sterilization may help achieve sterilization (pg. 2) Evers et al. teach a method comprising providing a column assembly of a radionuclide generator that includes a column having a long-lived parent radionuclide (pg. 2). The column assembly may be provided in combination with a shielded package (pg. 3). Evers teaches a view of a vented outlet cover with a vent opening to prevent the ingress of liquid and a column assembly assembled into a shielded package (Figs. 1, 3 and 4). The column assembly is typically positioned within a shielded package (pg. 5). Sterilization of the column assembly in this manner may provide for a terminally sterile column assembly given that no further manipulations of customer access points or internal portions of the flow path therebetween may be performed subsequent to sterilization and prior to the radionuclide generator being accessed by an end user. Alternatively, the column assembly may merely be assembled into a shielded package and readied for shipment. This may involve placing one or more column assemblies into a sterilization chamber having a vented cover. Steam is provided to the sterilization chamber as the pressure of the chamber is increased. Types of sterilization other than saturated steam may be used (pgs. 8-9). The column assembly may be positioned within a package that includes shielding to prevent radiation from the column assembly above a threshold value (pg. 13). The radionuclide generator is stored until the radionuclide generator is again to be eluted (pg. 15).
Aardaneh et al. teach radiochemical separation of 82Sr and the preparation of a sterile 82Sr/82Rb generator column (see title). Aardaneh et al. teach the manufacturing the 82Sr/82Rb generator column (preparing a generator column filled with particulate ion exchange matrix that elutes the desired radioisotope 82Rb). All components of the generator column, made from stainless steel (column is made of heat-resistant material and is resistant to heat at a temperature of about 110oC to about 280oC during sterilization or depyrogenation) were washed with soap and water, then rinsed with water and dried (undergoes a cleaning process). The solutions for conditioning the column were autoclaved before use. The column was made of a 4 cm stainless steel tube with 9.5 mm O.D. and 7.1 mm I.D. and two 20 µm frit. The hydrous tin dioxide suspended in 2 M NaCl solution obtained from the titration procedure, was transferred into the column under a very mild vacuum provided by a peristaltic pump attached to the other end of the outlet line. The tin dioxide (alpha stannic acid) was added. 200 mL 2M NaCl solution was pumped through the column at a flow rate of 0.5 mL/min (conditioning the column at a flow rate of about 0.5 mL/min or 30 mL/h) followed by 300 mL 0.9% NaCl solution at 10 mL/min (rinsing the column by the elution of 0.9% NaCl at a flow rate of 10 mL/min; see pg. 386). Aardaneh et al. teach loading 82Sr onto the generator column (column loading with desired radioisotope). The solution containing 82Sr obtained from the radiochemical separation was adjusted to pH 7.5-85 with the addition of 0.1 M NaOH solution and then pumped onto the column at a flow rate of 6 mL/h followed by a further 30 mL 0.9 NaCl solution pH 7.4-8.5). Aardaneh et al. teach the components of the 82Sr/82Rb generator column
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(comprises an inlet port, body and outlet port wherein body has a 4 cm length, 7.1 mm I.D., and 2.4 mm wall thickness; see Fig. 1).
The test for sterility was carried out under aseptic conditions inside a laminar airflow cabinet to avoid accidental contaminations. The chromogenic limulus amebocyte lysate (LAL) test was used for quantitative determination of endotoxin (see pg. 387). The sterility test of 82Rb showed not visible growth and the endotoxin concentration was less than 10 eu/mL (compliant to periodic quality assurance tests selected from LAL test) (see pg. 389).
2M NaCl solution was pumped through the generator column packed with the titrated hydrous tin dioxide at a flow rate of 0.5 mL/min. Pumping sodium chloride solution was continued until the effluent reached a pH of ~8.5 and a volume of ~250 mL 2M NaCl was consumed. After passing 300 mL 0.9% NaCl solution through the column at a flow rate of 10 mL/min, the pH of the eluate was still greater than 8. After using a 7-liter solution, the eluate had a pH 5.9, in which the distribution coefficient Sr2+ is still at the highest level (see pg. 389). Aardaneh et al. teach passing 0.1 M ammonia solution through the column at high flow rates and hydrous tin is soluble in solutions with pH>10.
Biosafety teaches decontamination methods for laboratory use. Biosafety teaches that cleaning is often required before sterilization or disinfection because it removes all material such as soil or organic material and reduces the number of microorganisms on the object. Wet heat sterilization uses saturated steam under pressure of approximately 15 psi to achieve a chamber temperature of at least 121oC for a prescribed time (30 to 60 min) to destroy all forms of microbial life. Sterilization by dry heat can usually be accomplished at 160oC-170oC for periods of 2 to 4 h. Monitor wet and dry heat sterilizers on a regular basis using appropriate biological indicator. Disinfectants can be classified into quaternary ammonium compounds.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Chudakov et al. (method of preparing a reusable stainless steel generator column for elution of 82Rb for PET imaging wherein the generator column gets placed in a generator compartment and passed all sorts of tests required for registration of a medical item) by conditioning the empty generator column at a flow rate of about 0.02 mL/h to about 1.0 mL/h and by further rinsing the empty generator column by the elution of 0.9% sodium chloride at a flow rate of 10 mL/min as taught Chudakov et al. and Aardenah et al. because the conditioning and rinsing would have been expected to advantageously enable cleaning the generator column at low backpressure and preparing the generator column for packing with a sorbent that gets eluted with sodium chloride. The flow rates are result effective variables that a person of ordinary skill in the art would have optimized based on duration of elution and working pressure. MPEP 2144.05.II. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chudakov et al. by further preliminarily sterilizing the generator column by dry heat optionally at a temperature of about 210oC to about 280oC for a period of 3 h to 12 h and storing the sterilized, empty generator column as taught by Chudakov et al. and Biosafety because the preliminary sterilization by dry heat would have been expected provide an equivalent means of sterilizing and decontaminating the generator column and because the storing would have been expected to advantageously enable positioning the column for its next use. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chudakov et al. so that after the generator column gets installed in the generator compartment, the generator compartment with generator column installed therein together get sterilized with steam to allow the column preparation steps in a non-sterilize environment optionally with steam at a temperature of about 110oC to about 150oC for a period of 20-60 min resulting in generator column subjected to only two sterilization steps and a generator column loaded with matrix subjected to only a single sterilization step as taught by Chudakov et al. and Evers et al. because combined sterilization would have been expected enable a singled combined sterilization of the column its compartment in final position with sorbent optionally allowing venting without ingress of contaminant vapor needing no final manipulations that expose the column to contaminants whereby enhancing simplicity and biosafety.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chudakov et al. so that the sterilized generator column is compliant to periodic quality assurance tests such as the LAL test optionally at least once a day prior to uses as taught by Chudakov et al., Aardaneh et al., Evers et al., and Biosafety because it would have been expected to enable a QC compliant 82Rb solution capable of use in PET. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chudakov et al. by further cleaning the reusable stainless steel generator column after eluting the radioactive solution wherein the cleaning process comprises the steps of: i) emptying the generator column by removing the matrix therefrom to provide an empty column; j) sterilizing the empty generator column in the previous step; and k) loading new particulate ion exchange matrix into the sterilized generator column as taught by Chudakov et al. and Aardaneh et al. because the cleaning process would have been expected to enable getting the sterilized generator column ready for its next use as a sterilized medical device. The dimensions of the generator column are result effective variables that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a length of about 3 cm to about 8 cm, an internal diameter of about 4 mm to about 12 mm and a wall thickness of about 0.4 mm to about 1.2 mm in order to arrive at an optimal operating pressure and shielding while minimizing the amount of steel used.
Claim(s) 1-4, 6-7, 9-10, and 12-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chudakov et al. (Radiochem.; published 2014), in view of Evers et al. (WO 2010/132043 A1; published 18 Nov. 2010) and Aadaneh et al. (J Radioanal. Nuc. Chem.; published 2006), and Biosafety (http://blink.uscd.edu/safety/research-lab/biosafety/decontamination/index/html; published 29 Sep. 2009), in further view of Verma et al. (WO 2017/192189 A1; published 9 Nov. 2017) for the reasons cited in the Office action filed on 7 Aug. 2025.
Chudakov et al. teach as discussed above.
Chudakov et al. do not expressly teach cleaning the generator column in a clean room optionally wherein the cleaning process of the generator column is performed in a clean area by washing with 0.01M NH4OH with a pH range of from about 9 to about 10 or wherein the cleaning process is performed by infusing about 10 mL to about 50 mL of NH4OH at a flow rate of about 10 mL/min to about 20 mL/min.
Evers et al. teach as discussed above.
Aardaneh et al. teach as discussed above.
Biosafety teaches as discussed above.
Verma et al. teach systems and methods for sterility testing of radionuclide generator column assemblies (see title). Verma et al. teach a wash/fill station ([0025] Verma et al. teach that a clean room environment minimizes possible sources of contamination ([0029]). Verma et al. teach embodiments where one or more stations are maintained in a clean room environment including pre-autoclave hot cells, the fill/wash station and the assay/autoclave loading station (see [0035]). Verma et al. teach aseptic assembly. Autoclave sterilization includes exposing a vented column assembly, having a column loaded with parent radionuclide, to a saturated steam or steam air mixture environment (see [0040]). A sterility test is collected from a column assembly within 4 h of sterilization (see [0067]). Minimizing the time between elution collection and sterility testing facilitates detection of viable microorganisms present in the column assembly ([0071]). Verma et al. teach reuse of column assemblies ([0073]).
It would have been obvious to a person ordinary skill in the art before the effective filing date to further modify Chudakov et al. by cleaning the generator column in a clean room optionally wherein the cleaning is performed in a clean area by washing with 0.1 M NH4OH with a pH range of 9 to about 10 or wherein the cleaning is performed by infusing about 10 mL to about 50 mL of NH4OH at a flow rate of about 10 mL/min to about 20 mL/min and so that the generator column is compliant to periodic assurance tests such as LAL test at least once per day as taught by Chudakov et al., Biosafety, and Verma et al. because the cleaning in a clean room would have been expected to enable minimizing the sources of contamination providing a column that passes quality control tests for a medical for use in PET and because a periodic quality assurance test performed at least once per day prior to use would have been expected to advantageously ensure sterility of the radiopharmaceutical throughout the column life and before radiopharmaceutical collection.
Claim(s) 13-15, 17-20, and 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Riddoch et al. (US 2021/0265069 A1; published 26 Aug. 2021; see attached 892), in view of Chudakov et al. (Radiochem.; published 2014) and Verma et al. (WO 2017/192189 A1; published 9 Nov. 2017).
Riddoch et al. teach a heat-resistant generator column for elution systems (see title, abstract). Riddoch et al. teach 82Sr/82Rb elution systems ([0002]-[0003]). Riddoch et al. teach preparing comprising the steps of a) loading the column with particulate ion exchange matrix; and b) charging the parent radioisotope on the matrix ([0007]-[0016], [0067]-[0079]). The column comprises a step of depyrogenation of the column prior to loading ([0017]). The column undergoes a cleaning process including the steps of a) removing the used matrix, b) sterilizing the empty column, and c) loading particulate ion exchange matrix into the sterilized column ([0025]-[0028],[0094]-[0097]). The matrix comprises alpha-stannic acid ([0045]). The flow during the conditioning step is preferably of about 0.02-1.0 mL/hr. The solution can be NH4OH/NH4Cl with a basic pH ([0050]). The rinsing step can be performed at by the elution of 0.9% sodium chloride at a flow rate of 10 mL/min ([0051]). The generator column is subjected to periodic quality assurance tests such as once per day including LAL test and radionuclidic purity ([0058]-[0062]). The column is made of heat resistant material such as stainless steel ([0066],[0081]). The depyrogenation consists of dry heating at a temperature from about 210oC to about 280oC for 3 to 12 h ([0084]). The body has a length of about 3 to 8 cm, an internal diameter of about 4 mm to about 12 mm, and a wall thickness from 0.4 mm to about 1.2 mm (claim 13). Sterilization is performed with steam at a temperature of about 110oC to about 150oC for 20 to 60 min (claim 18). The generator column gets installed into the generator compartment and the generator column and compartment therein get sterilized.
Riddoch et al. teach that the generator column is cleaned in a clean room optionally wherein the cleaning process of the generator column is performed in a clean area by washing with 0.1 M NH4OH with a pH range from 9-10 and wherein the cleaning process is performed by infusing about 10 mL to about 50 mL of NH4OH at a flow rate of about 10 mL/min to about 20 mL/min.
Chudakov et al. teach as discussed above.
Verma et al. teach as discussed above.
It would have been obvious to a person ordinary skill in the art before the effective filing date to further modify the method of Riddoch et al. by cleaning the generator column in a clean room optionally wherein the cleaning is performed in a clean area by washing with 0.1 M NH4OH with a pH range of 9 to about 10 or wherein the cleaning is performed by infusing about 10 mL to about 50 mL of NH4OH at a flow rate of about 10 mL/min to about 20 mL/min and so that the generator column is compliant to periodic assurance tests such as LAL test at least once per day as taught by Riddoch et al., Chudakov et al., and Verma et al. because the cleaning in a clean room would have been expected to enable minimizing the sources of contamination providing a column that passes quality control tests for a medical for use in PET and because a periodic quality assurance test performed at least once per day prior to use would have been expected to advantageously ensure sterility of the radiopharmaceutical throughout the column life and before radiopharmaceutical collection.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the method of Riddoch by conditioning the empty generator column at a flow rate of about 0.02 mL/h to about 1.0 mL/h and by further rinsing the empty generator column by the elution of 0.9% sodium chloride at a flow rate of 10 mL/min as taught Riddoch et al. and Chudakov et al. because the conditioning and rinsing would have been expected to advantageously enable cleaning the generator column and low backpressure and preparing the generator column for packing with a sorbent that gets eluted with sodium chloride.
Applicants Arguments
Applicants assert that claim 1 requires the generator column itself to be sterilized. Chudakov discloses sterilizing the unassembled parts of the generator column, not the empty generator column. Chudakov disclose sterilizing the assembled, loaded generator column and only then putting it in the generator. Chudakov fails to disclose steps c), d), and e). To the extent that Chudakov discloses an additional, third step of sterilizing, Chudakov subjects the generator column loaded with the particulate ion exchange matrix to two sterilization steps, not a single sterilization step. Evers describes experiments where a column is subjected to two steam sterilization cycles and the moisture weighed after each of the two cycles. Aardaneh does not disclose how the column is sterilized or how many times or whether the column is loaded or whether the column is in a generator that then is sterilized. Biosafety does not disclose how many times to sterilize a generator column or whether generator column is loaded or whether a loaded generator column is position within a generator. The claimed invention advantageously subjects the filled generator column to a single thermal sterilization. This protects the sorbent properties. The claimed proves avoids the alteration in sorbent properties occurring in Chudakov when the loaded generator is sterilized twice.
Applicant's arguments filed 7 Nov. 2025 have been fully considered but they are not persuasive. Chudakov provides a method of preparing a generator column for the elution of an 82Rb solution wherein the generator column is subject to only two sterilization steps and the generator column loaded with the ion exchange matrix is subject to only a single sterilization step. At pg. 537, when discussing sterilization, Chudakov teaches a first preliminary sterilization of an empty generator column in an autoclave at 120oC for 20 min. At pg. 538, Chudakov teaches a second sterilization where the column was hermetically sealed with standard Luer plugs, and thermally sterilized in an autoclave at 120-130oC for 30-60 min after which it is ready for 82Sr sorption. Chudakov’s teaching at page 539 that the generator should be sterilized prior to starting its medical use is not a teaching of a third sterilization after 82Sr sorption. Immediately afterwards Chudakov describes the second sterilization where the column gets hermetically when performing sterilization and Chudakov cautions that if the column does not get hermetically sealed the ion exchange properties becomes significant worse. Chudakov teaches radiation self-sterilization after sorption of 82Sr onto the column. Accordingly Chudakov reasonably describes a method of preparing a generator column for eluting a radioactive solution wherein the generator column is subject to only two external sterilization steps and the generator column loaded with the particulate ion exchange matrix is subject to only a single external sterilization step.
Evers teaches and suggests that Chudakov’s second sterilization is flawed because 1) it suggests separate sterilization of the column and its compartment prior to assembly and 2) after completion of the second sterilization the column needs to be attached to the rest of the column assembly or compartment whereby exposing the generator column to additional sources of contamination.
Evers provides some teaching, suggestion, and motivation for sterilizing the generator column filled with sorbent together with generator compartment because the combined sterilization would have been expected to enable a terminally sterilized solution obtained using no or few manipulations to the column assembly to provide less sources of contamination. A person of ordinary skill in the art would not have considered an additional third sterilization resulting in a more complex process. Instead, a person of ordinary skill would have considered simply moving Chudakov’s second sterilization step to the time after the column filled with sorbent gets installed in the generator compartment allowing a single combined sterilization of the generator column and its compartment prior to their medical use. Unexpected results require a comparison with the closest prior art. The Examiner is unable to locate a section of the specification that compares sorbent properties after Chudakov’s second sterilization step with sorbent properties after the claimed second sterilization step. Chudakov’s second sterilization conditions are nearly identical to the claimed sterilization conditions. For example, claim 1 allows for the use of any ion exchange matrix.
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 1.321which 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 §§ 706.07which and 714.13.
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Claims 1-4, 6-7, 9-10, and 12-23 are srejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,694,818 B2, in view of Aardaneh et al. (J. Radioanal. Nucl. Chem.; published 2006), Chudakov et al. (Radiochem.; published 2014), Verma et al. (WO 2017/192189 A1; published 9 Nov. 2017), and Biosafety (http://blink.uscd.edu/safety/research-lab/biosafety/decontamination/index/html; published 29 Sep. 2009).
Claims 1-20 of U.S. Patent No. 11,694,818 B2 claim a generator column of an elution system for elution of a radioactive solution wherein the column is prepared by loading a charged matrix onto the column wherein the charging of matrix with parent radioactive isotope is performed at a flow rate of about 0.5 mL/h to about 5 mL/h wherein the parent radioisotope is strontium-82 and the desired radioisotope is rubidium-82 wherein the charging is performed in a sterile environment, wherein the columns is cleaned following use by a process comprising the steps: a) emptying the used column be removing the used matrix, b)sterilizing the empty column., and c) loading new particulate ion exchange matrix into the sterilized column wherein the process comprises the steps of a conditioning step and a rinsing step wherein the conditioning step is performed using 2 M NaCl at a flow rate of about 0.5 mL/min and the rinsing is performed using 0.9% NaCl at a flow rate of about 10 mL/min, wherein the matrix comprises alpha-stannic acid wherein the generator column is installed into a generator compartment and the generator column and compartment are sterilized wherein sterilization is performed with steam at a temperature of about 110oC to about 150oC for a period of about 20 min to 60 min wherein the ion exchange matrix is washed with a buffer solution such as ammonium hydroxide with a basic pH wherein the charging of the matrix is performed in a non-sterile environment.
Claims 1-20 of U.S. Patent No. 11,694,818 B2 do not claim conditioning the generator column at a flow rate of about 0.02 mL/h to about 1 mL/h, sterilizing the generator column by dry heat optionally at a temperature of 210oC to 280oC prior to loading with particulate ion exchange matrix, storing the sterilized generator column or after installing the generator column into the compartment, sterilizing the generator compartment with the column with steam optionally at a pressure of about 15 psi to allow the column preparation steps in a nonsterile environment. Claims 1-20 of U.S. Patent No. 11,694,818 B2 do not claim a column made of heat-resistant material such as stainless steel and is resistant to a temperature of about 110oC to about 280oC and a generator column compliant to periodic quality tests such as a LAL test optionally at least once. Claims 1-20 of U.S. Patent No. 11,694,818 B2 do not claim that the generator column has undergone cleaning in a clean room optionally by washing with 0.1 NH4OH with a pH range of about 9 to 10 or by infusing 10 mL to about 50 mL of NH4OH at a flow rate of about 10 mL/min to about 20 mL/min.
Aardaneh et al. teach as discussed above.
Chudakov et al. teach as discussed above.
Biosafety teaches as discussed above.
Verma et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-20 of U.S. Patent No. 11,694,818 B2 so that the column is a stainless steel column and by conditioning the empty column at a flow rate of about 0.02 mL/h to about 1.0 mL/h as taught by Chudakov et al. and Aardenah et al. because the stainless steel column would have been expected to enable a heat and pressure resistant generator column and because the conditioning would have been expected to advantageously enable washing the column to remove contaminant prior to a preliminary first sterilization. MPEP 2144.05.II. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify claims 1-20 of U.S. Patent No. 11,694,818 B2 by further rinsing the empty generator column by elution of 0.9% sodium chloride at a flow rate of 10 mL/min as taught by claims 1-20 of U.S. Patent No. 11,694,818 B2 and Chudakov et al. because the rinsing would have been prepare the column for loading with ion exchange matrix that gets washed with sodium chloride at a flow rate that provides minimal hydrodynamic resistance and suitable column pressure. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify claims 1-20 of U.S. Patent No. 11,694,818 B2 by further firstly and preliminarily sterilizing the generator column by dry heat optionally at a temperature of about 210oC to about 280oC for about 3 to 12 h prior to loading with particulate ion exchange matrix and then storing that sterilized generator column as taught by Chudakov et al. and Biosafety because dry heat in that temperature range and for that time range would have been expected to provide an equivalent means of sterilizing the column assembly and all metal parts. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify claims 1-20 of U.S. Patent No. 11,694,818 B2 so that after the sterilized generator column gets installed into a generator compartment optionally comprising a vented outlet cover, the column and compartment together get sterilized with steam optionally at a temperature of 110oC to about 150oC for about 20 min to 60 min and optionally at a pressure of 15 psi to about 45 psi to allow the preparation in a non-sterile environment resulting in second sterilization such that column is subjected to only two sterilization steps and the loaded column is subjected to only a single sterilization step as taught by claims 1-20 of U.S. Patent No. 11,694,818 B2, Biosafety and Chudakov et al. because it would have been expected to enable terminally sterilized column assembly needing no further manipulations and less points of potent contamination whereby advantageously improving biosafety. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify claims 1-20 of U.S. Patent No. 11,694,818 B2 so that the sterilized generator column is compliant to periodic quality assurance tests such as the LAL test optionally at least once a day prior to use as taught by Chudakov et al., Aardaneh et al., and Biosafety because it would have been expected to advantageously enable compliant 82Rb solution for use in PET that passes all kinds of quality control tests. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify claims 1-20 of U.S. Patent No. 11,694,818 B2 so that the generator column is reusable and by further cleaning the stainless steel generator column after eluting the radioactive solution wherein the cleaning comprising the steps of: i) emptying the generator column by removing the matrix therefrom to provide an empty column; j) sterilizing the empty generator column in the previous step; and k) loading a new particulate ion exchange matrix into the sterilized generator column as taught by claims 1-20 of U.S. Patent No. 11,694,818 B2, Chudakov et al. and Aardenah et al. because it would have been expected to enable repeated use after one operation life while ensuring a sterilized medical device free of contaminants. The dimension of the generator column is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived a length of about 3.0 cm to about 8.0 cm, an internal diameter of about 4 mm to about 12 mm, and a wall thickness of about 0.4 mm to about 1.2 mm in order to arrive at an optimal operating pressure and shielding while minimizing the amount of steel used.
It would have been obvious to a person ordinary skill in the art before the effective filing date to further modify claims 1-20 of U.S. Patent No. 11,694,818 B2 by cleaning the generator column in a clean room optionally wherein the cleaning is performed in a clean area by washing with 0.1 M NH4OH with a pH range of 9 to about 10 or wherein the cleaning is performed by infusing about 10 mL to about 50 mL of NH4OH at a flow rate of about 10 mL/min to about 20 mL/min and so that the generator column is compliant to periodic assurance tests such as LAL test at least once per day as taught by claims 1-20 of U.S. Patent No. 11,694,818 B2, Chudakov et al., Biosafety, and Verma et al. because the cleaning in a clean room would have been expected to enable minimizing the sources of contamination providing a column that passes quality control tests for a medical for use in PET and because a periodic quality assurance test performed at least once per day prior to use would have been expected to advantageously ensure sterility of the radiopharmaceutical throughout the column life and before radiopharmaceutical collection.
Applicants Arguments
Applicants assert that the claims of the ‘818 patent fail to cure the deficiencies of Aardaneh, Chudakov, Verma, and Biosafety.
Applicant's arguments filed 7 Nov. 2025 have been fully considered but they are not persuasive. The ‘818 patent claims that the generator column is installed in a generator compartment, and the generator compartment and the column installed therein are sterilized. As discussed above, Chudakov provides a method wherein the generator column is subject to only two sterilization steps and the generator column loaded with ion exchange matrix is subject to only a single sterilization. Aardaneh, Chudakov, Verma, and Biosafety are not deficient for the reasons discussed above.
Conclusion
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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