Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 23 has been amended.
Claim 41-42 have been added.
Claims 23-27, 30-31 and 34-42 are pending.
Claims 1-22, 28-29 and 32-33 are cancelled.
Claims 30, 31, and 34 are withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 23-27, 35-37, 40 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over CHEN (US 20070269375 A1) in view of USACH (Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Adv. Ther. 2019.).
Regarding claim 23, CHEN teaches a method of making a stabilized radiopharmaceutical that comprises (abstract):
Adding thiamine hydrochloride, which is vitamin B1 (page 27, paragraph 0297).
A buffer solution was added which reads on a pH regulator (page 27, paragraph 0297).
Additional disclosures: The composition is designed for administration into a patient such as subcutaneous injection (page 11, paragraph 0140).
USACH teaches a pH of 7 for pharmaceutical injection prevents pain upon subcutaneous injection (page 2993, paragraph 4).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a pH of 7. The person of ordinary skill in the art would have been motivated to make those modifications, because it prevents pain upon injection, and reasonably would have expected success because the references are in the same field of endeavor, such an pharmaceutical subcutaneous injections.
Regarding claims 23, 24 and 25, Note, the prior art’s composition/method of making would have the same chemical/physical properties of “wherein the stabilizing agent maintains the radiochemical purity of the radiopharmaceutical in the composition to which the pH regulator is added”, “wherein the stabilized radiopharmaceutical composition has a radiochemical purity of at least 90% for 2 to 6 hours after the preparation of the radiopharmaceutical composition. as measured at conditions of a temperature of 40°C and pH of 6 to 8.” and “wherein the stabilized radiopharmaceutical composition has a radiochemical purity of at least 90% for 2 to 4 hours after preparation of the radiopharmaceutical composition, as measured at conditions of room temperature and pH of 6 to 7” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise.
Regarding claim 26, CHEN teaches vitamin B1 is added in 10 mg/mL concentration (page 27, paragraph 0297).
Regarding claim 27, CHEN teaches the composition can be in a liquid formulation (page 13, paragraph 0158).
Regarding claim 35, CHEN teaches the composition is designed to inhibit radiolysis (page 2, paragraph 0019).
Regarding claim 36, CHEN teaches the radiochemical purity was measured (page 17, paragraph 0178).
Regarding claim 37, CHEN teaches a phosphate buffer can be added (page 3, paragraph 0027).
Regarding claim 40, CHEN teaches the radioisotope can be 18F (page 6, paraph 0058) and is in a liquid formulation (page 13, paragraph 0158).
Regarding claim 42, CHEN teaches heating the composition which reads on the composition is at a temperature above room temperature, since instant claim 42 does not specify at what point during formulation the composition needs to be above room temperature.
Claims 23-27, 35-38, 40 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over CHEN (US 20070269375 A1) and USACH (Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Adv. Ther. 2019.) in view of MUELLER (Simplified NaCl Based 68Ga Concentration and Labeling Procedure for Rapid Synthesis of 68Ga Radiopharmaceuticals in High Radiochemical Purity. Bioconjugate Chemistry. 2012).
CHEN and USACH teach Applicant’s invention as discussed above.
CHEN and USACH do not specifically teach a sodium phosphate buffer, which comprises NaH2PO4 and Na2HPO4.
Regarding claim 38, MUELLER teaches using a sodium phosphate buffer for a stabilized radiopharmaceutical that has a high radiochemical purity of >99% (page 1714, paragraph 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a sodium phosphate buffer. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because a sodium phosphate buffer and a phosphate buffer are functional equivalents of buffers commonly used in the pharmaceutical industry. Furthermore, both references are towards stabilized radiopharmaceuticals.
Claims 23-27 and 35-42 are rejected under 35 U.S.C. 103 as being unpatentable over CHEN (US 20070269375 A1) and USACH (Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Adv. Ther. 2019.) and MUELLER (Simplified NaCl Based 68Ga Concentration and Labeling Procedure for Rapid Synthesis of 68Ga Radiopharmaceuticals in High Radiochemical Purity. Bioconjugate Chemistry. 2012) in view of NEWBERG (Initial Clinical Comparison of 18F-Florbetapir and 18F-FDG PET in Patients with Alzheimer Disease and Controls. The Journal of Nuclear Medicine. 2012.).
CHEN, USACH and MUELLER teach Applicant’s invention as discussed above. CHEN further teaches the radiopharmaceutical can be used for imaging (page 1, paragraph 0003 and page 7, paragraph 0058) and that the radioisotope in the radiopharmaceutical can be 18F (page 6, paragraph 0058).
CHEN, USACH and MUELLER do not teach adding 18F-florbetapir.
Regarding claim 39 and 41, NEWBERG teaches that both 18F-florbetapir and 18F-FDG can be used to perform PET imaging and perform well in imaging (abstract).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate 18F-florbetapir. The person of ordinary skill in the art would have been motivated to make those modifications, because it performs well in imaging, and reasonably would have expected success because the references are in the same field of endeavor such as radiopharmaceuticals. Furthermore, 18F-florbetapir is a specific species of the 18F taught in CHEN and CHEN teaches that the radiopharmaceutical is used for imaging.
Response to Arguments
Applicant argues, when vitamin B1 or vitamin B6 is used as a stabilizing agent, there is an
excellent effect in maintaining the purity of the radiopharmaceutical under the condition in which the pH regulator is added. CHEN mentions only vitamin B1, and is silent regarding vitamin B6. Further, in CHEN, vitamin B1 was tested as a candidate stabilizing agent, but CHEN itself acknowledges that it had no effect (Table 16, paragraph [0298]). None of the other cited prior art references discloses such a stabilizing effect by vitamin B1 or B6.
The examiner does not find the argument persuasive because, as discussed above, CHEN teaches using vitamin B1 as a stabilizer and that it provided 97% radiochemical purity when added. CHEN teaches that it did not provide stability at 72 hours, however it does not state it did not provide any stabilizing effect (page 27, paragraph 0298). Additionally, CHEN does not teach using vitamin B6, however only one vitamin, either B1 or B6, is required by the claim and CHEN teaches using vitamin B1.
Applicant argues CHEN discloses a list of about 20 compounds, including thiamine hydrochloride (vitamin B1), which were tested by direct addition to a labeling reaction mixture (paragraph [0210]). However, in paragraph [0211], CHEN identifies only PDTC (ammonium 1- pyrrolidinedithiocarbamate ), D-• L-• D,L-methionine, trisodium trithiocyanurate, L-cysteine, and L-selenomethionine among these compounds as "the best stabilizers for direct addition," and thiamine hydrochloride is not included in this list. Applicant argues, in particular, according to Table 16 shown below, and paragraph [0298] of CHEN, as a result of directly adding the test compounds, including thiamine hydrochloride, to the labeling reaction of 177Lu-A, thiamine hydrochloride decreased from an initial (t =Oh) radiochemical purity of 97.0% to 0% after 72 hours, and CHEN concludes with respect thereto that "None of the stabilizers tested provided significant stability for up to 72 hours of storage." According to this disclosure, CHEN is understood as actually testing thiamine hydrochloride, confirming that its stabilizing effect is not sufficient, and guiding a person of ordinary skill in the art to other groups of compounds. In other words, CHEN teaches away from thiamine hydrochloride.
Examiner does not find the argument persuasive because obviousness does not require complete predictability and less preferred embodiments do not constitute a teaching away. Additionally, CHEN is teaching a method of utilizing vitamin B1 as a stabilizing agent which is required by claim 1. Claim 1, nor any of the dependent claims, require stabilization up to 72 hours.
Applicant argues, the experimental results of the present specification (Table 5) show unexpected results over the combined teaching of CHEN and USACH. Under the condition in which a phosphate buffer (pH regulator) was added, vitamin B1 and vitamin B6 maintained radiochemical purity of 98.94% and 97.33%, respectively, even after the passage of time, which are significantly superior values compared to the control group (sodium ascorbate), which decreased to 90.04% under the same condition. These results are contrary to the insufficient stabilizing effect of thiamine hydrochloride confirmed by CHEN itself, and, with respect to vitamin B6, these results not disclosed in any cited reference, and thus are considered to be objective evidence supporting the non-obviousness of the present claims.
Examiner does not find the argument persuasive because although CHEN teaches that vitamin B1 did not provide stabilization at 72 hours. It does not teach if stabilization was seen at 2 hours, which is the time limit required instant claims 24 and 25 and no time limit is required by claim 1, but rather just the action of adding vitamin B1 as a stabilizer. Furthermore, since the prior art’s composition/method of making would have the same chemical/physical properties of “wherein the stabilizing agent maintains the radiochemical purity of the radiopharmaceutical in the composition to which the pH regulator is added”, “wherein the stabilized radiopharmaceutical composition has a radiochemical purity of at least 90% for 2 to 6 hours after the preparation of the radiopharmaceutical composition. as measured at conditions of a temperature of 40°C and pH of 6 to 8.” and “wherein the stabilized radiopharmaceutical composition has a radiochemical purity of at least 90% for 2 to 4 hours after preparation of the radiopharmaceutical composition, as measured at conditions of room temperature and pH of 6 to 7” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise.
Additionally, In order to overcome a prima facie case of obviousness, it is incumbent upon the Applicant to provide comparative test evidence that demonstrates unexpected superiority of the claimed compositions versus the closest prior art compositions, and not simply an advantage predictable from the prior art. See In re Chapman, 148 USPQ 711, 715 (CCPA, 1966). Moreover, such proffered comparisons must be commensurate in scope with the breadth of the claims. See In re Clemens, 206 USPQ 289, 296 (CCPA, 1980) and In re Coleman, 205 USPQ 1172, 1175 (CCPA 1980). In the instant case, stability over the passage of time is not required by instant claim 1. Therefor the comparisons are not commensurate in scope with the breadth of the claims
For a complete discussion of unexpected results, Applicants are referred to MPEP 716.02 et seq.
Applicant argues, the Office determined, with respect to Claims 24 and 25, to the effect that "since the prior art includes the same components as those claimed by Applicant, it would have the same chemical and physical properties unless there is evidence to the contrary." However, Table 16 and paragraph [0298] of CHEN show that thiamine hydrochloride failed to exhibit long-term stability under CHEN' s own test conditions, and thus this is considered to correspond to evidence to the contrary against the above inherency presumption. In view of these circumstances, it would not be expected that the same properties would be obtained merely because the stabilizing agent is the same.
Examiner does not find the argument persuasive because although CHEN teaches that vitamin B1 did not provide stabilization at 72 hours. It does not teach if stabilization was seen at 2 hours, which is the time limit required instant claims 24 and 25 and no time limit is required by claim 1, but rather just the action of adding vitamin B1 as a stabilizer. Furthermore, since the prior art’s composition/method of making would have the same chemical/physical properties of “wherein the stabilizing agent maintains the radiochemical purity of the radiopharmaceutical in the composition to which the pH regulator is added”, “wherein the stabilized radiopharmaceutical composition has a radiochemical purity of at least 90% for 2 to 6 hours after the preparation of the radiopharmaceutical composition. as measured at conditions of a temperature of 40°C and pH of 6 to 8.” and “wherein the stabilized radiopharmaceutical composition has a radiochemical purity of at least 90% for 2 to 4 hours after preparation of the radiopharmaceutical composition, as measured at conditions of room temperature and pH of 6 to 7” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise.
Applicant argues, the Office additionally combined MUELLER with CHEN and USACH with respect to Claim 38 (sodium phosphate buffer). MUELLER discloses a labeling procedure using a sodium phosphate buffer for rapid synthesis of a radiopharmaceutical labeled with 68Ga (page 1714, paragraph 2). However, the radiochemical purity of greater than 99% disclosed in MUELLER relates to the initial purity measured immediately after the labeling reaction (t = 0), and does not include data regarding radiolysis stability over time. Furthermore, MUELLER does not mention vitamin B1 or B6.
Examiner does not find the argument persuasive because as discussed CHEN teaches using vitamin B1 and Applicant has not proven that it would not stabilize for two hours, only that it would not stabilize for 72 hours.
Conclusion
No claims are allowable.
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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/S.L.M./ Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618
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