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 1-2, 6, 8, 10, 15-16, 21-22, 27, 31, 34, 37-39, 41, 44, 47, 50 and 54 are pending.
Claims 34, 37-39, 41, 44, 47, 50 and 54 are withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/27/2026 has been entered.
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 1, 6, 10, 15, 22, 27 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over SATO (WO 2015/153772 A2) in view of KELLY (US4335095).
Regarding claim 1, SATO teaches a method of making an 89Zr-oxine complex (abstract) comprising mixing a solution of 89Zr with oxine (claim 1) the mixing it with sodium bicarbonate (claim 4), which reads on base, and polysorbate 80 (claim 2), which is a surfactant. The oxine concentration is directly related to the labeling efficiency (column 2, paragraph 5). The solution needs a pH of 7 to 7.2 to allow for the chelation of 89Zr by oxine, thus allowing the product to form (Page 19, paragraph 0095).
SATO does not teach using the buffer solution HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid).
KELLY teaches a complex that is created by mixing a radioactive solution of indium-111, oxine, Tween-80, also known as polysorbate 80 and which reads on a surfactant, HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid), which reads on a buffering agent (column 6, paragraph 1), bicarbonate (column 3, paragraph 2) and hydrochloric acid (column 3, paragraph 4). The buffer is added to maintain the pH (column 3, paragraph 2). It is important to adjust to pH of the solution as necessary for stability of the complex and so it can be tolerated by blood cells (Column 2, paragraph 4). Tween-80 is used as a surface active agent that reduces adhesion to container walls (column 2, 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 the buffering agent, HEPES. The person of ordinary skill in the art would have been motivated to make those modifications, because it will create an optimal pH that is important for stability of the complex and SATO teaches that a pH of 7 to 7.2 allows for the chelation of 89Zr by oxine, thus allowing the product to form, and reasonably would have expected success because both references are in the same field of endeavor, such as radiolabeled oxine complexes created in similar methods.
Regarding claim 2 and 10, the references do not specifically teach the concentration of oxine as claimed by the Applicant. The concentration of oxine is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal concentration of oxine in order to best achieve desired results, such as a solution that can label efficiently. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the concentration of oxine would have been obvious at the time of Applicant’s invention.
Regarding claim 6, SATO teaches that the complex is with 89Zr-oxine.
Regarding claim 15, SATO teaches using polysorbate 80 (claim 2).
Regarding claim 16, the reference does not specifically teach the concentration of polysorbate 80 as claimed by the Applicant. The concentration of polysorbate 80 is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal concentration of polysorbate 80 in order to best achieve desired results, such as a solution that does not adhere to container walls. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the concentration of polysorbate 80 would have been obvious at the time of Applicant’s invention.
Regarding claim 21, KELLY teaches using HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) (column 6, paragraph 1).
Regarding claim 22, the reference does not specifically teach the concentrations of the buffer solution as claimed by the Applicant. The concentrations of the buffer solution is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal concentration of the buffer solution in order to best achieve desired results, such as an ideal pH for formation of the complex. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the concentrations of sodium bicarbonate or the buffer solution would have been obvious at the time of Applicant’s invention.
Regarding claim 27, SATO teaches the solution needs a pH of 7 to 7.2 to allow for the chelation of 89Zr by oxine, thus allowing the product to form (Page 19, paragraph 0095).
Regarding claim 31, KELLY teaches using hydrochloric acid (column 3, paragraph 4).
Claims 1, 2, 6, 8, 10, 15, 16, 21, 22, 27 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over SATO (WO 2015/153772 A2) and KELLY (US4335095) in view of JIANG (CN 106053463 A).
SATO and KELLY teach Applicant’s invention as discussed above.
SATO and KELLY do not teach where the base is a metal hydroxide.
Regarding claim 8, JIANG teaches an oxine complex (abstract) that uses sodium hydroxide, which is a metal hydroxide, to regulate the pH of the composition (claim 9).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate sodium hydroxide. The person of ordinary skill in the art would have been motivated to make those modifications, because it helps to regulate the pH of the composition, and reasonably would have expected success because the references are in the same field of endeavor such as oxine containing pharmaceutical compositions and both SATO and KELLY use various substances to regulate pH, including a base.
Response to Arguments
Applicant argues, since the formulation is required to comprise all of these components before addition of the radioactive metal, it is by definition a "preprepared" or "pre-mixed" formulation at the point at which the radioactive metal is added. Thus, the "preprepared" nature of the formulation is an inherent feature of the claimed method. None of the prior art documents describe a step of adding a radioactive metal to a formulation comprising all of: oxine, a surfactant, a base and a buffering agent. As a result of these differences, present claim 1 provides a more straightforward method
compared to the synthesis disclosed in WO 2015/153772, which requires the addition of a base
after mixing of the radioactive metal and oxine (see e.g. page 2 lines 17-19 of the present
application).
The Examiner does not find the argument persuasive because the claims as written do not require a specific order for the addition of the components. The terms "preprepared" or "pre-mixed" are not listed in the claims. The claims only require a solution of radioactive metal, oxine, surfactant, base and buffering agent, which is taught by the prior art.
Furthermore, even if the claims did require a specific order of addition, which they do not the selection of any order of process steps is prima facia obvious in the absence of new or unexpected results.” See MPEP § 2144.04, IV. It would be obvious to one of ordinary skill in the art to vary the order of steps because, in such a method, where the order of steps is not critical, one of ordinary skill in the art would have recognized that varying the order of steps would result in an equivalent means of carrying out the method.
Applicant argues, as a result of these differences, present claim 1 provides a more straightforward method compared to the synthesis disclosed in WO 2015/153772, which requires the addition of a base after mixing of the radioactive metal and oxine (see e.g. page 2 lines 17-19 of the present application). The claimed "one step" method is easier to use in a clinical setting. Specifically, the claimed method vastly simplifies the procedure for the operator in charge of radiolabeling cells. This leads to shortened procedure time, reduced risk of error and reduced exposure of the operator to ionizing radiation. Another benefit of the method is that the oxine-containing cell radiolabeling agent can be readily prepared without requiring specialized equipment. This allows procedures to be performed even in less well-equipped centers. These benefits are discussed at page 30 lines 5 to 14 of the present application. Additionally, the ZrCl4 used in WO 2015/153772 has to be synthesized from the commercially available Zr-oxalate (see paragraph [0093]). This additional preparation step is not necessary in the method of the present application in which the radioactive metal can be added in its commercially available oxalate form, i.e. directly from the suppliers (see page 19, line 36 to page 20, line 2 of the present application). This is a significant advantage. As indicated at paragraph [0095] of WO 2015/153772, the step of adding the base involves vertexing and requires a high level of precision to ensure that the desired pH is reached. This procedure must be performed with the radioactive formulation, and thus requires a skilled operator and specialized equipment, as well as increasing risk of radioactivity exposure.
The Examiner does not find the argument persuasive because unexpected results must be supported by factual evidence, and attorney argument is not evidence. See In re Pearson, 494 F.2d 1399,1405 (CCPA 1974). The cited paragraphs of the Specification detail benefits of the claimed method but do not state that unexpected results were obtained. Thus, Applicant has not provided evidence that unexpectedly superior results were obtained with the claimed method. "Mere improvement in properties does not always suffice to show unexpected results." In re Soni, 54 F.3d 746,751 (Fed. Cir. 1995). In the instant case, no data was provided demonstrating unexpected results, but rather broad statements of simplicity. Simpler methods are commonly designed/optimized by one skilled in the art. Additionally, as discussed above, the instant claims do not require a specific order for the addition of the components. The terms "preprepared" or "pre-mixed" are not listed in the claims. The claims only require a solution of radioactive metal, oxine, surfactant, base and buffering agent, which is taught by the prior art.
For a complete discussion of unexpected results, Applicants are referred to MPEP 716.02 et seq.
Applicant argues, US4335095 describes a multi-step process in which components are added one-by-one to a solution of radioactive metal chloride. CN106053463 describes a method of preparing a calcium detection reagent in which stock solutions of each component of the reagent are first prepared, followed by mixing of appropriate amounts of each stock solution. There is no suggestion in CN106053463 that the radioactive metal component should be added last.
The Examiner does not find the argument persuasive because US4335095 and CN106053463 are mot cited to show the radioactive metal component should be added last. Additionally, as discussed above, the claims do not require this limitation.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. MEJIAS whose telephone number is (703)756-5666. The examiner can normally be reached M-F.
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/S.L.M./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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