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 .
Receipt is acknowledged of IDS filed on 04/29/2026.
Claims 16-18 and 27 have been amended.
Claims 16-21, 23-25, 27-31, 33-36, 38-44 and 46-50 are pending.
Claims 1-15, 22, 26, 32, 37, and 45 are cancelled.
Claims 27-31, 33-36 and 38-44 are withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
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 1.321(c) 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 §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 16-21, 23-25 and 46-50 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 7, 21, 22 and 24 of U.S. Patent No. 10,596,276 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because:
The patent recites, a process for manufacturing a pharmaceutical aqueous solution (patent claim 1), the process according to claim 1, comprising:
(1) forming a complex of the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA by
(1.1) providing an aqueous solution comprising the radionuclide;
(1.2) providing an aqueous solution comprising a somatostatin receptor binding peptide linked to the chelating agent (which is a a cell receptor binding organic moiety linked to a chelating agent), and a first stabilizer against radiolytic degradation and optionally a second stabilizer against radiolytic degradation different from the first stabilizer; and
(1.3) mixing the solutions provided in steps (1.1) and (1.2) and heating the resulting mixture to form a solution comprising the complex;
(2) diluting the solution comprising the complex obtained by step (1) by
(2.1) providing an aqueous dilution solution optionally comprising at least one stabilizer against radiolytic degradation; and
(2.2.) mixing the solution comprising the complex obtained by step (1) with the dilution solution provided in step (2.1) to obtain the pharmaceutical aqueous solution;
The stabilizers in the composition are gentisic acid and ascorbic acid (claim 22).
This reads on instant claim 1, which recites a process for manufacturing a pharmaceutical aqueous solution, the process comprising diluting an aqueous complex solution with an aqueous dilution solution to form the pharmaceutical aqueous solution;
wherein the aqueous complex solution comprises:
a complex comprising (ai) the radionuclide 177Lull) and (aii) a cell receptor binding organic moiety linked to a chelating agent, and
at least one stabilizer(s) against radiolytic degradation; and
wherein the aqueous dilution solution comprises at least one stabilizer(s) against radiolytic degradation.
The patent further teaches the stabilizer/stabilizers provided in step (1.2) is/are present during the complex formation in step (1.3) in a total concentration of from 15 to 50 mg/mL (Patent claim 6) and the stabilizer/stabilizers provided in step (1.2) is/are present during the complex formation in step (1.3) in a total concentration of from 20 to 40 mg/mL (patent claim 7), which reads on instant claim 16 recitation of at least one stabilizer(s) against radiolytic degradation that is/are present in an amount to result in a concentration of at least 1 mg/mL in the pharmaceutical aqueous solution; and wherein the aqueous dilution solution comprises at least one stabilizer(s) against radiolytic degradation present in an amount to result in a concentration of at least 15 mg/mL in the pharmaceutical aqueous solution (instant claim 1). The patent recites the radionuclide 177Lu is present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL (patent claim 1), which reads on wherein the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of at least 370 MBq/mL. The patent recites the pharmaceutical aqueous solution is substantially free of ethanol (patent claim 21), which reads on the pharmaceutical aqueous solution comprises less than 5% ethanol by weight. The patent recites the pharmaceutical aqueous solution the radiochemical purity (determined by HPLC) is maintained at ≥95% for at least 72 h when stored at 25° C (patent claim 24), which reads on the radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC can be maintained at 95% for at least 72 hours when stored at 25C.
The difference between instant application and the patented claims is that the patent claims include additional limitations. Thus, the invention of the patent is in effect a “species” of the “generic” invention of the application claims. It has been held that the generic invention is “anticipated” by the “species”, and, therefore, the application claims are not patentably distinct from the claims of the patent and are rejected on the ground of nonstatutory obviousness-type double patenting. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Claims 16-21, 23-25, and 46-50 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 21 of copending Application No. 18/494,042 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The copending application recites in claim 1 a process for manufacturing a pharmaceutical aqueous solution, comprising:
providing a solution comprising a complex of the radionuclide 177Lu (Lutetium-177) and a somatostatin receptor binding peptide linked to the chelating agent DOTA; a first stabilizer against radiolytic degradation, and optionally a second stabilizer against radiolytic degradation different from the first stabilizer; which reads on wherein the aqueous complex solution comprises: (a) a complex comprising (ai) the radionuclide 177Luill) and (aii) a cell receptor binding organic moiety linked to a chelating agent, and (b) at least one stabilizer(s) against radiolytic degradation that is/are present in an amount to result in a concentration of at least 1 mg/mL in the pharmaceutical aqueous solution; and
diluting the solution comprising the complex with an aqueous dilution solution optionally comprising at least one stabilizer against radiolytic degradation to obtain the pharmaceutical aqueous solution; which reads on wherein the aqueous dilution solution comprises at least one stabilizer(s) against radiolytic degradation present in an amount to result in a concentration of at least 15 mg/mL in the pharmaceutical aqueous solution;
wherein if the solution comprising the complex comprises only the first stabilizer and not the second stabilizer, then the aqueous dilution solution comprises at least one stabilizer that is different from the first stabilizer, and in the obtained pharmaceutical aqueous solution, the radionuclide 177Lu is present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL and the stabilizers are present in a total concentration of from 0.2 to 20.0 mg/mL, which reads on at least one stabilizer(s) against radiolytic degradation that is/are present in an amount to result in a concentration of at least 1 mg/mL in the pharmaceutical aqueous solution; and the at least one stabilizer(s) against radiolytic degradation present in an amount to result in a concentration of at least 15 mg/mL in the pharmaceutical aqueous solution; wherein the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of at least 370 MBq/mL.
The pharmaceutical aqueous solution according to claim 20, which is free of ethanol (copending application claim 21).
The stabilizers used in the method are gentisic acid and ascorbic acid (claim 4).
The copending application does not teach the radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC can be maintained at 95% for at least 72 hours when stored at 25 0C.
With regard to claim 1, the wherein limitations of these claims, are considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).). In the instant case, the copending application teaches all active steps and components and would therefor have the same ability of having a “radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC can be maintained at 95% for at least 72 hours when stored at 25C” unless proven otherwise.
This is a provisional nonstatutory double patenting rejection.
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 16-21, 23-25, 27, and 46-50 are rejected under 35 U.S.C. 103 as being unpatentable over CHEN (US 2011/0206606 A1).
Regarding claim 16, CHEN teaches a method of making a pharmaceutical aqueous solution (Example 22) comprising:
diluting an aqueous complex solution with an aqueous dilution solution to form the pharmaceutical aqueous solution;
wherein the aqueous complex solution comprises the following in an aqueous form (page 29, paragraph 0314):
(a) a complex comprising
(ai) the radionuclide 177Lu (page 29, paragraph 0314) and
(aii) Compound B, which comprises DOTA linked to a Gastrin Releasing Peptide receptor targeting agent (page 1, paragraph 0013), which is a cell receptor binding organic moiety linked to a chelating agent, and
(b) L-Selenomethionine (page 29, paragraph 0314), which is a stabilizer against radiolytic degradation (page 29, paragraph 0314) in the pharmaceutical aqueous solution;
wherein the aqueous dilution solution comprises
Sodium ascorbate in an aqueous solution (page 29, paragraph 0314) which is a stabilizer against radiolytic degradation, in a concentration of at least 50 mg/mL (page 29, paragraph 0314) in the pharmaceutical aqueous solution;
wherein the 177Lu is present in the pharmaceutical aqueous solution in a concentration of roughly 817 MBq/mL (110.5 mCi=4088.5 MB, which is in a total solution of roughly 5mL);
the pharmaceutical aqueous solution does not comprise ethanol (page 29, paragraph 0314)
CHEN does not explicitly teach using ascorbic acid and gentisic acid in the above steps. However, CHEN does teach that using a combination of ascorbic acid, gentisic acid and other stabilizers provided 99.8 radiochemical purity of 5 days (page 21, paragraph 0256 and table 6).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using a combination of ascorbic acid and gentisic acid for stabilizing the composition. The person of ordinary skill in the art would have been motivated to make those modifications, because it provides a high radiochemical purity for 5 days, and reasonably would have expected success because CHEN teaches multiple experiments of using different stabilizers and different combinations of stabilizers. Interchanging the stabilizers, such as using the combination of ascorbic acid and gentisic acid, would be an obvious substitution to one skilled in the art. Interchanging stabilizers is a common technique.
The reference does not specifically teach the concentrations of ascorbic acid and gentisic acid as claimed by the Applicant. The concentrations of ascorbic acid and gentisic acid 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 concentrations of ascorbic acid and gentisic acid in order to best achieve desired results, such as having enough of each to properly stabilize the composition. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the concentrations of ascorbic acid and gentisic acid would have been obvious at the time of Applicant’s invention.
Regarding claim 17, CHEN teaches adding an ascorbic acid solution or a gentisic acid solution to the aqueous complex solution (example 9 and page 24, paragraph 0266).
Regarding claim 18, CHEN teaches adding an ascorbic acid solution to the already complexed solution (example 8 and page 23, paragraph 0266), which reads on wherein the at least one stabilizer against radiolytic degradation in the aqueous dilution solution comprises ascorbic acid.
Regarding claim 19-21, the pharmaceutical aqueous solution does not comprise ethanol (page 29, paragraph 0314)
Regarding claim 23 and 50, the radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC can be maintained at 99.8% for at least 5 days (table 6) when stored at room temperature (page 29, paragraph 0315), which is roughly 25C.
Regarding claim 24, 27, 48 and 49, the radiopharmaceutical has DOTA as the chelator (Page 19, paragraph 0225 and claim 16).
Regarding claim 25, the radiopharmaceutical has a Gastrin Releasing Peptide receptor (GRP-Receptor) targeting molecule attached to the chelator (abstract and claims 13, 16, 22), that is in the form of an antagonist (Page 9, paragraph 0120), which reads on a GRP receptor peptide antagonist binding moiety.
Regarding claim 46 and 47, a NaOAc buffer is added to the solution for a pH of 4.8 (page 29, paragraph 0314).
CHEN further teaches that injections of the composition uses a quantity of radioactivity that is sufficient to permit imaging or in the case of radiotherapy, to cause damage or ablation of the targeted tissue, but not so much that substantive damage is caused to non-target (normal tissue) (Page 12, paragraph 0145).
Although reference does not specifically teach the volumetric radioactivity as claimed by the Applicant. The volumetric radioactivity 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 volumetric radioactivity in order to best achieve desired results, such as having an appropriate amount of radioactivity to produce images and cause damage to targeted cancer tissue, but not so much to damage non targeted healthy tissue. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the volumetric radioactivity would have been obvious at the time of Applicant’s invention.
Response to Arguments
Applicant argues, First, the present claim 16 requires that the aqueous dilution solution comprises "at least one stabilizer(s) against radiolytic degradation that is/are selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof." Chen Example 22 does not include these recited stabilizers in the aqueous complex solution; thus Chen fails to include a feature of the present claim 16.
Examiner does not find the argument percussive CHEN does not explicitly teach using ascorbic acid and gentisic acid in the claimed steps. However, CHEN does teach that using a combination of ascorbic acid, gentisic acid and other stabilizers provided 99.8 radiochemical purity of 5 days (page 21, paragraph 0256 and table 6).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using a combination of ascorbic acid and gentisic acid for stabilizing the composition. The person of ordinary skill in the art would have been motivated to make those modifications, because it provides a high radiochemical purity for 5 days, and reasonably would have expected success because CHEN teaches multiple experiments of using different stabilizers and different combinations of stabilizers. Interchanging the stabilizers, such as using the combination of ascorbic acid and gentisic acid, would be an obvious substitution to one skilled in the art. Interchanging stabilizers is a common technique.
Applicant argues, CHEN teaches using 0.58 mg/mL in the pharmaceutical aqueous solution for the at least one stabilizer(s) in the aqueous complex solution lies outside the range of at least 1 mg/ml which is recited in instant claim 16.
Examiner does not find the argument persuasive because even though the reference does not specifically teach the concentrations of ascorbic acid and gentisic acid as claimed by the Applicant. The concentrations of ascorbic acid and gentisic acid 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 concentrations of ascorbic acid and gentisic acid in order to best achieve desired results, such as having enough of each to properly stabilize the composition. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the concentrations of ascorbic acid and gentisic acid would have been obvious at the time of Applicant’s invention.
Applicant argues, CHEN evaluated eight stabilizers, including ascorbic acid and gentisic acid sodium salts, and found that none of the eight reagents provided adequate radiostability for 48 hours (see paragraph [0265]). Chen further states that this result is "unexpected as gentisic acid, ascorbic acid, HSA, and 3,4-pyridinedicarboxylic acid have all been reported by others to provide satisfactory protection against radiolysis for other radiopharmaceuticals ... The reagent 3,4-pyridinedicarboxylic acid, previously reported as an effective radiostabilizer, was found to interfere badly with the labeling reaction." Id.; emphases added. As a result, a person skilled in the art reading Chen would not have been motivated to use a process with (a) gentisic acid or a salt thereof or ascorbic acid or a salt thereof in the aqueous complex solution, and (b) ascorbic acid or a salt thereof in the aqueous dilution solution, as recited in claim 16, with a reasonable expectation of success.
Examiner does not find the argument persuasive because, CHEN found that ascorbic acid and gentisic acid by themselves did not provide adequate stability, however found that when combined together stability was achieved and results in a RCP of 99.8 over 5 days (table 6).
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.
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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