DETAILED ACTION
Notice of Pre-AIA or AIA Status
This Office action details a first action on merits for the above referenced application No. Claims 1-25 are pending in this application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/09/2022 was noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings were received on 12/09/2022. These drawings are acknowledged.
Claim Objections
Claims 3-25 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-7, 12-14, 20, 23 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meijer et al. (US 2018/0370,925).
Meijer discloses methods for the preparation of DOTA (reads on tetraxetan) and also methods for the preparation of metal chelates of DOTA (abstract). Meijer discloses method of synthesis of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) wherein said method comprises steps: (a) reacting 1,4,7,10-tetraazacyclododecane (cyclen) with a halo-acetic acid and an excess of a NaOH at a pH of around 11; (b) crystallizing the reaction mixture obtained in step (a) wherein said crystallizing comprises addition of methanol and is carried out at pH 3-4, e.g. pH 3.2, and wherein the pH is adjusted by addition of HCl; (c) filtering an aqueous solution of the crystallized product of step (b) by electrodialysis or by nanofiltration; (d) crystallizing the filtered solution obtained in step (c) wherein said crystallizing comprises addition of methanol and is carried out at pH 3-4, e.g. pH 3.2, and wherein the pH is adjusted by addition of HCl. Step (a) may be carried out using methods known in the art for example as set out by Desreux (1980 Inorganic Chemistry; 19(5): 1319-1324), wherein reaction temperature was elevated to 80oC and pH maintained between 9 and 10) (0056-0061). Meijer discloses that crystallization techniques are well known to those of skill in the art and text books are available describing different methods (see for example “Crystallization: Basic Concepts and Industrial Applications”; 2013 Wiley-VCH: Wolfgang Beckmann, Ed.) and the pH of each of crystallization step (b) and filtration step (c) of the method of the invention is important in order to get a good purification and therefore a good yield of DOTA. pH values below 3 or above 3.5 may impact removal of sodium ions, which are mainly removed in steps (b) and (c). In step (c) in order for the positive ion Na+ to cross the membrane a negative ion is required and this is provided in one embodiment as Cl- in HCl (0062-0064). In one embodiment of the said filtering step (c) is carried out by electrodialysis. The membrane can be either cation- or anion-selective such that either positive ions or negative ions selectively flow through, and said filtering step (c) is carried out by nanofiltration (0052-0053). The precipitated crude DOTA obtained was dissolved in water and subjected to nanofiltrations whereby the sodium content was reduced, and washed with aqueous methanol. The resulting cake was dried in the filter using reduced pressure and heating (55oC jacket temperature, reads of spray drying) (0080-0081). In one embodiment, provides a method for preparing gadoterate meglumine comprising: (i) adding Gd2O3 to the DOTA obtained above (ii) adding meglumine to the complex DOTA-Gd obtained in the step (i) (0037). Additional disclosure includes that methods for the preparation of metal chelates of DOTA is characterized by very low levels of organic and inorganic impurities and are particularly suitable for industrial manufacturing of DOTA of sufficient purity to be used in pharmaceutical production of contrast agents for MRI.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Meijer et al. (US 2018/0370,925) in view of Meijer et al. (WO 2016/083600, herein after ‘600) and Anelli et al. (EP 2503990).
Meijer discloses methods for the preparation of DOTA (reads on tetraxetan) and also methods for the preparation of metal chelates of DOTA (abstract). Meijer discloses method of synthesis of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) wherein said method comprises steps: (a) reacting 1,4,7,10-tetraazacyclododecane (cyclen) with a halo-acetic acid and an excess of a NaOH at a pH of around 11; (b) crystallizing the reaction mixture obtained in step (a) wherein said crystallizing comprises addition of methanol and is carried out at pH 3-4, e.g. pH 3.2, and wherein the pH is adjusted by addition of HCl; (c) filtering an aqueous solution of the crystallized product of step (b) by electrodialysis or by nanofiltration; (d) crystallizing the filtered solution obtained in step (c) wherein said crystallizing comprises addition of methanol and is carried out at pH 3-4, e.g. pH 3.2, and wherein the pH is adjusted by addition of HCl. Step (a) may be carried out using methods known in the art for example as set out by Desreux (1980 Inorganic Chemistry; 19(5): 1319-1324), wherein reaction temperature was elevated to 80oC and pH maintained between 9 and 10) (0056-0061). Meijer discloses that crystallization techniques are well known to those of skill in the art and text books are available describing different methods (see for example “Crystallization: Basic Concepts and Industrial Applications”; 2013 Wiley-VCH: Wolfgang Beckmann, Ed.) and the pH of each of crystallization step (b) and filtration step (c) of the method of the invention is important in order to get a good purification and therefore a good yield of DOTA. pH values below 3 or above 3.5 may impact removal of sodium ions, which are mainly removed in steps (b) and (c). In step (c) in order for the positive ion Na+ to cross the membrane a negative ion is required and this is provided in one embodiment as Cl- in HCl (0062-0064). In one embodiment of the said filtering step (c) is carried out by electrodialysis. The membrane can be either cation- or anion-selective such that either positive ions or negative ions selectively flow through, and said filtering step (c) is carried out by nanofiltration (0052-0053). The precipitated crude DOTA obtained was dissolved in water and subjected to nanofiltrations whereby the sodium content was reduced, and washed with aqueous methanol. The resulting cake was dried in the filter using reduced pressure and heating (55oC jacket temperature, reads of spray drying) (0080-0081). In one embodiment, provides a method for preparing gadoterate meglumine comprising: (i) adding Gd2O3 to the DOTA obtained above (ii) adding meglumine to the complex DOTA-Gd obtained in the step (i) (0037). Additional disclosure includes that methods for the preparation of metal chelates of DOTA is characterized by very low levels of organic and inorganic impurities and are particularly suitable for industrial manufacturing of DOTA of sufficient purity to be used in pharmaceutical production of contrast agents for MRI.
NOTE: It would have been obvious to one of ordinary skill in the art at the time the invention was made to optimize the purification step, such as performing two consecutive electrodialysis, and maintaining the pH levels during electrodialysis and nanofiltration to obtain an optimal process conditions without undue experimentation. Further, Meijer discloses that monitoring and adjusting pH during alkylation and filtration may be carried out manually or in an automated fashion and crystallization and filtration methods most suitable for use would meet the requirements for pharmaceutical preparations, such so-called “good manufacturing practice” (GMP) requirements. One of ordinary skill in the art would have a reasonable expectation of success because routine optimization of the prior art purification procedure is within the capability of one of ordinary skill in the art. See MPEP § 2144.05 which states: [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Furthermore, the optimization of the pharmaceutical formulation with ingredients well known in the pharmaceutical art is considered well within the competence level of an ordinary skilled artisan in the pharmaceutical sciences, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980).
Meijer fails to disclose gadoterate meglumine and carrying out spray drying in which the temperature of the inlet air is 160-200oC and the outlet air is 90-120oC.
Meijer ‘600 discloses preparation of a liquid pharmaceutical formulation, comprising a meglumine salt of the metal complex Gd-DOTA, said process comprising the following steps: (i) an aqueous solution of a 1:1 molar ration of DOTA and meglumine with an excess of Gd2O3, whereby all the DOTA reacts to give Gd-DOTA; (ii) filtration of the solution to remove the excess undissolved Gd2O3, giving a second solution which comprises Gd-DOTA free from excess Gd2O3; (iii) addition of DOTA in uncomplexed form to said second solution to give said liquid pharmaceutical formulation; wherein said DOTA in uncomplexed form is free of coordinated metal ions (page 5 line 1-25). In one embodiment, discloses preparation of an MRI contrast agent comprising the step of diluting the liquid pharmaceutical formulation from the above with a biocompatible carrier, dispensing the formulation into pharmaceutically acceptable containers or syringes to give MRI contrast agent in said pharmaceutically acceptable container or syringes in a form suitable for mammalian administration (page 12 Line 8-20). Additional disclosure includes that, since the process provides an intermediate solution of Gd-DOTA metal complex without free gadolinium ions, the amount of excess DOTA to add to give the desired formulation having a defined excess of free chelator can be calculated readily and has the advantage that it can be carried out on an industrial scale.
Anelli discloses a process for the preparation of a solid form of a polyamino polycarboxylic gadolinium complex by a spray-drying procedure (abstract). The process is carried out at an inlet temperature of the spray-drying device comprised from 140oC to 280oC, whereas the outlet temperature has a value comprised from 70oC to 120oC (0014). Anelli discloses that process for the preparation of gadobenate dimeglumine by spray-drying is particularly advantageous for the industrial scale as the spray-drying form may be obtained by employing water as a solvent, which is easy to handle and basically not requiring troublesome health or safety precautions and further, the process advantageously enables the preparation of a suitable solid form of the gadobenate dimeglumine, in a solid form different from the one obtainable by using other commonly employed methodologies leading to solid forms with unfavourable handling, workability (gummy, sticky or glassy solids), and extremely low recovering yields, due to cumbersome and time consuming procedures required for their collection (0032).
Note: With respect to claims 19 and 23, they are considered as compound. The claim may for instance take the form product by process format. The 35 USC 103 rejection set forth above is proper because the product-by-process format that applicant incorporated does not impart any structural difference with the prior art product. Please note that in product-by-process claims, “once a product appearing to be substantially identical and a 35 U.S.C. 103 rejection [is] made, the burden shifts to the applicant to show an unobvious difference.” MPEP 2113. Applicants’ composite structure as recited differs and, if so, to what extent, from that of the discussed references. Therefore, with the showing of the references, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to incorporate the spray drying step with temperature of the inlet air is 160-200oC and the outlet air is 90-120oC into Meijer’s process for the preparation of DOTA (reads on tetraxetan). The person of ordinary skill in the art would have been motivated to make those modifications because Anelli teaches that spray-drying process advantageously enables the preparation of a suitable solid form of the gadobenate dimeglumine, in a solid form different from the one obtainable by using other commonly employed methodologies leading to solid forms with unfavorable handling, workability (gummy, sticky or glassy solids), and extremely low recovering yields, due to cumbersome and time consuming procedures required for their collection (0032) and reasonably would have expected success because spray-drying is particularly advantageous for the industrial scale as the spray-drying form may be obtained by employing water as a solvent, which is easy to handle and basically not requiring troublesome health or safety precautions.
Conclusion
No claims are allowed at this time.
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/J.R.S/Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618