DETAILED ACTION
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 .
This is a Final Office Action.
Election/Restrictions
Applicant's election with traverse of Group (I) in the reply filed on September 22, 2025 is acknowledged. Group (I), drawn to a process of preparing asenapine in the form of the free base, embraced by claims 1-6 and 11-13 was elected by Applicant.
Claims 1-17 are pending and claims 1-6 and 11-13 are under examination. Claims 7-10 and 14-17 are withdrawn based on the lack of unity.
Specification
The objection to the abstract of the disclosure is withdrawn based on the amendments received.
Claim Rejections - 35 USC § 112
The rejection of claim 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “the d50 particle diameter,” is withdrawn based on the amendments.
The rejection of claim 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “the d80 particle diameter,” is withdrawn based on the amendments.
The rejection of claim 5 under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for the phrase “125 μm or more, or less than 125 μm,” is withdrawn based on the amendments.
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-6 and 11-13 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Mϋller, W. (US 6620429, cited on the IDS) in view of Zheng, Z. (CN 110606852, cited on the IDS and translation provided by the WIPO website).
The present application is drawn to a process for the preparation of asenapine in the form of the free base comprising reacting asenapine maleate and an alkali metal silicate, e.g. sodium silicate, in a solvent, e.g. water and methanol, ethanol or propanol, followed by isolating the asenapine in the form of the free base.
The Mϋller reference teaches a process that transforms active substance salts into their free base prior to utilizing in transdermal systems, see column 1, lines 26-28. The process utilizes alkaline silicates, such as sodium and potassium meta- and trisilicates, which may be hydrated in various degrees, and in solvents such as methanol and ethanol, among others, for the transformation, see column 2, lines 18-26. The reference teaches several HCl and HBr salts as starting materials in the working examples, but not asenapine maleate.
Zheng teaches a process of making the free amine of asenapine from asenapine maleate using aqueous NaOH as the base, see the translated document, last page, Embodiment 6, with a yield of 93.1% and >99% purity by HPLC. The reference does not teach alkaline silicates as the base.
Thus, the combination of Mϋller and Zheng render obvious a process for the preparation of asenapine in the form of the free base comprising reacting asenapine maleate and an alkali metal silicate.
Claims 5 and 12 are drawn to a particle diameter of the alkali metal silicate. However, the alkali metal silicates can be purchased in various sizes depending on the utility. The size of the particle diameter for this process is trivial, evidence to the contrary, and there is nothing in specification that demonstrates otherwise.
Thus, it would be obvious to transform asenapine maleate to the free base of asenapine with an alkali metal silicate because Mϋller teaches the process with other salts and Zheng teaches the process with asenapine maleate with a different base. Therefore, the process is rendered obvious.
Applicant traverses by stating, “[P]resent claim 1 is specific to reacting asenapine maleate with an alkali metal silicate and obtaining a product mixture that contains dissolved asenapine in the form of its free base and alkali metal maleate in dispersed form. As discussed above, the formation of solid alkali metal maleate, alongside dissolved asenapine free base and solid silica, is pivotal: it precipitates ("dispersed form"), shifting equilibrium towards products and enabling simple solid-liquid separation.”
This is not persuasive. The Mϋller reference teaches, “It is surprising and unexpected that alkaline metal silicates, especially trisilicates and metasilicates of sodium and potassium, can be utilized for this purpose in organic solvents since both the active substance salts and the silicates have only very low solubility in these solvents.
The best solubility for these silicates was found in methanol and ethanol and was determined to be only 0.01% (g/g). Nevertheless, it is possible to use solvents with even less solubility for silicates, such as isopropanol, acetone, methyl ethyl ketone, ethyl acetate and mixtures of the aforementioned solvents.
It is furthermore surprising that despite this low solubility one is successful in achieving, within acceptable periods of time, a complete conversion of the active substance salts into their free bases. Normally, the complete conversion at room temperature takes only about 2-3 days; it can be shortened to about 24 hours by increasing the temperature to about 35-40º C. Attempts to use silicates of calcium or magnesium failed since, owing to the multivalent cations, they are practically insoluble in organic solvents. Basic aluminium-containing mixed silicates have proved just as unsuitable.”
Therefore, depending on the end-use of the product, an organic chemist would know which silicate and solvent to use so that the salt and the and silicates remain dispersed, while the free amine is soluble in the final mixture.
Applicant further states, “Even if a skilled artisan considered using a silicate per Mϋller, there is no articulated reason to expect that, for asenapine maleate, the reaction would yield the particular product state recited in claim 1 because Mϋller's generic silicate teaching does not address the counterion-dependent phase behavior critical to the claimed process, nor does it hint at designing the reaction to exploit precipitation of an alkali metal maleate.”
This is also not persuasive for the same reasons noted above. The Mϋller reference teaches both the active substance salts and the silicates have only very low solubility in these specific solvents and how this can be manipulated with other solvents, which is a result-effective variable, and obvious.
"Where 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." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). The adjustment of particular conventional working conditions (e.g., determining result effective amounts of the solvents taught by the cited references), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results, unless there is evidence to the contrary.
Applicant notes, “Zheng neither teaches nor suggests the claimed use of an alkali silicate not the claimed product-state outcome enabling simple filtration to isolate a solids-free solution containing dissolved asenapine free base. Moreover, Zheng's reliance on post-reaction crystallization teaches away from expecting high purity directly in solution, which is, however inherent to the inventive reaction outcome.”
This is also not persuasive. The Zheng reference was cited to show anesapine maleate may be converted to the free amine asenapine with a base, e.g. NaOH. The Mϋller reference was cited to show silicates may be substituted for NaOH to convert the asenapine maleate to the free amine asenapine in a dispersed mixture since Mϋller teaches both the active substance salts and the silicates have only very low solubility in these specific solvents.
Thus, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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 SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
Prosecution Insights