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 of Group (I) in the reply filed on October 17, 2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Group (I), drawn to a process for the preparation of an anticholinergic agent, embraced by claims 1-14 was elected by Applicant. Applicant has not pointed to any errors in the Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Claims 1-5, 7, 8, 10, 11 and 13-23 are pending and claims 1-5, 7, 8, 10, 11, 13, 14 and 23 are under examination. Claims 15-22 are withdrawn based on the restriction requirement.
Claim Objections
The objection to claim 1 because of the term “unsolvate” should be replaced with “unsolvated” is withdrawn based on the amendments.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 1-5, 7, 8, 10, 11, 13, 14 and 23 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Hossner et al. (US 9657011) in view of Mereu et al. (US 8865903), Turner et al. (WO 2018087561), Mandity et al. (ChemistryOpen, 2015, 4, pp. 212-223), Mendes et al. (US 20180105517) and Britton et al. (Chem. Soc. Rev., 2017, 46,1250-1271).
The present application teaches a process for the preparation of an anticholinergic agent, wherein the process is carried out in continuous flow mode (CFM) using a solvent consisting of one or more polar protic solvents, e.g., propanol. The reaction is provided below for the species in claim 3, umeclidinium bromide.
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The ‘011 reference teaches a batch process for the alkylation of cyclic tertiary amines, e.g., umeclidinium bromide, refluxing in propanol (boiling point is 97ºC, and recrystallized in propanol and water, see columns 11-12, Examples 5-8. The ‘011 reference further teaches the reaction done with an alcohol with a boiling point greater than about 80 ºC, and optionally recrystallizing, see column 2, lines 29-31.
The ‘011 reference does not teach a continuous flow process for the alkylation of cyclic tertiary amines, e.g., umeclidinium bromide.
The ‘903 reference teaches a CFM process for the alkylation of cyclic tertiary amines, e.g.,
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, see Example 3, Robinul®, see Example 5, and Ipratropium bromide, see Example 6, in a polar aprotic solvent or a combination of a polar aprotic and protic solvents, see Table 1, column 7, which teaches methanol and acetonitrile. The examples cited are compounds found on page 2 of the specification.
The reference provides a general teaching that states, “The method comprises: continuously feeding a solution of a cyclic tertiary amine in a suitable solvent or mixture of solvents and an alkylating agent, optionally dissolved in a suitable solvent or mixture of solvents, into a continuous-flow reactor; maintaining the temperature within the range of 20-140 ºC [(or 20-200 ºC, see claim 1, column 8)]; collecting the solution containing the pure quaternary cyclic ammonium compound; and isolating the pure quaternary cyclic ammonium compound, see column 3, lines 10-22.
The ‘903 reference further teaches a method for the continuous alkylation of cyclic tertiary amines, particularly useful for the production of cyclic quaternary ammonium compounds with high purity as required for pharmaceutical use, which is more efficient than the known quaternization processes, see column 3, lines 1-5. The reference further states, “The method of the present invention allows one to directly obtain the quaternary cyclic ammonium compound with high purity without the need of any further purification step. Moreover, the method offers several additional advantages over known methods such as better reaction control, better temperature control of the reaction and easy scale up for larger output,” see column 3, lines 23-29.
Furthermore, it is well established that batch and continuous processes are not patentably distinct. See, e.g., In re Dilnot, 319 F.2d 188, 138 USPQ 248 (CCPA 1963).
The advantages of using a CFM is taught by Mandity et al. (ChemistryOpen, 2015, 4, pp. 212-223). Mandity states, “Continuous-flow (CF) transformations are of considerable current interest, as they offer a substantial number of advantages over conventional batch procedures, such as inherently safer and greener chemistry, outstanding mass and heat transfer, increased parameter space with an unprecedented level of control over the most important reaction conditions, and higher reaction rates. Many of these advantages stem from the size of CF reactors, where the diameters of the pores and capillaries are mainly in the micro- or nanometer range. With such short
distances, the mass transfer is faster and results in more effective mixing of the substrates. The small internal dimensions are accompanied by high surface to volume ratios, which results in effective heat transfer, thereby allowing exact temperature
control. The major consequence of these advantages is that the reaction times can be decreased relative to those in conventional batch procedures,” see the first full paragraph.
The ‘903 reference does not teach a solvent consisting of one or more polar protic solvents as currently claimed. However, the ‘011 reference cited above does teach one or more polar protic solvents, e.g., propanol and water for recrystallizing.
The advantage of using propanol is that the ‘011 reference also teaches the final product may be crystallized from propanol and water, which means less resources must be used to change solvents.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "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). Therefore, adjustment of particular conventional working conditions e.g., determining result effective amounts, is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. This applies to solvents, concentrations of solvents, times and temperatures found in claims 6, 7 and 9-11, unless there is evidence to the contrary.
Moreover, as Applicant noted in the Remarks received on February 3, 2025, page 7, “[A] person of ordinary skill in the art would understand that other polar protic solvents may be used in the claimed process. For example, it is readily understood by a person of ordinary skill in the art that polar protic solvents are solvents that can form hydrogen bonds with the substrate. They can form hydrogen bonds because they contain at least one hydrogen atom that is directly connected to an electronegative atom (such as O-H or N-H bonds). Examples include water, ethanol, methanol, propanol, ammonia, acetic acid, and other polar protic solvents. Thus, while in the examples only 1-propanol is used as an example of polar protic solvent, Applicant respectfully submits that a person of ordinary skill in the art would readily understand that other polar protic solvents would also work based on the disclosure of the present application.”
Thus, the combination of solvents would be obvious to use for the presently claimed process.
Additionally, the ‘561 publication teaches, “The preparation of pure umeclidinium bromide in a single crystalline form has been a challenge for the industry as umeclidinium bromide is highly susceptible to forming solvates... 1-Propanol has been used as the solvent in the final process step to minimize solvate formation…avoiding the resuspension of the compound in ethyl acetate, methanol and water, which was previously required,” see page 3, second full paragraph. The publication further notes, “Additionally, it has been found that step d) of the present invention affords a product with a single, pure crystalline form with a consistent level of crystallinity and chemical purity. Therefore, one further advantage of the process of the present invention is that the umeclidinium bromide obtained during step d) of the present invention is a single, pure crystalline form with a consistent level of crystallinity and chemical purity,” see page 6, second full paragraph.
Claim 13 is drawn to precipitating the product from a solution, which is similar to a crystallization step, which is a conventional purification step used in the labs and manufacturing processes.
Claim 23 is drawn to a single crystalline form with greater than 98.5% purity by HPLC. The ‘903 reference teaches purities with different solvents greater than 98.5% using CFM, just not in a polar protic solvent. The combination of the ‘561 publication and the ‘011 patent provide a solvent system, while the ‘903 patent provides the CFM process to achieve a purity of 98.5% single crystalline form.
The ’517 reference teaches micronizing or jet milling of aclidinium bromide, see page 6, Example 12,
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, which is the same as formula (IV) on page 2 of the specification. This compound is similar in structure to umeclidinium bromide, and therefore, one would expect similar properties.
Hence, it would be obvious to one of ordinary skill in the art to use CFM as taught by Mereu et al. and Mandity et al. for the process of the alkylation of cyclic tertiary amines, e.g., umeclidinium bromide, by refluxing in propanol as taught by Hossner et al. and Turner et al.; followed by crystallizing as also taught by Hossner, and lastly the jet milling as taught by Mendes et al.
Britton et al. teaches “Finally, the continuous-flow system is normally operated under a level of backpressure, controlled by a backpressure regulator (Fig. 1H). Subjecting the continuous-flow stream to a backpressure allows solvents to be used above their atmospheric boiling points while ensuring reaction homogeneity as the solution passes between reactor coils at different temperatures. Such a large toolbox of continuous-flow equipment leads to reaction diversity and flexibility, allowing demanding chemical challenges to be met,” see page 1251, bottom of left-hand column.
Thus, said claims are rendered obvious over Hossner et al. in view of Mereu et al., Turner et al. Mandity et al., Mendes et al and Britton et al.
Applicant traverses by stating, “It Would Not Have Been Obvious to Operate a Continuous Flow Reactor Using a Solvent at a Temperature Above the Boiling Point of the Solvent.”
This is not persuasive. The Britton reference has been added to the rejection to address using solvents above the boiling point of the solvent in a continuous flow reactor.
Applicant further traverses by stating, “The Claimed Invention Achieves Unexpected Results” and addressing the following points: 1) high conversion with polar protic solvent above it’s boiling point; 2) stable operation without the reactor clogging; 3) dramatic reduction in reaction time with high purity; and 4) high purity at extreme temperatures without degradation.
This is also not persuasive. 1) The rejection addresses the conversion or yield with propanol as the solvent. 2) The rejection does not address the reactor clogging but this would be inherent if propanol is used as noted in the rejection. 3) The reduced time is addressed in the rejection. 4) The purity is also addressed in the rejection.
A declaration has been submitted by Marianna Katz, an inventor on the present application, as an expert in flow chemistry. The declaration states a CV has been provided as Exhibit A, but no CV has been received.
The declaration states, a continuous flow process was sought to improve efficiency, reduce reaction time, and produce umeclidinium bromide in high purity with requiring additional steps. The declaration further states significant problems were encountered when attempting to identify suitable solvents and reaction conditions for CF synthesis. The declaration goes on to address issues with methanol, e.g. low conversion, and dichloromethane (DCM), e.g. clogging issues, as solvents.
The declaration also states that nothing in the cited references would have caused POSA to use 1-propanol above it’s boiling point in a CF reactor to overcome the issues with methanol and DCM. The declaration further notes the prior art provides no suggestion of using 1-propanol at 120-200 C would be successful; and is contrary to the Mereu reference teaching methanol above it’s boiling point giving a poor conversion.
This is not persuasive. DCM will not be addressed further as DCM is not noted in the rejection. The Mereu reference does not discourage this approach; the reference teaches that methanol at this particular temperature was not suitable. Testing solvents, concentrations, and temperatures are considered routine optimization as being result-effective variables.
The declaration further provides Examples of successful processes, which are provided below:
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Even if these examples are acceptable as unexpected, the claims are not commensurate in scope with the examples.
MPEP 716.02(D) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). The non-obviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).
The rejection is maintained.
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 SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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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.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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