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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 dated 12/01/2025 has been entered pursuant to RCE filed on 12/01/2025.
Pursuant to the amendment dated 12/01/2025, claim 12 is newly added. Claims 1-2, 4-6, and 9-12 are pending in the instant application and are examined on the merits herein.
Priority
This application is a National Stage Application of PCT/IB2020/055950 filed on 06/24/2020 and claims foreign priority to INDIA 201921026759 filed on 07/04/2019.
Claim Objections
Claim 12 is objected to because of the following informalities: “of compound” is repeated twice on line 3. Appropriate correction is required.
New and Maintained Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant' s amendment with respect to amended claim 12 herein has been fully considered but is deemed to insert new matter into the claims since the specification as originally filed does not provide support for the steps of preparation as instantly claimed. Claim 12 is drawn to a process for the preparation of formula I according to instant claim 1, wherein the compound of formula IV obtained with the first base added in one lot and the first solvent is dimethyl sulfoxide has a yield greater than a yield of the compound of formula IV obtained with the first base added in one lot or two lots and the first solvent with acetonitrile. The instant specification provides an example of a process for the preparation of formula I according to instant claim 1. The instant specification discloses preparation of the compound of formula IV wherein the first base was added in one lot and the first solvent is dimethyl sulfoxide (DMSO). The instant disclosure, however, does not teach the compound of formula IV obtained with the first base added in one lot or two lots and the first solvent with acetonitrile (see MPEP 2163.I.B.).
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.
Claims 1-3, 6, and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Koyama et al. (US 8,357,808 B2, published 01/22/2023, see PTO-892 dated 06/30/2025), Zhou et al. (Chemical Engineering Science, published 11/19/2013, see PTO-892 dated 06/30/2025), Pirrung (Handbook of Synthetic Organic Chemistry, 2nd Ed., published 2017, see PTO-892 dated 06/30/2025), Murray et al. (Org. Biomol. Chem, published 12/15/2015, see PTO-892), and Phenomenex (www.research.cbc.osu.edu/turro.1/wp-content/uploads/2017/02/solvent.miscibility.pdf, published 01/23/2018, accessed 06/26/2025, see PTO-892 dated 06/30/2025).
Koyama is drawn to the process of producing an intermediate for production of an FXa inhibitor, wherein the intermediate meets the limitations of the instant formula II (abstract). Koyama teaches reacting the instant formula V with a compound of instant formula VI in the presence of tertiary amine and a C2-C4 nitrile solvent, wherein the C2-C4 nitrile solvent is acetonitrile, and triethylamine to form the instant formula IV (columns 3 and 4). Koyama teaches deprotecting the instant formula IV to remove the Boc group to obtain instant formula II (column 6, line 49). Koyama teaches the addition of triethylamine causes an increased formation of by-products and decrease in yield (column 2, lines 51-55). Koyama teaches to decrease the formation of by-products and increase the yield, the tertiary amine can be added in divided portions (column 3, lines 5-6). One of ordinary skill in the art would reasonably conclude that Koyama teaches the triethylamine could be added in one lot with a reduced yield. The reaction of a compound of instant formula II and a compound of instant formula III forms a compound of instant formula I-A (column 7, lines 5-45) and the reaction is preferably done in triethylamine (column 2, line11). Compound of instant formula I-A is reacted with para toluene sulfonic acid in ethanol to obtain a compound of instant formula I (column 7, line 49). Kayama teaches recrystallizing the compound of instant formula A-a in 15% ethanol in water (column 21, lines 17-20). Kayama teaches that by avoiding the solidification of the reaction system, the reaction yield is as high as 93-95% (column 7, lines 55-58). Koyama determined that the purity of the compound of instant formula IV obtained was greater than 99% pure as determined by HPLC (column 23, lines 5-14).
Koyama does not teach the use of DMSO in the instant claims 1(a) and 1(d). Koyama does not teach the use of the solvents listed in instant claim 1(e).
Zhou is drawn to a model-based method for the screen of solvents for chemical reactions (title). Zhou screened 136 solvents for SN2 reactions and found DMSO, acetonitrile, morpholine, and pyridine to be promising solvents which are all polar and aprotic. Zhou teaches that in SN2 reactions, protic solvents can form hydrogen bonds with the nucleophiles that hinders the nucleophile to attack the carbon of the substrate and reduce the reaction rates (page 183, column 1).
Murray is drawn to the application of design of experiments (DoE) reaction optimization and solvent selection in the development of new synthetic chemistry (title). Murray teaches that one of the most important parameters in reaction optimization is the choice of solvent. The vast majority of new synthetic methods employ a relatively small set of common laboratory solvents during the reaction optimization phase. Most reactions that are developed use of the following ten common laboratory solvents: diethyl ether, THF, acetonitrile, DMF, DMSO, ethanol, methanol, chloroform, PhMe, and acetone (page 2376).
Pirrung is drawn to the study of purifying compounds through crystallization. Pirrung teaches that most crystallization uses common laboratory solvents such as water, alcohols, acetone, ethyl acetate, cyclohexane, and toluene. Pirrung teaches that solubility should be considered for crystallization. Pirrung teaches that a solvent selection can be made by analogy-if similar compounds have been crystallized from a particular solvent, that provides good teaching about where to begin with the current compound. One of ordinary skill in the art would understand that would also mean that if one solvent has been show to successfully work to recrystallize a compound, similar polarity solvents should be considered on the same compound for recrystallization.
Phenomenex is drawn to a solvent miscibility table. The table teaches that acetone is miscible in water and has a polarity index of 5.1. The table teaches that ethanol is miscible in water and has a polarity index of 5.2.
It would have been prima facie obvious to combine Koyama, Zhou, Pirrung, Murray, and Phenomenex before the effective filing date of the claimed invention by replacing the acetonitrile solvent utilized by Koyama with DMSO as taught by Zhou to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to replace the acetonitrile solvent as taught by Koyama with DMSO because Zhou teaches that both acetonitrile and DMSO are polar aprotic solvents that are promising solvents for SN2 reactions and Murray teaches that both acetonitrile and DMSO are two of the top ten most common solvents used for synthesis development and that solvent is a common parameter in synthesis optimization. One of ordinary skill in the art would have a reasonable expectation of success because Zhou teaches that both acetonitrile and DMSO are polar parotic solvents suitable for SN2 reactions.
It would have been prima facie obvious to combine Koyama, Zhou, Pirrung, Murray, and Phenomenex before the effective filing date of the claimed invention by replacing the ethanol and water solvent utilized by Koyama with another polar mixture such as acetone in water as taught by Pirrung to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to replace the ethanol and water solvent as taught by Koyama with acetone and water because Pirrung teaches it is important to consider solubility and analogous solvents and Phenomenex teaches that both acetone and ethanol are miscible in water. One of ordinary skill in the art would have a reasonable expectation of success because Pirrung teaches that solubility should be considered and Phenomenex teaches that both acetone and ethanol are miscible in water.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Koyama et al. (US 8,357,808 B2, published 01/22/2023, see PTO-892 dated 06/30/2025), Zhou et al. (Chemical Engineering Science, published 11/19/2013, see PTO-892 dated 06/30/2025), Pirrung (Handbook of Synthetic Organic Chemistry, 2nd Ed., published 2017, see PTO-892 dated 06/30/2025), Murray et al. (Org. Biomol. Chem, published 12/15/2015, see PTO-892), and Phenomenex (www.research.cbc.osu.edu/turro.1/wp-content/uploads/2017/02/solvent.miscibility.pdf, published 01/23/2018, accessed 06/26/2025, see PTO-892 dated 06/30/2025) as applied to claim 1 above, and further in view of Coffey et al. (Organic Process Research & Development, published 10/20/2004, see PTO-892 dated 06/30/2025).
Claim 1 is rejected as discussed above.
The combined teachings of Koyama, Zhou, Pirrung, Murray, and Phenomenex are discussed above.
The combined teachings of Koyama, Zhou, Pirrung, Murray, and Phenomenex do not specify the deprotecting agent used. The combined teachings of Koyama, Zhou, Pirrung, Murray, and Phenomenex do not teach the formation of instant formula II-A after deprotecting compound instant formula IV.
Coffey is draw to the method of removing a BOC group using concentrated HCl and acetone on a kilogram scale (abstract).
It would have been prima facie obvious to combine the combined teachings of Koyama, Zhou, Pirrung, Murray, and Phenomenex with the teachings of Coffee before the effective filing date of the claimed invention by modifying the deprotection method taught by Koyama by using HCl and acetone to remove the BOC group as taught by Coffee to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the deprotection method taught by Koyama by using HCl and acetone as taught by Coffey to remove the BOC group and form the dihydrochloride salt, a compound of instant formula II-A because Coffey teaches the successful deprotection of the BOC group with HCl and acetone and the instant specification shows that the reaction of a compound of instant formula IV with HCl in acetone forms the dihydrochloride, a compound of instant formula II-A (instant specification paragraph 0029). One of ordinary skill in the art would have a reasonable expectation of success because Coffey exemplified the removal of the BOC group with HCl and acetone and the instant specification shows that the reaction would necessarily form the instant formula II-A.
Response to Arguments
Applicant's arguments filed 12/01/2025 have been fully considered but they are not persuasive.
Regarding the rejection of claims 1-3, 6 and 9-11 under 35 U.S.C. §103 as being unpatentable over Koyama, Zhou, Pirrung and Phenomenex, applicant argues that the combined teachings of Koyama, Zhou, Pirrung and Phenomenex fail to meet the particular recitations of the claims as originally filed and that there is no suggestion or motivation to combine the collective teachings of Koyama, Zhou, Pirrung and Phenomenex. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Koyama teaches the method of synthesizing the compound of formula IV through the reaction of compounds VI and V with the addition of the base in either one or two lots in acetonitrile solvent. In the current rejection, Murray teaches that optimizing solvent is standard in new synthesis and teaches that both acetonitrile and DMSO are two of the top ten most common solvents for synthesis. Zhou teaches that both acetonitrile and DMSO are protic solvents that work well in SN2 reactions. Therefore, it would have been obvious to one of ordinary skill to try different protic solvents such as DMSO to optimize the SN2 synthetic reaction taught by Koyama. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that Koyama explicitly teaches away from adding the base in one lot. Applicant further argues that a person of ordinary skill in the art would not consider using the base in one lot as it is expected to result in obtaining the desired product in decreased yield. The argument is unpersuasive. Applicant did not provide evidence to support the assertion that a person of ordinary skill in the art would not consider using the base in one lot. Koyama teaches both methods of either adding the base in one lot with a decrease in percent yield or adding the base in two lots with an increased percent yield. MPEP 2123 (II) states “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). ‘A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.' In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)… Furthermore, ‘[t]he prior art' s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….' In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).” The choice to add in the base in two lots or add in one lot is up to the person of ordinary skill to decide between the benefit of higher yield or of reduced synthetic steps.
Applicant argues that the unexpected results of the instant invention in that the addition of a base in one lot using dimethyl sulfoxide as a solvent resulted in an increase in yield of the desired product, and that such result is not obvious in view of teachings of Koyama that addition of base in one lot would result in decreased yield of desired product. The argument is unpersuasive. The theoretical yield calculations provided by the applicant in the response dated 12/01/2025 were calculated using the mass of the non-limiting reagent and therefore were not correct. The correct theoretical yield calculations are provided below. As shown, the instant inventive example 1B with DMSO in one lot has an 89.0% yield wherein Koyama’s invention with acetonitrile in one and two lots has 93.1% and 85.4% yield, respectively. Further, there are differences in the reaction times and temperatures throughout the reaction of Koyama and the inventive example and thus, a direct comparison for unexpected results cannot be made. Therefore, the inventive example does not support the claim of unexpected results as the yield was within the range of Koyama’s inventive method with acetonitrile in one lot and two lots. Further, without statistical data provided, there is no way for one of ordinary skill in the art to determine if the % yields calculated are statistically
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significant.
Conclusion
No claims are allowed.
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/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693 /SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693