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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous office action has been withdrawn pursuant to 37 CFR 1.114.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 filed 23 June 2026 has been entered.
The Request for Continued Examination filed has been considered. The following information has been made of record in the RCE filed for the instant application:
1. Claims 2-4, 7-8, 14-18, 20-94, 98-104, and 107 have been canceled.
2. No new Claims have been added.
3. Claims 1, and 11-13 have been amended.
4. Remarks drawn to rejection under 35 USC 103.
The rejection of claim 8 under 35 USC 103 as being unpatentable over Arosio et al (Org. Biomol. Chem., 2004, 2, 2113-2124; cited in IDS filed 04/17/2025; of record) in view of Smith (Organic Chemistry, Third Ed., 2011, page 842; of record) and further in view of Cairns et al (The Journal of Chemical Physics, 1960, 32(1), 169-175; of record) has been rendered moot by cancelation.
In claim 1 limitations regarding compound of formula (A) having an alpha conformation in the C1 position and time for which heating is done have been added. In claim 11 the claim dependency has been changed and the recitation ‘about 30min to’ has been deleted. In claims 12 and 13 the claim dependency has been changed.
Claims 1, 5-6, 9-13, 19, 95-97, and 105-106 are pending in the case.
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.
Claim(s) 1, 5-6, 9-13, 19, 95-97, and 105-106 are rejected under 35 U.S.C. 103 as being unpatentable over Arosio et al (Org. Biomol. Chem., 2004, 2, 2113-2124; cited in IDS filed 04/17/2025; of record) in view of Smith (Organic Chemistry, Third Ed., 2011, page 842; of record) and further in view of Cairns et al (The Journal of Chemical Physics, 1960, 32(1), 169-175; of record).
Arosio teaches a process for preparing a-1-allyl-2-N-acetylglucosamine (carbohydrate structurally close to the carbohydrate of formula Ao) wherein acetyl chloride is added to allylic alcohol under a nitrogen atmosphere at 0oC. Then, N-acetyl glucosamine is added at room temperature. The reaction mixture is stirred at 70oC for 3hrs. After completion of the reaction, the reaction mixture is neutralized to pH 7, washed and a-1-allyl-2-N-acetylglucosamine is isolated. The reaction solution after neutralization and washing contains the a-1-allyl-2-N-acetylglucosamine (page 2114, Scheme 2, conversion of compound 7 to 8 first step; page 2119, right col.-see synthesis of compound 8; first step to make a-1-allyl-2-N-acetylglucosamine; part of the limitations of claim 1 regarding method steps, reagents, reaction conditions and desired product, and limitations of claims 6, 9-10, 19, 95-97, and 105).
Even though Arosio does not expressly teach using the galactosamine Ao as starting material, it can be seen that in the reaction of Arosio the product obtained in the first step on reacting sugar 7 with allyl alcohol and acetyl chloride is allylated sugar with an a-configuration at the C1-position. After this reaction the product should be product 8 but without the pivaloyl groups on the hydroxyls at the 3- and 6-positions. This indicates that only the hydroxyl at the C-1 position (anomeric position) is allylated. From this reaction scheme one of ordinary skill in the art will recognize that if one were to use compound Ao as the starting material it should undergo the same type of reaction at the C1-position and give product A as instantly claimed.
Arosio et al does not teach that the intermediate reaction mixture at low temperature comprises the compound of formula Ao, HO-(CH2)n-CH=CH2 and HCl, and cooling the reaction mixture as in claim 1, and does not teach the limitations of claims 5, and 11-13.
According to Smith exposure of acid chloride to moist air leads to some hydrolysis leading to formation of HCl as by product (page 842-middle of the page on the left). In view of this teaching one of ordinary skill in the art would have a reasonable expectation that the bottle from which acetyl chloride was added in the method of Arosio was exposed to air, and would have resulted in the formation of HCl. Therefore, the intermediate reaction mixture would comprise the compound of formula Ao, HO-(CH2)n-CH=CH2 and HCl as in claim 1. After heating the reaction mixture, it would have been obvious to the artisan to cool the reaction mixture before isolating the desired product as in claims 1 and 19. Doing so would make it easy for workup and isolation of the desired product.
Cairns teaches that the reaction of acetyl chloride with water slows down at lower temperatures (page 172, Table II, k2 l/mol-sec). In view of this teaching and that of Smith one of ordinary skill in the art will add compound Ao to a solution of HO-(CH2)n-CH=CH2 and acetyl chloride at a temperature between about 0oC to about 25oC in order to reduce the hydrolysis of acetyl chloride with moisture in the air to generate excess acid. This would also slow down the reaction of the OH group of the allylic alcohol and acetyl chloride as a side reaction which can produce the allyl chloride. This would reduce the amount of the allylic alcohol available for reaction with the galactosamine to produce the desired compound (A).
Adjusting the temperature and reaction times as in claims 1, 5, 11-13, and 106 can be done as routine optimization of the reaction conditions. Using an excess of HO-(CH2)n-CH=CH2 such that it serves as the solvent as in amended claim 1 would also be obvious to the artisan. This would ensure that HO-(CH2)n-CH=CH2 is present in excess so that all of the starting N-acetyl galactosamine is alkoxylated in addition to serving as solvent.
It is well established that merely selecting proportions and ranges and modifying the process conditions such as temperature, reaction time and concentration is not a patentable modification absent a showing of criticality (In re Aller, 220 F.2d, 454, 105 U.S.P.Q 233 C.C.P.A, 1995 and In re Becket, 33 U.S.P.Q 33, C.C.P.A, 1937 and In re Russell, 439 F. 2d 1228, 169 U.S.P.Q. 426, C.C.P.A 1971).
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, the desired the compound of formula A can be prepared using the steps and reagents and reaction conditions as in claim 1 with a reasonable expectation of success (Aroso in view of Smith and Cairns).
Thus, the claimed invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art. One of ordinary skill in the art would be motivated to use the process as claimed as taught by the prior art since it is art tested and known to give the desired product in good yield. Modifying the method of Arosio by starting with N-acetylgalactosamine will directly give the desired product A. Using the method of Arosio, and substituting the N-acetyl glucosamine with N-acetylgalactosamine as in the instant process would reduce the number of steps to get to the desired product. This avoids the step of making the glucose derivative first and then epimerizing it to the galactose derivative.
Response to Applicant’s Remarks
Applicant has traversed the rejection of claims under 35 USC 103 of record arguing that Arosio, Smith and Cairns fail to teach or suggest every feature of amended claim 1.
Arosio eaches a multi-step synthesis in which N-acetylglucosamine is first reacted with allyl alcohol in the presence of acetyl chloride, and the resulting allyl glucosamine intermediate is then protected to form compound 8. Compound 8 is further converted into compound 9 through a subsequent epimerization at C-4, accompanied by migration of the protecting group, to obtain O4/O6-protected a-1-allyl-2-N-acetyl galactosamine derivative. Nowhere does Arosio teach or suggest the features of amended claim 1. Arosio does not disclose directly reacting an N-acetyl galactosamine derivative of formula Ao with HO-(CH2)n-CH=CH2 to obtain formula A, where R1 is H and n is form 1 to 5, having an a-configuration at C1. Arosio avoids the direct use of N-acetyl galactosamine as the starting material.
A person of ordinary skill in the art will understand from Arosio that preparation of the galactosamine derivative required the multi-step route reported in Scheme 2. Arosio describes the synthesis of Galb1,3GalNAc donor 5 as improved over reported procedures, yet still uses the glucosamine route and subsequent epimerization to obtain compound 9. This is a teaching away from the direct process of claim 1. Moreover, Arosio teaches heating the allylation reaction for 3 hours, not heating the intermediate mixture at about 60oC for about 30 minutes to about an hour as recited in claim 1. Arosio does not teach or suggest that a shorter heating period of about 30 minutes to about 1 hour would provide the claimed product of formula A and having the alpha confirmation in the C1 position, much less in high yield.
Smith relates to general organic chemistry principles concerning reactions of acid chlorides with nucleophiles. It teaches that acid chlorides react with alcohols and that HCl is usually formed as a reaction by-product. It further teaches that pyridine may be used to remove HCl formed during such reactions. Smith does not teach the features of claim 1. Smith does not relate to synthesis of reactive carbohydrates.
Cairns relates to kinetics of hydrolysis of acetyl chloride un acetone-water mixtures, including effect of temperature, water concentration, solvent composition on reaction rate. Cairns does not relate to the synthesis of reactive carbohydrates and does not disclose N-acetyl galactosamine derivatives. In view of he above the combination of the cited prior art rail to teach every element of claim 1. Therefore, claim1 and the dependent claims are patentable (pages 5-8 of Remarks).
Applicant’s arguments are not found to be persuasive. It has been acknowledged in the rejection that Arosio does not teach some of the limitations of amended claim 1. But one of ordinary skill in the art will recognize that in Arosio 2-N-acetylglucosamine is reacted with allyl alcohol and acetyl chloride in the first step to get the allyloxy group added to the C1-position of the carbohydrate. The process in amended claim is similar. So, starting with 2-N-acetyl galactosamine instead of the glucosamine should give the corresponding a-1-allyl-2-N-acetylgalactosamine when reacted with allyl alcohol and acetyl chloride. There need not be an express teaching in Arosio that the same reaction cannot be performed with 2-N-acetyl galactosamine. From the reaction shown in Scheme 2 of Arosio it would be obvious to the artisan that the compound of instant formula (A) as in amended claim 1 can also be obtained using the same reaction. The chemistry is the same and is also done at the same C-1 position of the sugar ring. There is no express teaching in Arosio that galactosamine cannot be allylated at the C1-position with the allyl moiety in the alpha-configuration. Applicant argues that Arosio avoids the direct use of N-acetyl galactosamine as the starting material. There is no teaching in Arosio as to why the direct use of N-acetyl galactosamine as starting material is avoided. Applicant has not provided an explanation either.
A person of ordinary skill in the art will not understand from Arosio that preparation of the galactosamine derivative requires the multi-step route reported in Scheme 2 just because Arosio has used it. Arosio describes the synthesis of Galb1,3GalNAc donor 5 as improved over reported procedures, yet still uses the glucosamine route and subsequent epimerization to obtain compound 9. Regarding this statement Arosio cites reference 4 which teaches the yield of the disaccharide and not the product as instantly claimed. Arosio may teach heating the allylation reaction for 3 hours, and not heating the intermediate mixture at about 60oC for about 30 minutes to about an hour as recited in claim 1. This does not necessarily mean that heating the intermediate mixture at about 60oC for about 30 minutes to about an hour as recited in claim 1 will not produce the desired product. As set forth in the rejection, merely selecting proportions and ranges and modifying the process conditions such as temperature, reaction time and concentration is not a patentable modification absent a showing of criticality. Applicant just argue that the conditions as in amended claim 1 are not taught but have not shown the criticality of the conditions used in the instant process.
Arosio teaches that the acetyl chloride was added dropwise to allylic alcohol under N2,. This is done to prevent exposure of acetyl chloride to air. This is done so that the acetyl chloride does not undergo further hydrolysis during the allylation reaction of the sugar in the reaction vessel. According to Smith a bottle of acetyl chloride when opened reacts with moist air to generate HCl. In addition, there would also be reaction between the allyl alcohol and the acetyl chloride which generates HCl. From the teaching of Smith the artisan would recognize that the mixture of HO-(CH2)n-CH=CH2 and acetyl chloride would still have some HCl in the mixture. This HCl is formed on exposure of the acetyl chloride to air (moisture) during transfer of the acetyl chloride from the bottle to the reaction vessel. One exposing the acetyl chloride in the bottle to air there will also be some hydrolysis within the bottle. Therefore, on adding the compound of formula (Ao) to the solution comprising HO-(CH2)n-CH=CH2 and acetyl chloride, HCl will also be present as in claim 1. Smith is cited to show that HCl will be present in the reaction mixture as in claim 1. Arosio teaches heating the reaction mixture to the claimed temperature range and cooling the mixture to obtain the corresponding allylated sugar. The same allylated sugar will also be obtained by substituting the glucosamine of Arosio with galactosamine as in the claimed process.
Cairns teaches the hydrolysis of acetyl chloride in acetone which also has water in it. From the teaching of Cairns it is seen that the reaction of acetyl chloride with water slows down at lower temperatures (page 172, Table II, k2 l/mol-sec). In view of this teaching and that of Smith one of ordinary skill in the art will add compound Ao to a solution of HO-(CH2)n-CH=CH2 and acetyl chloride at a temperature between about 0oC to about 25oC in order to reduce the hydrolysis of acetyl chloride with moisture in the air to generate excess acid. This would also slow down the reaction of the OH group of the allylic alcohol and acetyl chloride as a side reaction which can produce the allyl chloride. This would reduce the amount of the allylic alcohol available for reaction with the galactsamine to produce the desired compound (A). Therefore, the artisan would combine Arosio with Smith to arrive at the present process as claimed. The skilled person would refer to Cairns considering that the process of Arosio and the one of amended claim 1 is performed under inert atmosphere, thereby reducing the exposure of acetyl chloride to water as explained above. The combined teachings of the prior art do render the instant claims obvious. The rejection is maintained.
Conclusion
1. Pending claims 1, 5-6, 9-13, 19, 95-97, and 105-106 are rejected.
2. Claims 2-4, 7-8, 14-18, 20-94, 98-104, and 107 have been canceled.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693
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