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 .
The amendment filed 14 July 2026 has been received, entered and considered. The following information has been made of record in the instant amendment:
1. Claims 9 and 15 have been canceled.
2. No new Claims have been added.
3. Claims 1-2, 4, 6, 8, 10-11 and 14 have been amended.
4. Remarks drawn to rejections under 35 USC 112 and 103.
The following objection(s)/rejection(s) has/have been overcome:
5. The rejection of Claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph has been overcome by amendment. The rejection of claim 15 has been rendered moot by cancelation.
6. The rejection of Claim(s) 9 and 15 under 35 U.S.C. 103 as being unpatentable over Liotta et al (WO 2016145142 A1) in view of Obika et al (US 10961269) and further in view of Dess et al (Journal of Organic Chemistry, 1983, 48, 4155-4156), Ohrui et al (US 6333315), Gilbert et al (Journal of Organic Chemistry, 1982, 47, 1837-1845), Schinazi et al (WO 2019/133712) and Fukuyama et al (Organic Letters, 2015, 17, 828-831; cited in IDS filed 11/13/2023) has been rendered moot by cancelation.
Claims 1-8 and 10-14 are pending in the case.
The following rejections are necessitated by Applicant's amendment filed 14 July 2026 wherein the limitations in pending claims 1-2, 4, 6, 8, 10-11 and 14 have been amended.
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) 1-8 and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Liotta et al (WO 2016145142 A1; of record) in view of Obika et al (US 10961269; of record) and further in view of Dess et al (Journal of Organic Chemistry, 1983, 48, 4155-4156; of record), Ohrui et al (US 6333315; of record), Gilbert et al (Journal of Organic Chemistry, 1982, 47, 1837-1845; of record), Schinazi et al (WO 2019/133712; of record) and Fukuyama et al (Organic Letters, 2015, 17, 828-831; cited in IDS filed 11/13/2023; of record).
Liotta et al teaches conversion of compound 432 to compound 433 (page 331, Example 149):
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The above conversion is step 1 in claim 1. The selective hydroxyl protection reaction is conducted under the action of sodium hydride and benzyl bromide by using DMF as the solvent. The hydroxyl protection is conducted at -5oC. The ratio of the compound 432 (instant formula II), the sodium hydride, and the benzyl bromide is 1:1.16:1.16 (page 332, first para; part of the limitations of claim 2, and limitation of claim 3). In addition, in the above reaction scheme of Liotta, the conversion of compound 434 to 435 is similar to step 4 in claim 1 except that compound VI obtained in step 4 in claim 1 has an alkynyl substitution at the 4-position of the sugar ring, whereas in Liotta’s compounds 434 and 435 it is a fluoromethyl substitution. The conversion of the propylidene protecting group to acetyl groups is done under the action of acetic acid and acetic anhydride at ambient temperature overnight (page 332, last para; as in claim 8).
Liotta does not teach steps 2-3 and 5-8 in claim 1 and the ratios and conditions as in claim 1 step 5, the reaction time in claim 2, the limitations of claims 4-7, use of sulfuric acid, dichloromethane and ratio as in claim 8, and does not teach the limitations of claims 10-14.
Obika et al teaches the conversion of compound 2 to compound 40 (col. 141):
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This conversion is the hydroxyl oxidation step in step 2 of claim 1. Obika also teaches conversion of compound 42 to compound 43. This is similar to the conversion of compound V to compound VI as in step 4 in claim 1 except that compound 43 of Obika has azide substituted alkyl at the C4 position of the sugar ring. This conversion is also conducted in the presence of catalytic amount of sulfuric acid, acetic acid and acetic anhydride at 0oC as in claim 8 (col. 143). However, the hydroxyl oxidation as above is conducted using (COCl)2, DMSO, Et3N and CH2Cl2.
Dess et al teaches that periodinane, compound 2, is a stable solid oxidizing agent which is soluble in dichloromethane (aka methylene chloride). It is useful for oxidizing primary alcohols to aldehydes. As seen in Table 1 of Dess, it gives very high yields. One of ordinary skill in the art in view of this would substitute the reagents used by Obika with the Dess-Martin reagent and also use dichloromethane as the solvent for the oxidation of the primary alcohol in compound 2. The artisan will recognize that the oxidation using the Dess-Martin reagent is simpler to use compared to using carbonyl chloride gas, DMSO, Et3N and CH2Cl2. This also requires the use of only the starting alcohol, the Dess-Martin oxidizing agent (a solid) and dichloromethane. It is easy to manipulate and also avoids the additional DMSO and triethylamine. The artisan can adjust the reaction time, amounts of reagents and temperature as in claims 4-5 in view of Dess and Obika.
Ohrui et al teaches the conversion of compound 2 to compound 4 (col. 11 through col 12):
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The conversion of compound 2 to compound 4 is the same as step 3 in claim 1. However, the method of Ohrui involves the conversion to the bromoalkene first, which is then converted to the alkyne derivative in a subsequent step.
Gilbert et al teaches the conversion of aldehyde to the corresponding alkyne using methyl diazomethylphosphonate (page 1840, left col., see reaction (6)). The reaction is carried out for 16 hours (page 1844, left col., see preparation of 3-ethyl-1-heptyne-compound # 14). This reaction, which is conducted at -78oC using potassium t-butoxide and THF, converts the aldehyde group to an alkyne moiety as in step 3 in claim 1. The reagents and reaction conditions used are the same as in claims 6 and 7. It can be seen that this reaction can be used to convert compound 2 of Ohrui to compound 4 directly. Therefore, the reagent used by Ohrui can be substituted by methyl diazomethylphosphonate and potassium t-butoxide and THF for this conversion. This would give the alkyne moiety directly from the aldehyde and thus avoid going through additional steps to get the alkyne substitution as in Ohrui.
Schinazi et al teaches the conversion of compound 1, which is structurally close to instant compound of formula VI, to compound 2 by reacting it with uracil, BSA and TMSOTf, to compound 2 (page 83). A similar reaction has also been done with adenine (page 76, conversion of compound 13 to compound 67). This conversion is similar to the conversion of compound VI to compound VII as in step 5 of claim 1. Schinazi also teaches the reagents BSA, TMSOTf as in claim 1, step 5. Therefore, the same reaction can be performed using the diacetyl derivative 43 of Obika with the alkyne moiety at the C4 position to get instant compound VII as in claim 1, step 5. Obika also teaches acetonitrile as solvent as in claim 1.
Fukuyama et al, drawn to islatravir synthesis, teaches the deprotection of the hydroxyl group at the 2’ position of the sugar ring (page 829, Scheme 3, conversion of compound 16 to compound 19). This is step 6 in claim 1. Fukuyama uses methanol containing the base triethylamine. This same reaction can be used to deprotect the hydroxyl group at the same position in compound VII, which can be obtained as above from the compound of Obika. It would be obvious to substitute the triethylamine with ammonia, which is also a base, for the deprotection as in claim 10. The other conditions and ammonia in methanol concentration and amount and the reaction temperature and time can be adjusted for optimization. Fukuyama teaches the deoxidation of compound 19 to compound 1 by reacting compound 19 with 1,1’-thiocarbonyldiimidazole (compound 20) to form a reactive intermediate which is then treated with tributyltin hydride and AIBN using toluene as solvent at room temperature for about an hour (page 830, Scheme 4). This reaction is same as steps 7 and 8 in claim 1, the reagents recited in claim 11 and part of the limitations of claim 13 regarding an active intermediate and another reaction in situ. The only difference is that the alkyne group does not have the triethylsilyl (TES) substitution as in Fukuyama. The artisan would have a reasonable expectation that this reaction can be successfully carried out with the alkyne moiety having an H instead of TES. Fukuyama does not teach the limitations of claim 14.
Schinazi teaches debenzylation of the protecting groups at the 3’ and 5’ positions of the sugar ring in compound 4 using BCl3 and dichloromethane as solvent at -78oC for 3hrs (page 83, Example 2; part of the limitations of claim 14). These same reagents and reaction conditions can be used to arrive at islatravir.
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, it can be seen that the claimed steps are individually known in the art for making compounds similar to islatravir and islatravir. Even though none of the prior art individually teach all of the claimed steps to make islatravir, it would be obvious to the artisan to combine the prior art steps as individually taught above to arrive at the claimed method of making islatravir with a reasonable expectation of success.
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 choose the claimed combination of steps which is taught in the combined teachings prior art since this combination of steps is art tested and give good yields of the desired product in every step and also the number of steps needed will be minimal. This would reduce the cost as well as the number of steps needed.
One of ordinary skill in the art can adjust the reaction time, temperature, concentration and ratios of reagents as in claims 1-8 and 10-14 for optimal yields in the respective steps.
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).
Response to Applicants’ Arguments
Applicant has traversed the rejection of claims 1-8 and 10-14 as it applies now under 35 USC 103 of record arguing that:
Liotta fails to disclose the added limitation in claim 1 of subjecting the compound of formula VI to glycosylation reaction, such that the glycosidic bond is constructed to obtain a compound of formula VII, wherein the glycosylation reaction is conducted on the compound of formula VI and 2-fluoroadenine in acetonitrile in the presence of BSA and TMSOTf; the glycosylation reaction is conducted at a temperature of 20oC to 60oC for 0.5 hours to 12 hours, and the molar ratio of the reagents recited in claim 1. Furthermore, the compound of Liotta differs significantly in structure from the compound defined in amended claim 1. The final compound in Liotta is also different from the final compound prepared according to amended claim 1. The substituents in the two compounds are different. A person skilled in the art will have no motivation to arrive at amended claim1 in view of Liotta.
Additionally, after obtaining compound 433, Liotta obtains compound 433. In contrast, compound 2 in Obika is converted to compound 40. The reactions involved are notably different. There is no motivation to combine the reaction of Obika with Liotta to obtain a compound similar to formula IV as in amended claim 1.
Furthermore, the final compound and the reactions in volved in Obika and Ohumi are clearly different as well. In Obika compound 40 is converted to compound 42, whereas in Ohrui, compound 2 is converted to compound 4. There is no motivation to combine the reaction form Ohrui with Obika to arrive at a compound similar to formula IV in amened claim 1.
The reactions in Fukuyama and Liotta are fundamentally different. In Liotta compound 437 is converted to compound 438 whereas in Fukuyama, compound 19 is converted to compound 22. The reactions involved are clearly different.
The group in formula VI of amended claim 1 and the corresponding portion in Schinazi are significantly different in molecular structure and properties. In claim 1 the group in formula VI is an alkyne, while in Schinazi it is TES substituted alkyne, which is a silicon-containing alkyl group. This results in different reaction conditions for the compound of formula VI in amended claim 1 and compound 1 in Schinazi. Schinazi discloses molar ratios that are significantly higher than those recited in amended claim 1. The reaction conditions in Schinazi are very different from those in amended claim 1 and provide no motivation to arrive at amended claim 1.
The cited references pertain to synthesis of different compounds, each involving different products with different substituents and different reactions. The claimed invention achieves a shorter process and higher yield for the synthesis for islatravir by adopting such a specific route. For the above reasons the present invention is not rendered obvious by the cited references (Remarks-pages 7-15).
Applicants’ arguments are not persuasive. The conversion of compound 432 to compound 433 in Liotta is the conversion of formula II to formula III as in is step 1 in claim 1. The selective hydroxyl protection reaction is conducted under the action of sodium hydride and benzyl bromide by using DMF as the solvent. The hydroxyl protection is conducted at -5oC. The ratio of the compound 432 (instant formula II), the sodium hydride, and the benzyl bromide is 1:1.16:1.16 (page 332, first para; part of the limitations of claim 2, and limitation of claim 3). In addition, in the above reaction scheme of Liotta, the conversion of compound 434 to 435 is similar to step 4 in claim 1 except that compound VI obtained in step 4 in claim 1 has an alkynyl substitution at the 4-position of the sugar ring, whereas in Liotta’s compounds 434 and 435 it is a fluoromethyl substitution. The conversion of the propylidene protecting group to acetyl groups is done under the action of acetic acid and acetic anhydride at ambient temperature overnight (page 332, last para; as in claim 8). Liotta teaches steps 1 and 4 as in claim 1. The difference in Liotta’s process and the instant steps is also mentioned in the rejection. Liotta’s compound 435 is similar to formula VI in step IV, except that there is a fluoromethyl group 4- position of the ribose ring, whereas in instant formula VI there is an alkynyl moiety. The artisan, on reviewing the teaching of Liotta would recognize that compound 432 of Liotta can also be modified with an alkynyl moiety to get to compound 435 of Liotta. Liotta’s conversion of compound 437 to 438 is different. However, Liotta has added a different base to the 1’-positin of the ribose. From Fukuyama’s teaching it is known that a fluorine substituted purine base can be added to the 1’-position of the ribose. Therefore, the artisan would have a reasonable expectation that compound 435 of Liotta can be made with an alkynyl moiety at the 4-position to get compound of instant formula VI which can then be reacted with fluorine substituted purine base to get compound of formula VII. There may be structural differences. But the chemistry is the same. The artisan can use the same chemistry to get to the desired compounds by making some structural adjustments.
These same structural adjustments and reactions taught by the other secondary references can be used by one of ordinary skill in the art to arrive at islatravir. The final product in each of the references may be different. But the reaction schemes and reagents disclosed in the prior art can be adapted to the instant process since similar process steps and reagents/intermediates are taught in the prior art. The artisan just has to make a judicious choice of the reagents and steps taught in the prior art and adapt it to the synthesis of islatravir as claimed. This is obvious and is well within the skill level of the artisan to recognize and perform in view of the combined teachings of the cited prior art. Applicant has cited the structural differences in the prior art reaction schemes but has not explained why it is not possible to use the teachings of the prior art to make structural adjustments to arrive at the claimed steps to make the final product islatravir.
Applicant has argued that the claimed invention achieves a shorter process and higher yield for the synthesis for islatravir by adopting such a specific route. It has been stated in the rejection that one of ordinary skill in the art would be motivated to choose the claimed combination of steps which is taught individually in the prior art since this combination of steps is art tested and give good yields of the desired product in every step and also the number of steps needed will be minimal. This would reduce the cost as well as the number of steps needed.
One of ordinary skill in the art can adjust the reaction conditions, amounts and ratios of the reagents and the time period for which the reaction is conducted using the teachings of these parameters as a guide. The artisan will do this for optimal yields in the respective steps.
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).
Applicant has argued that the reaction conditions in Schinazi are very different from those in amended claim 1 and provide no motivation to arrive at amended claim 1. As stated in the previous paragraph modification of the reaction conditions, proportions of reagents and concentrations is not a patentable modification absent a showing of criticality. Applicant has not shown the criticality of such modifications.
The combined teachings of the cited prior art render the instant claims obvious. The rejection is maintained.
Conclusion
Pending claims 1-8 and 10-14 are rejected.
2. Claims 9 and 15 have been canceled.
Applicants’ 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.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693
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