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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on September 29, 2025 has been entered.
Detailed Action
This office action is a response to applicant’s communication submitted September 29, 2025 wherein the rejections of record in the previous action are traversed. This application is a national stage application of PCT/JP2019/018307, filed May 7, 2019, and JP2018-088911, filed May 2, 2018.
Claims 1-3 are pending in this application.
Claims 1-3 as amended are examined on the merits herein.
The following new grounds of rejection are introduced:
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 includes the proviso: “Wherein an excess diastereomer ratio of the optically active segment is more than 98%.” While it is clear that this limitation relates to the content of the specifically defined optically active oligonucleotide segment recited in formula (I), it is unclear exactly haw this numerical value is to be calculated. In accordance with the arguments submitted September 29, 2025, this value is defined with reference to the only discussion of this value in the specification, namely p. 44 paragraph 76 in the specification. In this example, the excess diastereomer ratio is not directly defined but is described as being calculated with reference to the integral of the peak at 5.75 minutes and the integral of the peak at 5.47 minutes in figure 1. Paragraph 15 on p. 27 of the specification describes figure 1 as a UPLC spectrum of an optically active tetranucleotide obtained in example 2. Example 2, appearing on pp. 36-43, describes a stepwise synthesis wherein two dinucleotides are first made by stereoselective coupling (step 9) and then deprotected and activated (steps 10-12) before being coupled to form the tetranucleotide and further deprotected. (Steps 13-15)
Despite containing three chiral phosphorothioate linkages, and thus having eight possible diastereomers resulting from the coupling reactions, only two minor peaks are observed in figure 1. One of these, at 6.07 minutes, is observed by mass spectrometry to be an incompletely deprotected product. The other, at 5.47 is presumed to be “the diastereomeric by-product.” There is no acknowledgement that there are actually seven possible diastereomeric by-products that could be obtained by the reaction scheme of steps 10-15, three of which could be arrived at by a single incorrect coupling and which would be expected to be seen in similar amounts in the crude reaction mixture. It is unclear whether the observed minor peak is a single diastereomer, or a combination of (probably three) multiple diastereomers. It is further noted that prior to coupling in step 13, the dimers produced in step 9 are purified by column chromatography several times, potentially eliminating any diastereomeric impurities and leaving the minor diastereomer of the step 13 coupling as the only minor product in the mixture.
While this ambiguity does not impinge on the ability of this example to provide enablement and written description under 35 USC 112(a) for the present claims, it does in fact make it very difficult to judge what the precise meaning of excess diastereomer ratio is, other than the integral of the 5.75min peak minus the 5.47min peak, divided by the sum of the two peaks, which appears to arrive at the stated value of 98.8%. In applying this calculation to another more complex sample, which could contain more than two diastereomers, it is unclear whether the “excess diastereomer ratio” should be calculated by the difference between the major diastereomer and the sum or all minor diastereomers, or the difference between the major diastereomer and the next-most-plentiful diastereomer.
In the absence of an exact definition of the term “excess diastereomer ratio” in the disclosure, the use of this term in the claims is indefinite.
The following rejections of record in the previous action are maintained:
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 are rejected under 35 U.S.C. 103 as being unpatentable over Ravikumar et al. (US patent 6294664, of record in previous action) in view of Oka et al. (of record in previous action)
The claimed invention is directed to a modified oligonucleotide having a phosphoramidite group on either the 3’- or 5’- end hydroxyl, comprising 2-6 nucleotide residues, wherein all of the phosphodiester linkages are chiral stereodefined phosphorothioate linkages protected by a chiral auxiliary which is an acylated tetrahydropyrrolylmehylene group.
Ravikumar et al. discloses oligonucleotides having a 3’- phosphoramidite wherein the internucleotide linkages can be phosphorothioate linkages bearing a phosphorus protecting group. (column 5 lines 1-56) Ravikumar et al. further discloses that oligonucleotides including tetramers or higher (e.g., n=2 in the present claims) can be prepared as phosphoramidites in this manner and used in solid phase synthesis methods in place of standard monomer phosphoramidites. (column 4 lines 17-40) Figure 2 of Ravikumar et al. further discloses a tetramer segment (compound 11) wherein all three internucleotide linkages are phosphorothioates furthermore protected by a protecting group. Jung et al. does not specifically disclose a phosphorothioate tetramer or higher phosphoramidite wherein the phosphorothioate linkages are sterodefined and bear a chiral protecting group as described in claim 1.
However, Oka et al. discloses a method for producing stereocontrolled phosphorothioate dinucleotides using chirally controlled cyclic phosphoramidite compounds. (p. 16034 scheme 2) The intermediate before deprotection (compound 11 in scheme 2) bears the same chiral protecting group recited in present claims 1 and 3. Oka et al. further discloses that the protected phosphorothioate can be carried forward into further cycles of solid-phase synthesis, indicating that it is compatible with conditions of phosphoramidite couplings. (p. 16035 scheme 3)
It would have been obvious to one of ordinary skill in the art at the time of the invention to attach a phosphoramidite group to a stereodefined tetranucleotide or higher oligonucleotide produced according to Oka et al., to produce a phosphorothioate containing segment for use as a building block as described by Ravikumar et al. One of ordinary skill in the art would have seen the description of phosphorothioates by Ravikumar et al. as suggesting incorporating prior art phosphorothioate oligonucleotides into the disclosed method. Furthermore the disclosure by Oka that stereoregular phosphorothioate linkages are desired would have motivated one of ordinary skill in the art to use oligonucleotide segments having such linkages in the synthesis method of Ravikumar in order to produce useful products.
Regarding the limitation requiring that the excess diastereomer ratio be more than 98%, a review of the supporting information for Oka et al. (Reference included with PTO-892) indicates that a linkage between two thymidine nucleosides was obtained in a diastereomeric ratio of >99.5:<0.5. (p. S17 figure S5) If this degree of diastereomeric excess was obtained for a dinucleotide having a single linkage, then if multiple coupling steps were carried out to make an oligonucleotide the diastereomer ratio for a tetranucleotide having three linkages should be >98.5:<1.5, a pentanucleotide having four linkages should be >98.0:<2.0, and a hexanucleotide having five linkages should have a ratio of >97.5:<2.5. Therefore for at least the embodiments wherein n=2 or 3 it is reasonable to conclude that using the method described by Oka to make an oligonucleotide phosphoramidite segment having 4-5 nucleotides for use in Ravikumar’s method would result in a segment having an excess diastereomer ratio of over 98%.
Additionally, even for the case where n=4, since Oka discloses the diastereomeric ratio of the internucleotide bond as being significant, one of ordinary skill in the art would have regarded it as a result-effective variable, and would have attempted to obtain the resulting oligonucleotides in higher diastereomeric purity. In particular, the supporting information for Oka discussed above discloses that the Rp and Sp diastereomers of a dinucleotide elute at different times, and additionally discloses using RP-HPLC to purify the resulting oligonucleotides. (p. S17 last paragraph) Therefore one of ordinary skill in the art would have had a reason to attempt to improve the stereochemical purity of the oligonucleotide and a reasonable expectation of success in doing so using HPLC purification.
Therefore the invention taken as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/051931 (US pre-grant publication 2021/0269470, of record in previous action, herein referred to as ‘931) in view of Ravikumar et al. (US patent 6294664, of record in previous action) in view of Oka et al. (of record in previous action)
Claim 1 of ‘931 claims an oligonucleotide phosphoramidite segment for use in synthesis of an oligonucleotide. However, the segment claimed is not a stereocontrolled segment having the particular stereodefined structure recited in the present claims. However, as discussed previously under 35 USC 103, such a structure is obvious over the disclosures of Ravikumar in view of Oka. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to make an optically active segment having this structure for reasons discussed above under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 17/595613 (US pre-grant publication 2022/0235089, of record in previous action, herein referred to as ‘613) in view of Ravikumar et al. (US patent 6294664, of record in previous action) in view of Oka et al. (of record in previous action)
Claim 3 of ‘613 claims an oligonucleotide phosphoramidite segment for use in synthesis of an oligonucleotide. However, the segment claimed is not a stereocontrolled segment having the particular stereodefined structure recited in the present claims. However, as discussed previously under 35 USC 103, such a structure is obvious over the disclosures of Ravikumar in view of Oka. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to make an optically active segment having this structure for reasons discussed above under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments, submitted September 29, 2025, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant argues that, even if one of ordinary skill in the art were to use the method described by Oka to make a stereochemcally defined phosphorothioate tetramer for use in the method of Ravikumar, the resulting tetramer would not necessarily have had an excess diastereomer ratio of greater than 98%. This is based on the idea that, because the supplementary material of Oka lists the diastereomer ratio of the coupling step as >99.5:<0.5, a tetramer would theoretically contain greater than about (0.995) to the third power, or 98.5% of the major diastereomer and less than 1.5% of a mixture other diastereomers, which Applicant asserts would result in an excess diastereomer ratio of greater than about 97%, which does not meet this claim limitation.
However, as discussed under 35 USC 112(b), the present specification does not actually define “excess diastereomer ratio” except implicitly with reference to the ratio of two peaks in figure 1. It is therefore unclear whether this ratio is based on the excess with respect to the total of all minor distereomers, or the excess with respect to the next-most-common diastereomer. Considering that, unlike the example given in the present specification, minor diastereomers are equally likely in each of the three coupling steps that would be involved in making a tetramer by Oka’s method, the distribution of products would not be cleanly 98.5:1.5, but rather 98.5:0.00495:0.00495:0.00495:5.2x10-5: 5.2x10-5: 5.2x10-5:1.25x10-7. While this could be interpreted as defining an “excess diastereomer ratio” of the major diastereomer to the sum of all other diastereomers, (hence Applicant’s value of 97) if it is interpreted as being with respect to the second-most-common diastereomer, (which would be about 0.495% of the total) then the actual excess diastereomer ratio would be greater than 99%.
Still further, even if the claim limitation at issue were interpreted as implied by Applicant, and the tetramer were to be judged as not necessarily having an excess diastereomer ratio of greater than 98%., it would still have been obvious to one of ordinary skill in the art at the time of the invention to purify said tetramer to an appropriately high diastereomer ratio. Specifically, Oka et al. (p. 16037 right column first paragraph, also p. S17 last paragraph of the supporting information) indicates that the oligonucleotides can be purified by RP-HPLC, suggesting that this technique would in fact be useful for increasing the stereochemical purity of a resulting oligomer. Still further, figures S11-S14 in the supporting information demonstrate the stereochemical purity of long purified oligomers by nuclease digestion with stereoselective nucleases.
It is additionally noted that, while it is possible, though never actually proven by Applicant’s arguments, that Applicant has developed a coupling method that allows for improved crude stereochemical yields compared to the method described by Oka, the presently elected claims are directed to a composition of matter, rather than to a specific method of making said composition of matter that might display unexpectedly high stereochemical yield. Therefore any evidence proffered of Applicant being able to carry out coupling with improved stereochemical yield would not serve to establish evidence of secondary considerations persuasive to overcome the rejection under 35 USC 103.
Finally, even if it were assumed for the sake of argument that the recitation of an excess diastereomer ratio of more than 98% does overcome the previously pending rejection, claims 1-2 are still unpatentable over the following combination of references:
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 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Ravikumar in view of Oka as applied to claims 1-3 above, and further in view of Wada et al. (US pre-grant publication 2013/0184450, cited in PTO-892)
The disclosures of Ravikumar and Oka are discussed above. Assuming for the sake of argument that Ravikumar et al. in view of Oka et al. does not disclose or render obvious an oligomer having an excess diastereomer ratio of 98% or more, said result would still have been obvious further in view of Wada et al.
Wada et al. references the same oxazaphosphazolidine method described by Oka. (p. 1 paragraph 7) This reference directly references a different publication by Oka et al. (Org Letters 2009, included with PTO-892) Wada et al. further describes Oka’s method as possessing low reactivity and condensing efficiency, and discloses that protecting the 2’- hydroxyl with a cyanoethoxymethyl protecting group improves the yield of the condensing reaction. (p. 1 paragraph 9) This reaction is also described as not involving loss of diastereoselectivity. (p. 2 paragraph 26) In one example diastereomerically pure phosphorothioate tetramers were made having a diastereoselectivity of greater than 99%. (p. 10 paragraph 89, p. 11 paragraph 90, table 3) If greater than 99% of the product is the preferred diastereomer, then by any calculation the excess diastereomer ratio is greater than 98%.
It would have been obvious to one of ordinary skill in the art at the time of the invention to utilize a 2’- cyanoethoxymethyl protecting group in order to improve the coupling efficiency and diastereoselectivity of the oxazolidine synthesis process described by Oka when making RNA oligomer building blocks for the method described by Ravikumar. In doing so one of ordinary skill in the art would have seen it to be both desirable and possible to produce the oligomers in a diastereomeric yield of over 99%, thereby producing the claimed level of excess diastereomer ratio. One of ordinary skill in the art would have been motivated to make this modification based on a rationale of applying a known improvement to a prior art method ready for improvement.
Therefore the invention taken as a whole is prima facie obvious.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ERIC OLSON/ Primary Examiner, Art Unit 1693 10/10/2025