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 07 April 2026 has been received, entered and considered. The following information has been made of record in the instant amendment:
1. No Claims have been canceled.
2. No new Claims have been added.
3. Claims 1-11, and 13-20 have been amended.
4. Remarks drawn to rejections under
The following objection(s)/rejection(s) has/have been overcome:
5. The objection to claims 2-3 and 13 has been overcome by amendment.
Claims 1-20 are pending in the case.
The following rejections are necessitated by Applicant's amendment filed 07 April 2026 wherein the limitations in pending claims 1-11, and 13-20 have been amended. In claim 1 limitation regarding the composition comprising a reversed-phase column chromatography eluate, and the integer n has been added. The substitution Z has been replaced by R1. In claims 2-11 and 14-20 a comma has been added at line 1. In claims 10-11, 13, 17-18 and 20 the term ‘the’ has been deleted. Support is seen at paragraphs 0038, 0045, 0072 and examples for the amendments.
Applicant’s statement regarding the second Preliminary amendment filed on October 6, 2023 is noted. The claims in the second Preliminary amendment filed on October 6, 2023 were the ones examined in the Non-final Action mailed 01/09/20.
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.
Claim(s) 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Krotz et al (WO 03/005822 A1; cited in IDS filed 01/13/2023; of record).
Krotz et al teaches a formulation comprising a nucleic acid oligomer having a phosphorothioate linkage (page 3, lines 9-14; page 14, lines 6-7; part of the limitations of claim 1 nucleic acid oligomer having a phosphorothioate bond). The composition can contain a-lipoic acid as an additive (page 3, lines 23-27; see also examples 4 and 5 at pages 46-47; additive of formula 3 as in claim 1, and claims 6, 7 and 14). The composition includes base addition salts with alkali metals and ammonium ions (page 25, lines 6-16; ammonium salt as in claim 1 and limitation for G in claim 1). This renders obvious the use of the ammonium salts as in claims 8 and 15. A suitable carrier is water and alcohol (page 26, lines 18-22; water and water-soluble organic solvent as in claim 1 and alcoholic water-soluble solvent as in claims 9, 16 and 19). The oligonucleotides used in the composition comprise from about 8 to about 30 nucleotides. More preferable is from about 10 to about 25 nucleotides (page 13, lines 1-3; limitation of claim 1 for 15 ≤ n). The bases can be any one of the unmodified or natural nucleobases (page 15, line 31 through page 16, line 24; limitation Bc in claim 1). The sugar modification includes oligonucleotides having substitutions at the 2’-position which can be OH, F, O-alkyl. Several other modifications are also taught including modifications at other positions of the ribose (page 17, line 3 through page 19, line 7; limitation R and Q in claim 1 and limitation for R in claims 10-11, 17-18 and 20). The invention encompasses RNA and DNA (page 8, lines 8-21; meets formula (1) and limitation of X and Y as in claim 1).
According to Krotz substances like glutathione and a-lipoic acid inhibited desulfurization of the oligonucleotide comprising phosphorothioate linkages. In addition, Krotz also teaches that even though certain antioxidants are exemplified, the use of any such antioxidant is within the scope of its invention (page 3, lines 23-31). Since both glutathione and a-lipoic acid have sulfur /sulfide linkages in them and they stabilize the oligonucleotide comprising phosphorothioate linkages one of ordinary skill in the art would substitute the glutathione and a-lipoic acid with the other additives of formula 3 and 4 as in claims 1-5 and 14 in order to look for oligonucleotide compositions that are stable since these are used for treating many disorders (page 1, line 15 through page 2, line 5).
Regarding claim 12, Krotz teaches precipitation of oligonucleotide using ethanol (C1 alcohol; Example 4 at page 46). In view of this teaching one of ordinary skill in the art will find it obvious to prepare a nucleic acid oligomer as in claim 12.
Krotz teaches preparation of oligonucleotides including the ones with phosphorothioate linkages (page 23). Regarding purification, Krotz teaches that after deblocking in concentrated ammonium hydroxide, the oligonucleotides were purified by precipitation with NaCl and ethanol and further purified by reverse phase high pressure liquid chromatography (page 41, part B). In view of this teaching one of ordinary skill in the art can carry out the process of preparing the composition as in claim 13 by mixing the components recited and subjecting it to reverse phase chromatography. This is well within the skill level of the artisan to conceive and perform in view of the teaching of Krotz.
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, compositions comprising the claimed components are known in the art as stable compositions for use in treating many disorders. Preparation and purification steps as claimed are also taught in the prior art. Thus, it is obvious to arrive at the claimed invention in view of the teachings of the prior art.
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. Product improvement is the motivation. The composition having the claimed components is also suggested by the prior art to be stable and useful in treating many disorders. Hence the artisan would look for such stable compositions comprising the nucleic acid oligomers of formula (1) comprising the phosphorothioate bond and the other components.
Response to Applicant’s Remarks
Applicant has traversed the rejection of claims 1-20 under 35 USC 103 over Krotz et al arguing that the claimed composition which is directed to a composition comprising a reversed-phase column chromatography eluate and an additive is different from the composition of Krotz, which is directed to a formulation agent comprising additive.
The invention of Krotz is characterized by converting the phosphorothioate bond (PS) of a nucleic acid oligomer into a phosphodiester bond (PO) in the formulation agent having a biphasic or multiphasic formulation, that is, by using additives for inhibiting a desulfurization reaction (page 2, lines 1-18, 11 to 14 and 25-29). Examples 4 and 5 relate to a cream formulation agent, in term of the effect due to additives, and it is evaluated based on full PS content %, that is, ratio based on the nucleic acid without any desulfurization reaction. Krotz also describes that peroxides derived form excipients may cause the desulfurization reaction on the nucleic acid oligomer (page 2, lines 1-3). The polyethyleneglycol-40-monostearate used as excipient in example 2 is described to form peroxides (page 44, lines 15-16), and accordingly BRIJ58 as a surfactant used in Examples 4 and 5 may probably form peroxides.
On the other hand, the invention according to amended claim1 is directed to a composition comprising a reversed-phase column chromatography eluate and an additive which is largely different for Krotz’s disclosure relating to a formulation agent comprising a nucleic acid oligomer in terms of the technical field.
The claimed invention is characterized by stabilizing the nucleic acid oligomer with the additive in aqueous solution. The effect due to additives in the claimed invention is evaluated based on the HPLC purity of the nucleic acid oligomer and the retention ratio of the nucleic acid, and accordingly it is clear the effect of the present invention is not necessarily limited to the inhibitory effect on desulfurization reaction by Krotz.
Here, in general, the nucleic acid oligomer is likely to be instable, and in the treatment with reversed-phase chromatography, the alkyl ammonium salt may be exposed to a solution state of alkyl ammonium salt, and then various impurities may be formed. Then, in the claimed invention the inclusion of particular additives in the eluate stabilizes the nucleic acid oligomer in the eluate. In other words, in the claimed invention the addition of particular additives stabilizes the nucleic acid oligomer against problems of instability of the nucleic acid oligomer containing phosphorothioate bonding in the eluates after treatment with reversed-phase chromatography.
Krotz is silent regarding the problem of nucleic acid oligomer containing phosphorothioate bonding in the eluates after treatment with reversed-phase chromatography. A person skilled in the art would not have been motivated to achieve the claimed invention on reading eh disclosure of Krotz.
The claimed composition is different in the chain length of the nucleic acid. In the claimed invention the nucleic acid oligomer has 60≤ n as the chain length and containing phosphorothioate bond. Krotz describes nucleic acid oligomers that have 20 as the chain length, and have a phosphorothioate bond. According to Krotz it is more preferred that the oligonucleotides comprise from about 10 to about 25 nucleotides (page 13, lines 1-3 and Examples 4-5). Here, in general, stability of the nucleic acid oligomer may be varied depending on a chain length, and it is well known that as the chain length becomes longer, the stability during the process course may be more problematic.
The claimed invention provides advantageous, excellent effect that cannot be foreseen based on the cited reference. The present invention demonstrates this via comparison Examples 1-3 (in Table 3 at para 0090) and comparative Example 1 in terms of the presence or absence of additives and examples 5-17 (in Table 5 at para 0013) and comparative example 4 in terms of the presence or absence of additives.
Example 4 of Krotz, and as shown in Table 3, in the case of no additives, full PS content % is 84.7%, while, in the case of the addition of L-cysteine, full PS content % is 89.6% to 94.5%. further according to Table 4 of Example 5, it is demonstrated that glutathione is also an additive showing excellent inhibitory effect on desulfurization reaction like cysteine.
According to the present invention, specifically, Table 3 (para 0030) the case of no addition of additives (comparative Example 1), the retention ratio of the nucleic acid is 70%, while in the case of addition of L-cysteine (comparative example 2), the retention ratio of the nucleic acid is 62%, and accordingly it demonstrates that L-cysteine is not an appropriate additive for eluates of reversed-phase chromatography containing nucleic acids. Further, in the case of oxidized glutathione as additive the retention is 79% which is higher than the 70% seen for no additives. However, when reduced glutathione is use the retention ratio is 41%. These results indicate that not all glutathione, whether oxidized or reduced are necessarily appropriate as additives. Thus, not all additives disclosed in Krotz can be used can be used as additives to the eluate of reversed-phase chromatography containing nucleic acid oligomers. For these reasons the claimed invention is not obvious over Krotz (Remarks, pages 11-15).
Applicant’s arguments are not persuasive. Instant claim 1 is drawn to a composition which comprises nucleic acid oligomer of formula (1) having a phosphorothioate bond, and an additive, and also has an alkylammonium salt, a water-soluble organic solvent and water. The formulation of Krotz also has a nucleic acid oligomer having phosphorothioate bond and an additive which can be a-lipoic acid. In addition, Krotz teaches that the composition includes base addition salts with alkali metals and ammonium ions, and water and alcohol are suitable solvents. Therefore, Krotz’s composition has the claimed components and is not largely different in terms of the technical filed. It does not matter if it is a reversed phase chromatography eluate and an additive. The instant specification, at paras 0006-0007, teaches that nucleic acid oligomers containing a phosphorothioate bond may have problems with stability and that it obtains a composition wherein the nucleic acid oligomer is mixed with and alkylammonium salt, water soluble organic solvent and water and certain additives. Krotz also teaches the same.
Examples 4-5 show the stability provided by a-lipoic acid as additive.
At page 2, lines 1-3, Krotz makes a general statement that peroxide impurities generated from excipients may lead to desulfurization. Applicant argues that that the polyethyleneglycol-40-monostearate used as an excipient in Example 2 of Krotz is described to form peroxides and accordingly BRIJ58 used as excipients in Examples 4-5 may also form peroxides. These examples of Krotz indicate that peroxide formation and desulfurization is a problem only if there is no antioxidant used. From this teaching the artisan will recognize that an antioxidant will be needed as a component in the composition comprising the nucleic acid oligomer having a phosphorothioate bond, and Krotz teaches the use of an antioxidant for stabilization. The use of the excipients should not pose a problem. From the teaching of Krotz one of ordinary skill in the art will also recognize that a stable composition comprising a nucleic acid oligomer having a phosphorothioate bond with an additive in the aqueous solution containing an alkyl ammonium salt, water soluble organic solvent and water can be made. Krotz teaches the use of reversed-phase chromatography. Therefore, inclusion of the additive taught by Krotz in the eluate after purification by reversed-phase chromatography should provide a stable eluate composition. Krotz is not silent regarding the problem of stability of a nucleic acid oligomer containing phosphorothioate bond. The artisan, on review the teachings of Krotz will be motivated to achieve the claimed invention and there is also reasonable expectation of success for the same.
Krotz may teach that the oligonucleotide used in its composition preferably comprises for about 8 to about 30 nucleotides and examples using 20mer chain length. However, this teaching does not necessarily mean that stabilizing higher chain lengths will be a problem. Applicant argues that as the chain length becomes longer, the stability thereof during the process course may be more problematic. Applicant has not pointed out to any such teaching regarding higher chain length being a problem. Krotz teaches stabilization using a-lipoic acid as an additive. a-lipoic acid is recited as an additive in claim 6.
The results disclosed in Table 3 of Kotz and in the present specification, Table 3, have been done under different conditions (cream heated at 40oC for 6 days in Krotz vs 60oC for 8 hours), and is not a proper comparison. Moreover, Krotz’s table 1 shows that the stability provided by the additive also depends on the particular additive and amount of the additive used, and it also shows that not all additives may be suitable as stabilizers.
Therefore, the teachings of Krotz do render the instant claims obvious. The rejection is maintained.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
The USPTO Internet website contains Terminal Disclaimer forms which may be used. Please visit www.uspto.gov/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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of copending Application No. 17/970,138 (‘138) in view of Krotz et al (WO 03/005822 A1; cited in IDS filed 01/13/2023; of record and newly cited in this rejection necessitated by amendment). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant Claims are drawn to a composition comprising a reversed-phase column chromatography eluate and an additive, wherein the eluate comprises a nucleic acid oligomer of formula (1) having a phosphorothioate bond and wherein there is 2’ position modification which includes 2’-OMe, and having 60≤n, alkylammonium salt, water soluble organic solvent, and water.
The copending claim 1 of ‘138 is drawn to a modified nucleic acid oligomer having a purity of at least 70% and a strand length of at least 90 nucleotides and having a 2’-OMe modification. Claims 2 and 3 of ‘138 recite limitations drawn to the nucleotide length being from 90 to 200 and the purity level is at least 90%.
The copending claims of ‘138 differ from the instant claims in that the instant claims do not recite the purity level and do not recite an eluate.
The instant specification, at page 32, para 0072, teaches nucleic acid oligomers of strand lengths of n ≥ 100, and also n ≤ 200. 94.2% purity level is also taught page 37, para 0082.
Krotz’s teachings are set forth above.
The claimed product is an obvious variant of the product made in the claims of ‘138 and in view of Krotz it is obvious to arrive at the claimed invention.
Product improvement is the motivation. The composition having the claimed components is also suggested by the prior art to be stable and useful in treating many disorders. Hence the artisan would look for such stable compositions comprising the nucleic acid oligomers of formula (1) comprising the phosphorothioate bond and the other components. Purity levels can be adjusted, especially in view of Krotz teaching purification by reverse phase chromatography.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Response to Applicant’s Remarks
Applicant has traversed the rejection of claims 1-20 under obviousness-type double patenting over unpatentable over claims 1-3 of copending Application No. 17/970,138 (‘138) arguing that the present claims are drawn to a composition, comprising a reversed-phase column chromatography eluate and an additive. The claims of ‘138 application do not recite or suggest such a composition as currently claimed (page 17-Remarks).
Applicant’s arguments are not persuasive. In view of the amendment the rejection is modified as above. From Krotz it is obvious to make a composition, comprising a reversed-phase column chromatography eluate and an additive, and including the other components recited in claim 1. Purity levels can be adjusted, especially in view of Krotz teaching purification by reverse phase chromatography.
The present invention is suggested by the combined teachings of the prior art. The rejection is maintained.
Conclusion
Pending claims 1-20 are rejected
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.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693
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