DETAILED ACTION
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 .
Application Status
This action is written in response to applicant’s correspondence received on 6/16/2026. Claims 19-25 are pending. Claims 1-18 have been cancelled. Claims 19-25 were newly added. All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. This Office Action is Final.
Oath/Declaration
The Applicant’s Declaration filed 6/16/2026 has been considered but is not persuasive to place the claims in condition for allowance for the reasons discussed in the “Response to Arguments” section following the 103 rejection, below.
Claim Objections – New Objection Necessitated by Amendment
Claim 19 is objected to because of the following informalities:
Claim 19 recites “antisense strange” (line 11) which should be amended to recite “antisense strand.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claims 19 and 21-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of synthesizing siRNA where the siRNA product has a residual rate of N +/- 1 mer impurities of from 23%-59%, does not reasonably provide enablement for impurity percentages below 23%. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Nature of the Invention/Breadth of the Claim
Regarding claim 19 and dependent claims 21-25, these claims in general are drawn to a method of making siRNA, where one requirement of the claims is that the impurity residuals in the product are no more than 59%. The scope of this claim limitation therefore includes embodiments of the method where there are, for instance, 0% impurities, or low impurity amounts in the product, such as 3%. This claim language is problematic because the specification did not show that such purity is possible using the method, where furthermore it is known the art that when synthesizing oligos, high impurities are known to occur during the synthesis process (see below).
Guidance in the Specification
Regarding the guidance provided in the specification regarding testing purify of the siRNA products, the Applicant provides Example 18, where impurities residuals were measured as a percentage of the total product using a known method (pages 66-70). The Applicant offers Table 17, which shows impurity values ranging from ~23%-59% (reproduced below):
PNG
media_image1.png
163
965
media_image1.png
Greyscale
However, the Applicant has not demonstrated that the use of their method to achieve impurity levels below 23% is possible, including extremely low impurity percentages including for instance 0-5% impurity, which is presently encompassed by claim 19.
State of the Art
Regarding the state of the art, it is known in the art that when synthesizing oligos the product will often comprise impurities. For instance, Sosic (Sosic A et al. Bioconjug Chem. 2014 Feb 19;25(2):433-41, of record) is a research article that teaches reactions comprising four strands which act as complementary pairs that are to make two fragments which are ligated together by DNA ligase to form short oligo ligation products, similar to the presently recited method (Title, Abstract, and throughout). Regarding additional product formations and impurities, Sosic teaches that
“The ligation reaction was performed at 16 °C instead than 21 °C due to the lower Tm of the S oligo: in these conditions we notice along with the PEGylated primary product the appearance of secondary products due to formation of mismatched dimers, as previously evidenced, demonstrating that secondary reactions do not depend on PEG but on the design of the ends of PEG-Donors and Acceptors and the temperature of annealing-ligation. An additional secondary band corresponds to a non-PEGylated oligonucleotide resulting from the ligation of S to A. Since the PEG conjugation to S is stable, this secondary product originates from unreacted s that became unspecifically absorbed into the PEG polymer, and copurified with the covalent PEG-s product in the HPLC purification step. This gel witnesses the power of the ligation method also in revealing otherwise undetectable impurities originating from the chromatographic purification of the high molecular weight polymer,” (page 439, right column, second paragraph).
Thus, Sosic teaches that, when using ligation reactions to formulate short oligos, it is known that impurities will be formed naturally (above). Thus, the art teaches that ultra-low impurities such as those presently recited, below 23%, are not known, where furthermore the Applicant has not demonstrated such ultra-pure products below 23% impurities in their specification.
Undue Experimental Burden
As discussed above in Sosic, experimental parameters can be determined and used to correct for impurities, such as modification of reaction conditions, design of the ends of donors, and the temperature of the annealing ligation (page 439, right column, second paragraph). However, the art does not teach that products with ultra-low impurities below 23% can be made, where the practitioner would be burdened with undue experimentation, where the practitioner would have to design experimental methods to reduce the formation of secondary products, to include embodiments where no secondary products are formed (0% impurity, as presently encompassed by the claim). The specification and the art do not offer guidance to arrive at such embodiments below 23% impurities, as presently recited in claim 19.
Claims 21-25 depend from claim 19 and do not resolve this 112(a) issue and are therefore also rejected.
Claim Rejections - 35 USC § 103 – New Rejection Necessitated by Amendment
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.
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.
Claims 19-21 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Sosic (Sosic A et al. Bioconjug Chem. 2014 Feb 19;25(2):433-41) in view of Jung (Jung S et al. J Control Release. 2010 Jun 15;144(3):306-13), Torchia (Torchia C et al. Nucleic Acids Res. 2008 Nov;36(19):6218-27), Kraynack (Kraynack BA et al. RNA. 2006 Jan;12(1):163-76), and Horspool (Horspool DR et al. BMC Res Notes. 2010 Nov 9;3:291).
Regarding claim 19, Sosic teaches a method for producing a modified oligonucleotide comprising a complementary portion having 28-37 nucleotide length, where the method comprises forming the modified oligonucleotide by treating four or more oligonucleotide raw material fragments in total in the presence of an oligonucleotide ligase (Title, Table 1, and e.g., Figure 5A, and throughout). Sosic teaches that the method comprises providing a composition comprising a first, second, third, and fourth oligonucleotide with complementary regions (Table 1). Sosic teaches that the first and second oligos form a first complementary strand, which comprises a first fragment linking site (e.g., s and s’, Table 1). Sosic teaches that the third and fourth oligonucleotide form a second complementary strand comprising a second fragment linking site (e.g., a and a’, Table 1). Sosic teaches that the two complimentary strands are sense and antisense strands (e.g., Table 1, Figure 5A). Sosic discloses that T4 DNA ligase was used as the ligase (Abstract). Furthermore, Sosic teaches that the oligonucleotides vary in length (e.g., 9, 12, 16, 18, 19, 21, and 28 nucleotides, Table 1). Sosic teaches that the fragment linking sites are 3 nucleotide sticky ends (e.g., Table 1, where the sticky ends of s+s’ and a+a’ are 3 nts in length). Sosic teaches that the fragments were chemically modified (PEG, Abstract, page 435, left column, third paragraph, and Abstract, “PEGylated nucleic acids”). Sosic teaches ligating the 1st-4th fragments/strands together to form a 28 nucleotide product (e.g., Figure 5).
Additionally, regarding the claim limitation that the modified oligonucleotide is “siRNA,” Sosic teaches that siRNA molecules attract great interest owing to their versatility to treat a wide range of diseases and their potential high selectivity (Abstract). Sosic further teaches that modified siRNA have demonstrated an improved cell internalization and stability with respect to free nucleic acids (Introduction, first paragraph). Sosic therefore directly teaches a motivation to create modified oligonucleotides that are siRNAs, because such molecules are known to be useful as therapeutics in disease contexts (Abstract).
Furthermore, given that Sosic teaches that fragments as short as 9-12 oligomers can be used in their methods (s and s’ in Table 1), it is within the ability of an ordinary practitioner to envision that an additional 9-12 oligomer could be used in the ligation to generate an oligo between 18-24 oligonucleotides in length (Table 1, s and s’).
Sosic, while teaching that siRNAs should be manufactured due to their therapeutic importance, did not specifically make siRNAs in their method. Sosic, while teaching the ligation of DNA using double-stranded DNA ligase, does not specifically teach a double stranded RNA ligase. Sosic, while teaching a motivation to modify oligonucleotides to enhance stability, does not teach that the modification is a 1’,2’,3’,or 4’ -O-C1-6 alkyl modification. Sosic, while teaching that the complementary strands can be as short as 9-12 oligos, and reduces to practice complementary portions that are 28-mers, does not teach that the complementary portions are 15-25 nucleotide oligomers. Sosic does not teach that the ligation product has a residual rate of N +/- 1 mer impurities of no more than 59%.
Sosic references Jung in the Introduction, first paragraph (line 7). Thus, Sosic and Jung directly overlap is subject matter and field of endeavor, as evidenced by the fact that Sosic directly references Jung. A practitioner would thus reasonably be directed to the teachings of Jung based on Sosic, as Jung is referenced by Sosic concerning siRNA molecules (introduction, line 7). Jung teaches that siRNA molecules are 19-21 nucleotides in length and can target mRNA molecules (Introduction, first line). Jung teaches and reduces to practice siRNA molecules with modifications and cleavable linking sites (Abstract). Jung teaches siRNA molecules that are 19-21 nucleotides in length, and that siRNA molecules are designed to bind to mRNA targets (Jung, Introduction, first paragraph). Thus, Jung teaches that siRNA molecules have complementary regions which are between 15-25 nucleotides in length because they teach that siRNAs are known to be between 19-21 nucleotides in length (Abstract).
Furthermore with regards to the length of the siRNA and its complementary regions, Jung who teaches that siRNAs can be between 19-21 nucleotides in length which target mRNA (i.e., have complementary regions). Thus, a practitioner would understand that the methods and products of Sosic could and should be designed with such lengths to act as siRNAs because Sosic teaches that siRNAs are known to be useful as therapeutics (Abstract and Introduction of Sosic). Jung also teaches sense and antisense strands of siRNA, and therefor teaches siRNAs are double-stranded RNA molecules (Abstract).
Sosic and Jung, while teaching the ligation of double-stranded DNA using a DNA ligase (Sosic, Abstract) and the ligation of RNA molecules using RNA ligase (Jung, page 307, right column, third paragraph), and furthermore teach that siRNAs are double-stranded RNA molecules which have important therapeutic roles (Sosic and Jung Abstracts), do not specifically teach double-stranded RNA ligases.
Torchia is a research article which teaches RNA ligases and their uses (Title, Abstract, and see document). Torchia teaches that there are different families of RNA ligases, including the single-strand break repair family Rnl1, and the double-strand ligation family Rnl2 (page 6218, right column, paragraphs 2-3). Torchia also teaches that such ligases, their structure, and their functionality are already known (page 6218, right column, final paragraph into page 6219, left column). Thus, Torchia teaches that double-stranded RNA ligases such as Rnl2 family ligases are known ligases with predictable functionality (page 6218, right column, final paragraph into page 6219, left column). Given that Jung teaches that siRNA is double-stranded RNA (Conclusion), a practitioner would be able to immediately envision using a double-stranded RNA ligase such as those taught by Torchia in order to make siRNAs as taught and suggested by Sosic/Jung.
Kraynack is a research article that teaches siRNA molecules comprising 2’-O-methyl modifications (Title, Abstract, and throughout). Kraynack teaches that such siRNA molecules comprising 2’O-methyl modifications have been reduced to practice (Abstract and Introduction). Kraynack teaches that it is known that 2’-O-methyl modifications in siRNA molecules show an increase in their resistance to nuclease degradation (page 163 final paragraph into page 164 first paragraph). Thus, Kraynack teaches a direct motivation to incorporate 2’-O-methyl modifications into siRNA molecules.
Furthermore, regarding the limitation that the complementary sense/antisense portions are between 15-25 oligonucleotides, oligo synthesis methods using short oligos and oligo ligase within this length range are already known in the art. For instance, Horspool is a research article concerning the synthesis of very short oligonucleotides (Title, Abstract, and throughout). Horspool teaches that “8-mers” can be joined together in such synthesis methods using the starting fragments and oligo ligases, and have reduced such methods to practice (Abstract, and see Figure 3). Thus, given that Sosic has already taught making complementary portions as short as 28 oligomers, where fragments can be as short as 9-mers (Figure 5, Table 1), and Horspool teaches that it is known in the art that oligos as short as “8-mers” can be successfully ligated using ligases, there is a high likelihood of success of making siRNAs as short as 19 basepairs as taught and suggested by Sosic/Jung to make siRNA using known ligase synthesis methods such as those taught by Sosic.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by Sosic to manufacture siRNA as taught by Jung because Sosic teaches a direct motivation to make siRNA molecules, namely, that siRNAs are known to be important molecules used in therapeutics. Furthermore, there is a reasonable expectation of success in making siRNAs because Sosic already reduced to practice their methods with other oligonucleotides of similar length and furthermore references Jung who also teaches that siRNAs have been reduced to practice.
Furthermore, a practitioner would be motivated to substitute the DNA ligase taught by Sosic for a double-stranded RNA ligase such as Rnl2 as taught by Torchia because Sosic teaches that double-stranded RNA products such as siRNA are known to be useful to produce, which would require ligation by a double-strand break ligation such as Rnl2 (Sosic, Abstract). Additionally, such a substitution would result in predictable results because Torchia teaches that the structure and functionality of Rnl2 family ligases is already well-understood (page 6218, right column paragraphs 2-4 into page 6219, left column). Sosic already teaches a motivation to apply their synthesis method to double-stranded RNA product such as siRNA because Sosic teaches the value of producing siRNA; a practitioner would therefore understand that they would simply use available tools in the industry (i.e., double-stranded RNA ligases) in order to make the product suggested by Sosic.
Additionally, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the oligonucleotide modifications taught by Sosic/Jung with the 2’-O-methyl modification taught by Kraynack because such a modification is the simple substitution of one known prior art element for another with predictable results. In the present case, a practitioner would simply substitute and/or augment the modifications taught by Sosic/Jung with the 2’-O-methyl modification taught by Kraynack with predictable results as Kraynack has already reduced to practice functional siRNA molecules with said 2’-O-methyl modification. Furthermore, a practitioner would be motivated to combine the prior art because Kraynack teaches that the 2’-O-methyl modification has the advantageous benefit of reducing nuclease degradation.
Regarding the limitation in claim 19 concerning the purity of the ligation product (59%), this limitation is simply reciting an inherent characteristic of the product made by a method rendered obvious by the combination of Sosic, Jung, Torchia, Kraynack, and Horspool. Presently, the method steps of oligo synthesis have been reduced to practice according to Sosic and Horspool, where the instant method differs only in that the product is a short RNA product as opposed to a short DNA product as taught by Sosic/Horspool. Further, Sosic directly teaches the practitioner to make siRNA, where the presently recited length of oligo is known to be the length of siRNA (Jung, Abstract). The method of producing the recited siRNA and its degree of impurity is therefore rendered obvious, where sufficient motive and reasonable expectation of success are given. Thus, the recited degree of impurity (59%) could be arrived at by routine experimentation and optimization, where the practitioner is already armed with the method steps of making the oligo, where the characteristics of purity level would simply flow naturally from the suggestion of making siRNA known in the art as taught by Sosic.
Regarding claim 20, as discussed above, the purity percentage of the product is simply an inherent characteristic of what would flow naturally from the suggestions of the known art to make siRNA following a known method (Sosic, Horspool, Jung, Torchia, and Kraynack). Thus, the percentage of impurities could be arrived at through routine experimentation and optimization within the means of a practitioner of ordinary skill in the art given that the method of making short oligos and the suggestion to make siRNA is already taught in the art (Sosic). Thus the practitioner following the teachings in the art would arrive at the presently recited purity range simply by the motivational teachings of the art (i.e., it was known and taught with strong motivation to make siRNA, because siRNA are valuable as therapeutics).
Regarding claim 21, Torchia teaches that the RNA ligase is in the Rnl2 family (page 6218, right column, paragraphs 2-3)
Regarding claim 23, Horspool teaches that ligation products can be purified. Furthermore, given that Sosic teaches that siRNAs are valuable as therapeutics (Abstract) it would be obvious to a person of ordinary skill in the art to purify the synthesized siRNA so that they could be used in a therapeutic application as taught and suggested by Sosic (Abstract, Introduction, first paragraph).
Regarding claim 24, Sosic teaches that the ligation reaction occurs at 16 degrees Celsius (page 439, right column, second paragraph).
Regarding claim 25, Kraynack teaches that the -O-C1-6 alkyl is 2’-O-methyl (Abstract, throughout).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Sosic (Sosic A et al. Bioconjug Chem. 2014 Feb 19;25(2):433-41) in view of Jung (Jung S et al. J Control Release. 2010 Jun 15;144(3):306-13), Torchia (Torchia C et al. Nucleic Acids Res. 2008 Nov;36(19):6218-27), Kraynack (Kraynack BA et al. RNA. 2006 Jan;12(1):163-76), and Horspool (Horspool DR et al. BMC Res Notes. 2010 Nov 9;3:291), as applied to claims 19-21 and 23-25, above, and further in view of Unciuleac (Unciuleac MC et al. RNA. 2015 May;21(5):824-32).
A discussion of Sosic, Jung, Torchia, Kraynack, and Horspool with respect to claims 19-21 and 23-25 is given above and incorporated herein.
Torchia, while teaching Rnl2 ligases, does not teach that the ligase is Rnl5.
Unciuleac is a research article which focuses on the characterization of Rnl5 ligases (Title, Abstract, and throughout). Unciuleac teaches that:
“we report that purified recombinant NgrRnl seals nicked 3′-OH/5′-PO4 duplexes in which the 3′-OH strand is RNA. It does so via the “classic” ligase pathway, entailing reaction with ATP to form a covalent NgrRnl–AMP intermediate, transfer of AMP to the nick 5′-PO4, and attack of the RNA 3′-OH on the adenylylated nick to form a 3–5 phosphodiester… NgrRnl, DraRnl,
and their homologs from diverse bacteria, viruses, and unicellular eukarya comprise a new “Rnl5 family” of nick-sealing ligases with a signature domain organization,” (Abstract).
Thus, Unciuleac teaches that the Rnl5 ligase family is a known RNA ligase which functions through a “classic” ligase pathway (Abstract). Unciuleac reduced to practice and characterized Rnl5 ligase family members (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Sosic, Jung, Torchia, Kraynack, and Horspool, as discussed above in the rejection of claim 19, where Torchia teaches Rnl2 ligases, to further modify the combination of references with the Rnl5 ligase taught by Unciuleac because such a combination is the simple substitution of one known prior art element for another with predictable results. In the present case, the practitioner would be substituting the known Rnl2 ligase as taught by Torchia for the Rnl5 ligase taught by Unciuleac. Furthermore, the results are predictable because Unciuleac has reduced such Rnl5 ligases to practice, has characterized these ligases, and has identified that they operate using the “classic” ligase pathway
Response to Arguments
Applicant's arguments filed 6/16/2026 have been fully considered but they are not persuasive.
The Applicant argues that their amended claims place the application in condition for allowance. The Applicant has amended the claims in the following ways: 1) deleted all previous claims and added new claims 19-25, where the new claims maintain the same basic method steps as previously recited along with similar elements previously recited and 2) new claim 19 includes limitations concerning the percentage of purity of the siRNA product recited in the method.
The Applicant’s amendments, which now include limitations regarding the purity of the siRNA product produced by the method, prompted new search and considerations, where Horspool is now applied which supports the rejection of the present claims as it teaches the feasibility of the presently recited method.
The Applicant argues that their method results in higher levels of purity when compared to the methods of the prior art. This argument is not found to be persuasive. The Applicant’s presently recited method simply involves ligating two fragments of RNA together using an RNA ligase, where the RNA is an siRNA with complementary region of between 15-25 nucleotides. The method steps of ligating together two double-stranded fragments of oligos, where each fragment comprises two strands (sense and antisense) using an oligo ligase, is a method which is already known in the art as taught by prior art documents such as Sosic and Horspool. The only distinction between the method of, for instance, Sosic and that presently recited is that the method recited uses RNA to produce siRNAs which are between 15-25 oligos. However, a prior art suggestion provided by Sosic already exists to make siRNA, which Jung teach is between 15-25 nuclotides in length (19-21, as taught by Jung). Sosic teaches that siRNA is a valuable therapeutic tool. Therefore, in response to applicant's argument that there method of making siRNA yielded higher purity than the method of the prior art, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the present case, the practitioner is already highly motivated to make siRNA using a synthesis method of Sosic, because Sosic teaches that siRNA is a valuable therapeutic product. The fact that the Applicant recognizes a purity advantage when using the method of Sosic to make siRNA using an RNA ligase therefore can not be the basis for patentability because the practitioner is already motived to make siRNA, as taught by Sosic/Jung.
The Applicant argues that, within the field, it was assumed that using shorter oligos in such annealing methods using ligases would not work, and that the present application challenges this assumption. This argument is not persuasive because in fact the prior art, Horspool, teaches that short oligos have been successfully used to make annealing products, where the starting fragments are as short as “8-mers.” Thus, the argument supplied in the declaration that it was assumed in the art that short oligos would not work in ligase reactions is not persuasive because the art teaches that using such short oligos was in fact known to work, where such ligase annealing reactions had been reduced to practice using oligos as short as 8-mers. The results are therefore obtained with a reasonable expectation of success.
The Applicant argues that they have obtained unexpected/surprising results, both in the Declaration filed 6/16/2026 and in the Remarks filed 6/16/2026, where it was a surprising result that synthesizing shorter oligos resulted in higher purity yields, where it would be expected that the purity would be lower for shorter oligos. The Applicant points to Example 18 and Table 17 of the specification. Applicant argues that because it was assumed that short oligos could not be synthesized using such a ligation method, it is further unexpected to observe such purity. This argument is not persuasive. Again, the prior art teaches that such short oligos, including 8-mers, can be synthesized and connected together using oligo ligases. Thus, contrary to the assertions, it was in fact known in the art that short oligos could be synthesized using such methods. Furthermore, regarding the state of the purity of the reaction, in light of the fact that a strong motivation already existed in the art to make oligos that were between 15-25 oligos (Sosic/Jung “siRNA”, Abstract and Introduction of Sosic, Jung throughout) and that is was furthermore already known that such synthesis products were possible to be made (Horspool), the discovery of the purity of the siRNA product can not stand as the basis for patentability because such a discovery would flow naturally from the suggestions already given in the prior art. The practitioner is already motivated to make siRNA using the method of Sosic, and characterizing the purity of the suggested product (siRNA) already taught and known in the art would flow naturally from the suggestions which exist in the art. Further, the method is obvious because the presently recited method steps do not deviate from the method of Sosic except that they recite components (RNA ligase, 15-25 complementary region) which are inherent to how the method of Sosic would be applied to make the recommended product: siRNA. Sosic teaches that siRNA should be made, the practitioner would understand that the method of Sosic would be modified to include an RNA ligase to make an RNA product (siRNA) and would furthermore understand that the length would be shortened, as it is known that siRNA is 19-21 nucleotides in length (Jung, Abstract).
The Applicant argues that the KSR rationales rely upon and incorporate the concept of predictability. As an initial matter, the rationale used in the rejection is “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,” which does not specifically reference “predictability,” but relies upon a reasonable expectation of success. Presently, there is a reasonable expectation of success at arriving the presently claimed subject matter because the method has been reduced to practice, the RNA ligases are known, and furthermore it was already known in the art that ligating such short oligos has been reduced to practice (Horspool, who teaches ligation of “8-mers”). Thus, the practitioner is armed with a strong motivation to make such short oligos, because Sosic teaches that such short oligso in the form of siRNAs are very valuable as therapeutics. Further, there is a reasonable expectation of success when arriving at the invention because such short oligos have been synthesized using a ligase (Horspool), and furthermore RNA ligases were well-known and characterized (Torchia, Unciuleac).
Furthermore, MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required. Thus, the MPEP makes clear that “absolute predictability” is not a requirement. In the present case, given that such oligo ligation methods have been reduced to practice (Sosic) using oligos which are as short as those required for the present claims (Horspool), where furthermore RNA ligases have been characterized to perform such ligation reactions, the practitioner is equipped with a reasonable expectation of success that such fragments could be ligated together, as such ligations of short oligos are known in the art.
The arguments supplied in the Declaration filed 6/16/2026 with respect to the unexpected results have been addressed above, where 1) a practitioner would be motivated to modify/use the method of Sosic to make siRNA with a reasonable expectation of success given that short oligos have been made by Sosic and 2) oligo ligation methods using even shorter fragments, including 8-mers, were already known, per Horspool. Given the strong motivation to manufacture siRNA, as taught by Sosic who teaches that it is valuable as an siRNA, the discovery of the purity values when synthesizing siRNA using the adapted method of Sosic can not stand as the grounds for patentability (above).
Double Patenting – New Rejection Necessitated by Amendment
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 19-21 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,525,132 B2 (‘132) in view of Sosic (Sosic A et al. Bioconjug Chem. 2014 Feb 19;25(2):433-41) and Jung (Jung S et al. J Control Release. 2010 Jun 15;144(3):306-13), Torchia (Torchia C et al. Nucleic Acids Res. 2008 Nov;36(19):6218-27), and Kraynack (Kraynack BA et al. RNA. 2006 Jan;12(1):163-76) and Horspool (Horspool DR et al. BMC Res Notes. 2010 Nov 9;3:291).
Regarding claim 1, claims 3-8 of ‘132 recite:
3. A method for producing a nucleic acid product, said method comprising linking two or more nucleic acid materials in the presence of a ligase mutant according to claim 1 to form said nucleic acid product, wherein said two or more nucleic acid materials are selected from the group consisting of one or more single-stranded nucleic acid materials, one or more double-stranded nucleic acid materials, and a mixture thereof.
4. The method according to claim 3, wherein said two or more nucleic acid materials are RNA.
5. The method according to claim 3, wherein said two or more nucleic acid materials are four or more single-stranded RNAs.
6. The method according to claim 3, wherein said nucleic acid product contains a complementary portion having a base length of 12 to 27.
7. The method according to claim 3, wherein said two or more nucleic acid materials are DNA and/or a modified nucleic acid.
8. The method according to claim 3, wherein said two or more nucleic acid materials have a concentration of 1 μM or more.
9. The method according to claim 3, wherein said nucleic acid product is siRNA.
Thus, claims 3-9 of ‘132 recite the claim limitations of instant claim 19 with the exception that claims 3-9 of ‘132 do not recite that the complementary regions comprise sticky ends.
Regarding claim 19, Sosic teaches a method for producing a modified oligonucleotide comprising a complementary portion having 28-37 nucleotide length, where the method comprises forming the modified oligonucleotide by treating four or more oligonucleotide raw material fragments in total in the presence of an oligonucleotide ligase (Title, Table 1, and e.g., Figure 5A, and throughout). Sosic teaches that the method comprises providing a composition comprising a first, second, third, and fourth oligonucleotide with complementary regions (Table 1). Sosic teaches that the first and second oligos form a first complementary strand, which comprises a first fragment linking site (e.g., s and s’, Table 1). Sosic teaches that the third and fourth oligonucleotide form a second complementary strand comprising a second fragment linking site (e.g., a and a’, Table 1). Sosic teaches that the two complimentary strands are sense and antisense strands (e.g., Table 1, Figure 5A). Sosic discloses that T4 DNA ligase was used as the ligase (Abstract). Furthermore, Sosic teaches that the oligonucleotides vary in length (e.g., 9, 12, 16, 18, 19, 21, and 28 nucleotides, Table 1). Sosic teaches that the fragment linking sites are 3 nucleotide sticky ends (e.g., Table 1, where the sticky ends of s+s’ and a+a’ are 3 nts in length). Sosic teaches that the fragments were chemically modified (PEG, Abstract, page 435, left column, third paragraph, and Abstract, “PEGylated nucleic acids”). Sosic teaches ligating the 1st-4th fragments/strands together to form a 28 nucleotide product (e.g., Figure 5).
Additionally, regarding the claim limitation that the modified oligonucleotide is “siRNA,” Sosic teaches that siRNA molecules attract great interest owing to their versatility to treat a wide range of diseases and their potential high selectivity (Abstract). Sosic further teaches that modified siRNA have demonstrated an improved cell internalization and stability with respect to free nucleic acids (Introduction, first paragraph). Sosic therefore directly teaches a motivation to create modified oligonucleotides that are siRNAs, because such molecules are known to be useful as therapeutics in disease contexts (Abstract).
Furthermore, given that Sosic teaches that fragments as short as 9-12 oligomers can be used in their methods (s and s’ in Table 1), it is within the ability of an ordinary practitioner to envision that an additional 9-12 oligomer could be used in the ligation to generate an oligo between 18-24 oligonucleotides in length (Table 1, s and s’).
Sosic, while teaching that siRNAs should be manufactured due to their therapeutic importance, did not specifically make siRNAs in their method. Sosic, while teaching the ligation of DNA using double-stranded DNA ligase, does not specifically teach a double stranded RNA ligase. Sosic, while teaching a motivation to modify oligonucleotides to enhance stability, does not teach that the modification is a 1’,2’,3’,or 4’ -O-C1-6 alkyl modification. Sosic, while teaching that the complementary strands can be as short as 9-12 oligos, and reduces to practice complementary portions that are 28-mers, does not teach that the complementary portions are 15-25 nucleotide oligomers. Sosic does not teach that the ligation product has a residual rate of N +/- 1 mer impurities of no more than 59%.
Sosic references Jung in the Introduction, first paragraph (line 7). Thus, Sosic and Jung directly overlap is subject matter and field of endeavor, as evidenced by the fact that Sosic directly references Jung. A practitioner would thus reasonably be directed to the teachings of Jung based on Sosic, as Jung is referenced by Sosic concerning siRNA molecules. Jung teaches that siRNA molecules are 19-21 nucleotides in length and can target mRNA molecules (Introduction, first line). Jung teaches and reduces to practice siRNA molecules with modifications and cleavable linking sites (Abstract). Jung teaches siRNA molecules that are 19-21 nucleotides in length, and that siRNA molecules are designed to bind to mRNA targets (Jung, Introduction, first paragraph). Thus, Jung teaches that siRNA molecules have complementary regions which are between 15-25 nucleotides in length.
Furthermore with regards to the length of the siRNA and its complementary regions, Jung who teaches that siRNAs can be between 19-21 nucleotides in length which target mRNA (i.e., have complementary regions). Thus, a practitioner would understand that the methods and products of Sosic could and should be designed with such lengths to act as siRNAs because Sosic teaches that siRNAs are known to be useful as therapeutics (Abstract and Introduction of Sosic). Jung also teaches sense and antisense strands of siRNA, and therefor teaches siRNAs are double-stranded RNA molecules (Abstract).
Sosic and Jung, while teaching the ligation of double-stranded DNA using a DNA ligase (Sosic, Abstract) and the ligation of RNA molecules using RNA ligase (Jung, page 307, right column, third paragraph), and furthermore teach that siRNAs are double-stranded RNA molecules which have important therapeutic roles (Sosic and Jung Abstracts), do not specifically teach double-stranded RNA ligases.
Torchia is a research article which teaches RNA ligases and their uses (Title, Abstract, and see document). Torchia teaches that there are different families of RNA ligases, including the single-strand break repair family Rnl1, and the double-strand ligation family Rnl2 (page 6218, right column, paragraphs 2-3). Torchia also teaches that such ligases, their structure, and their functionality is already known (page 6218, right column, final paragraph into page 6219, left column). Thus, Torchia teaches that double-stranded RNA ligases such as Rnl2 family ligases are known ligases with predictable functionality (page 6218, right column, final paragraph into page 6219, left column). Given that Jung teaches that siRNA is double-stranded RNA (Conclusion), a practitioner would be able to immediately envision using a double-stranded RNA ligase such as those taught by Torchia in order to make siRNAs as taught and suggested by Sosic/Jung.
Kraynack is a research article that teaches siRNA molecules comprising 2’-O-methyl modifications (Title, Abstract, and throughout). Kraynack teaches that such siRNA molecules comprising 2’O-methyl modifications have been reduced to practice (Abstract and Introduction). Kraynack teaches that it is known that 2’-O-methyl modifications in siRNA molecules show an increase in their resistance to nuclease degradation (page 163 final paragraph into page 164 first paragraph). Thus, Kraynack teaches a direct motivation to incorporate 2’-O-methyl modifications into siRNA molecules.
Furthermore, regarding the limitation that the complementary sense/antisense portions are between 15-25 oligonucleotides, oligo synthesis methods using short oligos and oligo ligase within this length range are already known in the art. For instance, Horspool is a research article concerning the synthesis of very short oligonucleotides (Title, Abstract, and throughout). Horspool teaches that “8-mers” can be joined together in such synthesis methods using the starting fragments and oligo ligases, and have reduced such methods to practice (Abstract, and see Figure 3). Thus, given that Sosic has already taught making complementary portions as short as 28 oligomers, where fragments can be as short as 9-mers (Figure 5, Table 1), and Horspool teaches that it is known in the art that oligos as short as “8-mers” can be successfully ligated using ligases, there is a high likelihood of success of making siRNAs as short as 19 basepairs as taught and suggested by Sosic/Jung to make siRNA using known ligase synthesis methods such as those taught by Sosic.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use to modify claims 3-9 of ‘132 to include sticky ends to manufacture siRNA as rendered obvious by Sosic/Jung because such a modification is the simple combination of known prior art elements to yield predictable results. Sosic teaches a direct motivation to make siRNA molecules, namely, that siRNAs are known to be important molecules used in therapeutics. Furthermore, the methods of Sosic use sticky ends (figure in the Abstract). There is a reasonable expectation of success in making siRNAs because Sosic already reduced to practice their methods with other oligonucleotides of similar length and furthermore references Jung who also teaches that siRNAs have been reduced to practice.
Furthermore, a practitioner would be motivated to substitute the DNA ligase taught by Sosic for a double-stranded RNA ligase such as Rnl2 as taught by Torchia because Sosic teaches that double-stranded RNA products such as siRNA are known to be useful to produce, which would require ligation by a double-strand break ligation such as Rnl2 (Sosic, Abstract). Additionally, such a substitution would result in predictable results because Torchia teaches that the structure and functionality of Rnl2 family ligases is already well-understood (page 6218, right column paragraphs 2-4 into page 6219, left column). Sosic already teaches a motivation to apply their synthesis method do double-stranded RNA product such as siRNA because Sosic teaches the value of producing siRNA; a practitioner would therefore understand that they would simply use available tools in the industry (i.e., double-stranded RNA ligases) in order to make the product suggested by Sosic.
Additionally, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the oligonucleotide modifications taught by Sosic/Jung with the 2’-O-methyl modification taught by Kraynack because such a modification is the simple substitution of one known prior art element for another with predictable results. In the present case, a practitioner would simply substitute and/or augment the modifications taught by Sosic/Jung with the 2’-O-methyl modification taught by Kraynack with predictable results as Kraynack has already reduced to practice functional siRNA molecules with said 2’-O-methyl modification. Furthermore, a practitioner would be motivated to combine the prior art because Kraynack teaches that the 2’-O-methyl modification has the advantageous benefit of reducing nuclease degradation.
Regarding the limitation in claim 19 concerning the purity of the ligation product (59%), this limitation is simply reciting an inherent characteristic of the product made by a method rendered obvious by the combination of Sosic, Jung, Torchia, Kraynack, and Horspool. Presently, the method steps of oligo synthesis have been reduced to practice according to Sosic and Horspool, where the instant method differs only in that the product is a short RNA product as opposed to a short DNA product as taught by Sosic/Horspool. Further, Sosic directly teaches the practitioner to make siRNA, where the presently recited length of oligo is known to be the length of siRNA (Jung, Abstract). The method of producing the recited siRNA and its degree of impurity is therefore rendered obvious, where sufficient motive and reasonable expectation of success are given. Thus, the recited degree of impurity (59%) could be arrived at by routine experimentation and optimization, where the practitioner is already armed with the method steps of making the oligo, where the characteristics of purity level would simply flow naturally from the suggestion of making siRNA known in the art as taught by Sosic.
Regarding claim 20, as discussed above, the purity percentage of the product is simply an inherent characteristic of what would flow naturally from the suggestions of the known art to make siRNA following a known method (Sosic, Horspool, Jung, Torchia, and Kraynack). Thus, the percentage of impurities could be arrived at through routine experimentation and optimization within the means of a practitioner of ordinary skill in the art given that the method of making short oligos and the suggestion to make siRNA is already taught in the art (Sosic). Thus the practitioner following the teachings in the art would arrive at the presently recited purity range simply by the motivational teachings of the art (i.e., it was known and taught with strong motivation to make siRNA, because siRNA are valuable as therapeutics).
Regarding claim 21, Torchia teaches that the RNA ligase is in the Rnl2 family (page 6218, right column, paragraphs 2-3)
Regarding claim 23, Horspool teaches that ligation products can be purified. Furthermore, given that Sosic teaches that siRNAs are valuable as therapeutics (Abstract) it would be obvious to a person of ordinary skill in the art to purify the synthesized siRNA so that they could be used in a therapeutic application as taught and suggested by Sosic (Abstract, Introduction, first paragraph).
Regarding claim 24, Sosic teaches that the ligation reaction occurs at 16 degrees Celsius (page 439, right column, second paragraph).
Regarding claim 25, Kraynack teaches that the -O-C1-6 alkyl is 2’-O-methyl (Abstract, throughout).
Claims 22 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,525,132 B2 (‘132) in view of Sosic (Sosic A et al. Bioconjug Chem. 2014 Feb 19;25(2):433-41) and Jung (Jung S et al. J Control Release. 2010 Jun 15;144(3):306-13), Torchia (Torchia C et al. Nucleic Acids Res. 2008 Nov;36(19):6218-27), and Kraynack (Kraynack BA et al. RNA. 2006 Jan;12(1):163-76) and Horspool (Horspool DR et al. BMC Res Notes. 2010 Nov 9;3:291), as applied to claims 19-21 and 2-25, above, and further in view of Unciuleac (Unciuleac MC et al. RNA. 2015 May;21(5):824-32).
.
A discussion of ‘132, Sosic, Jung, Torchia, Kraynack, and Horspool with respect to claims 19-21 and 23-25 is given above and incorporated herein.
Torchia, while teaching Rnl2 ligases, does not teach that the ligase is Rnl5.
Unciuleac is a research article which focuses on the characterization of Rnl5 ligases (Title, Abstract, and throughout). Unciuleac teaches that:
“we report that purified recombinant NgrRnl seals nicked 3′-OH/5′-PO4 duplexes in which the 3′-OH strand is RNA. It does so via the “classic” ligase pathway, entailing reaction with ATP to form a covalent NgrRnl–AMP intermediate, transfer of AMP to the nick 5′-PO4, and attack of the RNA 3′-OH on the adenylylated nick to form a 3–5 phosphodiester… NgrRnl, DraRnl,
and their homologs from diverse bacteria, viruses, and unicellular eukarya comprise a new “Rnl5 family” of nick-sealing ligases with a signature domain organization,” (Abstract).
Thus, Unciuleac teaches that the Rnl5 ligase family is a known RNA ligase which functions through a “classic” ligase pathway (Abstract). Unciuleac reduced to practice and characterized Rnl5 ligase family members (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of ‘132, Sosic, Jung, Torchia, Kraynack, and Horspool, as discussed above in the rejection of claim 19, where Torchia teaches Rnl2 ligases, to further modify the combination of references with the Rnl5 ligase taught by Unciuleac because such a combination is the simple substitution of one known prior art element for another with predictable results. In the present case, the practitioner would be substituting the known Rnl2 ligase as taught by Torchia for the Rnl5 ligase taught by Unciuleac. Furthermore, the results are predictable because Unciuleac has reduced such Rnl5 ligases to practice, has characterized these ligases, and has identified that they operate using the “classic” ligase pathway.
Response to Arguments
The Applicant’s arguments filed 6/16/2026 have been considered but are not persuasive. The Applicant argues that Sosic, Jung, Kraynack, and Torchia, do not remedy the deficiencies discussed in the 103 rejection. The Applicant’s amendments have prompted new search and consideration, where the rejection is now based upon the combination of Sosic, Jung, Kraynack, Torchia, Horspool, and Unciuleac. The Applicant argues that the double-patenting rejection should be withdrawn based upon the reasons outlined in the response to the 103 rejection. This argument is not persuasive because, as discussed above, the present 103 rejection is sufficient to render the presently recited obvious in view of the cited references. The double patenting rejection is therefore maintained.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights