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 . 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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 27 June, 2025 has been entered.
Claims Status
Claims 1, 2, 4, 5, 7-9, 11-13, and 15 are pending.
Maintained/Modified Rejections
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
first rejection
Claim(s) 1, 2, 4, 5, 7-9, 11, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Casale et al (US 20040137469) in view of Bray (Nat. Rev. Drug Discov. (2003) 2 p587-593).
Applicants are claiming a solution coupling of two PNA oligomers (2-4 bases long each). Dependent claims describe protecting groups and reaction conditions.
Casale et al discuss PNA synthesis (title). One synthesis method is to generate PNA oligomers, which are coupled to other PNA oligomers to form a longer oligomer (paragraph 51). Multiple ligation reactions are contemplated (paragraph 60). A non-reactive C-terminus is mentioned, along with protecting groups (paragraph 61), implying, but not explicitly mentioning solution phase chemistry. And the N-terminus can be protected or capped (paragraph 62). The oligomers can be less than 10 subunits in length (interpreted as bases), with 3-8 units and 4 units explicitly mentioned (paragraph 127). Note that this overlaps with the 2-4 bases required by applicant’s invention. The examples use Fmoc-Bhoc protected PNA monomers (note the generic example of paragraph 168, for example). A number of potential bases are considered, including the natural ones and some artificial ones (paragraph 114). Note the chemistry of PNA synthesis is identical to that of peptides (paragraph 66), which suggests that chemistry used for peptide synthesis can be used for PNA synthesis. The structure of the monomers used have an amine connected via an ethyl group to another amine, which has an amide group connecting it to a base, and an acetyl group connected via the non-carbonyl carbon (fig 2) – note that this is the same structure as examined claim 9 if conjugated into dimers, trimers, or tetramers. Coupling was conducted for 60 min (paragraph 180).
The difference between this reference and the examined claims is that this reference does not explicitly discuss solution phase synthesis.
Bray discusses large scale synthesis of peptide compounds (title). For smaller peptides, fragment condensation can be conducted more efficiently in solution phase (p588, 3d column, 3d paragraph). For larger sequences, the advantage shrinks, but both can be used – figuring out which one is better is part of development (p588, 3d column, 3d paragraph). Note that, for the example compound, both solution phase and solid phase processes were developed (p590, 1st column, 2nd paragraph). Selecting the best fragments for coupling cannot be easily determined a priori; this is mostly determined by trial and error (p590, 3d column, 2nd paragraph). Note that the examples use HBTU as a coupling agent (p590, 3d column, 3d paragraph), and the solvent used for the fragment condensation is DMF, with water added afterwards to precipitate the product (p591, 1st column, 3d paragraph). For at least some of the coupling steps, DIPEA was used as a base (fig 1, p589, 2nd and 3d columns). While this is not the same coupling as the fragment condensation, that reaction does not specify the base used, making this an obvious one to use. This reference discusses solution phase coupling using DMF, DIPEA, and HBTU, and precipitation with water.
Therefore, it would be obvious to use the solvent, coupling agent, and purification scheme of Bray as a simple substitution of one known element (the solvent, coupling agent, and purification scheme of Casale et al) for another (the solvent, coupling agent, and purification scheme of Bray), yielding expected results (synthesis of a PNA). As Casale et al explicitly states that the chemistry is similar, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Casale et al discusses fragment condensation of PNAs, while Bray discusses solution phase coupling for a similar compound. While the reference does not discuss adding the base last to the mixture, differences in the order of adding ingredients is not a patentable distinction (MPEP 2144.04(IV)(C)), rendering obvious claim 1.
Casale et al discusses fragments of less than 10 bases, which overlaps with the 2-4 bases of claim 2. Note that, to have a controllable synthesis, there must be one reactive site on each reacting compound, otherwise there will be uncontrolled polymerization. Thus, the combination of references renders obvious claim 2.
Bray uses diisopropylethylamine, rendering obvious claim 4.
Casale et al discusses repeated couplings, rendering obvious claim 5.
None of the references explicitly discuss the volume ratio of the PNAs and the solvent, or the mole ratios to each other. However, differences in concentration are not considered a patentable distinction, absent secondary considerations, because this parameter is routinely optimized (MPEP 2144.05(II)). Thus, the combination of references renders obvious claim 10.
Casale et al discusses nucleic acid bases that overlap with those of claims 7 and 15, rendering them obvious.
Casale et al discuss Fmoc and Bhoc protecting groups, rendering obvious claim 8.
Casale et al discusses the same structure for PNAs as applicants, rendering obvious claim 9.
Bray uses HBTU as a coupling reagent, rendering obvious claim 11.
Bray uses DMF as a solvent for coupling, rendering obvious claim 13.
response to applicant’s arguments
Applicants argue improved yield by adding the base last, that applicants get inferior results using the method of Casale et al, compared to their method, and that Christensen et al is not an appropriate reference because it is drawn to the synthesis of peptides rather than PNAs. This is supported by a declaration by Yongtae Kim, applicant.
Applicant's arguments filed 27 June, 2025 have been fully considered but they are not persuasive.
Applicants have not proven that they get superior results. In their declaration of 27 June, 2025, applicants vary more than just the order of adding reagents. In their first experiment, the reaction that matches their experimental protocol, the ingredients are all added together except for the base, then sat on ice for a short period of time followed by addition of the base. The comparison experiment, all ingredients but the base and one of the PNAs being coupled were added, sat on ice for a longer period of time, then the two ingredients added., and was run at a lower concentration. The second conventional method was run at room temperature. For the experiments with varied coupling reagents, the protocol that used the method of the claims used PyBop, the competing methods all used different coupling agents under different reaction conditions. There is no experiment measuring DCC/succinimide according to the claimed invention vs. DCC/succinimide as the prior art, for example. In other words, there is no apples to apples comparison.
It is also noted that the results that applicants are obtaining for their experiments give yields similar to those of Casale et al, and lower than that of Christensen et al. Applicants argue that it is ambiguous if the claimed yield of Casale et al is overall or per reaction. Even if we assume it is per coupling, the reference gives examples that are close to those of applicants; if we assume the yield is per synthesis, the yield of even the worse reactions of Casale et al are comparable to applicants; many reactions are much better. In other words, even though there is ambiguity in how to interpret Casale et al, by the comparison most favorable to applicant, the reference shows yields comparable to what applicants have obtained. Note that, as Christensen et al gives yields close to 100%, a person of skill in the art would assume that the results of Casale et al are for the entire synthesis – in which case every synthesis of Casale et al is comparable or better than to the results that applicants have demonstrated. Applicants argue that, in their hands, the method of Casale et al gives inferior results. However, the inability of applicants to reproduce the prior art is not given great weight (MPEP 716.07).
Finally, applicants argue that Christensen et al is not relevant, because it discusses the synthesis of peptides rather than peptide nucleic acids. The title of the article is “Solid phase synthesis of peptide nucleic acids.”
second rejection
Claim(s) 1, 2, 4, 5, 7-9, 11-13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Casale et al (US 20040137469) in view of Bray (Nat. Rev. Drug Discov. (2003) 2 p587-593) and Spasova et al (Comtes Rendus de l’Academie bulgare des Sciences (2004) 57(11) p53-58).
Casale et al and Bray were discussed above, and will not be repeated here. Note that those references render obvious claims 1, 2, 4, 5, 7-9, 11, 13, and 15.
The difference between these references and the remaining claims is that neither reference discusses coupling the reaction at -10 to 5°C for 10-60 min.
Spasova et al also discuss peptide synthesis (title). A number of different reaction protocols were used for coupling (p54, 2nd and 3d paragraphs, continues to p55, 2nd paragraph). Note a number of these reactions were run at reduced temperature (p54, 3d paragraph, continues to p55, 2nd paragraph). This reference discusses using reduced temperature to run the coupling reactions.
In general, differences in temperature are not considered a patentable distinction, absent secondary considerations, as this parameter is routinely optimized (MPEP 2144.05(II)). Note that Spasova et al runs some of their coupling reactions at room temperature, and others at around ice water temperature, showing that, at least some practitioners will use reduced temperatures. Alternatively, this is a simple substitution of one known element (the temperatures of Casale et al) for another (the temperature of Spasova et al) yielding expected results (reaction coupling).
response to applicant’s arguments
Applicants repeated the same arguments for both rejections, which were answered above.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Madhavan et al (IN201821001972). This reference discusses a peptide synthesis protocol where the base is added after adding the coupling agent and the two segments to be coupled.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658