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 .
The Response of 2 June 2026 has been entered.
Claims 1-5 and 7-22 are currently pending.
Election/Restrictions
Applicant’s election of the species of: magnesium as the divalent cations, ammonium ions as the monovalent ions, DNA polymerase as the nucleotidyltransferase and a nucleotide complex in solution in the reply filed on 2 June 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). In the interest of compact prosecution, the species elections with respect to species of monovalent cations and whether the complex is in solution are withdrawn.
Claims 9 and 10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2 June 2026.
Claims 1-5, 7, 8 and 11-22 are considered here with respect to the elected species.
Claim Rejections - 35 USC § 112(b) (indefiniteness)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 12, 13 and 21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 12 recites that “the nucleotides complexed with divalent cations is poorly soluble”. The term “poorly soluble” is a relative term which renders the claim indefinite. The term “poorly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention (it is unclear what level of solubility, under what conditions would qualify as “poorly soluble”).
Claim 21 recites “wherein the nucleotidyltransferase does not require a template.” The claim does not indicate what “does not require a template” means in the context of the claimed invention (e.g., does not require a template for what?). For purposes of applying prior art, the claim is construed to encompass any nucleotidyltransferase capable of template-independent activity. To the extent Applicant intends to recite a template-independent amplification process, the claims should be amended to recite such a process.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-5, 7, 8, 11 and 14-21 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 10501782 to Porter et al., as evidenced by Briggs, Biophysical Journal 111.2 (2016): 294-300 and (in the case of claim 21) Alsmadi et al., BMC Research Notes 2.1 (2009): 48.
Regarding claims 1-3, 7, 8, 16 and 19, Porter teaches a method for cell-free DNA synthesis, comprising: preparing a reaction mixture containing a DNA polymerase (nucleotidyltransferase), nucleotides and optionally a template DNA under conditions that allow for amplification of the DNA, wherein the method comprises adding additional nucleotides to the reaction mixture in a controlled manner over time (entire doc, including col. 2, line 5 to col. 5, line 50). The added nucleotides can be in the form of a salt (i.e. electrically neutral; see instant published spec. US 20230091493, [0054]) comprising the nucleotides and one or more ions that include divalent cations such as Mg2+ and monovalent ions such as K+, Li+ and Na+ (i.e. a nucleotide complex) such that nucleotides and cations are supplied to the reaction at the same time, resulting in improvements in the rate of DNA synthesis and/or the yield of DNA (claims 20-25; col. 3, line 36 to col. 4, line 21; col. 5, lines 21-46).
Regarding the ranges of divalent and monovalent cations in claims 1 and 5, Porter teaches that the ratio of cations:nucleotides can be between about 3:1 to 1:3, preferably about 3:1 (col. 5, lines 21-46; col. 13, lines 19-27; col. 23, lines 5-31), and that the cations preferably include Mg2+, which is required for polymerase activity and is consumed (in free form) during DNA amplification (col. 23, line 47 to col. 24, line 20; Example 3). Porter teaches that the ratio of Mg2+ to dNTP ratio is preferably within the range of 1.5-3.75 (Example 4, Table 7), and further exemplifies feeding a reaction mixture dNTP lithium salts along with Mg2+ (Example 4). While the magnesium/lithium of Example 4 is fed separately as dNTPs and MgCl2 salt, Porter teaches that the cations and nucleotides can be provided together (see above), and one would have been motivated to do so to eliminate an unnecessary step and thus enhance efficiency (see MPEP 2144.04, II., B. - omission of an element and retention of its function is an indicium of nonobviousness; see also, MPEP 2144.04, IV., C. – changes in the sequence of adding ingredients are prima facie obvious in the absence of new or unexpected results). Since Porter teaches that the nucleotide/cation composition can be in the form of a salt (i.e. electrically neutral), a nucleotide salt comprising Mg2+ and Li+ with 1.5 divalent Mg2+ ions per nucleotide would have about 1 Li+ (or other monovalent ion) per nucleotide, which is within the range of claims 1 and 5. One of ordinary skill in the art would have had a reasonable expectation of success in using a Mg2+/Li+ dNTP salt composition in the method of Porter because Briggs evidences that ATP and GTP can complex with both Mg2+ and Li+ (Briggs, Table S2).
Regarding claim 4, the instant specification evidences that a nucleotide salt dispersed in aqueous solution will dissociate in solution into anionic and cationic components and be surrounded by hydronium ions (Spec., [0008]; [0022]), and thus a nucleotide salt composition of Porter would comprise at least some hydronium ions.
Regarding claim 11, the recited mixing step would encompass any mixing of nucleotide salts, including e.g. mixing dATP, dGTP, dGTP and dCTP to form a mixture of all four required nucleotides (the claim requires only mixing a complex including divalent cations with a complex including monovalent cations and the complexes taught by Porter can comprise both (see above); there is nothing in the claim requiring mixing of a complex consisting of divalent cations with a complex consisting of monovalent cations). Porter further teaches that the ratio of cations:nucleotides can be between about 3:1 to 1:3, preferably about 3:1 (i.e. less than 4:1) (see above).
Regarding claims 14-15, Porter teaches that the nucleotide complex can be added to the reaction mixture so as to maintain a target concentration range of ions and/or nucleotide, e.g. between a low micromolar and low millimolar range (col. 16, lines 30-59; col. 21, lines 25-66). One of ordinary skill in the art would have recognized that the nucleotide complex could be formulated at any concentration higher than the target concentration such that its addition to (and dilution in) the reaction mixture would achieve the target concentration. For example, a 10X stock nucleotide solution of 30-40 mM could be added to a reaction mixture to achieve a low millimolar target concentration in the reaction mixture.
Regarding claim 17, Porter teaches that the nucleotide complex that is added to the reaction mixture preferably includes magnesium (see above). Moreover, Porter teaches that the reaction mixture can also comprise a template, primers, buffers, etc. (e.g., Example 1).
Regarding claim 18, Porter teaches that the ratio of Mg2+ to nucleotides can be less than 2:1 (col. 23, lines 21-30), and that the Mg2+ is also required for DNA polymerase activity (i.e. a cofactor) (col. 23, lines 64-66).
Regarding claim 20, Porter teaches that the DNA polymerase can be a strand-displacing polymerase capable of isothermal synthesis, e.g. Phi29 polymerase (col. 4, lines 34-57).
Regarding claim 21, Alsmadi evidences that Phi29 is capable of template-independent DNA polymerase activity (1st para. under Results, discussing “nonspecific template-independent priming”). It is noted that claim 21 does not recite a method for template-independent DNA amplification or any specific polymerase, but rather only that the enzyme “does not require a template”.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Porter as evidenced by Briggs and Alsmadi, as applied to claims 1-5, 7, 8, 11 and 14-21, further in view of Mohamady et al., Organic letters 18.3 (2016): 580-583.
The teachings of Porter are set forth above. Regarding claim 22, Porter further teaches that ammonium salts are among the salts that can be supplied to the reaction mixture (col. 15, lines 55-64; col. 20, lines 46-62).
Claim 22 differs from Porter as evidenced by Briggs and Alsmadi, as applied to claims 1-5, 7, 8, 11 and 14-21, in that the monovalent cations are ammonium cations.
Mohamady teaches that dNTPs can be prepared as ammonium salts (p. 582, 1st ¶; Scheme 4).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to prepare a nucleotide complex comprising dNTPs and a combination of monovalent and divalent (Mg2+) cations wherein the monovalent cations comprise ammonium ions because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to prepare a nucleotide complex comprising dNTPs and a combination of monovalent and divalent (Mg2+) cations wherein the monovalent cations comprise ammonium ions because Porter teaches that supplying additional ammonium ions to the reaction mixture and suppling such ammonium ions as part of the nucleotide complex would allow them to be supplied without need for a separate addition step, thus enhancing efficiency. Preparing a nucleotide complex comprising dNTPs and ammonium ions would have led to predictable results with a reasonable expectation of success because Mohamdy teaches that dNTPs can be prepared as ammonium salts.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The 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 1-5, 7, 8, 11 and 14-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 11, 12, 15, 16, 18-20, 22-24, 27, 28 and 30 of copending Application No. 18/684,090 in view of Porter as cited above.
Regarding instant claims 1 and 5, the claims of the ‘090 App teach a nucleotide complex comprising nucleotides that can be dNTPs and 0.2-1.5 divalent cations per nucleotide and up to 0.5 monovalent cations per nucleotide, and a cell-free process for DNA synthesis comprising obtaining the complex and adding a nucleotidyltransferase (‘090, claims 1-4, 6-7).
Regarding instant claims 3-4, Porter teaches a substantially identical method as the ‘090 claims and teaches that the nucleotide complex can be in the form of a salt (i.e. electrically neutral) (see above). Moreover, the instant specification evidences that a nucleotide salt dispersed in aqueous solution will dissociate in solution into anionic and cationic components and be surrounded by hydronium ions (Spec., [0008]; [0022]), and thus a nucleotide salt composition of Porter would comprise at least some hydronium ions.
Regarding instant claim 7, the ‘090 teaches that the divalent cation can be Mg2+ (‘090, claims 3-4).
Re instant claim 8, Porter teaches a substantially identical method as the ‘090 claims and teaches that the nucleotide complex can comprise K+, Li+ or Na+ (see above).
Re instant claims 14-15, the ‘090 claims teach obtaining the complex at a concentration of 40-160 mM (‘090, claim 8), and one of ordinary skill in the art would have recognized that the nucleotide complex could be formulated at any concentration higher than the target concentration such that its addition to (and dilution in) the reaction mixture would achieve the target concentration.
Re instant claims 16-18, the ‘090 claims teach forming a reaction mixture and adding magnesium such that the total ratio of Mg to nucleotide does not exceed 2:1 (‘090, claim 11).
Re instant claims 19-20, the ‘090 claims teach that the nucleotidyltransferase is a strand displacing isothermal DNA polymerase (‘090, claim 12)
Re instant claim 21, the ‘090 claims teach that the nucleotidyltransferase is a strand displacing isothermal DNA polymerase (‘090, claim 12). Porter teaches a substantially identical method as the ‘090 claims and teaches that Phi29 polymerase is such a strand-displacing polymerase (Phi29 is capable of template-independent activity; see above).
Re instant claim 22, the ‘090 claims teach that the monovalent cation can be an ammonium ion (‘090, claim 24).
This is a provisional nonstatutory double patenting rejection.
Claims 1-5, 7, 8, 11 and 14-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 10501782 to Porter et al. (cited in 103 rejection above) in view of WO2016034849 and (in the case of claim 22) Mohamady (cited in 103 rejection above).
The claims of the ‘782 patent teach a method for cell-free DNA synthesis comprising adding a combination of nucleotides and cations (i.e. a nucleotide complex) to a reaction mixture comprising a DNA polymerase (‘782, claims 1-31, esp claim 25). WO2016034849 is the corresponding PCT application to the ‘782 patent, and contains an identical disclosure as set forth in the 103 rejection above for the ‘782 patent. The instant claims are obvious over the ‘782 claim in view of WO2016034849 on the same basis as set forth in the 103 rejection above (see rejection for claim-by-claim breakdown).
Conclusion
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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