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 .
Applicant’s cancellation of claim 34, amendment of claims 1, 2, 11, 28, 29, 33, 35-38 and 40, in the paper of 5/14/2026, is acknowledged. Applicants' arguments filed on 5/14/2026, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 1-33, 35-40 are pending and at issue.
Election/Restrictions
Applicant's election without traverse of the invention of the following species:
Species Group I:
" (1) wherein at least one of the nucleotide polymerization initiation sites comprises
a nucleic acid primer that hybridizes to a portion of one of the nucleic acid template
molecules,
Species Group II:
" Claim 13: The composition of claim 9, wherein the composition comprises
a plurality of multivalent molecules including the multivalent molecule of claim 9, wherein the plurality of multivalent molecules comprise the same type of nucleotide unit selected from a group consisting of dATP, dGTP, dCTP, dTTP and dUTP;
Species Group III:
linear nucleic acid molecule
Species Group IV:
a copy of a target sequence of interest;
Species Group V:
the same target of interest sequence target of interest sequences;
Species Group VI:
an oligo ethylene glycol chain having 2-6 subunits;
Species Group VII:
" Claim 17: wherein the one or more nucleotide units comprises one type of
nucleotide unit selected from a group consisting of dATP, dGTP, dCTP, dTTP and
dUTP;
Species Group VIII:
" Claim 19: wherein the one or more nucleotide units comprises one type of
nucleotide unit selected from a group consisting of dATP, dGTP, dCTP, dTTP and
dUTP;
Species Group IX:
the one or more complexed polymerases further comprises a plurality of non-catalytic divalent cations that inhibit polymerase-catalyzed nucleotide incorporation (Claim 22);
in the paper of 1/8/2025, is acknowledged.
Claims 14, 18, 20 and 23 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13, 15-17, 19, 21, 22, 24-33, 35-40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 (claims 2-13, 15-17, 19, 21, 22, 24-33, 35-40) is indefinite in the recitation “wherein the engineered polymerase is a uracil-tolerant polymerase that exhibits increased tolerance for uracil in one or more nucleic acid template molecules”. The recitation is indefinite in that it is confusing and unclear what “increased tolerance for uracil in one or more nucleic acid template molecules” means. It appears that applicants are attempting to describe what a “uracil-tolerant polymerase” is, however, applicants description is confusing and unclear. While applicants specification at paragraph [00185] (page 57-58) states that the desirable characteristics include “improved ability to incorporate a dATP nucleotide opposite a uracil-containing template molecule (e.g., uracil-tolerant mutant polymerases)”, this is different than the above recitation “increased tolerance for uracil in one or more nucleic acid template molecules”. Accordingly the above recitation is indefinite.
Claim 2 (claims 3-13, 15-17, 19, 21, 22, 24-33, 35-40) is indefinite in the recitation “one or more engineered polymerases and one or more nucleic acid template molecules of claim 1” in that while claim 1 is drawn to “an engineered polymerase”, it is not drawn to “one or more nucleic acid template molecules”. Thus the reference to “one or more nucleic acid template molecules of claim 1” is indefinite in that it brings into question the antecedent basis of “one or more nucleic acid template molecules of claim 1”. While it is recognized that claim 1 does recite “one or more nucleic acid template molecules” this is in regard to describing a uracil-tolerant polymerase, as a characterization of the engineered polymerase.
Appropriate correction and/or comment is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1-13, 15-17, 19, 21, 22, 24-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim(s) 1 (claims 2-13, 15-17, 19, 21, 22, 24-40 dependent on) is directed to all possible engineered polymerases comprising: an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:1 and has amino acid substitutions Asp141Ala and Glul43Ala, and one or more additional amino acid substitutions, wherein the engineered polymerase has increased ability to incorporate a chain terminating nucleotide analog compared to a wild type polymerase having the amino acid sequence of SEQ ID NO:1, and wherein the engineered polymerase is a uracil-tolerant polymerase that exhibits increased tolerance for uracil in one or more nucleic acid template molecules compared to the wild-type Candidatus Altiarchaeales Family B DNA polymerase of SEQ ID NO: 1 (see also above rejection under 35 U.S.C. 112(b)). The specification, however, only provides the representative species of that engineered polymerase comprising: the amino acid sequence of SEQ ID NO:367, encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these engineered polymerases wherein said engineered polymerase is a uracil-tolerant polymerase by any identifying structural characteristics or properties, for which no predictability of structure is apparent.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim Rejections - 35 USC § 103
The rejection of claim(s) 1-8, 24-29, 31 under 35 U.S.C. 103 as being unpatentable over Sorge et al., U.S. Patent No. 8,268,605 and Dombrowski et al., (Uniprot Accession No: A0A497RSY7, August 2020) is withdrawn based upon applicants amendment of the claims and arguments presented in the paper of 5/27/2026. Specifically applicants argument and the statement by Dr. Lopez in the Declaration under 37 CFR 1.132 presented on 5/14/2026 that the “all variant polymerases tested in this study included the Asp141Ala and Glu143Ala substitutions” (paragraph 15) and “The incorporation data measures the ability of certain polymerase variants having the Asp141Ala and Glu143Ala substitutions, in addition to one or more additional substitutions, to synthesize DNA across uracil-containing template positions compared to the wild-type polymerase of SEQ ID NO: 1” (paragraph 17)are the basis of the withdrawal of the rejection. Thus a mutation in addition to the Asp141Ala and Glu143Ala substitutions is required for increased tolerance for uracil in the nucleic acid template.
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 §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-13, 15-17, 19, 21, 22, 24-33, 35-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of US 12,139,727. Although the conflicting claims are not identical, they are not patentably distinct from each other, claims 1-27 of US 12,139,727, drawn to method for performing nucleic acid sequencing, comprising: (a) contacting an engineered polymerase with (i) a nucleic acid template molecule and (ii) a nucleic acid primer, wherein said contacting is conducted under a condition suitable for the engineered polymerase to bind to the nucleic acid template molecule and the nucleic acid primer, thereby forming a complexed polymerase, wherein the complexed polymerase comprises an engineered polymerase bound to a nucleic acid duplex, wherein the nucleic acid duplex comprises the nucleic acid template molecule hybridized to the nucleic acid primer, wherein the engineered polymerase comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:1 and has amino acid substitutions Asp141Ala and Glu143Ala; (b) contacting the complexed polymerase with a multivalent polymer-nucleotide conjugate to form a multivalent-binding complex, wherein the multivalent polymer-nucleotide conjugate comprises a core attached to multiple nucleotide arms, wherein at least one of the nucleotide arms is attached to a nucleotide unit, wherein said contacting is conducted under a condition suitable for binding the nucleotide unit of at least one of the nucleotide arms of the multivalent polymer-nucleotide conjugate to a corresponding complementary nucleotide base of the nucleic acid template molecule, and inhibiting polymerase-catalyzed extension of the nucleic acid duplex; (c) detecting the multivalent-binding complex; and (d) determining the sequence of the nucleic acid template molecule anticipates/makes obvious instant claims 1-13, 15-17, 19, 21, 22, 24-33, 35-30 drawn to an engineered polymerase comprising: an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:1 and has amino acid substitutions Asp141Ala and Glul43Ala, and one or more additional amino acid substitutions, wherein the engineered polymerase has increased ability to incorporate a chain terminating nucleotide analog compared to a wild type polymerase having the amino acid sequence of SEQ ID NO:1, and wherein the engineered polymerase is a uracil-tolerant polymerase that exhibits
increased tolerance for uracil in one or more nucleic acid template molecules compared to the wild-type Candidatus Altiarchaeales Family B DNA polymerase of SEQ ID NO: 1.
Applicants have asked that this rejection be held in abeyance.
Claims 1-13, 15-17, 19, 21, 22, 24-33, 35-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of US 12/270,056 (previously claims 1-4, 6-8, 10-26, 28-35 of copending Application No. 17/705,020 (reference application, now allowed). Although the conflicting claims are not identical, they are not patentably distinct from each other, Claims 1-4, 6-8, 10-269, 28-35 of copending Application No. 17/705,020, drawn to a method of forming a complexed polymerase, comprising: contacting an engineered polymerase with (i) a nucleic acid template molecule and (ii) a nucleic acid primer to form a binding or ternary polymerase complex comprising: an engineered polymerase bound to a nucleic acid duplex, wherein the nucleic acid duplex comprises a nucleic acid template molecule hybridized to a nucleic acid primer, wherein the nucleic acid template molecule comprises at least one uracil base in the nucleic acid template molecule, and wherein the engineered polymerase comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1, and has amino acid substitutions Asp141Ala and Glul43Ala, and wherein the engineered polymerase is a uracil-tolerant polymerase that exhibits increased uracil-tolerance to the nucleic acid template molecule when compared with the wild type Candidatus Altiarchaeales Family B DNA polymerase anticipates/makes obvious instant claims 1-13, 15-17, 19, 21, 22, 24-33, 35-40 to an engineered polymerase comprising: an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:1 and has amino acid substitutions Asp141Ala and Glul43Ala, and one or more additional amino acid substitutions, wherein the engineered polymerase has increased ability to incorporate a chain terminating nucleotide analog compared to a wild type polymerase having the amino acid sequence of SEQ ID NO:1, and wherein the engineered polymerase is a uracil-tolerant polymerase that exhibits
increased tolerance for uracil in one or more nucleic acid template molecules compared to the wild-type Candidatus Altiarchaeales Family B DNA polymerase of SEQ ID NO: 1.
Applicants have asked that this rejection be held in abeyance.
Related ART:
U.S. Patent No. 11,220,707
U.S. Patent No. 10,768,173
Remarks
No claim is allowed.
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 RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached 6-3 EST Mon-Fri.
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rgh
7/7/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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