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 .
Claims Status
Claims 1-3 and 5-19 are pending.
Claims 1 and 5-11 are amended.
Claim 4 is cancelled.
Election/Restrictions
Applicant’s election of Invention I (Claims 1-16) in the reply filed on 06/24/2026 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)).
Applicant’s election of Species Group I: 1) LAMP method in the reply filed on 06/24/2026 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)).
Claims 17-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected non-elected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/24/2026.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/07/2024 and 04/01/2025 is acknowledged. The submission is in compliance with the provision of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered.
Claim Objections
Claims 1 and 19 are objected to because of the following informalities: With regards to claims 1 and 19, the claims recite “comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO. 1”. It is recommended that the term identity be clarified to “sequence identity”.
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 (and claims 2-3 and 5-16 dependent on) and 19 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.
With regards to Claim 1 (and claims 2-3 and 5-16 dependent on) and claim 19, the claims recite “wherein the consensus sequence comprises an N-linked sugar chain”. It is unclear what the meaning of comprising is in relationship to the structure of the N-linked sugar chain to the consensus sequence and therefore the claims are rendered indefinite. In the interest of compact prosecution, the examiner is interpreting the term comprising to mean that the N-linked sugar chain is attached to the consensus sequence.
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 1 (and claims 2-3 and 5-16 dependent on) and claim 19 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 (and claims 2-3 and 5-16 dependent on) and claim 19 are directed to all possible Bst DNA polymerases comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr) (X is any amino acid residue other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. Tikhonova et al. teach that DNA polymerases are enzymes that catalyze the synthesis of DNA molecules from deoxyribonucleotides using a DNA template (see pg. 1, introduction; Tikhonova et al. International Journal of Molecular Sciences, Vol. 27:4261; published May 11, 2026). Tikhonova et al. also teach that as of April 2026, a total of 56 structures of Bst DNA polymerase and its mutants have been determined and published in the PDB database (see pg. 7). However, Tikhonova et al. teach that the molecular mechanism of Bst DNA polymerase has not yet been fully elucidated (see pg. 7). Tikhonova et al. teach that the structural basis of the molecular mechanism of Bst DNA polymerase function is more complex than the combination of residues in the active site. The coordinated work of the Bst DNA polymerase and its environment is a complex mechanistic puzzle that remains to be solved in the future (see pg. 8). The specification also fails to describe additional representative species of Bst DNA polymerases comprising an amino acid sequence Asn-X-(Ser/Thr) and having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1.
Regarding the level of skill and knowledge of 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 column 1, top, pg. 7). 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 (column 1, pg. 1475).
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.
Claims 1 (and claims 2-3 and 5-16 dependent on) and claim 19 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 Bst DNA polymerase comprising an amino acid set forth in SEQ ID NO: 1, does not reasonably provide enablement for all possible Bst DNA polymerases comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr)(X is any amino acid other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1. 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 and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (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 those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claims 1 (and claims 2-3 and 5-16 dependent on) and claim 19 are so broad as to encompass all possible Bst DNA polymerases comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr)(X is any amino acid other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity. The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of “Bst DNA polymerases comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr)(X is any amino acid other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity” and variants broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the required Bst DNA polymerases comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr)(X is any amino acid other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to “Bst DNA polymerase comprising an amino acid set forth in SEQ ID NO: 1”.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass any possible Bst DNA polymerase comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr)(X is any amino acid residue other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity because the specification does not establish: (A) regions of the Bst DNA polymerase polypeptide which may be modified effecting the 5’-3’ DNA polymerase activity and displacement activity; (B) the general tolerance of enzymes of the Bst DNA polymerase group to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of an enzyme of the Bst DNA polymerase group with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required 5’-3’ DNA polymerase activity and displacement activity and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of Bst DNA polymerase polypeptides having 5’ to 3’ DNA polymerase activity and displacement activity of the claimed genus.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any Bst DNA polymerases comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr) (X is any amino acid residue other than proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity.
The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of a Bst DNA polymerase comprising an amino acid sequence comprising a consensus sequence Asn-X-(Ser/Thr)(X is any amino acid residue other than a proline residue) and comprising an amino acid sequence having 80% or more identity to the amino acid sequence set forth in SEQ ID NO: 1 and having 5’ to 3’ DNA polymerase activity and strand displacement activity is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 (and claims 2-3 and 5-13 dependent on) and 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite(s) a Bst DNA polymerase comprising: an amino acid sequence as set forth in SEQ ID NO: 1. This judicial exception is not integrated into a practical application because the additional elements do not contribute to any meaningful limitation to the natural product. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claims 1 and 19 recite “a Bst DNA polymerase comprising an amino acid sequence set forth in SEQ ID NO: 1”. The claims encompass a composition of a polypeptide that is structurally identical to a natural occurring polypeptide as evidenced by UniProt Database Entry: (Q45458_GEOSE; integrated into UniProtKB/TrEMBL November, 1, 1996) which discloses the sequence of a a Geobacillus stearothermophilus DNA polymerase I that comprises an amino acid sequence that is 100% identical to SEQ ID NO: 1 of the current instant application (see alignment below).
RESULT 1
Query Match 100.0%; Score 2961; Length 876;
Best Local Similarity 100.0%;
Matches 587; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 290 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 349
Qy 61 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 350 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 409
Qy 121 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 410 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 469
Qy 181 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 470 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 529
Qy 241 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 530 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 589
Qy 301 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 590 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 649
Qy 361 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 650 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 709
Qy 421 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 710 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 769
Qy 481 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 770 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 829
Qy 541 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 587
|||||||||||||||||||||||||||||||||||||||||||||||
Db 830 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 876
Because there is no difference in characteristics (structural, functional, or otherwise) between the claimed and naturally occurring composition, the claimed composition does not have markedly different characteristics and thus is a product of nature exception. Accordingly, the product is directed to an exception (Step 2A: Yes). Because the claims do not include any additional features that could add significantly more to the exception (Step 2B: No), the claims do not qualify as eligible subject matter and are rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2-3, 5-16 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Ong et al. (US Patent Application Publication No: US 2013/023/0230887 A1; published September 5, 2013), hereinafter referred to as Ong.
With regards to claims 1 and 19, Ong teaches a Bacillus stearothermophilus DNA polymerase I that comprises an amino acid sequence (SEQ ID NO: 25, see paragraph 0031) that is 100% identical to SEQ ID NO: 1 of the current instant application (see sequence alignment below).
Query Match 100.0%; Score 2961; Length 587;
Best Local Similarity 100.0%;
Matches 587; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 60
Qy 61 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 120
Qy 121 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 180
Qy 181 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 240
Qy 241 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 300
Qy 301 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 360
Qy 361 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 420
Qy 421 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 480
Qy 481 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 540
Qy 541 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 587
|||||||||||||||||||||||||||||||||||||||||||||||
Db 541 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 587
Claims 2-3 and 5-13 are included in the rejection as applied to the Bst DNA polymerase of part (1) of claim 1 as it appears that they further limit part (2) of claim 1 which is used in the alternative to define the Bst DNA polymerase.
With regards to claims 14-16, Ong discloses an embodiment in which one or more polymerases are added to a synthetic nucleic acid. Ong discloses that the polymerases may be bacterial DNA polymerases including SEQ ID NO: 25 (see paragraph 0029) and further discloses that amplification procedure includes isothermal amplification reactions such as LAMP (see paragraph 0030).
Therefore, claims 1, 2-3, 5-16 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-3, 5-10, 12-13 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013), hereinafter referred to as Ong, in view of Shi et al. (Current Drug Targets, Vol. 8, pg. 116-1125, published October 2007; PMID: 17979671), hereinafter referred to as Shi.
With regards to claims 1-3 and 19 Ong teaches a Bacillus stearothermophilus DNA polymerase I that comprises an amino acid sequence that is 100% identical to SEQ ID NO: 1 of the current instant application (see sequence alignment below). The DNA polymerase I taught by Ong comprises a consensus sequence Asn-X-(Ser/Thr) at residue positions 726-729 (see positioning number in reference to full-length DNA polymerase as shown in sequence alignment below), NIT (see underlined sequence in the sequence alignment below). The NIT consensus sequence of the DNA polymerase is inherently located in the finger domain of the Bst DNA polymerase as evidenced by Oscorbin et al. (Computational and Structural Biology Journal, Vol. 12, pg. 4519-4535; published September 21, 2023; PMID: 37767105), who teaches that Bst DNA polymerase fingers domain is formed by residues 668-796 (see Figure 2, pg. 4522). The 5’ to 3’ DNA polymerase activity and strand displacement activity is inherent to the polymerase as evidenced by Oscorbin et al. who teaches that Bst polymerase has innate strand-displacement activity (see pg. 4529).
Query Match 100.0%; Score 2961; Length 587;
Best Local Similarity 100.0%;
Matches 587; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 60
Qy 61 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 120
Qy 121 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 180
Qy 181 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 240
Qy 241 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 300
Qy 301 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 360
Qy 361 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 420
Qy 421 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 480
Qy 481 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 540
Qy 541 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 587
|||||||||||||||||||||||||||||||||||||||||||||||
Db 541 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 587
Sequence Alignment with Full-length Bst DNA Polymerase
Query Match 100.0%; Score 2961; Length 876;
Best Local Similarity 100.0%;
Matches 587; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 290 AEGEKPLEEMEFAIVDVITEEMLADKAALVVEVMEENYHDAPIVGIALVNEHGRFFMRPE 349
Qy 61 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 350 TALADSQFLAWLADETKKKSMFDAKRAVVALKWKGIELRGVAFDLLLAAYLLNPAQDAGD 409
Qy 121 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 410 IAAVAKMKQYEAVRSDEAVYGKGVKRSLPDEQTLAEHLVRKAAAIWALEQPFMDDLRNNE 469
Qy 181 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 470 QDQLLTKLEQPLAAILAEMEFTGVNVDTKRLEQMGSELAEQLRAIEQRIYELAGQEFNIN 529
Qy 241 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 530 SPKQLGVILFEKLQLPVLKKTKTGYSTSADVLEKLAPHHEIVENILHYRQLGKLQSTYIE 589
Qy 301 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 590 GLLKVVRPDTGKVHTMFNQALTQTGRLSSAEPNLQNIPIRLEEGRKIRQAFVPSEPDWLI 649
Qy 361 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 650 FAADYSQIELRVLAHIADDDNLIEAFQRDLDIHTKTAMDIFHVSEEEVTANMRRQAKAVN 709
Qy 421 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 710 FGIVYGISDYGLAQNLNITRKEAAEFIERYFASFPGVKQYMENIVQEAKQKGYVTTLLHR 769
Qy 481 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 770 RRYLPDITSRNFNVRSFAERTAMNTPIQGSAADIIKKAMIDLAARLKEEQLQARLLLQVH 829
Qy 541 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 587
|||||||||||||||||||||||||||||||||||||||||||||||
Db 830 DELILEAPKEEIERLCELVPEVMEQAVTLRVPLKVDYHYGPTWYDAK 876
Ong does not teach that the consensus sequence comprises an N-linked sugar chain, and the N-linked sugar chain is a structure represented by the following formula (I):
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182
644
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wherein Asn is an asparagine residue in the consensus sequence, Man is a mannose residue, GlcNAc is an N-acetyl D-glucosamine residue, Fuc is a fucose residue, m and n are each independently 0 or 1, andS1, S2, S3, and S4 are each independently absent or a sugar chain comprising one or more and five or less monosaccharide residues.
However, Shi teaches that the major advantages of the baculovirus-insect cell system is that it is a eukaryotic system that can provide posttranslational modifications, such as protein N-glycosylation (see Abstract, pg. 1116). Shi teaches that the baculovirus insect cell system can provide extremely high levels of heterologous gene expression (see pg. 1116, first paragraph). Shi teaches that the protein N-glycosylation pathway begins when oligosaccharyltransferese transfers a preassembled oligosaccharide to the asparagine residue within a specific recognition site (Asn-X-Thr/Ser) (see pg. 1116). Shi further teaches that the protein N-glycosylation pathways in insect cells includes a “paucimannosidic” pathway and that the major insect cell products are paucimannosidic N-glycans with or without core fucose residues as shown in the far left-hand side of the figure below (see Figure 1, pg. :
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896
805
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It would have been obvious to one of ordinary skill in the art of protein engineering and expression before the effective filing date of the current instant application to express the Geobacillus stearothermophilus DNA polymerase I taught by Ong in the baculovirus-insect cell system taught by Shi in order to produce a post-translationally modified Bst DNA polymerase with N-linked sugar chain at the consensus Asn-X-(Ser/Thr) sequence. As taught by Shi, the resulting N-glycosylation can result in the following glycosylation at the Asn of the consensus sequence (see Figure 1, pg. 1117):
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67
122
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media_image4.png
157
138
media_image4.png
Greyscale
where Asn is an asparagine residue in the consensus sequence, and m=1, n=1, and S1, S2, S3, and S4 are independently absent. Shi teaches that major insect cell products are paucimannosidic N-glycan with or without core fucose residues (see figure 1, legend, pg. 1117). The N-linked sugar chain also comprises less than nine mannose residues. One of ordinary skill in the art would be motivated to use the baculovirus-insect cell system taught by Shi to express the DNA polymerase taught by Ong because Shi teaches that the expression system can produce high level of protein and can provide post-translational modifications such as protein N-glycosylation. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Ong and Shi who provide all the necessary teachings and methods needed to do so.
With regards to claim 5-8, 10 and 12, in addition to the teachings of Ong as applied to claim 1 above, Shi teaches that a possible glycosylation product at the Asn of the consensus sequence can be (see Figure 1, pg. 1117):
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77
199
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157
138
media_image4.png
Greyscale
Therefore, it would have been obvious one of ordinary skill in the art of protein engineering and expression before the effective filing date of the current instant application to express the Geobacillus stearothermophilus DNA polymerase I taught by Ong in the baculovirus-insect cell system taught by Shi in order to produce a post-translationally modified Bst DNA polymerase with N-linked sugar chain at the consensus Asn-X-(Ser/Thr) sequence. As taught by Shi, the resulting N-glycosylation can result in the following glycosylation product at the Asn residue of the consensus sequence:
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77
199
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Greyscale
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media_image4.png
157
138
media_image4.png
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In this instance, S1, S2, S3, S4 comprises a GlcNAc (N-acetyl D-glucosamine residue). The Examiner is interpreting the glycosylation to follow the limitations of claim 1 which recites “S1, S2, S3, and S4 are each independently absent or a sugar chain comprising one or more and five or less monosaccharide residues”. Based on the claim language, the terminal GlnNac residues can be defined as either S1, S2, S3, or S4 in the above schematic depending on the absence of S1 or S2 and S3 or S4 above. Additionally, the glycosylation product has one non-reducing end of the N-linked sugar that is a N-acetyl D-glucosamine (GlcNAc) residue.
One of ordinary skill in the art would be motivated to use the baculovirus-insect cell system taught by Shi to express the DNA polymerase taught by Ong because Shi teaches that the expression system can produce high level of protein and can provide post-translational modifications such as protein N-glycosylation. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Ong and Shi who provide all the necessary teachings and methods needed to do so.
With regards to claim 9 and 13, in addition to the teachings of Ong as applied to claim 1 above, Shi teaches the following possible glycosylation product at the Asn of the consensus sequence (see Figure 1, pg. 1117):
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71
106
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media_image7.png
141
132
media_image7.png
Greyscale
where the S1, S2, S3, and S4 are absent and m=1, and n=0.
It would have been obvious one of ordinary skill in the art of protein engineering and expression before the effective filing date of the current instant application to express the Geobacillus stearothermophilus DNA polymerase I taught by Ong in the baculovirus-insect cell system taught by Shi in order to produce a post-translationally modified Bst DNA polymerase with N-linked sugar chain at the consensus Asn-X-(Ser/Thr) sequence. As taught by Shi, the resulting N-glycosylation can result in the following glycosylation product at the Asn residue of the consensus sequence:
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71
106
media_image6.png
Greyscale
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media_image7.png
141
132
media_image7.png
Greyscale
where the S1, S2, S3, and S4 are absent and m=1, and n=0.
One of ordinary skill in the art would be motivated to use the baculovirus-insect cell system taught by Shi to express the DNA polymerase taught by Ong because Shi teaches that the expression system can produce high level of protein and can provide post-translational modifications such as protein N-glycosylation. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Ong and Shi who provide all the necessary teachings and methods needed to do so.
Therefore, claims 1-3, 5-10, 12-13 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013) in view of Shi et al. (Current Drug Targets, Vol. 8, pg. 116-1125, published October 2007; PMID: 17979671).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013), hereinafter referred to as Ong, in view of Shi et al. (Current Drug Targets, Vol. 8, pg. 116-1125, published October 2007; PMID: 17979671), hereinafter referred to as Shi, as applied to claim 1 above, and further in view of Walski et al. (Insect Biochemistry and Molecular Biology, Vol. 83, pg. 21-34, published February 14, 2017; PMID: 28232040; PMID: 28232040), hereinafter referred to as Walski.
The teachings of Ong and Shi as applied to claim 1 are summarized above.
Neither Ong or Shi specifically teach a glycosylation of the Bst DNA polymerase of claim 1 where at least one sugar chain of S1, the S2, the S2, and the S4 has a structure represented by the following:
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193
647
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However, Walski teaches a diversity of protein glycosylation in insects (see Abstract, pg. 21). Walski teaches that N-linked glycans are attached almost exclusively to asparagine residues in a defined N-X-T/S sequence (X is any amino acid except proline) (see pg. 21). Walski also teaches N-glycan types present in insects (see Figure 1, pg. 23 and below).
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534
1424
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With regards to claim 11, Walski teaches that in the glycosylation pattern in Figure 1, panel II (3rd pattern from left), the S1 position comprises at least a mannose residue (See Figure 1, panel II pg. 21) and S5 and S6 are absent.
It would have been obvious to one of ordinary skill in the art of protein engineering and expression to express the Geobacillus stearothermophilus DNA polymerase I taught by Ong in the baculovirus-insect cell system taught by Shi in order to produce a post-translationally modified Bst DNA polymerase with N-linked sugar chain at the consensus Asn-X-(Ser/Thr) sequence. As taught by the combined teachings of Ong, Shi, and Walski, the resulting N-glycosylation in insect cells can result in the following glycosylation:
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415
103
media_image10.png
Greyscale
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109
1411
media_image11.png
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where S1 is attached to a mannose residue and S5 and S6 are absent.
One of ordinary skill in the art would be motivated to use the baculovirus-insect cell system taught by Shi to express the DNA polymerase taught by Ong because Shi teaches that the expression system can produce high level of protein and can provide post-translational modifications such as protein N-glycosylation and Walski further teaches additional N-glycan types that can be obtained in insects.. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Ong, Shi, and Walski who provide all the necessary teachings and methods needed to do so.
Therefore, claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013) in view of Shi et al. (Current Drug Targets, Vol. 8, pg. 116-1125, published October 2007; PMID: 17979671) as applied to claim 1 above, and further in view of Walski et al. (Insect Biochemistry and Molecular Biology, Vol. 83, pg. 21-34, published February 14, 2017; PMID: 28232040; PMID: 28232040).
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013), hereinafter referred to as Ong, as applied to claim 1 above, in view of Notomi et al. (Nucleic Acids Research, Vol. 28, e63, published June 2000; PMID: 10871386), hereinafter referred to as Notomi.
The teachings of Ong as applied to claim 1 are summarized above.
With regards to claims 14-16, Notomi teaches a novel method, termed loop-mediated isothermal amplification (LAMP) that amplifies DNA with high specificity, efficiency, and rapidity under isothermal conditions. Notomi teaches that the method employs a DNA polymerase and a set of four specially designed primers (see Abstract, pg. i). Notomi teaches that the method relies on auto-cycling strand displacement DNA synthesis that is performed by a DNA polymerase with high strand displacement activity (see pg. ii). Notomi does not specifically teach that the DNA polymerase is a Bst DNA polymerase comprising an amino acid sequence set forth in SEQ ID NO: 1.
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application, to use the DNA polymerase taught by Ong as the DNA polymerase in the LAMP method taught by Notomi. One of ordinary skill in the art would be motivated to do so because Ong teaches a DNA polymerase with stand displacement activity and Notomi teaches that the LAMP method uses a DNA polymerase with strand displacement activity to amplify DNA. Thus, the DNA polymerase taught by Ong would be beneficial in the LAMP method taught by Notomi. One of ordinary skill in the art of protein engineering would have expectations of success in doing so from the combined teachings of Ong and Notomi who teach all the methods and components needed to do so.
Therefore, claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ong et al. (US Patent Application Publication No: US 2013/0230887 A1; published September 5, 2013) as applied to claim 1 above, and further in view of Notomi et al. (Nucleic Acids Research, Vol. 28, e63, published June 2000; PMID: 10871386).
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure:
Maranhao et al. “An improved and readily available version of Bst DNA polymerase for LAMP, and applications to COVID-19 diagnostics” medRxiv, doi: https://doi.org/10.1101/2020.10.02.20203356; published October 5, 2020.
Conclusion
No claims are allowed.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
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