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 .
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 because there are sequences in figures 6, 7A, 10C, 12A, 12C, and 15B, for example, that do not contain a SEQ ID NO.
A complete response to this office action must correct the defects cited above regarding compliance with the sequence rules and a response to the action on the merits which follows.
The aforementioned instance of failure to comply is not intended as an exhaustive list of all such potential failures to comply in the instant application. Applicants are encouraged to thoroughly review the application to ensure that the entire application is in full compliance with all sequence rules. This requirement will not be held in abeyance.
Drawings
The drawings filed on 3/14/24 are objected to because they contain sequences that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), but each sequence does not contain a SEQ ID NO., as explained in the “Sequence Compliance” section above. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims , 4-9, 11, 13, 16, 18-23, 25, 26, 28-31, 34-38, 40-43, 53, and 73 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 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 is directed to a method for producing an oligonucleotide comprising incubating a DNA polymerase variant of any length (i.e. 10000 aa in length) that comprises an amino acid sequence of any length (i.e. 4 aa) that is at least 90% identical to SEQ ID NO: 1.
The specification does not adequately describe the structure required for the function. The species of the specification, SEQ ID NO: 1, is not representative of the entire claimed genus. Without further description of the structure required for the function, one would not be able to readily envision which amino acid sequences meet the instant limitation and function as required.
The specification does not adequately describe the structure required for the function. The species of the specification are not representative of the entire claimed genus. The structure recited encompasses a large genus of dsRNAs that would not likely have the function of inhibiting the expression of any HAO1 gene. The dsRNA agent can be very long (i.e. 1,000 nucleotides) and comprise 15 contiguous nucleotides of instant SEQ ID NO: 669 in the antisense strand in a different portion than the double-stranded region and have no other sequence specificity to any specific HAO1 target sequence. The species disclosed in the specification of siRNAs that comprise SEQ ID NO: 669 are not representative of the entire claimed genus.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for amino acid sequences within the instant enormous genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
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.
Claim(s) 44 and 62 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Pongracz (AU 2004271215 A1).
Pongracz teach antisense oligonucleotides that have at least 20 nucleotides that are perfectly complementary to the target sequence (page 10). Pongracz teaches a 30-mer antisense oligonucleotide on page 11 and teaches that the choice of the type of inter-nucleoside linkages used may be phosphodiester; phosphotriester; methylphosphonate; P3'-N5' phosphoramidate; N3'->P5' phosphoramidate; N3'--P5' thiophosphoramidate; and phosphorothioate linkages. N3'->P5' phosphoramidate and N3'-P5' thiophosphoramidate chemistries are preferred (page 11).
Pongracz teach that the N3'-P5' phosphoramidate internucleoside linkages are reported to display favorable binding properties, nuclease resistance, and solubility. Pongracz teach that the addition of a sulfur atom to the backbone in N3'->P5' thiophosphoramidate oligonucleotides provides enhanced acid stability.
Pongracz teach that: The oligonucleotide component 0 can be a ribo or deoxyribonucleic acid or modified forms thereof, and the linkages connecting the nucleobases 20 may be made with any compatible chemistry, including, but not limited to: phosphodiester; phosphotriester; methylphosphonate; P3'-N5' phosphoramidate; N3'->P5' phosphoramidate; N3'--P5' thiophosphoramidate; and phosphorothioate linkages. N3'->P5' phosphoramidate and N3'-P5' thiophosphoramidate chemistries are preferred.
Therefore, the claims are anticipated by Pongracz.
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.
Claim(s) 1, 4-9, 11, 13, 16, 18-23, 25, 26, 28-31, 34-38, 40-44, 53, 62, and 73 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lelyveld et al. (PNAS, March 31, 2020, 7276–7283, vol. 117, no. 13), in view of Filler et al. (US 2020/0197351 A1), Mazur et al. (US 2024/0287483 A1), Smith et al. (WO 2014/100498 A1), Springer (WO 2021/202158 A1), and Almogy et al. (WO 2019/191003 A1).
Lelyveld et al. teach synthesis of phosphoramidate-linked DNA by a modified DNA polymerase (title) (claims 1 and 73).
Lelyveld et al. teach a method of template-directed polymerization to form phosphoramidate (NP) linked DNA (page 7276).
Lelyveld et al. teach: Here, we report that 3′-amino terminated primers are, in fact, slowly extended by the DNA polymerase from B. stearothermophilus in a template-directed manner. When its cofactor is Ca2+ rather than Mg2+, the reaction is fivefold faster, permitting multiple turnover NP bond formation to yield NP-DNA strands from the corresponding 3′-amino-2′,3′-dideoxynucleoside 5′-triphosphates. A single active site mutation further enhances the rate of NP-DNA synthesis by an additional 21-fold (abstract).
Lelyveld et al. teach: Synthetic 3′-amino 2′,3′-dideoxyribonucleoside 5′-triphosphates (nNTPs) have long been considered inhibitors of primer extension catalyzed by polymerases (page 7276). The oligonucleotide is within the instantly recited size range of claim 29 and comprises phosphoramidate and phosphodiester linked nucleotides (Figure 2) (claims 29-31). The specific length of the oligonucleotide is a matter of design choice (instant claim 44).
Lelyveld et al. teach that relative to its native phosphodiester bond forming activity, the kinetic disadvantage of BF’s NP-DNA polymerase activity is approximately four orders of magnitude with F710Y (page 7279). Selection of quantity and placement of phosphoramidate linkages vs phosphodiester linkages is considered to be a matter of routine optimization of known design elements (instant claims 34 and 44).
Lelyveld et al. teach: We grew crystals of the large fragment of DNA polymerase I (BF) from the thermophilic bacterium Bacillus stearothermophilus (Bst, now classified as Geobacillus) complexed with a DNA duplex in which the primer contains a terminal 3′-amino-2′,3′-dideoxycytidine (nC) residue (Fig. 1) (page 7277) (instant claim 21).
Lelyveld et al. teach that the pH is 8.8 for the polymerase reaction (Figure 2) (instant claim 13).
Lelyveld et al. teach: We screened divalent metal cofactors under presteady-state conditions and observed strong cofactor dependent effects on activity. Kinetics of 3′-aminoprimer extension with 5mMCa2+,Mg2+,Ba2+, andSr2+wereall faster than in the absence of added divalent metals (page 7278) (instant claims 42 and 43).
Lelyveld et al. teach: With the enhanced kinetics afforded by Ca2+,BF was capable of catalyzing multiple-turnover condensation of nNTP monomers to form NP-DNA oligonucleotides in a DNA template directed manner (Fig. 2D) (page 7278)(instant claims 1, 18).
Lelyveld et al. teach: The mutant F710Y demonstrated a 21-fold increase in kpol for nCTP, as well as a 2.6-fold increase for dCTP (Fig.3E andTable1). This mutant could achieve extension to a full length+28-nt NP-DNA product in <24 h at 55 degrees C in the presence of Ca2+and all four nNTPs (Fig 3F)(page 7278) (instant claims 5, 9, 11).
Lelyveld et al. teach: dNTPs or nNTPs (page 7279) (instant claims 35 and 36).
Lelyveld et al. teach incorporation of a 3′-amino terminated DNA primer, and a DNA template (page 7280)(instant claim 1) comprising ribonucleotides or deoxyribonucleotides (instant claim 19).
The primer is 10 nucleotides in length and comprises phosphoramidate bonds and guanosine, cytidine, and adenosine (Figure 1)(instant claims 20, 23, 25, 26 and 28).
Lelyveld et al. teach that the primer is fluorescein-labeled (Figure 1)(instant claim 22).
Lelyveld et al. teach: Although WT BF has bona fide DNA-dependent NP-DNA polymerase activity, a substantial kinetic defect is associated with nNTP vs. dNTP addition to a 3′-amino terminal primer (Fig. 3A), demonstrating selection of nNTP or dNTP depending on conditions.
Although Lelyveld et al. teaches the benefits of incorporation of metal ion cofactors, Lelyveld et al. does not teach that the metal ion cofactor is trivalent.
However, it would have been obvious for the metal ion cofactor to be trivalent because the benefits were known, as taught by Filler et al. It would have been obvious to combine divalent and trivalent cations as a matter of design choice in view of the benefits known for each, as evidenced by Lelyveld et al. and Filler et al.
Filler et al. teach: TRIVALENT AND DIVALENT CATIONS AS ADMINISTRABLE AGENTS FOR INCREASED PROCESSIVITY AND IMPROVED FIDELITY OF REVERSE TRANSCRIPTASE IN TELOMERASE AND IN NUCLEIC ACID POLYMERASES (title).
Filler et al. teach: [0021] Cation Substitution to Alter the Function of Reverse Transcriptase and Nucleic Acid Polymerase
Filler et al. teach: [0023] The method increased the speed and accuracy of retroviral reverse transcriptase. However, the same method is applicable to RNA polymerase and DNA polymerase although those types of enzymes have far more elaborate arrays of methods to check accuracy and correct copying errors.
Filler et al. teach: [0066] By introducing a trivalent such as scandium (Sc3+), or a higher affinity divalent cation, where no significant toxicity results, it becomes possible to optimize and improve fidelity and processivity of nucleic acid polymerase and reverse transcriptase enzymes (instant claim 16).
Although Lelyveld et al. teach that they grew crystals of the large fragment of DNA polymerase I (BF) from the thermophilic bacterium Bacillus stearothermophilus (Bst, now classified as Geobacillus) complexed with a DNA duplex in which the primer contains a terminal 3′-amino-2′,3′-dideoxycytidine (nC) residue, Lelyveld et al. do not specifically teach instant SEQ ID NO: 1.
However, instant SEQ ID NO: 1 was a known DNA polymerase I (BF) from the thermophilic bacterium Bacillus stearothermophilus, as evidenced by Mazur et al. and therefore it would have been obvious to utilize this sequence.
Mazur et al. teaches a 580 amino acid sequence comprising instant SEQ ID NO: 1 at positions 2-580 and teach that the sequence is a nucleic acid polymerase for incorporating labeled nucleotides (see SEQ ID NO: 1 of Mazur et al.) (instant claims 1, 4, 6, 53, and 73).
Mazur et al. teaches incorporation of a mutation at F710Y into the nucleic acid polymerase [0007](instant claims 1 and 5).
Mazur et al. teach incorporation of dNTPs for DNA synthesis [0081].
Mazur et al. teach: [0015] Further described herein is a nucleic acid molecule encoding the any one of the above polymerases. Also described is an expression vector comprising said nucleic acid molecule. Further described is host cell, comprising said expression vector. Also described is method of making a polymerase, comprising culturing said host cell; expressing, using the host cell, the polymerase; and isolating the polymerase (instant claims 7 and 8).
Mazur et al. teach that the polymerase is from Bacillus stearothermophilus [0115].
Mazur et al. teach: [0018] In some embodiments, the disclosure relates to kits comprising one or more of the modified polymerases (instant claim 73).
Mazur et al. teach: [0048] In some instances, the methods described herein comprise: forming a reaction mixture comprising: (i) a template oligonucleotide sequence comprising a primer binding site, one or more nucleotide residues (e.g., a sequence segment comprising a single nucleotide residue, or two or more nucleotide residues) comprising the same base, and a first member of a fluorescence probe pair; (ii) a primer sequence configured to hybridize to the primer binding site; (iii) a first nucleotide set where a member of the first nucleotide set comprises a second member of the fluorescence probe pair, and where the first nucleotide set comprises one or more nucleotides that are not complementary to the one or more nucleotide residues; (iv) a second nucleotide set comprising one or more nucleotides that are complementary to the one or more nucleotide residues; and (v) a polymerase; and detecting a presence or absence of a fluorescence resonance energy transfer (FRET) signal, where a change in the FRET signal indicates that the polymerase has incorporated nucleotides of the first nucleotide set or has incorporated nucleotides of the second nucleotide set to extend the primer sequence through the one or more nucleotide residues (instant claim 1).
Mazur et al. teach: [0016] Also described is a method, comprising providing in a reaction mixture (i) a nucleic acid molecule, (ii) a labeled nucleotide, and (iii) the mutant polymerase according to any of the above, under conditions sufficient to extend the nucleic acid molecule with the labeled nucleotide. In some implementations, said labeled nucleotide comprises a fluorescent dye.
Mazur et al. teach: [0017] Further described is a method, comprising contacting a labeled nucleotide with the mutant polymerase of any of the above and extending a nucleic acid molecule to incorporate the labeled nucleotide. In some implementations, said labeled nucleotide comprises a fluorescent dye.
It is clear from the teachings of Lelyveld et al. that the instant claims are combinations of known design elements for methods of producing oligonucleotides. Although Lelyveld et al. do not teach polynucleotides comprising thiophosphoramidate-linked nucleotides, it would have been an obvious selection because both phosphoramidates and thiophosphoramidates were known to increase stability of oligonucleotides, as taught by Smith et al. (instant claims 53, 62, and 73). One would reasonably expect for either type of phosphoramidate to render the benefits.
It would have been obvious to include spermidine, which is not taught by Lelyveld, because Springer teaches that that spermidine is a ribonuclease inhibitor (instant claims 40 and 41). Therefore, one would have been motivated to incorporate spermidine with the expectation of ribonuclease inhibition in the cell.
Lelyveld et al. does not teach incorporation of 5’(α-P-thio)triphosphate (instant claim 53) or metal chelating agents (instant claims 37 and 38). However, it would have been obvious to incorporate each into the method of Lelyveld et al. because Almogy et al. teach incorporation of thio moieties including alpha thio triphosphates for increased stability and teach incorporation of metal chelators including citrate or isocitrate to modulate the level of free magnesium or manganese, which may in turn effect the rate of reaction [00202].
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, 4-9, 11, 13, 16, 18-23, 25, 26, 28-31, 34-38, 40-44, 53, 62, and 73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,428,658 B2, in view of Filler et al. (US 2020/0197351 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claim sets are directed to methods of producing oligonucleotides via the same method steps, the only difference being US ‘658 B2 claim 1 requiring a divalent metal ion cofactor and the instant claim 1 requiring a trivalent metal cofactor, which is an obvious substitution in view of Filler et al.
Filler et al. teach: [0066] By introducing a trivalent such as scandium (Sc3+), or a higher affinity divalent cation, where no significant toxicity results, it becomes possible to optimize and improve fidelity and processivity of nucleic acid polymerase and reverse transcriptase enzymes (instant claim 16).
It would have been obvious for the metal ion cofactor to be trivalent because the benefits were known, as taught by Filler et al. It would have been obvious to combine divalent and trivalent cations as a matter of design choice in view of the benefits known for each, as evidenced by Filler et al.
Filler et al. teach: TRIVALENT AND DIVALENT CATIONS AS ADMINISTRABLE AGENTS FOR INCREASED PROCESSIVITY AND IMPROVED FIDELITY OF REVERSE TRANSCRIPTASE IN TELOMERASE AND IN NUCLEIC ACID POLYMERASES (title).
Additionally, the instantly recited products are obvious in view of the method of making the product. The claim sets recite the same sequences and divalent metal cofactors, as well as reaction conditions. The claims are obvious variations of each other.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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