DETAILED ACTION
Notice of Pre-AIA or AIA Status
Claims 49-63 are pending and examined herein.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 49-63 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.
Claims 49, 53, and 56 recite the limitation "the primer" in step ii), a). There is insufficient antecedent basis for this limitation in the claim.
Claim 55 recites the limitation "step iv)" in (III). There is insufficient antecedent basis for this limitation in the claim.
Claim 55 is also indefinite because it is unclear which of the limitations of (III) are required. Specifically, it is unclear which preceding limitations are being placed in the alternative by the recitation of “and/or” following the first paragraph of (III). Additionally, the indented list under (III) begins with (b), not (a).
Claim 59 recites the limitation "the first nucleic acid" in step 3). There is insufficient antecedent basis for this limitation in the claim.
Claim 61 provides for the use of a nucleic acid polymerase, however, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced. See MPEP 2173.05(q)
Claim 63 recites the limitation "the polypeptide molecule" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claims 50-52, 54, 57-58, 60, and 62 are similarly rejected as they are dependent on an indefinite claim.
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.
Claim 61 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966). See MPEP 2173.05(q).
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.
Reed et al.
Claim 59 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Reed et al. (PG Pub No: US 2010/0009871). Reed discloses a method of preparing clusters of substrate-bound nucleic acids (p. 5-7; p. 16-19) comprising:
providing a template nucleic acid (p. 4, ¶[0051]; p. 16, ¶[0172]: template DNA);
hybridizing the template to a primer immobilized to a substrate (p. 5, ¶[0060]; p. 16, ¶[0174]: template hybridization);
contacting the hybridized template with a polymerase under conditions suitable for the extension of the immobilized primer to synthesize a nucleic acid complementary to the template (p. 6, ¶[0073]; p. 18, ¶[0205]; p. 19, Table 5: Bst polymerase); and
performing bridge amplification (p. 6, ¶[0071]) to generate clusters wherein there are 35 cycles (p. 17, Table 1, Step 2), an extension time of 72 seconds per cycle (p. 17, Table 1, Step 2: Amplification mix with Bst polymerase), comprises the use of an amplification buffer with an MgSO4 concentration of 2 mM (p. 19, Table 5, Amplification pre-mix), and comprises the use of 95-99.9% formamide as a denaturation buffer (p. 7, ¶[0076]: “95% formamide in water, or 100% formamide is used”; p. 18, ¶[0205]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Svensen et al. and Cozens et al.
Claims 49-51, 54-55, 57-58, 60, and 62-63 are rejected under 35 U.S.C. 103 as being unpatentable over Svensen et al. (ChemBioChem (2016), 17: 1628-1635; cited in IDS of 6/24/2024) in view of Cozens et al. (PNAS (2012), 109(21): 8067-8072; cited in IDS of 6/24/2024).
Regarding claim 49, Svensen discloses a method of displaying a non-DNA nucleic acid on a substrate (Scheme 1), comprising:
providing a DNA immobilized on a substrate (p. 1629, “Synthesis of complementary RNA…”, 3rd ¶: “cDNA clusters”), which is attached by the 5’ end (p. 1628, “Strategy for synthesis…”: “a DNA cluster is formed with all DNA bound at the 5’-end”);
generating cRNA by
contacting the DNA with a polymerase under conditions suitable for polymerization (p. 1629, “Synthesis…”, 3rd ¶: “transcription was performed by…”), wherein the primer is immobilized on the substrate such that a bridge forms and the RNA is immobilized on the substrate via the primer (Scheme 1), and
cleaving the DNA and linearizing the bridge (Scheme 1); and
removing the DNA to result in display of the cRNA (Scheme 1).
Svensen does not disclose that the primer for polymerization is a DNA primer, but rather a DNA-RNA hybrid primer (Figure 1A). Svensen teaches that the disclosed polymerase (3Dpol) strongly prefers an RNA primer, leading to the use of a DNA-RNA hybrid primer (p. 1629, “Synthesis…”, 1st ¶). Svensen also suggests that 3Dpol might be replaced with engineered RNA polymerases, directly citing Cozens (p. 1633, Conclusion, 2nd ¶). Based on the disclosure of Svensen, one of ordinary skill in the art would understand that the primer for polymerization is based on the chosen RNA polymerase, and that Cozens discloses engineered RNA polymerases that may be useful in this method.
Cozens discloses an engineered primer-dependent RNA polymerase (TGK) that is able to efficiently synthesize RNA from DNA using a variety of nucleic acid primers, including DNA primers (abstract; p. 8071, col. 2, 2nd full ¶). Cozens also teaches that the TGK polymerase also “has clear utility in biotechnology” (p. 8071, col. 2, 2nd full ¶).
Therefore, it would have been obvious to one of ordinary skill in the art to use the TGK polymerase disclosed by Cozens in place of 3Dpol used by Svensen, based on the suggestion of Svensen. In doing so, the ability of TGK to synthesize RNA from a DNA primer would obviate the need for modifying the flow-cell DNA primers, leading to the instantly claimed invention. Additionally, one of ordinary skill would also have a reasonable expectation of success as the TGK polymerase is disclosed as a primer-dependent RNA polymerase, as necessary for covalent product attachment in the method of Svensen (p. 1629, 1st ¶).
Regarding claims 50 and 51, the second nucleic acid is an RNA molecule. Additionally, Cozens discloses that the nucleic acid polymerase is TGK, which comprises an amino acid sequence more than 36% identical the amino acid sequence of SEQ ID NO: 1 (= TgoT), where the polymerase has Y409G and E664K mutations (Fig. 1A: TGK).
Regarding claim 54, Svensen discloses that the bridge is denatured by incubation with DNase I at 37°C, which is a temperature at which DNase I is active. Therefore, the bridge of Svensen is denatured due to the temperature.
Regarding claims 55, 57, 58,, Svensen further discloses that the second nucleic acid molecule encodes a peptide and that the method further comprises contacting the second nucleic acid with a ribosome under conditions suitable for translation (Scheme 2), wherein the ribosome-polypeptide complex is stabilized by a ribosome display buffer (p. 1634, “Translation of mRNA clusters…”: “in vitro translation kit”).
Regarding claim 60, Svensen discloses a substrate displaying an RNA molecule obtained by the method of 49, and a polypeptide molecule obtained by the method of 55.
Regarding claims 62 and 63, Svensen further discloses a method of screening a substrate with a library of biomolecules, comprising measuring affinity for a target molecule (p. 1631, “Measurement of protein and fluorophore..”, 2nd ¶: DFHBI).
Svensen et al., Cozens et al., Milligan et al., and Gilbert et al.
Claims 52 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Svensen et al. in view of Cozens et al. and further in view of Milligan et al. (Biochemistry (2018) 57(31): 4607-4619), as evidenced by Gilbert et al. (Curr. Opin. Genet. Dev. (2014) 25(100): 15-21). The limitations of claim 49 are rendered obvious by the disclosures of Svensen and Cozens as discussed previously. Claims 52 and 53 further limit the invention by stating that the nucleic acid is contacted with the polymerase again after cleaving the template strand and linearizing the bridge. Neither Svensen nor Cozens disclose re-contacting the template with the polymerase. However, Cozens does disclose that the TGK polymerase is less processive when synthesizing RNA, with a premature termination probability approaching 50% (Fig. S7; p. 8070, col. 2, lines 2-5). Therefore, one of ordinary skill in the art would likely expect to have to optimize the transcription step in order to achieve synthesis of full-length RNA.
Milligan teaches that certain DNA polymerases can achieve higher processivity on nicked (relaxed) template DNA than supercoiled template DNA (Fig. 6). Furthermore, it is well-known in the art that nucleic acid synthesis imparts torsional strain on a topologically constrained template strand (see Gilbert: p. 15, Introduction, 2nd ¶). As the immobilized ends of the bridge topologically restrain the nucleic acid, addition of twist by synthesis of a second strand would increase the overall torsion. As Milligan demonstrates that torsion can prevent DNA polymerase extension, one of ordinary skill in the art would be able to apply the teachings of Milligan to increase processivity of TGK by nicking the template strand and re-contacting the template with the polymerase. Additionally, there would be a reasonable expectation of success because the integrity of the template strand is unnecessary for the downstream steps as it is subsequently removed or degraded, and many methods of site-specific nicking are known in the art. Therefore, it would have been obvious to one of ordinary skill in the art to incorporate the teachings of Mulligan into the method of Svensen and Cozens, based on the motivations provided by Cozens and Mulligan, with a reasonable expectation of success.
Svensen et al., Cozens et al., Moriizumi et al., and Nagumo et al.
Claim 56 is rejected under 35 U.S.C. 103 as being unpatentable over Svensen et al. in view of Cozens et al. and further in view of Moriizumi et al. (ACS Synth. Biol. (2019), 8: 557-567; cited in IDS of 6/24/2024) and Nagumo et al. (J. Biochem (2016), 159(5): 519-526). Svensen and Cozens disclose all limitations recited in claims 49 and 55, as discussed previously. However, neither Svensen nor Cozens disclose that the first nucleic acid comprises an antisense sequence encoding a scFv, nor that the conditions for translation comprise TMAO. Svensen does disclose that the first nucleic acid comprises an antisense sequence encoding a protein (Scheme 2; p. 1631, Translation on the Illumina surface…, 1st ¶: cDNA) and also teaches that the method is intended to be adapted for the display of different libraries of proteins (p. 1633, Conclusion, 4th ¶).
Nagumo discloses a method for mRNA display of scFv antibodies (Fig. 1) for the development of antibodies with improved affinity and stability (p. 519, col. 2, 1st ¶). Furthermore, Svensen teaches that the method of peptide display is advantageous because it can spatially link the sequences of DNA clusters to the displayed protein, and that it is a convenient method because it is incorporated into a commercially available platform (p. 1628, Introduction, 3rd ¶). Therefore, it would have been obvious to one of ordinary skill in the art by the effective filing date to apply the scFv display of Nagumo to the peptide display method of Svensen and Cozens, based on the motivation provided by Svensen. Additionally, one of ordinary skill would have a reasonable expectation of success because of the overlap in methodology between Nagumo and Svensen, particularly in the use of cell-free translation and mRNA-protein conjugation via puromycin incorporation.
Moriizumi teaches that the presence of TMAO enhances translation of proteins during cell-free protein synthesis (abstract). Therefore, it would have been obvious to one of ordinary skill in the art by the effective filing date to add TMAO into the in vitro translation conditions of Svensen, based on the motivation to enhance protein synthesis. Additionally, there would have been a reasonable expectation of success as both Moriizumi and Svensen disclose the use of reconstituted translation systems (PURE), and Moriizumi demonstrates the positive effect of TMAO on the synthesis of several different proteins.
Conclusion
No claims are allowed.
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/ALEXANDRA OLSON/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
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