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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/14/2025 has been entered. Claims 1-7, 9, 11, 14-15, 21, 28-34, 37, 40, and 47 are pending and being considered on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. For example, see page 16, paragraph [0065] of the Specification (Sambrook et al. and Ausubel et al.). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 15 is objected to because of the following informalities: claim 15 currently reads “wherein the additional amplification buffers do not comprise any DNA polymerase and comprises the divalent metal cation” and should instead read “wherein the additional amplification buffers do not comprise any DNA polymerase and comprise[[s]] the divalent metal cation”. Appropriate correction is required.
Withdrawn Claim Rejections
35 USC § 112a – Written Description: The rejection of claim 14 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendment to the claim.
35 USC § 103: The rejections of claims 1, 3-7, 9, 11, 15, 21, 28-34 and 46 under 35 U.S.C. 103 as being unpatentable over Porter et al. (US Patent 10,501,782), in view of Godwin et al. (US Pub No. US 2013/0217023 A1);
claim 2 over Porter et al. (US Patent 10,501,782), in view of Godwin et al. (US Pub No. US 2013/0217023 A1) as applied to claims 1, 3-7, 9, 11, 15, 21, and 28-34 above, and further in view of Cao et al. (Sensors and Actuators B: Chemical, Jan. 2019; EPub Oct. 2018);
claim 37 over Porter et al. (US Patent 10,501,782), in view of Godwin et al. (US Pub No. US 2013/0217023 A1) and Cao et al. (Sensors and Actuators B: Chemical, Jan. 2019; EPub Oct. 2018) as applied to claim 2 above, and further in view of Vijayan et al. (US Patent 10,077,470); and
claim 40 over Porter et al. (US Patent 10,501,782), in view of Godwin et al. (US Pub No. US 2013/0217023 A1) as applied to claims 1, 3-7, 9, 11, 15, 21, and 28-34 above, and further in view of Ahern (1995).
are withdrawn in light of Applicant’s amendments to the claims. New rejections are presented below, necessitated by the amendments.
New Claim Rejections
35 USC § 112b – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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.
Claim 37 is 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 37 recites the limitation "the polymerase-nucleic acid complexes" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
35 USC § 112a – Written Description
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 31-33 and 47 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.
The claims are rejected for describing specific concentration ranges of a branched polyelectrolyte species without providing structural detail as to the nature of said species (polycationic, polyanionic, dendrimer, etc.). The specification details examples in which a specific polycationic PAMAM dendrimer species is used in the claimed amounts, but does not provide evidence for any other type of dendrimer species (paragraph [0050] states that the dendrimers used herein comprise positively charged terminal groups and therefore are polycationic; paragraphs [0125-0134]). The art has shown that, for example, polycationic versus polyanionic dendrimer species promote amplification efficiency at very different concentrations (Cao et al., 2009: “the enhancing effect of polyanionic dendrimers is weaker than that of polycationic dendrimers, and the optimum concentration of polyanionic dendrimers in optimizing PCR is required to be much higher”, Analysis of the possible mechanism). Therefore, it is art recognized that the structure/composition of the branched polyelectrolyte species will determine the amounts/concentrations that will be effective in promoting amplification efficiency.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. The courts have stated:
"To fulfill the written description requirement, a patent specification must describe an
invention and do so in sufficient detail that one skilled in the art can clearly conclude that
"the inventor invented the claimed invention.” Lockwood y. American Airlines, Inc., 107
F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008,
1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966." Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, 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; Jn 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 description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See Jn re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.") Accordingly, it is deemed that the specification, while providing for the structure/species of polycationic PAMAM dendrimer species, fails to provide adequate written description for the genus of the claims (any branched polyelectrolyte species) and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103
Claims 1, 3-7, 9, 11, 15, 21, 28-30, and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Porter et al. (US Patent 10,501,782; cited on PTO-892 of 1/15/2025), in view of Godwin et al. (US Pub No. US 2013/0217023 A1; cited on PTO-892 of 1/15/2025) and Cao et al. 2009 (Analyst, 2009).
Porter et al. teach a method of nucleotide amplification which involves the supplementation of the reaction with further solutions containing metal ions at varying timepoints post-amplification initiation.
Regarding claims 1, 3, 4, 11, 15, 21, and 28-30: Porter et al. teach that “a preferred strand displacement replication process is rolling circle amplification (RCA)” (col 11, ln 60-61) in which a primer which “may be specific for one or more sequences comprised within the DNA template" (relevant to claim 1, this reads on capture primer; col 12, ln 16-20) is contacted with a circular, single-stranded DNA template (relevant to claims 1 and 3; col 4, ln 35-45) within a “reaction vessel” (relevant to claim 1; claim 18, col 40, ln 12). The initial “reaction mixture” comprises a “combination of DNA template, polymerase and nucleotides” (col 13, ln 10-11; relevant to claim 1, reaction mixture reads on RCA mixture and loading buffer, polymerase reads on DNA polymerase and nucleotides read on a dNTP mix) as well as "divalent metal ions, such as…magnesium” (relevant to claims 1 and 4; col 13, ln 23-24; divalent metal ions read on divalent metal cation in claim 1). The initiation of the reaction results in the formation of “concatemers comprising tandem units of DNA sequence amplified from the DNA template" (col 4, ln 40-42; relevant to claim 1, this reads on amplified concatemers of the DNA template). Regarding claim 34, the formation of amplified concatemers indicates that the formation of DNA polymerase-nucleic acid complexes occurs, given that this necessarily happens for concatemers to be generated. Following the initiation of the reaction, after a certain duration, "further…metal cations are supplied in a controlled manner to the reaction mixtures" (with no mention of adding additional DNA polymerase, col 3, ln 61-63; relevant to claim 1, further…supplied reads on after the first duration) within an “aliquot” (col 22, ln 14-16; relevant to claims 1, 21, and 28-30, the aliquot in which the further cations are supplied reads on amplification buffer).
Porter et al. go on to teach that "further metal ions may be supplied at regular intervals throughout the duration of the process, optionally at least every 30 min" (relevant to claim 11; col 4, ln 62-64 and claim 12, col 39, ln 55-58) and that there may be “a plurality of aliquots [added] to the reaction mixture" (relevant to claim 15; col 4, ln 60-66). Porter et al. further teach that "the volume and/or concentration of metal cations in the aliquot can vary" (relevant to claim 21; col 22, ln 23-25). Porter et al. exemplify in Example 4 (col 37, Table 7) that the aliquots of Mg2+ added to the reaction mixture results in a final concentration of 18mM Mg2+, compared to a starting concentration of 9mM (relevant to claims 1, 28, and 29, 18mM final concentration reads on the divalent metal cation in the amplification buffer is in a concentration of at least 10mM and 9mM starting concentration reads on at least 2-fold higher than in the loading buffer and both together reads on wherein the divalent metal cation…in the amplification buffer is in a concentration higher than in the loading buffer; Example 4, Table 7, col 37). In addition, Porter et al. indicate that the starting concentration of their reaction mixture (which reads on loading buffer in claims 1 and 30) is anywhere from 2.24mM to 11.24mM (relevant to claim 30, this reads on from about 0.001mM to about 10mM; col 37, ln 13-27).
Porter et al. do not explicitly teach the retention of DNA polymerases following the addition of the “further…metal cations” (relevant to claim 34). However, because Porter et al. do not teach that any buffer is “washed out” or removed during or after buffer addition, all DNA polymerases present in the initial reaction are necessarily retained within the solution. It would be obvious to attempt to retain as much bound DNA polymerase (at least about 50%) as possible in order to keep the amplification process going without having to allow time for free/dissociated polymerase to bind/rebind.
Porter et al. teach that stabilizing and condensing agents can be included in the reaction mixture, including cationic polymers (col 16, ln 5-15). Porter et al. do not explicitly teach the inclusion of a branched polyelectrolyte species in either the initial loading buffer or RCA mixture (“reaction mixture”) or in the subsequent aliquots of solution that are added to the RCA reaction after the first duration (relevant to claims 1, 5-7, 9, 15, and 33).
Godwin et al. teach the use of a dendrimer species to compact amplified concatemer molecules produced through methods such as rolling circle amplification. Specifically, Godwin et al. teaches that dendrimers may be “added before or during the amplification process to induce folding and secondary structure formation as the concatemer grows with each amplified copy” (paragraph [0108], ln 7-10; relevant to claims 1 and 15, before reads on the first duration or step(a) and during reads on after the first duration or step(b); dendrimer reads on branched polyelectrolyte). Godwin et al. describe "one example of a class of branched polyelectrolytes [which] includes what are generally referred to as "dendrimers"” (relevant to claim 5; paragraph [0105], ln 1-2 and claim 3). In addition, Godwin et al. indicate that the branched polyelectrolyte is ideally a "branched polyamine that comprises a protonated structure" (relevant to claim 6, protonated structure reads on polycation; paragraph [0106], ln 2-3 and claim 2) and that the "poly(amidoamine) dendrimer species (also referred to as PAMAM) is one of the most well-known dendrimer species" (relevant to claim 7; paragraph [0106], ln 9-11; claim 4). Furthermore, these "species of dendrimer are available as Generation 0 (G0) up to Generation 10 (G10)" (relevant to claim 9, G0-G10 reads on G3; paragraph [0105], ln 7-9). Godwin et al. teach that the addition of dendrimers is an effective strategy for compacting amplified DNA through promotion of secondary structure formation. This compaction prevents dissolution of the concatemers and promotes their preservation for use in downstream processes, such as sequencing (see Godwin et al., paragraph [0108]). Godwin et al. specifically exemplify adding 0.1uM of G5 dendrimers to an RCA reaction (Figure 5 and paragraph [0140]). Godwin et al. teach that “dendrimers have an inhibitory effect on compaction during the RCA reaction at higher concentrations (>1uM)" suggesting that the loading buffer should contain less than 1uM (relevant to claim 33, together these read on a concentration from about 0.001uM to about 1uM; paragraph [0140], ln 5-8).
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to have modified the method described by Porter et al. to include a branched polyelectrolyte species in the loading buffer (as taught by Godwin et al.) and also in the amplification buffer added after the first duration of amplification (as suggested by Porter et al.). One would have been motivated to make such a modification in order to both prolong the amplification reaction through resupply of divalent metal cations (as taught by Porter et al.) and additionally promote stabilization of the concatemers during formation (as taught by Godwin et al.). Additionally, it is known in the art, as taught by Cao et al., that addition of PAMAM dendrimers to an amplification reaction increases both the specificity and the efficiency of amplification (Abstract). Porter et al. teach increasing the concentration of divalent metal cations with further buffer additions during amplification, and that additional elements may be added in the aliquots, such as condensing agents or stabilizing agents (col 22, ln 23-25; Example 4, Table 7, col 37; and col 16, ln 5-15). Cao et al. 2009 teach that increasing the concentration of PAMAM dendrimers in an amplification reaction increases the sensitivity and efficiency, therefore, it would be obvious to 1. Include PAMAM dendrimers in the reaction and 2. To increase the concentration of the dendrimers to promote increased efficiency and sensitivity (as taught by Cao et al. 2009). Improved and prolonged synthesis is recognized as desirable as this increases yield of DNA and additionally stabilizes the amplified DNA product for use in downstream processes such as sequencing (as taught by Godwin et al.). One would have had a reasonable expectation of successfully modifying the methodology of Porter et al. by including the branched polyelectrolyte as taught by Godwin et al. and Cao et al. 2009 in the further supplied aliquots which contained divalent metal cations (which read on amplification buffer), as both divalent metal cations and branched polyelectrolytes are known elements in the prior art and their combination would yield predictable results. Furthermore, Cao et al. 2009 demonstrate successful use of PAMAM dendrimers in amplification reactions.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Porter et al. (US Patent 10,501,782; cited on PTO-892 of 1/15/2025), in view of Godwin et al. (US Pub No. US 2013/0217023 A1; cited on PTO-892 of 1/15/2025) and Cao et al. 2009 (Analyst, 2009) as applied to claims 1, 3-7, 9, 11, 15, 21, 28-30, and 33-34 above, and further in view of Cao et al. 2019 (Sensors and Actuators B: Chemical, Jan. 2019; EPub Oct. 2018; cited on PTO-892 of 1/15/2025).
Porter et al. teach rolling circle amplification within a reaction vessel, but do not teach the use of a flow cell specifically (relevant to claim 2). Godwin et al. teach the use of a "flow cell" (relevant to claim 2; paragraph [0082], ln 8-9) for sequencing-by-synthesis reactions in which the products are produced by RCA, but do not teach performing RCA within the flow cell prior to this sequencing reaction. However, performing RCA within a flow cell was a technique known in the art at the time the instant application was filed, as taught by Cao et al. 2019.
Cao et al. 2019 describe performing RCA within a microfluidic environment for the amplification of miRNA. The microfluidic device reads on flow cell. RCA is performed within a microfluidic chamber off of an immobilized capture probe attached to the bottom of the microfluidic chamber (see Cao et al. 2019, Figure 1).
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to modify the method rendered obvious by Porter et al. in view of Godwin et al. to perform the RCA reaction within the flow cell itself, as taught by Cao et al. 2019. One would have been motivated to make such a modification in order to streamline the analytical pipeline to increase speed and reproducibility as well as decrease sample handling to reduce degradation or contamination of the sample (as taught by Cao et al. 2019). One would have a reasonable expectation of success, as the RCA reaction occurred with high efficiency in the experiments carried out by Cao et al. 2019 within the microfluidic device.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Porter et al. (US Patent 10,501,782; cited on PTO-892 of 1/15/2025), in view of Godwin et al. (US Pub No. US 2013/0217023 A1; cited on PTO-892 of 1/15/2025), Cao et al. 2009 (Analyst, 2009), and Cao et al. 2019 (Sensors and Actuators B: Chemical, Jan. 2019; EPub Oct. 2018; cited on PTO-892 of 1/15/2025) as applied to claim 2 above, and further in view of Vijayan et al. (US Patent 10,077,470; cited on PTO-892 of 1/15/2025).
Porter et al. in view of Godwin et al., Cao et al. 2009, and Cao et al. 2019 teach amplification of DNA via RCA within a flow cell, with the addition of buffers after amplification initiation containing additional divalent metal cations and branched polyelectrolytes, as described above.
Porter et al. in view of Godwin et al., Cao et al. 2009, and Cao et al. 2019 do not teach that introduction of additional buffers into the flow cell removes DNA polymerase that is not in the polymerase-nucleic acid complexes from the vessel. However, removal of unbound/unreacted reagents from a flow cell through reagent cycling was known in the art at the time the instant application was filed, as taught by Vijayan et al.
Vijayan et al. teach a method for sequencing within a flow cell that involves introduction of wash buffers (or reagent cycling) wherein “the wash step removes any non-bound reagents, e.g., unbound polymerases and/or nucleotides” (col 18, ln 58-60). Vijayan et al. teach washing steps that specifically remove “all excess polymerases and nucleotides not involved in a closed-complex” (relevant to claim 37, closed-complex reads on polymerase-nucleic acid complexes; col 50, ln 43-45).
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to modify the method rendered obvious by Porter et al. in view of Godwin et al., Cao et al. 2009, and Cao et al. 2019 to involve retention of DNA polymerases on nucleic acid templates upon addition of further buffers, as taught by Vijayan et al. When using a flow cell for RCA (as taught by Cao et al. 2019) or for sequencing reactions (as taught by Vijayan et al.), reaction buffers are necessarily removed following further addition of buffers given the inherent design of a flow cell. To input liquid into a flow cell environment, an outlet must be open. This will necessarily result in the removal of unbound or unreacted products from the reaction environment within the flow cell. The retention of bound DNA polymerases and removal of unbound DNA polymerases is rendered obvious in light of the inherent design of a flow cell and the teachings of both Cao et al. 2019 and Vijayan et al.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Porter et al. (US Patent 10,501,782; cited on PTO-892 of 1/15/2025), in view of Godwin et al. (US Pub No. US 2013/0217023 A1; cited on PTO-892 of 1/15/2025) and Cao et al. 2009 (Analyst, 2009) as applied to claims 1, 3-7, 9, 11, 15, 21, 28-30, and 33-34 above, and further in view of Ahern (1995; cited on PTO-892 of 1/15/2025).
Porter et al. teach a collection of regents for the amplification of DNA via methods such as rolling circle amplification. The reagents of Porter et al. include divalent metal cations and a DNA polymerase for initiation of the reaction (relevant to lines 2 and 3 of claim 40, first buffer). Porter et al. goes on to teach further aliquots that can be added to this reagent to extend and amplify the amplification reaction that includes divalent metal cations and no DNA polymerase (relevant to lines 4 and 5 of claim 40, second buffer). Godwin et al. teach the inclusion of branched polyelectrolytes in buffers that can be added before or during the amplification reaction (relevant to lines 2-5 of claim 40). Cao et al. 2009 teach the inclusion of PAMAM dendrimers in an amplification reaction to increase reaction specificity and efficiency (Abstract). Porter et al. teach increasing the concentration of divalent metal cations with further buffer additions during amplification, and that additional elements may be added in the aliquots, such as condensing agents or stabilizing agents (col 22, ln 23-25; Example 4, Table 7, col 37; and col 16, ln 5-15). Cao et al. 2009 teach that increasing the concentration of PAMAM dendrimers in an amplification reaction increases the sensitivity and efficiency, therefore, it would be obvious to 1. Include PAMAM dendrimers in the reaction and 2. To increase the concentration of the dendrimers to promote increased efficiency and sensitivity (as taught by Cao et al. 2009). Improved and prolonged synthesis is recognized as desirable as this increases yield of DNA and additionally stabilizes the amplified DNA product for use in downstream processes such as sequencing (as taught by Godwin et al.).
Porter et al. in view of Godwin et al. and Cao et al. 2009 do not teach the inclusion of the collection of reagents in a kit, as recited in the preamble of claim 40. However, the inclusion of reagents used for related purposes in kits was well known in the art at the time the invention was made and is taught by Ahern.
Ahern teaches aspects of kits of reagents. Ahern teaches that a kit supplies all of the necessary reagents for a particular application (page 20 - The kit concept, Saving time and money).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have packaged reagents of Porter et al. in view of Godwin et al. and Cao et al. 2009 in a kit as taught by Ahern.
Response to Remarks
Applicants have traversed the rejection of claims 1-7, 9, 11, 15, 21, 28-34, 37, 40, and 46 under 35 USC 103 (pages 7-13 of the Remarks of 11/14/2025).
RE: Rejection of claims 1, 3-7, 9, 11, 15, 21, 28-34, and 46 over Porter et al. in view of Godwin et al. and rejection of claim 40 in view of Porter et al. in view of Godwin et al. and further in view of Ahern.
Applicant’s arguments in regards to the rejection of claims 1, 3-7, 9, 11, 15, 21, and 28-34 over Porter et al. in view of Godwin et al. and rejection of claim 40 in view of Porter et al. in view of Godwin et al. and further in view of Ahern are moot given the withdrawal of said rejections in light of Applicant’s amendments to the claims and cancellation of claim 46. New rejections have been made in light of these amendments, as detailed above.
However, Applicant’s arguments regarding Porter et al. and Godwin et al. (pages 7-12 of Remarks) will be addressed. Applicant points out in the Examiner’s arguments in the previous Office Action that the teaching of Godwin using dendrimers in a concentration of 5mM MgCl2 is in the context of using already amplified concatemer molecules (pg 7 of Remarks). While this is true, Godwin still exemplifies performance of RCA in the presence of dendrimers (Figure 5 and paragraph [0140]), even if they do not specify what the Mg2+ concentration is. Godwin teaches that Mg2+ that are too “high” would inhibit the action of dendrimers, but goes on to teach that those skilled in the art would recognize which conditions would work for their specific purposes (paragraph [0109]). Godwin does not indicate what Mg2+ composition would be inhibitory, as “high” could vary greatly depending on the reaction components and other variables.
Applicant argues that Porter does not provide any indication suggesting that polymerase is not preferred in the replenishing buffer (pg 8 of Remarks). However, Porter specifically exemplifies adding replenishment buffers with additional divalent metal cations but no additional polymerase (Example 4, Table 7, col 37). Porter merely cites, as underlined in Applicant’s argument, that “as an example, the amount of polymerase present in the reaction mixture may be optimized” (pg 8 of Remarks). This is a single embodiment, which does not teach away from adding aliquots without further polymerase. Applicant asserts that “the common practice in RCA reaction would require polymerase replenishment in order for the amplification reaction to continue for a prolonged time period”, but no references have been presented to support this claim.
Applicant argues that “per the Examiner’s own reading of Godwin, dendrimers have an inhibitory effect on compaction during the RCA reaction especially at higher concentration (>1uM), which clearly teaches against the feature “wherein the branched polyelectrolyte in the amplification buffer is in a concentration of at least 5uM” recited in claim 31” (pg 9-10 of Remarks). The rejection of claims 31 and 32 over Porter et al. in view of Godwin et al. has been withdrawn in light of this argument and applicant’s amendments to the claims.
Applicant argues that “there is not any teaching, disclosure, or suggestion indicating that Godwin increases the dendrimer concentration during the RCA reaction” and that “Godwin teaches away from using a high concentration of dendrimer during the RCA reaction because of its inhibitory effect on compaction”. Godwin does teach that more than 1uM of dendrimer can inhibit RCA, but as included in the new rejection of claim 1 above, Cao et al. 2009 teach that there are optimal working concentrations of dendrimer in an amplification reaction that can be empirically determined. Cao et al. 2009 teach that increasing amounts of dendrimer in a reaction increases the efficiency and specificity up to a point. Therefore, adding a “higher concentration” during RCA would be an obvious benefit to enhance efficiency without impeding the reaction.
RE: Rejection of claim 2 over Porter et al. in view of Godwin et al. and further in view of Cao et al. and rejection of claim 37 in view of Porter et al. in view of Godwin et al. and further in view of Vijayan et al. and claim 40 over Porter in view of Godwin and further in view of Ahern.
Applicant’s arguments in regards to the rejection of claims 2, 37, and 40 over Porter et al. in view of Godwin et al. and rejection of claim 40 in view of Porter et al. in view of Godwin et al. and further in view of Ahern are moot given the withdrawal of said rejections in light of Applicant’s amendments to the claims. New rejections have been made in light of these amendments, as detailed above.
Conclusion
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683