DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Applicant’s amendment filed 2/2/2026 is acknowledged. Claims 1-24, 35, 37 and 45 have been canceled. Claim 24 has been canceled. Claims 24-34, 36, 38-44, 46-47 are pending. All of the amendment and arguments have been thoroughly reviewed and considered.
Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims.
This action is made Final.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejections
The prior art rejections under 35 USC 103 directed to the clams 24-34, 36, 38-44 and 46-47 as being unpatentable over Rigatti in view of Rasolonjatovo and further in view of Datta et al is maintained and discussed below.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 24-34, 36, 38-44 and 46-47 are finally rejected under 35 U.S.C. 103 as being obvious over Rigatti (WO 2008/041002) in view of Rasolonjatovo (WO 2015/189621) in further view of Datta et al (2005) {citation previously made of record}.
Regarding claims 24, 46 and 47, Rigatti teaches a method of strand resynthesis between two sequencing reads (e.g., Rigatti page 9, line 17), where the extension reaction is carried out using a non-thermostable strand displacement polymerase, Klenow, (e.g., Rigatti Claim 12, Example 12, page 84; p.43 ln 23 – p.44 ln. 3 a) to extend immobilized primers to copy the first template strand to produce the second template strand (e.g., Page 5, part a+d), reading on the limitation of “a method for carrying out a strand resynthesis extension reaction during pairwise sequencing, comprising performing a strand resynthesis extension reaction between a first sequencing read and a second sequencing read, and wherein said strand resynthesis extension reaction extends one or more immobilized primers to copy a first template strand to generate a second immobilized template strand; characterized in that the strand resynthesis extension reaction is carried out using a non-thermostable strand displacement polymerase” of the instantly rejected claim 24. Rigatti teaches the templates are immobilized on a solid support, and form into an array or cluster of amplified molecules (e.g., Rigatti page 12 lines 5-8), reading on the limitation “template strands are immobilized in a cluster on a substrate”.
With regards to the limitation, “repeating the strand resynthesis extension reaction for 2 to 12 cycles of extension, Rigatti teaches resynthesis of clusters wherein the clusters were treated to 15 cycles of isothermal amplification as previously described in the example 5 (page 94, Example 12a). While the reference does not limit the resynthesis reaction between 2 to 12 cycles, MPEP states “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Likewise, MPEP further discuss “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, lowering the resynthesis cycling number and duration of the cycles merely recite a plethora of conventional nucleic acid manipulation reagents and methodologies, as well as well as routine optimization of reaction components, concentrations, and parameters. Thus, one of ordinary skill in the art would have been motivated to modify the primary reference(s) in the manner of the claims to achieve the expected benefits, optimizations and/or expanded applications. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to carry out the claimed methods.
With regards to the resynthesis reaction temperature, Rigatti does not teach the resynthesis reaction temperature of less than 55oC, nor the use of the same polymerase during initial cluster generation and strand resynthesis extension as recited in the claim 24 and 46. However, these were known in the art as taught by Rasolonjatovo.
Rasolonjatovo teaches a method for estimating cluster numbers prior to sequencing. Their method includes immobilized primers on a solid platform and includes isothermal techniques where the hybridization, extension and denaturation steps are carried out at the same or substantially the same temperature, from 37oC to about 75oC (e.g., Rasolonjatovo page 29, para 2) and using a non-thermostable strand displacement polymerase (e.g., phi29 or BST, Rasolonjatovo page 12, para 2), reading on the limitation “the strand resynthesis extension reaction is carried out using a non-thermostable strand displacement polymerase at a temperature of less than 55 C.” of the instantly rejected claim 24. Rasolonjatovo teaches the method wherein the same reagents and components are used throughout amplification processes (e.g., Rasolonjatovo page 28, para 3; page 3 para 3) reading on the limitation “wherein the same non-thermostable strand displacement polymerase is used during initial cluster generation and the strand resynthesis extension reaction” of the instantly rejected claim 24.
It would have been prima facie obvious before the effective filing date of the claimed invention for one having ordinary skill in the art to have performed the method of strand re-synthesis between two sequencing reads of Rigatti using the lower reaction temperature of the method of Rasolonjatovo. The skilled artisan would have been motivated to adapt the method of Rigatti with the temperature of Rasolonjatovo based on the teachings of Rasolonjatovo that the isothermal temperature should be tailored to the choice of enzymes (e.g., Rasolonjatovo page 29, para 2), such as non-thermostable polymerase, and given that Rigatti uses Klenow in their method, and that Datta et al (2005) found the optimal temperature for Klenow to be 25-30o C, it would be obvious to optimize to accommodate this trait. Thus, the use of the lower temperature of Rasolonjatovo with the re-synthesis method of Rigatti would have been the combination of prior art elements according to known methods to yield predictable results.
Regarding claim 25, Rigatti teaches the method wherein the non-thermostable polymerase (i.e., Klenow) has an optimum incubation temperature and/or optimum activity temperature below 55oC (e.g., Rigatti page 84; Datta et al., 2005, page 1741, right column, Results).
Regarding claim 26, Rasolonjatovo teaches the method wherein the extension reaction is carried out at a temperature of less than 40oC (i.e., 37 oC), depending on the choice of enzyme (e.g., Rasolonjatovo page 29, para 2), and Datta et al teaches that the optimal temperature for Klenow is less than 40oC).
Regarding claim 27, Rigatti teaches wherein the non-thermostable polymerase is Bsu, phi29, Klenow, DNA Polymerase I (E. coli), or a functional fragment thereof (Klenow, Rigatti page 84).
Regarding claim 28, Rigatti teaches the method wherein the strand resynthesis extension reaction is repeated through multiple cycles of extension and denaturation (e.g., Rigatti page 57, lines 3-8, FIG 4b, step 6, resynthesis of strand (15 cycles)).
Regarding claim 29, Rigatti teaches the method wherein the strand resynthesis extension reaction is repeated for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more cycles (e.g., Rigatti page 57, lines 3-8, FIG 4b, step 6, resynthesis of strand (15 cycles)).
Regarding claim 30, Rigatti teaches the method wherein each cycle has a duration for a period in a range from 1 minute to 30 minutes (e.g., Rigatti page 74, example 5 step 1, 90 seconds).
Regarding claim 31, Rigatti teaches the method wherein the cycles of extension and denaturation comprise: 3 cycles, wherein each cycle has a duration for a period of about 5 minutes; 3 cycles, wherein each cycle has a duration for a period of about 30 minutes; 12 cycles, wherein each cycle has a duration for a period of about 2 minutes; 6 cycles, wherein each cycle has a duration for a period of about 4 minutes; or 2 cycles, wherein each cycle has a duration for a period of about 12 minutes (e.g., Rigatti FIG 4b, step 6, resynthesis of strand (15 cycles); page 74, example 5 step 1, 90 seconds).
Regarding claim 32, Rigatti teaches the method wherein denaturation is carried out substantially at the temperature of the extension reaction (e.g., Rigatti page 57, lines 3-8, isothermal).
Regarding claim 33, Rigatti teaches the method wherein denaturation is carried out using a formamide (e.g., Rigatti page 24 lines 12-13; example 5, page 74).
Regarding claim 34, Rigatti teaches an isothermal method for strand re-synthesis in pair-wise sequencing (e.g., Rigatti page 9, line 17; page 5, part a+d; page 57 lines 3-8), where the sequencing primer hybridization takes place at 60oC (e.g., Rigatti page 95 lines 10-15). Rigatti does not teach an extension/denaturation temperature below 55oC, as is taught by Rasolonjatovo for their cluster generation and strand re-synthesis (e.g., Rasolonjatovo page 29, para 2). Since the sequencing primer annealing temperature is set by the platform or kit manufacturer, the temperature for this cycle may not be alterable, thus would remain above the Rasolonjatovo isothermal method.
Regarding claim 36, Rigatti teaches the method wherein said cluster was initially generated by bridge amplification (e.g., Rigatti page 12, line 25).
Regarding claim 38, Rasolonjatovo teaches the method wherein said first template strands are generated by an amplification reaction using the same polymerase as the polymerase used in the strand resynthesis extension reaction (e.g., Rasolonjatovo page 28, para 3; page 3 para 3).
Regarding claim 39, Rigatti teaches the method wherein at least one of the immobilized primers is blocked at the 3' end, and the block is removed prior to the strand resynthesis extension reaction (e.g., Rigatti page 75-77, methods a+b).
Regarding claim 40, Rigatti teaches the method wherein the block is a phosphate group and is treated with a phosphatase to remove the block (e.g., Rigatti claim 26).
Regarding claim 41, Rigatti teaches the method further comprising a step of treating with a restriction enzyme prior to the strand resynthesis extension reaction to shorten the immobilized primer and release a free 3' hydroxyl for extension (e.g., Rigatti page 28, para 1).
Regarding claim 42, Rigatti teaches the method wherein the immobilized primer is extended prior to the strand resynthesis extension reaction (e.g., Rigatti page 54, lines 19-22; page 74, line 2).
Regarding claim 43, Rigatti teaches the method wherein the immobilized primer is extended by hybridization of a non-immobilized complementary sequence with a 5'-overhang, and the immobilized primer is extended to copy the overhang (e.g., Rigatti claim 29).
Regarding claim 44, Rigatti, Rasolonjatovo and Datta et al teach the limitations of claim 24 as shown above. Rigatti further teaches sequencing a first and second region, both being on the same target polynucleotide (e.g., Rigatti page 2, Field of the invention).
Regarding claim 45, Rigatti, Rasolonjatovo and Datta et al teach the limitations of claim 24 as shown above. Rigatti further teaches improving the data quality of a sequencing run on an immobilized template by performing their resynthesis method (e.g., Rigatti page 9, lines 21-25). Rasolonjatovo teaches a method of sequencing where the hybridization, extension and denaturation steps are carried out at the same or substantially the same temperature, and at temperature of less than 40oC (i.e., 37 oC), depending on the choice of enzyme (e.g., Rasolonjatovo page 29, para 2) and using a non-thermostable strand displacement polymerase (e.g., phi29 or BST, Rasolonjatovo page 12, para 2).
Response to Remarks
Applicant’s traversal
5. Applicant traverses the rejection on the following ground:
(a) Applicant states no combination of Rigatti, Rasolonjatovo and Datta teaches all elements of the claimed method. In particular, Rigatti relates to a method of paired- end sequencing comprising a first sequencing read, a resynthesis step, and a second sequencing read, in which the resynthesis step is performed at 60 °C with Taq polymerase in which 15 cycles were necessary to obtain resynthesis. See e.g., Rigatti at Example 12a, page 94; Example 13, page 105. Thus, if anything, Rigatti teaches away from a method of using 2-12 cycles of a strand resynthesis extension reaction as recited in the amended claims.
(b) Applicant states in contrast to Rigatti, Rasolonjatovo and Datta, claim 24 relates to a method wherein a strand resynthesis extension reaction is performed with a non-thermostable strand displacement polymerase at a temperature of less than 55 degrees for 2012 cycles of extension and denaturation. Therefore, no combination of the Rigatti, Rasolonjatovo and Datta teach all elements of the claimed method.
(c) Applicant states that the Office action acknowledges that Rigatti does not disclose the claimed method in which 2 to 12 cycles performed and states that Rigatties teaches resynthesis of clusters by treatment with 15 cycles of isothermal amplification and does not limit the resynthesis reaction between 2 to 12 cycles. Applicant states that the Office action provides conclusory statement that modifying the number of cycles in the method of Rigatti would have been routine optimization. Applicant states that such a conclusory statement cannot support a rejection for alleged lack of non0obviousness. Applicant cites MPEP 214405.II.B.
(d) Applicant states that the Office action does not articulate any rationale or reasoning as to why one of ordinary skill in the art would have modified the method of Rigatti to have fewer than the recited 15 cycles. Nor does the office action mention why one of ordinary skill in the art would have a reasonable expectation of success.
(e) Applicant states that in a prior remark Applicant disclosed unexpected efficiencies of the claimed method but the Office action implies that such unexpected efficiencies would have an inherent property of a method taught by the cited references. Applicant states that even if the efficiencies of the claimed methods would have been inherent to a method allegedly taught by the cited references, such efficiencies would have been unexpected because at least Rigatti teaches a method of paired-end sequencing, in which a resynthesis step includes 15 cycles. Rigatti does not teach any method with less than 15 cycles, which implies that at the time of the instant application was cited it would have been believed that no less than 15 cycles would have been required to produce a sufficient level of resynthesized strands for use during pairwise sequencing.
(f) Applicant discuss cycles at 2 – 3 cycles or 2 – 6 cycles which are recited in a dependent claim(s). Applicant states that the number of 15 cycles in the cited reference of Rigatti is substantially and significantly greater than the mere 2-6 cycles or 2 to 3 cycles as claimed and there is no reasonable expectation that such a reduced number of cycles would have produced a sufficient level of resynthesized strands for use during pairwise sequencing. Applicant concludes that there is no articulated rationale as to why it would have been routine optimization to arrive at the clamed invention.
Examiner’s Response
9. All of the amendment and arguments have been thoroughly reviewed and considered but are not found persuasive for the reasons that follows:
(i) In response to Applicant’s arguments at (a) through (f), concerning the argument that the cited prior art does not teach 2 – 12 cycles for resynthesis but rather teaches in Rigatti a necessary of 15 cycles, the examiner notes that while the claims recite 2-12 cycles used in the method, the specification at page 22, lines 3-5 states that the multiple cycles may comprise from 2-15 or more cycles. Thus, Applicant’s specification does not teach the criticality of the claimed range of 2-12 cycles and further suggest that 15 cycles is within the scope of the invention. MPEP 2144.05 states a “prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”.
Titanium Metals Corp. of Americav.Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. “The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.”).
Thus, given the lack of criticality of the claimed range as supported by the instant specification, it would have prima facie obvious for one skilled in the art to have expected that modifying the cycles to greater than 2-12 as supported by the specification or modifying the cycles to 15 cycles or less as supported by the specification and recited in Riggatti would have been within the ordinary artisan capability. The ordinary artisan would have also been expected to have a reasonable expectation of success of carrying a resynthesis reaction under the modifying conditions. Additionally, while Rigatti teaches 15 cycles, no where in the teachings of Rigatti
In response to Applicant’s arguments that Rigatti teaches away from the claimed invention, MPEP states “When a piece of prior art ‘suggests that the line of development flowing from the reference's disclosure is unlikely to be productive of the result sought by the applicant’ the piece of prior art is said to ‘teach away’ from the claimed invention. In re Gurley, 27 F.3d 551, 553 (Fed.Cir.1994). As with other subsidiary inquiries, ‘[w]hat a reference teaches and whether it teaches toward or away from the claimed invention are questions of fact.’ [Winner Intern. Royalty Corp. v. Wang, 202 F.3d 1340, 1349 (Fed. Cir. 2000)] (internal quotations omitted). However, obviousness must be determined in light of all the facts, and there is no rule that a single reference that teaches away will mandate a finding of nonobviousness. Likewise, a given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine. See id. at 1349 n. 8 (“The fact that the motivating benefit comes at the expense of another benefit, however, should not nullify its use as a basis to modify the disclosure of one reference with the teachings of another. Instead, the benefits, both lost and gained, should be weighed against one another.”). Where the prior art contains ‘apparently conflicting’ teachings (i.e., where some references teach the combination and others teach away from it) each reference must be considered “for its power to suggest solutions to an artisan of ordinary skill.... consider[ing] the degree to which one reference might accurately discredit another.’ In re Young, 927 F.2d 588, 591 (Fed.Cir.1991).” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (emphases added).
In this case, the cited prior art provides a similar teaching as recited in the instant invention and does not teach disclosure which discredit lowering the resynthesis cycling time or discredit the duration of the cycling time or disclosure that 15 cycles is necessary or critical to the invention of Rigatti. Additionally, the specification at page 22, lines 3-5 states that the multiple cycles may comprise from 2-15 or more cycles which suggested no criticality of the claimed resynthesis cycles of 2-12 cycles or less or discredits the teachings of Rigatti of using 15 cycles. Thus, this argument is not found persuasive. Applicant ls reminded that KSR forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 2007) (citing KSR, 82 USPQ2d at 1396).
Further in response to Applicant’s arguments concerning unexpected results MPEP states "T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). >In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)". MPEP 2112. In this case, the evidence presented by Applicant in the Table 1 and Figures 1 and does not discredit the teachings of the cited prior art. As the specification clearly provides evidence that that cycles greater than 12 and including 15 cycles are within the scope of the invention for performing a resynthesis reaction. Applicant’s arguments are not found persuasive to obviate the rejections above and accordingly the 103 rejection is maintained.
Conclusion
10. No claims are allowed. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
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/CYNTHIA B WILDER/Primary Examiner, Art Unit 1681