Office Action 5: Non-Final Rejection (2024-10-18)
Rejection types: 112 - Written Description/Enablement, Double Patenting

CLAIMS:
IN THE CLAIMS

The following listing of claims replaces all prior versions and listings of claims in the instant application.

1-20. (Canceled)219

21\. (Currently Amended) An apparatus, comprising:
a flow cell;
a plurality of reservoirs fluidically coupled to the flow cell, the plurality of reservoirs configured to respectively hold four different nucleotide species;
a sensor operably coupled to the flow cell, the sensor being configured to sense one or more signals produced from incorporations of a nucleotide species of the four different nucleotide species into a plurality oftemplate polynucleotide strands in the flow cell; and
a fluidics controller operably coupled to the plurality of reservoirs, the fluidics controller configured to individually control flow from the plurality of reservoirs to provide a series of nucleotide flows to the flow cell, wherein the series ofnucleotide flows comprises a plurality ofsequential repetitions offour successive flows ofthe four different nucleotide species flowed in a predetermined order, wherein each sequential repetition one flow ofeach offour different nucleotide species in the predetermined order.
wherein the series of nucleotide flows further comprises a nucleotide flow sequence included within the plurality ofseqiuential repetitions ofsuccessive flows ofthe four different nucleotide species, the nucleotide flow seqiuence meeting predefined criteria such that the nucleotide flow sequence includes:
each of the four different nucleotide species,
no consecutively repeated nucleotide flow of any of the four different nucleotide species, and
a flow ordering such that three different nucleotide species of the four different nucleotide species are flowed before a fourth nucleotide species of the four different nucleotide species is flowed, and such that one or more of the three different nucleotide species is flowed at least twice before the fourth nucleotide species is flowed,wherein the series of nucleotide flows includes one or more consecutive repeats of the nucleotide flow sequencSVG {EMBED HERE} 0.0930.157 wherein the flow ordering comprises a same number of nucleotide flows for each of the four different nucleotide species,

wherein the nucleotide flow sequence reduces dephasing effects that occurred during previous sequential repetitions of successive flows of the four different nucleotide species applied to the plurality of template polynucleotide strands in the flow cell.

22\. (Previously Presented) The apparatus of claim 21, wherein the flow cell comprises a plurality of reaction sites, the plurality of reaction sites comprising a reaction site associated with the polynucleotide.

23\. (Previously Presented) The apparatus of claim 22, wherein the plurality of reaction sites comprise a plurality of microwells.

24\. (Previously Presented) The apparatus of claim 22, wherein the apparatus comprises a plurality of sensors, the plurality of sensors comprising the sensor, the plurality of sensors aligned with the plurality of reaction sites, and each sensor of the plurality configured to sense one or more signals produced from incorporation of the nucleotide species at a corresponding reaction site.

25\. (Previously Presented) The apparatus of claim 21, wherein the sensor is configured to sense pH.

26\. (Previously Presented) The apparatus of claim 21, wherein the sensor comprises a field effect transistor (FET).

27\. (Previously Presented) The apparatus of claim 21, wherein the sensor is configured to sense one or more signals produced from incorporation each of the four different nucleotide species into the polynucleotide.

28\. (Previously Presented) The apparatus of claim 21, wherein the apparatus comprises a plurality of sensors, the plurality of sensors comprising the sensor, each sensor of the plurality configured to sense one or more signals produced from incorporation of the nucleotide species.

29\. (Previously Presented) The apparatus of claim 21, wherein the sensor is one of a plurality of sensors of a sensor array, and the apparatus further comprises a semiconductor substrate, the semiconductor substrate comprising the sensor array.

30\. (Previously Presented) The apparatus of claim 21, further comprising a reference electrode operatively coupled to the sensor.

31\. (Previously Presented) The apparatus of claim 21, wherein the polynucleotide is coupled to a support.

32\. (Previously Presented) The apparatus of claim 31, wherein the support comprises a bead in the flow cell.

33\. (Previously Presented) The apparatus of claim 31, wherein the support is operatively coupled to the sensor.

34\. (Previously Presented) The apparatus of claim 21, further comprising a valve block fluidically coupling the plurality of reservoirs and the flow cell, the fluidic controller operably coupled to control the valve block.

35\. (Previously Presented) The apparatus of claim 21, wherein two or more of the three different nucleotide species are flowed at least twice before the fourth different nucleotide species is flowed in the nucleotide flow sequence.

36\. (Previously Presented) The apparatus of claim 21, wherein all three of the three different nucleotide species are flowed at least twice before the fourth different nucleotide species is flowed in the nucleotide flow sequence.

37\. (Previously Presented) The apparatus of claim 21, wherein one or more of the three different nucleotide species are flowed at least three times before the fourth different nucleotide species is flowed in the nucleotide flow sequence.

38\. (Previously Presented) The apparatus of claim 21, wherein a first and second different nucleotide species of the three different nucleotide species are flowed at least twice and a third nucleotide species of the three different nucleotide species occurs at least three times before the fourth different nucleotide species is flowed in the nucleotide flow sequence.
Appl. No.: 16/535,565

39\. (Previously Presented) The apparatus of claim 21, wherein two or more of the three different nucleotide species are flowed at least three times before the fourth different nucleotide species is flowed in the nucleotide flow sequence.
40\. - 50. (Canceled)4149

OFFICE ACTION:
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 08/05/2024 has been entered.
Application Status
This action is written in response to applicant’s correspondence received on 08/05/2024.  Claims 21-39 are pending. Claim 21 has been amended. Claims 1-20 and 40-50 have been cancelled.  All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment.  Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Withdrawal of Rejection Under 35 USC 103
The Applicant’s amendments appear to render the claims free of the prior art.  There is no reasonable motive or suggestion in the prior art to arrive at the presently claimed subject matter of independent claim 21.  Although non-conventional nucleotide flow sequence dispensation strategies are known, as taught by Garcia (see for instance the 103 rejection of claim 21 in the Final rejection mailed 5/3/2024), the present claim set appears to claim both a combination of a conventional flow ordering, where the four nucleotides are flowed in a predetermined order but also comprise a flow sequence comprising non-conventional flow ordering.  The prior art previously cited in the final rejection mailed 5/3/2024, namely Rothberg, Garcia, Kim, Bankar, and Grimwood,  NCBI Database sequences, would not reasonably lead a practitioner to the presently claimed invention.
Claim Rejections - 35 USC § 112 – New Rejection Necessitated by Amendment
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 21-39 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.
Regarding claim 21, claim 21 recites “wherein the series of nucleotide flows comprises a plurality of sequential repetitions of four successive flows of the four different nucleotide species flowed in a predetermined order, wherein each sequential repetition one flow of each of four different nucleotide species in the predetermined order” (lines 10-13).  This phrase is unclear because it appears to recite in the first half of the phrase that there are “four successive flows of the four different nucleotide species flowed,” (i.e., for example, A-A-A-A, G-G-G-G, C-C-C-C, T-T-T-T repeated sequentially, “sequential repetitions of four successive flows of the four different nucleotides flowed in a predetermined order”), and later recites that each sequential repetition has only one flow of each of the four different nucleotide species.  Furthermore, the final phrase “wherein each sequential repetition one flow of each of four different nucleotide species in the predetermined order” is missing a verb, and is therefore also unclear.
In order to clarify what is being claimed, the following amendment is recommended:  “wherein the series of nucleotide flows comprises a plurality of sequential repetitions in each sequential repetition, each of the four different nucleotide species is flowed once in the predetermined order.”  This rewording appears to align with the Applicant’s specification (e.g., paragraph 31). It appears that claim 21 is attempting to claim a plurality of repetitions such as, for example, “A-T-G-C,” where the plurality of repetitions also comprises a flow sequence recited later in the claim, i.e., a conventional flow ordering combined with an alternate flow ordering, such as a flow ordering described in the specification (paragraph 31).  As the claim is currently written, it is unclear if the Applicant is claiming “repetitions of four successive flows of the four different nucleotide species” meaning e.g., A-A-A-A, G-G-G-G, etc., or for example “A-T-G-C,” repeated four times (note too that if the “repetition” recited is a sequence like “A-T-G-C” comprising each of the four nucleotides, the phrase “four successive flows of the four different nucleotide species flowed in a predetermined order” can be interpreted to mean that “A-T-G-C” is limited to be flowed only four times, which also does not seem to be in keeping with the spirit of the invention described in the specification).  The suggested amendments may help to clarify what is being claimed.
Claims 22-39 do not resolve this 112(b) issue and are therefore also rejected under 112(b).
Double Patenting - Maintained
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 21-39 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9,605,308.
The patented claims teach an apparatus for sequencing a polynucleotide strand comprising a flow chamber for receiving flows of different dNTP reagents, multiple reservoirs that contain a different dNTP, flow paths from each of the reservoirs to the flow chamber, and a fluidics controller that is programmed to successively provide flow from the multiple reservoirs to the flow chamber according to an alternate ordering (see patented claim 1). The patented claims teach that the alternate ordering comprises the same number of flows for each of four different dNTP reagent flows and comprises a flow of nucleotides N-W-N-Z and is successively repeated at least once (see patented claim 1). The patent’s specification teaches that a preferred nucleotide flow ordering is TACAT-ACGCA-CGTGC-GTATG (column 8, lines 1-5), and also includes claim language in claim 1 indicating that the flow sequence is repeated. The patent’s specification further describes the sequencing instrumentation (see columns 10-12), which further addresses the structural limitations of the current claims. These disclosures of the preferred alternate nucleotide sequence flow ordering and further the preferred structural features of the apparatus indicate that meet the limitations of the current claims indicates that the patented claims and the current claims each encompass overlapping subject matter.
Response to Arguments – Double Patenting
Applicant's arguments filed 08/05/2024 have been fully considered but they are not persuasive. The applicant has not provided an argument explaining why the recited claims are not instances of double patenting.  Applicants request only that the rejection be held in abeyance until allowable subject matter is indicated.  The non-statutory double patenting rejection is therefore maintained.
Conclusion

APPLICANT REBUTTAL: R
EMARKS
I.
Claim Status:
Claim 21 is amended. Claims 1-20 and 40-50 are cancelled. After the foregoing amendments are entered into the record, claims 21 - 39 will be pending in this case.
Support for the claim amendments can be found in the application as-filed, e.g., at paragraphs [0037]
- [0044]. Thus, no new subject matter is added as a result of these amendments.
II.
Claim Re
j
ections Under 35 U.S.C.
Claims 21-34 are rejected under 35 U.S.C. 103 as being unpatentable over Rothberg (US
2009/0127589) in view of Garcia (Garcia et al. (2000) Gene, 253:249-257), GenBank AL021938 (NCBI Database accession number: AL021938, portion of the coding region of the human JMJ protein, published 2008), and Kim (Kim TG et al. J Biol Chem. 2003 Oct 24;278(43):42247-55).
Claims 21-38 are rejected under 35 U.S.C. 103 as being unpatentable over Rothberg (US
2009/0127589) in view of Garcia (Garcia et al. (2000) Gene, 253:249-257), GenBank CR382129 (NCBI Database accession number: CR382129, Yarrowia lipolytica genome published 2008), and Bankar (Bankar AV et al. Appl Microbiol Biotechnol. 2009 Oct;84(5):847-65).
Claims 21-34, 37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Rothberg (US 2009/0127589) in view of Garcia (Garcia et al. (2000) Gene, 253:249-257), GenBank AC133089 (NCBI Database accession number: AC133089, Mus musculus genome published 2004), and Grimwood (Grimwood J et al. Nature. 2004 Apr 1 ;428(6982):529-35).
In response, while not necessarily agreeing with the grounds for the rejection and to advance
prosecution, Applicant has amended claim 21. Applicant respectfully traverses the rejection in view of the amended claim 21. With respect to Rothberg, the Office Action on page 5, 1st paragraph, states, "However, Rothberg does not teach that one or more of the three different nucleotide species occurs at least twice before the fourth nucleotide species, and that this nucleotide flow sequence would be consecutively repeated at least once. Rothberg also does not teach that the flow ordering comprises a same number of nucleotide flows for each of the four different nucleotide species." With respect to Garcia, the Office Action on page 6, 2nd paragraph, states, "As discussed above, Garcia teaches sequencing the p53 gene, but the specific sequence recited in their article is not repeated consecutively during the sequencing process, nor does the flow ordering
comprise a same number of flows for each of the four nucleotides." With respect to GenBank AL021938, the Office Action the Office Action on page 6, 2nd paragraph, states, "the sequence 'A-G-A-T-C-G-T-C' occurs successively at position 7896, and concludes, "Thus, a practitioner sequencing this region of the human genome using the predetermined/programmed nucleotide dispensation nucleotide flow technique taught by Garcia would flow the series 'A-G-A-T-C-G-T-C' twice (consecutively) during the sequencing process taught by Garcia." Similar arguments are made with respect to the sequence characteristics of GenBank CR382129 and GenBank AC133089.
Applicant respectfully disagrees in view of the amendments. Claim 21, as amended, recites (emphasis added):
An apparatus, comprising:
a flow cell;
a plurality of reservoirs fluidically coupled to the flow cell, the plurality of reservoirs configured to respectively hold four different nucleotide species;
a sensor operably coupled to the flow cell, the sensor being configured to sense one or more
signals produced from incorporations of a nucleotide species of the four different nucleotide species into a
plurality of template polynucleotide strands
in the flow cell; and
a fluidics controller operably coupled to the plurality of reservoirs, the fluidics controller
configured to individually control flow from the plurality of reservoirs to provide a series of nucleotide flows to the flow cell, wherein the series of nucleotide flows comprises a plurality of sequential repetitions of four successive flows of the four different nucleotide species flowed in a predetermined order, wherein each sequential repetition one flow of each of four different nucleotide species in the predetermined order,
wherein the series of nucleotide flows further comprises a nucleotide flow sequence included within the plurality of sequential repetitions of successive flows of the four different nucleotide species, the nucleotide flow sequence meeting predefined criteria such that the nucleotide flow sequence includes:
each of the four different nucleotide species,
no consecutively repeated nucleotide flow of any of the four different nucleotide species, and
a flow ordering such that three different nucleotide species of the four different nucleotide species are flowed before a fourth nucleotide species of the four different nucleotide species is flowed, and such that one or more of the three different nucleotide species is flowed at least twice before the fourth nucleotide species is flowed,
wherein the series of nucleotide flows includes one or more consecutive repeats of the nucleotide flow sequence, wherein the flow ordering comprises a same number of nucleotide flows for each of the four different nucleotide species,
wherein the nucleotide flow sequence reduces dephasing effects that occurred during
previous sequential repetitions of successive flows of the four different nucleotide species applied to the plurality of template polynucleotide strands in the flow cell.
The Office Action on page 7, last paragraph, states:
Furthermore, Garcia teaches the additional motivation of using their pre-programmed/predetermined nucleotide dispensation flow sequence when sequencing in general because such a method improves
the speed and read length of sequencing, and also corrects out-of-phase problems.
With respect to an out-of-phase signal due to Garcia's conventional DNA sequencing with cyclic nucleotide dispensation strategy in the order of A, G, T, C, Garcia points out an out-of-phase signal error on page 251, last sentence, and Fig 2, graph a). This error was not resolved by Garcia's programmed nucleotide dispensation, where "the nucleotide dispensation order is pre-determined according to the wild-type consensus sequence of the gene." (Garcia, page 253, Section 3.2, 1st paragraph) This error was resolved by reverse pyrosequencing, as shown in Fig. 2, graph b). Garcia states, "Reverse pyrosequencing of the same region resolved the ambiguity (Fig. 2)." (Garcia, page 253, first sentence). Therefore, Garcia does not teach or suggest "wherein the nucleotide flow sequence reduces dephasing effects that occurred during previous sequential repetitions of successive flows of the four different nucleotide species applied to the plurality of template polynucleotide strands in the flow cell," as recited in claim 1.
The deficiencies of Rothberg and Garcia are not cured by the respective sequences of GenBank
AL021938, GenBank CR382129, or GenBank AC133089 at least because those sequences are not "included within the plurality of sequential repetitions of successive flows of the four different nucleotide species," as required by claim 21.
For at least the above reasons, Applicant respectfully asserts that for the groups of references: Rothberg in view of Garcia, GenBank AL021938, and Kim; Rothberg in view of Garcia, GenBank CR382129, and Bankar; and Rothberg in view of Garcia, GenBank AC133089, and Grimwood; each reference alone or in combination with other references in its group, do not teach or suggest all the limitations of claim 21. Applicant respectfully asserts that claim 21 is allowable over the cited references. Claims 22-39 depend from claim 21 and are allowable for at least the same reasons as claim 21 and for the additional
limitations recited.
Accordingly, Applicant respectfully requests reconsideration and withdrawal of the rejection of claims under 35 U.S.C. §103.
III.
Claim Re
j
ections Under Double Patentin
g:
Claims 21-39 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9,605,308.
Applicant respectfully requests that the non-statutory double patenting rejections be held in abeyance until a determination of allowable subject matter has been finally made in the instant application.
Conclusion

NEXT OFFICE ACTION: 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 .
Application Status
This action is written in response to applicant’s correspondence received on 01/17/2025.  Claims 21-39 are pending. Claims 21 and 24 have been amended. Claims 1-20 and 40-50 have been cancelled.  All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment.
Withdrawn Claim Rejection – 35 USC 112(b)
The Applicant’s amendments to claim 21 render the claim definite.  The 112(b) rejection is therefore withdrawn.
Withdrawn – Double Patenting Rejection
The Applicant and owner of patent US 9,605,308 has submitted a terminal disclaimer along with the present application.  Thus, the double patenting rejection on the grounds of US 9,605,308 are hereby withdrawn.
Reasons for Allowance
Claims 21-39 are allowed.  With regards to claim 21, the only remaining outstanding rejections were the above-mentioned 112(b) and Double Patenting rejections.  The Applicant has amended claim 21 rendering the claim definite.  Furthermore, the Applicant has filed a terminal disclaimer with their existing patent US 9,605,308, the subject matter and claims of which are substantially similar to the present invention.
With regards to the prior art, as discussed in previous office actions (e.g., the Final action mailed 05/03/2024), apparatus for sequencing and dispensing nucleotides were known, as taught by Rothberg (US 2009/0127589).  Additionally, sequencing strategies with alternative nucleotide flow orderings, where such alternative flow orderings reduce dephasing effects, are also known as taught by Garcia (Garcia et al. Gene. 253:249-257, 2000, supplied with Final Office action mailed 05/03/2024, see 103 rejection of this action for discussion on obviousness).  However, the flow orderings of Garcia were based on alternative flow dispensations created using an anticipated sequence of the nucleotide to be sequenced.  The present apparatus, as recited, relies on successive, sequential flows of predetermined nucleotides interspersed with a flow ordering to reduce dephasing effects (see claim 21).  Previous rejections of the claims have relied upon sequences which could be sequenced using the predetermined flow ordering method of Garcia.  However, the amended claims do not appear to read on known sequences which would be sequenced using the method of Garcia, to the extent that such sequences could be searched.  Thus, the present invention appears to be free of the art.
Furthermore, the Applicants have reduced to practice the recited apparatus to sequence a fragment (Figure 7).  Such sequencing methodologies could therefore reasonably be applied to other sequences.  Furthermore, such sequencing apparatus, technologies, and methods are common as taught by Rothberg and Garcia:  a practitioner is therefore enabled to use the invention with a reasonable expectation of success.
Additionally, the Applicants have submitted a terminal disclaimer along with the present application in relation to their issued patent US 9,605,308.  Thus, the Applicant has nullified the original double patenting rejection.
Conclusion
Claims 21-39 are allowed.

CITED REFERENCE SUMMARIES: Ref US9605308: Claims:
1. An apparatus for sequencing a polynucleotide strand, comprising:
a flow chamber for receiving flows of different dNTP reagents;
multiple reservoirs that each contain a different dNTP reagent;
flow paths from each of the reservoirs to the flow chamber; and
a fluidics controller that controls the flow from the reservoirs to the flow chamber, wherein the fluidics controller is programmed to successively provide flow from the multiple reservoirs to the flow chamber according to a predetermined ordering, wherein the predetermined ordering comprises an alternate ordering which is not a continuous and ordered repeat of four different dNTP reagent flows, the alternate ordering comprising a same number of flows for each of four different dNTP reagent flows, a flow of a nucleotide N, which is followed directly by a flow of a different nucleotide W, which is followed directly by a flow of the same nucleotide N, wherein the N-W-N flow is further followed directly by a flow of a nucleotide Z that is different from N and W, and the alternate ordering being successively repeated at least once.
2. The apparatus of claim 1, wherein the alternate ordering is not a continuous repeat of an order of a first four dNTP reagent flows in the predetermined ordering.
3. The apparatus of claim 1, further comprising a flow cell loaded into the flow chamber, wherein the flow cell comprises a microwell array that contains multiple copies of the polynucleotide strand with a primer annealed thereto.
4. The apparatus of claim 3, wherein the flow cell further comprises a chemFET sensor array for detecting the reaction of the dNTP reagent with the contents of the microwell array.
5. The apparatus of claim 3, wherein the polynucleotide strands are attached to beads that are contained in the microwells of the microwell array.
6. The apparatus of claim 1, wherein the predetermined ordering consists of only the alternate ordering.
7. The apparatus of claim 1, wherein the predetermined ordering further comprises a continuous and ordered flow of the four different dNTP reagent flows as follows: dATP, then dCTP, then dGTP, and then dTTP.
8. The apparatus of claim 1, wherein a first four dNTP reagent flows of the continuous and ordered repeat of the four different reagent flows comprises: dATP, then dCTP, then dGTP, and then dTTP.
9. The apparatus of claim 1, wherein the predetermined ordering includes a first portion that comprises the alternate ordering and a second portion that does not comprise the alternate ordering.
10. The apparatus of claim 1, wherein in the predetermined ordering, the flow of one of the four dNTP reagent flows is always followed by a flow of a different one of the four dNTP reagent flows.
11. The apparatus of claim 1, wherein the predetermined ordering further comprises a continuous and ordered repeat of the four different dNTP reagent flows and is a permutation of a flow ordering of: dATP, then dCTP, then dGTP, and then dTTP.
12. The apparatus of claim 1, wherein the alternate ordering is repeated two or more times.
13. An apparatus for sequencing a polynucleotide strand, comprising:
a flow chamber for receiving flows of different dNTP reagents;
multiple reservoirs that each contain a different dNTP reagent;
flow paths from each of the reservoirs to the flow chamber; and
a fluidics controller that controls the flow from the reservoirs to the flow chamber, wherein the fluidics controller is programmed to successively provide flow from the multiple reservoirs to the flow chamber according to a predetermined ordering, wherein the predetermined ordering comprises an alternate ordering which is not a continuous and ordered repeat of four different dNTP reagent flows, the alternate ordering comprising a flow of one kind of dNTP reagent always followed by a flow of a different kind of dNTP reagent, at least one flow of each kind of dNTP reagent followed by a flow of the same kind of dNTP reagent after a single intervening flow of a different kind of dNTP reagent, a same number of flows of each of the four kinds of dNTP reagent flows in the alternate ordering, and wherein repetition of the alternate ordering successively occurs at least once to sequence a desired template length.
14. The apparatus of claim 13, wherein the alternate ordering is repeated two or more times.
15. The apparatus of claim 1, wherein the plurality of reagent flows in the alternate ordering comprises one of 8, 12, 16, 20, 24, 28 and 32 dNTP reagent flows.
16. The apparatus of claim 13, wherein the plurality of reagent flows in the alternate ordering comprises one of 8, 12, 16, 20, 24, 28 and 32 dNTP reagent flows.
17. An apparatus for sequencing a polynucleotide strand, comprising:
a flow chamber for receiving flows of different dNTP reagents;
multiple reservoirs that each contain a different dNTP reagent;
flow paths from each of the reservoirs to the flow chamber; and
a fluidics controller that controls the flow from the reservoirs to the flow chamber, wherein the fluidics controller is programmed to successively provide flow from the multiple reservoirs to the flow chamber according to a predetermined ordering, wherein the predetermined ordering consists of only an alternate ordering which is not a continuous and ordered repeat of four different dNTP reagent flows, the alternate ordering comprising a same number of flows for each of four different dNTP reagent flows, a flow of a nucleotide N, which is followed directly by a flow of a different nucleotide W, which is followed directly by a flow of the same nucleotide N, wherein the N-W-N flow is further followed directly by a flow of a nucleotide Z that is different from N and W, and the alternate ordering being repeated at least once.