Office Action 1: Non-Final Rejection (2022-12-15)
Rejection types: 102 - Lack of Novelty, 103 - Obviousness, 112 - Written Description/Enablement, Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS:

This listing of claims will replace all prior versions and listings of claims in the application:

1-20. (Cancelled) 219

21\. (New) 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 incorporation of a nucleotide species of the four different nucleotide species into a polynucleotide 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 nucleotide flow sequence meeting predefined criteria such that the nucleotide flow sequence includes:
each of the four different nucleotide species, no consecutive repeat of any of the four different nucleotide species, and
an order such that three different nucleotide species of the four different nucleotide species occur before a fourth nucleotide species of the four different nucleotide species, and such that one or more of the three different nucleotide species occurs at least twice before the fourth nucleotide species.

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

24\. (New) 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\. (New) The apparatus of claim 21, wherein the sensor is configured to sense pH.

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

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

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

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

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

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

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

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

38\. (New) The apparatus of claim 21, wherein a first and second different nucleotide species of the three different nucleotide species occur 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.

39\. (New) The apparatus of claim 21, wherein two or more of the three different nucleotide species occur at least three times before the fourth different nucleotide species is flowed in the nucleotide flow sequence.

40\. (New) 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 incorporation of a nucleotide species of the four different nucleotide species into a polynucleotide 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 palindromic nucleotide flow sequence meeting predefined criteria such that the palindromic nucleotide flow sequence includes a palindromic sequence having a length of at least five nucleotide flows and comprising at least three different nucleotide species of the four different nucleotide species.

41\. (New) The apparatus of claim 40, wherein the series of nucleotide flows comprises at least one non-palindromic nucleotide flow sequence.

42\. (New) The apparatus of claim 40, wherein the palindromic nucleotide flow sequence is one or both of dATP, dCTP, dGTP, dCTP, and dATP, and dCTP, dGTP, dTTP, dGTP, and dCTP.

43\. (New) The apparatus of claim 40, wherein the palindromic nucleotide flow sequence is a first palindromic nucleotide flow sequence and the series of nucleotide flows further comprises a second palindromic nucleotide flow sequence and the predefined criteria stipulate that the second palindromic nucleotide flow sequence comprises at least three of the four different nucleotide species and five or more nucleotide flows, wherein the second palindromic nucleotide flow sequence differs from the first palindromic nucleotide sequence.

44\. (New) The apparatus of claim 43, wherein the first palindromic nucleotide sequence comprises a palindromic flow ordering of dATP, dCTP, dGTP, dCTP, and
dATP, and the second palindromic nucleotide flow sequence comprises a palindromic flow ordering of dCTP, dGTP, dTTP, dGTP, and dCTP.

45\. (New) The apparatus of claim 40, wherein the series of nucleotide flows comprises at least four palindromic nucleotide flow sequences, the predefined criteria stipulate that each of the at least four palindromic nucleotide flow sequences comprises at least three of the four different nucleotide species and five or more nucleotide flows, the four palindromic nucleotide flow sequences differ from each other, and the at least four palindromic nucleotide flow sequences comprise the palindromic nucleotide flow sequence.

46\. (New) The apparatus of claim 40, wherein the predefined criteria stipulate that the palindromic nucleotide flow sequence comprises at least three of the four different nucleotide species and seven or more nucleotide flows.

47\. (New) The apparatus of claim 40, wherein the predefined criteria stipulate that the palindromic nucleotide flow sequence comprises at least three of the four different nucleotide species and nine or more nucleotide flows.

48\. (New) The apparatus of claim 40, wherein predefined criteria stipulate that none of the four different nucleotide species is consecutively repeated.

OFFICE ACTION:
DETAILED ACTION
Application Status
This action is written in response to applicant’s correspondence received December 22, 2020.  Claims 21-48 are currently pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA  35 U.S.C. 112, except for the best mode requirement.  See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 15/404,735, 13/689,252, 13/157,865, and US 61/354,173, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA  35 U.S.C. 112, first paragraph for one or more claims of this application.
In the response filed December 22, 2020, new claim 40 was added that recites “wherein the series of nucleotide flows comprises a palindromic nucleotide flow sequence meeting predefined criteria such that the palindromic nucleotide flow sequence includes a palindromic sequence having a length of at least five nucleotide flows and comprising at least three different nucleotide species of the four different nucleotide species”.
The recitation of “at least five” nucleotide flows refers to a range of five or more than five nucleotide flows and “at least” three different nucleotide species refers to the range of three or four different nucleotide species. These limitations of palindromic nucleotide flow sequences of more than five nucleotide flows or palindromic nucleotide flow sequences comprising all four different nucleotide species do not have support in the prior filed applications. The prior filed applications are silent with respect to the term “palindromic”. The only reduction to practice for a nucleotide flow sequence happens to be palindromic and meets the criteria of the limitation above is found in paragraph [0033] of the specification filed January 12, 2017 in 15/404,735, for example. This flow ordering is TACAT-ACGCA-CGTGC-GTATG, which comprises four different palindromic nucleotide flow sequences of exactly five nucleotide flows each with exactly three different nucleotide species.
However, current claim 40 refers to “a palindromic sequence having a length of at least five nucleotide flows and comprising at least three different nucleotide species of the four different nucleotide species”, which includes the language “at least”. There is no express, implicit, or inherent teaching from the prior filed applications for a palindromic nucleotide flow sequence that is more than five nucleotide flows that would support “at least” five nucleotide flows. There is also no express, implicit, or inherent teaching from the prior filed applications including any reduction to practice for a palindromic sequence that comprises four different nucleotide species that would support the “at least” three different nucleotide species. The specific working example of the alternate flow ordering of TACAT-ACGCA-CGTGC-GTATG is not sufficient to show possession of flow orderings that are longer.
In addition, new claims 43, 45, 46, and 47 contain similar recitations of “at least three of the four different nucleotide species” and “five or more nucleotide flows”. Claim 46 further recites “the palindromic nucleotide flow sequence comprises at least three of the four different nucleotide species and seven or more nucleotide flows”. Claim 47 further recites that “the palindromic nucleotide flow sequence comprises at least three of the four different nucleotide species and nine or more nucleotide flows”. These claims recite similar limitations that do not have support in the priority documents. In particular, the recitation in claim 46 and 47 that a “palindromic nucleotide flow sequence” contains “seven or more nucleotide flows” or “nine or more nucleotide flows”, respectively, is similarly not described in the priority documents. The longest palindromic sequence described by the priority documents contains five nucleotide flows as discussed above. There is no teaching or suggestion in the priority documents for palindromic sequences longer than the five.
Accordingly, the prior filed applications fail to provide adequate written descriptive support for the claimed subject matter. Therefore, the effective filing date of claims 40-48 is the filing date of the current application, which is August 8, 2019.
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 .
In the current case, since claims 40-48 have a priority date of August 8, 2019, which is after March 16, 2013, then this application is examined under the first inventor to file provisions of the AIA .
Applicants are respectfully reminded that the statement provisions of 37 CFR 1.55 and 1.78 require that if the later-filed transition application contains, or contained at any time, a claim to a claimed invention that has an effective filing date on or after March 16, 2013, the applicant must provide a statement to that effect (see MPEP 2159.04).
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.
Claim 45 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 45 recites “the four palindromic nucleotide flow sequences differ from each other”. However, the claim previously recites “the series of nucleotide flows comprises at least four palindromic nucleotide flow sequences”. The recitation “at least four palindromic nucleotide flow sequences” refers to four or more than four palindromic nucleotide flow sequences. It is not clear which four out of the “at least four palindromic nucleotide flow sequences” is being referred to by “the four palindromic nucleotide flow sequences”. It is not clear whether it is referring only to four or whether all of the “at least four palindromic nucleotide flow sequences” are required to “differ from each other”.
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 40-48 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 pre-AIA  the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description. According to MPEP § 2163.I.B, While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure and The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
In the instantly rejected claims, the new limitation of wherein the series of nucleotide flows comprises a palindromic nucleotide flow sequence meeting predefined criteria such that the palindromic nucleotide flow sequence includes a palindromic sequence having a length of at least five nucleotide flows and comprising at least three different nucleotide species of the four different nucleotide species” in claim 40 appears to represent new matter.
The recitation of “at least five” nucleotide flows refers to a range of five or more than five nucleotide flows and “at least” three different nucleotide species refers to the range of three or four different nucleotide species. These limitations of palindromic nucleotide flow sequences of more than five nucleotide flows or palindromic nucleotide flow sequences comprising all four different nucleotide species do not have support in the current specification. The current specification is silent with respect to the term “palindromic”. The only reduction to practice for a palindromic nucleotide flow sequence that meets the criteria of the limitation above is found in paragraph [0033], for example. This flow ordering is TACAT-ACGCA-CGTGC-GTATG, which comprises four different palindromic nucleotide flow sequences of exactly five nucleotide flows each with exactly three different nucleotide species.
However, current claim 40 refers to “a palindromic sequence having a length of at least five nucleotide flows and comprising at least three different nucleotide species of the four different nucleotide species”. There is no express, implicit, or inherent teaching from the current specification for a palindromic nucleotide flow sequence that is more than five nucleotide flows that would support “at least” five nucleotide flows. There is also no express, implicit, or inherent teaching from the current specification including any reduction to practice for a palindromic sequence that comprises four different nucleotide species that would support the “at least” three different nucleotide species. The specific working example of the alternate flow ordering of TACAT-ACGCA-CGTGC-GTATG is not sufficient to show possession of flow orderings that are longer.
In addition, new claims 43, 45, 46, and 47 contain similar recitations of “at least three of the four different nucleotide species” and “five or more nucleotide flows”. Claim 47 further recites that “the palindromic nucleotide flow sequence comprises…nine or more nucleotide flows”. These claims recite similar limitations that do not have support in the current specification. In particular, the recitation in claim 47 that a “palindromic nucleotide flow sequence” contains “nine or more nucleotide flows” is similarly not described in the current specification. The longest palindromic sequence described by the current specification contains five nucleotide flows. There is no teaching or suggestion in the current specification for palindromic sequences longer than the five.
No specific basis for this limitation was identified in the specification, nor did a review of the specification by the examiner find any basis for the limitation.  Since no basis has been identified, the claims are rejected as incorporating new matter.
Response to Arguments
It is noted that Applicant has indicated in the response filed December 22, 2020 that the new claims are supported by the originally-filed specification, claims, and drawings, for example at paragraphs [0010], [0019], [0030]-[0035], [0039], [0044], [0047]-[0051], and [0054]-[0056].
These disclosures have been fully considered but are not sufficient to overcome the rejection because these disclosures do not have provide express, implicit, or inherent support for palindromic nucleotide flow sequences of lengths greater than five and further do not provide any such support for any palindromic nucleotide flow sequence that utilizes all four different nucleotide species.
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 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.
Claim(s) 40-45 and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schultz (US 2017/0121766).
Schultz teaches an apparatus for sequencing a template polynucleotide strand that comprises a flow chamber (105) (i.e. flow cell), a plurality of reservoirs (114) configured to hold four different nucleotide species (see [0047] and FIG. 5). Schultz teaches that the apparatus further comprises a sensor array (100) that is operationally associated with the flow chamber that is loaded with a flow cell ([0050]). Schultz teaches that the sensor is configured to sense a signal produced from incorporation of a nucleotide species of the four different nucleotide species into a polynucleotide flow cell ([0025]). Schultz teaches that the apparatus further comprises a fluidics controller (118) that is operably coupled to the plurality of reservoirs and individually controls flow from the plurality of reservoirs to provide a series of nucleotide flows to the flow cell (see [0048] and FIG. 5). Schultz teaches that the series of nucleotide flows comprises: TACAT-ACGCA-CGTGC-GTATG, which contains four different palindromic nucleotide flow sequences in which each has a length of exactly five nucleotide flows and comprises exactly three different nucleotide species of the four different nucleotide species.
Regarding claim 41, Schultz teaches that the alternate ordering may be used with a conventional flow ordering ([0030]), which Schultz exemplifies as the flow ordering of ATGC (see FIG. 3A), which is not a palindromic nucleotide flow sequence.
Regarding claims 42-44, Schultz’s alternate flow ordering as discussed above comprises first and second palindromic nucleotide flow sequences of (1) ACGCA and (2) CGTGC, which are different from each other.
Regarding claim 45, Schultz’s alternate flow ordering as discussed above comprises four palindromic nucleotide flow sequences in which each comprises three of the four different nucleotide species and five nucleotide flows, the four palindromic nucleotide flow sequences differ from each other.
Regarding claim 48, Schultz teaches that the flow of a nucleotide species is always followed by a flow of a different kind ([0007]).
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.
Claims 21-35 and 37 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).
Regarding claim 21, Rothberg teaches an apparatus for the sequencing-by-synthesis of a polynucleotide strand (see [0124] and FIG. 8). In Fig. 8, Rothberg illustrates that it comprises a flow cell (200), a plurality of reservoirs (272) fluidically coupled to the flow cell and configured to hold dATP, dCTP, dGTP, and dTTP (i.e. four different nucleotide species), an ISFET array (100) (i.e. a sensor), and pumps (274) and valves (270) controlled by a computer (260) to individually control flow from the plurality of reservoirs (272) to provide a series of nucleotide flows to the flow cell (i.e. a fluidics controller) (see FIG. 8).
Regarding the ISFET array, Rothberg teaches that it comprises an “array” of “sensor elements” ([0015]) that facilitate measurement of the hydrogen ion concentration of a solution, commonly denoted as pH ([0003]). Rothberg teaches ISFET is a particular type of chemFET that is configured for ion detection ([0029]). Rothberg teaches that a new strand in synthesized by incorporating one or more of four different nucleotide triphosphates at the 3’ end of the sequencing primer, which is then detected by the chemFET ([0051] and [0122]).
Regarding the series of nucleotide flows, Rothberg teaches that the nucleotides are provided from the multiple reservoirs to the flow chamber in any sequential order ([0334]), and therefore teaches that the fluidics controller is programmed to successively provide nucleotide flows according to a predetermined ordering. Rothberg teaches a four nucleotide flow ordering of dATP, dCTP, dGTP, and dTTP, which can be repeated any number of times ([0335]), and therefore teaches a flow ordering that contains each of the four different nucleotide species, there is no consecutive repeat of any of the four different nucleotide species, and an order such that three different nucleotide species (e.g. dATP, dCTP, dGTP) occur before a fourth nucleotide species (e.g. dTTP).
However, Rothberg does not teach that one or more of the three different nucleotide species occurs at least twice before the fourth nucleotide species.
However, Rothberg does teach that the apparatus is intended to be used for the for sequencing-by-synthesis applications ([0124]) and further for the detection of mutations in certain genes such as deletions, additions, substitutions, and single nucleotide polymorphisms ([0353]).
In addition, Garcia teaches that pyrosequencing is a method for the sequencing-by-synthesis of a polynucleotide strand useful for the detection of mutations (see abstract and page 250, column 1, paragraph 1). Garcia teaches using a pyrosequencer apparatus (see page 250, column 2, last paragraph) that was programmed to successively deliver nucleotides to a polynucleotide template according to a customized programmed nucleotide dispensation order (i.e. a series of nucleotide flows) to detect mutations in the p53 gene (see Figure 4), as follows: A-G-T-C-T-G-A-G-A-G-A-C-G-C-G-C-A. Within this series of nucleotide flows that comprises a flow sequence of T-G-A-G-A-G-A-C, which comprises each of the four different nucleotide species, there no consecutive repeat of any of the four different nucleotide species, and it contains an order in which T, G, and A (i.e. three different nucleotide species) occur before C (i.e. the fourth nucleotide species), and G and A (i.e. one or more of the three different nucleotide species) occur three times (i.e. at least twice) before C (i.e. the fourth nucleotide species).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modified Rothberg’s pyrosequencing method by delivering nucleotides according to a predetermined ordering of Garcia because it would have merely required combining known elements according to known methods to yield predictable results. One would have been motivated to do so for the advantage of detecting p53 mutations, which have been associated with cancer, as taught by Garcia. It would have been predictable to do so because Rothberg teaches that the apparatus is intended to be used for sequencing-by-synthesis applications ([0124]) and further teaches that the nucleotides may be delivered in any order ([0334]), as discussed above.
Regarding claims 22 and 23, Rothberg teaches that the flow cell comprises a plurality of reaction chambers (i.e. reaction sites) comprising microwells ([0031]) that comprise a DNA template and sequencing primer (i.e. a polynucleotide) to which nucleotide triphosphates are sequentially incorporated ([0051] and [0124]).
Regarding claims 24 and 28, Rothberg teaches that the apparatus comprises a chemFET array (i.e. a plurality of sensors) comprising at least one chemFET (i.e. a sensor) for each reachtion chamber for the plurality of reaction chambers that detect incorporation of the nucleotide triphosphates ([0051]). Regarding claim 24, Rothberg further describes the alignment between the plurality of sensors and the plurality of reaction sites ([0251] and [0254]).
Regarding claims 25 and 26, Rothberg teaches that the sensor comprises an ion sensitive field effect transistor (ISFET) ([0003]), that is configured to measure pH ([0033]).
Regarding claim 27, Rothberg teaches that the sensor is configured to sense signals produced from incorporation of each of the four different nucleotide species into the polynucleotide ([0051]).
Regarding claim 29, Rothberg teaches that operation of an ISET is based on modulation of charge concentration caused by metal-oxide-semiconductor (MOS) capacitance ([0006]) and further teaches that the CMOS-fabricated sensors comprise the chemFET array (see [0037]).
Regarding claim 30, Rothberg teaches that the apparatus further comprises a reference electrode operatively coupled with the ISFET array ([0126]).
Regarding claims 31-33, Rothberg teaches that the polynucleotide is coupled to a bead in the flow cell that is attached to a chemFET array having separate reaction chambers for each sensor, wherein only one bead is situated in each reaction chamber ([0058]).
Regarding claim 34, Rothberg teaches that the apparatus comprises computer-controlled valves (i.e. a valve block) that fluidically couples the plurality of reservoirs (272) comprising the four different nucleotide species with the flow cell (200), the computer (260) (i.e. fluidic controller) operably coupled to control the valve block (see FIG. 8).
Regarding claim 35, the series of nucleotide flows of Garcia as discussed above comprises a nucleotide flow sequence of T-G-A-G-A-G-A-C in which G and A (i.e. two of the three different nucleotide species) occur three times (i.e. at least twice) before C (i.e. the fourth nucleotide species).
Regarding claim 37, the series of nucleotide flows of Garcia as discussed above comprises a nucleotide flow sequence of T-G-A-G-A-G-A-C in which G and A (i.e. one or more of the three different nucleotide species) occur three times before C (i.e. the fourth nucleotide species).
Claims 36, 38-40, 46, and 47 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), as applied to claim 21 above, and further in view of Raskind (US 2004/0106138).
The teachings of Rothberg and Garcia are discussed above,
Regarding claims 36, 38, and 39, the nucleotide flow sequence of Garcia does not meet the limitations of these claims.
However, Raskind further teaches that genetic mutations in protein kinase C gamma (PKC-gamma) are associated with ataxic neurological disease ([0006]). Raskind teaches that it is useful for identify genetic mutations to facilitate diagnosis of ataxic neurological disease and to identify carriers of the genetic defect ([0011]). Raskind teaches identifying PKC-gamma genetic mutations by amplifying the entire gene from genomic DNA followed by sequencing of the amplified DNA ([0031]). Raskind teaches using sequencing methods such as typical Sanger sequencing ([0033]). Raskind teaches a genetic mutation can be any alteration of the wild-type PKC-gamma sequence as provided by SEQ ID NO 3 including point mutations located in coding regions or even in regulatory regions that affect proper RNA processing or mRNA stability ([0036]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have configured the apparatus of Rothberg to detect mutations in the PKC-gamma gene according to Garcia’s programmed nucleotide dispensation strategy because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to do so for the advantage of detecting PKC-gamma mutations, specifically, which has been shown to be associated with disease, as taught by Raskind. One would have been motivated to use pyrosequencing to detect PKC-gamma mutations because Garcia teaches that it offers longer and faster reads and fewer out-of-phase problems (abstract).
Regarding the implementation of the programmed nucleotide dispensation ordering, Garcia illustrates how a programmed flow ordering is derived based on a target sequence. Garcia teaches that the p53 wild type sequence 5'-CTGGGAGAGACCGGCGCA-3' gives rise to the programmed flow ordering of C-T-G-A-G-A-G-A-C-G-C-G-C-A in which any consecutive nucleotide of the same kind is only represented by a single flow of that kind (see Figure 4). Raskind teaches that the PKC-gamma gene (SEQ ID NO 3) comprises the following sequence:
10481 CCGGCTCAGCGTGGAGGTGTGGGACTGGGACCGGACCTCC 10520
Accordingly, to apply Garcia's pyrosequencing method to the PKC-gamma gene would result in the following series of flows: C-G-C-T-C-A-G-C-G-T-G-A-G-T-G-T-G-A-C-T-G-A-C-G-A-C-T-C. This series of flows comprises the nucleotide flow sequence (underlined) of G-T-G-A-G-T-G-T-G-A-C.
Regarding claim 36, this nucleotide flow sequence comprises flows of G, T, and A at least twice before C (i.e. the fourth nucleotide species) is flowed.
Regarding claim 38, this nucleotide flow sequence comprises at least two flows of G and A (i.e. a first and second different nucleotide species) and three flows of T (i.e. the third nucleotide species) before the flow of C (i.e. the fourth different nucleotide species).
Regarding claim 39, this nucleotide flow sequence comprises five flows of G and three flows of T (i.e. two or more of the three different nucleotide species occur at least three times) before the flow of C.
Regarding claim 40, the teachings of Rothberg regarding the flow cell, the plurality of reservoirs, the sensor, and the fluidics controller are discussed above as applied to claim 21.
Rothberg does not teach that the series of nucleotide flows comprises a palindromic nucleotide flow sequence meeting predefined criteria such that the palindromic nucleotide flow sequence includes a palindromic sequence having a length of at least five nucleotide flows and comprises at least three different nucleotide species of the four different nucleotide species.
However, the obviousness of configuring the apparatus of Rothberg to sequence the PKC-gamma gene of Raskind by using the programmed nucleotide dispensation ordering strategy for the detection of gene mutations as described by Garcia is discussed above.
In addition, Raskind teaches that the PKC-gamma gene further comprises the following nucleotide sequence:
1621 ACTGCTGAGAACAGAGTGAG 1640
When Garcia’s programmed nucleotide dispensation strategy is applied to this sequence, it would give rise to the following series of nucleotide flows: ACTGCTGAGACAGAGTGAG, which comprises the palindromic nucleotide flow sequence of G-A-G-A-C-A-G-A-G, which comprises three different nucleotide species and nine (i.e. at least five) nucleotide flows. Accordingly, the obviousness of configuring the apparatus of Rothberg to sequence the PKC-gamma gene of Raskind by using the programmed nucleotide dispensation ordering strategy for the detection of gene mutations as described by Garcia also renders obvious a series of nucleotide flows that comprises a palindromic nucleotide flow sequence as required by claim 40.
Regarding claims 46 and 47, the palindromic nucleotide flow sequence G-A-G-A-C-A-G-A-G as identified above has a length of nine nucleotide flows (i.e. at least seven).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The 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 21-45 and 48 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). 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.
Conclusion
No claims are allowable.

APPLICANT REBUTTAL: R
EMARKS
I.
Claim Status:
Claim 21 is amended. Claims 40-48 are cancelled. New claims 49 and 50 are added. After the foregoing amendments are entered into the record, claims 21-39 and 49 and 50 will be pending in this case.
Support for the claim amendments can be found in the application as-filed, e.g., at paragraphs [0033], [0039] and [0042]. Thus, no new subject matter is added as a result of these amendments.
II.
Claim Re
j
ections Under 35 U.S.C.
X
Claim 45 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.
Claims 40-48 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.
In response, while not necessarily agreeing with the grounds for the rejection, Applicant has canceled claims 40-48, rendering the rejection under 35 U.S.C. § 112 moot.
III.
Claim Re
j
ections Under 35 U.S.C.
Claims 40-45 and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schultz (US 2017/0121766).
In response, while not necessarily agreeing with the grounds for the rejection, Applicant has canceled claims 40-45 and 48, rendering the rejection under 35 U.S.C. §102 moot.
IV.
Claim Re
j
ections Under 35 U.S.C.
Claims 21-35 and 37 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).
Claims 36, 38-40, and 46-47 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), as applied to claim 21 above,
and further in view of Raskind (US 2004/0106138).
In response, while not necessarily agreeing with the grounds for the rejection, Applicant has amended claim 21. The Office Action on page 11, 5th 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." The Office Action on page 12, 2nd paragraph, states:
In addition, Garcia teaches that pyrosequencing is a method for the sequencing -bysynthesis
of a polynucleotide strand useful for the detection of mutations (see abstract and page
250, column 1, paragraph 1). Garcia teaches using a pyrosequencer apparatus (see page 250,
column 2, last paragraph) that was programmed to successively deliver nucleotides to a
polynucleotide template according to a customized programmed nucleotide dispensation order (i.e. a series of nucleotide flows) to detect mutations in the p53 gene (see Figure4), as follows:
A-G-T-C-T-G-A-G-A-G-A-C-G-C-G-C-A. Within this series of nucleotide flows that comprises a
flow sequence of T-G-A-G-A-G-A-C, which comprises each of the four different nucleotide
species, there no consecutive repeat of any of the four different nucleotide species, and it
contains an order in which T, G, and A (i.e. three different nucleotide species) occur before C
(i.e. the fourth nucleotide species), and G and A (i.e. one or more of the three different
nucleotide species) occur three times (i.e. at least twice) before C (i.e. the fourth nucleotide species).
Claim 1 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 incorporation of a nucleotide species of the four different nucleotide species
into a polynucleotide 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 nucleotide flow sequence meeting
predefined criteria such that the nucleotide flow sequence includes:
each of the four different nucleotide species,
no consecutive repeat of any of the four different nucleotide species, and
an order such that three different nucleotide species of the four different nucleotide species
occur before a fourth nucleotide species of the four different nucleotide species, and such that one or more of the three different nucleotide species occurs at least twice before the fourth nucleotide species,
wherein the series of nucleotide flows includes one or more repeats of the nucleotide
flow sequence.
Applicant submits that Garcia does not teach or suggest that the programmed nucleotide flows "T-G- A-G-A-G-A-C" are repeated in the sequence "A-G-T-C-T-G-A-G-A-G-A-C-G-C-G-C-A" as shown in
Garcia's Figure 4. Garcia discloses a programmed nucleotide dispensation technique for detecting mutations of the human p53 gene. Garcia states, "In the programmed nucleotide dispensation strategy, the nucleotide dispensation order is pre-determined according to the wild-type consensus sequence of the gene." (Garcia at p. 253, left column, II. 9-13). Garcia's method does not repeat the nucleotide dispensation order "T-G-A-G- A-G-A-C" because it is not repeated in the wild-type consensus sequence of the p53 gene. Thus, Garcia does not cure the deficiencies of Rothberg with respect to claim 21.
For at least the above reasons, Applicant respectfully asserts that Rothberg and Garcia, alone or in combination, 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. Claims 40 and 46-47 are canceled. New claims 49 and 50 are allowable for at least the same reasons as claim 21 from which they depend.
Accordingly, Applicant respectfully requests reconsideration and withdrawal of the rejection of claims under 35 U.S.C. §103.
V.
Claim Re
j
ections Under Double Patentin
g:
Claims 21-45 and 48 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.
Claims 40-45 and 48 have been canceled. Applicant respectfully requests that the non-statutory double patenting rejections applied to claims 21-39 be held in abeyance until a determination of allowable subject matter has been fmally 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 4/17/2023.  Claims 21-39 and 49-50 are currently pending.  Claims 1-20 and 40-48 have been cancelled.  Claims 21-39 and 49-50 are presently under examination in this office action.
Any rejection or objection not reiterated herein has been overcome by amendment.  Applicant’s arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112 – New Rejection Necessitated by Applicant’s Amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA  35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA  35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 49 and 50 are rejected under 35 U.S.C. 112(d) or pre-AIA  35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 49, claim 49 recites “the one or more repeats of the nucleotide flow sequence includes a repeat of the whole nucleotide flow sequence”.  Claim 49 depends from claim 21, which recites that “the series of nucleotide flows includes one or more repeats of the nucleotide flow sequence.”  The broadest reasonable interpretation of claim 21 is that the nucleotide flow sequence, which is repeated, is repeated in full, because a repeat of a sequence would include the “whole” sequence being repeated.  Thus, claim 49 fails to further limit the scope of claim 21 from which it depends.
Regarding claim 50, claim 50 recites “the one or more repeats of the nucleotide flow sequence includes a repeat of a part of the nucleotide flow sequence.”  The broadest reasonable interpretation of a part of a nucleotide sequence is a single nucleotide.  The flow sequences of claim 21, from which claim 50 depends, contains each of the four possible nucleotides, which are recited in claim 21 to be repeated any number of times.  Thus, claim 50 is claiming any possible nucleotide sequence, in any flow order, because claim 50 is claiming that any individual part of a nucleotide flow sequence (i.e., any nucleotide) can be repeated any number of times.  This claim fails to limit the scope of its parent claim because it broadens the scope of the claim to include any nucleotide sequence which contains the nucleotide flow sequence claimed in claim 21.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103 - Maintained
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.
Claims 21-35 and 49-50 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) and GenBank p53 (NCBI Database accession number: AF307851.1, coding sequence of p53 gene published 1/29/2001, 2 pages).  This rejection is maintained but is updated as a result of applicant’s amendment.
Regarding claim 21, Rothberg teaches an apparatus for the sequencing-by-synthesis of a polynucleotide strand (see [0124] and FIG. 8). In Fig. 8, Rothberg illustrates that it comprises a flow cell (200), a plurality of reservoirs (272) fluidically coupled to the flow cell and configured to hold dATP, dCTP, dGTP, and dTTP (i.e. four different nucleotide species), an ISFET array (100) (i.e. a sensor), and pumps (274) and valves (270) controlled by a computer (260) to individually control flow from the plurality of reservoirs (272) to provide a series of nucleotide flows to the flow cell (i.e. a fluidics controller) (see FIG. 8).
Regarding the ISFET array, Rothberg teaches that it comprises an “array” of “sensor elements” ([0015]) that facilitate measurement of the hydrogen ion concentration of a solution, commonly denoted as pH ([0003]). Rothberg teaches ISFET is a particular type of chemFET that is configured for ion detection ([0029]). Rothberg teaches that a new strand is synthesized by incorporating one or more of four different nucleotide triphosphates at the 3’ end of the sequencing primer, which is then detected by the chemFET ([0051] and [0122]).
Regarding the series of nucleotide flows, Rothberg teaches that the nucleotides are provided from the multiple reservoirs to the flow chamber in any sequential order ([0334]), and therefore teaches that the fluidics controller is programmed to successively provide nucleotide flows according to a predetermined ordering. Rothberg teaches a four nucleotide flow ordering of dATP, dCTP, dGTP, and dTTP, which can be repeated any number of times ([0335]), and therefore teaches a flow ordering that contains each of the four different nucleotide species, there is no consecutive repeat of any of the four different nucleotide species, and an order such that three different nucleotide species (e.g. dATP, dCTP, dGTP) occur before a fourth nucleotide species (e.g. dTTP).
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 repeated at least once.
However, Rothberg does teach that the apparatus is intended to be used for the for sequencing-by-synthesis applications ([0124]) and further for the detection of mutations in certain genes such as deletions, additions, substitutions, and single nucleotide polymorphisms ([0353]).
In addition, Garcia teaches that pyrosequencing is a method for the sequencing-by-synthesis of a polynucleotide strand useful for the detection of mutations (see abstract and page 250, column 1, paragraph 1). Garcia teaches using a pyrosequencer apparatus (see page 250, column 2, last paragraph) that was programmed to successively deliver nucleotides to a polynucleotide template according to a customized programmed nucleotide dispensation order (i.e. a series of nucleotide flows) to detect mutations in the p53 gene (see Figure 4), as follows: A-G-T-C-T-G-A-G-A-G-A-C-G-C-G-C-A. Within this series of nucleotide flows that comprises a flow sequence of T-G-A-G-A-G-A-C, which comprises each of the four different nucleotide species, there are no consecutive repeats of any of the four different nucleotide species, and it contains an order in which T, G, and A (i.e. three different nucleotide species) occur before C (i.e. the fourth nucleotide species), and G and A (i.e. one or more of the three different nucleotide species) occur three times (i.e. at least twice) before C (i.e. the fourth nucleotide species).  Furthermore, Garcia teaches that there are advantages to using to using programmed nucleotide dispensation when sequencing, stating that this approach leads to “longer and faster reads, and fewer out-of-phase problems”, Abstract.  Thus, Garcia teaches that their method can be applied to sequencing in general with improved results including longer, fast reads and also corrects phase problems which occur when sequencing.
As discussed above, Garcia teaches sequencing the p53 gene, but the specific sequence recited in their article is not repeated during the sequencing process.  GenBank p53, the genomic sequence of the gene p53, teaches that the p53 gene contains the sequence “ATGAGC” twice in the sequence of the gene at positions 671-676 and 794-799, respectively.  Thus, a practitioner sequencing the p53 gene using the predetermined/programmed nucleotide dispensation nucleotide flow technique taught by Garcia would flow the series ATGAGC twice (i.e., at least one repeat) during the sequencing process taught by Garcia.  The sequence ATGAGC contains each of the four different nucleotide species, no consecutive repeats of any of the four different nucleotide species, and an order where three different nucleotide species occur before the fourth nucleotide species where one or more of the three occurs twice (“A” and “G” occur twice before “C”).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Rothberg’s pyrosequencing method by delivering nucleotides according to a predetermined ordering of Garcia because it would have merely required combining known elements according to known methods to yield predictable results. One would have been motivated to do so to properly and accurately sequence the p53 gene, which has been associated with cancer, as taught by Garcia.  Thus, there is motivation to sequence the p53 gene, which is relevant in human health.  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. It would have been predictable to do so because Rothberg teaches that the apparatus is intended to be used for sequencing-by-synthesis applications ([0124]) and further teaches that the nucleotides may be delivered in any order ([0334]), as discussed above.
Regarding claims 22 and 23, Rothberg teaches that the flow cell comprises a plurality of reaction chambers (i.e. reaction sites) comprising microwells ([0031]) that comprise a DNA template and sequencing primer (i.e. a polynucleotide) to which nucleotide triphosphates are sequentially incorporated ([0051] and [0124]).
Regarding claims 24 and 28, Rothberg teaches that the apparatus comprises a chemFET array (i.e. a plurality of sensors) comprising at least one chemFET (i.e. a sensor) for each reaction chamber for the plurality of reaction chambers that detect incorporation of the nucleotide triphosphates ([0051]). Regarding claim 24, Rothberg further describes the alignment between the plurality of sensors and the plurality of reaction sites ([0251] and [0254]).
Regarding claims 25 and 26, Rothberg teaches that the sensor comprises an ion sensitive field effect transistor (ISFET) ([0003]), that is configured to measure pH ([0033]).
Regarding claim 27, Rothberg teaches that the sensor is configured to sense signals produced from incorporation of each of the four different nucleotide species into the polynucleotide ([0051]).
Regarding claim 29, Rothberg teaches that operation of an ISET is based on modulation of charge concentration caused by metal-oxide-semiconductor (MOS) capacitance ([0006]) and further teaches that the CMOS-fabricated sensors comprise the chemFET array (see [0037]).
Regarding claim 30, Rothberg teaches that the apparatus further comprises a reference electrode operatively coupled with the ISFET array ([0126]).
Regarding claims 31-33, Rothberg teaches that the polynucleotide is coupled to a bead in the flow cell that is attached to a chemFET array having separate reaction chambers for each sensor, wherein only one bead is situated in each reaction chamber ([0058]).
Regarding claim 34, Rothberg teaches that the apparatus comprises computer-controlled valves (i.e. a valve block) that fluidically couples the plurality of reservoirs (272) comprising the four different nucleotide species with the flow cell (200), the computer (260) (i.e. fluidic controller) operably coupled to control the valve block (see FIG. 8).
Regarding claim 35, the series of nucleotide flows of Garcia as discussed above comprises a nucleotide flow sequence ATGAGC, which contains two “A” and “G” nucleotides before the fourth nucleotide (“C”) is flowed.
Regarding claim 49, as discussed above, the sequence ATGAGC occurs in its entirety twice in the p53 gene, and thus the whole nucleotide flow sequence ATGAGC would be repeated when sequencing the p53 gene according to the method of Garcia.
Regarding claim 50, the broadest reasonable interpretation of this claim is that any part of the nucleotide flow sequence would be repeated.  A “part” of the nucleotide flow sequence includes, for instance, any single nucleotide from the sequence.  The sequence ATGAGC occurs in the p53 gene and, additionally, a “part” of this sequence (i.e., either an “A”, “T”, “G”, or “C”) occurs after this sequence.  Thus, when sequencing the p53 genome using the method of Garcia, a practitioner would flow the sequence ATGAGC, which is not a sequence at the terminus of the p53 gene, and then later flow (i.e., repeat) another nucleotide (i.e., a “part of the” flow sequence ATGAGC), for instance, a “C” nucleotide.
Claims 21-39 and 49-50 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), as applied to claim 21 above, and further in view of Raskind (US 2004/0106138).
Regarding claims 21, the teachings of Rothberg and Garcia are discussed above.  Garcia teaches that their method of using a programmed or pre-determined nucleotide dispensation approach improves sequencing results because it is fast, allows for longer reads, and also corrects out-of-phase issues that arise when sequencing (Garcia’s Abstract).  Garcia also taught and demonstrated the accuracy of pyrosequencing (Abstract).
Raskind further teaches that genetic mutations in protein kinase C gamma (PKC-gamma) are associated with ataxic neurological disease ([0006]). Raskind teaches that it is useful to identify genetic mutations to facilitate diagnosis of ataxic neurological disease and to identify carriers of the genetic defect ([0011]). Raskind teaches identifying PKC-gamma genetic mutations by amplifying the entire gene from genomic DNA followed by sequencing of the amplified DNA ([0031]). Raskind teaches using sequencing methods such as typical Sanger sequencing ([0033]). Raskind teaches a genetic mutation can be any alteration of the wild-type PKC-gamma sequence as provided by SEQ ID NO 3 including point mutations located in coding regions or even in regulatory regions that affect proper RNA processing or mRNA stability ([0036]).  Thus, Raskind teaches the importance of sequencing the PKC-gamma gene in its entirety, because this gene is important in human health.  Raskind also teaches SEQ ID NO 3, the wildtype PKC-gamma sequence.
Regarding the implementation of the programmed nucleotide dispensation ordering, Garcia illustrates how a programmed flow ordering is derived based on a target sequence. Garcia teaches that the p53 wild type sequence 5'-CTGGGAGAGACCGGCGCA-3' gives rise to the programmed flow ordering of C-T-G-A-G-A-G-A-C-G-C-G-C-A in which any consecutive nucleotide of the same kind is only represented by a single flow of that kind (see Figure 4).
SEQ ID NO 3, as taught by Raskind, contains two instances of the sequence “AGTGATC”, occurring at positions 12,640-12,646 and 18,106-112, respectively.  Thus, a practitioner sequencing SEQ ID NO 3 according to the method of Garcia would flow the sequence AGTGATC twice (i.e., the flow would be repeated at least once).  The sequence AGTGATC contains three different nucleotide species (“A”, “G”, and “T”) which occur twice before the fourth nucleotide species (“C”) (i.e., one or more of the three different nucleotide species occurs at least twice before the fourth nucleotide species).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have configured the apparatus of Rothberg to sequence the PKC-gamma gene according to Garcia’s programmed nucleotide dispensation strategy because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because Garcia taught that their sequencing dispensation method offers sequencing advantages including correction for out-of-phase sequences, and also improves speed and the length of the reads. Additionally, a practitioner would be motivated to sequence the PKC-gamma gene because it has been shown to be associated with disease, as taught by Raskind. One would have been motivated to use pyrosequencing to detect PKC-gamma gene sequences because Garcia has taught that it is an accurate method for sequencing.
Regarding claims 22-34, these claim limitations are addressed above in the separate 103 rejection provided.
Regarding claims 35 and 36, as discussed above in the rejection of claim 21, Raskind’s SEQ ID NO 3 contains the sequence “AGTGATC” twice in its sequence.  This sequence contains all four nucleotide species, where A”, “G”, and “T” each occur twice before “C” (the “fourth” species).  A practitioner sequencing SEQ ID NO 3 of Raskind would flow the sequence “AGTGATC” twice (i.e., there would be one or more repeats of the flow sequence).
Regarding claim 37, as discussed above, Raskind teaches the sequence of PKC-gamma (SEQ ID NO 3).  SEQ ID NO 3 contains two occurrences of the sequence GCGCGAT, which contains three nucleotide species (“G”, “C”, and “A”) occurring before the fourth nucleotide species (“T”).  This sequence contains three “G” nucleotides, and corresponds to the criteria recited in present claim 37.  Because this sequence is repeated in SEQ ID NO 3 of Raskind (positions 8,261-8,267 and 17,591-17,597, respectively), a practitioner would flow this sequence twice (i.e., repeat the flow sequence at least once) when performing the sequencing method of Garcia to sequence SEQ ID NO 3.
Regarding claim 38, SEQ ID NO 3 of Raskind contains two occurrences of the sequence ACTCATCG, which contains three nucleotide species (“T”, “C”, and “A”) occurring before the fourth nucleotide species (“G”).  This sequence contains two different nucleotide species (“A” and “T”) which occur twice before the fourth species (“G”) and one species (“C”) which occurs three times before the fourth species (“G”).  Because this sequence is repeated in SEQ ID NO 3 of Raskind (positions 16,765-16,772, and 16,853-16,860 respectively), a practitioner would flow this sequence twice (i.e., repeat the flow sequence at least once) when performing the sequencing method of Garcia to sequence SEQ ID NO 3.
Regarding claim 39, SEQ ID NO 3 of Raskind contains three occurrences of the sequence AGAGAGATC, which contains three nucleotide species (“A”, “G”, and “T”) occurring before the fourth species (“C”). This sequence contains two or more species (“A” and “G”) which occur at least three times before the fourth species (“C”).  Because this sequence is repeated in SEQ ID NO 3 of Raskind three times (positions 3,649-3,657, 10,187-10,195, and 22,407-22,415, respectively), a practitioner would flow this sequence three times (i.e., repeat the flow sequence at least once) when performing the sequencing method of Garcia to sequence SEQ ID NO 3.
Regarding claim 49, as discussed above, the flow sequences discussed in the rejections of claims 36-39 are repeated in their entirety (“whole”) in SEQ ID NO 3, and a practitioner sequencing the SEQ ID NO 3 using the methods of Rothberg, Garcia, and Raskind would repeat the above nucleotide flow sequences in their entirety.
Regarding claim 50, recitation of the phrase “a part of the nucleotide flow sequence” is most reasonably interpreted to mean a single nucleotide from the flow sequence.  A repeat of “a part of the nucleotide flow sequence” therefore simply means that the flow series would contain a predefined flow sequence and also any other single nucleotide.  A practitioner sequencing SEQ ID NO 3 of Raskind following the teachings of Rothberg, Garcia, and Raskind would certainly flow at least one other nucleotide in order to sequence SEQ ID NO 3.
Response to Arguments - 103
Applicant's arguments filed 4/17/2023 have been fully considered but they are not persuasive. Applicant argues that:
“Garcia does not teach or suggest that the programmed nucleotide flows “T-G- A-G-A-G-A-C” are repeated in the sequence “A-G-T-C-T-G-A-G-A-G-A-C-G-C-G-C-A” as shown in Garcia’s Figure 4. Garcia discloses a programmed nucleotide dispensation technique for detecting mutations of the human p53 gene. Garcia states, “In the programmed nucleotide dispensation strategy, the nucleotide dispensation order is pre-determined according to the wild-type consensus sequence of the gene.” (Garcia at p. 253, left column, II. 9-13). Garcia’s method does not repeat the nucleotide dispensation order “T-G-A-G- A-G-A-C” because it is not repeated in the wild-type consensus sequence of the p53 gene. Thus, Garcia does not cure the deficiencies of Rothberg with respect to claim 21” page 8, first paragraph of applicant arguments and remarks.
This argument is not found persuasive because, as discussed above, the genome sequence of p53 contains other repeated elements which satisfy the claim requirements of claim 21 (see 103 rejection of claim 21).  Furthermore, there is sufficient motive to sequence the p53 gene because as discussed above p53 is an important gene in human health.  Thus, while the sequence listed in the argument above is not repeated in wildtype p53, other sequences which fit the criteria of the elements recited in claim 21 are repeated in the wildtype p53 gene, as taught by GenBank p53 (see claim 21-35 rejections, above).  Therefore, sequencing the wildtype p53 gene using the methods taught by Rothberg and Garcia would require a flow sequence such as that recited in claim 21, which would be repeated at least once.  Furthermore, claims 35-39 have additional limitations for sequences which are repeated in a target sequence.  Raskind discloses PKC-gamma, which is a gene that is relevant to human health and there therefore exists a motive to sequence this gene.  Sequencing PKC-gamma using the methods of Rothberg, Garcia, and Raskind would yield nucleotide flow sequences such as those recited in claims 35-39.
The sequences listed in the rejections of claims 21 and 35-39 are repeated in p53 (claims 21 and 35) or the PKC-gamma wildtype genes (claims 36-39, which sequences also read on claim 21).  The applicant’s arguments are therefore not persuasive because sequencing either the p53 or PKC-gamma genes using the methods of Rothberg, Garcia, and Raskind would yield nucleotide flow patterns such as those recited in the present claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The 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 and 49-50 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 4/17/2023 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.  The non-statutory double patenting rejection is therefore maintained.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action.  Accordingly, THIS ACTION IS MADE FINAL.  See MPEP § 706.07(a).  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 extension fee 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 date of this final action.

CITED REFERENCE SUMMARIES: Ref US9605308B2: Claims:
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.
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.
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.
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.
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.
The apparatus of claim 3 , wherein the polynucleotide strands are attached to beads that are contained in the microwells of the microwell array.
The apparatus of claim 1 , wherein the predetermined ordering consists of only the alternate ordering.
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.
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.
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.
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.
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.
The apparatus of claim 1 , wherein the alternate ordering is repeated two or more times.
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.
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.
The apparatus of claim 13 , wherein the alternate ordering is repeated two or more times.
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.
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.
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.
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.
Ref US20090127589A1: Claims:
An apparatus, comprising: an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) and occupying an area on a surface of the array of approximately ten micrometers by ten micrometers or less.
an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) and occupying an area on a surface of the array of approximately ten micrometers by ten micrometers or less.
- 20 . (canceled)
A sensor array ( 100 ), comprising: a two-dimensional array of electronic sensors ( 105 ) including at least 512 rows and at least 512 columns of the electronic sensors, each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) configured to provide at least one output signal representing a presence and/or concentration of an analyte proximate to a surface of the two-dimensional array.
a two-dimensional array of electronic sensors ( 105 ) including at least 512 rows and at least 512 columns of the electronic sensors, each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) configured to provide at least one output signal representing a presence and/or concentration of an analyte proximate to a surface of the two-dimensional array.
- 40 . (canceled)
An apparatus, comprising: an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ), wherein the array of CMOS-fabricated sensors includes more than 256 sensors, wherein a collection of chemFET output signals from all chemFETs of the array constitutes a frame of data, and wherein the apparatus further comprises: control circuitry ( 110 , 192 , 194 , 198 ) coupled to the array and configured to generate at least one array output signal (Vout) to provide multiple frames of data from the array at a frame rate of at least 1 frame per second.
an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ),
wherein the array of CMOS-fabricated sensors includes more than 256 sensors, wherein a collection of chemFET output signals from all chemFETs of the array constitutes a frame of data, and wherein the apparatus further comprises:
control circuitry ( 110 , 192 , 194 , 198 ) coupled to the array and configured to generate at least one array output signal (Vout) to provide multiple frames of data from the array at a frame rate of at least 1 frame per second.
- 50 . (canceled)
An apparatus, comprising: an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising a chemically-sensitive field effect transistor (chemFET) ( 150 ), the chemFET comprising: a floating gate structure ( 170 ); and a source ( 156 ) and a drain ( 158 ) having a first semiconductor type and fabricated in a region ( 154 ) having a second semiconductor type, wherein there is no electrical conductor that electrically connects the region having the second semiconductor type to either the source or the drain.
an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising a chemically-sensitive field effect transistor (chemFET) ( 150 ), the chemFET comprising: a floating gate structure ( 170 ); and a source ( 156 ) and a drain ( 158 ) having a first semiconductor type and fabricated in a region ( 154 ) having a second semiconductor type, wherein there is no electrical conductor that electrically connects the region having the second semiconductor type to either the source or the drain.
a floating gate structure ( 170 ); and
a source ( 156 ) and a drain ( 158 ) having a first semiconductor type and fabricated in a region ( 154 ) having a second semiconductor type, wherein there is no electrical conductor that electrically connects the region having the second semiconductor type to either the source or the drain.
- 73 . (canceled)
An apparatus, comprising: an array ( 100 ) of electronic sensors ( 105 ), each sensor consisting of three field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ).
an array ( 100 ) of electronic sensors ( 105 ), each sensor consisting of three field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ).
An apparatus, comprising: an array ( 100 ) of electronic sensors ( 105 ), each sensor comprising three or fewer field effect transistors (FETs), wherein the three or fewer FETs includes one chemically-sensitive field effect transistor (chemFET) ( 150 ).
an array ( 100 ) of electronic sensors ( 105 ), each sensor comprising three or fewer field effect transistors (FETs), wherein the three or fewer FETs includes one chemically-sensitive field effect transistor (chemFET) ( 150 ).
An apparatus, comprising: an array ( 100 ) of electronic sensors ( 105 ), each sensor comprising: a plurality of field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ); and a plurality of electrical conductors electrically connected to the plurality of FETs, wherein the plurality of FETs are arranged such that the plurality of electrical conductors includes no more than four conductors traversing an area occupied by each sensor and interconnecting multiple sensors of the array.
an array ( 100 ) of electronic sensors ( 105 ), each sensor comprising: a plurality of field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ); and a plurality of electrical conductors electrically connected to the plurality of FETs, wherein the plurality of FETs are arranged such that the plurality of electrical conductors includes no more than four conductors traversing an area occupied by each sensor and interconnecting multiple sensors of the array.
a plurality of field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ); and
a plurality of electrical conductors electrically connected to the plurality of FETs,
wherein the plurality of FETs are arranged such that the plurality of electrical conductors includes no more than four conductors traversing an area occupied by each sensor and interconnecting multiple sensors of the array.
An apparatus, comprising: an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising a plurality of field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ), wherein all of the FETs in each sensor are of a same channel type and implemented in a single semiconductor region of an array substrate.
an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising a plurality of field effect transistors (FETs) including one chemically-sensitive field effect transistor (chemFET) ( 150 ), wherein all of the FETs in each sensor are of a same channel type and implemented in a single semiconductor region of an array substrate.
A sensor array ( 100 ), comprising: a plurality of electronic sensors ( 105 ) arranged in a plurality of rows and a plurality of columns, each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) configured to provide at least one output signal representing a presence and/or a concentration of an analyte proximate to a surface of the array, wherein for each column of the plurality of columns, the array further comprises: column circuitry ( 110 ) configured to provide a constant drain current and a constant drain-to-source voltage to respective chemFETs in the column, the column circuitry including two operational amplifiers and a diode-connected FET arranged in a Kelvin bridge configuration with the respective chemFETs to provide the constant drain-to-source voltage.
a plurality of electronic sensors ( 105 ) arranged in a plurality of rows and a plurality of columns, each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) configured to provide at least one output signal representing a presence and/or a concentration of an analyte proximate to a surface of the array,
wherein for each column of the plurality of columns, the array further comprises:
column circuitry ( 110 ) configured to provide a constant drain current and a constant drain-to-source voltage to respective chemFETs in the column, the column circuitry including two operational amplifiers and a diode-connected FET arranged in a Kelvin bridge configuration with the respective chemFETs to provide the constant drain-to-source voltage.
A sensor array ( 100 ), comprising: a plurality of electronic sensors ( 105 ) arranged in a plurality of rows and a plurality of columns, each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) configured to provide at least one output signal representing a concentration of ions in an analyte proximate to a surface of the array; at least one row select shift register ( 192 ) to enable respective rows of the plurality of rows; and at least one column select shift register ( 194 ) to acquire chemFET output signals from respective columns of the plurality of columns.
a plurality of electronic sensors ( 105 ) arranged in a plurality of rows and a plurality of columns, each sensor comprising one chemically-sensitive field effect transistor (chemFET) ( 150 ) configured to provide at least one output signal representing a concentration of ions in an analyte proximate to a surface of the array;
at least one row select shift register ( 192 ) to enable respective rows of the plurality of rows; and
at least one column select shift register ( 194 ) to acquire chemFET output signals from respective columns of the plurality of columns.
- 85 . (canceled)
An apparatus, comprising: an array ( 100 ) of CMOS-fabricated sensors ( 105 ), each sensor comprising a chemically-sensitive field effect transistor (chemFET) ( 150 ), the chemFET comprising: a floating gate structure ( 170 ); and a source ( 156 ) and a drain ( 158 ) having a first semiconductor type and fabricated in a region ( 154 ) having a second semiconductor type, wherein there is no electrical conductor that electrically connects the region having the second semiconductor type to either the source or the drain, wherein: the array includes a two-dimensional array of at least 512 rows and at least 512 columns of the CMOS-fabricated sensors; each sensor consists of three field effect transistors (FETs) including the chemFET; each sensor includes a plurality of electrical conductors electrically connected to the three FETs; the three FETs are arranged such that the plurality of electrical conductors includes no more than four conductors traversing an area occupied by each sensor and interconnecting multiple sensors of the array; all of the FETs in each sensor are of a same channel type and implemented in a single semiconductor region of an array substrate; and a collection of chemFET output signals from all chemFETs of the array constitutes a frame of data, and wherein the apparatus further comprises: control circuitry ( 110 , 192 , 194 , 198 ) coupled to the array and configured to generate at least one array output signal (Vout) to provide multiple frames of data from the array at a frame rate of at least 20 frames per second.
an array ( 100 ) of CMOS-fabricated sensors ( 105 ), 
[Truncated to input limit]