Office Action 2: Final Rejection (2023-07-28)
Rejection types: 103 - Obviousness, Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS

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

Appl. No.: 16/53 5,565

1-20. (Canceled)219

21\. (Currently Amended) An apparatus comprising:
a flow cell;
a plurality of reservoirs fluidically coupled to the flow cell, the plurality of reservoirs configured to respectively hold four different nucleotide species;
a sensor operably coupled to the flow cell, the sensor being configured to sense one or more signals produced from 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 ofnucleotide flows includes one or more repeats ofthe nucleotide flow sequence.

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

23\. (Previously Presented) The apparatus of claim 22, wherein the plurality of reaction sites comprise a plurality of microwells.
24\. (Previously Presented) The apparatus of claim 22, wherein the apparatus comprises a plurality of sensors, the plurality of sensors comprising the sensor, the plurality of sensors aligned with the plurality of reaction sites, and each sensor of the plurality configured to sense one or more signals produced from incorporation of the nucleotide species at a corresponding reaction site.
25\. (Previously Presented) The apparatus of claim 21, wherein the sensor is configured to sense pH.
26\. (Previously Presented) The apparatus of claim 21, wherein the sensor comprises a field effect transistor (FET).
27\. (Previously Presented) The apparatus of claim 21, wherein the sensor is configured to sense one or more signals produced from incorporation each of the four different nucleotide species into the polynucleotide.
28\. (Previously Presented) The apparatus of claim 21, wherein the apparatus comprises a plurality of sensors, the plurality of sensors comprising the sensor, each sensor of the plurality configured to sense one or more signals produced from incorporation of the nucleotide species.
29\. (Previously Presented) The apparatus of claim 21, wherein the sensor is one of a plurality of sensors of a sensor array, and the apparatus further comprises a semiconductor substrate, the semiconductor substrate comprising the sensor array.
30\. (Previously Presented) The apparatus of claim 21, further comprising a reference electrode operatively coupled to the sensor.
31\. (Previously Presented) The apparatus of claim 21, wherein the polynucleotide is coupled to a support.

32\. (Previously Presented) The apparatus of claim 31, wherein the support comprises a bead in the flow cell.
33\. (Previously Presented) The apparatus of claim 31, wherein the support is operatively coupled to the sensor.
34\. (Previously Presented) The apparatus of claim 21, further comprising a valve block fluidically coupling the plurality of reservoirs and the flow cell, the fluidic controller operably coupled to control the valve block.
35\. (Previously Presented) The apparatus of claim 21, wherein two or more of the three different nucleotide species occur at least twice before the fourth different nucleotide species is flowed in the nucleotide flow sequence.
36\. (Previously Presented) The apparatus of claim 21, wherein all three of the three different nucleotide species occur at least twice before the fourth different nucleotide species is flowed in the nucleotide flow sequence.
37\. (Previously Presented) The apparatus of claim 21, wherein one or more of the three different nucleotide species occurs at least three times before the fourth different nucleotide species is flowed in the nucleotide flow sequence.
38\. (Previously Presented) The apparatus of claim 21, wherein a first and second different nucleotide species of the three different nucleotide species 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\. (Previously Presented) 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\. -48. (Canceled)4147

Appl. No.: 16/535,565

49\. (New) The apparatus of claim 21, wherein the one or more repeats of the nucleotide flow sequence includes a repeat of the whole nucleotide flow sequence.

50\. (New) The apparatus of claim 21, wherein the one or more repeats of the nucleotide flow sequence includes a repeat of a part of the nucleotide flow sequence.

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.

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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection.  Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.  Applicant's submission filed on 10/30/2023 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 10/30/2023.  Claims 21-39 are currently pending.  Claims 1-20 and 40-50 have been cancelled.  Claims 21-39 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 § 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 21-39 are rejected under 35 U.S.C. 103 as being unpatentable over Rothberg (US 2009/0127589) in view of Garcia (Garcia et al. (2000) Gene, 253:249-257), GenBank FJ883007 (NCBI Database accession number: FJ883007, portion of the coding region of Cercopithecine herpesvirus 5, 2 pages, published 2009), and Alcendor (Alcendor DJ et al. Virology. 2009 Dec 5;395(1):21-32).
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 consecutively 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 by sequencing (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 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 consecutively during the sequencing process.  GenBank FJ883007, a portion of the genomic sequence of the cercopithecine herpesvirus 5 virus, teaches that the sequence “T-G-T-G-A-G-A-T-A-C” occurs successively at position 546 (GenBank FJ883007, second page, beginning at position 546).  Thus, a practitioner sequencing this herpesvirus using the predetermined/programmed nucleotide dispensation nucleotide flow technique taught by Garcia would flow the series “T-G-T-G-A-G-A-T-A-C” twice (consecutively) during the sequencing process taught by Garcia.  The sequence “T-G-T-G-A-G-A-T-A-C” 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”, “G”, and “T” occur three times before “C”).
Furthermore, GenBank FJ883007 was uploaded in connection with the research article taught by Alcendor in 2009.  Alcendor teaches patterns of viral divergence in cytomegalovirus genomes (Abstract, throughout) where GenBank FJ883007 is one such virus (see page 1 of GenBank FJ883007, which indicates that the viral sequence was uploaded in conjunction with Alcendor).  Additionally, Alcendor references GenBank accession number FJ883007 directly (page 11, “GenBank accession numbers”, line 2) as one of the viral sequences which they sequenced.   Furthermore, Alcendor teaches that:
“Although the functions of most primate CMV vCXCLs and vGPCRs are unknown, most of them are dispensible in fibroblast cell cultures. Nonetheless, in our opinion, each paralog is likely to have its own role during infection in vivo, whether as a chemokine or as some other function. The limited information available points to a role in virus spread and dissemination in vivo for HCMV UL146 vCXCL, which binds in a species-specific fashion to human CXCLR2”, Introduction, fourth paragraph,
and
“we have compared the organization of the two clusters with those in other known primate CMVs, and attempted to deduce some of the duplication and deletion events that might have occurred during their capture and subsequent divergent evolution into the different viral lineages”, Introduction, final sentence.
Alcendor therefore teaches that more information of CMV viruses is required to understand their in vivo infection mechanisms, as there is limited information currently available for these viruses.  Alcendor further teaches that such information could be useful in understanding viral “spread” and “dissemination” in vivo for human cytomegaloviruses (HCMV) (Introduciton, fourth paragraph, above).  Thus, Alcendor teaches a motivation to sequence CMV viral genomes, including GenBank FJ883007 for the purposes of comparative viral evolutionary analysis.
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 combine Rothberg and Garcia to properly and accurately sequence the p53 gene taught by Garcia, which has 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.  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.  Therefore, the advantages of the sequencing method of Garcia can be broadly applied to sequencing of any organism.  As such, a practitioner would be further motivated to use the sequencing method of Garcia to sequence the cytomegalovirus taught by GenBank FJ883007 and Alcendor, as this was a known sequence, and Alcendor teaches motivation to sequence such viruses for comparative evolutionary biology purposes in order to better understand viruses which can infect humans.
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 claims 35-39, the sequence discussed above in the rejection of claim 21 found in GenBank FJ883007 (“T-G-T-G-A-G-A-T-A-C”) occurs consecutively (beginning at position 546 of GenBank FJ883007) and furthermore this sequence reads on the claim limitations set forth in claims 35-39.
Response to Arguments
Applicant's arguments filed 10/30/2023 have been fully considered but they are not persuasive. Applicant has amended independent claim 21 to specify that the series of nucleotide flows includes one or more consecutive repeats of the nucleotide flow sequence.  Applicant argues on page 7 of the remarks, second paragraph, that the previously recited prior art does not teach that the recited nucleotide flow sequences are “consecutive repeats”.  The Office maintains that the combination of Rothberg and Garcia arrives at alternative flow sequencing, and further The Office has expanded its search to include sequences which a practitioner would reasonably sequence which contain “consecutive” repeats which also adhere to the recited criteria of the claim limitations.  As a result, The Office argues that a practitioner would be motivated to sequence cytomegaloviruses such as those taught by Alcendor (see above), including the viral genome comprising the sequence taught in GenBank FJ883007 (above).  This sequence contains the sequence “T-G-T-G-A-G-A-T-A-C” consecutively:  this sequence reads on claims 21 and 35-39 and the limitations set forth in said claims.  Furthermore, The Office asserts that a practitioner would be motivated to sequence CMV viruses, to better understand viral lineages and evolutionary viral divergences, especially in light of the fact that Alcendor teaches a deficiency in such knowledge (see 103 rejection above). Furthermore, Alcendor’s sequencing of the CMV viruses discussed above alone is evidence that a virologist would be motivated to sequence such viruses.  As Garcia’s sequencing method is broadly applicable to sequencing strategies, and also has known advantages (above), a practitioner would be motivated to apply such sequencing strategies to a given sequence such as GenBank FJ883007.
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 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 10/30/2023 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

CITED REFERENCE SUMMARIES: Ref US20090127589: Claims:
1. 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.
2-20. (canceled)
21. 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.
22-40. (canceled)
41. 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.
42-50. (canceled)
51. 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.
52-73. (canceled)
74. 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).
75. (canceled)
76. 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).
77. 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.
78. 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.
79. (canceled)
80. 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.
81. 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.
82-85. (canceled)
86. 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.
87. A method for processing an array (100) of CMOS-fabricated sensors (105), each sensor comprising a chemically-sensitive field effect transistor (chemFET) (150), the method comprising:
A) dicing a semiconductor wafer including the array to form at least one diced portion including the array; and B) performing a forming gas anneal on the at least one diced portion.
88-93. (canceled)
94. A method for processing an array (100) of CMOS-fabricated sensors (105), each sensor comprising a chemically-sensitive field effect transistor (chemFET) (150) having a chemically-sensitive passivation layer of silicon nitride and/or silicon oxynitride deposited via plasma enhanced chemical vapor deposition (PECVD), the method comprising:
A) depositing at least one additional passivation material on the chemically-sensitive passivation layer so as to reduce a porosity and/or increase a density of the passivation layer.
95-101. (canceled)
102. An apparatus comprising
a chemical-sensitive field effect transistor (chemFET) having disposed on its surface a PPi receptor.
103. A fluidics assembly for use with an array of sensors on an active semiconductor device capped with a protective layer, comprising:
a first member having therein an aperture for mating to the sensor array; and a second member fixed to the first member in a fluid-tight seal therebetween, and having first and second fluid ports for supporting fluid passage, the first and second members and the sensor array defining a fluid chamber, whereby fluid introduced into one of said ports flows over the array before exiting via the other of said ports.
104. A fluidics assembly for use with an array of sensors on an active semiconductor device capped with a protective layer, comprising:
a microwell array configured and arranged to provide fluid access to said protective layer; a first member having therein an aperture for mating to the sensor array around the microwell array; and a second member fixed to the first member in a fluid-tight seal therebetween, and having first and second fluid ports for supporting fluid passage, the first and second members and the microwell array defining a fluid chamber over the protective layer of the semiconductor device when mated to the sensor array, whereby fluid introduced into one of said ports flows over the microwell array before exiting via the other of said ports and the active semiconductor device senses chemical activity in at least some of the microwells in the microwell array.
105-106. (canceled)
Ref US20040106138: Claims:
1. A method of identifying genetic mutations that are associated with ataxic neurological disease in a mammalian subject, said method comprising identifying a difference between a nucleic acid sequence of a protein kinase C gamma gene from a first mammalian subject exhibiting ataxia and a nucleic acid sequence of a protein kinase C gamma gene from a second mammalian subject which is not exhibiting ataxia, wherein the first and second mammalian subjects are members of the same species, and wherein the difference between the nucleic acid sequences is a genetic mutation that is associated with ataxic neurological disease.
2. The method of claim 1 wherein the nucleic acid sequence of said first subject and said second subject is determined by amplification of portions of protein kinase C gamma genes from genomic DNA isolated from said subjects to produce an amplified DNA and sequencing said amplified DNA.
3. The method of claim 1 further comprising determining whether the identified genetic mutations cosegregate with ataxia observed in the subjects suffering from ataxia.
4. The method of claim 3 wherein said cosegregation is detected by a method selected from the group consisting of direct sequencing, sequencing PCR-amplified DNA, single stranded conformation analysis, allele-specific PCR and restriction fragment length polymorphism.
5. The method of claim 4 wherein said cosegregation is detected by sequencing PCR-amplified DNA.
6. The method of claim 4 wherein said cosegregation is detected by restriction fragment length polymorphism wherein the presence of an aberrant restriction enzyme site is indicative of the presence of said genetic mutation and cosegregation is determined by the presence of said genetic mutation in a first population of mammalian subjects that exhibit ataxia and not present in a second population of subjects that do not exhibit ataxia.
7. The method of claim 1 wherein the protein kinase C gamma gene is at least 90% identical to the nucleic acid sequence set forth in SEQ ID NO: 3.
8. The method of claim 1 wherein the protein kinase C gamma gene is at least 95% identical to the nucleic acid sequence set forth in SEQ ID NO:3.
9. An isolated nucleic acid molecule encoding a protein kinase C gamma protein comprising a mutation selected from the group consisting of R41P, H101Y, S119P, Q127R, G128D, S361G and R597S.
10. An isolated nucleic acid molecule of claim 9 which encodes the mutation R41P.
11. An isolated nucleic acid molecule of claim 9 which encodes the mutation H101Y.
12. An isolated nucleic acid molecule of claim 9 which encodes the mutation S119P.
13. An isolated nucleic acid molecule of claim 9 which encodes the mutation Q127R.
14. An isolated nucleic acid molecule of claim 9which encodes the mutation G128D.
15. An isolated nucleic acid molecule of claim 9 which encodes the mutation S361G.
16. An isolated nucleic acid molecule of claim 9 which encodes the mutation R597S.
17. A method of screening a mammalian subject to determine if said subject has a genetic predisposition to develop an ataxic neurological disease, or is suffering from an ataxic neurological disease, said method comprising analyzing the nucleic acid sequence of a protein kinase C gamma gene in a mammalian subject to determine whether an identified genetic mutation that is associated with an ataxic neurological disease is present in the nucleic acid sequence, wherein the presence of an identified genetic mutation in the protein kinase C gamma gene that is associated with an ataxic neurological disease indicates that the mammalian subject has a genetic predisposition to develop an ataxic neurological disease or is suffering from an ataxic neurological disease.
18. The method of claim 17 further comprising determining whether the mammalian subject is exhibiting ataxia.
19. The method of claim 17 wherein said nucleic acid sequence is analyzed by a method selected from the group consisting of direct sequencing, sequencing PCR-amplified DNA, DNA hybridization, and restriction fragment length polymorphism.
20. The method of claim 17 wherein said identified genetic mutation that is associated with ataxic neurological disease resides in exon 4 of the protein kinase C gamma gene.
21. The method of claim 17 wherein said identified mutation is a missense mutation.
22. The method of claim 17 wherein said identified mutation consists of an alteration in the protein kinase C gamma gene in the codon encoding an amino acid residue selected from the group consisting of amino acid residues 41, 101, 119, 127, 128, 361, and 597.
23. The method of claim 22 wherein the alteration at protein position 41 is R41P.
24. The method of claim 22 wherein the alteration at protein position 101 is H101Y.
25. The method of claim 22 wherein the alteration at protein position 119 is S119P.
26. The method of claim 22 wherein the alteration at protein position 127 is Q127R.
27. The method of claim 22 wherein the alteration at protein position 128 is G128D.
28. The method of claim 22 wherein the alteration at protein position 361 is S361G.
29. The method of claim 22 wherein the alteration at protein position 597 is R597S.
30. A kit for determining susceptibility or presence of ataxic neurological disease in a mammalian subject based on the detection of a mutation in a protein kinase C gamma gene, said kit comprising (i) one or more nucleic acid primer molecules for amplification of a portion of a protein kinase C gamma gene and (ii) written indicia indicating a correlation between the presence of said mutation and risk of ataxic neurological disease.
31. The kit of claim 30 further comprising means for determining whether a mutation associated with ataxic neurological disease is present.
32. The kit of claim 30 further comprising nucleic acid primer molecules for sequencing across an amplified portion of a protein kinase C gamma gene.
33. The kit of claim 30 further comprising control DNA.
34. The kit of claim 30 wherein said mutation consists of an alteration in the nucleic acid sequence of protein kinase C gamma gene that encodes an amino acid residue selected from the group consisting of amino acid residues 41, 101, 119, 127, 128, 361, and 597.
35. The kit of claim 30 wherein said mutation encodes R41P and wherein said primers comprise SEQ ID NO:4, SEQ ID NO:7 and SEQ ID NO:5.
36. The kit of claim 30 wherein said mutation encodes H101Y and wherein said primers comprise SEQ ID NO:10, SEQ ID NO:11and SEQ ID NO:13.
37. The kit of claim 30 wherein said mutation encodes S119P and wherein said primers comprise SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:13.
38. The kit of claim 30 wherein said mutation encodes Q127R and wherein said primers comprise SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:13.
39. The kit of claim 30 wherein said mutation encodes G128D and wherein said primers comprise SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:13.
40. The kit of claim 30 wherein said mutation encodes S361G and wherein said primers comprise SEQ ID NO:20, SEQ ID NO: 21 and SEQ ID NO:23.
41. The kit of claim 30 wherein said mutation encodes R597S and wherein said primers comprise SEQ ID NO: 32, SEQ ID NO:33 and SEQ ID NO:35.
42. The kit of claim 30 wherein each primer molecule is identical to at least 10 contiguous nucleotides occuring in the sequence of the protein kinase C gamma gene disclosed in SEQ ID NO:3, or the complement thereof.
Ref US9605308: Claims:
1. An apparatus for sequencing a polynucleotide strand, comprising:
a flow chamber for receiving flows of different dNTP reagents;
multiple reservoirs that each contain a different dNTP reagent;
flow paths from each of the reservoirs to the flow chamber; and
a fluidics controller that controls the flow from the reservoirs to the flow chamber, wherein the fluidics controller is programmed to successively provide flow from the multiple reservoirs to the flow chamber according to a predetermined ordering, wherein the predetermined ordering comprises an alternate ordering which is not a continuous and ordered repeat of four different dNTP reagent flows, the alternate ordering comprising a same number of flows for each of four different dNTP reagent flows, a flow of a nucleotide N, which is followed directly by a flow of a different nucleotide W, which is followed directly by a flow of the same nucleotide N, wherein the N-W-N flow is further followed directly by a flow of a nucleotide Z that is different from N and W, and the alternate ordering being successively repeated at least once.
2. The apparatus of claim 1, wherein the alternate ordering is not a continuous repeat of an order of a first four dNTP reagent flows in the predetermined ordering.
3. The apparatus of claim 1, further comprising a flow cell loaded into the flow chamber, wherein the flow cell comprises a microwell array that contains multiple copies of the polynucleotide strand with a primer annealed thereto.
4. The apparatus of claim 3, wherein the flow cell further comprises a chemFET sensor array for detecting the reaction of the dNTP reagent with the contents of the microwell array.
5. The apparatus of claim 3, wherein the polynucleotide strands are attached to beads that are contained in the microwells of the microwell array.
6. The apparatus of claim 1, wherein the predetermined ordering consists of only the alternate ordering.
7. The apparatus of claim 1, wherein the predetermined ordering further comprises a continuous and ordered flow of the four different dNTP reagent flows as follows: dATP, then dCTP, then dGTP, and then dTTP.
8. The apparatus of claim 1, wherein a first four dNTP reagent flows of the continuous and ordered repeat of the four different reagent flows comprises: dATP, then dCTP, then dGTP, and then dTTP.
9. The apparatus of claim 1, wherein the predetermined ordering includes a first portion that comprises the alternate ordering and a second portion that does not comprise the alternate ordering.
10. The apparatus of claim 1, wherein in the predetermined ordering, the flow of one of the four dNTP reagent flows is always followed by a flow of a different one of the four dNTP reagent flows.
11. The apparatus of claim 1, wherein the predetermined ordering further comprises a continuous and ordered repeat of the four different dNTP reagent flows and is a permutation of a flow ordering of: dATP, then dCTP, then dGTP, and then dTTP.
12. The apparatus of claim 1, wherein the alternate ordering is repeated two or more times.
13. An apparatus for sequencing a polynucleotide strand, comprising:
a flow chamber for receiving flows of different dNTP reagents;
multiple reservoirs that each contain a different dNTP reagent;
flow paths from each of the reservoirs to the flow chamber; and
a fluidics controller that controls the flow from the reservoirs to the flow chamber, wherein the fluidics controller is programmed to successively provide flow from the multiple reservoirs to the flow chamber according to a predetermined ordering, wherein the predetermined ordering comprises an alternate ordering which is not a continuous and ordered repeat of four different dNTP reagent flows, the alternate or
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