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 .
The amended claims filed 6/11/2026 are under consideration.
It is noted that claim 9 is indicated as being cancelled on p. 4 of the 6/11/2026 claim set. The text of the claim is also set forth on p.4. The Remarks state that only 1, 4 and 5 have been cancelled. Thus, claim 9 is being considered in this Office action. Applicant is requested to properly identify which claims have been cancelled in any future amended claim sets.
The amendments and arguments presented in the papers filed 6/11/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 12/12/2025 listed below have been reconsidered as indicated.
a) The objection of the specification is withdrawn in view of the amendments to the specification.
b) The rejections of claims 1, 4 and 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn.
c) The rejections of claim(s) 1, 4-6 and 9-15 under 35 U.S.C. 102(a)(1) as being anticipated by Douville (PNAS. 2018. 115(8):1871-1876 with Supporting Information and Dataset) are withdrawn.
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Priority
The present application is a 371 national stage entry of PCT/US2022/012423 (filed 1/14/2022), which claims benefit of US provisional 63/137,546 (filed 1/14/2021).
Priority to the ‘546 provisional application is not fully recognized. The priority document does not disclose gains and/or losses in chromosome regions 8p and/or 17q. It is also noted the present specification is 117 pages, while the specification of the ‘546 provisional application is only 68 pages.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Claim Interpretation
Independent claim 6 is drawn to a “method of detecting Barrett's esophagus with low grade dysplasia (BE with LGD), or Barrett's esophagus with high grade dysplasia (BE with HGD), or adenocarcinoma of the esophagus (EAC) or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer in a subject”; however, the active method steps do not explicitly require an active method step of “detecting” any type of condition, e.g., BE with LGD, BE with HGD, or EAC or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer in a subject. MPEP 2111.02 states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction.
Accordingly, the claim language of "method of detecting Barrett's esophagus with low grade dysplasia (BE with LGD), or Barrett's esophagus with high grade dysplasia (BE with HGD), or adenocarcinoma of the esophagus (EAC) or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer in a subject" in the preamble merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims. The claims are given the broadest reasonable interpretation as requiring active method steps of:
1) applying a parallel sequencing methodology to a biological sample from the esophagus of the subject; and
2) identifying copy number alterations in a panel of chromosome alterations.
The step of “applying a parallel sequencing methodology” is done “to determine a global aneuploidy score (GAS)” as an intended purpose. The instant specification describes a GAS as being determined “using a supervised machine learning model” (para. 35) and further describes “non-acrocentric Zw values serve as features that are integrated and modeled with a support vector machine (SVM) to provide a summary Global Aneuploidy Score (GAS)” (para. 112). The specification also states:
Zw scores for each of the 39 non-acrocentric chromosome arms in each sample were calculated. These chromosome arm level Zw scores were then integrated into a single Global Aneuploidy Score (GAS) reflecting the number and similarity of the alterations to those commonly observed in cancers. (para. 153)
It is noted the claim does not specify an active method step of “determining a global aneuploidy score”, nor does it require the use of “machine learning model” or calculating Zw values. The “applying” step is broadly interpreted as encompassing collecting data via the use of parallel sequencing methodologies. The intended purpose does not limit how the step of “applying a parallel sequencing methodology” is performed.
The step of “identifying copy number alterations” is done “to determine a Barrett's Aneuploidy Decision (BAD) classifier” as an intended purpose. The instant specification provides the following information about a BAD classifier:
the combined GAS score and the identified individual chromosome alterations can be used to provide a Barrett’s Aneuploidy Decision (BAD) classifier (para. 10); and
being based on “specific chromosome changes plus GAS scores” (para. 159).
It is noted the claim does not require calculating any GAS scores, nor does it require combining any chromosomal alterations identified with a GAS score. The “identifying” step is broadly interpreted as encompassing identifying copy number alterations, for example by using the data collected by “applying a parallel sequencing methodology”. The intended purpose does not limit how the step of “identifying copy number alterations” is performed.
In view of the above interpretation of the preamble and the positively recited active method steps, the claim is interpreted as broadly encompassing performing a “parallel sequencing methodology” and identifying a copy number alteration for a panel of chromosome alterations.
The claim limits the “chromosomal alterations to comprising “chromosome gains and/or losses of any of chromosome regions 8p, 8q24, 1q, 7p, 20q, 2q, 13q, 5p, 12p, 5q, 17p, 4p, 4q, 9p, 17q, 18q, 16q, 21q, 22q, or 10p”.
The claim provides information about the GAS score in a “wherein” clause stating “GAS is indicative of presence of BE with LGD, or BE with HGD, or EAC of the esophagus or increased risk of progression to low grade dysplasia, or high grade dysplasia, or cancer”. The claim also provided information about the BAD classifier in a “wherein” clause stating “the BAD classifier distinguishes stages of Barrett's esophagus progression or increased risk of progression”. These clauses are intended functions or properties of the GAS score and the BAD classifier. However, as noted above, the claim does not require active method steps of calculating or determining either a GAS score or a BAD classifier. The information in the “wherein” clauses does not limit how the steps of “applying a parallel sequencing methodology” and “identifying copy number alterations” are performed.
Independent claim 31 is drawn to a “method for detecting progression or increased risk of progression of Barrett’s esophagus”; however, the active method steps do not explicitly require an active method step of “detecting” progression or increased risk of progression of Barrett’s esophagus. MPEP 2111.02 states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction.
Accordingly, the claim language of "method for detecting progression or increased risk of progression of Barrett’s esophagus" in the preamble merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims. The claims are given the broadest reasonable interpretation as requiring active method steps of:
obtaining a brushing sample of the esophagus;
extracting DNA from the sample; and
assaying the DNA for chromosomal gains and losses of the recited chromosome regions.
The step of “assaying the DNA for chromosomal gains and loses” is done “to determine a Barrett's Aneuploidy Decision (BAD) classifier” as an intended purpose. The instant specification provides the following information about a BAD classifier:
the combined GAS score and the identified individual chromosome alterations can be used to provide a Barrett’s Aneuploidy Decision (BAD) classifier (para. 10); and
being based on “specific chromosome changes plus GAS scores” (para. 159).
It is noted the claim does not require “determining” a BAD classifier or calculating any GAS scores, nor does not it require combining any chromosomal alterations identified with a GAS score. The “assaying” step is broadly interpreted as encompassing performing a technique that assays DNA for chromosomal gains and losses. The intended purpose does not limit how the step of “assaying the DNA” is performed.
In view of the above interpretation of the preamble and the positively recited active method steps, the claim is interpreted as broadly encompassing performing the above three identified steps.
The claim provides information about the BAD classifier in a “wherein” clause stating “the BAD classifier distinguishes stages of Barrett's esophagus progression or increased risk of progression”. The clause is an intended function or property of the BAD classifier. However, as noted above, the claim does not require active method steps of calculating or determining a BAD classifier. The information in the “wherein” clauses does not limit how the three above identified steps are performed.
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.
Claims 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 31-33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 6, it is not clear how the recited preamble is intended to breathe life and meaning into the claims. The preamble of the claim recites a “method of detecting Barrett's esophagus with low grade dysplasia (BE with LGD), or Barrett's esophagus with high grade dysplasia (BE with HGD), or adenocarcinoma of the esophagus (EAC) or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer in a subject”. However, the method steps in the claim only require “applying a parallel sequencing methodology to a biological sample from the esophagus of the subject” and “identifying copy number alterations in a panel of chromosome alterations”. Thus, it is unclear whether applicant intends to cover any method of performing these two steps, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal of “detecting” BE with LGD, BE with HGD, or EAC or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer in a subject as set forth by the preamble of the claim. Amending the claim to include an active process step directed towards detecting Barrett's esophagus with low grade dysplasia, or Barrett's esophagus with high grade dysplasia, or adenocarcinoma of the esophagus based calculated GAS scores and a BAD classifier may aid in overcoming this rejection.
Claims 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22 are similarly indefinite because they directly or indirectly depend from claim 6.
Regarding claim 6, the claim recites the “applying a parallel sequencing methodology” is done in order “to determine a global aneuploidy score (GAS)” and the “identifying copy number alterations” is done “to determine a Barrett’s Aneuploidy Decision (BAD) classifier”. It is unclear how these purposes further limit the two active method steps, if at all. For example, a GAS score is described as being determined by using a “machine learning model” or calculating Zw values. It is unclear if such additional elements are required as part of the “applying a parallel sequencing methodology”.
Claims 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22 depend from claim 6 and are rejected for the same reason.
Regarding claim 20, the claim is incomplete because it refers to a determination about a subject that is not required by the claim. Claim 6 does not require an active method step of “detecting” or “determining” anything about the subject’s condition. Thus, claim 20 sets forth a step that is conditioned on a “determination” that is not required. The lack of this “determination” being made about the subject renders the claim incomplete.
Regarding claim 31, the claim recites the “assaying the DNA” is done in order “to determine a Barrett’s Aneuploidy Decision (BAD) classifier”. It is unclear how this purposes further limit the “assaying” method step, if at all. For example, a BAD classifier is based on more than just “assaying” DNA. It is unclear if such additional elements are required as part of the “assaying the DNA”.
Response to the traversal of the 112(b) rejections
The Remarks argue the amendments to the claims overcome the 112(b) rejections (p. 10-12).
The arguments have been fully considered but are not persuasive. The claims remain rejected for the reasons provided above.
Claim Rejections - 35 USC § 112
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.
Claim 9 is 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 9, the claim recites information about the “global aneuploidy score” but does not recite any further or additional active method steps, nor does is limit how the step of claim 6 is performed. Claim 9 thus fails to further limit the scope of claim 6.
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.
Response to the traversal of the 112(d) rejections
The Remarks argue in regards to claim 9, the claim limits the threshold for when a GAS is indicative of the presence of dysplasia or cancer, or increased risk of progression to low grade dysplasia, or high grade dysplasia, or cancer (p. 13).
The arguments have been fully considered but are not persuasive. Claim 6 does not require determining or calculating a GAS score. The Remarks do not demonstrate how claim 9 further limits how the two positively recited, active method steps of claim 6 are to be performed.
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 (i.e., changing from AIA to pre-AIA ) 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) 6, 9, 10, 11, 12, 13 and 14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Douville (PNAS. 2018. 115(8):1871-1876 with Supporting Information and Dataset; previously cited).
The broadest reasonable interpretation of claim 6 is detailed above.
Regarding claim 6, Douville teaches applying parallel sequencing methodology to biological samples of tumor using FAST-SeqS (Supporting Information, p. 1, Fast-SeqS).
The tumor samples include those from the esophagus as demonstrated by the Dataset. It is noted the DataSet has been truncated by the Examiner to provide information about esophagus samples. For example the following samples were analyzed:
Sample Name
Cancer Type
Histopathology
Stage
Grade
INDI 076
Esophagus
Squamous Cell Carcinoma
IIA
G3
INDI 112
Esophagus
Squamous cell carcinoma, NOS
IIA
G2
INDI 119
Esophagus
Adenocarcinoma, NOS
IB
G3
The claim recites the intended purpose of the “applying a parallel sequencing methodology” is to “determine the global aneuploidy score (GAS)”, which as noted in the above claim interpretation section does not limit how the “applying” step is performed.
Douville further teaches “identifying” gains and losses in some the claimed chromosome regions as demonstrated in the DataSet:
Sample Name
chr1q
chr8p
chr8q
chr20q
Cancer Type
Histopathology
INDI 076
0.839
-1.245
11
3.042
Esophagus
Squamous Cell Carcinoma
INDI 112
3.035
0.149
1.452
0.027
Esophagus
Squamous cell carcinoma, NOS
INDI 119
4.5
1.27
11
5.838
Esophagus
Adenocarcinoma, NOS
The claim recites the intended purpose of the “identifying copy number alterations” is “to determine a Barrett's Aneuploidy Decision (BAD) classifier”, which as noted in the above claim interpretation section does not limit how the “identifying” step is performed.
It is further noted that Douville teaches determining a global aneuploidy score as depicted in panel C of Figure S2.
Douville anticipates claim 6 because it teaches all the positively recited, active method steps of claim 6.
Regarding claim 9, the claim provides information regarding the intended use of a GAS score. As noted above, the claim does not require any active method steps of determining or calculating a GAS score. The claim does not limit how the only positively recited, active method steps of claim 6 are performed. Claim 9 is anticipated for the same reason as claim 6.
Regarding claims 10 and 11, Douville teaches determining in a panel of chromosomes including at least loss in chromosome region 18q:
Sample Name
Chr8p
chr18q
Cancer Type
INDI 076
-1.599
Esophagus
INDI 465 PT1
4.662
Esophagus
Regarding claim 12, the claim provides information regarding the intended use of the global aneuploidy score. As noted above, the claim does not require any active method steps of detecting or indicating the presence of any dysplasia or cancer or increased risk of any type of progression. The claim does not limit how the only active method step of claim 6 is performed.
As noted above, Douville identifying a gain in chromosome 8p.
Claim 12 is anticipated for the same reason as claim 6.
Regarding claim 13, the claim provides information regarding the intended use of the global aneuploidy score. As noted above, the claim does not require any active method steps of detecting or indicating the presence of any dysplasia or cancer or increased risk of any type of progression. The claim does not limit how the only active method step of claims 6 or 12 is performed.
As noted above, Douville identifying a gain in chromosome 8p.
Claim 13 is anticipated for the same reason as claims 6 and 12.
Regarding claim 14, the claim provides information regarding the intended use of the global aneuploidy score. As noted above, the claim does not require any active method steps of detecting or indicating the presence of any dysplasia or cancer or increased risk of any type of progression. The claim does not limit how the only active method step of claims 6, 12 or 13 is performed.
It is noted Douville teaches identifying a gain in chromosome 1q in patient INDI 112 and INDI 125.
Claim 14 is anticipated for the same reason as claims 6, 12 and 13.
Response to the traversal of the 102 rejections over Douville
The Remarks argue claim 6, as amended, is not anticipated by Douville because Douville does not teach a method of detecting Barrett's esophagus with low grade dysplasia (BE with LGD), or Barrett's esophagus with high grade dysplasia (BE with HGD), or adenocarcinoma of the esophagus (EAC) or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer in a subject, the method comprising applying a parallel sequencing methodology to a biological sample from the esophagus of the subject to determine a global aneuploidy score (GAS); and identifying copy number alterations in a panel of chromosome alterations to determine a Barrett's Aneuploidy Decision (BAD) classifier, wherein the GAS is indicative of presence of BE with LGD, or BE with HGD, or EAC of the esophagus or increased risk of progression to low grade dysplasia, or high grade dysplasia, or cancer; and wherein the BAD classifier distinguishes stages of Barrett's esophagus progression or increased risk of progression (p. 14).
It is the Examiner’s position that Douville anticipates claim 6 in view of the broadest reasonably interpretation detailed in the Claim Interpretation section above.
The Remarks provide a summary of the requirements of anticipation of a claim (p. 14-15).
The Examiner’s position is detailed above.
The Remarks characterize the teachings of Douville (p. 15) and argue Douville does not teach that the WALDO method therein should be used on esophageal samples from a subject to detect BE with LGD, BE with HGD, or EAC or increased risk of progression to low grade dysplasia, high grade dysplasia, or cancer (p. 15). The Remarks further argue Douville does not teach to identify copy number alterations in a panel of chromosome alterations to determine a Barrett's Aneuploidy Decision (BAD) classifier, the chromosomal alterations including chromosome gains and/or losses of any of chromosome regions 8p, 8q24, 1q, 7p, 20q, 2q, 13q, 5p, 12p, 5q, 17p, 4p, 4q, 9p, 17q, 18q, 16q, 21q, 22q, or 10p; wherein the BAD classifier distinguishes stages of Barrett's esophagus progression or increased risk of progression (p. 15-16). The Remarks argue Douville does not mention Barrett's esophagus at all, let alone provide a set of chromosomal alterations that could be used to distinguish stages of Barrett's esophagus progression or increased risk of progression as in the present invention and instead, Douville provides a list of chromosome arms with the most gains and losses in primary tumor samples, but fails to identify which of those chromosome gains or losses were associated with Barrett's esophagus and/or adenocarcinoma of the esophagus (p. 16).
The arguments have been fully considered but are not persuasive. As noted in the above claim interpretation section, claim 6 broadly encompasses performing two steps. While the claim sets forth different intended uses, properties and functions of the method and its steps, these features do not limit how the two positively recited active method steps are performed. The above arguments focus on these intended uses, properties and functions and does not argue that Douville does not perform steps of “applying sequencing methodology” or “identifying copy number alterations”. The argument is that Douville does not perform these steps for the same reason as applicant. The reason for performing a step does not alter the fact that Douville performs the two steps as encompassed by the broadest reasonable interpretation.
The Remarks discuss the present specification and its teachings (p. 16-17).
The teachings of the present specification focus on elements that are not required by the claim in view of the broadest reasonable interpretation detailed in the above claim interpretation section.
The Remarks recite amended claim 6 and again argue Douville does not teach such a method or the methods of claims 9-15 (p. 17).
The arguments are not found persuasive for the reasons provided above.
The Remarks argue claims 10 and 12-14 are further allowable because Douville does not teach that the panel of chromosome alterations comprise gains and losses as recited because Douville only provides that the chromosome arms with the most gains were 1q, 3q, 7p, 7q, 8q, and 20q, the most losses were 4p, 4q, 8p, and 18q, and fewest gains or losses were 10p, 16p, 19p, and 19q (p. 17). The Remarks argue Douville does not teach that tumor samples had chromosome gains in 12p or chromosome losses in 9p or 17p or that identifying these copy number alterations could be used to determine a BAD classifier that distinguishes stages of Barrett's esophagus progression or increased risk of progression (p. 17-18).
Regarding claim 10 and 12-14, Douville identifies copy number losses and gains for at least some of the chromosome regions recited in the claims. The claims do not require determining copy number gains and losses for all of the recited chromosomes as they are recited in the alternative. Douville anticipates those embodiments in which the particular chromosome alterations noted in the above rejections are identified.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claim(s) 15, 16, 17, 18, 19, 20 and 31-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Douville (PNAS. 2018. 115(8):1871-1876 with Supporting Information and Dataset; previously cited) in view of Ahlquist (WO 2016/160454 A1; previously cited).
Claims 16, 17, 18, 19 and 20 depend from claim 6, and the broadest reasonable interpretation of claim 6 is relevant to these claims.
Regarding claims 16, 17, 18, 19 and 20, Douville teaches applying parallel sequencing methodology to biological samples of tumor using FAST-SeqS (Supporting Information, p. 1, Fast-SeqS).
The tumor samples include those from the esophagus as demonstrated by the Dataset. It is noted the DataSet has been truncated by the Examiner to provide information about esophagus samples. For example, the following samples were analyzed:
Sample Name
Cancer Type
Histopathology
Stage
Grade
INDI 076
Esophagus
Squamous Cell Carcinoma
IIA
G3
INDI 112
Esophagus
Squamous cell carcinoma, NOS
IIA
G2
INDI 119
Esophagus
Adenocarcinoma, NOS
IB
G3
The claim recites the intended purpose of the “applying a parallel sequencing methodology” is to “determine the global aneuploidy score (GAS)”, which as noted in the above claim interpretation does not limit how the “applying” step is performed.
Douville further teaches “identifying” gains and losses in some the claimed chromosome regions as demonstrated in the DataSet:
Sample Name
chr1q
chr8p
chr8q
chr20q
Cancer Type
Histopathology
INDI 076
0.839
-1.245
11
3.042
Esophagus
Squamous Cell Carcinoma
INDI 112
3.035
0.149
1.452
0.027
Esophagus
Squamous cell carcinoma, NOS
INDI 119
4.5
1.27
11
5.838
Esophagus
Adenocarcinoma, NOS
The claim recites the intended purpose of the “identifying copy number alterations” is to “determine a Barrett's Aneuploidy Decision (BAD) classifier”, which as noted in the above claim interpretation does not limit how the “identifying” step is performed.
It is further noted that Douville teaches determining a global aneuploidy score as depicted in panel C of Figure S2.
Regarding claims 20, 21 and 22, Douville further teaches it was determined at some point the patient had adenocarcinoma as depicted in the rejection of claim 6 described above.
The patients would have been treated for their esophagus cancer given that some had stage II1 and grade 2 to grade 3 as noted above.
The broadest reasonable interpretation of claim 31 is provided above.
Regarding claims 31-33, Douville teaches obtaining a sample, extracting DNA from the sample and assay chromosomal DNA by applying parallel sequencing methodology to biological samples of tumor using FAST-SeqS (Supporting Information, p. 1, Fast-SeqS).
The tumor samples include those from the esophagus as demonstrated by the Dataset. It is noted the DataSet has been truncated by the Examiner to provide information about esophagus samples. For example, the following samples were analyzed:
Sample Name
Cancer Type
Histopathology
Stage
Grade
INDI 076
Esophagus
Squamous Cell Carcinoma
IIA
G3
INDI 112
Esophagus
Squamous cell carcinoma, NOS
IIA
G2
INDI 119
Esophagus
Adenocarcinoma, NOS
IB
G3
Douville teaches determining detecting gains and losses in the recited chromosomes as demonstrated panel C of Figure S2, which is reproduced below:
PNG
media_image1.png
654
633
media_image1.png
Greyscale
It is further noted that Douville does detect gains and losses in some the claimed chromosome regions as demonstrated in the DataSet:
Sample Name
chr1q
chr8p
chr8q
chr20q
Cancer Type
Histopathology
INDI 076
0.839
-1.245
11
3.042
Esophagus
Squamous Cell Carcinoma
INDI 112
3.035
0.149
1.452
0.027
Esophagus
Squamous cell carcinoma, NOS
INDI 119
4.5
1.27
11
5.838
Esophagus
Adenocarcinoma, NOS
Regarding claims 15 and 33, Douville teaches:
Amplifying genomic nucleic acid of the sample targeted by a single primer pair (Supporting Information, p. 1, Fast-SeqS);
Matching the unique loci to a control by aligning the sequences to a human reference genome as a “control” (Supporting Information, p. 1, Sample alignment and genomic interval grouping);
Calculating the statistical gains and losses for each non-acrocentric chromosome arm as presented in Table S4 and calculating Z-scores (Supporting Information, p. 2, Identifying chromosome arm gains or losses in a test sample);
Integrating the chromosome arms into a “global aneuploidy score” by performing Genome-wide aneuploidy detection using a two-class support vector machine (Supporting Information, p. 4, Genome-wide aneuploidy detection); and
Quantifying chromosome arm levels and querying focal changes of interest by determining allelic imbalances and analyzing somatic sequence mutations and microsatellite instability (Supporting Information, p. 4 and 5).
It is noted that the instant specification in paragraph 16 describes “RealSeqS” as involving the above identified steps.
Douville does not teach the specific samples of claims 16-19 and 31-33, the treatments of claims 20-22.
However, Ahlquist teaches elements relative to evaluating esophagus samples.
Regarding claims 16-19 and 31-33, Ahlquist teaches esophagus samples are obtained through endoscopic brushing or nonendoscopic whole esophageal brushing or swabbing using a tethered device, such as a capsule sponge, balloon, or other device (p. 3, lines 9-17). Ahlquist further teaches the samples may be frozen (p. 36, lines 13-29).
Regarding claims 20-22, Ahlquist teaches treatments with histamine 2-receptor blocking agents (p. 1, lines 30-33) and anti-reflex surgery (p. 1, lines 27-29).
It would have been prima facie obvious to the ordinary artisan at the time of filing to have modified the methods of Douville by treating those patients known to have Barrett's esophagus with low grade dysplasia, or Barrett's esophagus with high grade dysplasia, or adenocarcinoma of the esophagus with known treatments and to have used the known sources of esophagus samples taught by Ahlquist. The modifications have a reasonable expectation of success as they simply involve implementing well known sample sources and treatments relevant to the context of the patients analyzed by Douville.
Response to the traversal of the 103 rejections over Douville and Ahlquist
The Remarks argue claims 16-20 are allowable for the same reasons argued for claim 6 (p.18).
The arguments have been considered but are not persuasive for the reasons detailed above.
The Remarks argue claim 31 is not obvious and characterizes the standard for a rejection under section 103 (p. 18-19).
The claims remain rejected as being obvious in view of the broadest reasonable interpretation described above.
The Remarks reiterative the arguments applied to claim 6 in the context of claim 31 (p. 19).
The arguments are not persuasive in view of the broadest reasonable interpretation discussed above.
The Remarks argue Ahlquist does not cure the deficiencies of Douville as Ahlquist focuses on methylation analyses (p. 19-20).
Conclusion
No claims allowed.
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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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOSEPH G. DAUNER/Primary Examiner, Art Unit 1682
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