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 .
Interview Summary
The Examiner would like to note the inclusion of the Applicant’s interview summary regarding the telephonic interview on November 17th, 2025. With the inclusion of this summary, the interview record is complete.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 9th, 2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Response to Amendment
The amendment filed December 30th, 2025 is acknowledged. Regarding the Office Action mailed July 1st, 2025:
The objections to the specification are withdrawn in view of the amendments.
The rejections set forth under 35 U.S.C. 112(b) is withdrawn in view of the amendments.
Maintained or modified rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1-2, 6, 12, 14, 19 and 25 have been amended. Claims 27 and 28 have been added. Claims 1-28 are pending. Claims 1-28 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 101 – Modified – Necessitated by Amendment
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-11, 13-24, and 26-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and abstract ideas without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claims recite the natural correlation between amount of viral DNA/size of viral DNA and relapse of a pathology, as well as the abstract ideas of comparing values to cutoffs and determining classification of relapse. The correlation is a natural phenomenon because it describes a consequence of natural processes in the human body (e.g. viral DNA indicating relapse of pathology). The abstract ideas represent mental processes that could be performed in the human mind.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon and abstract ideas: the natural correlation between amount of viral DNA/size of viral DNA and relapse of a pathology, and the abstract ideas of comparing values to cutoffs and determining classification of relapse.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of sequencing cell-free nucleic acid molecules; aligning to a viral reference genome to determine an amount of sequencing reads; comparing the reads to a cutoff to determine a classification for relapse of a pathology; measuring sizes of cell-free nucleic acid molecules; determining whether the sized cell-free nucleic acids come from the reference; determining a statistical value for the sizes of cell-free nucleic acids to compare to a second cutoff for determining classification of relapse of a pathology; determining the statistical value using a ratio of proportions of cell-free nucleic acids from viral and human genomes; determining cutoffs with training samples; the pathology being a cancer selected from nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, and hepatocellular carcinoma; enriching the sample for nucleic acids from the virus; the virus being selected from EBV DNA, HPV DNA, HBV DNA, HCV nucleic acids, or fragments thereof; the subject being a pregnant woman; the classification comprising remission, relapse, loco-regional failure, or distant metastasis; and responsive to determining classification, performing sequencing analysis on new samples from the subject at a frequency dependent on the classification, the claims do not improve upon sequencing techniques, techniques to determine cutoff values for determining pathology relapse, or comparison techniques for determining relapse. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology. That the above steps were known in the prior art will be shown below.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of sequencing cell-free nucleic acid molecules; aligning to a viral reference genome to determine an amount of sequencing reads; comparing the reads to a cutoff to determine a classification for relapse of a pathology; measuring sizes of cell-free nucleic acid molecules; determining whether the sized cell-free nucleic acids come from the reference; determining a statistical value for the sizes of cell-free nucleic acids to compare to a second cutoff for determining classification of relapse of a pathology; determining the statistical value using a ratio of proportions of cell-free nucleic acids from viral and human genomes; determining cutoffs with trainings samples; the pathology being a cancer selected from nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, and hepatocellular carcinoma; enriching the sample for nucleic acids from the virus; the virus being selected from EBV DNA, HPV DNA, HBV DNA, HCV nucleic acids, or fragments thereof; the subject being a pregnant woman; the classification comprising remission, relapse, loco-regional failure, or distant metastasis; and responsive to determining classification, performing sequencing analysis on new samples from the subject at a frequency dependent on the classification, no such machines are required by the claims, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a specific sequencer, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, sequencing does not transform cell-free nucleic acid molecules into something else during the sequencing process.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between amount of viral DNA/size of viral DNA and relapse of a pathology, and the abstract ideas of comparing values to cutoffs and determining classification of relapse in the instant case have to do with sequencing cell-free nucleic acid molecules; aligning to a viral reference genome to determine an amount of sequencing reads; comparing the reads to a cutoff to determine a classification for relapse of a pathology; measuring sizes of cell-free nucleic acid molecules; determining whether the sized cell-free nucleic acids come from the reference; determining a statistical value for the sizes of cell-free nucleic acids to compare to a second cutoff for determining classification of relapse of a pathology; determining the statistical value using a ratio of proportions of cell-free nucleic acids from viral and human genomes; determining cutoffs with trainings samples; the pathology being a cancer selected from nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, and hepatocellular carcinoma; enriching the sample for nucleic acids from the virus; the virus being selected from EBV DNA, HPV DNA, HBV DNA, HCV nucleic acids, or fragments thereof; the subject being a pregnant woman; the classification comprising remission, relapse, loco-regional failure, or distant metastasis; and responsive to determining classification, performing sequencing analysis on new samples from the subject at a frequency dependent on the classification. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as will be discussed below, these limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exceptions are the natural correlation between amount of viral DNA/size of viral DNA and relapse of a pathology, and the abstract ideas of comparing values to cutoffs and determining classification of relapse. The additional elements recited in the claims (i.e. sequencing cell-free nucleic acid molecules; aligning to a viral reference genome to determine an amount of sequencing reads; comparing the reads to a cutoff to determine a classification for relapse of a pathology; measuring sizes of cell-free nucleic acid molecules; determining whether the sized cell-free nucleic acids come from the reference; determining a statistical value for the sizes of cell-free nucleic acids to compare to a second cutoff for determining classification of relapse of a pathology; determining the statistical value using a ratio of proportions of cell-free nucleic acids from viral and human genomes; determining cutoffs with trainings samples; the pathology being a cancer selected from nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, and hepatocellular carcinoma; enriching the sample for nucleic acids from the virus; the virus being selected from EBV DNA, HPV DNA, HBV DNA, HCV nucleic acids, or fragments thereof; the subject being a pregnant woman; the classification comprising remission, relapse, loco-regional failure, or distant metastasis; and responsive to determining classification, performing sequencing analysis on new samples from the subject at a frequency dependent on the classification) do amount to mere instructions to apply the correlation, since the collection of particular biological samples from particular subjects, sequencing cell-free nucleic acid molecules, and determining the amount and size of the nucleic acid molecules as they relate to classification of relapse serve as mere conventional steps taken for the purpose of gathering data about the cell-free nucleic acid molecules in the subject, which any practical use of the natural correlation would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that MPEP 2106.05(g) ex. “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to gathering samples, sequencing cell-free nucleic acid molecules from those samples, and determining the amount and size of the nucleic acid molecules as they relate to classification of relapse.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being used to determine relapse of a pathology, is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. The judicial exceptions are the natural correlation between amount of viral DNA/size of viral DNA and relapse of a pathology, and the abstract ideas of comparing values to cutoffs and determining classification of relapse, and the claims amount to using known steps for the correlation and abstract ideas.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was known in the prior art to ascertain pathology by determining aspects of viral nucleic acids.
For example, Lo teaches a method of analyzing a biological sample from a subject with a level of pathology, the method comprising: performing a first assay, wherein the first assay comprises analyzing a first plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject, wherein the biological sample includes a mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000); performing a second assay, wherein the second assay comprises: for each of a second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject: measuring a size of the cell-free nucleic acid molecule (Page 31, paragraph [0384]); and determining whether the cell-free nucleic acid molecule is from a reference genome, the reference genome corresponding to the virus (Pages 31-32, paragraph [0386]); determining an amount of the first plurality of cell-free nucleic acid molecules that align to the reference genome (Page 15, paragraphs [0196] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0383]: the method of 2200 used in combination in method 6000); determining a statistical value derived from the measured sizes of the second plurality of cell-free nucleic acid molecules that are from the reference genome (Page 20, paragraph [0260] and Figure 40: determining size distribution alone, block 4030; Pages 31-32, paragraph [0386]: the method of 4030 used in combination); comparing the amount to a first cutoff, comparing the statistical value to a second cutoff, and determining a level of pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000; Page 32, paragraph [0389]). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
While, Lo does not directly teach determining a classification for a relapse of the pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that viral DNA levels can be used to determine a classification of future relapse. Chan teaches that serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2). Therefore, it was known in the art before the effective filing date of the claimed invention there were different classifications of relapse.
It is noted by the Examiner that claims 12 and 25 contain treatment steps that are sufficient to overcome the 101 rejection presented above.
Response to Arguments
Applicant's arguments filed December 30th, 2025 have been fully considered but they are not persuasive.
The Applicant first summarizes the Examiner’s previous rejection (Page 12 of the Remarks filed December 30th, 2025). The Applicant then approaches arguments via the different steps of the subject matter eligibility guidelines, which will be summarized in kind:
Step 2A, Prong 1: The Applicant summarizes the required steps for determining if a claim recites an abstract idea (Page 13 of the Remarks filed December 30th, 2025). The Applicant notes that the Examiner has acknowledged the first 4 steps of claim 1 as additional elements (Page 13 of the Remarks filed December 30th, 2025).
Step 2A, Prong 2: The Applicant summarizes the required steps for evaluating whether a claim as a whole integrates the recited judicial exception into a practical application (Page 13 of the Remarks filed December 30th, 2025). The Applicant argues that the claimed method provides a substantive improvement because it predicts when a future relapse may occur, rather than merely determining whether cancer is currently present (Page 13 of the Remarks filed December 30th, 2025). The Applicant then directs the Examiner to Figures 13 and 17 for surprising results (Page 13 of the Remarks filed December 30th, 2025).
In response to these arguments, determining a classification of a future relapse still presents an issue because it is also an abstract idea. The process of classifying, without further limitation provided, can still reasonably be performed in the human mind. This does not serve to impose a meaningful limit of the judicial exception such that the claim is more than a drafting effort designed to monopolize the judicial exception.
Step 2B: The Applicant summarizes the required steps for determining whether the additional elements in a claim amount to an inventive concept (i.e. whether the additional elements amount to significantly more than the exception itself), and the steps for determining and supporting a well-understood, routine, and conventional activity (Page 14 of the Remarks filed December 30th, 2025). The Applicant argues that the following limitations are unconventional: “sequencing a first plurality of cell-free nucleic acid molecules from a mixture of nucleic acid molecules of the biological sample to obtain first sequence reads, wherein the biological sample includes the mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus; aligning the first sequence reads to a reference genome, the reference genome corresponding to the virus; determining an amount of the first sequence reads that align to the reference genome; comparing the amount to a first cutoff.” (Page 14 of the Remarks filed December 30th, 2025). The Applicant notes the Examiner’s reference to Lo and Chan, and argues that two references from the instant inventors do not make any limitation routine (Page 14 of the Remarks filed December 30th, 2025). The Applicant further argues that the Examiner refers to obviousness, and that obviousness is not relevant to whether a combination of elements is routinely performed together. The Applicant argues that all elements must be performed together in the prior art and be routinely performed together (Page 15 of the Remarks filed December 30th, 2025).
In response to these arguments, the Examiner would first like to note that the memorandum cited by the Applicant (Berkheimer Memorandum) does not state that all elements of the Applicant’s provided list are required to support a well-understood, routine, and conventional activity. Only one is necessary, which is what is addressed with the provided art in the 101 rejection. Furthermore, the additional limitations cited by the Applicant amount to methods that are generally routine in the relevant field outside of the inventors own references (e.g. sequencing cell-free DNA, aligning to a genome, counting sequence reads). See, for instance, Garafalo (Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies, Blood, November 2019, 1-4), Chudova (WO 2016094853 A1, particularly at paragraph [0010]), and Deciu (WO 2013052913 A2, particularly at pages 3-4). The limitation “comparing the amount to a first cutoff” has been identified as one of the judicial exceptions, and therefore was not an additional limitation as previously analyzed. With regard to the arguments about the obviousness statements, it is noted by the Examiner that this statement is used to indicate details of the mentioned reference that would be obvious to one of ordinary skill in the art based on what was presented in a single reference, not for specifically combining references together. Finally, with regard to the argument about all elements being performed together in the prior art, all additional elements beyond the cited judicial exceptions are found together in the prior art and are considered to be routine.
Taken together, the arguments are not found to be persuasive.
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.
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.
Modified – Necessitated by Amendment
Claims 1-10, 12-23, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (US20180208999A1; previously cited), in view of Chan (Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma, Chinese Journal of Cancer, December 2014, 33, 598-603; cited on the IDS filed February 24th, 2023).
Regarding instant claim 1, Lo teaches a method of analyzing a biological sample from a subject with a level of a pathology, the method comprising: sequencing a first plurality of cell-free nucleic acid molecules from a mixture of nucleic acid molecules of the biological sample to obtain first sequence reads, wherein the biological sample includes the mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000); aligning the first sequence reads to a reference genome, the reference genome corresponding to the virus (Page 15, paragraph [0195] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraph [0383]: the method of 2200 used in combination in method 6000); determining an amount of the first sequence reads that align to the reference genome (Page 15, paragraphs [0196] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0383]: the method of 2200 used in combination in method 6000); comparing the amount to a first cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000), and determining a level of the pathology based on the comparing of the amount to the first cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining a classification for a relapse of the pathology based on the comparing of the amount to the first cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that cell-free viral DNA levels can be used to determine a classification of future relapse.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo with detecting relapse in different classifications of relapse of Chan. Since both Lo and Chan are in the same field of endeavor, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2).
Regarding instant claim 2, Lo, in view of Chan, teaches the method of claim 1. Lo further teaches further comprising: for each of a second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject: measuring a size of a cell-free nucleic acid molecule (Page 31, paragraph [0384]); and determining whether the cell-free nucleic acid molecule is from the reference genome (Pages 31-32, paragraph [0386]); determining a statistical value derived from the measured sizes of the second plurality of cell-free nucleic acid molecules that are from the reference genome (Page 20, paragraph [0260] and Figure 40: determining size distribution alone, block 4030; Pages 31-32, paragraph [0386]: the method of 4030 used in combination); and comparing the statistical value to a second cutoff (Page 21, paragraph [0263] and Figure 40: method 4000 determining size distribution alone, specifically block 4040; Page 31, paragraph [0384]: second assay performed as described for method 4000), wherein determining the level of the pathology is further based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff (Page 32, paragraph [0389]). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining the classification for the relapse of the pathology is further based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that cell-free viral DNA levels can be used to determine a classification of future relapse. See the above 103 analysis for claim 1.
Regarding instant claim 3, Lo, in view of Chan, teaches the method of claim 2. Lo further teaches wherein measuring the size of the cell-free nucleic acid molecule includes sequencing the second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample to obtain second sequence reads, wherein the size of the cell-free nucleic acid molecule is measured using the second sequence reads (Page 20, paragraphs [0256]-[0257] and Figure 40: method 4000 determining size distribution alone, specifically block 4010; Page 31, paragraph [0384]: second assay performed as described for method 4000; Figure 60: blocks 6022 and 6024).
Regarding instant claim 4, Lo, in view of Chan, teaches the method of claim 2. Lo further teaches wherein the first plurality of cell-free nucleic acid molecules is the second plurality of cell-free nucleic acid molecules (Page 31, paragraph [0384]).
Regarding instant claim 5, Lo, in view of Chan, teaches the method of claim 2. Lo further teaches wherein the statistical value includes a ratio of: a first proportion of the second plurality of cell-free nucleic acid molecules that are from the reference genome of the virus with the size within a given range; and a second proportion of the second plurality of cell-free nucleic acid molecules that are from a human reference genome with the size within the given range (Page 20, paragraph [0262]; Page 31, paragraph [0384]: the second assay is performed in a similar manner as method 4000).
Regarding instant claim 6, Lo, in view of Chan, teaches the method of claim 2. Lo further teaches wherein the first cutoff and the second cutoff are determined from training samples having a known classification of the pathology (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0198]: cutoff values determined for method 2200; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining the cutoff levels from training samples with a known classification of the relapse. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that cell-free viral DNA levels can be used to determine a classification of future relapse. See the above 103 analysis for claim 1.
Regarding instant claim 7, Lo, in view of Chan, teaches the method of claim 1. Lo further teaches wherein the pathology is a cancer (Page 29, paragraph [0360]; Figure 54).
Regarding instant claim 8, Lo, in view of Chan, teaches the method of claim 7. Lo further teaches wherein the cancer is nasopharyngeal cancer (Page 29, paragraph [0360]; Figure 54).
Regarding instant claim 9, Lo, in view of Chan, teaches the method of claim 1. Lo further teaches further comprising enriching the biological sample for nucleic acid molecules from the virus (Page 33, paragraph [0408]).
Regarding instant claim 10, Lo, in view of Chan, teaches the method of claim 1. Lo further teaches wherein the virus comprises EBV DNA (Page 29, paragraph [0360]; Figure 54).
Regarding instant claim 12, Lo, in view of Chan, teaches the method of claim 1.
Lo does not teach responsive to determining the classification, initiating another treatment to the subject to prevent the future relapse of the pathology.
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that cell-free viral DNA levels can be used to determine a classification of future relapse. Chan further teaches that patients with significant levels of viral DNA, indicating the pathology, after treatment have a high chance of progression of the disease, and that further treatment can be applied to those subjects before clinical progression (Page 601, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo with the initiation of treatment of Chan. Since both Lo and Chan are in the same field of endeavor, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because further treatment before clinical progression may be useful for improving treatment outcome (Chan, Page 601, column 1, paragraph 1).
Regarding instant claim 13, Lo, in view of Chan, teaches the method of claim 1. Chan further teaches that viral DNA can be used to detect relapse in different classifications of relapse, wherein the classification comprises remission, relapse, loco-regional failure, or distant metastasis (Page 600, column 1, paragraph 2).
Regarding instant claim 14, Lo teaches a method of analyzing a biological sample from a subject with a level of a pathology, the method comprising: performing a first assay, wherein the first assay comprises analyzing a first plurality of cell-free nucleic acid molecules from a mixture of nucleic acid molecules of the biological sample of the subject, wherein the biological sample includes the mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000); performing a second assay, wherein the second assay comprises: for each of a second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject: measuring a size of a cell-free nucleic acid molecule (Page 31, paragraph [0384]); and determining whether the cell-free nucleic acid molecule is from a reference genome, the reference genome corresponding to the virus (Pages 31-32, paragraph [0386]); determining an amount of the first plurality of cell-free nucleic acid molecules that align to the reference genome (Page 15, paragraphs [0196] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0383]: the method of 2200 used in combination in method 6000); determining a statistical value derived from the measured sizes of the second plurality of cell-free nucleic acid molecules that are from the reference genome (Page 20, paragraph [0260] and Figure 40: determining size distribution alone, block 4030; Pages 31-32, paragraph [0386]: the method of 4030 used in combination); comparing the amount to a first cutoff, comparing the statistical value to a second cutoff, and determining a level of pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000; Page 32, paragraph [0389]). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining a classification for a relapse of the pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that cell-free viral DNA levels can be used to determine a classification of future relapse.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo with detecting relapse in different classifications of relapse of Chan. Since both Lo and Chan are in the same field of endeavor, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2).
Regarding instant claim 15, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein measuring the size of the cell-free nucleic acid molecule includes sequencing the second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample to obtain sequence reads, wherein the size of the cell-free nucleic acid molecule is measured using the sequence reads (Page 20, paragraphs [0256]-[0257] and Figure 40: method 4000 determining size distribution alone, specifically block 4010; Page 31, paragraph [0384]: second assay performed as described for method 4000; Figure 60: blocks 6022 and 6024).
Regarding instant claim 16, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein the first assay includes sequencing (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2220; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000).
Regarding instant claim 17, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein the first plurality of cell-free nucleic acid molecules is the second plurality of cell-free nucleic acid molecules (Page 31, paragraph [0384]).
Regarding instant claim 18, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein the statistical value includes a ratio of: a first proportion of the second plurality of cell-free nucleic acid molecules that are from the reference genome of the virus with the size within a given range; and a second proportion of the second plurality of cell-free nucleic acid molecules that are from a human reference genome with the size within the given range (Page 20, paragraph [0262]; Page 31, paragraph [0384]: the second assay is performed in a similar manner as method 4000).
Regarding instant claim 19, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein the first cutoff and the second cutoff are determined from training samples having a known classification of the pathology (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0198]: cutoff values determined for method 2200; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining the cutoff levels from training samples with a known classification of the relapse. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that viral DNA levels can be used to determine a classification of future relapse. See the above 103 analysis for claim 1.
Regarding instant claim 20, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein the pathology is a cancer (Page 29, paragraph [0360]; Figure 54).
Regarding instant claim 21, Lo, in view of Chan, teaches the method of claim 20. Lo further teaches wherein the cancer is nasopharyngeal cancer (Page 29, paragraph [0360]; Figure 54).
Regarding instant claim 22, Lo, in view of Chan teaches the method of claim 14. Lo further teaches further comprising enriching the biological sample for nucleic acid molecules from the virus (Page 33, paragraph [0408]).
Regarding instant claim 23, Lo, in view of Chan, teaches the method of claim 14. Lo further teaches wherein the virus comprises EBV DNA (Page 29, paragraph [0360]; Figure 54).
Regarding instant claim 25, Lo, in view of Chan, teaches the method of claim 14.
Lo does not teach responsive to determining the classification, initiating another treatment to the subject to prevent the relapse of the pathology.
Furthermore, Chan, in the same field of endeavor, teaches that viral DNA can be used to detect relapse in different classifications of relapse (Page 600, column 1, paragraph 2). Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that cell-free viral DNA levels can be used to determine a classification of future relapse. Chan further teaches that patients with significant levels of viral DNA, indicating the pathology, after treatment have a high chance of progression of the disease, and that further treatment can be applied to those subjects before clinical progression (Page 601, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo with the initiation of treatment of Chan. Since both Lo and Chan are in the same field of endeavor, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because further treatment before clinical progression may be useful for improving treatment outcome (Chan, Page 601, column 1, paragraph 1).
Regarding instant claim 26, Lo, in view of Chan, teaches the method of claim 14. Chan further teaches that viral DNA can be used to detect relapse in different classifications of relapse, wherein the classification comprises remission, relapse, loco-regional failure, or distant metastasis (Page 600, column 1, paragraph 2).
Claims 11 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (US20180208999A1; previously cited) and Chan (Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma, Chinese Journal of Cancer, December 2014, 33, 598-603; cited on the IDS filed February 24th, 2023), in view of Sun (Treatment of nasopharyngeal carcinoma in unique scenarios, Annals of Nasopharynx Cancer, November 2020, 1-7; previously cited).
Regarding instant claims 11 and 24, Lo, in view of Chan, teaches the method of claims 1 and 14 as discussed above.
Neither Lo or Chan teaches wherein the subject is a pregnant woman.
Sun, in the same field of endeavor, teaches on pregnancy associated nasopharyngeal cancer and potential EBV reactivation induced by immune suppression (Page 3).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo, in view of Chan, with subject of Sun. Since Lo, Chan, and Sun are in the same field of endeavor, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because immune suppression in pregnant women may be associated with EBV reactivation (e.g. an increase in EBV DNA) (Sun, Page 3), and an increase in EBV is associated with nasopharyngeal cancer (Chan, whole document).
Response to Arguments
Applicant's arguments filed December 30th, 2025 have been fully considered but they are not persuasive.
The Applicant first gives a brief summary of the Examiner’s previous rejections (Page 15 of the Remarks filed December 30th, 2025). The Applicant disagrees that the Examiner’s determination of recurrence of cancer being reasonably considered to be a relapse of cancer (Page 15 of the Remarks filed December 30th, 2025). The Applicant argues that the method of Lo determines whether cancer is currently present, while the claimed method now emphasizes classifying a prediction of whether a relapse will occur at a future time point (Page 15 of the Remarks filed December 30th, 2025).
In response to these arguments, the Examiner would first like to acknowledge that while the Applicant has indicated that they disagree with the recurrence of cancer being reasonably considered to be a relapse of cancer, there is no further explanation of what aspects of this argument the Applicant disagrees with. The argument the Applicant follows this statement with relates to Lo determining whether cancer is currently present versus the claimed method determining a future relapse. While active relapse and future relapse are acknowledged to be different, this does not indicate that recurrence and relapse mean different things and therefore they will continue to be considered equivalent terms. With respect to the method of Lo, ultimately the method is detecting an amount of circulating viral DNA and relating it to a level of cancer. As cited above, level of cancer can mean any measure of a severity of cancer, including a recurrence of cancer and monitoring the progress of cancer over time (Lo, Pages 4-5, paragraph [0077]). While this does not directly teach looking at a future relapse, Chan teaches that an increase in the amount of plasma viral DNA can be related to future disease relapse (Chan, Page 600, column 1, paragraph 2). Chan explicitly states that “The surge in plasma EBV DNA concentration could occur up to 6 months before clinical deterioration. Thus, serial monitoring of plasma EBV DNA would be useful for monitoring the treatment and disease progression for NPC patients” (Chan, Page 600, column 1, paragraph 2), and also includes a full section on “Posttreatment Prognostication” detailing detecting viral plasma DNA and relating this to later disease progression (Chan Page 600 column 2, paragraph 2 to Page 601, column 1, paragraph 1). Therefore, as has been analyzed above, it would be obvious that the method of Lo could be used to measure an amount of plasma viral DNA and relate it to future relapse given the teachings of Chan. Overall, this argument is not considered persuasive.
The Applicant further notes the cited prior teachings of Chan (Page 16 of the Remarks filed December 30th, 2025). The Applicant notes that Chan refers to a clinical trial and includes a citation to that clinical trial, stating it is referenced in paragraphs [0071]-[0072] of the instant specification (Page 16 of the Remarks filed December 30th, 2025). The Applicant argues that because the clinical trial did not show any significant difference in the relapse-free survival between the adjuvant chemotherapy group and the observation group, Chan and Chan 2018 teach away from using amount of viral DNA to predict a future relapse (Page 16 of the Remarks filed December 30th, 2025). The Applicant then argues that the instant application provides surprising results that show sequencing can predict disease relapses, with a provided summary and graphs from the instant application (Page 16 and 17 of the Remarks filed December 30th, 2025). The Applicant argues that these results are not taught nor suggested by Lo, Chan, or Chan 2018 (Page 17 of the Remarks filed December 30th, 2025).
In response to these arguments, the Examiner would first like to address the argument regarding adjuvant chemotherapy not appearing to have a significant difference in relapse-free survival when given after detecting plasma EBV DNA after treatment. This argument is based on a reference that the Examiner has not cited in rejecting the relevant claims, and thus there is no relevant basis for making an argument using it. The claims as written focus on prediction of future relapse, and the teachings of Chan as presented are sufficient to meet the claim limitations. Chan has reasonably suggested that an increase plasma viral DNA can predict future relapse (Chan, Page 600, column 1, paragraph 2), which is all that is needed to sufficiently meet the claims. In addition, it is noted that any method related to Chan is not relied upon to teach the method aspects of the claimed invention as Lo teaches all aspects as they relate to sequencing. As has already been stated above, it would be obvious that the method of Lo could be used to measure an amount of plasma viral DNA and relate it to future relapse given the teachings of Chan. Overall, this argument is not considered persuasive.
Finally, the Applicant argues that the teachings of Sun as applied to claims 11 and 24 do not remedy the defects of Lo and Chan (Page 17 of the Remarks filed December 30th, 2025).
In response to this argument, given that Lo and Chan are still considered to teach the claims as amended, Sun does not need to remedy the supposed defects of Lo and Chan, and therefore this argument is not considered persuasive.
New – Necessitated by Amendment
Claims 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over (US20180208999A1; previously cited), in view of Chan (Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma, Chinese Journal of Cancer, December 2014, 33, 598-603; cited on the IDS filed February 24th, 2023).
Regarding instant claims 27 and 28, Lo, in view of Chan, teaches the methods of claims 1 and 14. Lo, as previously cited, teaches on sequencing analysis of cell-free viral DNA (see rejection of claim 1). Chan, as previously cited, teaches that plasma viral DNA levels increase in individuals who subsequently develop recurrence or metastasis, which reasonably indicates that plasma viral DNA levels can be used to determine a classification of future relapse (see rejection of claim 1).
Neither reference as currently cited teaches the method further comprising: responsive to determining the classification, performing a sequencing analysis of new biological samples from the subject at a frequency dependent on the classification.
However, Chan does teach that an increase in plasma viral DNA concentration could occur up to 6 months before clinical deterioration (Page 600, column 1, paragraph 2). Chan further teaches that serial monitoring of plasma viral DNA would be useful for monitoring disease progression (Page 600, column 1, paragraph 2). Therefore, it would be obvious to one of ordinary skill in the art that a sequencing analysis, such as that of Lo, of new biological samples taken at a time interval frequency such as 6 months would be useful for monitoring a determined classification of future relapse given that plasma viral DNA levels increase up to 6 months before clinical deterioration (e.g. future relapse).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo with the testing frequency of Chan. Since both Lo and Chan are in the same field of endeavor, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2).
Double Patenting – Modified – Necessitated by Amendment
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of U.S. Patent No. 11479825 B2 in view of Lo (US20180208999A1), Chan (Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma, Chinese Journal of Cancer, December 2014, 33, 598-603; cited on the IDS filed February 24th, 2023) and Sun (Treatment of nasopharyngeal carcinoma in unique scenarios, Annals of Nasopharynx Cancer, November 2020, 1-7).
Both sets of identified claims are drawn to methods for sequencing cell-free nucleic acid molecules, determining the amount of viral DNA in cell-free nucleic acid molecule samples, determining size measurements of viral DNA in cell-free nucleic acid molecule samples, determining appropriate cutoffs for each of those determined outcomes, and determining pathology based on the comparison to the cutoffs. More specific parts of both methods claimed include wherein the cutoffs are determined from training samples with known pathology, wherein the pathology is cancer, wherein the cancer can be nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, or hepatocellular carcinoma, and wherein the viral DNA is EBV DNA, HPV DNA, HBV DNA, HCV nucleic acids, or fragments thereof.
U.S. Patent No. 11479825 B2 claims systems for analyzing a biological sample to determine a level of pathology or screening a biological sample for a pathology, these systems capable of performing the method of the instant claims. It would be obvious to one of ordinary skill that a system that can perform a method would obviate the method itself. Any additional limitations of the claims of U.S. Patent No. 11479825 B2 are encompassed by the open claim language “comprising” found in the instant claims.
The claims of U.S. Patent No. 11479825 B2 do not require that the amount of viral cell-free nucleic acids and the size measurements of nucleic acids are performed on a first plurality of nucleic acid molecules and a second plurality of nucleic acid molecules. In addition, the claims of U.S. Patent No. 11479825 B2 do not require that a classification of relapse is determined. In addition, the claims of U.S. Patent No. 11479825 B2 do not require that the subject is a pregnant woman. Finally, the claims of U.S. Patent No. 11479825 B2 do not require that responsive to determining a classification, performing a sequencing analysis of new biological samples from the subject at a frequency dependent on the classification.
However, Lo teaches a method of analyzing a biological sample from a subject for a level of a pathology, the method comprising: performing a first assay, wherein the first assay comprises analyzing a first plurality of cell-free nucleic acid molecules from a mixture of nucleic acid molecules of the biological sample of the subject, wherein the biological sample includes a mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000) and determining an amount of the first plurality of cell-free nucleic acid molecules that align to the reference genome (Page 15, paragraphs [0196] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0383]: the method of 2200 used in combination in method 6000), as well as performing a second assay, wherein the second assay comprises: for each of a second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject: measuring a size of the cell-free nucleic acid molecule (Page 31, paragraph [0384]); determining whether the cell-free nucleic acid molecule is from a reference genome, the reference genome corresponding to the virus (Pages 31-32, paragraph [0386]); and comparing the amount to a first cutoff, comparing the statistical value to a second cutoff, and determining a level of pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000; Page 32, paragraph [0389]). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining a classification for a relapse of the pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that viral DNA levels can be used to determine a classification of future relapse.
In addition, Sun teaches on pregnancy associated nasopharyngeal cancer and potential EBV reactivation induced by immune suppression (Page 3).
Finally, Chan does teach that an increase in plasma viral DNA concentration could occur up to 6 months before clinical deterioration (Page 600, column 1, paragraph 2). Chan further teaches that serial monitoring of plasma viral DNA would be useful for monitoring disease progression (Page 600, column 1, paragraph 2). Therefore, it would be obvious to one of ordinary skill in the art that a sequencing analysis, such as that of Lo, of new biological samples taken at a time interval frequency such as 6 months would be useful given that plasma viral DNA levels increase up to 6 months before clinical deterioration.
It would have been obvious to one of ordinary skill in the art to have modified the claims of U.S. Patent No. 11479825 B2 with the teachings of Lo, Chan, and Sun to arrive at the instantly claimed method with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2), and immune suppression in pregnant women may be associated with EBV reactivation (e.g. an increase in EBV DNA) (Sun, Page 3), and an increase in EBV is associated with nasopharyngeal cancer (Chan, whole document).
Response to Arguments
Applicant's arguments filed December 30th, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments regarding this double patenting rejection rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claims remained rejected based on the prior art citations presented in the rejections.
Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of copending Application No. 17/968,155 in view of in view of Lo (US20180208999A1), Chan (Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma, Chinese Journal of Cancer, December 2014, 33, 598-603; cited on the IDS filed February 24th, 2023) and Sun (Treatment of nasopharyngeal carcinoma in unique scenarios, Annals of Nasopharynx Cancer, November 2020, 1-7).
Both sets of identified claims are drawn to methods for sequencing cell-free nucleic acid molecules, determining the amount of viral DNA in cell-free nucleic acid molecule samples, determining size measurements of viral DNA in cell-free nucleic acid molecule samples, determining appropriate cutoffs for each of those determined outcomes, and determining pathology based on the comparison to the cutoffs. More specific parts of both methods claimed include wherein the cutoffs are determined from training samples with known pathology, wherein the pathology is cancer, wherein the cancer can be nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, or hepatocellular carcinoma, and wherein the viral DNA is EBV DNA, HPV DNA, HBV DNA, HCV nucleic acids, or fragments thereof.
Application No. 17/968,155 claims a computer product that controls a system for analyzing a biological sample to determine a level of pathology or screening a biological sample for a pathology, these systems capable of performing the method of the instant claims. It would be obvious to one of ordinary skill that a computer product that controls a system that can perform a method would obviate the method itself. Any additional limitations of the claims of Application No. 17/968,155 are encompassed by the open claim language “comprising” found in the instant claims.
The claims of Application No. 17/968,155 do not require that the amount of viral cell-free nucleic acids and the size measurements of nucleic acids are performed on a first plurality of nucleic acid molecules and a second plurality of nucleic acid molecules. In addition, the claims of Application No. 17/968,155 do not require that a classification of relapse is determined. In addition, the claims of Application No. 17/968,155 do not require that the subject is a pregnant woman. Finally, the claims of Application No. 17/968,155 do not require that responsive to determining a classification, performing a sequencing analysis of new biological samples from the subject at a frequency dependent on the classification.
However, Lo teaches a method of analyzing a biological sample from a subject for a level of a pathology, the method comprising: performing a first assay, wherein the first assay comprises analyzing a first plurality of cell-free nucleic acid molecules from a mixture of nucleic acid molecules of the biological sample of the subject, wherein the biological sample includes a mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000) and determining an amount of the first plurality of cell-free nucleic acid molecules that align to the reference genome (Page 15, paragraphs [0196] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0383]: the method of 2200 used in combination in method 6000), as well as performing a second assay, wherein the second assay comprises: for each of a second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject: measuring a size of the cell-free nucleic acid molecule (Page 31, paragraph [0384]); determining whether the cell-free nucleic acid molecule is from a reference genome, the reference genome corresponding to the virus (Pages 31-32, paragraph [0386]); and comparing the amount to a first cutoff, comparing the statistical value to a second cutoff, and determining a level of pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000; Page 32, paragraph [0389]). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining a classification for a relapse of the pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that viral DNA levels can be used to determine a classification of future relapse.
In addition, Sun teaches on pregnancy associated nasopharyngeal cancer and potential EBV reactivation induced by immune suppression (Page 3).
Finally, Chan does teach that an increase in plasma viral DNA concentration could occur up to 6 months before clinical deterioration (Page 600, column 1, paragraph 2). Chan further teaches that serial monitoring of plasma viral DNA would be useful for monitoring disease progression (Page 600, column 1, paragraph 2). Therefore, it would be obvious to one of ordinary skill in the art that a sequencing analysis, such as that of Lo, of new biological samples taken at a time interval frequency such as 6 months would be useful given that plasma viral DNA levels increase up to 6 months before clinical deterioration.
It would have been obvious to one of ordinary skill in the art to have modified the claims of Application No. 17/968,155 with the teachings of Lo, Chan, and Sun to arrive at the instantly claimed method with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2), and immune suppression in pregnant women may be associated with EBV reactivation (e.g. an increase in EBV DNA) (Sun, Page 3), and an increase in EBV is associated with nasopharyngeal cancer (Chan, whole document).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed December 30th, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments regarding this double patenting rejection rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claims remained rejected based on the prior art citations presented in the rejections.
Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 17/884,498 in view of in view of Lo (US20180208999A1), Chan (Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma, Chinese Journal of Cancer, December 2014, 33, 598-603; cited on the IDS filed February 24th, 2023) and Sun (Treatment of nasopharyngeal carcinoma in unique scenarios, Annals of Nasopharynx Cancer, November 2020, 1-7).
Both sets of identified claims are drawn to methods for sequencing cell-free nucleic acid molecules, determining the amount of viral DNA in cell-free nucleic acid molecule samples, determining size measurements of viral DNA in cell-free nucleic acid molecule samples, determining appropriate cutoffs for each of those determined outcomes, and determining pathology based on the comparison to the cutoffs. More specific parts of both methods claimed include wherein the pathology is cancer and wherein the cancer can be nasopharyngeal cancer, and wherein the viral DNA is EBV DNA. Any additional limitations of the claims of Application No. 17/884,498 are encompassed by the open claim language “comprising” found in the instant claims.
The claims of Application No. 17/884,498 do not require that the amount of viral cell-free nucleic acids and the size measurements of nucleic acids are performed on a first plurality of nucleic acid molecules and a second plurality of nucleic acid molecules. In addition, the claims of Application No. 17/884,498 do not require that a classification of relapse is determined. In addition, the claims of Application No. 17/884,498 do not require that the subject is a pregnant woman. Finally, the claims of Application No. 17/884,498 do not require that responsive to determining a classification, performing a sequencing analysis of new biological samples from the subject at a frequency dependent on the classification.
However, Lo teaches a method of analyzing a biological sample from a subject for a level of a pathology, the method comprising: performing a first assay, wherein the first assay comprises analyzing a first plurality of cell-free nucleic acid molecules from a mixture of nucleic acid molecules of the biological sample of the subject, wherein the biological sample includes a mixture of nucleic acid molecules from the subject and nucleic acid molecules from a virus (Page 14, paragraphs [0189]-[0192] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 31, paragraphs [0382]-[0383]: the method of 2200 used in combination in method 6000) and determining an amount of the first plurality of cell-free nucleic acid molecules that align to the reference genome (Page 15, paragraphs [0196] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2240; Page 15, paragraph [0383]: the method of 2200 used in combination in method 6000), as well as performing a second assay, wherein the second assay comprises: for each of a second plurality of cell-free nucleic acid molecules from the mixture of nucleic acid molecules of the biological sample of the subject: measuring a size of the cell-free nucleic acid molecule (Page 31, paragraph [0384]); determining whether the cell-free nucleic acid molecule is from a reference genome, the reference genome corresponding to the virus (Pages 31-32, paragraph [0386]); and comparing the amount to a first cutoff, comparing the statistical value to a second cutoff, and determining a level of pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff (Page 15, paragraph [0197] and Figure 22: method 2200 determining amount of sequence reads alone, specifically block 2250; Page 32, paragraph [0387]: the method of 2200 used in combination in method 6000; Page 32, paragraph [0389]). Lo teaches a “level of pathology” can refer to level of pathology associated with a pathogen, where the level can be a level of cancer. When the cancer is associated with a pathogen, a level of cancer can be a type of a level of pathology (Pages 4-5, paragraph [0077]. Lo teaches that a level of cancer can refer to measure of severity of a cancer, e.g. recurrence of cancer (Pages 4-5, paragraph [0077]). Recurrence of cancer can be reasonably considered to be a relapse of cancer. Lo teaches many examples of adjusting cutoff values depending on the level of pathology being detected (one example at Page 21, paragraph [0263]).
Lo does not directly teach determining a classification for a relapse of the pathology based on the comparing of the amount to the first cutoff and the comparing of the statistical value to the second cutoff. However, given the prior teachings of Lo, it would be obvious to one of ordinary skill in the art that different levels of pathology could be determined using different cutoff values (Lo, Page 15, paragraph [0203]; Page 19, paragraphs [0243] and [0244]; Page 21, paragraph [0263]).
Furthermore, Chan also teaches that the detection of relapse can be performed after treatment on individuals in continuous remission (e.g. asymptomatic individuals) (Page 600, column 1, paragraph 2). Viral DNA levels increase in individuals who subsequently develop recurrence or metastasis (Page 600, column 1, paragraph 2; Page 600, column 2, paragraph 2), which reasonably indicates that viral DNA levels can be used to determine a classification of future relapse.
In addition, Sun teaches on pregnancy associated nasopharyngeal cancer and potential EBV reactivation induced by immune suppression (Page 3).
Finally, Chan does teach that an increase in plasma viral DNA concentration could occur up to 6 months before clinical deterioration (Page 600, column 1, paragraph 2). Chan further teaches that serial monitoring of plasma viral DNA would be useful for monitoring disease progression (Page 600, column 1, paragraph 2). Therefore, it would be obvious to one of ordinary skill in the art that a sequencing analysis, such as that of Lo, of new biological samples taken at a time interval frequency such as 6 months would be useful given that plasma viral DNA levels increase up to 6 months before clinical deterioration.
It would have been obvious to one of ordinary skill in the art to have modified the claims of Application No. 17/968,155 with the teachings of Lo, Chan, and Sun to arrive at the instantly claimed method with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because serial monitoring of viral DNA, such as plasma EBV DNA, would be useful for monitoring the treatment and disease progression for cancer patients (Chan, Page 600, column 1, paragraph 2), and immune suppression in pregnant women may be associated with EBV reactivation (e.g. an increase in EBV DNA) (Sun, Page 3), and an increase in EBV is associated with nasopharyngeal cancer (Chan, whole document).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed December 30th, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments regarding this double patenting rejection rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claims remained rejected based on the prior art citations presented in the rejections.
Conclusion
All claims stand rejected.
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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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683