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 amendment filed on 04/27/2026 has been entered.
Claims 1, 2, and 10 were amended in the claim set filed on 04/27/2026.
Applicant’s election without traverse of Group I, claims 1-17, drawn to a method for the diagnosis of human subjects at risk of developing advanced colorectal adenomas and species of m3 in the reply filed on 07/17/2025 is acknowledged. Applicant’s election of species, in the reply filed on 12/18/2025, was incomplete as the claims are drawn to more than one generic invention as recited in claims 1 and 10. In order to expedite prosecution, the specie election requirement was withdrawn and claims 10-17 were objected to in the non-final office action, filed on 01/27/2026.
Claims 21, 27 and 23 are withdrawn drawn to a nonelected Group II and non-elected species.
Claims 1-17 in the claim set filed on 04/27/2026 are currently under examination.
Response to the Arguments
Objections to the Specification in the previously mailed non-final have been maintained in light of applicants lack of Specification arguments, as documented below in the Specification section in this office action on Pg. 4.
Objections to claims 10-17 in the previously mailed non-final have been maintained in light of applicants arguments on Pg. 9., as documented below in the Claim objection section in this office action on Pg. 5-7.
Applicant’s arguments regarding previous rejection(s) of claim(s) 2 under 35 U.S.C. 112 have been fully considered and are persuasive. The 35 U.S.C. 112 rejections documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments and arguments on Pg. 9. However, upon further consideration of the amendments, new grounds of rejection are made as documented below in the 35 U.S.C. 112 rejection in this office action on Pg. 7.
Applicant’s arguments regarding previous rejection(s) of claim(s) 1-17 under 35 U.S.C. 101 have been fully considered and but are not persuasive. Applicant' s argument on Pg. 10, states that “Since independent claims 1 and 10 as amended now both recite a treatment step, ''administering to the individual colonoscopy every 1-2 years," which incorporates the alleged judicial exception into a practical application and therefore amounts to ''significantly more." The 35 U.S.C. 101 rejections documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 10, as documented below in the 35 U.S.C. 101 rejection in this office action on Pg. 7-13.
As necessitated by amendment, the 35 U.S.C. 103 rejections of claim(s) 1-17 documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 10-11, as documented below in the 35 U.S.C. 103 rejection in this office action on Pg. 14-21.
As necessitated by amendment, the Nonstatutory Double Patenting (NDSDP) rejections of claim(s) 1-17 documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 12, as documented below in the 35 U.S.C. NSDP rejection in this office action on Pg. 24-26.
The revised and new grounds of rejections for claims 1-17 are documented below in this Final Office Action are necessitated by claim amendments filed on 04/27/2026.
Priority
This application is a 371 U.S. national phase application of PCT Application No. PCT/CN2021/131499, filed November 18, 2021, which claims priority to U.S. Provisional Patent Application No. 63/116,104, filed November 19, 2020, and U.S. Provisional Patent Application No. 63/196,582, filed June 3, 2021.Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The priority date of the instant claim set is determined to be November 19, 2020.
Specification
The disclosure is objected to because of the following informalities:
The listing of references in the specification is not a proper information disclosure
statement. The specification filed on 05/18/2023 includes a list of references on pages 43-44. 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, they have not been
considered.
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed 04/27/2026 with respect to the specification lack a response to the specification section. To clarify, the specification is objected to for the listing of references in the specification not disclosed in the IDS.
Claim Objections
Claim 10 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 11 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 3. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 12 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 4. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 13 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 5. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 14 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 6. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 15 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 7. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 16 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 8. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 17 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 9. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Response to Arguments
Applicant's arguments filed 04/27/2026 (Pg. 9) with respect to claims 10-17 have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 04/27/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Claim 1 requires the use of a first stool sample taken from the individual prior to the removal of colorectal cancer or adenoma, for example, whereas claim 10 does not require the use of such a ''pre-removal'' sample. Claim 10 therefore cannot be said as a substantial duplicate of claim 1."(Pg. 9)
Response: Applicant’s arguments have been fully considered and found unpersuasive because applicants amendments as discussed in the Final action below under the 103 rejection section, it would be obvious to one of ordinary skill in the art to assess the risk of colorectal cancer or adenoma before and/or after a sample is removed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is indefinite over the table incorporated into claim 2 because it is unclear what the abbreviations stand for under the Calculation for combined scores column, besides the genetic markers recited in claim 1 from which claim 2 depends on.
Response to Arguments
Applicant's arguments filed 04/27/2026 do not apply to the new grounds of rejection.
Claim Rejections - 35 USC § 101
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 1-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards abstract ideas of obtaining levels, calculating score, detecting the value higher than the control and determining increased risk for recurrence for colorectal adenoma recurrence and routine and conventional method of obtaining level of bacterial species in a stool sample, without significantly more. The claim(s) recite(s) abstract ideas and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are not considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 1 is directed towards: A method for assessing risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma, comprising the steps of: (a) obtaining in a first stool sample taken from the individual prior to the removal of colorectal cancer or adenoma a baseline level of one or more of four bacterial species of a Lachnoclostridium species carrying genetic marker m3 (m3), Fusobacterium nucleatum (Fn), Clostridium hathewayi (Ch), and Bacteroides clarus (Bc); (b) obtaining in a second stool sample taken from the individual after the removal of colorectal cancer or adenoma a follow-up level of the one or more of the four bacterial species; (c) calculating a combined score from the baseline level and follow-up level of any one more of the four bacterial species Fn, m3, Bc, and Ch; d) detecting the value to be higher than a standard control value and determining the individual as having increased risk for colorectal adenoma recurrence; and (e) administering to the individual colonoscopy every 1-2 years.
The obtaining levels, calculating score, detecting the value higher than the control and determining increased risk for recurrence are abstract ideas.
“obtaining … a baseline level…obtaining a … follow-up level and detecting the value higher than the control and determining increased risk for recurrence” is considered an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and is considered to be active steps requiring the analysis of a sample.
“calculating a combined score” is considered an abstract idea related to a mathematical relationship.
The administering to the individual colonoscopy every 1-2 years is not considered a particular treatment, as colonoscopies can be performed as a preventative surveillance step and not necessarily a treatment step.
The method of obtaining level of bacterial species in a stool sample, detecting the value higher than the control and determining increased risk for recurrence is considered to be an active step requiring the analysis of a sample. The active step is routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about the calculation of combined score of baseline and follow-up levels, individual, type of level, measurement of level, and stool samples.
The instant claim 10 is directed towards: A method for assessing risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma, comprising the steps of: (a) obtaining in a stool sample taken from the individual after the removal of colorectal cancer or adenoma a value of (1) level of one or more of three bacterial species of a Lachnoclostridium species carrying genetic marker m3 (m3), Fusobacterium nucleatum (Fn), and Clostridium hathewayi (Ch); or (2) combined score of levels of two bacterial species m3 and Ch, which is calculated by I2+β5*m3+β6*Ch; or (3) combined score of levels of three bacterial species Fn, m3, and Ch, which is calculated by I3+β7*Fn+β8*m3+β9*Ch; or (4) combined score of levels of four bacterial species Fn, m3, Bc, and Ch, which is calculated by I1+β1*Fn+β2*m3+β3*Bc+β4*Ch; and (b) detecting the value to be higher than a standard control value and determining the individual as having increased risk for colorectal adenoma recurrence; and (c) administering to the individual colonoscopy every 1-2 years.
The obtaining levels, calculating score, detecting the value higher than the control and determining increased risk for recurrence are abstract ideas.
“obtaining … a baseline level…obtaining a … follow-up level and detecting the value higher than the control and determining increased risk for recurrence ” is considered an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and is considered to be active steps requiring the analysis of a sample.
“calculating a combined score” is considered an abstract idea related to a mathematical relationship.
The administering to the individual colonoscopy every 1-2 years is not considered a particular treatment, as colonoscopies can be performed as a preventative surveillance step and not necessarily a treatment step.
The method of obtaining level of bacterial species in a stool sample, detecting the value higher than the control and determining increased risk for recurrence is considered to be an active step requiring the analysis of a sample. The active step is routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract ideas.
With regard to claim 1, the claim recites “A method for assessing risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma, comprising the steps of: (a) obtaining in a first stool sample taken from the individual prior to the removal of colorectal cancer or adenoma a baseline level of one or more of four bacterial species of a Lachnoclostridium species carrying genetic marker m3 (m3), Fusobacterium nucleatum (Fn), Clostridium hathewayi (Ch), and Bacteroides clarus (Bc); (b) obtaining in a second stool sample taken from the individual after the removal of colorectal cancer or adenoma a follow-up level of the one or more of the four bacterial species; (c) calculating a combined score from the baseline level and follow-up level of any one more of the four bacterial species Fn, m3, Bc, and Ch; d) detecting the value to be higher than a standard control value and determining the individual as having increased risk for colorectal adenoma recurrence; and (e) administering to the individual colonoscopy every 1-2 years.” The obtaining levels, calculating score, detecting the value higher than the control and determining increased risk for recurrence are abstract ideas. The “obtaining … a baseline level…obtaining a … follow-up level and detecting the value higher than the control and determining increased risk for recurrence ” is considered an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work. The “calculating a combined score” is considered an abstract idea related to a mathematical relationship.
With regard to claim 10, the claim recites, “A method for assessing risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma, comprising the steps of: (a) obtaining in a stool sample taken from the individual after the removal of colorectal cancer or adenoma a value of (1) level of one or more of three bacterial species of a Lachnoclostridium species carrying genetic marker m3 (m3), Fusobacterium nucleatum (Fn), and Clostridium hathewayi (Ch); or (2) combined score of levels of two bacterial species m3 and Ch, which is calculated by I2+β5*m3+β6*Ch; or (3) combined score of levels of three bacterial species Fn, m3, and Ch, which is calculated by I3+β7*Fn+β8*m3+β9*Ch; or (4) combined score of levels of four bacterial species Fn, m3, Bc, and Ch, which is calculated by I1+β1*Fn+β2*m3+β3*Bc+β4*Ch; and (b) detecting the value to be higher than a standard control value and determining the individual as having increased risk for colorectal adenoma recurrence; and (c) administering to the individual colonoscopy every 1-2 years.” The obtaining levels, calculating score, detecting the value higher than the control value and determining increased risk for recurrence are abstract ideas. The “obtaining … a baseline level…obtaining a … follow-up level and detecting the value higher than the control and determining increased risk for recurrence ” is considered an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work. The “calculating a combined score” is considered an abstract idea related to a mathematical relationship.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Although the independent claim 1 claim 10 step (c) recites an administering step, the administering to the individual colonoscopy every 1-2 years is not considered a particular treatment, as colonoscopies can be performed as a preventative surveillance step and not necessarily a particular treatment step.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claims 1 and 10, the claims require the routine and conventional active steps of obtaining level of bacterial species in a stool sample, detecting the value higher than the control and determining increased risk for recurrence similar to that of Yu et al. (“Yu”; Patent App. Pub. WO 2018036503 A1, Mar. 1, 2018, filed on Aug. 25, 2016).
Yu discloses “Provided is a non-invasive method for diagnosing colorectal cancer in a subject by detecting enrichment or reduction of certain bacterial species. A kit and device useful for such methods are also provided. In addition, a method for reducing the risk of colon cancer by regulating the pertinent bacterial species in human colon is also provided.” (Abstract). Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require calculation of combined score levels, individual, type of level, measurement of level, and stool samples which are all routine and conventional based on Yu et al. (“Yu”; Patent App. Pub. WO 2018036503 A1, Mar. 1, 2018, filed on Aug. 25, 2016).
Response to Arguments
Applicant's arguments filed 04/27/2026 (Pg. 10) with respect to claims 1-17 have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 04/27/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Since independent claims 1 and 10 as amended now both recite a treatment step, ''administering to the individual colonoscopy every 1-2 years," which incorporates the alleged judicial exception into a practical application and therefore amounts to ''significantly more."(P. 10)
Response: Applicant’s arguments have been fully considered and found unpersuasive because applicants amendments do not overcome the lack of patentably matter under U.S.C. 35 101. The previously presented and amended claims recite abstract ideas of obtaining levels, calculating score, detecting the value higher than the control and determining increased risk for recurrence for colorectal adenoma recurrence and routine and conventional method of obtaining level of bacterial species in a stool sample, detecting the value higher than the control and determining increased risk for recurrence. The judicial exceptions are not integrated into a practical application because the claim limitations do not appear to improve the current technology or technical field beyond well-understood, routine, conventional activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no specific limitations that provide significantly more.
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.
Claim(s) 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (“Yu”; Patent App. Pub. WO 2018036503 A1, Mar. 1, 2018, filed on Aug. 25, 2016).
Yu discloses “Provided is a non-invasive method for diagnosing colorectal cancer in a subject by detecting enrichment or reduction of certain bacterial species. A kit and device useful for such methods are also provided. In addition, a method for reducing the risk of colon cancer by regulating the pertinent bacterial species in human colon is also provided.” (Abstract).
Regarding claims 1 and 10, Yu teaches a method comprising “The present invention relates to measuring the level or amount of a signature DNA or RNA for one or more bacterial species found in a person's stool sample as a means to detect the presence, to assess the risk of developing, and/or to monitor the progression or treatment efficacy of colon cancer, including assessing the likelihood of disease recurrence.” (Para. 110; Para. 6). Yu teaches a method comprising “Stool samples were collected from individuals referred to colonoscopy due to symptoms associated with CRC or from patients who had been diagnosed with CRC and referred to large bowel resection for their primary cancer disease” (Para. 197). Yu teaches a method comprising “Such increased or decreased presence of these bacterial species results in higher or lower levels of signature DNA, RNA, and protein species unique to these species, which in turn can be used for detection, both qualitatively and quantitatively, the abnormally enriched/suppressed bacteria population in the samples, thus providing critical information relating to the presence of or a heightened risk of CRC in a human subject, including an increased risk of recurrence of CRC after initial treatment (e.g., surgical intervention, chemotherapy, and/or radiation therapy) in a patient who has been diagnosed of the disease” (Para. 5).
Regarding claims 1 and 10, Yu teaches a method comprising “steps of: (a) quantitatively determining level of at least one of the bacterial species of … Bacteroides clarus… Clostridium hathewayi in a stool sample taken from the subject; (b) comparing the level obtained in step (a) with a standard control; (c) determining the level obtained in step (a) as increased or decreased from the standard control; and (d) determining the subject as having an increased risk for colon cancer.” (Para. 7). Yu teaches a method comprising “determining the level of a DNA unique to each of Bacteroides clarus and Clostridium hathewayi, optionally further comprising determining the level of a DNA unique to Fusobacterium nucleatum.” (Para. 9) and Marker gene id “482585” (Pg. 86, Table S13). Yu also teaches a method comprising “Lachnospiraceae” Firmicutes. “Marker gene id 482585” reads on Lachnoclostridium species carrying genetic marker M3. “Lachnoclostridium species carrying genetic marker M3” reads on the Lachnospiraceae family. Yu teaches a method wherein “A simple linear combination of four bacterial marker candidates (Fn, Bc, Ch, and …) improves the diagnostic ability of Fn alone for CRC.” (Para. 104) “A simple linear combination” reads on calculating a combined score.
Regarding claims 1 and 10, Yu teaches a method comprising “In addition, upon detecting the enrichment of certain bacterial species in a patient's gut, which is shown by the present inventors as relevant to colon cancer, one may establish the presence of colon cancer in the patient or an increased risk of later developing the disease in the patient. As a result of this determination, the patient may be subject to subsequent therapies or preventive/monitoring measures… undergo regularly scheduled screening/examination such as colonoscopy every 5 years).” (Para. 133). Yu teaches a method comprising “A stool sample is obtained from a person to be tested or monitored for colon cancer using a method of the present invention” (Para. 111). The teaching “undergo regularly scheduled screening/examination” reads on about one to five years. “preventive/ monitoring measures” read on earlier or more frequent screening/examination such as individual colonoscopy every 1-2 years. Of note, the MPEP states "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." (MPEP 2144.05). In addition, the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946). (MPEP 2144.04)
Thus, Yu suggests a method for assessing risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma, comprising the steps of: (a) obtaining in a first stool sample taken from the individual prior to the removal of colorectal cancer or adenoma a baseline level of one or more of four bacterial species of a Lachnoclostridium species carrying genetic marker m3 (m3), Fusobacterium nucleatum (Fn), Clostridium hathewayi (Ch), and Bacteroides clarus (Bc); (b) obtaining in a second stool sample taken from the individual after the removal of colorectal cancer or adenoma a follow-up level of the one or more of the four bacterial species; (c) calculating a combined score from the baseline level and follow-up level of any one more of the four bacterial species Fn, m3, Bc, and Ch; d) detecting the value to be higher than a standard control value and determining the individual as having increased risk for colorectal adenoma recurrence and (e) administering to the individual colonoscopy every 1-2 years.; and a method for assessing risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma, comprising the steps of: (a) obtaining in a stool sample taken from the individual after the removal of colorectal cancer or adenoma a value of (1) level of one or more of three bacterial species of a Lachnoclostridium species carrying genetic marker m3 (m3), Fusobacterium nucleatum (Fn), and Clostridium hathewayi (Ch); or (2) combined score of levels of two bacterial species m3 and Ch, which is calculated by I2+β5*m3+β6*Ch; or (3) combined score of levels of three bacterial species Fn, m3, and Ch, which is calculated by I3+β7*Fn+β8*m3+β9*Ch; or (4) combined score of levels of four bacterial species Fn, m3, Bc, and Ch, which is calculated by I1+β1*Fn+β2*m3+β3*Bc+β4*Ch; and (b) detecting the value to be higher than a standard control value and determining the individual as having increased risk for colorectal adenoma recurrence and (c) administering to the individual colonoscopy every 1-2 years.
Yu also mentions that “Because of the high prevalence of colorectal cancer and vital importance of early diagnosis on patients' life expectancy, there exists an urgent need for new and more effective methods for early diagnosis of colorectal cancer” (Para. 4) and “Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same or similar results” (Para. 167). The ordinary artisan would know that colorectal cancer develops from colorectal adenomas. Yu also teaches “The present invention relates to measuring the level or amount of a signature DNA or RNA for one or more bacterial species found in a person's stool sample as a means to ….to monitor the progression or treatment efficacy of colon cancer, including assessing the likelihood of disease recurrence.” (Para. 110). Thus, one of ordinary skill in the art would be motivated to provide a method for assessing the risk for colorectal adenoma recurrence in the essence of assessing the likelihood of disease recurrence.
Therefore, the methods as recited in claims 1-10 are prima facie obvious over the prior art Yu et al. It would have been obvious to provide a method for assessing the risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma according to the limitations of the instant application claims 1 and 10 based on Yu et al. (Patent App. Pub. No. WO 2018036503 A1). These claim elements were known in the prior art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 10. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claims over the teachings of Yu et al. Doing so would allow for early detection of colorectal adenoma recurrence and a reduction of CRC-associated mortality.
The teachings of Yu are documented above in the rejection of claims 1 and 10 under 35 U.S.C. 103. Claims 2-9 depend on claim 1. Claim 7 depends on claim 6, which depends on claim 1. Claim 9 depends on Claim 8, which depends on claim 1. Claims 11-17 depend on claim 10. Claim 15 depends on claim 14, which depends on claim 10.
Regarding claim 2, Yu also teaches a method wherein “It was found that a simple linear combination of the four-bacteria (0.886) gave an increased AUROC as compared to three-bacteria (0.877), Fn only (0.868), and the logistic regression model with inclusion of all four bacteria (0.869) in the first cohort (Figure 19a). The combined abundance of four-bacteria was significantly higher in CRC patients as compared to healthy controls (P<0.0001) (Figure 19b)” (Para. 116). Furthermore, Yu teaches a method wherein “Values were all expressed as mean ± SD or median (interquartile range [IQR]) as appropriate. The differences in specific bacterial abundance were determined by Wilcoxon signed-rank test or Mann-Whitney U test. Continuous clinical and pathological variables were compared by T-test, whilst categorical variables were compared by Chi-square test. Spearman’s correlation coefficient was used to estimate the association of the bacterial abundances and several factors of interest. Factors independently associated with CRC diagnosis were estimated using univariate and multivariate linear regression. Receiver Operating Characteristic (ROC) curve was used to evaluate the diagnostic value of bacterial candidates in distinguishing CRC. Logistic regression model was applied to obtain probability plot values for estimating the incidence of CRC among all subjects. ROC curves were then constructed for the logistic regression models.” (Para. 257). It would be obvious to a person of ordinary skill in the art to calculate the combined score based on the teaching of Yu above and use the previously calculated combined score as the control for comparison when measuring for recurrence related to the disease. “Continuous clinical and pathological variables” reads on detecting levels at baseline and follow-up assessments. Thus, Yu suggests a method wherein the combined score of the baseline and follow-up levels of any one, two, three, or four of the four bacterial species is calculated by a method listed below:
PNG
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120
1225
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Greyscale
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396
1217
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Greyscale
Regarding claims 3 and 11, Yu teaches a method wherein “Marker gene id “482585” (Pg. 86, Table S13). “Marker gene id 482585” reads on genome of m3 and SEQ ID:19. Thus, Yu suggests a method wherein the genome of m3 comprises the nucleotide sequence of SEQ ID NO:19, or wherein the genome of Ch comprises the nucleotide sequence of SEQ ID NO:20, or wherein the genome of Fn comprises the nucleotide sequence of SEQ ID NO:21, or wherein the genome of Bc comprises the nucleotide sequence of SEQ ID NO:22.
Regarding claims 4 and 12, Yu teaches a method wherein “Patients were diagnosed by colonoscopic examination and histopathological review of any biopsies taken.” (Para. 251). “colonoscopic examination and biopsies” reads on adenoma removed by polypectomy. Thus, Yu suggests a method wherein the individual had colorectal adenoma removed by polypectomy.
Regarding claims 5 and 13, Yu teaches a method wherein “level of a DNA, RNA, or protein” and “determining the level of a DNA unique to each of Bacteroides clarus and Clostridium hathewayi, optionally further comprising determining the level of a DNA unique to Fusobacterium nucleatum.” (Para. 9). Furthermore, Yu teaches a method wherein “case-enriched …gene markers …their abundances were measured by qPCR…m482585” (Para. 184).” m482585” reads on m3. Thus, Yu suggests a method wherein steps (a) and (b) each comprises obtaining the level of a DNA, RNA, or protein unique to at least one of the bacterial species Fn, m3, Bc, and Ch.
Regarding claims 6-7 and 15-14, Yu teaches a method wherein “Once DNA or mRNA is extracted from a sample, the amount of a predetermined bacterial DNA or RNA (such as 16s rDNA or RNA encoded by a bacterial gene unique to the bacterial species) may be quantified. The preferred method for determining the DNA or RNA level is an amplification-based method, e.g., by polymerase chain reaction (PCR), including reverse transcription-polymerase chain reaction (RT-PCR) for RNA quantitative analysis.” (Para. 114). Thus, Yu suggests a method wherein steps (a) and (b) each comprises a polymerase chain reaction (PCR) for measuring the level or levels of the bacterial species; and wherein the PCR is a quantitative polymerase chain reaction (qPCR) or reverse transcription polymerase chain reaction (RT-PCR)
Regarding claims 8 and 16, Yu teaches a method wherein “when the subject is determined as having an increased risk for colon cancer, a repeat … is performed at a later time using another stool sample from the subject at the later time.” (Para. 11). Yu teaches a method wherein “increased or decreased presence of these bacterial species results in higher or lower levels of signature DNA, RNA, and protein species unique to these species, which in turn can be used for detection, both qualitatively and quantitatively, the abnormally enriched/suppressed bacteria population in the samples, thus providing critical information presence of or a heightened risk of CRC in a human subject, including an increased risk of recurrence of CRC after initial treatment (e.g., surgical intervention)” (Para. 5). Furthermore, Yu teaches a method wherein “In addition, upon detecting the enrichment of certain bacterial species in a patient's gut, which is shown by the present inventors as relevant to colon cancer, one may establish the presence of colon cancer in the patient or an increased risk of later developing the disease in the patient… undergo regularly scheduled screening/examination … every 5 years).” (Para. 133). “at a later time” reads on about one to five years. Thus, Yu suggests a method wherein the second stool sample is taken from the individual about one to five years after the removal of the colorectal cancer or adenoma.
Regarding claims 9 and 17 Yu teaches a method wherein “when the subject is determined as having an increased risk for colon cancer, a repeat … is performed at a later time using another stool sample from the subject at the later time.” (Para. 11). “at a later time” reads on about one year after. Thus, Yu suggests a method wherein the second stool sample is taken from the individual about one year after the removal of the colorectal cancer or adenoma.
Response to Arguments
Applicant's arguments filed 04/27/2026 (Pg. 6-7) with respect to claims 1-17 have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 04/27/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Yu' s methods relates to the assessment of various aspects (presence, risk, progression, therapeutic efficacy, etc.) of colorectal cancer (CRC). CRC is a disease entirely different from colorectal adenoma. Yu does not teach colorectal adenoma, let alone recurrence of colorectal adenoma.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive because as stated in the Final office action above “Yu mentions that “Because of the high prevalence of colorectal cancer and vital importance of early diagnosis on patients' life expectancy, there exists an urgent need for new and more effective methods for early diagnosis of colorectal cancer” (Para. 4) and “Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same or similar results” (Para. 167). The ordinary artisan would know that colorectal cancer develops from colorectal adenomas. Yu also teaches “The present invention relates to measuring the level or amount of a signature DNA or RNA for one or more bacterial species found in a person's stool sample as a means to ….to monitor the progression or treatment efficacy of colon cancer, including assessing the likelihood of disease recurrence.” (Para. 110) Thus, one of ordinary skill in the art would be motivated to provide a method for assessing the risk for colorectal adenoma recurrence in the essence of assessing the likelihood of disease recurrence.” Thus, Yu does suggest colorectal adenoma and recurrence of colorectal adenoma.
Applicants’ argument: “nowhere in Yu can one find any teaching or suggestion for taking a stool sample from an individual who has had a colorectal cancer or adenoma previously removed.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive because as stated in the Final action above Yu teaches a method comprising "The present invention relates to measuring the level or amount of a signature DNA or RNA for one or more bacterial species found in a person's stool sample as a means to … monitor the progression or treatment efficacy of colon cancer, including assessing the likelihood of disease recurrence" (Para. 110) and “A stool sample is obtained from a person to be tested or monitored for colon cancer using a method of the present invention” (Para. 111). Hence, it would be obvious to one of ordinary skill in the art to obtain a stool sample of a person being monitored for treatment efficacy, wherein the treatment comprised colorectal cancer or adenoma removal. Thus, Yu does suggest taking a stool sample from an individual who has had a colorectal cancer or adenoma previously removed.
Applicants’ argument: “Yu provides no suggestion for calculating combined scores of bacterial marker levels, let alone determining the risk for colorectal adenoma recurrence based on the combined scores.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive because, briefly, as stated in the Non-Final office action above “Yu also teaches a method wherein “… The combined abundance of four-bacteria was significantly higher in CRC patients as compared to healthy controls (P<0.0001) (Figure 19b)” (Para. 116). Furthermore, Yu teaches a method wherein “…Continuous clinical and pathological variables were compared by T-test, whilst categorical variables were compared by Chi-square test. Spearman’s correlation coefficient was used to estimate the association of the bacterial abundances and several factors of interest. Factors independently associated with CRC diagnosis were estimate using univariate and multivariate linear regression. Receiver Operating Characteristic (ROC) curve was used to evaluate the diagnostic value of bacterial candidates in distinguishing CRC. …” (Para. 257). It would be obvious to a person of ordinary skill in the art to calculate the combined score based on the teaching of Yu above and use the previously calculated combined score as the control for comparison when measuring for recurrence related to the disease. “Continuous clinical and pathological variables” reads on detecting levels at baseline and follow-up assessments. Thus, Yu does suggest calculating combined scores of bacterial marker levels, let alone determining the risk for colorectal adenoma recurrence based on the combined scores.
Applicants’ argument: “Having failed to provide all elements of the pending claims of this application, nor any suggestion to modify Yu's methods, nor any reasonable expectation of success, the Yu reference cannot support a prima facie case of obviousness.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive as indicated in the above response and because as stated in the Final office action above, “Therefore, the invention as recited in claims 1-10 are prima facie obvious over the prior art Yu et al. It would have been obvious to provide a method for assessing the risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma according to the limitations of the instant application claims 1 and 10 based on Yu et al. (Patent App. Pub. No. WO 2018036503 A1). These claim elements were known in the prior art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 10. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claims over the teachings of Yu et al. Doing so would allow for early detection of colorectal adenoma recurrence and a reduction of CRC-associated mortality.” Thus, Yu does provide a suggestion to modify Yu's methods and an reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The 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.
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Claims 1-17 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. US 11603567 B2, Mar. 14, 2023, filed Aug. 23, 2017) in view of Yu et al. (“Yu”; Patent App. Pub. WO 2018036503 A1, Mar. 1, 2018, filed on Aug. 25, 2016). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims 1-3 of U.S. Patent No. US 11603567 B2.
The claims of U.S. Patent No. US 11603567 B2 are drawn to:
“1. A method for assessing risk for colon cancer in a subject, comprising the steps of: (a) performing a polymerase chain reaction to amplify the nucleotide sequence set forth in SEQ ID NO:3, thereby quantitatively determining level of a bacterial species whose genome comprises the nucleotide sequence set forth in SEQ ID NO:3 in a stool sample taken from the subject; (b) comparing the level obtained in step (a) with a standard control; (c) determining the level obtained in step (a) as increased from the standard control; (d) determining the subject who has an increased level in step (c) as having an increased risk for colon cancer; and (e) administering colonoscopy to the subject who has been determined in step (d) as having an increased risk for colon cancer/examination.
2. The method of claim 1, further comprising quantitatively determining Parvimonas micra, Solobacterium moorei, Clostridium hathewayi, or Fusobacterium nucleatum level in the sample.
3. The method of claim 1, further comprising quantitatively determining Bacteroides clarus or Roseburia intestinalis level in the sample.”
The teachings of Yu are documented above in the rejection of claims 1-17 under 35 U.S.C. 103.
Claims 1-3 of U.S. Patent No. of U.S. Patent No. US 11603567 B2 in view of Yu make obvious claims 1-17 of the instantly claimed invention. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claims over U.S. Patent No. US 11603567 B2 in view of Yu. It would have been obvious to provide a method for assessing the risk for colorectal adenoma recurrence in an individual after removal of colorectal cancer or adenoma according to the limitations of the instant application claims 1-17 based on U.S. Patent No. US 11603567 B2 in view of Yu (Patent App. Pub. No. WO 2018036503 A1).
Response to Arguments
Applicant's arguments filed 04/27/2026 (Pg. 6-7) with respect to claims 1-17 have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 04/27/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “As discussed in the last section, the Yu reference, W02018/036503, fails to support a prima facie case of obviousness due to its failure to provide all claim elements nor the requisite motivation to modify or reasonable expectation of success. Since U.S. Patent No. 11,603,567 is a patent issued from a U.S. patent application corresponding to W02018/036503, it cannot support any obviousness-type double patenting rejection either.” (Pg. 12)
Response: Applicant’s arguments have been fully considered and found unpersuasive as stated in the responses of the 103 rejection above.
Conclusion of Response to Arguments
In view of the amendments, revised and new grounds of rejections and above responses to arguments, no claims are in condition for allowance.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's
disclosure: Feng et al. Patent No. US 10526659 B2, Jan. 7, 2020, filed on Feb. 5, 2016. (entire document; Claim 3 SEQ ID No:10, 17, 14 and 19 have 100% identity to SEQ ID No: 19-22, respectively); Sears et al. Patent App. Pub. No: US 20160223553 A1, filed on Aug. 4, 2016. (entire document) Claim 1.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
