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 .
Election/Restrictions
Applicant's election with traverse of the restriction requirement in the reply filed on 19 March 2026 is acknowledged. The traversal is on the ground(s) that, in view of the claim amendments, each of Groups I, II, and III now share a common technical feature of the combination of biomarkers that is a special technical feature defining a contribution over the prior art, and there would not be a serious search burden on the Office.
This argument is found persuasive in part.
The restriction requirement between the method of Group I and the apparatus of Group II has been withdrawn because the inventions as amended have unity of invention.
However, the restriction requirement between Groups I and III and Groups II and III is maintained for the following reasons.
Claim 26 recites “A biomarker combination, which is a combination of the biomarkers according to claim 1”. Molparia (previously cited; cited in IDS filed 05 Nov. 2021) discloses downloading whole genome copy number variation data (i.e. including all positions on all chromosomes) (pg. 13, para. 3), which is considered to be a biomarker combination that includes the combination of biomarkers according to claim 1. Therefore, the combination of biomarkers is not a special technical feature as claimed. Claim 26 does not share the technical feature of applying ratios A/B determined from the biomarker combination to classify target cfDNA, as performed in the invention of Groups I and Group II. Regarding Applicant’s argument that a search burden does not exist, whether there is a search burden is not considered when establishing unity of invention. See MPEP 1893.03(d).
The requirement between Groups I and III and Groups II and III is still deemed proper and is therefore made FINAL.
Claim 26 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 19 March 2026.
Status of Claims
Claims 8, 11, 20, 22, and 24-25 are cancelled.
Claims 1-7, 9-10, 12-19, 21, 23, and 26-30 are pending.
Claim 26 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-7, 9-10, 12-19, 21, 23, and 27-30 are rejected.
Claims 5 and 16 are objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, PCT/CN2020/087830 filed 29 April 2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority to App. No. CN201910374094.1, filed 07 May 2019, under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Accordingly, the effective filing date of the claimed invention is 07 May 2019.
Drawings
The replacement drawings filed 14 Nov. 2022 have been entered.
The drawings received on 05 Nov. 2021 and 14 Nov. 2022 are objected to because:
The drawings fail to comply with 37 CFR 1.84(u)(1), which states view numbers must be preceded by the abbreviation "FIG.". Each figure should be relabeled as “FIG. 1”, “FIG. 2”, … , and “FIG. 12D”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because:
the abstract discusses its purported merits and compares the invention with the prior art in lines 8-10
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 5 and 16 are objected to because of the following informalities:
Claim 5 recites “the random forest model is at least 3 random forest binary classifiers, and is any one, two, three, or four groups selected from the group consisting of…”. To increase clarity and fix a grammatical issue, claim 5 should be amended to recite “at least 3 random forest binary classifiers that are any one, two, three or four groups of classifiers selected from the group consisting of the following Groups….”.
Claim 16 recites “comprising the following steps (1), step (2)…, and step (4)”. To fix a grammatical error, the claim should be amended to recite “the following steps, comprising step (1), step (2), optionally step (3), and step (4):…”, or a similar amendment.
Appropriate correction is required.
Claim Interpretation
Claim 16 recites “A method…comprising the following steps (1), step (2), optionally step (3), and step (4):…”. Therefore, under the broadest reasonable interpretation of the claims, the method of claim 16 is interpreted to comprise steps (1), (2), and (4).
Claim 21 recites a “normal decision-making unit”, “renal caner decision-making unit”, a “urothelial cancer decision-making unit”, and a “prostate cancer decisions-making unit”. Claim 21 recites these units comprise “3 random forest binary classifiers” and include instructions executed by a processor. Accordingly, each decision-making unit is interpreted to correspond to instructions for 3 random forest binary classifiers stored in memory and executable by a processor. Thus claim 21 recites sufficient structure for the function of “decision-making” of the various units, and do not invoke 35 U.S.C. 112(f).
Claim Rejections - 35 USC § 112(b)
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.
.
Claims 1-7, 9-10, 12-19, 21, 23, and 27-30 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the cfDNA copy number variation data of each category label”. There is insufficient antecedent basis for this limitation in the claim because claim 1 only previously recites “a copy number variation data of cfDNA in a target sample”, but does not recite cfDNA copy number variation data of any category labels. As a result, it is further unclear what category labels are being referenced. It is noted that later in the claim, categories including “renal cancer”, “normal”, etc. are recited in Tables 1-7. If Applicant intends for each category label to refer to these categories, the claim should be amended accordingly. For purpose of examination, the category labels will be interpreted to refer to any two or more disease categories recited in Tables 1-7.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the category to which the target cfDNA belongs””. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not previously recite a category to which the target cfDNA belongs. Furthermore, given the target cfDNA could belong to multiple categories (e.g. multi-label classification), it is not clear which category is being referenced.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “determining the category…according to the similarity degree by using…”. Claim 1 previously recites “calculating a similarity degree between the target cfDNA copy number variation data and the cfDNA copy number variation data of each category label”, such that there is a similarity degree corresponding to each category label. As a result, it is not clear which similarity degree, “the similarity degree” is referring to.
Dependent claim 2 also recite “the similarity degree”, and thus is indefinite for the same reasons as discussed above for claim 1.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the sequencing data” and “the number of reads corresponding to each bin” in lines 11-12 and “the total number of reads measured in the sample” in lines 15-16. There is insufficient antecedent basis for these limitations in the claim because claim 1 does not previously recite any sequencing data or reads in each bin from sequencing data, let alone measured in the sample. Regarding, “the number of reads in each bin”, it is further unclear what number this is referring to, given there may be different numbers corresponding to a bin (see definitions of A and B). With further respect to the total number of reads measured in “the sample”, it is further unclear if this is referring to the “target sample” in line 2 or “the sample to be tested” in line 10. For purpose of examination, the limitation is interpreted to mean that sequencing data comprising reads of the sample to be tested is normalized, a ratio A/B of a number of reads corresponding to each bin is calculated, and B is obtained by dividing the total number of reads measured in the sample to be tested.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the ratio A/B represents the copy number variation”. Claim 1 previously recites “copy number variation data of cfDNA in the target sample and/or the cfDNA copy number variation data of each category label”, which may include multiple copy number variations (e.g. in the various bins). As a result, it is unclear what copy number variation is being referenced. Furthermore, since claim 1 previously recites “calculating a ratio of A/B of the number of reads corresponding to each bin”, it is further unclear if claim 1 intends to require that a copy number variation is determined in each bin of the 5,000 to 500,000 bins, or if the ratio A/B is simply intended to represent copy number, which may include a copy number variation. For purpose of examination, the limitation is interpreted to mean that the determined A/B ratios correspond to the copy number variation data of the cfDNA in the target sample and/or the cfDNA copy number variation data of each category label.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “wherein the ratio A/B is a ratio A/B of each biomarker in a biomarker combination, wherein the biomarker combination comprises m biomarkers, and m represents…greater than or equal to 50…”. It is not clear if a single ratio A/B is calculated corresponding to each of the m biomarkers of the biomarker combination (suggested by “the ratio A/B is...”), or if Applicant intends for a ratio A/B to be calculated for each biomarker.. Furthermore, claim 1 previously recites “dividing…into 5,000 to 500,000 bins with equal lengths or equal theoretical simulation copy numbers…calculating a ratio A/B…corresponding to each bin”, such that each ratio A/B corresponds to a bin of the 5,000 to 500,000 bins (e.g. of equal length). As a result, it is further unclear if (1) each ratio A/B corresponds to a bin (e.g. of a set length), (2) if each ratio A/B corresponds to a specific biomarker (which have varying lengths as recited in the Tables), (3) if each ratio A/B corresponds to a specific combination of biomarkers, and/or (3) if the biomarkers or biomarker combinations are supposed to correspond to the bins. It is further noted the recited biomarker combinations do not include 5,000 to 500,000 biomarkers (and are only required to be over 50 biomarkers), and thus the bins do not appear to correspond to the biomarkers, raising confusion on what regions of the genome each ratio is intended to correspond to. Clarification is requested. A review of Applicant’s specification at para. [0187]-[0188] discloses ratios of A/B corresponding to the groups of biomarkers are used for classification. Therefore, for purposes of applying prior art, the claims are interpreted to mean A/B ratios are determined for each of the bins and the chromosomal region of each biomarker of the biomarker combination (any one to seven of the recited groups), and the A/B ratio of the combination of biomarkers corresponds to the copy number variation data. .
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the biomarker is a DNA fragment”. It is unclear what biomarker is being referenced given claim 1 previously recites “a biomarker combination, wherein the biomarker combination comprises m biomarkers”. For purpose of examination, claim 1 is interpreted to mean “ each biomarker in the biomarker combination is a DNA fragment….”.
Claim 14 also recites “the biomarker” in line 2, and thus is indefinite for the same reasons discussed above for claim 1.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the biomarker is a DNA fragment…on the chromosome”. There is insufficient antecedent basis for a chromosome in claim 1, and as a result it is unclear which chromosome, “the chromosome” is referring to. The claim is interpreted to mean “on a chromosome”.
Claim 1, and claims dependent therefrom, are indefinite for recitation of “the biomarker…having an initiate site of A…and a termination site of B…wherein the chromosome, A and B” and the recited Tables 1-7 which have columns for “A” and “B”. Claim 1 previously recites a ratio A/B, and defines A to represent an actual number of reads in a bin, and B to be a theoretical number of reads in a bin. Therefore, it is unclear if the initiate and termination sites of “A” and “B” are supposed to be the same as the A and B in the ratio, or if these are separate variables. If Applicant intends for the A and B to be the same, then it is further unclear if A and B each correspond to a bin, or a particular position in a chromosome as recited in the tables. If these are intended to be different variables, then Applicant should amend the claims to use different letters for each variable. Clarification is requested.
Claims 16 and 21, and claims dependent therefrom, recite and “classifying…according to the classification method according to claim 1” and “configured to execute the classification method according to claim 1…”, respectively, and thus are also indefinite for each of the reasons set forth above with respect to claim 1.
Claim 2, and claims dependent therefrom, are indefinite for recitation of “…the correlation degree” in the last line of the claim. Claim 2 previously recites “determining a correlation degree between the cfDNA copy number variation data of each category label and a…tumor”. It is unclear if claim 2 intends for there to be a single correlation degree (suggested by “the correlation degree”), or if claim 2 intends for there to be a correlation degree for each category label. Given claim 3 recites, “the correlation degree between the cfDNA copy number variation data of the category label” in how the correlation degree between each category label and the tumor is determined, it appears claim 2 intends to determine a correlation degree for each category label. If Applicant intends for there to be a single correlation degree corresponding to all of the category labels and the tumor, then claim 3 is indefinite for recitation of “the correlation degree… of the category label and the…tumor”, since claim 2 would only recite a single correlation degree of each of the category labels. If Applicant does intend for there to be a correlation degree for each category label, then “the correlation degree” in the last two lines of the claim is indefinite since it is not clear which correlation degree is being referenced. For purpose of examination, claim 2 is interpreted to mean a correlation degree is determined for each category label, and the category is determined according to each correlation degree by using the classifier model.
Claim 3 is indefinite for recitation of “sorting the cfDNA copy number variation data according to the correlation degree…”. Claim 3 previously recites “determining a correlation degree between the cfDNA copy number variation data of each category label and a human urogenital system tumor”. Therefore, it is unclear what cfDNA copy number variation data (e.g. which category), “the cfDNA copy number variation data” is referring to. Furthermore, given claim 2 recites a correlation degree for each category label (as interpreted above), it is further unclear what correlation degree is being referenced. For purpose of examination, the limitation is interpreted to mean “the cfDNA copy number variation data of the category label according to the correlation degree for the category label”.
Claim 3 is indefinite for recitation of “wherein determining the correlation degree…comprises: sorting the cfDNA copy number variation data according to the correlation degree to form a vector sequence; inputting the vector sequence…and determining the correlation degree between…”. The metes and bounds of the claim are unclear because the claim requires forming a vector sequence by sorting copy number variation data according to the correlation degree, but then uses the vector to determine the correlation degree (that was apparently already determined and used to form the vector). As a result, it is unclear if the correlation degree in the first sorting limitation is intended to be a different correlation degree than in the inputting limitation, or if these are the same correlation degree. If they are intended to be the same, it is not clear in what way the correlation degree that has not been determined yet is used to form the vector. Clarification is requested.
Claim 6 is indefinite for recitation of “The classification method according to claim 5, wherein each group is voted, the category corresponding to the group with the highest number of votes is the final category…with the highest prediction probability…is the final category” for the followings reasons:
First, is unclear what “the category corresponding to the group with the highest number of votes” is referring to. Each of group I-IV in claim 5 recite multiple classifiers for different disease “categories” (e.g. Group 1 includes normal, renal cell, urothelial caner, and prostate cancer categories); claim 1 also recites “each category label” (interpreted to refer to two or more of the disease categories in tables 1-7). As a result, it is not clear if (1) “the category” is supposed to refer to an entire group of categories (in claim 5) given claim 6 recites “the category corresponding to the group”, (2) the category is one of the categories within a group of claim 5 (e.g. prostate cancer), or (3) if the category is referring to a category label of claim 1.
Further regarding claim 6, there is insufficient antecedent basis for “the final category” and “the highest prediction probability”, because claims 1-3 and 5, from which claim 6 depend, do not recite “a final category” or any prediction probabilities. It is not clear if “the final category” is intended to be “the category to which the target cfDNA belongs” or a different category. Clarification is requested.
Last regarding claim 6, the limiting effect of the wherein clause “wherein each group is voted, the category…is the final category…” is unclear. MPEP 2111.04 states examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are: (B) "wherein" clauses, and furthermore, a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps. In the instant case, it is unclear which manipulative step of claims 1-3 or 5, the wherein clause is intending to refer to, or if the wherein clause of claim 6 is simply reciting an intended use of the groups of claim 5. Clarification is requested.
For purpose of examination, claim 6 is interpreted to mean that in determining the category to which the target cfDNA belongs, voting of categories of each of the one, two, three, or groups is performed, and a category of a group with the highest number of votes (or with a highest prediction probability) is the determined category.
Claim 7 is indefinite for recitation of “preferably, the sequencing data is whole-genome sequencing data; preferably, its sequencing depth is…”. First, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, it is unclear if “the sequencing data” is referring to the “sequencing data of cfDNA in a urine sample” in lines 3-4 of claim 7, if “the sequencing data” is referring to “the sequencing data” in line 11 of claim 1, or if these are intended to all be the same sequencing data. For purpose of examination, the sequencing data is interpreted to refer to the sequencing data of cfDNA in a urine sample, which may be the same sequencing data as in claim 1, and the limitations following “preferably” are not required by the claim.
Claim 9 is indefinite for recitation of “is divided…by Varbin, CNVnator, ReadDepth, or SegSeq; and/or caluculating…by Varbin, CNVator, ReadDepth, or SegSeq”. The metes and bounds of claims are unclear because it is unclear what processing steps are encompassed by each of Varbin, CNVnator, ReadDepth, or SegSeq. Each of the recited software are subject to updates and/or changes in what method steps are performed by each software, and as a result, the names of the software cannot be used to properly identify a particular step or steps to perform the dividing and calculating. Therefore, the metes and bounds of the claims are unclear.
Claim 12 is indefinite for recitation of “such as 50 to 100…, 250 or 300”. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purpose of examination, the limitation following “such as” is not required by the claim.
Claim 14 is indefinite for recitation of “preferably, the cfDNA is derived from a human urine or a human urine supernatant”. The phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, it is not clear if “the cfDNA” is referring to the “cfDNA fragment” in line 2 of claim 14, the “cfDNA fragment” in the 7th line from the bottom of the first page of claim 1, or the “cfDNA” in the target sample in line 2 of claim 1. For purpose of examination, the limitation following “preferably” is not required by the claim.
Claim 27 is indefinite for recitation of “wherein the human urogenital system tumor is diagnosed by tissue biopsy of a surgical sample”. Claim 2, from which claim 27 depends, recites “determining a correlation between the cfDNA copy number variation data…and a human urogenital system tumor”, but does not recite any steps of diagnosing a human urogenital system tumor. MPEP 2111.04 states examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are: (B) "wherein" clauses.. In the instant case, it is unclear if claim 27 is intended to require a step of diagnosing the human urogenital system tumor by a tissue biopsy of a surgical sample, or if claim 27 is defining the process in which the human urogenital system tumor of claim 2 was previously diagnosed. For purpose of examination, claim 27 is interpreted to be a product by process limitation. If Applicant agrees, the claim can be interpreted to recite “was diagnosed…”, and if Applicant intends to recite a step of diagnosing, the claim can be amended to recite “The classification method according to claim 3, further comprising diagnosing the urogenital system tumor…”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-15, 17, 23, and 29 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 recites “wherein the biomarker is a cfDNA fragment; preferably…”, wherein the limitation following “preferably” is interpreted to not be required by the claim as discussed under 35 U.S.C. 112(b) above. Claim 1, from which claim 14 depends, recites “wherein the copy number variation data of cfDNA in the target sample and/or the cfDNA copy number variation data…is calculated according to the following methods:…wherein:…the biomarker is a DNA fragment…”. Given claim 1 already recites the copy number variation data is calculated for cfDNA, using the recited method of calculating the ratio(s) A/B for each biomarker, this already requires that the DNA fragment of the biomarker is a cfDNA fragment. As a result, claim 14 fails to further limit the subject matter of claim 14 from which it depends. To overcome the rejection, claim 14 can be amended to require the cfDNA is from a human urine or human urine supernatant.
Claim 15 recites “the chromosome, A and B are shown in any one, any two, any three, any four, any five, any six, or all seven group selected from the group consisting of Groups (1) to (7)”, which claim 1 already requires in the last two lines of the first page of claim 1. Therefore, claim 15 fails to further limit the subject matter of claim 1, from which it depends.
Claim 17 recites “The method according to claim 16, wherein the urogenital system tumor is one or more selected from the group…”. Claim 16, from which claim 17 depends, recites “A method for the detection…of a human urogenital system tumor, comprising the following steps:…(4) classifying the cfDNA fragments according to the classification method according to claim 1. However, claim 16 recites a structurally complete invention and the steps of claim 16 do not require classifying the cfDNA fragments as a urogenital system tumor. See Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). See MPEP 2111.02. Similarly, the classification method according to claim 1 does not require that the determined category to which the cfDNA belongs is a urogenital system tumor (instead, only biomarkers used for classification correspond to prostate, urothelial, and/or renal cancer). As a result, claim 17 only “further limits” the intended use of the method of claim 16, and does not further limit the claimed subject matter of claim 16.
Claim 29, which depends from claim 17, recites “wherein the renal is clear cell renal cell carcinoma, the urothelial cancer comprises upper urothelial cell cancer and bladder cancer, and the prostate cancer is prostate adenocarcinoma”, which only “further limits” the intended use of the method of claims 16-17 for the same reasons discussed above. Therefore, claim 29 also fails to further limit the subject matter of claim 16, from which it depends.
Claim 23 recites “The apparatus according to claim 21, wherein the urogenital system tumor is one or more selected from the group consisting of prostate cancer, urothelial cancer and renal cancer”. However, claim 21 only refers to the urogenital system tumor in the preamble, reciting the intended use of the apparatus of “for the detection…of a human urogenital system tumor”. However, claim 23 does not serve to further limit the actual programming of the claimed apparatus. Furthermore, claim 21, from which claim 23, also already requires instructions comprising at least on of four decision-making units, selected from a closed group and including the claimed prostate, urothelial, and/or renal cancers. Thus claim 21 is already for detecting a cancer from the group consisting of prostate cancer, urothelial cancer, and renal cancer”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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 1-7, 9-10, 12-19, 21, 23, and 27-30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1, 16, and 21 being representative) is directed to a method and apparatus for cancer diagnosis. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 1 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
calculating a copy number variation data of cfDNA in a target sample;
calculating a similarity degree between the target cfDNA copy number variation data and the cfDNA copy number variation data of each category label; and
determining the category to which the target cfDNA belongs according to the similarity degree by using a classifier model;
wherein the copy number variation data of cfDNA in the target sample and/or the cfDNA copy number variation data of each category label is calculated according to the following method:
dividing a genome of a sample to be tested into 5,000 to 500,000 bins with equal lengths or equal theoretical simulation copy numbers; normalizing the sequencing data, and calculating a ratio A/B of the number of reads corresponding to each bin
wherein: A represents the actual number of reads in a bin after GC content correction; B represents the theoretical number of reads in the bin, which is obtained by dividing the total number of reads measured in the sample by the total number of bins; the ratio A/B represents the copy number variation;
wherein the ratio A/B is a ratio A/B of each biomarker in a biomarker combination, wherein. the biomarker combination comprises m biomarkers, and m represents a positive integer greater than or equal to 50; the biomarker is a DNA fragment, correspondingly having an initiate site of A±n1 and a termination site of B+n2 on the chromosome; wherein, the n1 and n2 are independently non-negative integers less than or equal to
60,000;
wherein, the chromosome, A and B are any one, any two, any three, any four, any five, any six or all seven groups selected from the group consisting of the following Groups (1) to (7) (including the recited Tables).
Claims 16 recites the same abstract idea as identified above for claim 1 by reciting “classifying the cfDNA fragments according to the classification method according to claim 1”.
Claim 21 recites the same abstract idea as identified above for claim 1 by reciting “execute the classification method according to claim 1…”.
Claim 21 further recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
any one, any two, any three, or all of four decision-making units selected from the group consisting of the following four decision-making units, wherein each decision-making unit comprises 3 random forest binary classifiers:
I. 'normal decision-making unit':
normal-vs-renal cancer, normal-vs-urothelial cancer, normal-vs-prostate cancer;
II. 'renal cancer decision-making unit':
renal cancer-vs-normal, renal cancer-vs-urothelial cancer, renal cancer-vs-prostate cancer;
III. 'urothelial cancer decision-making unit:
urothelial cancer-vs-normal, urothelial cancer-vs-renal cancer, urothelial cancer-vs-prostate cancer;
IV. "prostate cancer decision-making unit':
prostate cancer-vs-normal, prostate cancer-vs-renal cancer, prostate cancer-vs-urothelial cancer
The following limitations fall into the group of abstract ideas of mental processes for the following reasons. In this case, the step of calculating a copy number variation data of cfDNA comprising dividing a genome into 5,000 to 500,000 bins, normalizing sequencing data, and calculating an A/B ratio of each bin can be practically performed in the mind because it encompasses organizing positions in a genome into bins (e.g. positions 1-10,000, positions 10,001 to 20,000, etc.), dividing a count of reads in each bin a fixed value to obtain normalized data, and then performing division between values representing the actual reads and theoretical reads. The human mind is practically able to organize information and perform division. Calculating a similarity degree between the target cfDNA copy number variation data and cfDNA copy number variation data of category labels encompasses comparing copy number variation data of the cfDNA to copy number data of a category label to determine a difference between the copy numbers in each sample. Determining the category to which the target cfDNA belongs according to the similarity degree using a classifier model encompasses performing a clustering analysis on the copy number data, which merely involves calculating distances between the target cfDNA and copy numbers of category labels to determine which cluster the target cfDNA belongs. Furthermore, the limitations relating to the combination of biomarkers defines the ratio being calculated, and thus is part of the mental process identified above.
The steps of calculating a copy number variation data including normalizing sequencing reads and calculating a ratio of A/B for each bin, calculating a similarity degree, determining the category to which the target cfDNA belongs using a classifier model, and various decision-making units comprising three random forest classifiers further recite a mathematical concept. Performing normalizing on a count of sequencing reads amounts to a textual equivalent to performing division or multiplication. Furthermore, calculating a ratio of A/B also clearly recites a mathematical calculation and further recites a mathematical relationship between actual counts and theoretical counts. Calculating a similarity degree and determining a category to which the target cfDNA belongs according to the similarity degree using a classifier model encompasses calculating a difference between copy numbers to determine a similarity and performing a mathematical analysis, such as a random forest model, clustering, or a linear regression (the classifier model) using the similarity degree to determine the category. Last, the random forest classifiers of each decision making unit recite a mathematical relationship between copy number variation data and a disease probability. Therefore, these limitations recite a mathematical concept. See MPEP 2106.04(a)(2) I.
Dependent claims 2-7, 9-10, 12-17, 21, 23, and 27-30 further recite an abstract idea and/or are part of the abstract idea of claims 1, 16, and 21. Dependent claim 2 further recites the mathematical concept of determining a correlation degree between the copy number variation data of each category label and a tumor according to the similarity degree by using a random forest model, and then further limits the mental process and mathematical concept of determining the category of claim 1 to be according to the correlation degree. Dependent claim 3 further recites the mental process of sorting cfDNA copy number data according to the correlation degree to form a vector sequence, and the mathematical concept of inputting the vector sequence into the random forest model and determining the correlation degree. Dependent claim 4 further limits the mathematical concept of the correlation degree of claim 3 to correspond to a tumor selected from prostate cancer, urothelial cancer, and renal cancer. Dependent claim 5 further limits the mathematical concept of claim 3 of applying the random forest model to be three random forest classifiers from the recited group. Dependent claim 6 further recites the mental process of voting on each group and assigning a category with the highest number of votes as a final category. Dependent claims 7 and 10 further limits the mental process and mathematical concept of determining copy number variation data to be calculated from a sequencing data of cfDNA from a morning urine or morning urine supernatant. Dependent claim 9 further limits the mental process of dividing the genome into bins and/or the mental process and mathematical concept of calculating the ratio A/B. Dependent claims 12-13 further limit the mental process and mathematical calculations of calculating a ratio A/B for the m biomarkers to be performed for a particular number of biomarkers of a certain length. Dependent claims 14-15, 17, 23, and 29 fail to further limit the subject matter of claim 1 and thus are part of the abstract idea of claims 1 and 21. Claim 27 recites the process in which the urogenital system tumor was previously diagnosed, and thus is part of the mental process and mathematical concept of determining the correlation degree for the tumor of claim 3. Dependent claim 28 further limits the mental process and mathematical concept of claim 4.
Last, the claims further recite a law of nature of a natural correlation between copy number variations of specific regions of a chromosome (biomarkers) and the presence of a urogenital system tumor, analogous to the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of a medication called iloperidone, Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018). See MPEP 2106.04(b).
Therefore, claims 1-7, 9-10, 12-19, 21, 23, and 27-30 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
The additional elements of claim 16 include:
(1) collecting a urine sample and extracting cfDNA;
(2) screening to obtain cfDNA fragments of 90 to 300 bp or cfDNA fragments of 100 to 300 bp;
(3) (optionally) using the obtained cfDNA fragments to construct a whole genome library; and
The additional elements of dependent claims 18-19 include:
wherein the urine sample is a morning urine or a morning urine supernatant;
wherein in step (2) the screening is a screening by magnetic beads;
The additional elements of claim 21 include:
a memory…wherein, the memory stores a program instruction to be executed; and
a processor.
First, the additional elements of claims 16 and 18-19 of collecting a morning urine and screening cfDNA fragments using magnetic beads is not sufficient to integrate the recited judicial exception because they only serve to collect the necessary data for the abstract idea. Therefore, the additional elements amount to insignificant extra-solution activity. See MPEP 2106.05(g).
The additional elements of a memory and processor of claim 21 are generic computer components used to carry out the abstract idea. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
Therefore, the additionally recited elements amount to insignificant extra-solution activity and/or merely invoke computers as a tool, and as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1-7, 9-10, 12-19, 21, 23, and 27-30 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
The additional elements are outlined above under Step 2A, prong 2.
The additional elements of claims 16 and 18-19 of collecting a morning urine or morning urine supernatant and screening cfDNA fragments using magnetic beads to obtain fragments of 90 to 300 bp or of 100 to 300 bp are well-understood, routine, and conventional. This position is supported by Lin et al. (Emerging Utility of Urinary Cell-free Nucleic Acid Biomarkers for Prostate, Bladder, and Renal Cancers, 2017, European Urology Focus, 3 , pg. 265-272) and Ralla et al. (Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies, 2014, Crit Rev Clin Lab Sci, 51(4), pg. 200-231). Lin reviews the current status of urinary cell-free nucleic acid in genitourinary (GU) caners (Abstract), and discloses that urine has been found to be a comparable bodily fluid source for detecting cfDNA, citing numerous studies (pg. 266, col. 1, para. 2-3). Lin reviews numerous studies that have analyzed cfDNA in urine supernatant or whole urine (pg. 266, col. 2, para. 5 to pg. 267, col. 1, para. 1), and that urine collection comprises using first-void morning samples (pg. 268, col. 2, para. 1). Lin further discloses that cfDNA isolation requires recovery of ~150 base pair sizes because it is the urinary subfraction enriched for tumor-derived DNA (i.e. screening for fragments from 90 to 300 base pairs) (pg. 268, col. 2, para. 3). Similar to Lin, Ralla reviews nucleic acid biomarkers in bodily fluids, including blood and urine, and their application in diagnosing urologic malignancies (Abstract), and discloses there are numerous isolation procedures for cell-free DNA published by several companies as commercial ready to use kits, including extraction with organic solvents, isolation by selective binding properties on silica-gel material, and the use magnetic beads (pg. 205, col. 1, para. 3). Thus even considered in combination, these additional elements are well-understood, routine, and conventional
The additional elements of a memory and processor of claim 21 are conventional computer components used to carry out the abstract idea. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Baslan et al., Genome-wide copy number analysis of single cells, 2012, Nat Protoc., 7(6), pg. 1024-1041; cited in IDS filed 05 Nov. 2021.
Conclusion
No claims are allowed.
Claims 1-7, 9-10, 12-19, 21, 23, and 27-30 appear free of the prior art.
Claim 1 recites determining a “ratio A/B” as defined in the claim of “each biomarker in a biomarker combination”, wherein the combination of biomarkers comprises one to seven of the recited groups Groups (1) to Group (7), each biomarker in the recited groups having a specifically defined region on a chromosome (plus or minus 60,000 base pairs) to which the A/B ratio corresponds (as interpreted in the 112(b) rejections above). This specific “A/B ratio” data corresponds to target cfDNA copy number variation data used to determine a category to which the target cfDNA belongs in claim 1, as discussed in the various claim interpretations under 35 U.S.C. 112(b) above.
The prior art does disclose methods for using copy number variation data determined from cell-free DNA to classify, using random forests, a urogenital cancer in a target cfDNA. For example, Molparia (Assessment of circulating copy number variation detection for cancer screening, 2017, PLOS ONE, pg. 1-18; cited on IDS filed 05 Nov. 2021; previously cited) discloses a method for assessing ctDNA comprising determining genome-wide copy number variation (CNV) profiles for cfDNA (pg. 4, para. 1-5), clustering the target CNV profile with CNVs from other cancers to calculate a similarity score (pg. 4, para. 5 to pg. 5, para. 3; pg. 14, para. 3-5), and classifying the target cfDNA to a cancer type using the clustering model and similarity score (pg. 5, para. 1-3; Table 1). Molparia discloses the different cancer categories used in the classification include prostate cancer, renal cancer, and bladder (i.e. urothelial) cancer (Table 1). Molparia discloses the classification is performed only using genomic segments deemed as important for differentiation by the random forest model (pg. 14, para. 2), but does not disclose the copy numbers used for classification were for the specific combination of biomarkers encompassing genomic segments as claimed.
Furthermore, the ratios A/B are determined by known software algorithms, described in Baslan. Baslan discloses the Varbin algorithm divides the genomes into bins of variable length adjusted so that the number of potential uniquely mapping reads in each bin is normalized across the genome and determines segment ratios based on a ratio of bin counts relative to a theoretical number of reads representing a copy number of two (pg. 4, para. 2; pg. 22, para. 1).
However, the prior at does not disclose the specifically calculating such A/B ratios for regions of the specific combination of biomarkers recited in the claims, and using this copy number data for classification of target cfDNA.
It is noted that the above statements are made with respect to claim interpretations set forth in the 35 U.S.C. 112(b) section above.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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