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 .
Applicant’s Amendment/Request for Reconsideration-After Non-Final Rejection, filed 5/28/2026, has been entered and fully considered.
Status of Claims
Claims 3, 6, 8-11, 23 and 27-46 are cancelled.
Claims 1, 2, 4-5, 7, 12-13, 15-22, 24-26 and 47 are pending.
Claims 4, 5, 7, 12, 13, 15-22 and 24-26 are withdrawn.
Claims 1, 2, 14 and 47 are examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of US application 62/753,265 filed 10/31/2018 is acknowledged.
Withdrawn Rejections/Objections
The rejection to claims 1-2 and 14 under 35 USC § 103 in the Office action posted 10 March 2026 is withdrawn in view of claim amendments filed 28 May 2026. However, new rejection is applied.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 recites “at least one miR” in step a) second line, which should read as “at least one miRNA”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
This rejection is newly applied. Necessitated by claim amendments.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 14 and 47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the subject" in step f) 3rd line. There is insufficient antecedent basis for this limitation in the claim. It is not clear which subject claim 1 step f) refers to. Similar problems also identified at step h) and step i). Both step h) and step i) recite “the subject” without an antecedent.
claim 1 recites “the at least one miRNA derived from the quantitative algorithm for endometriosis” at step g. There is insufficient antecedent basis for this limitation in the claim.
In claim 1, regarding the recitation “the subject in need thereof” in step i), it is not clear whether this mean THE subject in h or only if h determines that the subject has endometriosis (i.e. in need of therapy).
Step i) says “the subject in need thereof identified by the quantitative algorithm…” It is not clear what “the quantitative algorithm” refers to. Step e has an antecedent for a “quantitative algorithm” but without a definition. Step h suggests an algorithm “based on the comparison of level of the at least miRNA to the cutoff value”.
Further, it is not clear whether the recitation “the quantitative algorithm as having endometriosis according to step h” means the endometriosis is identified, or it depends.
Claim Rejections - 35 USC § 101
This rejection is maintained from the 3/10/2026 Office action. Modifications are necessitated by claim amendments.
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 1-2 and 14 are rejected under 35 USC 101 because the claimed invention is directed to non-statutory subject matter.
Step 1: Process, Machine, Manufacture or Composition
Claim 1, 2, 14 and 47 are directed to a process, here a "method," for assessing endometriosis, with process steps like "inputting”, “assessing”, “combining", “assigning”, “using” (or “to develop”), “obtaining” and “administering”.
Step 2A Prong One: Identification of Abstract Ideas
Claim 1 recites:
inputting a level of a combination of miRNA into an algorithm, wherein the combination of miRNA comprises of miR-34c, miR-141, miR-200, miR-200a, miR-200b, miR-449, miR-449a, and miR-466.
---- Inputting data into an algorithm is interpreted as part of the mathematical operation (as the algorithm is directed to math). Therefore this step equates to abstract ideas of mathematical concepts.
b) quantitatively assessing the performance of the at least one miRNA or the algorithm using receiver operating characteristic (ROC) analysis and understanding AUC (Area Under the Curve),
----This element recites mathematical calculation (“quantitatively assessing”) and mathematical concepts (“receiver operating characteristic (ROC) analysis and understanding AUC (Area Under the Curve)”), which can be done in human mind with the help of a pen/paper. Additionally “understanding AUC” reads on a mental activity. Hence this element equates to an abstract idea of mathematical concepts and mental processes.
c) combining at least one of the at least one miRNA into a mathematical formula,
---- This element recites mathematical calculation (“combining at least one of the at least one miRNA into a mathematical formula”), which can be done in human mind with the help of a pen/paper under a BRI. Hence this element equates to an abstract idea of mathematical concepts and mental processes.
d) assigning weights to at least one of the at least one miRNA within the formula, and
---- This element recites data manipulation (“assigning weights …”), hence this element equates to an abstract idea of mental processes.
e) using the assigned weights to develop a quantitative algorithm to distinguish the presence or absence of endometriosis.
---- This element recites a mathematical operation (“to develop a quantitative algorithm …”), which can be done in human mind with the help of a pen/paper under a BRI. Hence this element equates to an abstract idea of mathematical concepts and mental processes.
g) comparing the level of the at least one miRNA in the sample from f) with a cutoff value for the at least one miRNA derived from the quantitative algorithm for endometriosis;
---- comparing one data from an quantitative algorithm to a cutoff value interpreted as mathematical operations. Therefore this step equates to abstract ideas of mathematical concepts.
h) identifying the subject as having endometriosis based on the comparison of the level of the at least one miRNA to the cutoff value;
----this step recites a judgement/opinion that can be achieved in the human mind based on data observations (the comparison of the level of the at least one miRNA to the cutoff value). Therefore this step equates to an abstract idea of mental processes.
administering a therapeutic agent for the treatment of endometriosis to the subject in need thereof identified by the quantitative algorithm as having endometriosis according to step h), wherein the therapeutic agent is selected from the group consisting of hormone therapy, chemotherapy, and immunotherapy.
----The limitation "a subject in need thereof identified by the quantitative algorithm as having endometriosis” correlates the quantitative result of biomarkers with having endometriosis or not. The step is hence directed to law of nature.
Dependent claims 2, 14 and 47 recite more elements that are directed to abstract ideas in the mental process grouping and in the mathematical concept grouping.
The claims must therefore be examined further to determine whether the claims integrate the above-identified abstract ideas into a practical application (MPEP 2106.04(d)).
Step 2A Prong Two: Consideration of Practical Application
The claims result in a process of “i) administering a therapeutic agent for the treatment of endometriosis to the subject in need thereof identified by the quantitative algorithm as having endometriosis, wherein the therapeutic agent is selected from the group consisting of hormone therapy, chemotherapy, and immunotherapy.” However, it is not clear if the abstract idea steps (a) to (h) actually require administering. First, step h says identifying ..”based on the comparison of the level” of miRNA to the cutoff. What if the comparison identifies the subject as not having endometriosis. Second, step i says “the subject in need thereof identified by the quantitative algorithm…” Step h suggests an algorithm “based on the comparison of level of the at least miRNA to the cutoff value”. Further, it is not clear whether the recitation “the quantitative algorithm as having endometriosis according to step h” means the endometriosis is identified, or it depends. The claim appears to be conditional, and the abstract idea (a) to (h) is not integrated with the step (i) of administrating.
Obtaining patient samples is an insignificant extra-solution activity (MPEP 2106.05(g)). Additionally, the abstract idea of determining miRNA level in “the subject” using a quantitative algorithm is not bounded to any subject, because “the subject” has no antecedent.
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than
a drafting effort designed to monopolize the exception.
Step 2B: Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea. The recited additional elements are drawn to:
f) obtaining a blood, serum, plasma, saliva, sputum, urine, lymphatic fluid, synovial fluid, cerebrospinal fluid, stool, or mucus sample from the subject, wherein the blood, serum, plasma, saliva, sputum, urine, lymphatic fluid, synovial fluid, cerebrospinal fluid, stool, or mucus sample comprises miRNA associated with endometriosis (claim 1 step f); and
i) administering a therapeutic agent for the treatment of endometriosis to the subject in need thereof identified by the quantitative algorithm as having endometriosis according to step h), wherein the therapeutic agent is selected from the group consisting of hormone therapy, chemotherapy, and immunotherapy (claim 1 step i).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not include additional elements that are sufficient to amount of significantly more than the judicial exception because obtaining patient samples through non-invasive method such as blood, serum, …and treating a subject with endometriosis using a therapeutic agent of hormone therapy, chemotherapy, or immunotherapy, is considered routine and conventional in clinical industry.
Viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Applicant’s Arguments
Applicant's arguments filed 28 May 2026 have been fully considered but they are not persuasive. Particularly:
In the Remarks filed 5/28/2026, Applicant argued (page 11, penultimate para through page 13, 1st para) that the claims are not directed to a judicial exception. Further, Applicant argued that the reason no judicial exceptions are recited is because (pages 12-13, the connection para) “application of the quantitative algorithm to a sample obtained from a subject and administration of specific therapeutic agents to the subject as a result of identifying the subject as having endometriosis using the quantitative algorithm as recited in claim 1 serves to integrate the mental process and mathematical formula into a practical application of the process for the assessment and treatment of endometriosis.”
In response, Applicant’s argument refers to Step 2A/Prong two in the 101 analysis, relating to whether the therapeutic agent treatment of endometriosis integrates claims into a practical application or not. As discussed above, claim 1 last step do recite “i) administering a therapeutic agent for the treatment of endometriosis to the subject in need thereof identified by the quantitative algorithm as having endometriosis according to step h), wherein the therapeutic agent is selected from the group consisting of hormone therapy, chemotherapy, and immunotherapy” However, the abstract idea of determining miRNA level in “the subject” using a quantitative algorithm is not bounded to any subject, because “the subject” has no antecedent in claim 1.
It is not clear if the abstract idea steps (a) to (h) actually require administering. First, step h says identifying ..”based on the comparison of the level” of miRNA to the cutoff. What if the comparison identifies the subject as not having endometriosis. Second, step i says “the subject in need thereof identified by the quantitative algorithm…” Step h suggests an algorithm “based on the comparison of level of the at least miRNA to the cutoff value”. Further, it is not clear whether the recitation “the quantitative algorithm as having endometriosis according to step h” means the endometriosis is identified, or it depends. The claim appears to be conditional, and the abstract idea (a) to (h) is not integrated with the step (i) of administrating.
Other additional elements, such as obtaining samples non-invasively, is an insignificant extra-solution activity (MPEP 2106.05(g)).
Therefore, at Step 2A/Prong two, claims are not integrated into a practical application.
In the Remarks, Applicant argued (page 13, 2nd para through page 14, 1st para) that claims recite significantly more than the judicial exception, because “administration of hormone therapy, chemotherapy, or immunotherapy to a subject identified as having endometriosis through the analysis of the biomarkers input into the quantitative algorithm as recited in claim 1, upon which claims 2 and 14 depend goes beyond what is standard or routine for endometriosis treatment.”
In response, Applicant's arguments have been fully considered but they are not persuasive. Under Step 2B, the additional element “administering a therapeutic agent for the treatment of endometriosis to the subject in need thereof identified by the quantitative algorithm as having endometriosis according to step h), wherein the therapeutic agent is selected from the group consisting of hormone therapy, chemotherapy, and immunotherapy” (claim 1 step i) is considered routine and conventional. Treating endometriosis patients with a therapeutic agent selected from the group consisting of hormone therapy, chemotherapy, and immunotherapy is a routine practice in the clinical industry.
Additionally, obtaining patient samples through non-invasive method such as blood, serum, …, is considered routine and conventional in clinical industry. For obtaining (step f) and comparing (step g) the at least one miRNA biomarker level, the courts have recognized the following laboratory techniques that are very similar to the sample acquiring and miRNA biomarker measuring as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (MPEP 2106.05(d).II):
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Therefore, the claims do not recite anything significantly more. Consequently, claims are not integrated into a practical application and the claims are not eligible under 35 USC 101.
Double Patenting
This rejection is maintained from the 3/10/2026 Office action. Modifications are necessitated by claim amendments.
Claims 1-2 and 47 of this application is patentably indistinct from claims 8-10 and 22 of Application No. US 10982282B2. Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2 and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-10 and 22 of U.S. Patent No. US 10982282B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the missed part in reference claims regarding the quantitative analysis of biomarkers are provided in the following disclosure (emphasis added):
(col 37, 2nd para through col 38, 1st para) Because the level of circulating miRNA in a test sample from a patient relates to the prognosis of a patient in a continuous fashion, the determination of prognosis can be performed using statistical analyses to relate the determined circulating miRNA levels to the prognosis of the patient. A skilled artisan is capable of designing appropriate statistical methods. For example, the methods may employ the chi-squared test, the Kaplan-Meier method, the log-rank test, multivariate logistic regression analysis, Cox's proportional-hazard model and the like in determining the prognosis. Computers and computer software programs may be used in organizing data and performing statistical analyses. The approach by Giles et. al., British Journal of Hematology, 121:578-585, is exemplary. As in Giles et al., associations between categorical variables (e.g., miRNA levels and clinical characteristics) can be accessed via cross-tabulation and Fisher's exact test. Unadjusted survival probabilities can be estimated using the method of Kaplan and Meier. The Cox proportional hazards regression model also can be used to assess the ability of patient characteristics (such as miRNA levels) to predict survival, with ‘goodness of fit’ assessed by the Grambsch-Therneau test, Schoenfeld residual plots, martingale residual plots and likelihood ratio statistics (see Grambsch et al, 1995). In some embodiments, this approach can be adapted as a simple computer program that can be used with personal computers or personal digital assistants (PDA). The prediction of patients' survival time in based on their circulating miRNA levels can be performed via the use of a visual basic for applications (VBA) computer program developed within Microsoft Excel. The core construction and analysis may be based on the Cox proportional hazard models. The VBA application can be developed by obtaining a base hazard rate and parameter estimates. These statistical analyses can be performed using a statistical program such as the SAS proportional hazards regression, PHREG, procedure. Estimates can then be used to obtain probabilities of surviving from one to 24 months given the patient's covariates. The program can make use of estimated probabilities to create a graphical representation of a given patient's predicted survival curve. In certain embodiments, the program also provides 6-month, 1-year and 18-month survival probabilities. A graphical interface can be used to input patient characteristics in a user-friendly manner. In some embodiments of the disclosure, multiple prognostic factors, including circulating miRNA level, are considered when determining the prognosis of a patient. For example, the prognosis of an endometriosis subject or may be determined based on the presence of miRNA in a body fluid and one or more prognostic factors selected from the group consisting of cytogenetics, performance status, age, gender and previous diagnosis. In another example, the prognosis of a cancer patient may be determined based on circulating miRNA and one or more prognostic factors selected from the group consisting of cytogenetics, performance status, age, gender and previous diagnosis. In certain embodiments, other prognostic factors may be combined with the circulating miRNA level or other biomarkers in the algorithm to determine prognosis with greater accuracy.
(col 44, 2nd para) Assessment of the Diagnostic Value of Circulating miRNAs in Endometriosis
The ROC curve analysis of serum miRNAs that were differentially expressed between the two groups, was performed. AUC values of the differentially expressed miRNAs are shown in Table 2 and FIG. 3. Among the differentially expressed miRNAs, miR-125b-5p expression levels had the highest AUC (0.974, 95% Confidence Interval [CI], 0.00-1.00, p<0.001), with a sensitivity and specificity of 100% and 96%, respectively, for the cut off value of 0.0688. miRNA expressions in diagnosing endometriosis was improved by applying a logistic regression model to data with disease versus control samples. Since the distributions of all the biomarkers were not skewed normally, the variables were logarithmically transformed (FIGS. 3A-3C). A high AUC was observed for miR-125b-5p alone. A further increase in the AUC to 1.000 was achieved when combining the predictors 125b-5p, 451a and 3613-5p (FIG. 3D). The sensitivity and specificity reached 100% when these three microRNAs were combined. Therefore, the combination of micro RNAs demonstrated improved diagnostic ability over any individual micro RNAs. The following logistic model was selected: miRNA combination=118.406+108.751×log 10(125b-5p)+41.015×log 10(451a)−57.935×log 10(3613-5p). The microarray data shown in Table 3 demonstrates the top miRNA hits and the comparison of endometriosis (E1) upregulation vs. control (C1), E1 downregulation vs. C1.
The highlighted part clearly teaches a mathematical formula for quantifying the miRNA measurement for diagnostic/prognostic decisions. Therefore, instant claims 1, 2 and 47 are obvious over the combination of explicit claims 8-10 and 22, plus the disclosure discussed above.
Response to Applicant’s Arguments
Applicant's arguments filed 28 May 2026 have been fully considered but they are not persuasive. Particularly:
In the Remarks filed 5/28/2026, Applicant argued (page 16, 1st para) that “that Taylor '109 does not teach or suggest a method of assessing endometriosis which includes a step of inputting a level of a combination of miRNA into an algorithm, wherein the combination of miRNA comprises at least one miR selected from the group consisting of miR-34c, miR-126, miR-141, miR-200, miR-200a, miR-200b, miR-214, miR-449, miR-449a, miR-553, and miR-4668 as recited in claim 1, upon which claim 2 depends. Therefore, Applicant submits that claims 1 and 2 are patentably distinct from claims 8-10 and 22 of Taylor '109”.
In response, Applicant’s argument is not persuasive. Both Taylor '109 claim 8 and instant claim 1 require the detected level of at least one of miRNA from a big overlapping list of miRNAs. Although Taylor '109 claim 8 is not explicit on a “quantitative algorithm” in assessing the miRNA level, Taylor '109 requires “quantitative PCR” in claim 12. Further, as discussed above over the Double Patenting analysis, the Taylor ‘109 teaches (col 37, 2nd para) “the methods may employ the chi-squared test, the Kaplan-Meier method, the log-rank test, multivariate logistic regression analysis, Cox's proportional-hazard model and the like in determining the prognosis. Computers and computer software programs may be used in organizing data and performing statistical analyses”; and (col 44, 2nd para) “Therefore, the combination of micro RNAs demonstrated improved diagnostic ability over any individual micro RNAs. The following logistic model was selected: miRNA combination=118.406+108.751×log 10(125b-5p)+41.015×log 10(451a)−57.935×log 10(3613-5p).” Hence, the reference patent does teaches a quantitative algorithm to assess the miRNA level.
Therefore, the Double Patenting rejection is maintained.
Claim Rejections - 35 USC § 103
This rejection is newly applied. The new rejection is necessitated by Applicant’s amendments filed 5/28/2026.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Cosar et al. ("Serum microRNAs as diagnostic markers of endometriosis: a comprehensive array-based analysis." Fertility and sterility 106.2 (2016): 402-409. Cited on the 4/5/2024 IDS), in view of Taylor et al. (“Circulating MicroRNA As Biomarkers For Endometriosis”, US 20170175190 A1, Date Published: 2017-06-22. Cited on the 4/5/2024 IDS). Saare et al. "High-throughput sequencing approach uncovers the miRNome of peritoneal endometriotic lesions and adjacent healthy tissues." PLoS One 9.11 (2014): e112630. Newly cited.
Claim 1 is interpreted as a method to assess endometriosis quantitatively. Regarding claim 1, Cosar discloses a method to assess endometriosis using serum microRNAs. Particularly,
Cosar provides (page 402, Section Abstract) “miRNA from women with without endometriosis were used for microarray profiling and confirmed by means of quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was performed on differentially expressed miRNAs. Result(s): miR-3613-5p, miR-6755-3p were down-regulated and miR-125b-5p, miR-150–5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, miR-18a-5p were up-regulated more than 10-fold in the microarray. These results were confirmed with the use of qRT-PCR”, which teaches a) inputting the levels of miR-125b-5p, miR-150–5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, and miR-18a-5p into the ROC algorithm.
Cosar provides (page 402, Section Abstract) “Result(s): miR-3613-5p, miR-6755-3p were down-regulated and miR-125b-5p, miR-150–5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, miR-18a-5p were up-regulated more than 10-fold in the microarray. These results were confirmed with the use of qRT-PCR. Among the differentially expressed miRNAs, miR-125b-5p expression levels had the highest area under the ROC curve (AUC). The maximum AUC score of 1.000 was achieved when combining miR-125b-5p, miR-451a, and miR-3613-5p with the use of a logistic regression model.”, which teaches b) quantitatively assessing the performance of miRNAs using ROC analysis and understanding AUC.
Cosar provides (page 406, col 1, 1st para) “To improve the performance of miRNA expressions in diagnosing endometriosis, we applied the logistical regression model to the data for disease versus control samples. Because the distributions of the biomarkers were not skewed normally, the variables were logarithmically transformed (Fig. 3A). A high AUC was observed only for miR-125b-5p. A further increase in the AUC to 1.000 was achieved when combining the predictors 125b-5p, 451a, and 3613-5p (Fig. 3B). Sensitivity and specificity both reached 100% when these three miRNAs were combined. Therefore the combination of miRNAs may offer slightly improved diagnostic ability than any individual micro RNAs. The following logistic model was selected:
miRNA combination = 118.406
+ 108.751 x log10(125b-5p)
+ 41.015 x log10(451a)
+ 57.935 x log10(3613-5p)”
and Figure. 3B (page 407, Fig. 3B).
Therefore, Cosar teaches:
c) combining at least one of the at least one miRNA into a mathematical formula,
d) assigning weights to at least one of the at least one miRNA within the formula, and
e) using the assigned weights to develop a quantitative algorithm to distinguish the presence or absence of endometriosis.
Cosar provides (page 403, col 2, 2nd para) “Blood samples (10 mL) were collected after 8 hours of fasting before surgery. Sterile tubes containing no additives were used. The samples were immediately centrifuged and the sera frozen at _80_C for further analysis. One-half of the sample from each individual was pooled with the others for group microarray analysis, and the remaining one-half of the sample was used for individual analysis of miRNAs”, which teaches f) obtaining blood samples comprising miRNA associated with endometriosis because Cosar’s research is about endometriosis.
Cosar provides (page 404, col 1, 2nd para) “Based on ROC analysis, the best statistical cutoff values of plasma miRNAs were calculated, and the sensitivity and specificity for selected cutoff points were then assessed” and (page 406, col 1, 1st para) “Among the differentially expressed miRNAs, miR-125b-5p expression levels had the highest AUC (0.974, 95% confidence interval, 0.00–1.00; P<.001) and sensitivity and specificity of 100% and 96%, respectively, for the cutoff value of 0.0688”, which teaches g) comparing the miRNA level in sample with a cutoff value derived from quantitative algorithm for endometriosis. It is obvious that Cosar also teaches h) identifying the subject as having endometriosis based on the comparison of the miRNA level vs the cutoff value.
However, Cosar’s list of miRNAs do not overlap with the miRNAs listed in claim 1 step a). Cosar does not teach treating endometriosis.
Saare provides (page 1, section “Abstract”) “We found five miRNAs specific to epithelial cells – miR-34c, miR-449a, miR-200a, miR-200b and miR-141 showing significantly higher expression in peritoneal endometriotic lesions compared to healthy peritoneal tissues”; and (page 5, col 2, 2nd para) “As the level of investigated miRNAs was much higher in endometriotic lesions than healthy tissues we tested their ability to discriminate between endometriotic lesions (n= 22) and non-diseased tissues (n= 24). The ROC analysis revealed that all miRNAs enabled a correct classification of diseased and non-diseased tissues (AUC values for miR-449a, miR-34c, miR-200a, miR-200b and miR-141 were 0.92, 0.81, 0.91, 0.90, and 0.83, respectively). The combined signature of five miRNAs showed high sensitivity (91.7%) and specificity (95.5%), (AUC =0.94, CI 0.83–0.99) but the subset of three miRNAs – miR-449a/miR-200a/miR-200b – showed the best discriminating power with the highest sensitivity (95.8%) and specificity (95.5%) (AUC = 0.95, CI 0.83–0.99) (Figure 3)”. Cosar teaches five miRNAs recited in claim 1 step a).
Neither Cosar no Saare teaches treating endometriosis. Taylor provides (paragraph [0126]) “once a patient is diagnosed with having or is at risk of having endometriosis, the patient can be treated using methods known in the art. Well known treatments for endometriosis include, but are not limited to, pain killers, hormonal treatments, chemotherapy, and surgical treatments”, which teaches i) hormone therapy and chemotherapy for women with endometriosis.
Regrading claim 2, Cosar does not teach determining whether a subject will respond to a treatment or not. Taylor provides (paragraph [0029]) “the present disclosure provides biomarkers for the diagnosis and prognosis of endometriosis. Generally, the methods of this disclosure find use in diagnosing or for providing a prognosis for endometriosis by detecting the expression levels of biomarkers, which are differentially expressed (up- or down-regulated) in blood, plasma or serum from a patient. Similarly, these markers can be used to diagnose reduced fertility in a patient with endometriosis or to provide a prognosis for a fertility trial in a patient suffering from endometriosis. The present disclosure also provides methods of identifying a compound for treating or preventing endometriosis. The present disclosure provides kits for the diagnosis or prognosis of endometriosis”, which teaches iv) developing a quantitative algorithm to determine whether a patient is likely to respond to a particular medical or surgical treatment.
Regarding claim 47, Cosar provides (page 402, Section Abstract) “miRNA from women with without endometriosis were used for microarray profiling and confirmed by means of quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was performed on differentially expressed miRNAs. Result(s): miR-3613-5p, miR-6755-3p were down-regulated and miR-125b-5p, miR-150–5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, miR-18a-5p were up-regulated more than 10-fold in the microarray. These results were confirmed with the use of qRT-PCR”, which teaches inputting the levels of miR-125b-5p, miR-150–5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, and miR-18a-5p into the ROC algorithm.
It would have been prima facie obvious to replace the miRNA biomarkers used in Cosar’s method of quantitative assessment of endometriosis using non-invasive microRNA biomarkers with Saare’s miRNA biomarkers. One would be motivated to do so because Saare’s biomarkers achieved good ROC/AUC curves in differentiating endometriosis vs non-endometriosis samples.
One would reasonably expect success as this is a “simple substitution of one known element for another to obtain predictable results” (MPEP 2141.III.(B)), as both Cosar and Saare are in the same field of endeavor.
It would have been prima facie obvious to combine the combined Cosar’s and Saare’s method of quantitative assessment of endometriosis using non-invasive microRNA biomarkers with Taylor’s method of treating endometriosis patients using a hormonal treatment, or chemotherapy. One would be motivated to do so because treating patients is the natural next step after diagnosis or prognosis, and Taylor’s method is established in the field of endometriosis treatment for years.
One would reasonably expect success as Cosar pointed out that (page 406, col 1, 2nd para. Emphasis added) “endometriosis is associated with a 6.7-year average diagnostic delay, resulting in progression of the disease and impairment in quality of life (39). Early diagnosis of endometriosis would allow prompt treatment, improvement in quality of life, and potentially preservation of fertility.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Cosar, Saare and Taylor, as applied to claims 1-2 and 47 above, and further in view of Taylor et al. ("Infrared spectroscopy with multivariate analysis to interrogate endometrial tissue: a novel and objective diagnostic approach." British journal of cancer 104.5 (2011): 790-797. Previously cited. Hereafter referred as “Taylor SE”).
Regarding claim 14, Cosar, Saare and Taylor teach claims 1-2 above. None of Cosar, Saare or Taylor teaches the Fisher discriminant analysis. Taylor SE provides (page 790, Section Abstract) “derived data was subjected to principal component analysis followed by linear discriminant analysis”, which teaches the Fisher discriminant analysis because linear discriminant analysis is the Fisher discriminant analysis.
It would have been prima facie obvious to modify the mathematical method (Cosar: page 406, col 1, 1st para) used in the combined Cosar’s, Saare’s and Taylor’s method of quantitative assessment of endometriosis using microRNA biomarkers, with Taylor SE’s Fisher discriminant analysis. One would be motivated to do so because (Taylor SE: page 791, col 1, 1st para) “Linear discriminant analysis demonstrates separation between different categories” (such as different microRNAs).
One would reasonably expect success as Cosar, Saare, Taylor and Taylor SE are all about endometrial diseases, and Taylor SE already demonstrated that his approach is possible to distinguish benign from malignant endometrial tissues, as well as various subtypes of both.
Response to Applicant’s Arguments
Applicant's arguments filed 28 May 2026 have been fully considered but they are not persuasive. Particularly:
In the Remarks filed 5/28/2026, Applicant argued (page 14, last para through page 15, last para) that “Taylor '190 does not cure the deficiencies of Cosar as Taylor '190 does not teach” “the use of at least one of miR-34c, miR-126, miR-141, miR-200, miR-200a, miR-200b, miR-214, miR-449, miR-449a, miR-553, and miR-4668 for developing an algorithm for assessing endometriosis as recited in claim 1, upon which claims 2 and 47 depend. Therefore, Applicant submits that the combination of Cosar and Taylor '190 does not teach or suggest each and every element of claims 1 and 2”.
In response, Applicant’s argument is not persuasive. Applicant’s amendment necessitated a new search for art and “at least one of miR-34c, miR-126, miR-141, miR-200, miR-200a, miR-200b, miR-214, miR-449, miR-449a, miR-553, and miR-4668” is taught by Saare. As discussed above over the 103 rejection, claim 1 is fully taught, claims 2, 14 and 47 do not recite new limitations that differentiate the prior art (wherein claim 47 is a part of previous claim 1).
With newly amended claim 1 rejected, the following two arguments (page 15, penultimate para) are not persuasive:
Applicant submits that the amendments and arguments discussed above in view of the rejection of claims 1 and 2 over Cosar and Taylor '190 are equally applicable to the instant rejection. Briefly, Applicant submits that the combination of Cosar and Taylor '190 does not teach or suggest inputting a level of a combination of miRNA into an algorithm, wherein the combination of miRNA comprises at least one of miR-34c, miR-126, miR-141, miR-200, miR-200a, miR-200b, miR-214, miR-449, miR-449a, miR-553, and miR-4668 as recited in claim 1, upon which claim 14 depends.
Claims 2 and 14 stay unamended in the current version. Saare cured the deficiency caused by miRNA modifications. With newly amended claim 1 rejected by art, above argument is not persuasive. Applicant submits that Taylor SE does not cure the deficiencies of the combination of Cosar and Taylor '190 as Taylor SE does not teach or suggest inputting a level of a combination of miRNA into an algorithm, wherein the combination of miRNA comprises at least one miR of miR-34c, miR-126, miR-141, miR-200, miR-200a, miR-200b, miR-214, miR-449, miR-449a, miR-553, and miR-4668. Therefore, Applicant submits that the combination of Cosar, Taylor '190 and Taylor SE does not teach or suggest each and every element of claim 1 upon which claim 14 depends.
Claims 2 and 14 stay unamended in the current version. The reference of Saare cured the deficiency caused by miRNA modifications. With newly amended claim 1 rejected by art, above argument is not persuasive.
Therefore, the 103 rejections for claims 1-2, and 14 are maintained. Claim 47 is newly rejected.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights