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 .
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.
Withdrawn Objections/rejections
The objections to the drawings are withdrawn in response to the amendments.
The objections to the claims are withdrawn in response to the amendments.
The rejections of the claims under 35 U.S.C. 112b are withdrawn in response to the amendments.
Priority
The present application was filed on 01/13/2022 and is a continuation of PCT/EP2020/070416, filed 07/20/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 19187475.9, filed on 07/22/2019 in Europe.
Status of the Claims
Claims 1-4, 7-11, 13-19, 21-22, 25 and 27-38 are pending; claims 1-3, 19, 21 and 27 are amended, claims 5-6, 12, 20, 23-24 and 26 are canceled; claims 28-38 are newly recited. Claims 1-4, 7-11, 13-19, 21-22 and 25 and 27-38 are examined below.
Information Disclosure Statement
The information disclosure statement filed 12/2/2025 and the information disclosure statement filed 12/18/2025 are being considered by the examiner.
Maintained Rejection
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 7-11, 13-16, 19, 21-22 and 28-31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception (i.e., natural correlation or abstract idea) without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims recite “a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis (claims 1 and 19), a non-invasive method of selecting a patient for drug-based therapy or surgical therapy (laparoscopy) of endometriosis (claim 2), a non-invasive method of monitoring a patient suffering from endometriosis or being treated for endometriosis (claim 3) comprising measuring the amount or concentration of Substance P in a sample of the patient”, “and assessing whether the patient has endometriosis or is at risk of developing endometriosis” (claim 19).
The natural relationship to which the claims are directed (i.e., the relation between the amount or concentration of Substance P and endometriosis) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring amount or concentration of Substance P and endometriosis or risk of developing endometriosis.
The correlation between amount of concentration of Substance P and endometriosis is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that the amount or concentration of Substance P is elevated to different extents in a patient that has endometriosis or is at risk of developing endometriosis.
Additionally, the claims also recite steps of “comparing the measured amount or concentration to a reference”
The claimed steps of assessing whether a patient has endometriosis or is at risk of developing endometriosis (claims 1 and 19), selecting a patient for drug-based therapy or surgical therapy of endometriosis (claim 2), and monitoring a patient suffering from endometriosis or being treated for endometriosis (claim 3) by comparing the determined amount or concentration to a reference may also be categorized as abstract ideas, namely mental processes/ concepts performed in the human mind (such as a doctor simply thinking about the measured amount or concentration of Substance P in relation to a reference and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of assessing, selecting and monitoring solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a reference data (in this case, comparing a numerical amount or concentration to a reference) represents abstract ideas.
Similar concepts involving comparing information regarding a sample of a patient to a reference have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo.
Claims 1-3 and 19 further require wherein endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging. This limitation merely limits the claim to a particular stage of endometriosis; therefore, this limitation is also directed to the judicial exception(s).Claim 4 recites “wherein an elevated amount or concentration of Substance P in the sample of the patient is indicative of the presence of endometriosis in the patient”.
As explained above, the amount or concentration of Substance P in the sample of the patient and the presence of endometriosis in the patient is a natural correlation.
Furthermore, similarly to above, the elevated amount or concentration of Substance P in the sample of the patient refers to the comparison to the reference, therefore, it is also an abstract idea because this can be accomplished in the human mind. The recited “elevated amount” also constitutes abstract ideas (an elevated amount being itself a mathematical concept).
Claim 7 recites “wherein the patient is a female patient”. This merely narrows the population used in the natural correlation.
Claims 9-11 further limits claim 1 to a specific stage or type of endometriosis, which is used in the natural correlation and mental comparison. Thus, dependent claims 9-11 are a further statement of the judicial exception.
Claim 14 recites “further comprising calculating a ratio of at least one of the amount or concentration of Substance P and dysmenorrhea or of the amount or concentration of Substance P and lower abdominal pain according to the VAS scale”. The limitation limits the claim to include a ratio, which is a mathematical concept that can be performed in the human mind or with a pen and paper.
Claim 15 recites “further comprising calculating a ratio of the amount or concentration of Substance P and the amount or concentration of CA-125 in a sample of the patient”. The limitation limits the claim to include a ratio, which is a mathematical concept that can be performed in the human mind or with a pen and paper.
Claim 16 recites “wherein the patient is a human female patient”. This merely narrows the population used in the natural correlation.
Step 2A, Prong 2
The above-discussed steps of “determining the amount or concentration of Substance P” and “comparing” the Substance P concentration to a reference are insufficient to integrate the judicial exception into a practical application because steps corresponding to mental activity, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In this case, assessing disease, selecting a patient and monitoring a patient by comparing values, represent judicial exceptions and not a practical application thereof.
Furthermore, the additional limitations of claims 1-2 and 19, i.e. “wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma” merely limits the sample to which the natural correlation is being used for.
The additional limitation of claim 1, i.e. “determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to the VAS scale” , is drawn to insignificant presolution activity (data gathering steps)., This additional limitation fails to use, rely on or apply the judicial exception such to amount to a practical application thereof. Therefore, this limitation does not integrate the judicial exception into a practical application.
Furthermore, claims 1-3 recite the additional limitation “wherein the measuring is performed using a quantitative immunoassay and by detectably labeling Substance P”, and claim 19 recites “wherein the second antibody is detectably labeled”. These limitations are also insignificant presolution activity, i.e. steps drawn to data gathering. Therefore these also fail to integrate the judicial exception into a practical application.
The additional limitation of claim 19, i.e. “wherein the measuring comprises incubating the sample of the patient with a first antibody and a second antibody, each specifically binding to Substance P at different epitopes thereby generating a sandwich complex comprising the first antibody, Substance P, and the second antibody, wherein the second antibody is detectably labeled, and quantifying the complex thereby quantifying the amount of Substance P in the sample of the patient” is also drawn to mere data gathering steps. The claim is not limited to a particular testing technique or platform, but rather is generally recited. For example, although the claim recites “a first antibody and a second antibody”, no particular or specific antibody is set forth.
Claim 8 also recites “wherein the assessment is performed independent of the rASRM staging”. This merely limits the claimed method to be independent of a specific limitation, is the claim limitation is interpreted as a limitation on how the collection of data is performed.
Claims 13 and 22 recite “further comprising measuring the amount or concentration of Carbohydrate antigen 125 (CA-125) in a sample of the patient”. The limitation merely limits the claim to include determination of an amount or concentration, this limitation is directed to the collection of data. Furthermore, the claim is not limited to a particular testing technique or platform, but rather is generally recited. Therefore, this amounts to insignificant presolution activity.
Claim 14 recites “further comprising calculating a ratio of at least one of the amount or concentration of Substance P and dysmenorrhea or of the amount or concentration of Substance P and lower abdominal pain according to the VAS scale”. The limitation merely limits the claim to include a ratio, which is a mathematical concept that can be performed in the human mind or with a pen and paper, and is also a collection of data.
Claim 15 recites “further comprising calculating a ratio of the amount or concentration of Substance P and the amount or concentration of CA-125 in a sample of the patient”. The limitation limits the claim to include a ratio, which is a mathematical concept that can be performed in the human mind or with a pen and paper, and is also a collection of data.
Claim 21 recites “ wherein the second antibody is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye”. These claims do not go beyond insignificant presolution activity, i.e., a mere data gathering steps necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Therefore, claims 20-21 are insufficient to integrate the judicial exceptions into a practical application.
Claims 28 and 31 recite “further comprising administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy”.
Claim 29 recites “further comprising administering the drug-based therapy or performing the surgical therapy on the patient selected for therapy”.
Claim 30 recites “further comprising administering a therapy for endometriosis to the patient based on the monitoring”.
These treatment steps are insufficient to integrate the judicial exception(s) as it is not limited to a particular treatment. Although a claim limitation can integrate a judicial exception by applying or using the judicial exception(s) to effect a particular treatment or prophylaxis for a disease or medical condition, in this case no specific or particular treatment is set forth.
The level of generality in the instant claims stands in contrast to the treatment claims found patent-eligible in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018) and Natural Alternatives Int’l v. Creative Compounds LLC, 2017 WL 1216226 (Fed. Cir. Mar. 15, 2019). The claims at issue in Vanda recited administering a specific drug (iloperidone) at specific dosage ranges based on a patient’s genotype. Vanda, 887 F.3d at 1135. Accordingly, the court found that although the inventors recognized the relationships between iloperidone, a patient’s genotype, and QTc prolongation, what they claimed is “an application of that relationship,” i.e., “‘a new way of using an existing drug’ that is safer for patients because it reduces the risk of QTc prolongation.” Id. (quoting Mayo, 566 U.S. at 87). The Federal Circuit characterized the Vanda claims as being directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.” Id. at 1136. Similarly, the Federal Circuit found that the claims in Natural Alternatives “contain specific elements that clearly establish they are doing more than simply reciting a natural law,” such as specifying a patient population, particular results to be obtained, specific compounds to be administered to achieve the claimed results, and dosages via an “effective” limitation. Natural Alternatives, 4-5.
In contrast to the claims in Vanda and Natural Alternatives, the present claims do not specify a particular result to be obtained, a compound to be administered to achieve a claimed result, or any specific dosage of a specific compound. The recited treating step does not limit the claim to a particular application; instead, the effect of the treatment limitation “is simply to tell doctors to apply the law somehow when treating their patients.” Mayo, 566 U.S. at 81-82.
Here, the claimed treatment steps are instead merely an instruction to “apply” the exception in a generic way. Thus, the treatment step does not integrate the judicial exceptions into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of limiting the claim to be independent of a specific limitation (claim 8), further determinations of an amount or concentration (claim 13) and calculating ratios (claims 14-15) do not add significantly more to the judicial exception(s) because these are all insignificant extra-solution activities.
Furthermore, determining an amount or concentration of substance P and comparing the determined amount or concentration to a reference was well-understood, routine and conventional in the art at the time. The instant disclosure page 16 lines 30-32 discloses that “[a] variety of methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention”. The instant disclosure page 23 lines 23-26 discloses that “[t]he detection of anti-Substance P antibody/Substance P complex can be performed by any appropriate means.. The person skilled in the art is absolutely familiar with such means/methods”. Also, the instant specification page 11 lines 15-16 discloses that “[t]he expression “comparing the amount or concentration determined to a reference” is merely used to further illustrate what is obvious to the skilled artisan anyway”. Therefore, this is evidence that it is well-understood routine and conventional to compare the determined amount or concentration of Substance P to a reference.
Also, determining an amount or concentration of substance P and comparing the determined amount or concentration to a reference was well-understood, routine and conventional in the art in view of Bokor et al., Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis; Human Reproduction, 2009, Vol. 24, No. 12, pp. 3025-3032-Cite No. 5 of IDS filed 6/1/2022 (hereinafter Bokor). Bokor teaches a method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising determining the amount or concentration of Substance P in a sample of the patient, and comparing the determined amount or concentration to a reference (“[t]he aim of our study was to test the hypothesis that multiple-sensory small-diameter nerve fibres are present in a higher density in endometrium from patients with endometriosis when compared with women with a normal pelvis… Sections were immunostained with… anti-substance P (SP)… The density of small nerve fibres was 14 times higher in endometrium from patients with minimal–mild endometriosis (1.96±2.73) when compared with women with a normal pelvis (0.14±0.46, P < 0.0001). The combined analysis of neural markers PGP9.5, VIP and SP could predict the presence of minimal –mild endometriosis with 95% sensitivity, 100% specificity and 97.5% accuracy” Abstract).
Furthermore, measuring the amount or concentration of Substance P in a sample of the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma was known in the art. For example, Qiong et al., Clinical Effect of Dahuang Zhechong Wan on Pelvic Pain Caused by Endometriosis with Qi Stagnation and Blood Stasis Syndrome, Chinese Journal of Experimental Traditional Medical Formulae, vol. 25, no. 12, 121-126 (Cited on PTO-892 5/20/2025 & Cite No. 41 of IDS filed 2/17/2025) teaches measuring Substance P in the serum of endometriosis patients before and after treatment (section 2.6, page 10).
Ovakimyan A.S., et al. Obstetrics and Gynecology. - 2015. - N. 3. - P. 79-86 (“Ovakimyan”) teaches measuring Substance P in the plasma of patients with endometriosis (“plasma…substance P levels in patients with different forms of external genital endometriosis and chronic pain” Title, “[t]o estimate the levels of … substance P in the plasma (P) …of reproductive-aged women… [t]he concentrations of … substance P were estimated by enzyme immunoassay.” Abstract).
Also, measuring Substance P, wherein the measuring is performed using a quantitative immunoassay and by detectably labeling Substance P, is well-understood, routine and conventional. For example, Horak et al. Biosensors and Bioelectronics 58 (2014)186–192 (Cited on PTO-892 5/20/2025) teaches a “[s]ensitive, rapid and quantitative detection of substance P in serum samples using an integrated microfluidic immunochip” (Title). Horak further teaches wherein Substance P is detectably labeled (“In the last step, the bound complexes are labeled with a GOx conjugated avidin” (page 190 col. 1 para. 1, see Fig. 1).
The courts have recognized the following laboratory techniques 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:
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);
Furthermore, every application of the judicial exception would require determination of the amount or concentration of Substance P in a sample. Limitations that are necessary for all practical applications of a judicial exception, such that everyone practicing the judicial exception would be required to perform those steps or every product embodying that judicial exception would be required to include those features, would not be sufficient to confer patent eligibility. In this case, everyone practicing the judicial exception would need to determine the concentration of Substance P.
Furthermore, there is evidence that administering a therapy for endometriosis to the patient based on the monitoring is well-understood, routine and conventional. For example, Qiong (Cited on PTO-892 5/20/2025 & Cite No. 41 of IDS filed 2/17/2025) teaches measuring Substance P in the serum of endometriosis patients before and after treatment (section 2.6, page 10). Qiong further teaches that “[b]oth groups of patients took dydrogesterone tablets… Sanjie Zhentong Capsule… The observation group took Dahuang Michong Pills… The treatment course of both groups of patients was observed for 3 consecutive menstrual cycles” (section 1.5, page 5).
See also, Taylor (WO 2018/044979 Al ) -Cite No. 1 of IDS filed on 5/31/2023 teaches that “[o]nce 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. Pain killers used for the treatment of endometriosis include both simple analgesics, such as paracetamol, COX-2 inhibitors, aspirin, and other non-steroidal anti-inflammatory drugs well known in the art, and narcotic analgesics, such as morphine, codine, oxycodone, and others well known in the art. Hormonal treatments include, but are not limited to, oral contraceptives, progestins, such as Dydrogesterone, Medroxyprogesterone acetate, Depot medroxyprogesterone acetate, Norethisterone, Levonorgestrel, and others well known in the art, progesterone and progesterone-like substances, GnRH agonists, such as leuprorelin, buserelin, goserelin, histrelin, deslorelin, nafarelin, and triptorelin, androgens and synthetic androgens like Danazol, and aromatase inhibitors. Surgical treatments include, but are not limited to, laparoscopic surgery, hysterectomy, and oophorectomy. Other treatments particularly well suited for use in the present disclosure are well known in the art. In some embodiments, the patient can be treated using a statin, including but not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.” (page 54 lines 3-20).
Olive et al. N Engl J Med, Vol. 345, No. 4 · July 26, 2001 (“Olive”) teaches that “Medical treatments for endometriosis have focused on the hormonal alteration of the menstrual cycle” (page 266 col. 2 para. 3). Olive further teaches that “[m]any other hormones and drugs have been used to treat endometriosis” (page 268 col. 1 para. 2). Olive further teaches that “Surgical therapy is also used widely to treat endometriosis” (page 268 col.1 para. 3).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 7-11, 16-18,25, 27 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan (Cited on PTO-892 5/20/2025) in view of Bokor et al., Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis; Human Reproduction, 2009, Vol. 24, No. 12, pp. 3025-3032-Cite No. 5 of IDS filed 6/1/2022 (hereinafter Bokor) and Horak et al. Biosensors andBioelectronics58(2014)186–192 (Cited on PTO-892 5/20/2025).
Regarding claims 1-3, 17-18,25,27 and 35 Ovakimyan suggests a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, and of monitoring a patient suffering from endometriosis or being treated for endometriosis, and of detecting an elevated amount or concentration of Substance P in a patient, and for measuring the amount of Substance P in a sample from a patient, and of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising obtaining a sample from the patient, measuring the amount or concentration of Substance P in the sample of the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma (“[t]he P [plasma]…levels of…substance P were determined in 62 women with external genital endometriosis with varying degrees of the extent and intensity of pain syndrome and in 24 women without endometriosis or pain syndrome…P…levels of…substance P were higher in the women with endometriosis” Abstract, “The study included 86 women aged 21 to 44 years who were undergoing inpatient treatment” page 4 paragraph 4), wherein the measuring is performed using a quantitative immunoassay (“The concentrations of…substance P were estimated by enzyme immunoassay” Abstract, “substance P - using the test system of Peninsula Laboratories, LLC (USA)…The data are presented as mean ± error of the mean” page 6 paragraph 5, see Figure 1) comparing the measured amount or concentration to a reference (Abstract), and detecting the elevated amount or concentration of Substance P in the sample of the patient (“plasma…substance P levels in patients with different forms of external genital endometriosis and chronic pelvic pain” Title, “The P [plasma]… levels of … substance P were higher in the women with endometriosis” Abstract), and/by contacting the sample, or a portion thereof, with a binding agent, wherein the binding agent is an antibody and detecting the binding between Substance P and the binding agent, wherein the binding agent specifically binds to Substance P (“[t]he concentrations of …substance P were estimated by enzyme immunoassay” Abstract). Note that although Ovakimyan fails to use the language “contacting the sample, or a portion thereof, with a binding agent that specifically binds Substance P and detecting the binding between Substance P and the binding agent”, the teaching of “enzyme immunoassay” inherently provides an agent that specifically binds Substance P as well as contacting and detection steps. Ovakimyan further suggests assessing whether the patient has endometriosis or is at risk of developing endometriosis (Abstract, “All women in the main group were diagnosed with external genital endometriosis is intraoperatively and confirmed histologically” page 4 paragraph 6), and determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to the VAS scale (“chronic pelvic pain” Title, “[t]he visual analogue scale was used to evaluate pain syndrome” Abstract). Ovakimyan further teaches a difference in blood Substance P levels in stage IV endometriosis patients compared to controls ("The content of substance P in both types of biological fluids is significantly higher: in the subgroup with stage IV endometriosis (Fig. 1) both in relation to the results of the comparison group and the subgroup of patients with stage Ill endometriosis" page 7 last paragraph).
Although suggested by Ovakimyan (“enzyme immunoassay” Abstract), Ovakimyan fails to explicitly teach by detectably labeling Substance P or wherein Substance P is detectably labeled. Ovakimyan fails to further teach wherein endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging. Ovakimyan also fails to further teach selecting a patient for drug-based therapy or surgical therapy of endometriosis. Ovakimyan fails to further teach wherein the binding agent is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye.
Bokor suggests a method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising determining the amount or concentration of Substance P in a sample of the patient, and comparing the determined amount or concentration to a reference (“[t]he aim of our study was to test the hypothesis that multiple-sensory small-diameter nerve fibres are present in a higher density in endometrium from patients with endometriosis when compared with women with a normal pelvis… Sections were immunostained with… anti-substance P (SP)… The density of small nerve fibres was 14 times higher in endometrium from patients with minimal–mild endometriosis (1.96±2.73) when compared with women with a normal pelvis (0.14±0.46, P < 0.0001). The combined analysis of neural markers PGP9.5, VIP and SP could predict the presence of minimal –mild endometriosis with 95% sensitivity, 100% specificity and 97.5% accuracy” Abstract). Bokor further teaches the above steps are used for selecting a patient for surgical therapy (laparoscopy) of endometriosis (“[a]n early semi-invasive diagnosis of minimal –mild endometriosis in women with or without pain who try to conceive should enable gynaecologists to select them for laparoscopic excision of endometriosis” page 3030 column 2 paragraph 2). Note that claim 2 recites the optional limitation of selecting a patient for drug-based therapy therefore this are not specifically required of the claim as presented. Bokor further teaches “wherein endometriosis is stage I endometriosis according to rASRM staging and stage II endometriosis according to rASRM staging (“[t]wenty endometrial samples were selected from women with laparoscopically and histologically confirmed minimal (n = 10) or mild (n = 10) endometriosis (mean age 33±10 years), staged according to the revised staging system of American Society for Reproductive Medicine (American Society for Reproductive Medicine, 1996)” page 3026 column 2 paragraph 2). Note that minimal and mild endometriosis correspond to rASRM stages 1 & 2, respectively as per page 9 lines 9-10 of the instant disclosure. Bokor further teaches that “[o]wing to the lack of a no- or semi-invasive diagnostic tool, the delay between onset of pain symptoms and surgically confirmed endometriosis can be as long as 8 years in the UK and USA (Hadfield et al., 1996; Sinaii et al., 2008). The current delay in diagnosis and treatment contributes to years of suffering and potential infertility if the disease is left untreated. Clearly, a simple non-invasive diagnostic method may greatly help to reduce this delay, especially for minimal–mild endometriosis which cannot be diagnosed by clinical examination or ultrasound” (page 3025, col. 2 paragraph 3, page 3026 column 1 paragraph 1).
Horak teaches “Sensitive, rapid and quantitative detection of substance P in serum samples using an integrated microfluidic immunochip” (Title). Horak further teaches that “[t]he chip-based assay procedure and result calculation was performed according to the benchtop SP assay described above and in S1…primary antibody was…incubated…a mixture in the proportion 1:1:1, containing secondary antibody…, SP–biotin…and…human serum sample was…incubated for 1h”( page 187 column 2 paragraph 5 and page 188 column 1 paragraphs 1-2, See figure Fig. 1 showing a schematic). Horak further teaches the measuring by detectably labeling Substance P (“In the last step, the bound complexes are labeled with a GOx conjugated avidin” page 190 col. 1para. 1, see Fig. 1). Horak further teaches wherein the binding agent is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye (page 190 col. 1para. 1, see Fig. 1). Horak further teaches that “[o]ur on- chip sensing method requires 20 times less reagent/sample volume, reduces the total assay preparation in half and performs fast detection within 10 min read-out time. Another attractive feature of this approach is the ability to use reagents and workflow developed for standard ELISA procedure” (page 190 column 2 paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan to include selecting a patient for surgical therapy of endometriosis and wherein endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging taught by Bokor because Bokor suggests that this may help reduce the delay between pain symptom onset and treatment, which could reduce years of suffering and potential infertility for stage I and/or stage II patients. A person having ordinary skill in the art would have had a reasonable expectation of success because, both Bokor and Ovakimyan teach methods involving assessing whether a patient has endometriosis comprising measuring Substance P in a sample of endometriosis patients. Furthermore, Ovakimyan teaches that stage IV endometriosis patients had significantly higher blood Substance P levels than controls.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor to rely on the measuring by detectably labeling Substance P wherein the binding agent is detectably labeled with a chemiluminescent dye or electrochemiluminescent dye, taught by Horak because Horak teaches that this enables fast and efficient measurements. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ovakimyan and Horak teach measuring Substance P in a serum sample using immunoassays.
Regarding claim 4, Ovakimyan in view of Bokor and Horak teach the method of claim 1 as discussed above.
Ovakimyan further suggests wherein an elevated amount or concentration of Substance P in the sample of the patient is indicative of the presence of endometriosis in the patient (Abstract).
Regarding claims 7 and 16, Ovakimyan in view of Bokor and Horak teach the method of claim 1 as discussed above.
Ovakimyan further teaches wherein the patient is a human female patient (Abstract).
Regarding claim 8, Ovakimyan in view of Bokor and Horak teach the method of claim 1 as discussed above.
Ovakimyan further teaches wherein the assessment is performed independent of the rASRM staging (Abstract). Furthermore, the broadest reasonable interpretation of the claim as recited does not limit the scope of the claim to the rASRM staging of the subject since it merely states that the method steps of claim 1 are executed independently of the rASRM staging, i.e., without being influenced by the rASRM staging. In this case, the methods of Ovakimyan clearly state that only “[t]he P [plasma]…levels of…substance P were determined in 62 women with external genital endometriosis with varying degrees of the extent and intensity of pain syndrome and in 24 women without endometriosis or pain syndrome”” (Abstract) independently of the rASRM staging. Therefore, the teachings of Ovakimyan teach the claim because the step of determination of Substance P in a sample of the patient in Ovakimyan is not influenced by the rASRM staging.
Regarding claims 9-10, Ovakimyan in view of Bokor and Horak teach the method of claim 1 as discussed above.
Bokor further teaches wherein endometriosis is stage I endometriosis according to rASRM staging and stage II endometriosis according to rASRM staging (“[t]wenty endometrial samples were selected from women with laparoscopically and histologically confirmed minimal (n = 10) or mild (n = 10) endometriosis (mean age 33±10 years), staged according to the revised staging system of American Society for Reproductive Medicine (American Society for Reproductive Medicine, 1996)” page 3026 column 2 paragraph 2). Note that minimal and mild endometriosis correspond to rASRM stages 1 & 2, respectively as per page 9 lines 9-10 of the instant disclosure.
Regarding claim 11, Ovakimyan in view of Bokor and Horak teach the method of claim 1 as discussed above.
Bokor further teaches wherein endometriosis is peritoneal endometriosis (“[t]wenty endometrial samples were selected from women with laparoscopically and histologically confirmed minimal (n = 10) or mild (n = 10) endometriosis (mean age 33±10 years), staged according to the revised staging system of American Society for Reproductive Medicine (American Society for Reproductive Medicine, 1996)” page 3026 column 2 paragraph 2). Note that minimal and mild endometriosis correspond to rASRM stages 1 & 2, respectively, and is “defined by superficial peritoneal endometriosis” as per page 9 lines 9-11 of the instant disclosure.
Claims 13, 32 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan in view of Bokor and Horak as applied to claims 1 and 17-18 above, and further in view of Taylor (WO 2018044979 A1)-Cite No. 1 of IDS filed on 5/31/2023 and Giudice (US PGPub 20080318237 A1) -Cite No. 1 of IDS filed on 06/01/2022.
Regarding claims 13, 32 and 36, Ovakimyan in view of Bokor and Horak teach the method of claims 1 and 17-18 as discussed above.
Ovakimyan in view of Bokor and Horak fail to teach determining the amount or concentration of CA-125 in a sample of the patient.
Taylor teaches determining the amount or concentration of CA-125 (“Pretreatment serum CA-125 levels in all patients were measured using CA-125 II electro-chemiluminescence immunoassay (ECLIA)” page 58 lines 11-13). Taylor further discloses that “CA-125 values were significantly higher in endometriosis group than control but highly variable (103.3±121.7, 17.5±6.3 respectively, p<0.003)” (page 61 lines 7-8).
Giudice teaches “biomarkers for the diagnosis and prognosis of endometriosis” (Abstract). Giudice teaches that “[t]hese markers can also be used to provide a prognosis for the course of treatment in a patient with endometriosis” (paragraph 10). Giudice further teaches that “[i]t will be understood by the skilled artisan that markers may be used in combination with other markers or tests for any of the uses, e.g., prediction, diagnosis, or prognosis of fertility or endometriosis, disclosed herein” (paragraph 47). Giudice teaches in Example 1, that the biomarker “analysis was applied to investigate cycle phase-dependent differences in the eutopic endometrial gene expression signatures across the menstrual cycle of women” (paragraph 117). Therefore, Giudice teaches monitoring women suffering from endometriosis.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor and Horak to include the determination of the amount or concentration of CA-125 in a sample of the patient taught by Taylor because Taylor suggests that this is a biomarker of endometriosis. One would be motivated to make such a modification because Giudice suggests that it is obvious to a person having ordinary skill in the art to combine biomarkers for the prediction, diagnosis, or prognosis of endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success because Ovakimyan , Bokor, Taylor and Giudice teach methods for diagnosing endometriosis.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan in view of Bokor, Horak, Taylor and Giudice as applied to claim 13 above, and further in view of Yang et al. (US PGPub US 20070087386 A1) (hereinafter Yang) (Cited on PTO-892 1/16/2025).
Regarding claim 15, Ovakimyan in view of Bokor, Horak, Taylor and Giudice address the method of claim 13 as discussed above.
Ovakimyan in view of Bokor and Horak fail to teach comprising calculating a ratio of amount or concentration of Substance P and the amount or concentration of CA-125.
Taylor teaches “methods useful for the diagnosis, assessment, and characterization of endometriosis in a subject in need thereof, based upon the expression level of at least one miRNA that is associated with endometriosis” (Abstract). Taylor further teaches assessment of lower abdominal pain according to the VAS scale (“Pelvic pain intensity of the endometriosis group determined with VAS (visual analogue scale) was higher than the control group (5.4±3.4, 2.1±2.4 respectively, p<0.001)” page 61 lines 5-7). Taylor further discloses measuring miRNAs in serum of endometriosis patients and controls and finding that “[o]ut of these miRNAs 11,653 were down regulated and 10,010 were upregulated. Differentially expressed miRNAs with more than 10-fold change in their expression between the endometriosis and the control groups were selected (Figure 1)” (page 61 lines 13-18). Taylor further teaches that “the ratio of the biomarker and a reference molecule is determined to aid in the monitoring of the treatment” (page 56 lines 26-27).
Taylor suggests calculating the ratio of a biomarker of endometriosis and CA-125 (page 56, lines 26-27). However, Taylor does not explicitly teach to use CA-125 in the ratio, and there is not enough motivation to combine CA-125 into a ratio from the teachings of Ovakimyan in view of Bokor, Horak and Taylor alone.
Yang teaches “a non-invasive diagnosis method of endometriosis by detecting biochemical marker in serum or peritoneal fluid” (Abstract). Yang further teaches that CA-125 is a well-known serum biomarker of endometriosis (“In fact, in the diagnosis application of CA125, the level of CA125 in a patient's serum is measured monthly when menstrual sign begins. This helps to diagnose depth endometriosis. When the baseline level of CA125 in serum is set to be 25 U/ml, the sensitivity and specificity with respect to endometriosis are respectively 67% and 90%. Therefore, CA125 is now taken by some doctors as a help of diagnosing endometriosis” paragraph 6).
Giudice teaches “biomarkers for the diagnosis and prognosis of endometriosis” (Abstract). Giudice teaches that “[t]hese markers can also be used to provide a prognosis for the course of treatment in a patient with endometriosis” (paragraph 10). Giudice further teaches that “[i]t will be understood by the skilled artisan that markers may be used in combination with other markers or tests for any of the uses, e.g., prediction, diagnosis, or prognosis of fertility or endometriosis, disclosed herein” (paragraph 47). Giudice teaches in Example 1, that the biomarker “analysis was applied to investigate cycle phase-dependent differences in the eutopic endometrial gene expression signatures across the menstrual cycle of women” (paragraph 117). Therefore, Giudice teaches monitoring women suffering from endometriosis.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor, Horak, Taylor and Giudice to include the CA-125 limitation taught by Yang because Yang teaches it is a well-known non-invasive serum biomarker of endometriosis. One would be motivated to make such a modification because Giudice suggests that it is obvious to a person having ordinary skill in the art to combine biomarkers for the prediction, diagnosis, or prognosis of endometriosis. A person having ordinary skill in the art would be motivated to make such a modification take the ratio of Substance P and CA-125 in order to receive the expected benefit of aiding the monitoring of the treatment as taught by Taylor. A person having ordinary skill in the art would have had a reasonable expectation of success because Ovakimyan, Bokor, Taylor, Giudice and Yang teach methods of diagnosing endometriosis.
Claims 19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan in view of Bokor, Horak, Rodriguez et al. J Vet Res 62, 193-197, 2018 DOI:10.2478/jvetres-2018-0029-Cite No. U of PTO 892 10/2/2025 ("Rodriguez") and Cox et al. Immunoassay Methods. 2012 May 1 [Updated 2019 Jul 8]. In: Markossian S, Grossman A, Baskir H, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-(Cited on PTO-892 5/20/2025).
Regarding claim 19, Ovakimyan suggests a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of Substance P in a sample of the patient, wherein the measuring comprises incubating the sample of the patient with antibodies specifically binding to Substance P, comparing the measured amount or concentration to a reference, and assessing whether the patient has endometriosis or is at risk of developing endometriosis, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma (Abstract, page 4 paragraph 6). Ovakimyan further teaches a difference in blood Substance P levels in stage IV endometriosis patients compared to controls (page 7 last paragraph).
Although suggested by Ovakimyan (“enzyme immunoassay” Abstract), Ovakimyan fails to explicitly teach wherein the measuring comprises incubating the sample of the patient with a first antibody and a second antibody, each specifically binding Substance P at different epitopes, thereby generating a sandwich complex is formed comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P, wherein the second antibody is detectably labeled. Ovakimyan fails to further teach wherein endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging.
Bokor suggests a method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising determining the amount or concentration of Substance P in a sample of the patient, and comparing the determined amount or concentration to a reference (Abstract). Bokor further teaches “wherein endometriosis is stage I endometriosis according to rASRM staging and stage II endometriosis according to rASRM staging (page 3026 column 2 paragraph 2). Bokor further teaches that “[o]wing to the lack of a no- or semi-invasive diagnostic tool, the delay between onset of pain symptoms and surgically confirmed endometriosis can be as long as 8 years in the UK and USA (Hadfield et al., 1996; Sinaii et al., 2008). The current delay in diagnosis and treatment contributes to years of suffering and potential infertility if the disease is left untreated. Clearly, a simple non-invasive diagnostic method may greatly help to reduce this delay, especially for minimal–mild endometriosis which cannot be diagnosed by clinical examination or ultrasound” (page 3025, col. 2 paragraph 3, page 3026 column 1 paragraph 1).
Horak teaches “Sensitive, rapid and quantitative detection of substance P in serum samples using an integrated microfluidic immunochip” (Title). Horak further teaches incubating the sample of the patient with a first and a second antibody, each specifically binding to Substance P thereby generating a complex between the one or more antibodies and Substance P, and quantifying the complex thereby quantifying the amount of Substance P in the sample of the patient (page 187 column 2 paragraph 5 and page 188 column 1 paragraphs 1-2, See figure Fig. 1 showing a schematic). Horak further teaches wherein the binding agent is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye (page 190 col. 1para. 1, see Fig. 1). Horak further teaches that “[o]ur on- chip sensing method requires 20 times less reagent/sample volume, reduces the total assay preparation in half and performs fast detection within 10 min read-out time. Another attractive feature of this approach is the ability to use reagents and workflow developed for standard ELISA procedure” (page 190 column 2 paragraph 2).
Rodriguez teaches “[p]lasma concentration of … substance P in lame dairy cows” (Title). Rodriguez teaches measuring the amount or concentration of Substance P in a plasma sample of a patient and comparing the measured amount or concentration to a reference (“The main finding in our study is that cows with intense lameness-associated pain reflected by their mobility score (MS 3) had a higher plasma concentration of…SP” page 196 col. 1 para. 1). Rodriguez further suggests wherein a sandwich complex is formed comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P, wherein the second antibody is detectably labeled (“using a sandwich ELISA” page 194 col. 2 para. 1).
Note that although suggested by “sandwich method”, Rodriguez fails to explicitly teach a first antibody and a second antibody, each specifically binding to Substance P at different epitopes, thereby generating a sandwich complex comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P
Cox et al. teaches that “sandwich immunoassay is a method using two antibodies, which bind to different sites on the antigen or ligand (Figure 1)” (page 7 last paragraph, see Figure 1). Note that although Cox fails to use the language “at different epitopes”, the teaching of “bind to different sites on the antigen or ligand” inherently provides “at different epitopes”. Cox et al. further teaches that “Sandwich assays tend to be more sensitive and robust and therefore tend to be the most commonly used” (page 7 paragraph 6). Cox further teaches that “[t]he signal generated is proportional to the amount of target antigen present in the sample” (page 8 paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan to include wherein endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging taught by Bokor because Bokor suggests that this may help reduce the delay between pain symptom onset and treatment, which could reduce years of suffering and potential infertility for stage I and/or stage II patients. A person having ordinary skill in the art would have had a reasonable expectation of success because, both Bokor and Ovakimyan teach methods involving assessing whether a patient has endometriosis comprising measuring Substance P in a sample of endometriosis patients. Furthermore, Ovakimyan teaches that stage IV endometriosis patients had significantly higher blood Substance P levels than controls.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor to rely on the incubating the sample of the patient with a first and a second antibody, each specifically binding to Substance P thereby generating a complex between the one or more antibodies and Substance P, and quantifying the complex thereby quantifying the amount of Substance P in the sample of the patient taught by Horak because Horak teaches that this enables fast and efficient measurements. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ovakimyan and Horak teach measuring Substance P in a serum sample using immunoassays.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor and Horak to rely on a sandwich complex comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P, wherein the second antibody is detectably labeled taught by Rodriguez because Cox et al. teach that this generates sensitive and robust signals proportional to the amount of target antigen present in the sample, thereby motivating a person having ordinary skill in the art to use such technique. A person having ordinary skill in the art would have had a reasonable expectation of success because Ovakimyan, Horak, and Rodriguez teach measuring Substance P in a blood sample.
Regarding claim 21, Ovakimyan in view of Bokor, Horak, Rodriguez and Cox teach the method of claim 19 as discussed above.
Ovakimyan in view of Bokor, Horak, Rodriguez and Cox further suggests wherein the second antibody is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye (page 190 col. 1para. 1, see Fig. 1 of Horak).
Claims 22 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan in view of Bokor, Horak, Rodriguez and Cox as applied to claim 19 above, and further in view of Taylor and Giudice.
Regarding claim 22, Ovakimyan in view of Bokor, Horak, Rodriguez and Cox teach the method of claim 19 as discussed above.
Ovakimyan in view of Bokor, Horak, Rodriguez and Cox fail to teach determining the amount or concentration of CA-125 in a sample of the patient.
Taylor teaches determining the amount or concentration of CA-125 (page 58 lines 11-13). Taylor further discloses that “CA-125 values were significantly higher in endometriosis group than control but highly variable (103.3±121.7, 17.5±6.3 respectively, p<0.003)” (page 61 lines 7-8).
Giudice teaches “biomarkers for the diagnosis and prognosis of endometriosis” (Abstract). Giudice teaches that “[t]hese markers can also be used to provide a prognosis for the course of treatment in a patient with endometriosis” (paragraph 10). Giudice further teaches that “[i]t will be understood by the skilled artisan that markers may be used in combination with other markers or tests for any of the uses, e.g., prediction, diagnosis, or prognosis of fertility or endometriosis, disclosed herein” (paragraph 47). Giudice teaches in Example 1, that the biomarker “analysis was applied to investigate cycle phase-dependent differences in the eutopic endometrial gene expression signatures across the menstrual cycle of women” (paragraph 117). Therefore, Giudice teaches monitoring women suffering from endometriosis.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor, Horak, Rodriguez and Cox to include the determination of the amount or concentration of CA-125 in a sample of the patient taught by Taylor because Taylor suggests that this is a biomarker of endometriosis. One would be motivated to make such a modification because Giudice suggests that it is obvious to a person having ordinary skill in the art to combine biomarkers for the prediction, diagnosis, or prognosis of endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success because Ovakimyan , Bokor, Taylor and Giudice teach methods for diagnosing endometriosis.
Regarding claim 31, Ovakimyan in view of Bokor, Horak, Rodriguez and Cox teach the method of claim 19 as discussed above.
Ovakimyan in view of Bokor, Horak, Rodriguez and Cox fail to teach further comprising administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy.
Taylor further suggests further comprising administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy (“[o]nce 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. Pain killers used for the treatment of endometriosis include both simple analgesics, such as paracetamol, COX-2 inhibitors, aspirin, and other non-steroidal anti-inflammatory drugs well known in the art, and narcotic analgesics, such as morphine, codine, oxycodone, and others well known in the art. Hormonal treatments include, but are not limited to, oral contraceptives, progestins, such as Dydrogesterone, Medroxyprogesterone acetate, Depot medroxyprogesterone acetate, Norethisterone, Levonorgestrel, and others well known in the art, progesterone and progesterone-like substances, GnRH agonists, such as leuprorelin, buserelin, goserelin, histrelin, deslorelin, nafarelin, and triptorelin, androgens and synthetic androgens like Danazol, and aromatase inhibitors. Surgical treatments include, but are not limited to, laparoscopic surgery, hysterectomy, and oophorectomy. Other treatments particularly well suited for use in the present disclosure are well known in the art. In some embodiments, the patient can be treated using a statin, including but not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin” page 54 lines 3-20). Taylor further suggests that this enables the eradication or amelioration of endometriosis (“As used herein, the terms "treat," "ameliorate," "treatment," and "treating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but are not limited to, therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit means eradication or amelioration
of the underlying disorder being treated” page 28 lines 8-12).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ovakimyan in view of Bokor, Horak, Rodriguez and Cox to rely on the administering of a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy taught by Taylor because Taylor suggests this eradicates endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success because Taylor teaches that the treatments are well known in the art.
Claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan in view of Bokor and Horak as applied to claims 1-3 above, and further in view of Taylor.
Regarding claims 28-30, although claim 29 is indefinite (see 112b rejection above), in the interest of compact prosecution, “the drug-based therapy” and “the surgical therapy” are interpreted to be referring to a step of administering a drug-based therapy or a surgical therapy. Ovakimyan in view of Bokor and Horak teach the methods of claims 1-3 as discussed above.
Ovakimyan in view of Bokor and Horak fail to teach further comprising administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy; further comprising administering the drug-based therapy or performing the surgical therapy on the patient selected for therapy; and further comprising administering a therapy for endometriosis to the patient based on the monitoring.
Taylor suggests further comprising administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy; further comprising administering the drug-based therapy or performing the surgical therapy on the patient selected for therapy; and further comprising administering a therapy for endometriosis to the patient based on the monitoring (page 54 lines 3-20). Taylor further suggests that this enables the eradication of endometriosis (page 28 lines 8-12).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ovakimyan in view of Bokor, Horak, Rodriguez and Cox to rely on the administering of a therapy for endometriosis to the patient, or to the patient selected for therapy, or based on the monitoring, wherein the therapy is selected from the group consisting of drug-based therapy, surgical therapy, and hormonal therapy, taught by Taylor because Taylor suggests this eradicates endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success because Taylor teaches that the treatments are well known in the art.
Claims 33-34 and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Ovakimyan in view of Bokor and Horak as applied to claims 17-18 above, and further in view of Rodriguez and Cox.
Regarding claims 33 and 37, Ovakimyan in view of Bokor and Horak teach the methods of claims 17-18 as discussed above.
Ovakimyan in view of Bokor and Horak fail to teach wherein detecting comprises forming a sandwich complex comprising a first antibody to Substance P, Substance P (analyte), and a second antibody to Substance P, wherein the second antibody is detectably labeled.
Rodriguez teaches “[p]lasma concentration of … substance P in lame dairy cows” (Title). Rodriguez teaches measuring the amount or concentration of Substance P in a plasma sample of a patient and comparing the measured amount or concentration to a reference (page 196 col. 1 para. 1). Rodriguez further suggests wherein a sandwich complex is formed comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P, wherein the second antibody is detectably labeled (page 194 col. 2 para. 1).
Note that although suggested by “sandwich method”, Rodriguez fails to explicitly teach a first antibody and a second antibody, each specifically binding to Substance P at different epitopes, thereby generating a sandwich complex comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P
Cox et al. teaches that “sandwich immunoassay is a method using two antibodies, which bind to different sites on the antigen or ligand (Figure 1)” (page 7 last paragraph, see Figure 1). Note that although Cox fails to use the language “at different epitopes”, the teaching of “bind to different sites on the antigen or ligand” inherently provides “at different epitopes”. Cox et al. further teaches that “Sandwich assays tend to be more sensitive and robust and therefore tend to be the most commonly used” (page 7 paragraph 6). Cox further teaches that “[t]he signal generated is proportional to the amount of target antigen present in the sample” (page 8 paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ovakimyan in view of Bokor and Horak to rely on a sandwich complex comprising a first antibody to Substance P, Substance P (analyte) and the second antibody to Substance P, wherein the second antibody is detectably labeled taught by Rodriguez because Cox et al. teach that this generates sensitive and robust signals proportional to the amount of target antigen present in the sample, thereby motivating a person having ordinary skill in the art to use such technique. A person having ordinary skill in the art would have had a reasonable expectation of success because Ovakimyan, Horak, and Rodriguez teach measuring Substance P in a blood sample.
Regarding claims 34 and 38, Ovakimyan in view of Bokor, Horak, Rodriguez and Cox teach the method of claims 33 and 37 as discussed above.
Ovakimyan in view of Bokor, Horak, Rodriguez and Cox further suggests wherein the second antibody is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye (page 190 col. 1para. 1, see Fig. 1 of Horak).
Response to Arguments
Applicant's arguments filed 1/2/2026 have been fully considered but they are not persuasive.
Regarding the 101 rejections,
Applicant argues that “(1) determining that the patient has dysmenorrhea and/or lower abdominal pain according to a Visual Analog Scale (VAS), (2) measuring Substance P specifically in a body fluid selected from blood, serum, or plasma using a quantitative immunoassay with detectable labeling, and (3) assessing specifically Stage I or Stage II endometriosis according to rASRM staging…represents a particular, practical diagnostic protocol….generating a sandwich complex, wherein the second antibody is detectably labeled, and quantifying that complex to determine the amount of Substance P. This is not an abstract instruction to "apply" a natural correlation using any technique; it specifies an antibody-based sandwich immunoassay methodology with detectably labeled antibodies. These specific limitations transform the claims from abstract correlations into practical diagnostic methods” (page 11 paras. 2-4).
However, determining that the patient has dysmenorrhea and/or lower abdominal pain according to a Visual Analog Scale (VAS) and antibody-based sandwich immunoassay methodologies with detectably labeled antibodies are considered insignificant data gathering steps that do not integrate the judicial exceptions into a practical application (see rejection above).
Applicant further argues that “the Office's analysis conflates two distinct inquiries: whether Substance P protein could be detected in blood samples, and whether using Substance P as a diagnostic biomarker for early-stage endometriosis was routine or conventional. The Office cites Ovakimyan, Bokor, Horak, and Qiong to establish that Substance P detection was "well-understood, routine and conventional." Office Action, pp. 13-15. However, these references demonstrate only that Substance P could be measured in biological samples. They do not establish that the diagnostic application claimed here, namely using Substance P as a blood-based biomarker specifically for Stage I or Stage II endometriosis diagnosis, was routine or Conventional… The mere existence of detection tools does not render every possible diagnostic application of those tools routine or conventional” (page 12 paras. 3-4 and page 13 para. 2).
However, step 2B asks whether the additional elements beyond the judicial exception are well-understood, routine and conventional, not whether Substance P as a diagnostic biomarker for early-stage endometriosis was routine or conventional. In this case, the additional elements of the claims are all well-understood, routine and conventional.
Applicant further argues that “The assertion that blood-based Substance P detection for early-stage endometriosis was "routine and conventional" contradicts the recognized state of the art.” (page 13 para. 3).
However, the assertion made is that the additional elements beyond the judicial exception are routine and conventional, not that blood-based Substance P detection for early-stage endometriosis was routine and conventional (see rejection above).
Applicant further argues that “[t]he claims specifically target Stage I and Stage II (minimal/mild) endometriosis, where detection is particularly challenging… The prior art cited by the Office provides no guidance for overcoming these challenges… The specification demonstrates that the claimed methods achieved diagnostic results that were entirely unpredictable from the prior art… early-stage disease shows higher blood levels than advanced-stage disease… synergistic diagnostic performance… "levels of Substance P are already increased in early endometriosis rASRM stages I and II” (page 13 last paragraph and page 14 paras. 1-4).
However, the claims are rejected under 101 because the additional elements of the claims fail to add significantly more than the judicial exception for the reasons stated above (see rejection above). The fact that early-stage detection is challenging or that the specification demonstrates that the claimed methods achieved unpredictable results is not a persuasive argument regarding the 101 rejections.
Applicant further argues that “Here, the "significantly more" is not the Substance P detection step itself, but the discovery that Substance P serves as an effective blood-based biomarker for early-stage endometriosis” (page 14 last paragraph).
However, the “significantly more” analysis is directed to the additional elements beyond the judicial exceptions. Here, the correlation of blood Substance P levels and early stage endometriosis cannot add significantly more because it is the judicial exception itself, i.e. a natural correlation.
Applicant further argues that “Applicant has added new dependent claims 28-31, which recite administering therapy for endometriosis to the patient. These claims further integrate the diagnostic method into a practical application by including an affirmative treatment step” (page 15 para. 3).
However, the claims fail to integrate the judicial exceptions into a practical application because the claims fail to recite a particular treatment (see rejection above).
Regarding the 103 rejections,
Applicant argues that: “Ovakimyan studied only Stage III and Stage IV patients…A reference that provides no data on the claimed patient population cannot establish that a method for that population would have been obvious. Ovakimyan' s data on Stage III and Stage IV patients simply does not teach or suggest what blood Substance P levels would be in Stage I or Stage II patients, which is the specific limitation recited in the claims” (page 17 para. 3 and page 18 para. 1).
However, Bokor is relied upon for the limitation of Stage I or Stage II patients (see rejection above).
Applicant further argues that: “[e]ven for the late-stage disease it did study, Ovakimyan reaches internally contradictory conclusions that provide no reliable guidance for predicting early-stage behavior… "But no difference in the content of substance P between groups with different types of prevalence of ectopic foci, as well as in the level of cytokines, was found." Ovakimyan, English Translation (emphasis added). Ovakimyan further states: "In subgroups with different degrees of prevalence of endometrioid heterotopias, the content of cytokines and substance P differs significantly from the values in the comparison group, with no difference between the subgroups."… A reference that contradicts itself on the fundamental question of stage-dependent Substance P expression cannot provide a reliable basis for predicting how blood Substance P levels would behave in unstudied stages (I and II)” (page 18 paras. 2, and 4-5).
However, the fact that Ovakimyan did not find a difference in the content of Substance P between patients with different prevalence of ectopic foci or endometrioid heterotopias does not mean that there would not be a motivation and reasonable expectation of success in including patients that are stage I or stage II (see rejection above). For example, the fact that Ovakimyan found a difference in blood Substance P levels between stage IV endometriosis patients and controls provides a reasonable expectation of success in including patients that are stage I or stage II in the method (see rejection above).
Applicant further argues that: “Bokor and the claimed invention measure entirely different biological parameters using entirely different methodologies…. They measure fundamentally different biological phenomena in fundamentally different biological compartments…. A person having ordinary skill in the art (hereinafter, "PHOSITA") would understand that local tissue expression does not predict, and has no known correlation to, systemic circulating levels of the same molecule”(page 18 para. 6 and page 19 paras. 2-3).
However, although Bokor measures Substance P using immunohistochemistry in nerve fibers of the endometrium, Bokor still reliable provides the measuring of Substance P in early stage endometriosis. In this case, Ovakimyan, the primary reference, provides the measuring of Substance P in blood samples of endometriosis patients, Bokor is relied upon for its teachings regarding measuring Substance P in early stage endometriosis and motivation to measure Substance P in early stage endometriosis (see rejection above for a complete analysis). The fact that Ovakimyan found a difference in blood Substance P levels between stage IV endometriosis patients and controls provides a reasonable expectation of success in including patients that are stage I or stage II in the method. Furthermore, looking at Ovakimyan as a whole, Ovakimyan contemplates a reasonable expectation of success in measuring blood Substance P levels in stage I or II endometriosis patients.
Applicant further argues that: “The Office has not articulated a valid reason why a PHOSITA would apply Bokor's tissue-based Stage I/II findings to modify or inform Ovakimyan' s blood-based method. The Office's implicit rationale appears to be that because Bokor found elevated Substance P-positive nerve fiber density in Stage I/II endometrial tissue, a PHOSITA would have expected elevated Substance P concentration in Stage I/II blood” (page 19 para. 4). However, an obviousness analysis is set forth above, in summary, it would have been obvious to include early stage endometriosis patients in Ovakimyan’s method in order to diagnose endometriosis earlier and prevent unnecessary pain (see rejection above). Applicant further argues that “Bokor itself acknowledges this challenge: "Attempts for non-invasive diagnosis of endometriosis based on the analysis of biomarkers in peripheral blood have been limited by insufficient sensitivity and specificity." Bokor, p. 3026 (citing D'Hooghe et al., 2004; Kyama et al., 2006, 2008) (emphasis added)” (page 20 para. 2).
However, as stated in the Advisory Action (7/31/2025), “Bokor teaches that the contemporary non-invasive diagnostic tests at the time were not sensitive enough citing "(D'Hooghe et al., 2004; Kyama et al., 2006, 2008)" (page 3026 column 1 paragraph 2 of Bokor), but none of these cited references are drawn to substance P. Therefore, Bokor is not suggesting that non-invasive substance P tests are not sensitive enough” (page 5).
Applicant further argues that “[t]he Office has not established that a PHOSIT A would have had a reasonable expectation of success in using blood Substance P measurement for Stage I/II endometriosis diagnosis” (page 20 para. 4).
However, the analysis above also contemplates a reasonable expectation of success given that Ovakimyan teaches that blood Substance P levels in stage IV patients is elevated compared to controls (see rejection above).
Applicant further argues that “[g]iven the state of the prior art, a PHOSITA would have recognized multiple possible outcomes for Stage I/II blood Substance P levels, with no basis for predicting which would occur: Pattern 1 (Progressive Increase):… Pattern 2 (Threshold Effect):… Pattern 3 (Uniform Elevation):… Pattern 4 (Higher in Early Stages):… The prior art provided no basis for selecting among these possibilities…Where "the inventor is faced with 'numerous possible choices ... where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful,"' obviousness cannot be established” (page 20 paras. 5-7 and page 21 paras. 1-4).
However, the claims are not limited to choosing one of the patterns above, therefore, these arguments are not considered persuasive.
Applicant further argues that “Early-stage disease shows higher blood Substance P levels than late-stage disease…This unexpected result demonstrates the unpredictability in the art… Here, the totality of the prior art would have led a PHOSITA to predict either (a) decreasing blood levels with earlier stages, or (b) no detectable difference from controls in early stages” (page 21 paras. 5-7).
However, the claims are not limited to predicting the amount of Substance P in early stage endometriosis in relation to late stage endometriosis. Furthermore, the fact that “Early-stage disease shows higher blood Substance P levels than late-stage disease” only supports the assertion of a reasonable expectation of success in detecting Substance P levels in early endometriosis.
Applicant further argues that “[t]he Office's analysis relies on Applicant's own data to conclude that the claimed methods would have been obvious. Office Action, p. 34 (citing Applicant's Figure 3B). This is classic hindsight reconstruction prohibited by KSR and its progeny… The Office cannot use Applicant's demonstration that Stage I/II blood levels are diagnostically useful to argue it was obvious they would be.” (page 22 paras. 1, 3).
However, the obviousness analysis does not rely on the instant specification (see rejection above). Applicant cites a response to the argument filed 8/20/2025 that “[Ovakimyan] supports the hypothesis that the substance P level increases with the severity of endometriosis. This in turn reasonably means that in the early mild stages, the levels are too low to serve as a biomarker” (page 15 para. 4). Given that Applicant argued that Substance P levels are too low at early stages, the specification was cited to show that the disclosure contradicts the argument made, not to provide reasons of obviousness.
Applicant further argues that “Based solely on the prior art, a PHOSITA would have known that Ovakimyan studied only late-stage disease and reached contradictory conclusions, that Bokor measured tissue parameters rather than blood biomarkers, and that blood biomarkers generally fail for early-stage endometriosis. Looking forward from this prior art, a PHOSITA would have had no basis to predict that blood Substance P would be detectably elevated in Stage I/II patients, that Stage I/II blood levels would equal or exceed Stage III/IV levels, or that blood-based testing would succeed where prior blood biomarkers had failed” (page 22 para. 4).
However, Ovakimyan teaches throughout the reference that blood Substance P levels are elevated in endometriosis. Bokor teaches that Substance P is elevated in early stage endometriosis and motivates measuring Substance P at early stages in order to start treatment early and prevent pain. Based on these facts, a person having ordinary skill in the art would have found it obvious to measure blood Substance P levels at early stage endometriosis with a reasonable expectation of success. As stated above, although Bokor teaches a different sample type and detection technique than Ovakimyan, Bokor still measures Substance P at early stage endometriosis and Ovakimyan demonstrates that measuring Substance P in the blood of endometriosis patients is predicable. Therefore, the combination of Ovakimyan and Bokor addresses measuring Substance P in the blood of early stage endometriosis patients. See rejection above for the complete analysis.
Applicant further argues that “The Secondary References Do Not Cure the Deficiencies of the Base Combination” (page 23 para. 2).
However, there are no deficiencies in the base combination (see rejections above).
Applicant further argues that “The specification further emphasizes the "unmet medical need for a noninvasive test for the diagnosis of endometriosis, in particular for the diagnosis of early, minimal and mild endometriosis… Bokor acknowledges that "[o]wing to the lack of a no- or semi-invasive diagnostic tool, the delay between onset of pain symptoms and surgically confirmed endometriosis can be as long as 8 years in the UK and USA" Bokor, pp. 3025-3026 ( citing Hadfield et al., 1996; Sinaii et al, 2008)” (page 24 paras. 2-3).
However, the fact that the specification discloses that biomarkers of early endometriosis are a long-felt but unmet need is not a persuasive argument against the obviousness rejections set forth above. Furthermore, the fact that Bokor teaches that there is a lack of a non-invasive tool for diagnosis of early endometriosis is not sufficient evidence that combining Ovakimyan with Bokor would not have been obvious to a person having ordinary skill in the art.
The arguments are not persuasive and the 103 rejections are maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677