Diagnostic and Therapeutic Approaches for Endometriosis: A Patent Landscape

doi:10.21203/rs.3.rs-2474522/v1

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Research Article

Diagnostic and Therapeutic Approaches for Endometriosis: A Patent Landscape

https://doi.org/10.21203/rs.3.rs-2474522/v1

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Journal Publication

published 25 Aug, 2023

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Objective

The aim of this review is to analyse the patent filings and to systematize the main technological trends in patent protection for the diagnosis and therapeutics for Endometriosis. Patent literature has also been explored to find out active inventors and applicants in this field.

Methodology

Patent Search is carried in the freely accessible Patent search databases namely Patentscope using Various combinations of the key words “Endometriosis OR Adenomyosis” AND “Diagnostic OR Therapeutics”, were used along with wildcard search query in the “Title”, “Abstract” and “Descriptions” fields.

Results

Patent search revealed one hundred forty-four patents which describes invention for endometriosis diagnostic and therapeutic purposes. These patents includes twenty six patent applications in diagnostic utility, one hundred sixteen patents applications under the therapeutic approaches and forty three patent applications describes under traditional medicines for endometriosis.

Conclusion

Hormonal alteration is the most active field of invention followed by surgical interventions. Although there is a general trend of increase in patent applications has been observed but there is slight decrease in the recent years has also been observed.

Adenomyosis

Diagnostics

Endometriosis

Patent

Therapeutics

Endometriosis is a multifactorial gynaecological disease characterized by growth of endometrial-like tissue outside the uterine cavity often with chronic pelvic pain and dysuria [1]. The benign overgrowth of endometrial tissue often invades the ovaries, pelvic peritoneum, fallopian tubes and recto-vaginal septum [2]. About 6–10% of reproductive-age women suffer from this condition worldwide [3].

Genetic, environmental factors and lifestyle variables have been considered as risk factors for the condition [4]. Gene-environment interactions can also lead to conversion of benign endometrial tissues into malignant tissues which proliferates rapidly compared to normal tissue. Endometriosis has certain similarities to carcinoma, such as invasiveness, progressive growth, estrogen-dependent growth and recurrence [5].

Timely accurate etiological diagnosis is required to improve prognosis. But, due to lack of sensitive and reliable diagnostic indicators it gets delayed sometimes. Also, some of the women remains asymptomatic making diagnosis difficult. The diagnostic techniques employed are mostly imaging techniques like endometriosis laparoscopy, MRI (Magnetic resonance imaging), cystoscopy, sigmoidoscopy or colonoscopy, and ultrasound-guided fine-needle aspiration are gold-stranded methods [6] [7]. Various researchers are exploring the possibility of using genetic biomarkers for diagnosis [8]. Depending on the symptoms, the severity of the disorder, and necessity to maintain fertility, various endometriosis treatments have been described in this review [9].

At present, the condition is treated with medication, surgery or combination of both [10]. These interventions have limited efficacy with numerous side effects. Further, prolonged drug use may increase the risk of inflammation, menstrual cycle disturbances, unusual bleeding, nausea, heavy weight, and osteoporosis, breast soreness, trouble sleeping and depressed mood [11] [12]. If the endometrial lesions are not completely removed after surgery, pain may return along with urological, gastro, vascular, and neurological problems [13]. Traditional herbal medicine including natural plant extract(s) [14] and dietary intervention with supplements such as vitamins D, C and E, a few Probiotics, Zn, Mg, are believed to aid in the treatment. Despite it a well-designed randomized controlled trials is desired to accurately determine the effectiveness and safety [15] [16].

Patent Search was carried in the freely accessible Patent search databases namely Patentscope, which has records from almost all the World Intellectual Property Organization (WIPO) member countries. In order to ensure that that none of the important patent is missed, search was repeated in the country specific databases, USPTO for US filed patents, Espacenet for European countries patents along with some other countries and inPASS for Indian patents. Various combinations of the key words “Endometriosis OR Adenomyosis” AND “Diagnostic OR Therapeutics”, were used along with wildcard search query in the “Title”, “Abstract” and “Descriptions” fields. To make search more specific, patent applications were screened using few filters and irrelevant patents applications were excluded. Information about title, applicant, inventor, IPC code and year of publication was extracted from each patent application.

3.1. Patent analysis:

Using selected keywords and after applying suitable filters one hundred forty four patents had been shortlisted. The applications were further analysed to classify them into three categories namely diagnostics, therapeutics, and both. The diagnostic and therapeutic patent applications were further sub-classified into various sub-categories based on their usage and mode of action (Figure: 2 a,b).

In general, there is an upward trend in number of patent applications being filed which seems to slow down in recent years (Fig. 3a). Abbvie INC7 is the most active applicant in this field (Fig. 3b). Most of the patent applications belong to A61K and A61P category as per IPC. In the subsequent subsections, the patents have been discussed under various sub-categories based on their applications.

3.2. Diagnostic agents

Twenty six patent applications which describe inventions of diagnostic utility for endometriosis have been classified into various sub-categories on the basis of their detection using different methods/techniques. These techniques include use of biomarkers (genetic markers, serum markers, and other biological markers); physical examination of both endometrial tissue and out-growth using different hysteroscopic techniques like laparoscopy, MRI, Ultra-sonography and biopsy, and myomectomy.

3.2.1. Biomarkers for the diagnosis of Endometriosis

I. Genetic markers

Genetic markers play a crucial role in the diagnosis of endometriosis. Nine patent applications describes usage of genetic marker for the prediction of endometriosis. The patent application numbers WO2020234280 and WO2019106034 claim for high expression of ESR, CXCL12, and CXCR4 genes that indicates the presence of endometriosis [17][18]. CN113736875 patent claims that expression of some miRNAs such as miR-22-3p, miR-182-5p, and miR-103a-3p is associated with endometriosis [19]. Detection of GPR30 mRNA in a sample of a suspected patient is described in patent application KR1020180083178 [20]. RU0002730952, and CN113186311 are the patent application which are claiming for the detection of CA125 as a biomarker for the diagnosis in unsuspected patient [21]. Also, the RU0002677866 patent describes that usage of Single nucleotide polymorphisms (SNPs) rs2241423, rs7766109, rs4953655, and rs9939609, for evaluation as genetic risk-associated variations for endometriosis [22]. RU0002766750 patent application describes PAI1-675 5G/4G, MTHFR C677T, MTRR A66G, NOS3 C-786T associated genetic polymorphisms. Alongwith these around 40 nucleotide sequence has been claimed under patent application WO2018049946 for disease prediction.

II. Serum markers

Serum markers can play an excellent role in the prediction of diseases. For examples include description of serum ezrin, phospho-ezrin, and their combination in the sample protein given in the patent number KR1020170068169. The RU0002676035 patent application has claimed that the level of serum interleukin-6 (IL-6) and alpha-2-glycoprotein (ABG) are being associated with endometriosis [23][24]. Also, RU0002676050 patent application has considered that increase in the level of IL-6 can be helpful in the detection of endometriosis.

III. Other Biological markers

Some biological sample reveals that few micro-organisms are found at the site of infection, which might be suspected to be associated with endometriosis. As given in the patent application number CN113186311, the biological biomarkers “Clostridium disporicum” and “Lactobacillus reuteri” are micro-organisms found in the endometrial tissues of affected women [25].

3.2.2. Devices or Methods of Physical examination of Endometriosis

The physical examination is an easiest method for the detection of endometriosis. Several methods come under the physical examination; such as Laparoscopy, MRI, Biopsy, hysterectomy and myectomy. In physical examination the clinician figures out the abnormality of the pelvic-peritoneal region using given techniques as per the type of infection.

3.2.3. Laparoscopy

Currently laparoscopy is a gold-stranded method for the diagnosis of endometriosis. This is a preferred approach for observing endometriosis lesions under magnification both inside and outside the pelvis [26]. The condition may have multiple appearance, and the red, black and white lesions on the various region of pelvis which may turn out to be non-endometriotic lesions in certain cases, thus making the confirmatory tests essential to avoid unnecessary medication [27]. Patent applications CN212679168 and RU0002775664 describes a laparoscopic instrument/technique for accurate result.

3.2.4. MRI (Magnetic Resonance Imaging) and Ultra-sonography

Magnetic resonance imaging (MRI) and Ultra-sonography are another methods being used for the detection of endometriosis [28]. Patent application RU0002618923 and RU0002757755 describes a modification of MRI method in which the maximum thickness of the connective zone between the endometrium, myometrium and Endometriosis can be identified by measuring blood flow characteristics in uterine tissue in uterine myomas. RU0002764106, RU0002437615 and IN201741019461 are the patent applications which are dealing with the use of A-focused (HIFU) high intensity focused ultrasound instrumentation, for detection of destruction, loss of villi, shed down mucus membrane, Homogeneity and echogenicity using 2D and 3D mode examination using the ultra-sonographic technique [29]. In hysteroscopy the uterine cavity is examined [30], and suspicious adenomyosis sections of the mucosa are marked. Oxytocin is introduced into the cervix in the presence of adenomas, dark colour blood begins to flow from endometriosis suspicious area as a better inspect for endometriosis as mentioned under the application SU01398871.

3.2.5. Biopsy

The technique of taking tissue samples from the suspected endometrial region is also give excellent output as a results for diagnosis. CN111397943, CN111317564, CN212281620, and US20210321993 are mentioned with a microwave ablation needle used to ablate endometrial tissue to take the samples for the site of infection. Also, there is another method use to take samples from the endometrial lesions using a specific mounting rod highly focused device claim in patent application CN109700546.

3.2.6. Myomectomy

A patent application RU0002711297 has claimed for the S.N.A.L.T.A. uterotomy score scale that has been designed for the detection of nodule size tissue sample in case of endometriosis gives an accurate result of presence of endometriosis in suspected women.

3.3. Therapeutic agents

The patent applications that we have retrieved in our landscape study includes One hundred sixteen patents applications under the therapeutic approaches for endometriosis. These therapeutic agents have sub-divided into 5 different classes; these classes include hormonal therapies [13], neutralizing antibodies and pathway blockers [31], biotechnological instruments [32], Surgical & radiolabel treatment [33] and the vastest one is traditional chinese medicines [34] which includes forty three patent applications out of one hundred sixteen. Hormonal therapies have further sub-classified on basis of different hormones like GnRH (gonadotrophin releasing hormone) agonists & antagonists, progesterone & progestin antagonists, estrogen antagonists, interleukin antagonists, chymase inhibitors and erythropoietin antagonists [35] [36] [37].

3.3.1. Hormonal therapies

The objective of using hormonal therapy for endometriosis is to prevent menstruation by disrupting the hypothalamus-pituitary-ovary pathway or by producing pseudo-decidualization and amenorrhea, which inhibits the proliferation of endometriotic implants [13]. In case of women suffering from endometriosis, hormone medications are recommended as the first line of therapy to reduce symptoms, delay surgery, or minimize post-surgical disease recurrence [38].

3.3.1.1. GnRH agonists and Antagonists

Modern therapeutic methods are GnRH agonists & antagonists, which are used to reduce ovarian activity in case of endometriosis [35] [39]. GnRH antagonists influence the pituitary-ovarian function, GnRH agonists and antagonists are well known therapeutic which are comparatively rapid against endometriosis [40]. Agonist of GnRH acts on the cellular membranes of the gonadotrophic cell, while GnRH antagonists completely block the GnRH receptors causing down-regulation, de-sensitization and causing more of side effects. A study had been conducted by kupker et.al, on patients confirmed symptoms free periods during use of GnRH antagonists these symptoms were loss of vaginal dryness, hot flashes, mood swings etc [41]. Agonists and antagonists are comprising of some pharmaceutical compounds, like N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N’-methoxyurea from 10 mg to 60 mg per day alone is delivered effectively in endometrial tissues. A p-glycoprotein inhibitor and a CYP3A (cytochrome3A) inhibitor study is given under the patent applications WO2018060501 and WO2022101303 which is playing a crucial role in the treatment of endometriosis. 3-[2-fluoro-5-(2,3-difluoro-6-methoxy-benzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]pyrimidine-5-carboxylic acid is another GnRH antagonists in patent application WO2020089190, that control the high menstrual bleeding in endometriosis. Elagolix, another GnRH antagonists along co-administration of a CYP2B6 substrate (e.g., bupropion) or a CYP2C19 substrate (e.g., omeprazole) or a CYP3A4 substrate (e.g., ethinyl estradiol and/or levonorgestrel) has claimed as a therapeutic agent for endometriosis in patent application US20210275527, WO2022165097 and US20220257597. NZ580457, WO2019036713, WO2019036712 and WO2020028630 patent applications claim for 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridine-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxyl-butyric acid, that is used as a GnRH antagonists to control the menstrual cycle by regulation of LH and FSH hormones. Benzo (4, 5) thieno (2, 3-d) pyrimidine − 4-one compounds also play an excellent role to control the menstrual bleeding. There are some derivatives compounds like 5,6-dihydro and 5, 6, 7, 8-tetrahydro used to inhibits 17-hydroxysteroid dehydrogenase enzymes (WO2005032527) compounds are used as a GnRH antagonist. Patent application RU0002694901 deals with the administration of goserelin acetate into the uterus for treatment of endometriosis. R-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-1-yl)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione as compound B given in US20190054088 claims for the treatment of endometriosis. RU02406497 a patent application claims for the 3,3’-diindolylmethane and epigallocatechine-3-gallate which are useful for estradiol conversion into two forms-2-HE1 and 16α-conditioner that act as endometriosis treatment methods.

3.3.1.2. Progesterone or Progestin antagonists

Progestins often treat patients for a long term and it has numerous sites of their action. Progesterone is a steroid hormone that is primarily produced by the placenta, adrenal glands, and ovaries. The Progesterone which is secreted from the corpus luteum followed ovulation. As a synthetic mimics, progestins promote the activities of progesterone. This takes into account of their profile and degree of involvement on the anterior pituitary axis, metabolic functions, mammary glands, and genitalia. Progestins restrict the endometrium's ability to proliferate throughout the menstrual cycle [37]. The endometrium then enters the secretory phase, when the tissue re-modelling is stimulated until pregnancy or periodic shedding occurs. IN7561/DELNP/2009 and TN2006000070 are patent applications that are dealing with the transvaginal, and open surgical delivery of progestogen, including a laparotomy. NZ612295 patent claims for 19-norpregna-4,9-diene-3,20-dione compound used as a progesterone antagonist in the treatment of endometriosis. “Diene” used as inhibitor of progesterone in endometriosis claimed under the RU0002715097 patent application. US20150044291 deals with different anti-Progesterone such as desogestrel, etonogestrel, gestodene, levonorgestrel, medroxyprogesterone, norgestimate, and norgestrel, when these are taken per lesion for endometriosis they show comparative effect on it. [42]. RU0002428974 application of invention makes it possible to extend the arsenal of medications for treatment of endometriosis due to obtaining novel transport nano-form of trans-resveratrol. An oral dose of the progestogen; levonorgestrel equivalent to 3-500 mg, and either 5-250 mg of dehydroepiandrosterone, or 1 to 50 mg of undecanoate testosterone is regarded as a progestogen and androgen combination given in WO2003041741. The use of ulipristal acetate, or any metabolite selected from the group comprising CDB-3877, CDB-3963, CDB-3236, and CDB-4183, in the manufacture of a medicine for normalizing menstrual bleeding in endometriosis given in patent application NZ619478. The KR1020130009990 patent application has given with aziridinyl, azirinyl, azetidinyl, pyrrolidinyl, ethoxypyrrolidinyl, methoxypyrrolidinyl, piperidinyl as progesterone antagonists. Pyrazolyl-4-oxy-benzonitrile or 4-cyanophenyloxypyrazole compounds are also used to suppress the progesterone level in endometrial tissues given under the patent US20080096950. Benzaldehyde, 4-[(11β, 17β)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4,9-dien-11-yl]-, 1-oxim has taken as progesterone receptor modulator claims under US20060241125. Norethisterone and Dienogest are two common progesterone antagonists used for the treatment of endometriosis [43]. WO2006111856 also a Progestron antagonism claiming patent application which contain few five member ring structures for the treatment of endometriosis. WO2020161739 Found a patent application which disclosing the new method for progesterone antagonism using Norethisterone, Dienogest control the C-125 receptor for treatment.

3.3.1.3. Estrogen antagonists

The main factors that lead to the ectopic implant of endometrial cells are estrogen dependency and progesterone resistance, which inhibit apoptosis and promote oxidative stress, inflammation, and neuro-angiogenesis alternatively [36]. WO2018212256 and WO2017010515 patent applications deal with tamoxifen as an estrogen receptor α inhibiting β partial agonist which replaces the un-regulated estrogen. A 3-substituted mono-D-homo-1,3,5 (10) -estratriene compound has mentioned in WO1998011124 as an estrone sulfatase inhibitor used in the regulation of estrogen. Aromatase inhibitors, cyclo-oxygenase 2 inhibitors, and 17 ß-hydroxysteroid dehydrogenase type 1 blockers make up the selective estrogen enzyme modulator (SEEM) as reported under the WO2003017973 patent application [44]. WO2003017974 patent application deal with the administration of ethinyl estradiol as anti-estrogen compound meant for treatment of endometriosis. 3,3'-diindolylmethane and epigallocatechine-3-gallate estradiol can be converted into two forms such as 2-HE1 and 16α-conditioner, the formation of which is catalyzed by different cytochrome P450 isoenzymes useful in treatment of endometriosis. RU0002465912 dealing with the epigallocatechine-3-gallate that has taken as blocker of co-polymer of oxyethylene and oxypropylene used in treatment of endometrial lesions. WO2010052625 patent application dealing with prostaglandin antagonists compound pyrrolidine compounds which control the expulsion of menstrual lining to stop the accumulation of endometrial tissue in the abdominal cavity which later give rise to endometriosis. Medicine controls the moderate expression of Ki-67, moderate or high expression of progesterone receptors, moderate or high expression of vimentin receptors, moderate or high expression of collagen receptors, and presence of vascular anastomoses between uterus and ovaries that has been mentioned under RU0002718267 patent application which is useful to stop high menstrual bleeding in the suffering women.

3.3.1.4. Interleukin antagonists

Increased cytokine levels have been observed in the peritoneal fluid of endometrial hyperplasia women, Because the peritoneal environment may be controlled by locally regulated variables, cytokines are thought to play a part in the beginning and progression of endometriosis. Cytokines and endometriosis may be associated through a pathogenic mechanism [45]. So, to target the signaling pathways and cytokines of the IL-1 family can provide with the endometriosis therapeutic targets [46]. RU0002766112 has given anti-IL-8 antibody inhibits the inflammation of the endometrial tissue .WO2019045075 given as Inteleukin-33 antagonist that suppresses the expression of interleukin to prevent inflammation of pelvic region. CN107029232 dealing with IL-22 antibody which use to inhibit the expression of IL-22 to stop inflammation.

Some androgen receptor target agents (ARTA), selective androgen receptor modulators (SARM), has found under patent application CN1646479 are useful for the treatment of endometriosis.

3.3.1.5. Chymase inhibitors

Chymase causes the breakdown of focal adhesions as well as the destruction of extracellular matrix proteins such fibronectin, procollagen, and vitronectin. Transforming growth factor beta is activated and released from its inactive state as a result of chymase. Transforming growth factor beta is a key player in the development of peritoneal adhesions as well as in endometriosis [47]. WO2018114514 patent application consist of cyclically-substituted uracil derivatives as chymase inhibitor in mast cell to restrict the chronic inflammation in patients. CN1837169 patent application claims for a 1,2,3-trihydroxy benzene and its derivatives or pharmaceutically acceptable salts for zinc ion metal-protease in inhibition of MMP glycoproteins that are used as therapeutic agent.

3.3.1.6. Erythropoietin antagonists

Erythropoietin (EPO) is a crucial molecular regulator of the activation, proliferation, and differentiation of cells of the erythroid lineage, which participates in estrogen-dependent angiogenesis which helps in the growth of endometriosis [48]. Erythropoietin mimetic peptide (EMP) contains a low-molecular peptide which has an erythropoietin receptor antagonism. Therapeutic agent containing a peptide an amino acid sequence similar to a partial sequence of erythropoietin is used for the endometriosis, it has claimed under the patent application JP2017025022.

3.3.1.7. Neutralising antibody & pathway blockers

We have observed that use of Apelin-36 & Apelin-17 antibodies are mentioned in WO2019040390 patent application. Apelin-neutralizing monoclonal antibody (mAb) can specifically bind to apelin and block its biological activity on cells that express the apelin receptor APJ in endometrial cells [31]. Antigen-binding fragments, the neutralizing prolactin receptor antibody 002-H08 (WO2011069797), and mammary epithelial cell growth inhibitors all prevent prolactin receptor-mediated signaling. Patent application WO2011069794 deals with the blocking of prolactin receptor-mediated signaling. A mTOR inhibitor including temsirolimus, rapamycin, everolimus and ridaforolimus when used along hormonal contraceptive control the inflammation of endometriosis mentioned in US20170095456 [49]. Endometriosis therapy with an antibody or antigen-binding fragment that blocks prolactin receptor (PRLR)-mediated signaling has also been reported under the patent application WO2011069798.

3.3.1.8. Biotechnological instruments

An assistant device used in a HIFU treatment method. Especially this invention relates to the assistant device used for changing uterus location in case of endometriosis. This method has given under patent application KR1020140069474, While CN215024998 patent application has mentioned about a intrauterine drug releasing instrument for the precise reach up to a particular tissue in endometriosis lesions.

3.3.1.9. Surgical tools & Radiolabel treatment

Endometriosis is a progressive condition which can result in the physiological loss of the reproductive organs and a surgical treatment is required for the long-term effect of treatment. RU0002661701 include an Invention relates to gynaecology and vascular surgery, that can be used for laparoscopic treatment of endometriosis. Under the patent number WO2007027392, a non-invasive uterine artery occlusion device reduces blood flow by occluding uterine arteries. Metroplasty in females has been used as another aspects for treatment of diffuse hyper-nodular endometriosis. RU0002692732 has given a specific surgical method to remove the endometrial lesions from the uterine body in which operation is carried out through a small transverse supra-pubic incision. SU01521455 dealing with a highly accurate hysterectomy in which patient is injected with a solution of double-substituted sodium phosphate P32 with activity of 180–220 µk, then after 23–24 hours a radioisotope study will be performed finally hysterectomy is performed. Laparoscopic treatment of endometriosis has been carried under the patent application RU02217086 which describe the peculiar case, one should tighten internal iliac arteries at mini laparotomy and one should clip internal iliac arteries through laparoscopic access for the surgical procedure. RU02243009 is taken as radiolabel therapeutic patent which deals with the polychromatic linearly polarized noncoherent light of wavelength 400 − 200 nm for treatment of endometriosis. A levonorgestrel intrauterine contraceptive ring has been described under patent application CN214342878 for treating endometrial lesions. CN215536068 patent application has mentioned about a surgical nursing device comprises a shell, a liquid storage tank is formed in the left end of an inner cavity has been used for the surgical procedure to remove the endometriosis tissues. Some digging knives, in particular to a digging knife structure based on endometriosis, which comprises a fixed rod, an excision mechanism is mounted on the fixed rod, given under CN114469271 used for the endometriosis treatment. Also, patent application CN113143423 claims for a bead string guide piece which is a uterine implantation device for protection of uterus while surgery. CN216394214 patent application claims for a diffuse endometriosis uterus protection U operation arch-shaped cutter that relates to medical instrument prepared for the endometriosis treatment, while one patent describe about the use of scalpel comprises a scalpel handle and a scalpel blade, the outer side of both the scalpel handle and the scalpel blade are coated with a corrosion-resistant layer. Each corrosion-resistant layer comprises an aluminium oxide ceramic coating and a glass fiber reinforced plastic resin coating along anti-bacterial layer specific for the surgical sectioning of endometriosis tissues, is disclosed under patent application CN215534836.

3.3.1.10. Specific pharmaceutical compounds

N-[3-aminocarbonyl-1-(tetrahydro-2-H-pyran-4-yl)-1-H-pyrazole-4-yl]-2-(2-methyl-4-pyridinyl)-4-oxazole carboxamide hydrochloride has taken as pharmaceutical compound from patent application JP2019043949 play a role as a MyD88-IRAK4 signal transduction pathway inhibitor [46]. Uripriori (CDB − 22914), for e.g., monodemethylated CDB 2914 (CDB − 3877), dide-methylated CDB 2914 (CDB − 3963), 17 alpha-hydroxy CDB 2914 (CDB − 336), CDB − 22914 (CDB − 4183) metabolites drug formulation methods are useful in reducing or stopping pain and bleeding in case of endometriosis disclosed in JP2016175943 patent application [50]. Pyrroloquinoline quinone (PQQ) and its derivatives, used as a therapeutic agents given under WO2016173435. 3-ethyl pyridine, 3-methylpyridine, 2-ethyl pyridine and 2-methylpyridine are some pharmaceutical derivatives dealing with endometriosis given under application WO2006098371. WO2016097013 has Pyridyl-cycloalkyl-carboxylic acids useful as inhibitors of phosphodiesterase 4 (PDE4). Epigallocatechin-3-gallate (EGCG) a pharmaceutical compound delivered peroral into the endometrial lesions given in patent US20140235708 [51][52]. Cyclopenta-hydrophenanthrene mifepristone tibolone are few pharmaceutical compounds which helps in the inhibition of endometrial tissue growth (WO2009037704). Patent application WO2017203012 claims for (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione a pharmaceutical compound as therapeutics for endometriosis. WO2001002349 is dealing with phenyl sulfamate, that shows a Steroid sulfatase inhibitory activity and act as therapeutic agents for endometriosis [53]. Danazol and a prostaglandin production inhibitor (JP2003221338) are play role as aromatase inhibitor [54] [55]. Admistration of a dienogest and levonorgestrel in uterus with a slow release system used as a treatment for endometriosis mention in patent application CN111686115 [56]. US20160250234 Anther patent application dealing with Sorafenib, Metacycline, Diphenyl difluoroketone, Resveratrol, Curcumin, and Emodin as Epithelial-to-mesenchymal transition altering compound for the treatment of endometriosis.

3.4. Traditional medicines

The most reliable sources for the development of novel pharmaceuticals are believed to be traditional medicines for Several reproductive disorders, especially endometriosis, which have been treated with a variety of therapeutic herbs and metabolites derived from plants. Many gynaecologic disorders’ symptoms now are frequently remedied using medicinal herbs and traditional medicines [57]. As we have seen natural products are less side-effective but more curative. Anti-proliferative, antioxidant, and anti-inflammatory properties have been found in medicinal plants products and their active ingredients. These qualities may assist in the treatment of endometriosis [58] [59]. In this patent analysis, we have retrieved forty three patent applications for traditional herbal products. All these patent applications are belonging to a specific country, the majority of the traditional medicine and herbal products in the field of therapeutic approaches for endometriosis has owned by China and these applications are increasing every-year. All the herbal products and medicines prepared from the plant extracts have been patented by the Chinese assignees in the traditional Chinese medicine category. These traditional plant medicine applications have been patented mainly under two major IPC (International Patent Classification) A61B and C12Q. All these patent applications has no patent family, as we can see in our observed data that each patent has been considered as a single patent application under a standard IPC classification.

These traditional Chinese medicines are required to take a certain amount for effective results. Several pharmaceutical compounds have been mentioned as traditional therapeutics that contain some raw material such as peach kernel, rhizoma sparganii, rhizoma curcumae, rhizoma corydalis, curcuma zedoaria, cortex moutan, thallus laminariae, poria cocos and prunella vulgaris in patent applications CN104740536, CN101011563 and CN109045205 for the preparation of these unique medicines. Anorectal medication administration, also known as Chinese herbal hydrotherapy, which is a way of treating certain disorders that entails seeping Chinese natural herbs into the vagina and having left it for a few hours to permit the Chinese herbal medications to swallow into the intestinal mucosa. Patent application CN105920260 deals with the Lotus pod, rodgersflower rhizome, ramie leaf, hang rock wind, Artemisia anomala, excrementum pteropi, three Blue or green leaf, wilson passionflower herb, Auricularia on Weigelae, Euonymus euscaphis Hand Mazz and thunder slender acanthopanax used as a raw material for treatment of endometriosis. Also, there are some specific composition of a traditional medicine using transferrin, iron oxide black and beta-cyclodextrin meant for treatment of the endometriosis (CN113559221). Patent applications CN101020030 and CN109674903, deal with snow lotus, cnidium fruit, broom cypress, flavescent sophora root, tuckahoe, herba boschniakia rossica, lucid ganoderma, alumen, wild ginseng, semen persicae, and saffron for treatment of endometriosis. Earthworm, dried ginger, dried fennel, fructus aurantii, corydalis tuber, radix paeoniae rufa, astragalus membranaceus, flos carthami, fructus aurantii, fennel, dried radix paeoniae rufa, trogopterus dung, cortex moutan, lindera aggregata, rhizome cyperi, Szechwan chinaberry fruit, pollen typhae, scorpion, rhizome sparganii, Cinnamomum cassia\ curcuma zedoary, cassia twig, resina draconis, pangolin and spina gleditsiae as the raw medicines are claims under CN1712047, CN105456974, CN111568989, CN112870325, CN101104007 and CN108567931 for the treatment of endometriosis. Traditional chinese medicine composite as Chinese angelica, herba leonuri, fried cattail pollen, rhizoma chuanxiong, trogopterus dung, radix paeoniae rubra, cassia twig, bighead atractylodes rhizome, poria cocos, peach kernels, and flos cartham; Used for treatment of endometriosis has given under CN106902193, patent applications. Medicine enema is prepared with raw materials herba patriniae, herba epimedii, rhizoma sparganic, flos carthami, honeysuckle stem, angelica sinensis, herba leonuri, soapberry, folium artemisiae argyi, rhizoma corydalis, caulis sargentodoxae, red peony root, dragon's blood, notoginseng, tangerine seed, campsis grandiflora, rhizoma cyperi, ligusticum wallichii, caulis spatholobi, peach kernels, dipsacus asperoids, salviae miltiorrhizae achyranthes bidentata and loranthus parasiticus each required 10–20 parts as a stranded quantity for treatment claims in CN104667074, CN112957447 and CN1133734 patent application. Similarly, Traditional medicine composition of “cassia twigs, herb of Tuberculate speranskia, Rhizoma sparganii, Rhizoma curcumae, Folium artemisiae argyi, Dahurian angelica roots, Sappan wood, fennel, clove, fructus aurantii, leech and Myrrh” has used for the preaparation of therapeutic medicine (CN105497705, CN105456909). Also, “Chinese angelica, motherwort herbs, fried cattail pollen, Sichuan lovage rhizome, flying squirrels droppings, red peony roots, cassia twigs, large head atractylodes rhizome, Indian bread, peach kernels and red flowers” water has suspected as medicinal role in CN1927359, and CN102861185. Patent application CN101015504 deals with the administration of oxirane, pingyangmycin with saline using aspetic gelatin sponge and syringe in the uterus give suppository source to the women. In patent applications CN1911422, and CN104208227, Semen cuscutae, dried human placenta, Radix Angelicae Sinensis, Ligusticum wallichii, corydalis tuber, placenta hominis, ligusticum wallichii, Chinese herbaceous peony, salvia miltiorrhiza, turmeric, Ramulus euonymi used for the preparation of medicine. Patent applications CN112826914, CN112755136, CN109925495, CN108671125, and CN108567838 claims for peach kernels, safflower, galangal, angelica Sinensis, cinnamon, fennel, dried ginger, astragalus mongholicus, citron, fingered citron, purple perilla, and orange peel raw material used as therapeutic agents as a raw material used in the treatment of endometriosis [14]. Cassia twig and Poria cocos pills are used for pill preparation patented in CN111624269. Soybean and lotus stamen are used as raw materials in CN101569662 for the preparation of endometriosis. The active component in the treatment of endometriosis is andrographolide as mentioned in CN103520152 patent application. CN105816762, CN106975065 and CN112957422 are the patent application which claims for the radix ginseng rubra, trogopterus dung, radix notoginseng, tubers of scirpus planiculmis, rhizoma polygoni paleacei, Cantonese speranskia herba houttuyniae, root of red-rooted salvia and rhizoma smilacis glabrae, which are used for the preparation of an effective medicine for endometriosis. Patent application CN106138372 and CN108888647 has mentioned some specific plants extract such as fiber crops, owe quintessence oil, endothelium corneum gigeriae galli, kelp, deerblood, gynura procumbens, and ginseng play effective role in the treatment of endometriosis. Rhizoma Pinelliaes as main supplement claims under CN103893449 and CN107335009 deal with Rhizoma polygonati with yellow rice wine and Rhizoma curcumae rhizoma cyperi for endometriosis treatment. Also, CN114452368, CN107496826, CN103536843 and CN105944033 are patent application which is dealing with the few radix aconiti lateralis preparata, fructus evodiae, rhizoma zingiberis, cortex cinnamomi, flos carthami, rhizoma curcumae processed with vinegar, rhizoma sparganii processed with vinegar, banksia rose, Ramulus euonymi, salvia flava, red stalk grass, rhizoma corydalis processed with vinegar, radix angelicae sinensis, radix paeoniae alba, radix rehmanniae preparata, radix astragali preparata, poria cocos, rhizoma atractylodis macrocephalae, semen coicis, semen plantaginis, fried pollen typhae, charred pollen typhae and radix glycyrrhizae preparata for the preaparation of a traditional medicine. Nature provides a tremendous resource for the identification of novel therapeutic chemicals for the treatment of severely debilitating disorders with the least side-effects because of the enormous structural and biological variability of natural products. Combining therapies is the best course of action for endometriosis. In terms of downstaging and symptom reduction (disease-free duration), combination therapy appears to have a better advantage when these therapeutic approaches are compared.

3.5. Combined Patent applications for Diagnostic and therapeutic Patent applications

There are certain inventions which can be utilized both for diagnostic and therapeutic purposes. In the current patent analysis, two patent application fall under this category. WO2001032920 patent application disclose the invention relates to the discovery of genes and their products that are associated with the disease endometriosis. It has been discovered that cathepsin D, AEBP-1, stromelysin-3, cystatin B, protease inhibitor 1, sFRP4, gelsolin, IGFBP-3, dual specificity phosphatase 1, PAEP, immunoglobulin chain, ferritin, complement component 3, pro-alpha-1 type III collagen, proline 4-hydroxylase, alpha-2 type I collagen, claudin-4, melanoma adhesion protein, procollagen C-endopeptidase enhancer, nascent-polypeptide-associated complex alpha polypeptide, elongation factor 1 alpha, vitamin D3 25 hydroxylase, CSRP-1, steroidogenic acute regulatory protein, apolipoprotein E, transcobalamin II, prosaposin, early growth response 1 (EGR1), ribosomal protein S6, adenosine deaminase RNA-specific protein, RAD21, guanine nucleotide binding protein beta polypeptide 2-like 1 (RACK1) and podocalyxin are all implicated in this disease. Also, EP1767632 patent applications deals with the nucleic acid molecules, including dsRNA, siRNA, antisense, 2,5-A chimeras, aptamers, and enzymatic nucleic acid molecules, such as hammerhead ribozymes, DNAzymes, and allozymes for the diagnosis and treatment of endometriosis.

Although endometriosis affects a large number of women globally, there are few and perhaps insufficient therapies available. In this special feature, we examine what the most recent research has to say about the most promising future directions for the treatment of endometriosis. A personalised strategy aiming to reduce suffering, stress, stress-related pathologies and enhance quality of life should be adopted for an optimal care based on the patient's symptom [60] [61]. A non-invasive endometriosis diagnosis is helpful for research as well as the healthcare system as it enables the construction of population-scale epidemiological studies that show the specific prevalence of the condition and potential ethnic differences among others [62]. Medical assistance is based on the fact that endometriosis is dependent on a woman's cyclical production of hormones during her menstrual cycle. Gonadotropin-releasing hormone agonists, progestins, oral contraceptives, and androgens are presently advised medications. Each of them prevents the reproductive hormones' regular cyclical production. Through use of aromatase inhibitors for resistant or recurrent endometriosis is supported by certain studies [63]. Today's treatments include both medicinal and surgical procedures. Painkillers and hormone therapies are the foundation of medical therapy. The most successful medications for the treatment of endometriosis are hormone therapies because they target the pathological pathways that cause the disorder. The proliferation or activity of endometriotic implants is restricted by the blockage of menstruation. Modern endometriosis management comprises a patient-centred strategy that focuses to overall wellbeing despite taking stress, quality of life, and systemic problems into considerations. Non-coding RNAs may regulate the expression of genes linked to endometriosis by acting with pathways, acting as a molecular sponge for miRNAs, or by specifically targeting regulatory areas through associations with chromatin or transcription factors, according to mechanistic studies. Future research should focus on figuring out the significance of non - coding RNAs linked to the disorder through in vitro and animal model studies, as well as the importance of uncharacterized non - coding RNAs discovered by endometriosis transcriptome investigations [64]. Knowing the fundamental etiology of the condition can help with diagnosis and treatment, as well as the identification of endometriosis risk factors and the creation of preventative measures. Research funding should be increased for advance scientific awareness of endometriosis as a chronically benign gynaecologic disorder among the women. So new researches could be conducted to improve the women health.

This landscape study reflects the current diagnostic and therapeutic approaches for endometriosis with considerable improvements. Several biomarkers and physically examination techniques have found to be effective and coming up with accurate results for the diagnosis. Along with the diagnosis of endometriosis therapeutic approaches are also getting advanced with time as we have observed in our searched data. There are not only the hormonal therapies but also the other pharmaceutical compounds which play role as agonists, antagonists, inhibitors and pathway blockers, are excellent ways for the treatment. Along with these therapeutic methods, there is another aspect called traditional chinese medicines which also play an excellent role in the treatment of endometriosis. Also, in current literature it has been found that advanced technologies which are working as a genetic alternation methods are upcoming in future.

Compliance with Ethical Standards

The manuscript complies with ethical standards. The study does not involve human samples

Funding

“The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.”

Competing Interests

“The authors have no relevant financial or non-financial interests to disclose.”

Author Contribution

Singh M: Data collection and analysis, draft writing

Jassal R: Data collection and analysis, draft writing

Khetarpal P: Conceptualisation, supervision and manuscript checking and finalization

Declaration of Interest form

There are no relevant financial or non-financial competing interests to report.

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Diagnostic and Therapeutic Approaches for Endometriosis: A Patent Landscape

Status:

Journal Publication

Version 1

Abstract

Objective

Methodology

Results

Conclusion

Figures

1. Introduction

2. Methodology

3. Results

3.1. Patent analysis:

3.2. Diagnostic agents

3.2.1. Biomarkers for the diagnosis of Endometriosis

3.2.2. Devices or Methods of Physical examination of Endometriosis

3.2.3. Laparoscopy

3.2.4. MRI (Magnetic Resonance Imaging) and Ultra-sonography

3.2.5. Biopsy

3.2.6. Myomectomy

3.3. Therapeutic agents

3.3.1. Hormonal therapies

3.3.1.1. GnRH agonists and Antagonists

3.3.1.2. Progesterone or Progestin antagonists

3.3.1.3. Estrogen antagonists

3.3.1.4. Interleukin antagonists

3.3.1.5. Chymase inhibitors

3.3.1.6. Erythropoietin antagonists

3.3.1.7. Neutralising antibody & pathway blockers

3.3.1.8. Biotechnological instruments

3.3.1.9. Surgical tools & Radiolabel treatment

3.3.1.10. Specific pharmaceutical compounds

3.4. Traditional medicines

3.5. Combined Patent applications for Diagnostic and therapeutic Patent applications

4. Discussion

5. Conclusion

Declarations

References

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Journal Publication

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