DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-8, 14-18, 21-26, and 32-34 are pending.
Preliminary Amendment
Applicant’s preliminary amendment filed on 11/20/2023 is acknowledged. Claims were amended to (1) cancel claims 9-13, 19, 20, 27-31, and 35-68; and (2) remove multiple claim dependencies found in claims 3, 7, 8, 14, 17, 18, and 32-34.
Election
Applicant’s election without traverse of genetic variation 6:127125465:G:C (rs9482771) in the reply filed on 1/28/2026 is acknowledged.
Claim(s) 1-8, 14-18, 21-26, and 32-34 are under consideration.
Priority
Acknowledgement is made of Applicant’s claim for priority based on provisional application(s) filed as 63/405,787 on 09/12/2022 and 63/414,748 on 10/10/2022.
All claims are given the priority date of 09/12/2022.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 03/02/2026 is acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Claim Objections
Claim 1 is objected to because of the following informalities: line 2 recites, “…the method comprising administering an R-Spondin (RSPO3) inhibitor…”. It would be remedial to insert “3” after “R-Spondin” and before “(RSPO3) inhibitor” to recite, “R-Spondin 3 (RSPO3) inhibitor”.
Claim 21 is objected to because of the following informalities: line 11 recites, “endometriosis therapy in a standard dosage amount to a subject that is RSPO3 reference; or”. It would be remedial to add an “an” before RSPO3 reference to recite, “… to a subject that is an RSPO3 reference.”
Appropriate correction is required.
Claim Interpretation
Claim 14 depends upon claim 13, which is a cancelled claim. For the purpose of compact prosecution, and given that claim 13 is cancelled, claim 14 will be interpreted as being dependent upon claim 1.
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.
Claim(s) 21, 33, and 34 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature without significantly more.
The independent claim recites “…having determined whether the subject has an R-Spondin 3 (RSPO3) variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising an RSPO3 variant nucleic acid molecule; …”. These steps read on “having determined” by looking at a genotype printed on a piece of paper or displayed on a computer screen or thinking about acts having been carried out in the past. The “having determined” recites an embodiment where the claim limitation is practically performed in the mind. Thus, the steps fall within the Mental Process group of abstract ideas. Dependent claim(s) 33 and 34 do not require one to actively carry out the steps by limiting the claims to only active steps rather than steps that have been carried out in the past. The dependent claims read on an embodiment where one is only thinking about the genotype.
The claim(s) recite(s) “… wherein the presence of a genotype having the RSPO3 variant nucleic acid molecule indicates the subject has an increased risk of developing endometriosis.” This is a natural law of correlation.
The judicial exception is not integrated into a practice application. The independent claim recites the additional limitation of “administering or continuing to administer the endometriosis therapeutic agent or endometriosis therapy in a standard dosage amount to a subject that is RSPO3 reference; or administering or continuing to administer the endometriosis therapeutic agent in an amount that is the same as or less than a standard dosage amount or endometriosis therapy to a subject that is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule, and/or administering an RSPO3 inhibitor and/or an RSPO3 Receptor blocker to the subject”. This step reads on an embodiment where the subject, independent of the genotype, is continuing to be administered a general endometriosis therapeutic agent at the standard dosage. The administered treatment is not a particular treatment that relies upon the judicial exception(s) in a meaningful way. The same treatment is applied regardless of genotype.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the administering steps discussed above would be routinely used by those ordinary skill in the art. “Continuing to administer” a “standard dosage” of an endometriosis therapeutic agent, such as ibuprofen (listed on page 26 of the specification) is well-understood, routine, and conventional activity in the art. When looking to Advil® (How Much Ibuprofen Can I Take? | AdvilSymptoms; www.advil.com/symptoms-tips/pain/how-much-ibuprofen-can-i-take/) for “How much ibuprofen can I take?”.
Advil® discloses, “The amount of ibuprofen that you can take in a day depends on the strength of the medicine and what you’re taking it for. Adults treating menstrual cramps or mild aches and pain can take 400mg every 4-6 hours as needed. However, adults and teens who are treating rheumatoid or osteoarthritis may be directed by their healthcare provider to take 1200mg up to 3200mg per day, divided into three or four equal doses. Where children are concerned, the ibuprofen dose is often determined by age or body weight when treating pain or fever. Follow the directions of your healthcare provider to ensure you’re taking the right amount for what you need and that you’re not taking too much. For OTC ibuprofen products for children and adults, always follow the dosing directions in the Drug Facts label box on the product packaging.”.
The additional elements do not add significantly more. The claim(s) as a whole does/do not amount to significantly more than a judicial exception.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 14-18, 21-26, and 32-34 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 14 recites the limitation "The method of claim 13…" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 13 is a cancelled claim. For the purposes of compact prosecution, claim 14 will be interpreted as depended upon claim 1.
Claim(s) 15-18 are rejected for being dependent on claim 14.
Regarding claim(s) 15, 16, 21, and 32, the term “standard dosage amount” is a relative term which renders the claim indefinite. The term “standard dosage amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim(s) 16, 21, and 32, the term “an amount that is the same as or less than a standard dosage amount” is a relative term which renders the claim indefinite. The term “an amount that is the same as or less than a standard dosage amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Combined reasoning for the indefiniteness of “standard dosage amount” and “an amount that is the same as or less than a standard dosage amount” is described below.
The term(s) “standard dosage amount” and “an amount that is the same as or less than a standard dosage amount” are refereeing to an amount of “endometriosis therapeutic agent” that is to be administered to a subject. To understand a dosing regimen or standard, one must be familiar with the agent that is being utilized for therapeutic treatment.
The specification defines “endometriosis therapeutic agent”:
“In some embodiments, the endometriosis therapeutic agents may include, but are not limited to, analgesics (e.g., non-steroidal inflammatory drugs (NSAIDS) such as ibuprofen and naproxen), hormones (e.g., estrogen and progestin), gonadotropin-releasing hormone (GnRH) analogues, which may be GnRH agonists (e.g., goserelin, leuprolide, and nafarelin) or antagonists (e.g., elagolix), androgen receptor agonists (e.g., danazol) and aromatase inhibitors. Additional endometriosis therapies include any therapy used to reduce or manage endometriosis risk factors. In some embodiments, the endometriosis therapeutic agent or endometriosis therapy can be combined with an RSPO3 inhibitor and/or an RSPO3 Receptor blocker. In some embodiments, the treatment therapy for endometriosis may include surgery to remove endometrial implants, drain endometrial cysts, and/or remove the cyst wall. These treatment therapies may be delayed or avoided altogether by treatment with an RSPO3 inhibitor and/or an RSPO3 Receptor blocker as described herein.”, (page 26, lines 11-23).
The specification further defines the term(s) “standard dosage amount” and “less than a standard dosage amount” as:
“In some embodiments, the dose of the endometriosis therapeutic agents that treat, prevent, or inhibit endometriosis can be decreased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous or homozygous for an RSPO3 variant nucleic acid molecule (i.e., a less than the standard dosage amount) compared to subjects that are RSPO3 reference (who may receive a standard dosage amount). In some embodiments, the dose of the endometriosis therapeutic agents that treat, prevent, or inhibit endometriosis can be decreased by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In addition, the subjects that are heterozygous or homozygous for an RSPO3 variant nucleic acid molecule can be administered less frequently compared to subjects that are RSPO3 reference. In some embodiments, the dose of the endometriosis therapeutic agents that treat, prevent, or inhibit endometriosis can be decreased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, for subjects that are homozygous for an RSPO3 variant nucleic acid molecule compared to subjects that are heterozygous for an RSPO3 variant nucleic acid molecule. In some embodiments, the dose of the endometriosis therapeutic agents can be decreased by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In addition, the dose of endometriosis therapeutic agents in subjects that are homozygous for an RSPO3 variant nucleic acid molecule can be administered less frequently compared to subjects that are heterozygous for an RSPO3 variant nucleic acid molecule.”, (Pages 26-27).
Each therapeutic agent has a different “standard” of dosage, and even the same agent may have different standards of dosing depending on how severe the pain associated with endometriosis is. For example, ABBVIE (Orilissa Dosing Information; Abbive; Captured by WaybackMachine on August 20th, 2019) discloses that ORILISSA® (elagolix) can either be taken once a day for a maximum of 24 months at 150mg, or twice a day for a maximum of 6 months at 200mg if a patient has a coexisting condition such as dyspareunia (see page 4, table).
Thus, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim(s) 22-26 and 33-34 are rejected for being dependent on claim 21.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1-8, 14-18, 21-26, and 32-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim(s) 1-8, 14-18, 21-26, and 32-34 are drawn to the genera of (1) “R-spondin (RSPO3) inhibitor”, (2) “RSPO3 Receptor blocker”, (3) “endometriosis therapeutic agent”, and/or (4) an “endometriosis therapy” for treating a subject having endometriosis or at risk of developing endometriosis. The rejected claims thus comprise a genus of (1/2) RSPO3 inhibitor and/or RSPO3 Receptor blocker and further comprise administering an (3/4) endometriosis therapeutic agent or an endometriosis therapy, and are defined as belonging to the broad class of RSPO3 inhibitors, RSPO3 receptor blockers, endometriosis therapeutic agents, and/or endometriosis therapy and as having the function of treating a subject having endometriosis or at risk of developing endometriosis.
Claim(s) 3 and 22 limit the “RSPO3 inhibitor” to an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule. Accordingly, claim(s) 3 and 22 are drawn to a genus of inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule with limited structural definition that must function as treating a subject having endometriosis or at risk of developing endometriosis.
Claim(s) 4-6 and 23-25 limit the inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule to an antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA). Accordingly, claim(s) 4 and 23 are drawn to a subgenus defined by antisense nucleic acid molecule, a siRNA, and/or a shRNA that must function as treating a subject having endometriosis or at risk of developing endometriosis.
Claim 7 and 26 limits the “RSPO3 inhibitor” to an antibody that decreases the expression of the RSPO3 protein. Accordingly, claim(s) 7 and 26 are drawn to a subgenus defined by an antibody that decreases the expression of the RSPO3 protein and that must function as treating a subject having endometriosis or at risk of developing endometriosis.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent
specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “… disclosure of relevant, identifying characteristics, i.e.,
structure or other physical and/or chemical properties, by functional characteristics coupled with
a known or disclosed correlation between functional and structure, or by a combination of such
identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The specification envisions the RSPO3 inhibitor as:
“The gene [RSPO3] has three transcripts (i.e., splice variants) and 242 orthologues have been identified to date. So far, over 100 single nucleotide polymorphisms (SNPs) have been mapped to the RSPO3 gene, and the gene has been linked to at least 62 phenotypes. However, to date, no RSPO3 SNPs have been associated with endometriosis.”, (see page 2, paragraph 1) - [RSPO3] added for clarity.
“In some embodiments, the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Such inhibitory nucleic acid molecules can be designed to target any region of an RSPO3 nucleic acid molecule. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within an RSPO3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the RSPO3 polypeptide in a cell in the subject.….” (Page 10, Lines 4-10).
“The inhibitory nucleic acid molecules can comprise RNA, DNA, or both RNA and DNA. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label.…” (Page 10, Lines 19-21).
“The inhibitory nucleic acid molecules can comprise, for example, nucleotides or
non-natural or modified nucleotides, such as nucleotide analogs or nucleotide substitutes. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-natural moiety in its structure...” (Page 11, Lines 13-16).
“The inhibitory nucleic acid molecules can also comprise one or more nucleotide analogs or substitutions. A nucleotide analog is a nucleotide which contains a modification to either the base, sugar, or phosphate moieties…” (Page 11, Lines 19-21).
“Nucleotide analogs can also include modifications of the sugar moiety. Modifications to the sugar moiety include, but are not limited to, natural modifications of
The ribose and deoxy ribose as well as synthetic modifications...” (Page 12, Lines 5-7).
“Nucleotide analogs can also be modified at the phosphate moiety…” (Page 12, Line 26).
“In some embodiments, the antisense nucleic acid molecules are gapmers, whereby the first one to seven nucleotides at the 5' and 3' ends each have 2'-methoxyethyl (2'-MOE) modifications.…” (Page 13, Lines 8-11).
“In some embodiments, a representative siRNA has the following formula:
Sense: mN*mN*/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/
i2FN/*mN*/32FN/
Antisense/52FN/*/i2FN/*nN/i2FN/mN/i2EN/mN/i2FN/mN/2FN/mN/i2FN/mN/i2EN/mN/i2FN/mN/i2FN/mN*N*N
wherein: "N" is the base; "2F" is a 2'-F modification; "m" is a 2'-O-methyl modification, "I" is an internal base; and "*" is a phosphorothioate backbone linkage.” (Page 14, Lines 8-14).
“In some embodiments, the RSPO3 inhibitor comprises a nuclease agent that
induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA-binding protein that binds to a recognition sequence within an Rspo3 genomic nucleic acid molecule….” (Page 15, Lines 3-6).
“Suitable nuclease agents and DNA-binding proteins for use herein include, but are not limited to, zinc finger protein or zinc finger nuclease (ZFN) pair, Transcription Activator-like Effector (TALE) protein or Transcription Activator-Like Effector Nuclease (TALEN), or Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) systems….” (Page 15, Lines 23-27).
“In some embodiments, the RSPO3 inhibitor is a small molecule. In some
embodiments, the small molecule is low molecular weight (< 900 daltons) organic compound…” (Page 23, Lines 12-14).
“In some embodiments, the RSPO3 inhibitor comprises an antibody, or antigen binding fragment thereof. In some embodiments, the antibody, or antigen-binding fragment thereof, binds specifically to human RSPO3. In some embodiments, the antibody is a fully human monoclonal antibody (mAb), or antigen-binding fragment thereof, that specifically binds and neutralizes, inhibits, blocks, abrogates, reduces, or interferes with, at least one activity of RSPO3, in particular, human RSPO3…” (Page 23, Lines 15-20).
To summarize the RSPO3 inhibitor written description: the specification envisions three different splice variants of RSPO3, any of which an antisense nucleic acid of any number or variation of modifications of (DNA, RNA, a mix of RNA and DNA, single stranded or double-stranded) can target at any genomic locus (introns, exons, UTRs) or pre-mRNA or mRNA. An RSPO3 inhibitor can also be a nuclease agent. An RSPO3 inhibitor can be any small molecule <900 daltons. An RSPO3 inhibitor can be an RSPO3 antibody or antigen-binding fragment.
The specification envisions the RSPO3 receptor blocker as:
“Studies using these proteins have identified multiple RSPO receptors that are involved in regulation of the WNTsignaling pathway. The RSPO3 protein, also known as Pwtsr and Thsd2, is a 272 amino acid protein that acts as a ligand for the LGR4-6 receptor, a key regulator of angiogenesis, and that is encoded by the RSPO3 gene, which spans nucleotides 127,118,671-127,199,481 on human chromosome 6…” (Page 1, Lines 25-30).
“The RSPO3 Receptors are leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), and leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6). In some embodiments, the RSPO3 Receptor blocker comprises an antibody, or antigen-binding fragment thereof, directed to LGR4, LGR5, and/or LGR6. In some embodiments, the antibody, or antigen binding fragment thereof, binds specifically to human LGR4, LGR5, and/or LGR6. In some embodiments, the antibody is a fully human monoclonal antibody (mAb), or antigen-binding fragment thereof, that specifically binds and neutralizes, inhibits, blocks, abrogates, reduces, or interferes with, at least one activity of LGR4, LGR5, and/or LGR6, in particular, human LGR4, LGR5, and/or LGR6….In some embodiments, the RSPO3 Receptor blocker comprises an antibody that decreases expression of the LGR4, LGR5, and/or LGR6 protein.” (Page 24, Lines 28-30 to Page 25, Lines 1-8 and 19-20).
To summarize the RSPO3 receptor blocker written description: the specification envisions targeting LGR4, LGR5, and/or LGR6. Targeting LGR4, LGR5, or LGR6 is envisioned by an antibody toward one or a combination of those receptors or targeting a potential upstream regulator of LGR4, LGR5, and/or LGR6 to decrease the expression of any or all of those receptors.
The specification envisions the endometriosis therapeutic agent as:
“In some embodiments, the endometriosis therapeutic agents may include, but are not limited to, analgesics (e.g., non-steroidal inflammatory drugs (NSAIDS) such as ibuprofen and maproxen), hormones (e.g., estrogen and progestin), gonadotropin-releasing hormone (GnRH) analogues, which may be GnRH agonists (e.g., goserelin, leuprolide, and nafarelin) or antagonists (e.g., elagolix), androgen receptor agonists (e.g., danazol) and aromatase inhibitors…” (Page 26, Lines 11-16).
The specification envisions the endometriosis therapy as:
“Additional endometriosis therapies include any therapy used to reduce or manage endometriosis risk factors. In some embodiments, the endometriosis therapeutic agent or endometriosis therapy can be combined with an RSPO3 inhibitor and/or an RSPO3 Receptor blocker. In some embodiments, the treatment therapy for endometriosis may include surgery to remove endometrial implants, drain endometrial cysts, and/or remove the cyst wall. These treatment therapies may be delayed or avoided altogether by treatment with an RSPO3 inhibitor and/or an RSPO3 Receptor blocker as described herein.” (Page 26, Lines 16-22).
There are no examples provided for, in the specification, that meet the claim limitations of the rejected claims in regard to structure. The lack of results for a singular (1) RSPO3 inhibitor, (2) RSPO3 receptor blocker, (3) endometriosis therapeutic agent, or (4) endometriosis therapy in an art accepted model of any form of endometriosis proves to be not predictive of any/all (1) RSPO3 inhibitor and/or (2) RSPO3 receptor blocker, further comprising a (3) endometriosis therapeutic agent, and/or (4) endometriosis therapy capable of treating a subject having endometriosis or at risk of developing endometriosis. Thus, it is impossible for one to extrapolate that the (1) RSPO3 inhibitor, (2) RSPO3 receptor blocker, (3) endometriosis therapeutic agent, or (4) endometriosis therapy described above would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of (1) RSPO3 inhibitor, (2) RSPO3 receptor blocker, (3) endometriosis therapeutic agent, or (4) endometriosis therapy capable of treating a subject having endometriosis or at risk of developing endometriosis.
Looking to the art on “RSPO3 inhibitor” Chang et al (WO 2021/080396 A1; published April 29th, 2021; machine translation of the specification provide under NPL section, full disclosure under Foreign Documents) describes “RSPO3 inhibitor” structure for the purpose of preventing or treating vascular or valve calcification involving heart valve disease:
Chang et al discloses, “The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating vascular or valve calcification, which comprises an inhibitor of the expression or activity of RSPO3 (R-spondin 3) as an active ingredient.”, (paragraph [0005]).
More specifically, Chang et al discloses, “The above RSPO3 may be composed of an amino acid sequence of sequence number 1, and the gene encoding the RSPO3 may be composed of a base sequence of sequence number 2.”, (paragraph [0041]). “The above RSPO3 expression or activity inhibitor may be an expression inhibitor of the RSPO3 gene or an expression or activity inhibitor of the RSPO3 protein. The above RSPO3 gene expression inhibitor may be any one selected from the group consisting of an antisense oligonucleotide, siRNA (small interfering RNA), shRNA (short hairpin RNA), and aptamer that complementarily bind to the mRNA of the RSPO3 gene, but is not limited thereto.”, (paragraph [0042]).
“The above "siRNA" is a double-stranded RNA consisting of a sense sequence and an antisense sequence of 15 to 30 bp in length that can complementarily bind to the mRNA base sequence of the target gene and suppress the expression of the target gene through RNAi (RNA interference) by mRNA cleavage, and can be used for gene knockdown or gene therapy. In the present invention, the siRNA may be an RNA molecule having a sense sequence (UGUGAUACCUGUUUCAACAtt) consisting of a base sequence of SEQ ID NO: 3 and an antisense (UGUUGAAACAGGUAUCACAgt) consisting of a base sequence of SEQ ID NO: 4, which can complementarily bind to the mRNA of the RSPO3 gene.”, (see paragraphs [0045] to [0046] and Figure 6A-C).
Looking to another patent application publication on “RSPO3 inhibitor” and “RSPO3 Receptor Blocker” Storm (US 20210369841 A1, Published December 2nd, 2021) describes “RSPO3 inhibitor” and “RSPO3 Receptor Blocker” structure for the purpose treating tumors, cell proliferative disorders, and/or cancer.
Storm discloses, “In one aspect, an anti-RSPO3 antibody for use as a medicament is provided. In further aspects, an anti-RSPO3 antibody for use in treating tumors, cell proliferative disorders, and/or cancer is provided. In some embodiments, an anti-RSPO3 antibody is provided for use in promoting differentiation of cells including terminal differentiation of cancer cells. In certain embodiments, an anti-RSPO3 antibody for use in a method of treatment is provided. In certain embodiments, the invention provides an anti-RSPO3 antibody for use in a method of treating an individual having tumor, cell proliferative disorder, and/or cancer comprising administering to the individual an effective amount of the anti-RSPO3 antibody. In some embodiments, the cancer is adrenal cancer, bladder cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer (e.g., NSCLC), lymphoid cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectum cancer, skin cancer (e.g., melanoma), stomach cancer, thyroid cancer, and/or uterine cancer. In some embodiments, the cancer is lung cancer (e.g., NSCLC), ovarian cancer, breast cancer, liver cancer, or multiple myeloma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastrointestinal cancer, stomach cancer, colon cancer, colorectal cancer, lung cancer, or rectal cancer. In some embodiments, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described below.”, (paragraph [0272]).
Storm discloses in examples I-V, (I) Developing and characterizing rat anti-human RSPO3 hybridoma antibodies; (II) the humanization and binding affinity of humanized anti-RSPO3 antibodies; (III) In vivo efficacy; (IV) the pharmacokinetics of anti-RSPO3 antibodies in mice and cynomolgus monkeys; and (V) competition ELISA assays showing the effect of anti-RSPO3 antibodies on blocking RSPO3 binding to LGR4, LGR5, and RNF43.
Storm discloses sequences of the anti-RSPO3 antibodies in FIGS. 1 and 2, and table 6.
Looking to an overview on treating a subject having endometriosis, NICHD (Title: What are the treatments for endometriosis? Article from NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development. Content Owner: Office of Communications; Pages 1-8, Last Reviewed: 12/11/2025; www.nichd.nih.gov/health/topics/endometri/conditioninfo/treatment#med) describes “endometriosis therapeutic agents” and “endometriosis therapy”.
NICHD discloses current treatments for endometriosis.
“There is currently no cure for endometriosis, but there are treatment options for related pain and infertility. Healthcare providers consider several factors when determining the best treatment for endometriosis symptoms, including: Your age, How severe your symptoms are, How severe the disease is, Whether you want children. Not all treatments work well for all women with endometriosis. Also, endometriosis symptoms may return after the treatment is stopped or, in the case of surgery, as more time passes after the procedure.” (Page 1)
“Hormone Therapy: Because hormones cause endometriosis patches to go through a cycle similar to the menstrual cycle, hormones also can be effective in treating endometriosis symptoms. Additionally, different hormones may alter our perception of pain. Hormone therapy is used to treat endometriosis-associated pain. Hormones come in the form of a pill, a shot or injection, or a nasal spray. Hormone treatments stop the ovaries from producing hormones, including estrogen, and usually prevent ovulation. This may help slow the growth and local activity of both the endometrium and the endometrial lesions. Treatment also prevents new areas and scars (adhesions) from growing, but it will not make existing adhesions go away.
Healthcare providers may suggest one of the following hormone treatments to treat pain from endometriosis: Gonadotropin-releasing hormone (GnRH) medicines… Oral contraceptives, or birth control pills … Progesterone and progestin … Danazol.
Pain Medications: Pain medications may work well if pain or other symptoms are mild. These medications range from over-the-counter pain relievers to strong prescription pain relievers. The most common types of pain relievers are nonsteroidal anti-inflammatory drugs, also called NSAIDS. Evidence on the effectiveness of these medications for relieving endometriosis-associated pain is limited. Understanding which drugs relieve pain associated with endometriosis could also shed light on how endometriosis causes pain.
Surgical Treatments: Research shows that some surgical treatments can provide significant, although short-term, relief from endometriosis-related pain, so healthcare providers may recommend surgery to treat severe pain from endometriosis. During the operation, the surgeon can locate any areas of endometriosis and examine the size and degree of growth; he or she also may remove the endometriosis patches at that time… Healthcare providers may suggest one of the following surgical treatments for pain from endometriosis: Laparoscopy… Laparotomy… Surgery to sever pelvic nerves.” (See pages 1-6).
Despite Chang et al and Storm disclosing the structure of two species of “RSPO3 inhibitor”, namely an siRNA sequence (sense and antisense), and three anti-RSPO3 antibodies, respectively, this art does not offset the deficiencies of the envisioned genera of “RSPO3 inhibitor” and “RSPO3 receptor blocker” of the specification. Moreover, Chang et al and Storm do not disclose that their described species of RSPO3 inhibitor or RSPO3 receptor blocker has the function of treating a subject having endometriosis or at risk of developing endometriosis. This lack of function is further confirmed by NICHD, which discloses there are no cures for endometriosis and the only treatment options available are for endometriosis-related pain and infertility. NICHD describes that hormone therapy, pain medications, and surgical treatments are used for short-term pain relief, however, NICHD is silent on the combining of “RSPO3 inhibitor” and/or “RSPO3 receptor blocker” with “endometriosis therapeutic agent” or an “endometriosis therapy”.
Therefore, the art does not appear to offset the deficiencies of the specification. Merely describing a “RSPO3 inhibitor”, “RSPO3 receptor blocker”, “endometriosis therapeutic agent” and/or “endometriosis therapy” capable of treating a subject having endometriosis or at risk of developing endometriosis without sufficient detail relating to the genera of “RSPO3 inhibitor”, “RSPO3 receptor blocker”, “endometriosis therapeutic agent” and/or “endometriosis therapy” in treating a subject having endometriosis or at risk of developing endometriosis does not allow the skilled artesian to reasonably conclude that the Applicants were in possession of the claimed invention in claim(s) 1-8, 14-18, 21-26, and 32-34.
Claim Rejections - 35 USC § 112(a) –Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1-8, 14-18, 21-26, and 32-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is drawn to a method for treating a subject having endometriosis, or a risk of developing endometriosis, the method comprising administering an R-Spondin (RSPO3) inhibitor and/or an RSPO3 receptor blocker to a subject. The nature of the invention is complex in that the RSPO3 inhibitor and/or RSPO3 receptor blocker must be capable of treating a subject having endometriosis, or a risk of developing endometriosis.
Claim 21 is drawn to a method of treating a subject having endometriosis or at risk of
developing endometriosis by administering an endometriosis therapeutic agent or an
endometriosis therapy, the method comprising: determining or having determined whether the
subject has an R-Spondin 3 (RSPO3) variant nucleic acid molecule, by: obtaining or having
obtained a biological sample from the subject; and performing or having performed a sequence
analysis on the biological sample to determine if the subject has a genotype comprising an
RSPO3 variant nucleic acid molecule; and administering or continuing to administer the
endometriosis therapeutic agent or endometriosis therapy in a standard dosage amount to a
subject that is RSPO3 reference;
or administering or continuing to administer the endometriosis therapeutic agent in an
amount that is the same as or less than a standard dosage amount or endometriosis therapy to a
subject that is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule,
and/or administering an RSPO3 inhibitor and/or an RSPO3 Receptor blocker to the
subject;
wherein the presence of a genotype having the RSPO3 variant nucleic acid molecule indicates the subject has an increased risk of developing endometriosis.
The nature of the invention is complex in that the endometriosis therapeutic agent or an
endometriosis therapy and/or administering an RSPO3 inhibitor and/or RSPO3 receptor blocker
must be capable of (1) treating a subject having endometriosis or (2) treating a subject at risk of developing endometriosis by: determining or having determined whether a subject has an RSPO3 variant nucleic acid molecule (heterozygous, homozygous, or RSPO3 reference -i.e., no detection of an RSPO3 variant nucleic acid molecule) and varying the dosages of endometriosis therapeutic agent of endometriosis therapy (standard, same, or less than standard) depending on which RSPO3 variant nucleic acid the subject is determined to have (heterozygous, homozygous, or reference).
Breadth of the claims:
The broadest reasonable interpretation of claim 1 is that the invention is drawn to a method for treating a subject having any/all forms of endometriosis, or treating a subject who is at risk of developing any/all endometriosis, the method comprising administering any/all RSPO3 inhibitors and/or any/all RSPO3 receptor blockers. The claims broadly encompass “RSPO3 inhibitors” and/or “RSPO3 receptor blockers”, where “RSPO3 inhibitors” and “RSPO3 receptor blockers” are defined solely or primarily by function.
The broadest reasonable interpretation of claim 21 is that the invention is drawn to a method for treating a subject having any/all forms of endometriosis, or treating a subject who is at risk of developing any/all endometriosis by administering any/all endometriosis therapeutic agents or any/all endometriosis therapies, the method comprising: determining or having determined whether the subject has any/all RSPO3 variant nucleic acid molecules, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has any/all genotypes comprising any/all RSPO3 variant nucleic acid molecules; and administering or continuing to administer any/all endometriosis therapeutic agents or any/all endometriosis therapies in a standard dosage amount to a subject that is an RSPO3 reference; or administering or continuing to administer any/all therapeutic agents in an amount that is the same as or less than a standard dosage amount or any/all endometriosis therapies to a subject that is heterozygous or homozygous for any/all RSPO3 variant nucleic acid molecules, and/or administering any/all RSPO3 inhibitors and/or any/all RSPO3 receptor blockers to the subject; wherein the presence of a genotype having any/all RSPO3 variant nucleic acid molecules indicates the subject has an increased risk of developing endometriosis. The claims broadly encompass “endometriosis therapeutic agent”, “endometriosis therapy”, “RSPO3 inhibitors”, and “RSPO3 receptor blockers”, where “endometriosis therapeutic agent”, “endometriosis therapy”, “RSPO3 inhibitors” and “RSPO3 receptor blockers” are defined solely or primarily by function.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification:
Looking to the specification for guidance on (a) treating endometriosis (b) forms of endometriosis, (c) risk factors for developing endometriosis, (d) RSPO3 inhibitors, (e) RSPO3 receptor blockers, (f) endometriosis therapeutic agent, (g) endometriosis therapy, and (h) RSPO3 variant nucleic acid molecules.
(a) “The terms "treat", "treating", and "treatment" and "prevent", "preventing", and "prevention" as used herein, refer to eliciting the desired biological response, such as a therapeutic and prophylactic effect, respectively. In some embodiments, a therapeutic effect comprises one or more of a decrease/reduction in endometriosis, a decrease/reduction in the severity of endometriosis (such as, for example, a reduction or inhibition of development of endometriosis), a decrease/reduction in symptoms and disease-related effects, delaying the onset of symptoms and disease-related effects, reducing the severity of symptoms of disease-related effects, reducing the number of symptoms and disease-related effects, reducing the latency of symptoms and disease related effects, an amelioration of symptoms and disease-related effects, reducing secondary symptoms, reducing secondary infections, preventing relapse to endometriosis, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, increasing time to sustained progression, speeding recovery, or increasing efficacy of or decreasing resistance to alternative therapeutics, and/or an increased survival time of the affected host animal, following administration of the agent or composition comprising the agent. A prophylactic effect may comprise a complete or partial avoidance/inhibition or a delay of endometriosis development/progression (such as, for example, a complete or partial avoidance/inhibition or a delay), and an increased survival time of the affected host animal, following administration of a therapeutic protocol. Treatment of endometriosis encompasses the treatment of a subject already diagnosed as having any form of endometriosis at any clinical stage or manifestation, the delay of the onset or evolution or aggravation or deterioration of the symptoms or signs of endometriosis, and/or preventing and/or reducing the severity of endometriosis.”, (Page 28, lines 5-27).
(b) “In any of the embodiments described herein, the subject can have endometriosis. In any of the embodiments described herein, the subject can be at risk of developing endometriosis. In any of the embodiments described herein, the endometriosis may comprise superficial peritoneal endometriosis, endometrioma-containing, endometriosis, deeply infiltrating endometriosis (DIE), or abdominal wall endometriosis.” (Page 9, lines 9-17)
(c) “In any of the embodiments described herein, the subject in whom endometriosis is prevented by administering an RSPO3 inhibitor and/or an RSPO3 Receptor blocker can be anyone at risk for developing endometriosis including, but not limited to, subjects with a genetic predisposition for developing endometriosis. Additional risk factors for endometriosis may include, but are not limited to, having a family member diagnosed with endometriosis, being nulliparous, starting menstruation at an early age (e.g., before 11 years of age), short menstrual cycles (e.g., less than 27 days), heavy menstrual cycles lasting greater than seven days, and going through menopause at an older age.” (Page 8, Lines 18-25)
(d) A detailed list of RSPO3 inhibitors can be found above in the “Written Description” section, however, a summary of those RSPO3 inhibitors and the related pages is as follows:
(1) an inhibitory nucleic acid molecule (e.g., antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs)), wherein such inhibitory nucleic acid molecules can be designed to target any region of an RSPO3 nucleic acid molecule and can comprising RNA, DNA, both RNA and DNA, modifications (natural and non-natural), analogs/substitutions, and can be represented by
Sense: mN*mN*/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/ i2FN/*mN*/32FN/ Antisense/52FN/*/i2FN/*nN/i2FN/mN/i2EN/mN/i2FN/mN/2FN/mN/i2FN/mN/i2EN/mN/i2FN/mN/i2FN/mN*N*N wherein: "N" is the base; "2F" is a 2'-F modification; "m" is a 2'-O-methyl modification, "I" is an internal base; and "*" is a phosphorothioate backbone linkage (Page 10, Lines 4-10), (Page 10, Lines 19-21), (Page 11, Lines 13-16), (Page 11, Lines 19-21), (Page 12, Lines 5-7), (Page 12, Line 26), (Page 13, Lines 8-11), and (Page 14, Lines 8-14);
(2) a nuclease agent, (Page 15, Lines 3-6) and (Page 15, Lines 23-27);
(3) a small molecule (Page 23, Lines 12-14); and
(4) an antibody or antigen binding fragment (Page 23, Lines 15-20).
(e) A detailed list of RSPO3 receptor blockers can be found above in the “Written Description” section, however, a summary of those RSPO3 receptor blockers and the related pages is as follows:
(1) antibody or antigen binding fragments directed toward LGR4;
(2) antibody or antigen binding fragments directed toward LGR5;
(3) antibody or antigen binding fragments directed toward LGR6;
(4) a combination of 1-3; and
(5) any antibody that decreases the expression of LGR4, LGR5, and/or LGR6 protein (Page 24, Lines 28-30 to Page 25, Lines 1-8 and 19-20).
(f) The endometriosis therapeutic agents may include, but are not limited to:
(1) analgesics (e.g., non-steroidal inflammatory drugs (NSAIDS) such as ibuprofen and maproxen);
(2) hormones (e.g., estrogen and progestin);
(3) gonadotropin-releasing hormone (GnRH) analogues, which may be
(a) GnRH agonists (e.g., goserelin, leuprolide, and nafarelin); or
(b) antagonists (e.g., elagolix);
(4) androgen receptor agonists (e.g., danazol); and
(5) aromatase inhibitors
(Page 26, Lines 11-16).
(g) Endometriosis therapies include any therapy used to reduce or manage endometriosis
risk factors. … In some embodiments, the treatment therapy for endometriosis may
include:
(1) surgery to remove endometrial implants;
(2) drain endometrial cysts; and/or
(3) remove the cyst wall.
(Page 26, Lines 16-22).
(h) “The gene [RSPO3] has three transcripts (i.e., splice variants) and 242 orthologues have been identified to date. So far, over 100 single nucleotide polymorphisms (SNPs) have been mapped to the RSPO3 gene, and the gene has been linked to at least 62 phenotypes. However, to date, no RSPO3 SNPs have been associated with endometriosis.”, (see page 2, paragraph 1) - [RSPO3] added for clarity.
“RSPO3 variant nucleic acid molecules can be any nucleic acid molecule (such as, a
genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule produced from an mRNA molecule) that results in the increased expression or activity of an RSPO3 polypeptide. In some embodiments, the RSPO3 variant nucleic acid molecule is a missense variant nucleic acid molecule. In some embodiments, the RSPO3 variant nucleic acid molecule comprises a variation in a coding region. In some embodiments, the RSPO3 variant nucleic acid molecule comprises a variation that is cis in regard to the RSPO3 gene. In some embodiments, the RSPO3 variant nucleic acid molecule comprises a variation that is trans in regard to the RSPO3 gene. In some embodiments, the RSPO3 variant nucleic acid molecule comprises a variation in a non-coding region. In some embodiments, the RSPO3 variant nucleic acid molecule does not comprise a variation in a non-coding region, except for splice acceptor regions (two bases before the start of any exon except the first). In some embodiments, the RSPO3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, or an in-frame indel variant. In some embodiments, the RSPO3 variant nucleic acid molecule is any nucleic acid molecule resulting in increased expression of RSPO3 mRNA or RSPO3 polypeptide. In some embodiments, the RSPO3 variant nucleic acid molecule is a variant that causes or is predicted to cause a nonsynonymous amino-acid substitution in a nucleic acid molecule and whose allele frequency is less than 1/100 alleles in the population from which the subject is selected. In some embodiments, the RSPO3 variant nucleic acid molecule is any rare
missense variant (allele frequency < 0.1%; or 1 in 1,000 alleles), or any splice-site, stop-gain,
start-loss, stop-loss, frameshift, or in-frame indel, or other frameshift RSPO3 variant.” (Page 6, Lines 13-30 to Page 7, Lines 1-4).
A list of SNPs found on page 7, lines 14-29 to page 8, lines 1-3.
Specifically, “In any of the embodiments described herein, the RSPO3 variant nucleic acid molecule can comprise the genetic variation 6:127125465:G:C (rs9482771). In some embodiments, the RSPO3 variant nucleic acid molecule is a RSPO3 variant genomic nucleic acid molecule that comprises the genetic variant rs9482771, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule. In some embodiments, the RSPO3 variant nucleic acid molecule is a RSPO3 variant genomic nucleic acid molecule that comprises a cytosine at position 127,125,465 of chromosome 6, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.” (Page 8, Lines 4-12).
The SNP rs9482771 is the elected species of the claimed invention.
Existence of working examples:
Example 1: A study was carried out to determine the association of 6:127125465:G:C (rs9482771) with endometriosis (see table 1, table 2, and figure 1). The example declares that rs9482771 is significantly associated (genome-wide) in the meta-analysis with endometriosis, and that RSPOR3 has consistent results between cis and trans estimates, i.e., lower levels of protein are associated with lower endometriosis disease (see pages 46-49).
Example 2: Uterine tissues were acquired from vendors: endothelial, fibroblast, smooth muscle, and endometrial epithelial. These tissues were lysed and underwent single-cell sequencing to observe the expression of RSPO3 and other genes in the WNT pathway. RSPO3 expression was mainly observed in smooth muscles, and fibroblasts, with some expression in endothelial cells (see pages 49 and 50; see figure 4).
The cellular studies provided by working example 2 is only done in wild-type cells to observe whether RSPO3 is expressed in various cell types that make up the uterine tissues. There are no examples provided to show that endometriosis diseased cells of the uterine tissue contain the SNPs that are associated with endometriosis as explained in example 1. Although this is a promising field, there are no cellular studies or additional studies to corroborate the association of RSPO3 variance and endometriosis.
Predictability and state of the art:
Turning to two review article(s) on the state-of-the-art for diagnostics and therapies:
Scheck et al (A promising future for endometriosis diagnosis and therapy: extracellular vesicles – a systematic review, Reprod Biol Endocrinol, Vol 20, Issue 1, Pages 1-18, Published December 21st, 2021) teaches, “Endometriosis is a chronic, inflammatory gynaecological disease that can have severe negative impacts on quality of life and fertility, placing burden on patients and the healthcare system. Due to the heterogeneous nature of endometriosis, and the lack of correlation between symptom and surgical disease severity, diagnosis and treatment remain a significant clinical challenge.”, (Abstract).
“The diagnosis of endometriosis at present is reliant on clinical history and examination, ultrasound, and ultimately laparoscopic surgery and biopsy. Whilst endometriomas and deep infiltrating endometriosis can be diagnosed with increasing reliability by ultrasound, the more common manifestation of superficial peritoneal disease is poorly predicted without surgery.”, (page 2, column 1, paragraph 1).
“Extracellular vesicles (EVs) are non-replicating particles delimited by a lipid bilayer that are released by all cells. EVs carry a variety of cargo involved in extracellular communication, altering the recipient cell phenotype. … EVs contain bioactive cargo such as selective packaging of proteins, mRNA and miRNA species, which are reflective of the cell of origin and can provide insight into the physiological state of the tissue. EVs are abundant in bodily fluids making them prime candidates for use as “liquid biopsy”, having been successfully isolated from blood, urine and saliva. There is hope that EVs may replace tissue diagnosis as a reliable and non-invasive diagnostic tool for many pathological processes.”, (Page 2, column 1, paragraph 4).
Sahni and Day (Nanotechnologies for the detection and treatment of endometriosis. Front. Front. Biomater. Sci. Vol 2, Issue 1279358, pages 1-13, published November 16th, 2023) to teach nanotechnologies for the detection and treatment of endometriosis.
Sahni and Day teach “Endometriosis is an incurable gynecologic disease characterized by endometrial-like tissue growth outside of the uterine cavity.”, (abstract). More specifically, “It is unknown why some women develop endometriosis and others do not, but there are multiple factors and theories behind what contributes to endometriosis onset and development. One possible cause is retrograde menstruation, which is when menstrual blood travels back through the fallopian tubes instead of outward through the cervix and vagina (Figure 1) (Agostinis et al., 2021). This backflow of blood can result in the implantation and growth of endometrial cells outside the uterus. Another possible cause could be cellular metaplasia, which is when cells outside the uterus differentiate into endometrial-like cells due to an environmental stimulus such as hormones or immunological factors (Giroux and Rustgi, 2017). For example, some studies suggest increased estrogen levels could be an inducing factor for endometriosis. Finally, certain hereditary and/or physical factors can increase the risk of a woman developing endometriosis, such as having a mother, sister, or daughter with endometriosis, having an abnormal uterus, starting menstruation before the age of 11, and having either shorter menstrual cycles that are less than 27 days or heavy and long menstrual periods lasting more than 7days (Tsamantioti and Heba, 2023).” (Page 1, column 1, paragraph 2 to page 2, column 1, paragraph 1).
“One challenge in the development of new diagnostics and therapeutics for endometriosis is the paucity of preclinical animal models that accurately represent the human disease. Most studies rely on rodent models wherein endometriotic cells or donor uterine tissue are transplanted subcutaneously or intraperitoneally into recipient animals to induce disease. An alternative model is macaques which can naturally develop the disease, but these are more expensive and less readily accessible.” (Page 2, column 2, paragraph 3 to page 3, column 1, paragraph 1).
“Surgical ablation of endometriotic lesions via laparoscopy is the primary treatment option for patients with endometriosis. However, this treatment is invasive and incomplete removal of diseased tissue could lead to free endometriotic cells that can develop into recurrent lesions.” (Page 5, column 1, paragraph 3).
“Although there are drugs currently used to assist with management of endometriosis, none are curative and they lack stability and specificity.” (Page 7, Column 2, paragraph 2).
Looking to the prior art for RSPO3 inhibitors, Chang et al (WO 2021/080396 A1; published April 29th, 2021; machine translation of the specification provided under NPL section, full disclosure under Foreign Documents) and Storm (US 20210369841 A1, Published December 2nd, 2021) teach “RSPO3 inhibitor” and “RSPO3 Receptor Blocker” for the purpose treating (1) vascular or valve calcification involving heart valve disease and (2) tumors, cell proliferative disorders, and/or cancer, respectively.
Chang et al discloses, “The above RSPO3 may be composed of an amino acid sequence of sequence number 1, and the gene encoding the RSPO3 may be composed of a base sequence of sequence number 2.”, (paragraph [0041]). “The above RSPO3 expression or activity inhibitor may be an expression inhibitor of the RSPO3 gene or an expression or activity inhibitor of the RSPO3 protein. The above RSPO3 gene expression inhibitor may be any one selected from the group consisting of an antisense oligonucleotide, siRNA (small interfering RNA), shRNA (short hairpin RNA), and aptamer that complementarily bind to the mRNA of the RSPO3 gene, but is not limited thereto.”, (paragraph [0042]).
“The above "siRNA" is a double-stranded RNA consisting of a sense sequence and an antisense sequence of 15 to 30 bp in length that can complementarily bind to the mRNA base sequence of the target gene and suppress the expression of the target gene through RNAi (RNA interference) by mRNA cleavage, and can be used for gene knockdown or gene therapy. In the present invention, the siRNA may be an RNA molecule having a sense sequence (UGUGAUACCUGUUUCAACAtt) consisting of a base sequence of SEQ ID NO: 3 and an antisense (UGUUGAAACAGGUAUCACAgt) consisting of a base sequence of SEQ ID NO: 4, which can complementarily bind to the mRNA of the RSPO3 gene.”, (see paragraphs [0045] to [0046] and Figure 6A-C).
Storm discloses in examples I-V, (I) Developing and characterizing rat anti-human RSPO3 hybridoma antibodies; (II) the humanization and binding affinity of humanized anti-RSPO3 antibodies; (III) In vivo efficacy; (IV) the pharmacokinetics of anti-RSPO3 antibodies in mice and cynomolgus monkeys; and (V) competition ELISA assays showing the effect of anti-RSPO3 antibodies on blocking RSPO3 binding to LGR4, LGR5, and RNF43.
Storm discloses sequences of the anti-RSPO3 antibodies in FIGS. 1 and 2, and table 6.
Lastly, looking to the art on interpreting correlation of a genetic variants versus disease causation, Burgess et al (Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data, Annu Rev Genomics Hum Genet, Vol 19, Pages 303-327, Published August 31st, 2018) teaches reviewing the Mendelian randomization paradigm for making causal inferences using genetic variants.
More specifically Burgess et al teaches, “An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious.”, (abstract).
The state-of-the-art teaches in Scheck et al and Sahni and Day that it is unknown why some women develop endometriosis and some do not, as well as diagnosing subtypes of endometriosis varies from ultrasound to surgery with the potential of patient-derived EVs aiding in the future of diagnosing endometriosis. The art is silent on whether genetic variants of any gene can accurately diagnose endometriosis, however, the art (in Burgess et al) states that correlation is not causation, and even if one has strong indications of a variant(s) relation to a disease, the most that indication will provide is either a reliable or relevant casual inference. The prior art teaches RSPO3 inhibitors such as siRNA in Chang et al for cardiac-related diseases, and the three disclosed anti-RSPO3 antibodies in Storm are for tumors, cell proliferative disorders, and cancer.
Thus, one of ordinary skill in the art would appreciate the unpredictability of treating a subject having any/all forms of endometriosis, or treating a subject who is at risk of developing any/all forms of endometriosis by administering any/all endometriosis therapeutic agents or any/all endometriosis therapies, and/or administering any/all RSPO3 inhibitors and/or any/all RSPO3 receptor blockers to the subject; wherein the presence of a genotype having any/all RSPO3 variant nucleic acid molecules indicates the subject has an increased risk of developing endometriosis.
Amount of experimentation necessary:
The quantity of experimentation required to carry out the scope of the invention is large. One would be required to (1) screen random RSPO3 inhibitors targeting all three splice variants of RSPO3 that cover the various functions of the broad genus of RSPO3 inhibitors for the ability of treating endometriosis; (2) screen random RSPO3 receptor blockers that cover the broad genus of RSPO3 receptor blockers for the ability for treating endometriosis; (3) screen random endometriosis therapeutic agents that cover the various functions of the broad genus of endometriosis therapeutic agents for the ability for treating endometriosis in combination with a chosen RSPO3 inhibitor and/or RSPO3 receptor blocker from the random screen in (1) and (2); and (4) screen random endometriosis therapies that cover the various functions of the broad genus of endometriosis therapies for the ability for treating endometriosis in combination with a chosen RSPO3 inhibitor and/or RSPO3 receptor blocker from the random screen in (1) and (2). This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering any positive results (e.g., successful treatment of endometriosis) would amount to a significant advancement in the state-of-the-art, additional experimentation required is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention.
Therefore, claims Claim(s) 1-8, 14-18, 21-26, and 32-34 are not considered to be enabled by the instant disclosure.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637