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, 2, 4-6, 8, 14-18, 21, 23-25, 32-34, and 69-72 are pending.
This action is in respond to the amendment filed 06/18/2026, in which claim(s) 3, 7, 22, and 26 were cancelled; claim(s) 1, 4, 8, 14-16, 18, 21, 23, 32, and 34 were amended; and claim(s) 69-72 were newly added.
Applicant’s arguments filed 06/18/2026 have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
Election/Restrictions
Applicant’s election without traverse of genetic variation 6:127125465:G:C (rs9482771) in the reply filed on 1/28/2026 is acknowledged.
Newly added claim(s) 69 and 70 of the current claim set filed 06/18/2026, read on the elected species.
Claim(s) 1, 2, 4-6, 8, 14-18, 21, 23-25, 32-34, and 69-72 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.
New – Claim Objections
Claim(s) 69-72 are objected to because of the following informalities: The preamble “The method according to claim X” is different than all of the other claims, which recites, “The method of claim X”. It would be remedial to amend these claims to recite, “The method of claim X” for consistency.
Appropriate correction is required.
Response to Arguments – Claim Objections
Claim 1 was previously objected to because of the following: line 2 recites, “…the method comprising administering an R-Spondin (RSPO3) inhibitor…”. Applicant amended the claim to recite the suggested insertion of “3” after R-Spondin but before “(RSPO3)”. Thus, this objection has been withdrawn in view of the amendment filed 06/18/2026.
Claim 21 was previously objected to because of the following: line 11 recites, “endometriosis therapy in a standard dosage amount to a subject that is RSPO3 reference; or”. Examiner thanks the Applicant for pointing to the specification where “[a] subject is RSPO3 reference. . .” is defining the language of “RSPO3 reference”. Accordingly, in view of the Applicants arguments presented in the remarks filled 06/18/2026, this objection has been withdrawn.
Response to Arguments - Claim Interpretation
Applicant has amended claim 14 to be dependent upon claim 1, thus remedying the claim interpretation set for in the Office action dated 03/19/2026.
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- 34, 70, and 72 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. This rejection has been rewritten to address the amendments to the claims filed 06/18/2026.
Step 2A: Prong One
The independent claim recites, “. . . performing or having performed a genotyping analysis on a biological sample obtained from the subject to determine whether the subject has a genotype comprising an RSPO3 variant nucleic acid molecule. . .”. These steps read on “determining/determine” via the steps of “having performed. . . on a biological sample obtained [past tense]” 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 “determining/determine” via the steps of “having performed. . . on a biological sample obtained [past tense]” recite 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, 34, 70, and 72 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 claim(s) 33-34 and 70 read on an embodiment where one is only thinking about the genotype. Dependent claim 72 limits the sample to a human sample.
Step 2A: Prong Two
The judicial exception is not integrated into a practical application. The independent
claim as a whole, looking at the additional elements individually and in combination, does not
integrate the judicial exception into a practical application.
The independent claim recites the additional limitation, “administering or continuing to administer the endometriosis therapeutic agent 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 to a subject that is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule, and/or administering an RSPO3 inhibitor to the subject, wherein the endometriosis therapeutic agent comprises an analgesic, a gonadotropin-releasing hormone (GnRH) analog, an androgen receptor agonist, or an aromatase inhibitor; and wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule.” This step reads on an embodiment where the subject, independent of the genotype, is continuing to be administered a general endometriosis therapeutic agent. 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 and defined as an analgesic) 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/; PTO 892 filed 03/19/2026) 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.
Response to Arguments – Claim Rejections - 35 USC § 101
The previous rejection of claim(s) 21, 33, and 34 under 35 U.S.C 101 for reciting an abstract idea and law of nature without significantly more, Applicant's arguments at page 9 of the reply filed 06/18/2026 have been fully considered but they are not persuasive.
Applicant’s remarks received on 06/18/2026 have been fully considered but they are not persuasive for at least the following reasons.
Of note, the previously rejected claims under 35 U.S.C 101 were rejected for containing two judicial exceptions without significantly more: (1) an abstract idea recited as “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 (2) a law of nature recited as “wherein the presence of a genotype having the RSPO3 variant nucleic acid molecule indicates the subject has an increased risk of developing endometriosis.”
Examiner agrees that the amendment to remove “wherein the presence of a genotype having the RSPO3 variant nucleic acid molecule indicates the subject has an increased risk of developing endometriosis” obviates this second judicial exception i.e., the law of nature, however, the abstract idea is still present in the amended claims.
Despite removing “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;. . .”, Applicant amended the claims to add the following underlined portions to the claim language of claim 21, “performing or having performed a genotyping analysis on a biological sample obtained from the subject to determine whether the subject has a genotype comprising an RSPO3 variant nucleic acid molecule;”. The phase “obtained from the subject” and “performing or having performed” to “determine” is merely the abstract idea rewritten.
Accordingly, the rejection under 35 U.S.C 101 for reciting an abstract idea is maintained for claim(s) 21, 33, and 34.
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.
Claim(s) 34 and 69 is 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. These are new rejects necessitated by amendments to the claims filed 06/18/2026.
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Regarding claim 34, it is unclear the coordinate locations of the variant nucleic molecules listed in claim 34, e.g., 6:127125465:GC, because the coordinates lack a reference to genome assembly, whereas previously the “rs” location was utilized throughout the specification to define the location. For instance, dbSNP (NCBI - Short genetic variations, rs9482771, pages 1-8; accessed August 8th, 2026) discloses “The anchor position for this RefSNP. Includes all nucleotides potentially affected by this change, thus it can differ from HGVS, which is right-shifted.”, (see p. 1). Furthermore, on page 3, dbSNP discloses that 6:127125465:GC, previously had a different location in comparison to the data base being used.
It would be remedial to add “. . . according to GRCh38/hg38 assembly coordinates.”, to the claim.
Claim 69 recites the limitation "wherein the RSPO3 variant nucleic acid molecule" in 1-2 there is insufficient antecedent basis for this limitation in the claim. Claim 69 depends from claim 1, which recites “. . . wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule.”
It would be remedial to have claim 69 depend from claim 14, which recites “. . . further comprising detecting the presence or absence of an RSPO3 variant nucleic acid molecule in a biological sample from the subject.”
Accordingly, claim(s) 34 and 69 are rejected for being indefinite.
Response to Arguments – Claim Rejections - 35 USC § 112(b) – Indefiniteness
The previous rejection of claim(s) 22 and 26 under 35 U.S.C 112(b) for being dependent upon a rejected claim is moot in view of Applicant’s cancellation of the claims filed 06/18/2026.
The previous rejection of claim(s) 15, 21, 23-25, and 32-34 under 35 U.S.C 112(b) for “standard dosage amount” has been withdrawn in view of Applicant’s amendments and arguments on pages 9-11 of the reply filed 06/18/2026, that of which have been fully considered and are persuasive.
Applicant contends that a person of skill in the art, such as a physician would have understood that the endometriosis therapeutic agents recited in the such claims would have had a standard dosage amount that is routinely administer to the subject. Applicant points to the ABBVIE report, “[b]ased on the severity of symptoms and treatment objectives, use the lowest effective dose of ORILISSA [elagolix]” (emphasis added). Applicant adds that ABBVIE reports a number of standard dosage amounts depending on whether a subject has a particular co-existing condition. Lastly, Applicant contends that a person skilled in the art would have recognized that one particular set of symptoms and treatment objectives would mandate administration of one particular standard dosage amount of an endometriosis therapeutic agent while another such set would mandate administration of another such amount.
Examiner agrees that with the amendment made to the claims to include the subgenera of therapeutic agents, one of skill in the art would be able to select an agent, such as elagolix (a species of GnRh analog), or an analgesic, and administer a “standard dosage”.
Accordingly, the 35 U.S.C 112(b) rejection of claim(s) 16, 21, 23-25, and 32-34 has been withdrawn in view of the reply filed on 06/18/2026.
Regarding the prior 35 U.S.C 112(b) rejection on claim 14, Applicant contends that the rejection was “improper”. Applicant asserts that claim 14 does note recite the language “standard dosage amount.” However, the prior rejection of claim 14 was for the following (directly inserted from the Office action filed 03/19/2026):
“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.”
Thus, claim 14 was properly rejected for being dependent upon a cancelled claim, See MPEP 2173.05(e); 608.01(n), part (V).
Applicant does not address the remedies of this rejection in the section IV on page 9 of the reply filed 06/18/2026 however, Applicant does acknowledge this in the claim interpretation section and amended claim 14 to be dependent upon claim 1.
Therefore, amending claim 14 to be dependent on claim 1, remedies this 35 U.S.C 112(b) rejection of claim 14 and its subsequent dependent claims, i.e., claims 15-18.
The 35 U.S.C 112(b) rejection of claim(s) 14-18 has been withdrawn in view of the amendments filed on 06/18/2026.
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) 1-2, 8, 14-18, 21, 23-25, 32-34, and 69-72 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. This rejection was made in the Office action mailed 03/19/2026 and has been rewritten to address the amendment to the claims in the reply filed on 06/18/2026.
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, 2, 8, 14-18, 69, and 71 are drawn to a genus of “RSPO3 inhibitor, wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule” for the treating a subject having endometriosis or at risk of developing endometriosis. The rejected claims thus comprise a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and are defined as belonging to the broad class of “RSPO3 inhibitory nucleic acid molecules” and having the function of treating a subject having endometriosis or at risk of developing endometriosis.
Claim 8 is drawn to “wherein the subject is also administered an endometriosis therapeutic agent comprising an analgesic, a hormone, a gonadotropin-releasing hormone (GnRh) analog, an androgen receptor agonist, or an aromatase inhibitor.” Thus, claim 8 is drawn to the genus and subgenera of “endometriosis therapeutic agent comprising an analgesic, a hormone, a gonadotropin-releasing hormone (GnRh) analog, an androgen receptor agonist, or an aromatase inhibitor”. The rejected claims comprise a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and subgenera of “endometriosis therapeutic agent” and are defined as belonging to the broad class of “RSPO3 inhibitory nucleic acid molecules” and “endometriosis therapeutic agents” and having the function of treating a subject having endometriosis or at risk of developing endometriosis.
Claim 14 is drawn to “further comprising detecting the presence or absence of an RSPO3 variant nucleic acid molecule in a biological sample from the subject”. The rejected claims thus comprise a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and are defined as belonging to the broad class of “RSPO3 inhibitory nucleic acid molecules” and having the function of treating a subject having endometriosis or at risk of developing endometriosis.
Claims(s) 15-16 are drawn to “further comprising administering an endometriosis therapeutic agent in a standard dosage amount to the subject when the RSPO3 variant nucleic acid molecule is absent from the biological sample, wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a gonadotropin- releasing hormone (GnRH) analog, an androgen receptor agonist, or an aromatase inhibitor.”, (of claim 15) and “further comprising administering an endometriosis therapeutic agent in a dosage amount that is less than a standard dosage amount to the subject when the subject is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule, wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a gonadotropin-releasing hormone (GnRH) analog, an androgen receptor agonist, or an aromatase inhibitor.”, (of claim 16), both of which depend from claim 14. The rejected claims comprise a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and subgenera of “endometriosis therapeutic agent” and are defined as belonging to the broad class of “RSPO3 inhibitory nucleic acid molecules” and “endometriosis therapeutic agents” and having the function of treating a subject having endometriosis or at risk of developing endometriosis when (a) the RSPO3 variant nucleic acid molecule is absent from the biological sample or (b) the subject is heterozygous or homozygous for the RSPO3 variant nucleic acid.
Claim(s) 21, 32-34, 70, and 72 are drawn to the genera of (1) an “endometriosis therapeutic agent. . . wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a gonadotropin-releasing hormone (GnRH) analog, an androgen receptor agonist, or an aromatase inhibitor. . . ”, and/or (2) an “RSPO3 inhibitor. . . wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule”, for the treating a subject having endometriosis or at risk of developing endometriosis. The rejected claims thus comprise subgenera of “endometriosis therapeutic agents” and/or a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and are defined as belonging to the broad class “endometriosis therapeutic agents” and “RSPO3 inhibitory nucleic acid molecules” and having the function of treating a subject having endometriosis or at risk of developing endometriosis.
Claim(s) 23-25 are drawn to “The method of claim 21, wherein the wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA).”, (of claim 23), “wherein the inhibitory nucleic acid molecule comprises an siRNA.”, (of claim 24), and “wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.”, (of claim 25). The rejected claims thus comprise subgenera of “endometriosis therapeutic agents” and/or a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and are defined as belonging to the broad class “endometriosis therapeutic agents” and “RSPO3 inhibitory nucleic acid molecules” and having the function of treating a subject having endometriosis or at risk of developing endometriosis.
Claim 32 is drawn to “wherein the subject is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule; the subject is administered or continued to be administered the endometriosis therapeutic agent in an amount that is less than a standard dosage amount; and the subject is administered the RSPO3 inhibitor.” The rejected claims thus comprise subgenera of “endometriosis therapeutic agents” and a genus of “inhibitory nucleic acid molecules that hybridize the an RSPO3 nucleic acid molecule” and are defined as belonging to the broad class “endometriosis therapeutic agents” and “RSPO3 inhibitory nucleic acid molecules” and having the function of 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 wherein the inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule 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).
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 that binds to a recognition sequence within an Rspo3 genomic nucleic acid molecule.”
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).
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims in regard to structure and function, the examples are only representative of (a) three inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule i.e., an (1) siRNA, (2) shRNA, and/or (3) an antisense; and (b) eight endometriosis therapeutic agents, i.e., (1) ibuprofen, (2) naproxen, (3) progestin, (4) goserline, (5) leuprolide, (6) nafarelin, (7) elaglix, and (8) danazol. These results are not necessarily predictive of all “inhibitory nucleic acid molecules hybridizing to an RSPO3 nucleic acid molecule” and/or “endometriosis therapeutic agents” capable of treating a subject having endometriosis or at risk of developing endometriosis. Thus, it is impossible for one to extrapolate from the three examples of “inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule” or from the eight examples of “endometriosis therapeutic agents” that those would necessarily meet the structural/functional characteristics of the rejected claims.
For instance, the subgenus of “hormones” under the genus of endometriosis therapeutic agents is broad. The specification list “estrogen” as a hormone for the subgenus of endometriosis therapeutic agents, however, Chantalat et al (Estrogen Receptors and Endometriosis, Int J Mol Sci, vol 21, issue 8, pages 1-17, published April 17th, 2020) teaches “. . . the main trophic factor in endometriosis is estrogen and estrogen exposure plays a crucial role in the development of the disease via estrogen receptors (ERs). . . 17β-Estradiol (E2) is a key hormone for the growth and persistence of endometriotic tissue as well as the inflammation and pain associated with it. Estradiol reaches endometriosis by the circulation but it is mainly produced locally in the endometriotic tissue. This local estrogen accumulation has been considered to play an important role in the development and progression of endometriotic lesions by binding and activating ERs. . . The enzyme aromatase is a member of the cytochrome P450 superfamily and is responsible for the last step in the synthesis of E2, i.e., the aromatization of androgens (androstenedione and testosterone) into estrogens (oestrone and E2, respectively).”, (p.3, para 2-3).
As for inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule, the specification describes inhibitory nucleic acid molecules hybridizing to an RPSO3 RNA molecule, i.e., siRNA, shRNA, and/or antisense with described modifications. However, the specification fails other inhibitory nucleic acid molecules hybridizing to an RSPO3 nucleic acid molecules such as aptamers, which cannot be predicted based on sequence complementarity.
Zhuo et al (Recent Advances in SELEX Technology and Aptamer Applications in Biomedicine, Int J Mol Sci, vol 18, issue 2142, pates 1-19, published October 14th, 2017) teaches: “Aptamers are short DNA/RNA oligonucleotides capable of binding to target molecules with high affinity and specificity. The process of selecting an aptamer is called Systematic Evolution of Ligands by Exponential Enrichment (SELEX).”, (abstract). Moreover, Zhuo et al teaches, “The conventional SELEX method mainly consists of the following three steps: selection, partitioning and amplification (Figure 1). Before the selection, a library of oligonucleotides is synthesized, which generally contains up to 1015 different unique sequences [1]. Each unique sequence contains random bases (20–50 nt) flanked by two conserved primer binding sites, which are used for PCR amplification by annealing primers. In the selection step, the library is incubated with target molecules for the indicated time. After incubation, the unbound sequences are separated from those that bound by different methods. The target-bound sequences are amplified by PCR(DNASELEX)or reverse transcription PCR (RNA SELEX). The PCR products, being a new sub-pool, are utilized for the next round of selection. After several selection rounds, the enriched sequences are sequenced, and their binding abilities are further evaluated. Generally, it takes from weeks to months to obtain specific aptamer candidates, and the hit rates are low. Thus, the obtainment of high quality aptamers against relevant targets still remains a bottleneck.”, (page 2, para 5).
Therefore, the art does not appear to offset the deficiencies of the specification. Merely describing a “inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule” and “an endometriosis therapeutic agent comprising an analgesic, a hormone, a gonadotropin-releasing hormone (GnRh) analog, an androgen receptor agonist, or an aromatase inhibitor” capable of treating a subject having endometriosis or at risk of developing endometriosis without sufficient detail relating to the genera of “inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule” and/or “endometriosis therapeutic agent comprising an analgesic, a hormone, a gonadotropin-releasing hormone (GnRh) analog, an androgen receptor agonist, or an aromatase inhibitor” 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) 1-2, 8, 14-18, 21, 23-25, 32-34, and 69-72.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Written Description
The previous rejection of claim(s) 3, 7, 22, and 26 under 35 U.S.C 112(a) for written description is moot in view of Applicant’s cancellation of the claims filed 06/18/2026.
The previous rejection of claim(s) 4-6 under 35 U.S.C 112(a) for written description has been withdrawn in view of Applicant’s amendments of the claim(s) 1 and 21 filed 06/18/2026.
With respect to the rejection of claim(s) 1, 2, 8, 14-18, 21, 23-25, and 32-34 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, Applicant’s argument on page 11 of the reply filed 06/18/2026 has been fully considered but it is not persuasive.
Applicant contends that the amended claims recite “particular RSPO3 inhibitors”, and that the specification of the present application “contains sufficient written description conveying possession of claims 1, 2, 4-6, 8, 14-18, 21, 23-25, and 32-34 at least because the independent claims at issue are effectively original (see, M.P.E.P. §2163(I)(A) (2024) ("There is a presumption that an adequate written description of the claimed invention is present when the application is filed.") (emphasis added) (citing In re Wertheim, 541 F.2d 257, 263 (C.C.P.A. 1976), for the proposition that "the [Office] has the initial burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the [claimed subject matter]")).”
Examiner would like to point to the Office Action filed 03/19/2026, where “RSPO3 inhibitors” was one of four genera i.e., “(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.”, for the written description rejection. It is acknowledged that Applicant amended the claims to remove (2) and (4). Applicant does not address (3) “endometriosis therapeutic agent” in the reply but does amend the claims in which “endometriosis therapeutic agent” proceeds a wherein clause of “wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a gonadotropin-releasing hormone (GnRh) analog, an androgen receptor agonist, or an aromatase inhibitor”. Applicant’s “particular” RSPO3 inhibitor is the genus of “inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule.” The written description rejection has been rewritten to address the claim amendments to the genera of (1) and (3), see rejection above.
As for the MPEP 2163(I)(A) section, Applicant omitted the broader guidance of the section. The full section is as follows, emphasis on the portion omitted in the reply filed 06/18/2026:
There is a presumption that an adequate written description of the claimed invention is present when the application is filed. In re Wertheim, 541 F.2d 257, 263, 191 USPQ 90, 97 (CCPA 1976) ("[W]e are of the opinion that the PTO has the initial burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims."). However, as discussed in subsection I, supra, issues of adequate written description may arise even for original claims, for example, when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the inventor had possession of the claimed invention at the time of filing. The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional or known in the art.
Accordingly, the rejection on 35 U.S.C. 112(a) for lack of written description is
maintained for claim(s) 1, 2, 8, 14-18, 21, 23-25, 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, 2, 4-6, 8, 14-18, 21, 23-25, 32-34, and 69-72 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 3 (RSPO3) inhibitor, wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule. The nature of the invention is complex in that the RSPO3 inhibitor, i.e., wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule must be capable of treating a subject having endometriosis, or a risk of developing endometriosis.
Claim 2 is drawn to The method of claim 1, wherein the endometriosis comprises superficial peritoneal endometriosis, endometrioma-containing endometriosis, deeply infiltrating endometriosis (DIE), or abdominal wall endometriosis. The nature of the invention is complex in that the RSPO3 inhibitor, i.e., wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule must be capable of treating a subject having superficial peritoneal endometriosis, endometrioma-containing endometriosis, deeply infiltrating endometriosis (DIE), or abdominal wall endometriosis or a risk of developing endometriosis said forms of endometriosis.
Claim(s) 4-6 are drawn to The method of claim 1, wherein the inhibitory nucleic acid molecule comprises an antisense (of claim 6), a siRNA (of claim 5), and/or a shRNA. The nature of the invention is complex in that the RSPO3 inhibitor, i.e., an antisense, an siRNA, and/or a shRNA must be capable of treating a subject having endometriosis, or a risk of developing endometriosis.
Claim 8 is drawn to the method of claim 1, wherein the subject is also administered an endometriosis therapeutic agent comprising an analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor. The nature of the invention is complex in that the RSPO3 inhibitor, i.e., wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule and an endometriosis therapeutic agent, i.e., analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor must be capable of treating a subject having endometriosis, or a risk of developing endometriosis.
Claim(s) 14-18 are drawn to the method of claim 1, further comprising detecting the presence or absence of an RSPO3 variant nucleic acid molecule in a biological sample from the subject (claim 14); further comprising administering an endometriosis agent in a standard dosage amount to the subject when the RSPO3 variant nucleic acid molecule is absent from the biological sample, wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor (of claim 15); and further comprising administering an endometriosis therapeutic agent in a dosage amount that is less than a standard dosage amount to the subject when the subject is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule, wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a gonadotropin-releasing hormone (GnRH) analog, an androgen receptor agonist, or an aromatase inhibitor (of claim 16). The nature of the invention is complex in that the RSPO3 inhibitor, i.e., wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule and an endometriosis therapeutic agent, i.e., analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor must be capable of treating a subject having endometriosis, or a risk of developing endometriosis wherein the subject is an RSPO3 reference, heterozygous, or homozygous for an RSPO3 variant.
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 and/or an R- Spondin 3 (RSPO3) inhibitor, the method comprising: performing or having performed a genotyping analysis on a biological sample obtained from the subject to determine whether the subject has a genotype comprising an RSPO3 variant nucleic acid molecule; and administering or continuing to administer the endometriosis therapeutic agent 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 to a subject that is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule, and/or administering an RSPO3 inhibitor to the subject wherein the endometriosis therapeutic agent comprises an analgesic, a hormone, a gonadotropin-releasing hormone (GnRH) analog, an hormone, a gonadotropin-releasing hormone (GnRH) analog, an increased risk of developing endometriosis androgen receptor agonist, or an aromatase inhibitor; and wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule. The nature of the invention is complex in that endometriosis therapeutic agent, i.e., analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor and/or the RSPO3 inhibitor, i.e., wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule must be capable of treating a subject having endometriosis, or a risk of developing endometriosis wherein the subject is an RSPO3 reference, heterozygous, or homozygous for an RSPO3 variant.
Claims 23-25 are drawn to the method of claim 1 wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA). The nature of the invention is complex in that the antisense, siRNA, and/or shRNA and an endometriosis therapeutic agent, i.e., analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor must be capable of treating a subject having endometriosis, or a risk of developing endometriosis wherein the subject is an RSPO3 reference, heterozygous, or homozygous for an RSPO3 variant.
Claim 32 is drawn to the method of claim 21 wherein: the subject is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule the subject is administered or continued to be administered the endometriosis therapeutic agent in an amount that is less than a standard dosage amount; and the subject is administered the RSPO3 inhibitor. The nature of the invention is complex in that the RSPO3 inhibitor, i.e., wherein the RSPO3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule and an endometriosis therapeutic agent, i.e., analgesic, a hormone, a GnRh analog, an androgen receptor agonist, or an aromatase inhibitor must be capable of treating a subject having endometriosis, or a risk of developing endometriosis wherein the subject is an heterozygous, or homozygous for an RSPO3 variant.
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 an RSPO3 inhibitors, wherein the inhibitor comprises any/all inhibitory nucleic acid molecules that hybridize to an RSPO3 nucleic acid molecules. The claims broadly encompass “RSPO3 inhibitors wherein the inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid molecule” and is 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 endometriosis therapeutic agents (wherein the endometriosis therapeutic agents comprises any/all analgesics, any/all hormones, any/all GnRH analogs, any/all androgen receptor agonists, or any/all aromatase inhibitors), and/or an RSPO3 inhibitors (wherein the inhibitor comprises any/all inhibitory nucleic acid molecules that hybridize to an RSPO3 nucleic acid molecules), the method comprising: performing or having performed a genotyping analysis on a biological sample obtained from the subject to determine whether the subject has a genotype comprising an any/all RSPO3 variant nucleic acid molecule; and administering or continuing to administer the endometriosis therapeutic agent 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 to a subject that is heterozygous or homozygous for the RSPO3 variant nucleic acid molecule, and/or administering an RSPO3 inhibitor to the subject. The claims broadly encompass “endometriosis therapeutic agent (wherein the endometriosis therapeutic agents comprises any/all analgesics, any/all hormones, any/all GnRH analogs, any/all androgen receptor agonists, or any/all aromatase inhibitors)” and “RSPO3 inhibitors (wherein the inhibitor comprises any/all inhibitory nucleic acid molecules that hybridize to an RSPO3 nucleic acid molecules)”, where “endometriosis therapeutic agent” and “RSPO3 inhibitors” 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 (inhibitory nucleic acid molecules), (e) endometriosis therapeutic agent, and (f) 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);
(e) 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).
(f) “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 three 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; see PTO 892 filed 03/19/2026) 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; see PTO 892 filed 03/19/2026) 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).
Chantalat et al (supra) teaches “. . . the main trophic factor in endometriosis is estrogen and estrogen exposure plays a crucial role in the development of the disease via estrogen receptors (ERs). . . 17β-Estradiol (E2) is a key hormone for the growth and persistence of endometriotic tissue as well as the inflammation and pain associated with it. Estradiol reaches endometriosis by the circulation but it is mainly produced locally in the endometriotic tissue. This local estrogen accumulation has been considered to play an important role in the development and progression of endometriotic lesions by binding and activating ERs. . . The enzyme aromatase is a member of the cytochrome P450 superfamily and is responsible for the last step in the synthesis of E2, i.e., the aromatization of androgens (androstenedione and testosterone) into estrogens (oestrone and E2, respectively).”, (p.3, para 2-3).
Moreover, Chantalat et al teaches, “Hormonal treatment alone does not provide long-term disease control because it is often interrupted due to a significant amount of untoward side effects.”, (p. 3, para 1).
Further, “Several risk factors including endocrine, genetic, biochemical, environmental,
and immunological factors are effective in the initiation and progression of the disease [6,23]. These mechanisms might act in unison to cause endometriosis, but the main trophic factor in endometriosis is estrogen and estrogen exposure plays a crucial role in the development of the disease via estrogen receptors (ERs).”, (p.3, para 2).
As for inhibitory nucleic acid molecule hybridizing to an RSPO3 nucleic acid molecule, Zhuo et al (supra) teaches: “Aptamers are short DNA/RNA oligonucleotides capable of binding to target molecules with high affinity and specificity. The process of selecting an aptamer is called Systematic Evolution of Ligands by Exponential Enrichment (SELEX).”, (abstract). Moreover, Zhuo et al teaches, “The conventional SELEX method mainly consists of the following three steps: selection, partitioning and amplification (Figure 1). Before the selection, a library of oligonucleotides is synthesized, which generally contains up to 1015 different unique sequences [1]. Each unique sequence contains random bases (20–50 nt) flanked by two conserved primer binding sites, which are used for PCR amplification by annealing primers. In the selection step, the library is incubated with target molecules for the indicated time. After incubation, the unbound sequences are separated from those that bound by different methods. The target-bound sequences are amplified by PCR(DNASELEX)or reverse transcription PCR (RNA SELEX). The PCR products, being a new sub-pool, are utilized for the next round of selection. After several selection rounds, the enriched sequences are sequenced, and their binding abilities are further evaluated. Generally, it takes from weeks to months to obtain specific aptamer candidates, and the hit rates are low. Thus, the obtainment of high quality aptamers against relevant targets still remains a bottleneck.”, (page 2, para 5).
Lastly, Zhang et al (The risk of miRNA Therapeutics: In a Drug Target Perspective, Drug Design, Development and Therapy, volume 15, pages 721-733, published February 22nd, 2021) teaches, “Beyond our expectation, the targets of the miRNA drug ranged from 30 to 250 in number and almost all miRNA drug* were over 500 and even 1000, but the si0052NA drug generally targets 1–3 genes (Figure 2B). The majority of miRNA targets tens and hundreds of genes, and we named it “too many targets for miRNA effect” (TMTME).”, (p.722, col 2, para 2).
Further, Zhang et al teaches, “TMTME (“too many targets for miRNA effect”) is a typical and inevitable property of miRNA molecules, which is caused by incomplete complementation with the target sequence. TMTME leads to that miRNA could bind to various sequences suitable for the interaction (including protein-coding genes, lncRNA, circRNA, etc), which is different from all approved drugs (including siRNA drugs) with only a few targets… Therefore, both introduction and removal of miRNA in humans can lead to changes of a wide series of pathways and some of them are unknown, even unpredictable, probably triggering disorders of physiological function or the occurrence of additional disease.”, (Page 729, column 1, paragraph 2 to column 2, paragraph 1).
Zhang et al teaches, “Moreover, due to instability of unprotected miRNAs, delivering miRNAs required chemical modifications to avoid rapid degradation in serum, which may impair specificity of miRNAs and lead to off-target effects… Another challenge is that exogenous artificial miRNAs will trigger competition and saturation effect, a competition among exogenous and the endogenous miRNAs for the intracellular machinery, and thus affecting unexpected gene expression and leading to untoward side effects.”, (page 730, column 1, paragraph 1).
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 and that the main factor in endometriosis is estrogen. The art teaches that estrogen exposure plays a significant role in the development of endometriosis and that hormones alone do not provide long-term disease control due to untoward side effects. Lastly, the art teaches the extensiveness of producing an aptamer, which is an inhibitory nucleic acid that hybridizes and the unpredictability of an miRNA drug.
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 endometriosis therapeutic agents such as a hormone (e.g., estrogen), and/or administering RSPO3 inhibitory nucleic acid molecules (e.g., an aptamer) to the subject.
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 inhibitory nucleic acid molecules targeting all three splice variants of RSPO3 that cover the various functions of the broad genus of inhibitory nucleic acid molecule for the ability of treating endometriosis; (2) screen random analgesics, hormones, GnRH analogs, androgen receptor agonists, and aromatase inhibitors that cover the various functions of the broad subgenera of endometriosis therapeutic agents for the ability for treating endometriosis in combination with a chosen RSPO3 inhibitory nucleic acid; 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 with estrogen for example) 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, claim(s) 1, 2, 4-6, 8, 14-18, 21, 23-25, 32-34, and 69-72 are not considered to be enabled by the instant disclosure.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Enablement
The previous rejection of claim(s) 3, 7, 22, and 26 under 35 U.S.C 112(a) for written description is moot in view of Applicant’s cancellation of the claims filed 06/18/2026.
With respect to the rejection of claim(s) 1, 2, 4-6, 8, 14-18, 21, 23-25, and 32-34 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, Applicant’s argument on page 12-13 of the reply filed 06/18/2026 has been fully considered but it is not persuasive for at least the following reasons.
Applicant contends that a person of skill in the art would have been able to practice the claimed subject matter without being required to perform undue experimentation. Applicant points to antisense therapeutics and contends that a person skilled in the art could have relied on such reference (“Wong and Goldberg”) for the determination of a therapeutic antisense nucleic acid and associated clinical trials. As such, a person of skill in the art could have relied on such reference to discern the appropriate dose and method of use of at least the siRNA recited in the Applicant’s claims.
Applicant contends that as of the earliest filing date that that present application claims, the inhibitory nucleic acid molecule design was sufficiently mature that software was available that could generate the nucleotide sequences of the inhibitory nucleic acids.
Lastly, Applicant contends that “Khvorova” reports that “[t]he ability to use the [reported] algorithms, which are not sequence or species specific, allows for the cost-effective selection of optimized siRNAs for specific target sequences; and that ii) there will be both greater efficiency and reliability in the us of siRNA technologies.”, thus the Applicant concludes Khvorova favors their position.
Amended claim 1 added “wherein the inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an RSPO3 nucleic acid.” The claim broadly emcompasses not only, antisense molecules, but aptamers and microRNAs as well. Zhang et al (supra) teaches that both the introduction and removal of miRNAs in humans can lead to changes of a wide series of pathways and some of them are unknown, even unpredictable, probably triggering disorders of physiological function or the occurrence of additional disease. Further, Zhang et al teaches that another challenge [for miRNA therapy] is that exogenous artificial miRNAs will trigger competition and saturation effect, a competition among exogenous and the endogenous miRNAs for the intracellular machinery, and thus affecting unexpected gene expression and leading to untoward side effects.
As for software/algorithms that is available to generate nucleotide sequences of inhibitory nucleic acids, this is not the case for Apatmers. Zhuo et al (supra) teaches that the process of aptamer design and testing is arduous: “After several selection rounds, the enriched sequences are sequenced, and their binding abilities are further evaluated. Generally, it takes from weeks to months to obtain specific aptamer candidates, and the hit rates are low. Thus, the obtainment of high quality aptamers against relevant targets still remains a bottleneck.”
Lastly, it is emphasized that the phrase “at risk of developing” is one that lacks enablement. Sahni and Day (supra) to teaches “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.”
Accordingly, the rejection on 35 U.S.C. 112(a) for Enablement is maintained for claim(s) 1, 2, 4-6, 8, 14-18, 21, 23-25, and 32-34.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/L.M.T./Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
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