DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
2. Applicant’s response, submitted December 1, 2025, has been reviewed by the examiner. No claim is amended, canceled, or added.
3. Claims 16-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, without traverse, there being no allowable generic or linking claim.
4. Claims 1-15 are under examination and are the subject of this office action.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on December 1, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Previous Claim Rejections - 35 USC § 103
6. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
7. Claims 1-15 remain rejected under 35 U.S.C. 103 as being unpatentable over Archer et al., Gynecology (2017), in view of Jo et al., EP 2535342 A1 (cited on Applicant’s IDS of January 26, 2024), as evidenced by The Medical-Dictionary/ The Free Dictionary.com (see webpage printouts of https://medical-dictionary.thefreedictionary.com/metrofibroma and https://medical-dictionary.thefreedictionary.com/fibroma, cited on Applicant’s IDS of January 26, 2024).
Claim 1 is drawn to a method of reducing the volume of menstrual blood loss in a female human patient, (more specifically wherein the patient has uterine fibroids (claim 2)), the method comprising orally administering (claim 7) to the patient a therapeutically effective amount of a compound 3-[2-fluoro-5-(2,3- difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4- tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof (claim 5), (more specifically, the choline salt (claim 6)), in an amount of about 200 mg per day (claim 4), once daily (claim 8).
Claim 9 is drawn to a method of treating uterine fibroids in a female human patient in need thereof, the method comprising orally administering (claim 14) to the patient a therapeutically effective amount of a compound 3-[2- fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo- 1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof (claim 12) , (more specifically the choline salt (claim 13), in an amount of about 200 mg per day (claim 11), once daily (claim 15).
8. Archer et al. teach that the administration of the GnRH antagonist elagolix resulted in significant reductions in heavy menstrual bleeding in women with uterine fibroids (See Abstract: Results). In particular, Archer et al. disclose that when orally administered at a dosage of 100 mg twice daily (“E100 BID”) elagolix resulted in at least a 40% reduction in fibroid volume (page 155, left column, under “Results,” and see Table 1 at page 154). A dosage of 100 mg twice daily meets the limitation of “about 200 mg per day,” required by claims 4 and 11.
9. Archer et al. do not teach the administration of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid.
10. Yet, Jo et al. specifically teach that the well-known GnRH antagonist “compound (B),” which is the same as Applicant’s recited compound, 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid, and its choline salt, “compound (A)”:
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, demonstrates efficacy in the treatment of metrofibroma, (see paragraphs [0001]-[0002] and page 2, lines 39-41). It is clear as evidenced by The Medical-Dictionary/ The Free Dictionary.com that a metrofibroma is also known as a uterine fibroma (see https://medical-dictionary.thefreedictionary.com/metrofibroma), and a fibroma is a type of fibroid, i.e. a tumor composed mainly of fibrous or fully developed connective tissue, see fibroid, (see https://medical-dictionary.thefreedictionary.com/fibroma).
11. Jo et al. additionally teach that the choline salt, compound (A), demonstrates excellent solubility, oral absorbability and storage stability in Examples 1-3, (see page 9, paragraph [0038]).
12. Thus, one of skill in the art would be motivated to select the choline salt of the GnRH antagonist compound taught by Jo et al., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid, to substitute for elagolix in a method of treating uterine fibroids in a female patient in need thereof, and would have a reasonable expectation of success in its administration at 200 mg/day.
13. And, as noted by the court in In re Font, 675 F.2d 297 (CCPA 1982), an express suggestion to substitute one equivalent component (i.e., an equivalent GnRH antagonist) for another is not necessary to render such substitution obvious. In the instant case, (1) the prior art element of Archer et al. performs the function specified in the claim with only insubstantial differences; (2) the claimed component and its function was known in the art (i.e., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof and its efficacy for treating metrofibroma/fibroids as taught by Jo et al.); (3) a person of ordinary skill in the art would have recognized the interchangeability of the elements and could have substituted one known element for another; and (4) the results of the substitution would have been predictable, i.e., successful reduction of menstrual blood loss and reduction of fibroid volume in a female patient in need thereof.
As such, claims 1, 2, 4-9 and 11-15 are prima facie obvious.
Claim 3 is drawn to claim 1 and limits wherein the compound is administered in an amount of about 100 mg per day.
Claim 10 is drawn to claim 9 and limits wherein the compound is administered in an amount of about 100 mg per day.
14. Archer et al. in view of Jo et al. suggest the administration of the choline salt of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid for reducing menstrual blood loss and treating uterine fibroids in a female patient in need thereof, but do not teach its administration at 100 mg/day.
15. However, dose regimen optimization is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Moreover, the determination of known effective amounts of known active agents to be administered to treat the same disease is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. As Archer et al. teach various dosage regimens for administering a GnRH antagonist to reduce menstrual blood loss and treat uterine fibroids, dose amount is considered a result effective variable. Thus, one of skill in the art would have been motivated to optimize the dosage amount in order to reduce side effects, for example, in a known method of reducing menstrual blood flow or treating uterine fibroids in a patient in need thereof.
As such, claims 3 and 10 are prima facie obvious.
Response to Arguments
16. Applicant traverses the previous obviousness rejection of claims 1-20 over Archer et al. in view of Jo et al., and argues the following points:
(i) Applicant argues that guided by the cited references, one would have had no reason to select the specific dosage quantities recited in the instant independent claims.
Applicant alleges that in view of the significant chemical differences between elagolix and presently claimed compound (I), one of skill in the art would have had no reason to expect that a dosage quantity that is useful for elagolix would be in any way applicable to the selection of a dosage quantity for compound (I).
Applicant contends that elagolix is not a structural analog of compound (I), as the two compounds have altogether different chemical scaffolds, and that it has been established that there is substantial variation in pharmacokinetic and pharmacodynamic properties even among elagolix and its close chemical derivatives. Applicant argues that one would have had no reason whatsoever to expect that a dosage quantity that is useful for elagolix would be in any way relevant to the selection of a dosage quantity for compound (I).
Applicant references Chen et al., J. Med. Chem. 51:7478-7485 (2008) as evidence of the pharmacokinetic and pharmacodynamic differences among elagolix and its close structural analogs. Applicant argues that in Chen, Table 1 discloses the inhibitory constant (Ki) and half- maximal inhibitory concentration (IC50) values for elagolix and various structural analogs against their biological target, human gonadotropin-releasing hormone (GnRH) receptor. Table 1 shows that elagolix (compound "10b") exhibits substantially different Ki and IC50 values toward human GnRH receptor when compared to closely related variants sharing the same chemical scaffold. Critically, the Ki values reported in Table 1 span two orders of magnitude. For example, Table 1 shows that elagolix inhibits human GnRH receptor with a Ki that is 78-fold stronger than that of compound "8," which differs from elagolix merely by the absence of two methylene groups. Moreover, elagolix exhibits an IC50 for human GnRH receptor that is 18-fold stronger than that of compound "10a" - these two compounds differ solely by way of the identity of the chemical substituent at the "X" position of the benzyl ring shown above.
Applicant argues that in Table 2, elagolix exhibits a systemic clearance rate that is > 4.6-fold different from that of compound 10a, which has the close structural similarity noted above. And, strikingly, the cell permeability values shown in Table 2 span over an order of magnitude: there is a 44-fold difference between the permeability of the most (compound 4a) and least (compound 10a) permeable compounds in Table 2, with elagolix falling in the middle of the range.
Importantly, given the high degree of variability in pharmacological properties exhibited by elagolix and even closely related compounds sharing the same chemical core, one of skill in the art would have had no reasonable expectation that the dosage quantities disclosed in Archer would even apply to elagolix's close analogs-much less to compound (I), which has an altogether different structural nucleus. The evidence presented above objectively demonstrates that the Office's simple-substitution obviousness rationale is improper. Given these findings, Applicant contends that one would have had no reason to expect that an elagolix dosage amount could be predictably applied to a compound that differs in even slight structural ways, let alone to present compound (I).
17. Applicant's arguments have been fully considered but they are not persuasive. Regarding the teaching of Chen et al., while Tables 1 and 2 teach the pharmacokinetic activity of elagolix and some of its closely related variants, Chen et al. fails to disclose Applicant’s instantly claimed compound (3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid, aka “linzagolix”) in any capacity. Therefore, Chen et al. fails to discourage one of skill in the art from administering the known GnRH antagonist linzagolix for the treatment of uterine fibroids in a female human patient.
And, in U.S. Pat. No. 9,040,693 B2, Ohno et al. also suggest the treatment of metrofibroma (i.e., uterine fibroma, which is a type of fibroid) comprising administering a GnRH antagonist and specifically teach Applicant’s instantly recited compound, 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno-[3,4d]-pyrimidine-5-carboxylic acid, aka “linzagolix” in Table 79 as Example 233:
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(columns 207-208). Ohno et al. disclose the IC50 (at which 50% GnRH is inhibited) of 15 GnRH antagonists including Example 233 (see Table 108 at column 265) and the Cmax of 9 GnRH antagonists including Example 233 (see Table 110 at column 266). Ohno et al. go on to teach that Example 233 demonstrates superior pharmacokinetics in relation to the other disclosed compounds:
“ As shown above, a fused heterocyclic derivative of the present invention is more superior in blood kinetics such as availability and sustainability by oral administration than the Control compounds. For example, the fused heterocyclic derivatives of Examples 48, 146, 191, 202, 233, 271, 367, 414 and 420 exert more excellent availability than the compound of Example 22 having a sulfonamide group and the compound of Example 95 having an amide group, and thus, is more preferable as a pharmaceutical composition for oral administration. In addition, the fused heterocyclic derivatives of Examples 146, 202, 233, 271, 367, 414 and 420, more preferably Examples 146, 233, 271, 367 and 414, maintain their blood concentrations 6 hours after the oral administrations and more superior in sustainability than the Control compounds.”
[emphasis added] (see column 268, lines 1-13). Ohno et al. teach oral administration at a dosage “within the range of from 0.1 to 1,000 mg per day per adult human in case of oral administration” (column 18, lines 56-61). Therefore one skilled in the art would have reasonably considered that the dosage amount taught by Archer and embraced in the prior art by Ohno et al. could be applied to Applicant’s instantly recited compound, with a reasonable expectation of success.
(ii) Applicant argues that the claimed dosing regimens effectuate an unexpected and advantageous result that indicates nonobviousness.
Applicant alleges that the disclosure provides evidence that the claimed dosing schedules of compound (I) achieve a surprising and beneficial treatment outcome: the ability to not only effectively reduce uterine fibroids symptoms, but also to simultaneously avoid substantial reductions in bone mineral density. Applicant argues that in Example 1, the claimed dosages of both 100 mg and 200 mg of compound (I) suppressed uterine blood loss in human clinical trials, without causing substantial loss of bone mineral density.
Applicant argues that compound (I) is a GnRH antagonist that treats uterine fibroids by inhibiting the secretion of endogenous estradiol, which is responsible for the development of uterine fibroids when produced at high levels. But estradiol is also necessary for bone mineralization. Applicant alleges that one could not have predicted that any particular dosage of a GnRH antagonist - much less the specific doses recited in the instant claims - would be capable of not only treating uterine fibroids, but of doing so without simultaneously causing a substantial reduction in bone mineral density.
Applicant references Schlaff et al., N. Engl. J. Med. 382:328-340 (2020), which describes the clinical development of elagolix, during which, two potential dosing options were explored: (i) a stand-alone dosing regimen involving administration of elagolix alone, and (ii) a dosing regimen in which elagolix is administered in combination with estradiol-containing "add-back" therapy. The second dosing regimen was explored as a precaution because as a GnRH antagonist, elagolix treats uterine fibroids symptoms by suppressing endogenous estradiol, but since estradiol is also necessary for maintaining bone mineral density, reductions in estradiol can lead to losses in bone mineralization. Accordingly, the second dosing regimen included add-back therapy as a way of replenishing endogenous estradiol in an effort to mitigate the risk of reductions in bone mass, even though the added estradiol may counteract elagolix's therapeutic effect. Applicant notes that Figure S8 shows after 6 months of continuous treatment with elagolix, the stand-alone dosage reduced bone mineral density at the lumbar spine in approximately half of the patients treated such that add-back therapy was necessary to curtail bone mineral density loss relative to the stand-alone treatment cohort. Applicant argues that one could not have predicted that any specific dosage of a GnRH antagonist would be capable of not only reducing uterine fibroids symptoms, but doing so while simultaneously avoiding substantial reductions in bone mineral density.
Applicant contends that the present disclosure provide evidence that the claimed dosages of compound (I) achieve reductions in uterine fibroids symptoms while improving upon the safety profile of elagolix. Applicant refers to Example 1 of the specification which describes the results of a human clinical trial in which compound (I) was administered to subjects in amounts of 100 mg or 200 mg per day, with or without estradiol add-back therapy. Importantly, not only were the 100 mg and 200 mg stand-alone dosages of compound (I) capable of suppressing uterine blood loss (Figures 20 and 23), but these dosages were capable of avoiding statistically significant reductions in biomarkers of bone mineral density (Figures 25-29) without the need for add-back therapy. As Figures 25-29 show, among subjects treated with the 100 mg and 200 mg stand-alone doses of compound (I), biomarkers of bone mineral density did not show statistically meaningful changes between measurements taken on day 1 of the trial and following 42 days of continuous treatment. As Figure 27 shows, measurements of BAP at baseline (day 1 of the trial) did not exhibit a statistically significant change on day 43 of the trial in subjects treated with the stand-alone 100 mg and 200 mg daily doses of compound (I). Applicant contends that add-back therapy was not needed to avoid substantial reductions in bone mineral density for the 100 mg and 200 mg dosages of compound (I) in the studies reported in the instant specification.
Applicant argues that the data above illustrate that the claimed dosages of compound (I) achieve an unexpected and advantageous improvement in safety relative to other GnRH antagonists for the treatment of uterine fibroids. The claimed dosages of compound (I) effectively treat uterine fibroids symptoms while avoiding the need for add-back therapy, offering patients a treatment option for suppressing heavy menstrual bleeding without necessitating concomitant estradiol supplementation.
18. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the feature upon which Applicant relies (i.e., treating uterine fibroids by inhibiting the secretion of endogenous estradiol without causing substantial loss of bone mineral density) is not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In this case, the claims are limited to reducing the volume of menstrual blood loss and/or the treatment of uterine fibroids in a female patient, and the limitation of avoiding substantial reductions in bone mineral density is not recited in any of the pending claims.
Therefore, Applicant’s arguments are insufficient to overcome the previous obviousness rejections over Archer et al. in view of Jo et al.
Conclusion
19. Claims 1-20 are present in the application. Claims 16-20 are currently withdrawn from consideration. Claims 1-15 are rejected. No claim is presently allowable.
20. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628