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 .
DETAILED ACTION
Claims 220, 223-225, 228, and 235-236 are pending and examined on the merits herein.
Priority
This application claims the following priority:
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Response to Arguments
On pg. 4, Remarks, Applicant argues that “there is virtually no teaching of a correlation between the ‘OBE2109’ codename and a chemical structure, much less the chemical structure of present compound (VI).”
On pg. 5, Remarks, Applicant argues that the CAS STN Registry and PubChem SID entries are dynamic internet databases which are periodically updated to display additional information over time as such information becomes available, and that the structure of “OBE2109” was not available prior to the instant priority date of 11/07/2018.
In view of these arguments the rejection has been modified to clearly show that the structure of OBE2109 was known as instant formula (VI) prior to the instant effective filing date.
REJECTIONS—MODIFIED
The below rejections rely on the same prior art as applied in the previous Office Action. Three references are added to clearly show that OBE2109 was identified as the compound of instant formula (VI), prior to the instant effective filing date.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 220, 223-225, 228, and 235-236 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03070951 (‘951) Clinical Trial (published 09/25/2017, PTO-892 of 06/12/2024) in view of Biospace (ObsEva and Kissei Pharmaceutical Co., Ltd. Announce Global Agreement to Develop and Commercialize KLH-2109 For the Treatment of Endometriosis, published 2015, PTO-892), PubChem (KLH-2109, 2016 date of deposit and availability, PTO-892), WO2011099507 (Translation, published 2011, PTO-892), WO 2018/030317 to Takura (published 02/2018, Translation-PTO-892 of 05/04/2023, Original Doc.-IDS of 05/04/2023), ClinicalLeader (published 04/25/2017, PTO-892 of 06/12/2024), and US 2021/0154207 to Chwalisz (effectively filed 07/28/2018, PTO-892 of 05/04/2023), as evidenced by SciFinder (PTO-892 of 05/04/2023).
NCT ‘951 teaches a method of treating heavy menstrual bleeding associated with uterine fibroids in pre-menopausal women by the daily oral administration of OBE2109 alone and in combination with add back therapy (“Study Identification,” Official Title).
The minimum age of the women is 18 (‘951, “Eligibility”).
Regarding OBE2109, Biospace, published in 2015, teaches “Under the terms of the agreement, ObsEva will acquire the exclusive rights to develop and commercialize KLH-2109 worldwide, excluding Asia. Both companies will collaborate in parallel in the development of KLH-2109, represented in ObsEva’s pipeline as OBE2109” (pg. 1, 1st paragraph).
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(pg. 2).
PubChem teaches KLH-2109 as having the structure of instant formula (VI) and as being deposited on 10/26/2016, and as being available as of 10/26/2016.
WO2011099507 and WO2018030317 (Takura) are both assigned to Kissei Pharmaceutical Co Ltd and list their applications as filed by Kissei Pharmaceutical Co. Ltd.
WO ‘507 teaches 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, which is instant Formula (VI) (abstract), and teaches this compound as a gonadotropin releasing hormone antagonist for use in prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, amenorrhea, and more (pg. 1, “Claims,” “Description”).
WO ‘317 teaches 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, which is instant Formula (VI) for the treatment of endometriosis (pg. 1, Claims). This compound is taught as a GnRH antagonist for use in prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, amenorrhea, and more (pg. 2).
Thus, in view of the teachings of BioSpace, PubChem, WO ‘507, and WO ‘317, OBE2109 is KLH-2109, which is 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, the compound of instant Formula (VI), and its structure was known prior to the effective filing date.
Regarding claims 220, 235 and 236, while NCT ‘951 teaches a method of treating heavy menstrual bleeding in premenopausal women with uterine fibroids by administering OBE2109, it differs from that of claims 220, 235 and 236 in that it does not teach the choline salt of OBE2109.
Takura teaches the compound of instant formula (VI), (referenced as Compound 1 by Takura and as OBE2109 by ‘951), or the choline salt of the compound of instant formula (IV) as a GnRH antagonist useful for the treatment of uterine fibroids (pg. 2, translation, last paragraph).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to substitute the OBE2109 of NCT ‘951 with the OBE2109 choline taught by Takura, to arrive at the choline salt of instant formula (VI). One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Takura teaches that either the compound of instant formula (VI), or the choline salt of the compound of instant formula (VI), can be administered as an GNRH antagonist for the treatment of uterine fibroids, and
-substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06.
As such, an artisan having ordinary skill in the art would have been motivated to make such a substitution to predictably arrive at a structurally and functionally similar OBE2109 GnRH antagonist.
Further regarding claims 220, 235, and 236, while the combination of NCT ‘951 and Takura teaches a method of treating heavy menstrual bleeding in premenopausal women with uterine fibroids by administering OBE2109 choline and add-back therapy, it differs from that of independent claims 220, 235 and 236, in that it does not teach its administration in an amount of about 100 or 200mg per day.
ClinicalLeader teaches, regarding the above NCT ‘951 clinical trials of OBE2109 in Uterine Fibroids, that the subjects are administered either 100mg or 200mg OBE2109 (pg. 1, 3rd paragraph).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select 100 or 200mg of the OBE2109 choline to administer in the combination of ‘951 and Takura, to arrive at the instantly claimed dosage amount. One of ordinary skill in the art would have been motivated to administer such a selection, with a reasonable expectation of success, because ClinicalLeader teaches that the OBE2109 in the clinical trial of NCT ‘951, is administered in 100 or 200mg amounts for the treatment of uterine fibroids.
Thus, an ordinary skilled artisan would have reasonably expected the administration of 100 or 200mg amounts of OBE2109 choline to be clinically effective in the treatment of heavy menstrual bleeding and heavy menstrual bleeding in premenopausal women with uterine fibroids.
Further regarding claims 220, 235 and 236, while the combination of NCT ‘951, Takura and ClinicalLeader teaches a method of treating heavy menstrual bleeding in premenopausal women with uterine fibroids by administering about 100 or about 200 mg/day of OBE2109 choline, it differs from that of independent claims 220, 235 and 236 in that it does not teach the add-back therapy as 1mg/day beta17-estradiol and 0.5mg/day of norethindrone acetate.
Chwalisz teaches a method of treating heavy menstrual bleeding in a subject with uterine fibroids by administering a GnRH receptor antagonist in combination with the add-back therapy of estrogens and progestogen (abstract, paragraph 11, pg. 27-28-claims 1-3, 19-21).
Chwalisz specifically teaches 1mg estradiol and 0.5mg norethindrone acetate administered once per day as the add-back therapy (pgs. 27-28, claims 1-7).
As evidenced by SciFinder, estradiol is 17beta-estradiol (pg. 2).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select 1mg estradiol and 0.5mg norethindrone acetate administered once per day as the add-back therapy in NCT ‘951, to arrive at the claims 220, 235 and 236. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Chwalisz teaches administration of 1mg estradiol and 0.5mg norethindrone acetate once per day as the add-back therapy in combination with a GnRH antagonist, for the treatment of bleeding associated with uterine fibroids, and
-NCT ‘951 teaches combining an add-back therapy with its GnRH antagonist, OBE2109, for the treatment of bleeding associated with uterine fibroids.
Thus, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method that prevents hypoestrogenic symptoms, such as bone mineral loss, which is known to occur with the administration of GnRH antagonists ([0079] and [0390], Chwalisz).
Regarding claims 235 and 236, since the combination of NCT ‘951, Takura, ClinicalLeader, and Chwalisz, teaches the instantly claimed methods, these methods reduce the volume of menstrual blood loss and induce amenorrhea; if the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See MPEP 2111.02 and 2112.02.
Regarding claim 223, NCT ‘951 teaches oral administration.
Regarding claims 224, 225 and 228, NCT ‘951 teaches daily administration of OBE2109 and add-back therapy (pg. 4).
Claims 220, 223, 224, 225, 228, 235 and 236, are rendered obvious.
Response to Arguments
On pgs. 10-11, Remarks, Applicant argues that compound (VI), when administered along with 1mg of E2 and 0.5mg of NETA, results in a more robust reduction of uterine bleeding than when compound (VI) is administered with no add-back therapy at all. Applicant further argues that due to the add-back therapy’s function of partially neutralizing the E2 reducing therapeutic effects of the GnRH antagonist, one would have expected higher doses of add-back therapy to result in diminished treatment efficacy. As evidence of this result, Applicant points to the Donnez publication (IDS of 10/03/2023), Fig. 1, pg. 901.
This argument has been fully considered, but is not found persuasive.
First, it is respectfully pointed out that BioSpace teaches KLH-2109/OBE2109 as a best-in-class profile that allows for partial estrogen suppression. “It maintains estradiol in the low-normal range, providing symptom reduction while avoiding significant bone loss or other adverse effects that can be associated with excessive suppression of estrogen” (pg. 1, BioSpace). As such, the prior art teaches that the compound of NCT ‘951 is already known to have the property of maintaining estradiol in the low-normal range.
Moreover, NCT ‘951 is the closest prior art and teaches instant compound (VI), i.e., OBE2109, administered alone or in combination with add-back therapy, for the treatment of heavy menstrual bleeding associated with uterine fibroids. As such, it is not clear how this is an unexpected result since the prior art (NCT ‘951) already teaches such a combination for the treatment of the same disease, and the prior art already teaches instant compound (VI) as having the benefit of only partially suppressing estrogen.
Since Applicant has not provided comparative results with the closest prior art, it is not possible to evaluate whether or not that is an unexpected result.
Though no comparison with the closest prior art is provided, the arguments in reference to the Donnez publication are addressed below.
Regarding Figure 1 of Donnez, which is reproduced on pg. 11, Remarks, it is respectfully pointed out that y-axis is the “percentage of participants who met the criteria for the primary endpoint,” wherein the primary endpoint is a reduction in heavy menstrual bleeding.
However, it is respectfully pointed out that Table 1 on pg. 900 of Donnez shows that the change in menstrual blood loss is relatively unaffected by add back therapy (see below). Moreover, in Primrose 1, patients administered 100mg linzagolix experienced less blood loss with the add back therapy, and in Primrose 2, patients administered 100 mg linzagolix experienced significantly less blood loss with the add back therapy, which is contrary to Applicant’s arguments of unexpected results.
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It is further noted that quality of life was relatively unchanged for patients administered 100mg linzagolix or linzagolix plus add back therapy, but that quality of life was increased for 200mg linzagolix plus add back therapy.
Further regarding Figure 1, it is respectfully pointed out that Applicant is only referencing and reproducing in Remarks pg. 11, the Primrose 2 bar graph. Figure 1 of Donnez on pg. 901 contains both a Primrose 1 and a Primrose 2 bar graph, wherein there is little difference in the percentage of participants with reduction in heavy menstrual bleeding between the linzagolix groups and the linzagolix plus add-back therapy groups. Lastly, Figure 1 only shows the reduction in heavy menstrual bleeding at 24 weeks. However, Donnez teaches that the add back therapy for the 200mg linzagolix does not begin until after 24 weeks (pg. 898, Col. 2). In view of this teaching, it is not possible to evaluate the percentage of participants with reduction in heavy menstrual bleeding in the patients receiving 200mg linzagolix and add-back therapy since the add-back therapy begins at 24 weeks, and the graphs provide data at 24 weeks.
Lastly, it is respectfully pointed out that independent claim 220 is directed toward a method of treating uterine fibroids, and pg. 904, Col. 2 of Donnez states “Substantial reductions. . .in uterine and fibroid volume. . .were consistently observed only with the 200 mg dose alone group.”
For these reasons, the data in the Donnez publication is not persuasive to demonstrate unexpected results.
On pg. 11, Remarks, Applicant further argues that Chwalisz, in Figures 1-3, teaches that each time add-back therapy was included in an elagolix dosing regimen, the efficacy of elagolix in suppressing uterine blood loss decreased. Applicant additionally argues that guided by Chwalisz and the knowledge of how add-back therapy functions, one could not have foreseen or reasonably predicted that the claimed add-back therapy regimen would actually augment the therapeutic activity of compound (VI).
These arguments have been fully considered, but are not found persuasive.
First, it is respectfully pointed out that it is not clear how if the timing of the add-back therapy impacted the results of both Donnez and Chwalisz.
Regarding Chwalisz, it appears that the administration of elagolix occurred simultaneously with the add-back therapy (estradiol and norethindrone acetate, referenced as Activella) ([0255]), though it is not abundantly clear from the text.
Regarding the test results, Chwalisz states “all Elagolix treatments (with and without add-back therapy) reduced uterine fibroid volumes within 3 months and Elagolix 300 mg BID showed the strongest effects. Additionally, both add-back therapy regimens did not substantially reduce Elagolix effects on volume reduction. . .All elagolix treatments (with or without add-back therapy) showed an improvement in quality of life measures” ([0272]). Thus, Chwalisz teaches the benefits of its methods.
Donnez teaches administration of 100mg linzagolix per day with once-per-day add-back therapy, or 200mg linzagolix with add back therapy after 24 weeks (pg. 898, Col. 2).
Thus, it would be reasonably expected that the results of Chwalisz and Donnez would be distinct since a) linzagolix and elagolix are structurally distinct compounds, and b) the add-back therapy of Chwalisz and Donnez is administered at different times in relation to the linzagolix and elagolix administration.
Regarding Figure 1 of Chwalisz, it is respectfully pointed out that there is only a small difference (85 vs 82) in the percentage of subjects with a blood loss reduction of less than 80 ml/cycle and less than or equal to 50% reduction in blood loss, compared to baseline, in the 200mg elagolix group vs the 200mg plus Activella group.
Regarding Figure 2 of Chwalisz, it is respectfully pointed out that the group with the least reduction of blood loss is 100mg elagolix, wherein no add-back therapy is administered.
Regarding Figure 3 of Chwalisz, both 200mg elagolix and 200mg elagolix plus Activella resulted in approximately the same average blood loss per cycle 66-95 days post-baseline.
For these reasons the results of Chwalisz are not persuasive as a baseline to show that the results of Donnez are unexpected.
Moreover, it is respectfully pointed out that only independent claim 235 is directed toward a method of reducing the volume of menstrual blood loss in patients with uterine fibroids or endometriosis. As such, independent claims 220 and 236 are outside the scope of the purported unexpected results.
For these reasons, the instant arguments are not persuasive to overcome the instant rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 220, 223-225, 228 and 235-236 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 398-417 of copending Application No. 17/633,479 (claim set dated 01/27/2026, reference application).
‘479 claims:
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and choline salts thereof (claims 400-401).
Daily administration is claimed in the amount of 100-200mg (claims 404-405).
Add-back therapy is claimed, wherein the therapy comprises beta17-estradiol administered at 1mg/day and norethindrone acetate administered at 0.5 mg/day (claims 410-413). Premenopausal females from 18-48 are claimed as patients (claim 414).
‘479 differs from that of the instantly claimed invention in that it does not specifically claim a method of treating uterine fibroids in a premenopausal female from 18-48 years old by combining the choline salt of
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with the add-back therapy of beta17-estradiol administered at 1mg/day and norethindrone acetate administered at 0.5 mg/day.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method of ‘479 by selecting the choline salt of
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as the GnRH agonist, for administration in premenopausal women and combining it with the add-back therapy of beta17-estradiol administered at 1mg/day and norethindrone acetate administered at 0.5 mg/day, to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because ‘479 claims:
-the choline salt of
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,
-premenopausal women of 18-48 as patients, and
- beta17-estradiol administered at 1mg/day and norethindrone acetate administered at 0.5 mg/day as an add-back therapy that is combined with its methods.
Thus, an ordinary artisan would be motivated to combine these claims to arrive at the instantly claimed invention.
Regarding claims 235 and 236, since ‘479 claims administering the same compounds to the same patient population (18-48 year old, pre-menopausal females) in the same dosage amount, this method would necessarily reduce the volume of menstrual blood loss and/or induce amenorrhea. See MPEP 2112.02
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues that the rejection should be withdrawn per MPEP804(I)(1)(b)(i), since the instant application has an earlier effective filing date than that of the ‘479 Applicant.
This argument has been fully considered, but is not found persuasive. MPEP804(I)(1)(b)(i) states “If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent.” Since the NSDP rejection is not the only rejection remaining in the application, this rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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/LAUREN WELLS/Examiner, Art Unit 1622