DETAILED ACTION
The receipt is acknowledged of applicants Declaration of Enrico Colli under 37 C.F.R. § 1.132 filed 01/22/2026.
Claims 1, 4, 5, 16, and 23-38 are pending.
Claims 30-38 have been withdrawn without traverse in the reply filed on 07/24/2024.
Claims 1, 4, 5, 16, 23-29 are subject of this office 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 .
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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 (i.e., changing from AIA to pre-AIA ) 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 1, 4, 5, 16 and 23-29 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of the article by Bahamondes et al. (Use of levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea), the article by Ji et al. (Clinical investigation of a low-dose levonorgestrel-releasing vaginal ring), the article by Rafiei et al. (Development of Hormonal Intravaginal Rings: Technology and Challenges), and Loxley et al. (US 2013/0209539), all references are of record.
Applicant Claims
Claim 1 is directed to a method for providing contraception in a female subject, comprising continuously administering levonorgestrel to said subject, wherein the levonorgestrel is continuously administered in an average daily amount ranging from 70 ug/day to 80 µg/day, wherein the administration route is vaginal administration.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Bahamondes teaches using levonorgestrel (LNG)-releasing intrauterine device (IUD) in women who do not wish to become pregnant, and provides highly effective contraception. The device further treats endometriosis, chronic pelvic pain and dysmenorrhea (see the entire document, and in particular: abstract, abstract, page 135, left column, page 138, left column).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While Bahamondes teaches contraception using LNG administered by IUD, the reference however does not teach the vaginal administration of LNG, and the dose of LNG as claimed by claim 1.
Ji teaches intravaginal administration of LNG-releasing ring for contraception. The ring causes amenorrhea. The ring provides advantage over oral and IUD devices by providing long term continuous and constant release of LNG which results in steady plasma levels. Further, the ring has advantage over IUD of gradually decreasing menstrual blood loss with using the ring so that hemoglobin concentration significantly improves during use (see the entire document, in particular: abstract; table 2, page 628, last paragraph of right column; page 629; page 630, left column).
Rafiei teaches intravaginal rings (IVR) are minimally invasive designed to be used for sustained and prolonged release of hormones, i.e. continuous release, to provide higher concentration to the target site with fewer side effects. Contraception can be improved by the administration of hormone via IVR (abstract). Levonorgestrel (LNG) can be sustainedly delivered from IVR (page 792, left column; page 793, left column; page 800, right column; conclusion).
Loxley teaches device for delivering hormone vaginally in the form of ring useful for contraception. Preferably the hormone is LNG. The device allows the release of 50-200 µg per 24 hours over a period of 24-28 days. Example 2 teaches ring comprising only LNG. The device is stable at room temperature and has the advantage that it does not require expensive storage and transport conditions (abstract; ¶¶ 0043-0047, 0054, 0068, 0073, example 2).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the present invention achieve contraception by delivering LNG using IUD as taught by Bahamondes, and replace IUD with vaginal ring taught by Ji and Rafiei. One would have been motivated to do so because Ji teaches LNG releasing ring provides the advantage over oral and IUD devices by providing long term continuous and constant release of LNG which results in steady plasma levels, and because Ji teaches the ring has advantage over IUS of gradually decreasing menstrual blood loss so that hemoglobin concentration significantly improves during use of the ring, and because Rafiei teaches that intravaginal rings (IVR) are minimally invasive designed to be used for continuous release, to provide higher concentration to the target site with fewer side effects, and it can improve contraception. One would reasonably expect achieving improved contraception using intravaginal ring releasing LNG that provides continuous and constant delivery of LNG with minimal side effects, while decreasing blood loss, therefore hemoglobin concentration significantly improves, and meanwhile useful for treating dysmenorrhea and endometriosis if present.
Further, one having ordinary skill in the art would have achieved contraception using vaginal ring as taught by the combination of Bahamondes, Ji and Rafiei, and further confidently use ring that delivers 50-200 µg per 24 hours as taught by Loxley. One would have been motivated to do so because Loxley teaches vaginal rings delivering such dose of LNG are contraceptive, and are stable at room temperature and has the advantage that they do not require expensive storage and transport conditions. One would reasonably expected achieve contraception using vaginal ring that deliver 50-200 µg per 24 hours while the ring is inexpensive and stable at room temperature.
Regarding the claimed administered amounts of LNG from about 60 µg/day to about 100 µg/day as claimed by claim 1, Loxley teaches preferable administration of 50-200 µg/day that overlaps within the claimed amount. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5].
Regarding claim 4 that no further contraceptive ingredient is administered to the female subject at the same time, all the cited references teach administering LNG alone with no additional contraceptive ingredient.
Regarding claim 5 that wherein said administering of Levonorgestrel also induces amenorrhea, Ji teaches amenorrhea in the subject receiving LNG.
Regarding claim 16 that no further contraceptive estrogen, all the cited references teach administering LNG alone with no estrogen.
Regarding claim 23 that administering of Levonorgestrel also induces amenorrhea, Bahamondes and Ji teach amenorrhea in the subject receiving LNG.
Regarding claim 24 that the average daily amount of levonorgestrel that is continuously administered is about 75 µg/day, Loxley teaches 50-200 µg/24 hr. wherein the claimed amount falls within the amount taught by the prior art. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5].
Regarding claim 25 that levonorgestrel is administered continuously to said subject for 28 days, Rafiei teaches continuous administration, and Loxley teaches continuous administration for 28 days.
Regarding claim 26 that administering inhibits 100% of ovulation in said subject, this is expected from administering the amount of LNG taught by the cited references for 28 days as claimed. Complete inhibition of ovulation is expected, contraception being achieved.
Regarding claim 27 that the administering suppresses estrogen production in said subject, this is an expected property from administering the amount of LNG taught by the cited references for 28 days as claimed wherein contraception is achieved.
Regarding estrogen is suppressed in the subject to a range above 30 pg/ml, and to a range of 40 to 60 pg/ml as claimed by claims 28 and 29, respectively, this is an expected property from administering the amount of LNG taught by the cited references for 28 days as claimed wherein contraception is achieved.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention.
Response to Arguments &
Declaration under C.F.R. § 1.132
Applicant's arguments filed 01/22/2026 have been fully considered but they are not persuasive.
Rejections Under 35 U.S.C. § 103
Applicants argue that none of the cited references teach or suggest the method recited in the present claims, even when considered in combination. Accordingly, the Examiner has failed to establish a prima facie case of obviousness.
In response to this argument, the examiner respectfully disagrees because the instantly claimed method is taught by combination of the cited references. Motivation to combine the references exists, as well as reasonable expectation to achieve the present invention, as set forth in this office action.
Applicants argue that the Declaration (and the present specification) explains that it was previously known that a dose of 40 µg via a vaginal ring was not effective to inhibit ovulation (see, e.g., specification, paragraph [0008]). However, it was not known to the inventors or others what the lowest effective dose administered via a vaginal ring was and there is no evidence of record to the contrary (see, e.g., Declaration, section 6).
In response to this argument and section 6 of the declaration, it is argued that the cited reference Loxley teaches preferable administration of 50-200 µg/day of LNG that embraces the claimed amount using intravaginal ring. It had been decided by Courts that the indiscriminate selection of "some" from among "many" is considered prima facie obvious. In re Lemin, 141 USPQ 814 (1964); National Distillers and Chem. Corp. V. Brenner, 156 USPQ 163.One having ordinary skill in the art would have determined the dose in between the dose taught by the prior art.
It is well settled that “the discovery of an optimum value of a variable in a known process is usually obvious.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007). The rationale for determining the optimal parameters for prior art result effective variables “flows from the ‘normal desire of scientists or artisans to improve upon what is already generally known.’” (quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). One having ordinary skill in the art would have determined the dose of LNG that achieves contraception within the dose of the prior art. Maintaining the E2 serum level is expected from administering the dose of LNG of the prior art wherein contraception is achieved.
Applicants argue that considering the disclosure of Duijkers¹ in combination with Devoto² would lead to the conclusion that the lowest effective oral dose would be ~115 µg/day, but in no instance would it be lower than 95 µg/day (Declaration, paragraph 7). Specifically, Duijkers describes testing oral dosages of 95 µg/day, 115 µg/day, and 135 µg/day and the lowest oral dose that effectively inhibits ovulation is 115 µg/day, while the 95 µg/day dose does not effectively inhibit ovulation (Declaration, paragraph 7). Additionally, these doses lead to plasma concentrations of 618 pg/mL and 548 pg/mL, respectively (see, e.g., Declaration, table from paragraph 7). Put another way, the data of Duijkers would lead one of skill in the art to conclude that a plasma concentration above ~600 pg/mL would be necessary to achieve effective inhibition of ovulation (Declaration, paragraph 7). Furthermore, Devoto indicates that oral administration of LNG results in greater plasma concentrations than vaginal administrations. Specifically, Devoto compares the pharmacokinetics for oral and vaginal administration using the same dosage and concluded that the plasma concentration for LNG is greater for the oral administration when dosages are the same (Declaration, paragraph 10). Thus, one of ordinary skill in the art would expect that a vaginally administered dose of at least 125 µg/day or 150 µg/day would be needed to effectively achieve 100 % inhibition of ovulation (Declaration, paragraph 10). Accordingly, it was surprising and unexpected that a dose of 75 µg/day of LNP administered vaginally provides a sufficient plasma concentration to achieve 100% inhibition of ovulation (Declaration, section 10).
In response to this argument and sections 7 and 10 of the declaration, it is argued that Duijkers as a whole and Table 4 of the reference is directed to oral administration of contraceptive, and not vaginal administration. The oral dose of LNG cannot be compared with vaginal dose of LNG. Even the same dose if administered by two different routes and formulations, e.g. oral formulation that deliver 95 µg/day LNG and vaginal formulation that deliver the same 95 µg/day, they are not expected to provide the same pharmacokinetics, the same plasma level for the same period of time. The route of administration and the formulation itself plays role in the plasma level and affects pharmacokinetics of the drug. The results obtained by Duijkers after oral administration is incomparable with virginal administration and not expected to give the same results. This evidenced by the article by Devoto et al. (“Pharmacokinetics and endometrial tissue levels of levonorgestrel after administration of a single 1.5 mg dose by the oral and vaginal route”, currently provided). The article shows that the same does of levonorgestrel orally administered achieves higher plasma levels sooner than vaginally administered levonorgestrel. However, plasma levels after vaginal administration are more sustained and were likely to be sufficient for ovarian suppression. The different routes of administration show different pharmacokinetic. Devoto teaches in page 50, left column:
PNG
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400
525
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Devoto further teaches in page 50, right column:
PNG
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467
589
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Therefore, the above applicant’s argument and comparison is unfair comparison between oranges and apples.
Applicants argue that even if a prima facie showing of obviousness has been made (which Applicant submits is not the case) the unexpected results presented in the Declaration are sufficient to rebut the same. That is, one of ordinary skill in the art would not have expected that a vaginally administered dose of 75 µg/day of LNG would provide effective contraception (Declaration, section 11).
In response to this argument and to paragraph 11 of the declaration, it is argued that the declaration under 37 CFR 1.132 filed 01/22/2026 is insufficient to overcome the rejection of claims 1, 4, 5, 16, 23-29 based upon Bahamondes, Ji, Rafiei and Loxley as set forth in the last Office action because: it include(s) statements which amount to an affirmation that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716. The prior art teaches dose embracing the claimed dose.
Further, applicants had shown the effect of 75 µg/day, while the claims has a range of 70-80 µg/day. Applicants did not show the effect of the claimed range of dose by showing the criticality of the upper and lower limits of the claimed dose, i.e. showing dose of 69.9 µg/day and 80.1 µg/day would not provide the desired effect in order to establish criticality of the claimed range.
The claimed range of dose is taught by combination of the cited references. The effect of LNG is a property inseparable for LNG. In addition, it is the examiner's position that the data in the specification regarding E2 levels are not unexpected results, rather are properties inseparable from the vaginal ring comprising the dose that suggested by the prior art as taught by the combination of the cited references, and therefore cannot rebut prima facie obviousness. Further, the plasma concentration is a result of the used vaginal formulation, not only the dose per se.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Finally, obviousness does not require absolute predictability of success all that is required is a reasonable expectation of success. See In re Kubin, 561 F.3d at 1360. The Court has held that "the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965). "There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. v. Interdigital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir.1997). An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Isis A D Ghali whose telephone number is (571)272-0595. The examiner can normally be reached Monday through Friday, 8:30 AM to 5:00 PM EST.
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/Isis A Ghali/Primary Examiner, Art Unit 1611 /I.G./
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