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 . Claims included in the prosecution are claims 1-8.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4 and 6-8 are 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.
Claims 1-4 recite a Tmax of 1.98 ± 1.29 hr or Tmax of 9.12 ± 8.83 hr. The claims are indefinite since it is unclear which compound the property applies to. For example, it is unclear whether the Tmax recited in claim 1 is in regard to 17β-estradiol or to another compound like estrone.
Claims 6 and 7 recite the term “significantly different.” The term “significanly” is a relative term which renders the claim indefinite. The term “significantly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear when a systemic estradiol exposure difference between the softgel insert and placebo would be considered a “significant” difference.
The term “statistically different” in claim 8 is a relative term which renders the claim indefinite. The term “statistically different” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear to what degree the difference in AUC0-24 values between the claimed composition and a placebo must be to be considered “statistical.”
Claim Rejections - 35 USC § 103
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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Meignant (US 6,060,077, May 9, 2000) in view of Grasset et al. (US 6,165,491, Dec. 26, 2000), Giorgetti (US 6,291,527, Sep. 18, 2001), and Sun et al. (US 2013/0150334, Jun. 13, 2013).
Meignant discloses a galenical formulation comprising 17β-estradiol and its salts in solution or in suspension in a lipophilic agent, with an estrogen content which corresponds to an equivalent unit dose of at most 15 µg, a hydrophilic gel-forming bioadhesive agent, a gelling agent for the lipophilic agent, and a hydrodispersible agent. The inner phase of a gelatin soft capsule contains the lipophilic agent with the estrogen in solution or in suspension, the bioadhesive agent, the gelling agent for the lipophilic agent, and the hydrodispersible agent (abstract). The formulation is used to treat vaginal dryness which may cause dyspareunia (i.e. symptom of vulvovaginal atrophy) (col. 1, lines 5-8). In contact with vaginal secretions, the hydrophilic bioadhesive agent gels and the presence of the hydrodispersible agent causes the galenical formulation to emulsify, enabling direct passive diffusion of the active principle between the emulsified excipient and the vaginal mucous membrane with which it is in contact with (i.e., the soft capsule is an intravaginal insert) (col. 2, lines 13-18). The dosage must be selected so as to relieve local problems and prevent transvaginal absorption to a maximum extent. These aims are achieved by selecting a dose of 10 µg of 17β-estradiol (col. 4, lines 20-24). The lipophilic agent is selected from liquid triglycerides (col. 2, line 40). Suitable liquid triglycerides include Miglyol ® 812 (col. 5, line 49). As noted by paragraph [00100] of the instant specification, MIGLYOL 812 is a C8-C10 triglyceride because the fatty acid composition is at least about 80% triglyceride esters of caprylic acid (C8) and capric acid (C10).
Meignant differs from the instant claims insofar as not disclosing wherein the formulation comprises a nonionic surfactant consisting of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate.
However, Grasset et al. disclose a pharmaceutical composition comprising 17-estradiol valerate dissolved in a lipophilic medium (claim 1). The composition may be formulated for vaginal administration (col 4, lines 47-48). The composition may be in the form of soft capsules (col. 4, lines 49-50). The lipophilic medium may also contain a surfactant (claim 4). The surfactant is present in proportions of 0.5 to 5% by weight relative to the weight of the oil (claim 7). Surfactants are capable of improving the solubilization of the estradiol in a lipophilic medium (col. 3, lines 26-32).
Giorgetti discloses vaginal cream comprising Tefose 63 as an excipient (Example No. 22).
Sun et al. discloses wherein Tefose ® 63 is a surfactant (¶ [0113]). As noted by paragraph [00109] of the instant specification, TEFOSE 63 comprises PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have incorporated a surfactant into the formulation of Meignant since a surfactant improves the solubilization of estradiol in a lipophilic medium, which is desirable as taught by Grasset et al. It would have been prima facie obvious to one of ordinary skill in the art to have incorporated Tefose 63 into the formulation of Meignant since this is a known and effective surfactant suitable for vaginal administration as taught by Giorgetti and Sun et al.
In regard to instant claims 1 and 5 reciting treating a female patient with a symptom of vulvovaginal atrophy, the formulation of Meignant treats vaginal dryness and one problem associated with vaginal dryness is dyspareunia (i.e., symptom of vulvovaginal trophy). Therefore, by treating vaginal dryness, the formulation treats dyspareunia as well.
In regard to instant claims 1 and 5 reciting consisting essentially of, the specification does not disclose what ingredients would affect the basic and novel characteristics of the claimed composition. Absent a clear indication in the specification or claims of what the basic and novel characteristics of the claimed composition actually are, the term “consisting essentially of” is construed as being equivalent in meaning to the term “comprising”. PPG v. Guardian, 156 F.3d 1351, 1354 (Fed. Cir. 1998).
In regard to instant claims 1, 5, and 8 reciting a 9:1 ratio of (i) one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol and (ii) a nonionic surfactant consisting of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate, the ratio would have been obvious from Grasset et al. disclosing 0.5 to 5% by weight of surfactant relative to the weight of the oil (i.e., lipophilic agent). Furthermore, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed ratio depending on the amount of surfactant needed to improve the solubilization of the estradiol. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In regard to the properties recited in the instant claims 1, 2 and 8, paragraph [0018] of the instant specification discloses wherein 10 µg estradiol provides a Cmax of about 12 pg/ml to about 18 mg/ml, an AUC0-24 of about 42 pg*hr/ml to about 63 pg*hr/ml, and a Tmax of about 1 hr to about 3 hours. Meignant discloses a formulation comprising 10 µg estradiol.
In regard to instant claims 3 and 4, paragraph [0019] of the instant specification discloses wherein about 10 µg estradiol provides a Cmax of estrone of about 4 pg/ml to about 7 pg/ml, a AUC0-24 of estrone of about 20 pg*hr/ml to about 31 pg*hr/ml, and a Tmax of estrone of about 4 hrs to about 8 hrs. About 31 pg*hr/ml would reasonably encompass about 34.7051 ± 27.9541 and about 8 hrs would reasonably encompass 9.12 ± 8.83 hrs. Meignant discloses a formulation comprising 10 µg estradiol.
In regard to the properties recited in instant claim 5, paragraph [00214] of the instant specification discloses wherein 10 µg estradiol provides 28.7 ± 5.89 estradiol in one hour, 25.7 ± 5.71 estradiol in three hours, and 23.4 ± 7.91 estradiol in six hours. Meignant discloses a formulation comprising 10 µg estradiol.
In regard to instant claims 6 and 7 reciting wherein systemic estradiol exposure following administration of the softgel insert is not significantly different than systemic estradiol exposure resulting from administration of a placebo, paragraph [00213] of the instant specification discloses wherein no statistically significant difference in the systemic concentration of estradiol 10 µg versus the placebo group was observed, which suggests the estradiol is not carried into the blood stream where it will have a systemic effect. Thus, since Meignant discloses wherein the formulation avoids systemic passage, the formulation should not be significantly different from a placebo.
In regard to instant claim 8 reciting administering an effective amount of estradiol to the proximal region of a vagina, since estradiol treats vaginal dryness, it would have been obvious to one of ordinary skill in the art to have selected a region of the vagina where treatment of dryness is desired.
In regard to instant claim 8 reciting wherein the AUC0-24 achieved after a single intravaginal administration is not statistically different from the AUC0-24 achieved after administration of a placebo, paragraph [00238] of the instant specification discloses wherein the AUC levels of estradiol relative to placebo are not statistically differentiable, which suggests that the formulations disclosed herein have a negligible systemic effect. Thus, since Meignant discloses wherein the formulation avoids systemic passage, the formulation has a negligible systemic effect and thus the AUC levels should not be statistically different from a placebo.
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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application Nos. 16/912,665 and 18/936,633 in view of Meignant (US 6,060,077, May 9, 2000), Grasset et al. (US 6,165,491, Dec. 26, 2000), Giorgetti (US 6,291,527, Sep. 18, 2001), and Sun et al. (US 2013/0150334, Jun. 13, 2013). Although the claims at issue are not identical, they are not patentable distinct from each other because both direct towards a vaginal composition comprising estradiol and in view of those secondary reference teaching as discussed above, it would have been obvious to produce the pending claimed invention to treat a symptom of vulvovaginal atrophy.
This is a provisional nonstatutory double patenting rejection.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent Nos. 9,180,091, 10,806,697, 10,537,581, 10,888,516, 9,289,382, 10,568,891, 10,398,708, 10,258,630, 10,471,072, 10,835,487, 11,497,709, 11,351,182, 11,241,445, 11,065,197, 11,116,717, 11,123,283, 11,304,959, 11,622,933, 11,246,875, 11,266,661, in view of Meignant (US 6,060,077, May 9, 2000), Grasset et al. (US 6,165,491, Dec. 26, 2000), Giorgetti (US 6,291,527, Sep. 18, 2001), and Sun et al. (US 2013/0150334, Jun. 13, 2013). Although the claims at issue are not identical, they are not patentable distinct from each other because both direct towards a vaginal composition comprising estradiol and in view of those secondary reference teaching as discussed above, it would have been obvious to produce the pending claimed invention to treat a symptom of vulvovaginal atrophy.
Conclusion
Claims 1-8 are rejected.
No claims are allowed.
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/TRACY LIU/Primary Examiner, Art Unit 1614
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