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 . 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.
Status of the Claims
The response and amendment filed 11/17/2025 is acknowledged.
Claims 1, 7, 9-10, 19-21, 28-29, and 66-68 are pending.
Claims 1 is independent.
Claims 8, 18, and 22-27 were cancelled.
Applicant’s election of the species a female subject having a sexual dysfunction and associated symptoms thereof or at risk of sexual dysfunction and associated symptoms thereof, wherein the sexual dysfunction is a desire disorder, an arousal disorder, an orgasm disorder, or a sexual pain disorder in the reply filed on 10/28/2022 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1, 7, 9-10, 19-21, 28-29, and 66-68 are treated on the merits in this action.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/17/2025 has been considered by the examiner.
Response to Arguments
Applicant's arguments filed 11/17/2025 have been fully considered but they are not persuasive.
Applicant further traverses the rejection in view of the amended claims. Applicant argues neither Lederman, ‘568 nor Yehuda, teaches a 5.6 mg daily dose of a sublingual cyclobenzaprine HCl mannitol eutectic in a method for treating female sexual dysfunction.
This argument is unpersuasive.
As set forth in the 112(b) rejection below, the claimed method is not limited to a 5.6 daily dose administered as a sublingual tablet. Therefore, each of Applicant’s arguments are predicated on a limitation which is not required.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., administering a 5.6 mg daily dose of a sublingual cyclobenzaprine HCl mannitol eutectic) are not recited in the rejected claim(s). 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).
Applicant acknowledges that Lederman ‘568 and Yehuda suggest treating a subset of the subjects treated in the methods of the amended claims, i.e., subjects suffering from a sexual dysfunction whether or not as a comorbidity of PTSD or whether or not the PTSD was caused by a sexually traumatic event. However, Applicant argues that while Yehuda points to data suggesting the co-occurrence of sexual dysfunction and PTSD in a subset of patients suffering from PTSD, Yehuda does not establish that PTSD is causative of sexual dysfunction. Applicant argues the fact that the comorbidity is observed in only a subset of PTSD patients suggests that it is not. Applicant argues that indeed, Yehuda says as much: "It is not yet known whether problems with sexual function are better explained by the cognitive, emotional, and behavior symptoms of PTSD.... It is also unclear whether PTSD is associated with an overall inability to function sexually (i.e., alone, with a relative stranger), or only in the context of an affiliative, intimate relationship." See, e.g., Yehuda: Page 1117, Conclusion, Lines 14-24. it was not clear whether or not PTSD is proximal to the development of sexual dysfunction. Applicant has argued that Yehuda further elaborates that the loss of libido and sexual function seen in PTSD may be a consequence of depression, another frequently comorbid condition with PTSD, or may be induced by the use of medications used to treat depression and PTSD, e.g., antidepressants and SSRIs, respectively. See Yehuda: Pages 1115-1116, Other Factors that May Interfere with Sexual Function; and Page 1117, Conclusion. Applicant has argued that sexual dysfunction may instead be a consequence of or caused by comorbid conditions of PTSD or other factors related to its treatment. Applicant argues that for these reasons, the skilled worker would not have believed that treating PTSD, as disclosed in Lederman '568, would have treated sexual disfunction with a reasonable expectation of success.
These arguments are unpersuasive.
The rejection does not rely on PTSD causing sexual dysfunction. The rejection is not based on whether PTSD is proximal to the development of sexual dysfunction. The rejection relies on Yehuda to answer the question: was there a known subset of female patients having PTSD and sexual dysfunction before the effective filing date of the presently claimed invention? The answer from Yehuda is yes.
As acknowledged by Applicant Yehuda teaches subjects having a PTSD and sexual dysfunction (Yehuda, e.g., pg. 1116: Treatment Implications: increasing documentation of comorbidity of PTSD and sexual dysfunction). Before the effective filing date of the presently claimed invention, Yehuda identified female subjects having PTSD – i.e., subject which Lederman teaches administering cyclobenzaprine to – and which have sexual dysfunction. Subjects in need of treatment for PTSD include subjects having PTSD and sexual dysfunction. The claimed invention requires administering cyclobenzaprine to a female subject having a sexual dysfunction and associated symptoms thereof, e.g., desire disorders. The prior art (Lederman and Yehuda) teaches administering cyclobenzaprine to women suffering from PTSD and having symptoms of sexual dysfunction, e.g., difficulty with sexual desire and function in persons with posttraumatic stress disorder (Yehuda, e.g., Abstract). Yehuda suggests any treatment of PTSD must include attention to sexual dysfunction and vice versa (Yehuda, e.g., Abstract).
Thus, while it may be true that Lederman '568 does not explicitly teach treating sexual dysfunction, it is clear that Lederman ‘568 teaches treating subjects having PTSD, and it is true that Yehuda identified female subjects having PTSD – i.e., subject which Lederman teaches administering cyclobenzaprine to – and which have sexual dysfunction. From the combined teachings of Lederman ‘568 and Yehuda, the skilled artisan understood that subjects in need of treatment for PTSD include subjects having PTSD and sexual dysfunction.
The claimed invention requires administering a therapeutically effective amount of a eutectic of cyclobenzaprine-HCl and mannitol, and a pharmaceutically acceptable carrier, to a female subject having sexual dysfunction and associated symptoms thereof. The combined teachings of the cited prior art suggest it would have been obvious to practice the method as claimed.
In fact, Yehuda teaches symptoms associated with PTSD may be difficult to distinguish from symptoms of sexual dysfunction, e.g., It may be difficult for clinicians to distinguish low desire or inability to perform from symptoms reflecting interpersonal withdrawal or fear (Yehuda, e.g., pg. 1116, Treatment implications, ¶ 1). To the extent that the claimed invention reads on treating subjects having symptoms associated with sexual dysfunction, e.g., a desire disorder, the prior art suggests desire disorder symptoms associated with sexual dysfunction are difficult to distinguish from interpersonal withdrawal or fear symptoms associated with PTSD. In this manner, Yehuda suggests it would be difficult to distinguish treatments which resolve symptoms of PTSD from treatments which resolve sexual desire disorder in a patient which suffers from both PTSD and sexual dysfunction symptoms.
Applicant has argued Yehuda also does not teach or suggest that treating PTSD results in the amelioration of sexual dysfunction in a female subject. Applicant argues Yehuda states that "[w]hen sexual dysfunction and PTSD co-occur, it is unclear whether these problems should be treated sequentially, together, or whether treating PTSD will resolve symptoms of sexual dysfunction even if they are not a treatment target." See, Yehuda: Page 1116, sentence bridging left and right columns. Applicant argues that Yehuda further refers to a study by Schnurr et al., J. Womens Health (2009), which assessed the sexual dissatisfaction, dysfunction, and dysfunctional sexual behavior among female veterans and active-duty personnel, with a history of sexual trauma, pre- and post-PTSD- treatment. Applicant has argued that Yehuda, referring to Schnurr, notes that female subjects who recovered from PTSD reported a significant improvement in sexual satisfaction, but also reported no changes in dysfunctional sexual behavior. See, Yehuda: Page 1111, Table 1 and Page 1116, right column, lines 3-12.
Applicant argues that a skilled worker with Yehuda in-hand would have had no motivation to treat sexual dysfunction in PTSD patients using the claimed method and certainly that POSITA would have had no reasonable expectation that treatment of PTSD would improve sexual dysfunction.
These arguments are unpersuasive.
The claimed method does not require improving sexual dysfunction. The claimed method requires treating sexual dysfunction and associated symptoms thereof by administering a therapeutically effective amount of a eutectic of cyclobenzaprine-HCl and mannitol, and a pharmaceutically acceptable carrier, wherein the eutectic comprises 5.6 mg or less of cyclobenzaprine-HCl to a female subject having sexual dysfunction and associated symptoms thereof. The cited prior art teaches a method within the claim scope.
Even if the claims required improving sexual dysfunction, the combined teachings of Lederman, Yehuda, and Lederman ‘515 teach this feature. Yehuda suggests treatment of PTSD must include attention to sexual dysfunction and treatment of sexual dysfunction must include attention to PTSD (Yehuda, e.g., Abstract), and Yehuda teaches subject having PTSD share symptoms with subjects having sexual dysfunction, e.g., desire difficulty, and there is strong overlap between subjects having PTSD and subjects having sexual dysfunction (Yehuda, e.g., Abstract: difficulties in sexual desire and function often occur in persons with PTSD). Thus, improvements to PTSD symptoms will improve sexual dysfunction and associated symptoms to at least some degree.
Regarding Schnurr, it is noted that Schnurr is silent to cyclobenzaprine-HCl treatment. While Schnurr investigates treatment with cognitive therapy, the treatment methods do not address pharmacological treatment.
Additionally, like Yehuda, Schnurr clearly teaches an overlap in symptoms associated with PTSD and sexual dysfunction. For example, Schnurr recognized the range of problems associated with PTSD includes lack of desire, lower satisfaction, orgasmic dysfunction, and in men, erectile dysfunction (Schnurr, e.g., pg. 1549, c2: ¶). Moreover, Schnurr recognizes the limitations of their study, e.g., our patients had extensive trauma histories and multiple comorbid conditions and, on average, had chronic and severe PTSD (Schnurr, e.g., pg. 1555, c2, ¶ 2). Schnurr concludes their results may not generalize to all women with PTSD, particularly women with less severe PTSD symptoms where standard PTSD treatments may be sufficient to improve sexual outcomes in these women. Thus, at least for female subjects having PTSD and sexual dysfunction with less severe symptoms there was still a reasonable expectation that treating PTSD would improve sexual dysfunction outcomes, i.e., treat sexual dysfunction in female subjects. The presently claimed invention is silent to severity of symptoms and encompasses subjects with less severe symptoms.
Applicant argues the Specification reports actual data demonstrating the efficacy of the 5.6 mg or less dose of cyclobenzaprine-HCl on improving sexual functioning in female subjects.
This argument is unpersuasive.
It is noted that each of the subjects treated in the examples were subjects having PTSD and sexual dysfunction which is the same patient population suggested by the combined teachings of Lederman and Yehuda. It is further noted that the only dose tested was 5.6 mg/day. The presently claimed method recites 5.6 mg or less over any time frame. There is no data for data for doses of less than 5.6 mg/day. There is no data for treating female subjects having sexual dysfunction not associated with PTSD. Given the difficulty in distinguishing between symptoms of PTSD and sexual dysfunction noted by the cited art, it is not clear from the presented data that the disclosed benefits can be generalized to any female subject having sexual dysfunction and associated symptoms thereof as claimed, e.g., absent PTSD. The results presented are not commensurate in scope with the claimed invention.
Applicant argues that Lederman '568 and Yehuda, Lederman '515 neither mentions nor suggests the use of a eutectic of cyclobenzaprine-HCl and mannitol in treating sexual dysfunction and associated symptoms thereof in a female subject, wherein the sexual dysfunction is a desire disorder, an arousal disorder, or an orgasm disorder.
This argument is unpersuasive.
The combined teachings of Lederman and Yehuda teach treating female subjects having sexual dysfunction and associated symptoms thereof, e.g., desire difficulty, by administering cyclobenzaprine to the female subjects as required by claim 1.
The cyclobenzaprine HCl eutectic formulations of Lederman can be formulated in a tablet for oral administration (Lederman, e.g., 0065, Table), which tablets are bioequivalent to non-eutectic cyclobenzaprine HCl formulations (Lederman, e.g., 0069).
Lederman teaches the eutectic, when formulated for a specific route of administration, e.g., orally, may be formulated to be bioequivalent to, e.g., 5mg cyclobenzaprine HCl oral tablets, or 10 mg cyclobenzaprine HCl oral tablets (Lederman, e.g., 0069). Lederman also provides an example of an amount of eutectic, e.g., 13.4 mg, which corresponds to 10 mg cyclobenzaprine HCl (Lederman, e.g., Table in ¶ 0065). Therefore, the skilled artisan understood that Lederman’s eutectic formulation of cyclobenzaprine HCl were bioequivalent to the doses of Lederman,’515. Moreover, Lederman suggests the eutectic formulation of cyclobenzaprine HCl offers benefits including increased stability of cyclobenzaprine HCl (Lederman, e.g., 0004), and increased dissolution rate of cyclobenzaprine relative to previous cyclobenzaprine HCl formulations (Lederman, e.g., 0066-0067).
Therefore, the skilled artisan would have understood that compositions comprising a eutectic offered improved stability and dissolution and were expressly suggested as interchangeable and bioequivalent to non-eutectic formulations of cyclobenzaprine HCl based on the cited prior art.
Applicant has argued the Examiner's reliance on the statement regarding the bioequivalence of oral and eutectic compositions is not supported in the cited documents. For example, the Examiner refers to Lederman '568, which specifically states that "wherein the composition is an oral composition, the oral composition is bioequivalent to 5 mg cyclobenzaprine HCl oral tablets (e.g., Flexeril 5 mg)" (emphasis added). Applicant has argued oral formulations of cyclobenzaprine HCl are swallowed and absorbed in the gastrointestinal tract. See Lederman '568: Paragraphs [0069]- [0070]. Applicant argues that by contrast, the composition of the claims is administered as a sublingual tablet (i.e., a completely different mode of administration from the cyclobenzaprine HCl oral tablets). Applicant argues a POSITA would understand that different routes of administration can influence the effectiveness and bioavailability of a drug. For example, Applicant argues Lederman '515 provides data comparing the pharmacokinetics of sublingual cyclobenzaprine tablets and cyclobenzaprine 5 mg oral tablets: "Compared to 5 mg of oral cyclobenzaprine, 4.8 mg of sublingual cyclobenzaprine HCl significantly increased the rate of absorption in the first two hours after administration. Indeed, at some time points, the sublingual cyclobenzaprine produced approximately 20-fold higher mean dose-adjusted plasma levels of cyclobenzaprine as compared to oral administration. Applicant argues the sublingually administered cyclobenzaprine also resulted in a higher AUC than the orally administered cyclobenzaprine." See Lederman '515: Paragraph [0405] and FIGs. 14 and 15. Applicant argues a POSITA would understand that the compositions of Lederman '568 and Lederman '515 are not interchangeable. Applicant argues a POSITA with Lederman '568's eutectic in hand would have had no motivation to use the cyclobenzaprine HCl and mannitol eutectic of Lederman '568 at the same doses of Lederman '515's non-eutectic composition.
These arguments are unpersuasive.
As set forth in the 112(b) rejection below, the claimed method is not limited to a 5.6 daily dose administered as a sublingual tablet. Therefore, Applicant’s arguments are predicated on a limitation which is not required.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., administering a 5.6 mg daily dose of a sublingual cyclobenzaprine HCl mannitol eutectic) are not recited in the rejected claim(s). 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).
Even if there are differences in absorption time and AUC between sublingual and conventional tablets, the skilled artisan understood those differences from Lederman ‘515. Further, the skilled artisan understood that sublingual dosing is effective for treating the same indications as oral dosing. Compare Lederman ‘515, claim 68 with Lederman ‘568, e.g., 0122.
Further, the teachings of Lederman ‘515 are not limited to 5.6 mg. Lederman, ‘515 teaches effective amounts of cyclobenzaprine for treating PTSD are found in the range of from 0.1 to 10 mg, e.g., about 2.8 mg, or less than about 2.8 mg, or about 5.6 mg, or less than about 5.6 mg (Lederman, ‘515, e.g., 0014 and 0028 and 0138-0139 and 0228). Effective amounts may be administered once (Lederman, ‘515, e.g., 00222 and 0228), e.g., daily administration (Lederman, ‘515, e.g., claim 125). Lederman, ‘515 teaches once daily or bedtime administration (Lederman, e.g., 0249).
The claimed dose is within the range suggested as effective by Lederman ‘515. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Applicant traverses the double patenting rejection of record in view of the amended claims. Applicant argues Yehuda does not mention or suggest the use of cyclobenzaprine, much less the sublingual cyclobenzaprine-HCl and mannitol eutectic and basifying agent of the amended claims at the recited 5.6.mg daily dose of cyclobenzaprine-HCl, in treating female sexual dysfunction. Applicant argues Lederman '568's composition comprising a cyclobenzaprine HCl and mannitol eutectic is not interchangeable with the non-eutectic cyclobenzaprine composition claimed in the '948 patent. Second, Applicant argues the claims of the '948 patent do not recite a cyclobenzaprine salt at all, much less cyclobenzaprine HCl or its mannitol eutectic. Third, Applicant has argued the '948 patent also does not claim a sublingual cyclobenzaprine- HCl formulation.
These arguments are unpersuasive.
As set forth in the 112(b) rejection below, the claimed method is not limited to a 5.6 daily dose administered as a sublingual tablet. Therefore, Applicant’s arguments are predicated on a limitation which is not required.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., administering a 5.6 mg daily dose of a sublingual cyclobenzaprine HCl mannitol eutectic) are not recited in the rejected claim(s). 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).
Applicant’s argument that Lederman '568's composition comprising a cyclobenzaprine HCl and mannitol eutectic is not interchangeable with the non-eutectic cyclobenzaprine composition claimed in the '948 patent is unpersuasive at least because the ‘948 patent does not claim a non-eutectic cyclobenzaprine composition.
Applicant’s argument that the '948 patent does not recite a cyclobenzaprine salt at all, much less cyclobenzaprine HCl or its mannitol eutectic is unpersuasive because Lederman '568 teaches these features.
Applicant’s argument that the '948 patent also does not claim a sublingual cyclobenzaprine- HCl formulation is unpersuasive at least because these features are known from Lederman ‘568.
Rejections Addressing Applicant’s Amendment
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, 7, 9-10, 19-21, 28-29, and 66-68 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.
Claim 1 includes the limitation of wherein the pharmaceutical composition is administered in a daily dose comprising 5.6 mg of cyclobenzaprine-HCl in one or more dosage units, and wherein the dosage form of the pharmaceutical composition is a sublingual tablet.
Applicant’s remarks, filed 11/17/2025, suggest the claimed invention is limited to a daily dose of 5.6 mg of cyclobenzaprine -HCl.
However, from the language of claim 1 it is not clear that the claim limits the daily dose to 5.6 mg of cyclobenzaprine -HCl.
First, it is not clear from claim 1 if the 5.6 mg of cyclobenzaprine -HCl refers to the daily dose or to the amount in the recited one or more dosage units.
Second, the claim states the daily dose comprises 5.6 mg of cyclobenzaprine -HCl. This suggests that even if, arguendo, the limitation of 5.6 mg of cyclobenzaprine -HCl refers to the daily dose, the claim encompasses daily doses beyond only 5.6 mg since multiple doses may be administered, e.g., one or more dosage units, and since “administered in a daily dose comprising” indicates the claim is open to additional unrecited daily doses.
Third, there is no clear antecedent basis for “the dosage form” since the claim instead recites one or more dosage units.
To overcome this rejection, it is suggested to amend claim 1 to recite:
Claim 1. A method for treating sexual dysfunction and associated symptoms thereof, wherein the sexual dysfunction is a desire disorder, an arousal disorder, or an orgasm disorder, comprising administering to a female subject in need thereof, a pharmaceutical composition comprising a eutectic of cyclobenzaprine-HCl and mannitol, a basifying agent, and a pharmaceutically acceptable carrier,
wherein the pharmaceutical composition is administered in a daily dose of 5.6 mg [[of]] cyclobenzaprine -HCl, wherein the daily dose is administered in one or more dosage units, and wherein the dosage unit is a sublingual tablet.
Clarification is required.
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 of this title, 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.
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.
Claim(s) 1, 7, 9-10, 19-21, 28-29, and 66-68 are rejected under 35 U.S.C. 103 as being unpatentable over Lederman, US 20170281568 in view of Yehuda, J Sex Med, 12, 2015 and further in view of Lederman, US 20140171515 A1 (Lederman, ‘515, previously cited).
Lederman teaches pharmaceutical compositions comprising a eutectic of cyclobenzaprine HCl and mannitol (Lederman, e.g., Abstract).
Lederman teaches treating a subject having post-traumatic stress disorder (PTSD) with a eutectic of cyclobenzaprine HCl and mannitol, wherein the PTSD results from, e.g., sexual assault and/or sexually traumatic events (Lederman, e.g., 0107). The skilled artisan would have at once envisaged treating a female subject having female genital organs by birth because there are only two sexes at birth. The recitation of premenopausal, perimenopausal, or postmenopausal encompasses all females. Lederman teaches adults and children.
To the extent that claim 1 requires treating a female subject having sexual dysfunction: Lederman does not expressly teach administering the eutectic of cyclobenzaprine HCl and mannitol to a female subject in need of treatment for sexual dysfunction, wherein the sexual dysfunction is a desire disorder, an arousal disorder, or an orgasm disorder.
Yehuda teaches sexual dysfunction is a comorbidity of PTSD (Yehuda, e.g., Abstract) Yehuda teaches a female patient population that is affected by both PTSD and sexual dysfunction, i.e., females having sexual dysfunction were a known subset of patients suffering from PTSD (Yehuda, e.g., abstract). PTSD leads to sexual dysfunction because aversive hyperarousal is a symptom of PTSD (Yehuda, e.g., Abstract). In subjects with PTSD, sexual difficulties including desire, arousal and orgasm difficulties, occur because of an inability to regulate and redirect the physiological arousal needed for healthy sexual function away from hyperarousal and aggression which leads to anxiety, fear, and other PTSD symptoms (Yehuda, e.g., pg. 1108, c1-c2). Applicable to claim 68: Other factors include the fact that sexual dysfunction is a known side effect of SSRIs taken for treating PTSD (Yehuda, e.g., pp. 1115-1116). SSRIs are antidepressants/anxiolytics/psychoactive agents.
Yehuda teaches symptoms associated with PTSD may be difficult to distinguish from symptoms of sexual dysfunction, e.g., it may be difficult for clinicians to distinguish low desire or inability to perform from symptoms reflecting interpersonal withdrawal or fear (Yehuda, e.g., pg. 1116, Treatment implications, ¶ 1). To the extent that the claimed invention reads on treating subjects having symptoms associated with sexual dysfunction, e.g., a desire disorder, the prior art suggests desire disorder symptoms associated with sexual dysfunction are difficult to distinguish from interpersonal withdrawal or fear symptoms associated with PTSD. In this manner, Yehuda suggests it would be difficult to distinguish treatments which resolve symptoms of PTSD from treatments which resolve sexual desire disorder in a patient which suffers from both PTSD and sexual dysfunction symptoms.
Yehuda teaches subjects having a PTSD and sexual dysfunction (Yehuda, e.g., pg. 1116: Treatment Implications: increasing documentation of comorbidity of PTSD and sexual dysfunction). Before the effective filing date of the presently claimed invention, Yehuda identified female subjects having PTSD – i.e., subject which Lederman teaches administering cyclobenzaprine to – and which have sexual dysfunction. Subjects in need of treatment for PTSD include subjects having PTSD and sexual dysfunction. The claimed invention requires administering cyclobenzaprine to a female subject having a sexual dysfunction and associated symptoms thereof, e.g., desire disorders. The prior art (Lederman and Yehuda) teaches administering cyclobenzaprine to women suffering from PTSD and having symptoms of sexual dysfunction, e.g., difficulty with sexual desire and function in persons with posttraumatic stress disorder (Yehuda, e.g., Abstract). Yehuda suggests any treatment of PTSD must include attention to sexual dysfunction and vice versa (Yehuda, e.g., Abstract).
At least this clear suggestion in Yehuda represents a teaching which would have prompted the skilled artisan to modify a treatment for PTSD by administering cyclobenzaprine eutectics as understood from Lederman by including female subjects suffering from sexual dysfunction and associated symptoms thereof, including difficulty with desire.
Since Lederman teaches treating subjects having PTSD symptoms, including hyperarousal symptoms, by administering a eutectic of cyclobenzaprine HCl and mannitol to ameliorate or eliminate PTSD symptoms, the skilled artisan would have reasonably expected success in treating subjects having PTSD and sexual dysfunction identified in Yehuda with the same treatment. The skilled artisan would have been motivated to treat female subjects having PTSD and sexual dysfunction identified in Yehuda to ameliorate or eliminate hyperarousal from PTSD thereby allowing the female subjects to regulate and redirect physiological arousal needed for healthy sexual function (Yehuda, e.g., Abstract and pg. 1108, c1, ¶ 3). That is, resolving the hyperarousal symptoms of PTSD by administering a eutectic of cyclobenzaprine HCl and mannitol would have enabled the treated female subjects to regulate and redirect arousal for healthy sexual function away from feelings of impending threat, anxiety, and/or fear.
It would have been obvious before the effective filing date of the presently claimed invention to modify Lederman’s method of administering a eutectic of cyclobenzaprine HCl and mannitol by administering the composition to female subjects having PTSD and sexual dysfunction identified by Yehuda with a reasonable expectation of success. The skilled artisan would have been motivated to treat female subjects having PTSD and sexual dysfunction by administering a eutectic of cyclobenzaprine HCl and mannitol to ameliorate or eliminate hyperarousal symptoms of PTSD. The skilled artisan would have reasonably expected that eliminating or ameliorating PTSD symptoms including hyperarousal by administering a eutectic of cyclobenzaprine HCl and mannitol would successfully improve desire, arousal, and/or orgasm disorders by allowing the female subjects to regulate and redirect the physiological arousal needed for healthy sexual function.
The combined teachings of Lederman and Yehuda teach a method according to claim 1, but do not expressly teach wherein the pharmaceutical composition is administered in a daily dose comprising 5.6 mg of cyclobenzaprine-HCl in one or more dosage units, and wherein the dosage form of the pharmaceutical composition is a sublingual tablet.
However, Lederman, ‘515 teaches effective amounts of cyclobenzaprine for treating PTSD are found in the range of from 0.1 to 10 mg, e.g., about 2.8 mg, or less than about 2.8 mg, or about 5.6 mg, or less than about 5.6 mg (Lederman, ‘515, e.g., 0014 and 0028 and 0138-0139 and 0228). Effective amounts may be administered once (Lederman, ‘515, e.g., 00222 and 0228), e.g., daily administration (Lederman, ‘515, e.g., claim 125). Lederman, ‘515 teaches once daily or bedtime administration (Lederman, e.g., 0249).
The claimed dose is within the range suggested as effective by Lederman ‘515. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
It would have been obvious before the effective filing date of the presently claimed invention to modify a method for treating female subjects suffering from PTSD and sexual dysfunction comprising administering a eutectic of cyclobenzaprine HCl and mannitol to female subjects in need thereof by optimizing the dosage and administration using guidance from Lederman, ‘515 with a reasonable expectation of success. The skilled artisan would have been motivated to consult known prior art dosing and administration schedules such as Lederman, ‘515 to optimize the dose of cyclobenzaprine for treating PTSD with a reasonable expectation of success. Since Lederman, ‘515 teaches dosing and administration schedules for cyclobenzaprine in treatments for PTSD, the skilled artisan would have had a reasonable expectation of successfully starting with doses and schedules known from Lederman, ‘515 to optimize dosing for a eutectic of cyclobenzaprine HCl and mannitol to treat PTSD in female subjects having PTSD and sexual dysfunction.
Applicable to claim 7: Lederman teaches the composition comprising a eutectic of eutectic of 75%±2% Cyclobenzaprine HCl and 25%±2% mannitol by weight (Lederman, e.g., claim 4).
Applicable to claim 8: Lederman teaches the composition further comprising a basifying agent (Lederman, e.g., claim 7).
Applicable to claim 9: Basifying agents within the scope of claim 9, e.g., potassium dihydrogen phosphate are found in Lederman, e.g., 0112, 0140, and claims 8-9.
Applicable to claims 10 and 21: dipotassium hydrogen phosphate is found in Lederman, e.g., claim 8.
Applicable to claims 22-23: daily administration is taught in Lederman, e.g., 0104.
Applicable to claims 24-27: Lederman teaches tablets and sublingual tablets (Lederman, e.g., 0070, 0097, and 0103).
Applicable to claims 28-29: Lederman teaches the method further comprising administering prazosin, escitalopram, tramadol, bupropion, anticonvulsants, antidepressants, or selective serotonin reuptake inhibitors (Lederman, e.g., 0123).
Applicable to claim 68: Yehuda teaches PTSD and sexual dysfunction associated with antidepressants/anxiolytic/psychoactive agents, e.g., SSRI. Lederman teaches the method further comprising administering prazosin, escitalopram, tramadol, bupropion, anticonvulsants, antidepressants/SSRIs (citalopram, paroxetine, fluoxetine, citalopram). See Lederman, e.g., 0123.
Accordingly, the subject matter of claims 1, 7, 9-10, 19-21, 28-29, and 66-68 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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 1, 7, 9-10, 19-21, 28-29, and 66-68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9918948 in view of Lederman, US 20170281568 and Yehuda, J Sex Med, 12, 2015.
The claims of the reference are directed to a method for treating post-traumatic stress disorder (PTSD) following a traumatic event, comprising: administering to a human in need of such treatment a pharmaceutical composition comprising cyclobenzaprine in a therapeutically effective amount and a therapeutically effective carrier, wherein such treatment eliminates or ameliorates the PTSD. Doses less than 5 mg/day are claimed. The method further comprises administering sequentially or concurrently a drug selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.
The claims of the reference patent do not expressly teach the method comprising administering a eutectic of cyclobenzaprine HCl. However, the teachings of Lederman enumerated above cures this defect.
It would have been obvious before the effective filing date of the presently claimed invention to modify methods claimed by the reference patent by administering a eutectic of cyclobenzaprine HCl to subjects suffering from PTSD with a reasonable expectation of success. Lederman teaches treating subjects having PTSD symptoms, including hyperarousal symptoms, by administering a eutectic of cyclobenzaprine HCl and mannitol to ameliorate or eliminate PTSD symptoms. This teaching would have prompted the skilled artisan to use compositions comprising a eutectic of cyclobenzaprine HCl and mannitol as known from Lederman to practice the methods claimed by the reference patent with a reasonable expectation of success. Lederman suggests the eutectic formulation of cyclobenzaprine HCl offers benefits including increased stability of cyclobenzaprine HCl (Lederman, e.g., 0004), and increased dissolution rate of cyclobenzaprine relative to previous cyclobenzaprine HCl formulations (Lederman, e.g., 0066-0067). Therefore, the skilled artisan would have understood that compositions comprising a eutectic of cyclobenzaprine HCl and mannitol offered improved stability and dissolution and were expressly suggested as interchangeable and bioequivalent to non-eutectic formulations of cyclobenzaprine in methods of treating PTSD.
The reference patent claims modified by Lederman do not expressly teach treating sexual dysfunction and associated symptoms thereof, wherein the sexual dysfunction is a desire disorder, an arousal disorder, or an orgasm disorder, comprising administering to a female subject in need thereof.
However, the teachings of Yehuda enumerated above cures this defect. For example, Yehuda suggests any treatment of PTSD must include attention to sexual dysfunction and vice versa (Yehuda, e.g., Abstract). Yehuda teaches symptoms associated with PTSD may be difficult to distinguish from symptoms of sexual dysfunction, e.g., it may be difficult for clinicians to distinguish low desire or inability to perform from symptoms reflecting interpersonal withdrawal or fear (Yehuda, e.g., pg. 1116, Treatment implications, ¶ 1). Yehuda clearly notes the overlap in patient population between those suffering from PTSD and sexual dysfunction in female patients, and Yehuda clearly notes the similarity in symptoms between PTSD and sexual dysfunction in female patients (Yehuda, e.g., Abstract, and pg. 1116, Treatment implications, ¶ 1).
It would have been obvious before the effective filing date of the presently claimed invention to modify methods claimed by the reference patent improved by the teachings of Lederman by practicing the method on female subjects having PTSD and sexual dysfunction and associated symptoms thereof identified by Yehuda with a reasonable expectation of success. Yehuda represents a teaching which would have prompted the skilled artisan to modify a treatment for PTSD comprising administering cyclobenzaprine eutectics as understood from the reference patent claims modified according to Lederman by administering compositions comprising a eutectic of cyclobenzaprine HCl and mannitol to female subjects suffering from sexual dysfunction and associated symptoms thereof, including difficulty with desire with a reasonable expectation of success. The skilled artisan would have been motivated to make this modification to ameliorate or eliminate hyperarousal symptoms of PTSD as related in Lederman which would, in turn, successfully improve desire, arousal, and/or orgasm disorders by allowing the female subjects to regulate and redirect the physiological arousal needed for healthy sexual function as related in Yehuda with a reasonable expectation of success. The skilled artisan would have had a reasonable expectation of success because PTSD and sexual dysfunction in females display similar symptoms.
Accordingly, the subject matter of claims 1, 7, 9-10, 19-21, 28-29, and 66-68 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
No claim is 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM A CRAIGO whose telephone number is (571)270-1347. The examiner can normally be reached on Monday - Friday, 9am - 6pm, PDT.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
/SUSAN T TRAN/Primary Examiner, Art Unit 1615