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 .
DETAIED ACTION
A request for continued examination under 37 C.F.R. 1.114, including the fee set forth in 37 C.F.R. 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. 1.114, and the fee set forth in 37 C.F.R. 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 C.F.R. 1.114. Applicant’s submission filed July 31, 2025 has been received and entered into the present application.
Status of claims
The amendment filed on July 31, 2025 is acknowledged. Claims 2-3, 5-8, 13, 15-19, 21-22, 24, and 26-75 have been canceled. Claims 1, 4, 9-12, 14, 20, 23, 25, and 76-77 are under examination in the instant office action.
Applicants' arguments, filed on July 31, 2025, have been fully considered but they are not moot in view of a new ground of rejection. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
Claim Interpretation
Claim 1 as amended recites that “wherein the time between traumatic event and the commencement of treatment with the pharmaceutical composition is between about 1 year and about 9 years”. Thus, the target patient population of the claimed method is directed to those with PTSD who has experienced a traumatic event between about 1 year and 9 years before the commencement of the treatment.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 4, 9-12, 14, 20, 23, 25, and 76-77 are rejected under 35 U.S.C. 103 as being unpatentable over WO2014/145156 (hereafter, NEBULONI) in view of Maguen et al. (Psychiatric Services, 65 (12): 1414-1419, Dec. 2014).
NEBULONI teaches pharmaceutical compositions comprising cyclobenzaprine HCl and a method of using the composition for treating or preventing the development (either the initiation, consolidation or perpetuation) of a PTSD symptom following a traumatic event (abstract and [0166]).
NEBULONI discloses that the compositions may be used to treat different phases of PTSD development at various time intervals after a traumatic event ([0167]). For example, treating the initiation phase of PTSD may require the administration of the composition soon after the traumatic event, for example within the first week, within the second week, within the third week, or within the fourth week or later ([0167]). NEBULONI further discloses that when treating the consolidation phase of PTSD, the skilled worker may be able to administer the composition later after the traumatic event and later during the development of the symptoms, for example, within the first month, within the second month, or within the third month or later ([0167]). NEBULONI further discloses that the perpetuation phase of PTSD may be treated with the composition administered 3 months or longer after the traumatic event, for example within the third month, within the fourth month, within the fifth month, or later. NEBULONI teaches that as a result of treatment at the initiation, consolidation, or perpetuation phase, PTSD symptoms will be ameliorated or be eliminated ([0167]).
NEBULONI teaches that the initiation of a PTSD symptom typically occurs immediately following the traumatic event, during which the symptoms of PTSD appear and become increasingly severe and one theory of how PTSD develops is that there is a type of "learning" or reinforcement process during which the memories of the trauma are engrained in the mind ([0166]). As these memories become more fixed (a process called consolidation), symptoms such as flashbacks and nightmares grow in severity and frequency and interventions during this critical time may prevent some patients from developing full-blown PTSD ([0166]). The consolidation of a PTSD symptom typically occurs during the weeks and months following a traumatic event. A person's memories of that event become consolidated into highly vivid and concrete memories that are re-experienced with increasing frequency either as flashbacks or nightmares. During this time, hyperarousal symptoms and avoidant behavior can become increasingly severe and disabling. The perpetuation of a PTSD symptom occurs once traumatic memories are consolidated, and the re- experienced symptoms (flashbacks and nightmares) and hyperarousal symptoms become persistent and remain at a level that is functionally disabling to the patient ([0166]-[0167]).
NEBULONI teaches that doses and dosing regimens can be determined by one of skill in the art according to the needs of a subject to be treated and the skilled worker may take into consideration factors such as the age or weight of the subject, the severity of the disease or condition being treated, and the response of the subject to treatment ([0163]). NEBULONI teaches that a composition of the invention can be administered, for example, as needed or on a daily basis and a composition can be administered immediately prior to sleep or several hours before sleep ([0163]). This teaching reads on “administering once daily” (once before sleep).
As to claim 9-10, NEBULONI teaches that the pharmaceutical composition is formulated for sublingual, buccal, or oral administration ([0161] and [0162]). NEBULONI further teaches that a composition may be administered for sublingual absorption through sublingual tablets, sublingual films, liquids, sublingual powders, and sublingual spray solutions ([0162]).
As to claims 11-12, NEBULONI teaches that the pharmaceutical composition further comprising a basifying agent wherein the basifying agent includes potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2H PO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (mono sodium phosphate, monobasic sodium phosphate, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), trisodium citrate anhydrous, bicarbonate or carbonate salts, borate, hydroxide, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids (including bicarbonate), and sulfide), that raises the pH of a solution containing Cyclobenzaprine HCl ([0171])
As to claim 20, NEBULONI teaches that a composition is combined with a drug which may further alleviate the symptoms of PTSD wherein the drugs include an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, and an analgesic ([0182]).
As to claims 23 and 25, NEBULONI teaches the treatment may be combined with a psychotherapeutic intervention to improve the outcome of the treatment and the intended result is generally an improvement in the symptoms of PTSD or the reduction of occurrences of symptoms, as evidenced in terms of physiological responding, anxiety, depression, and feelings of alienation (mood symptoms) ([0181]).
As to claim 76, NEBULONI teaches a pharmaceutical composition comprising a eutectic of mannitol and Cyclobenzaprine HC1 wherein 75%+2% Cyclobenzaprine HCl or 65%+2% Cyclobenzaprine HCl and 35%+2% mannitol, wherein the mannitol is β mannitol or δ mannitol and specifically discloses a eutectic composition comprising 75%+2% Cyclobenzaprine HCl and 25%+2% β-mannitol by weight (claims 1, 4, 11, 50, 52 and [0260]).
As to claim 77, NEBULONI teaches that the composition may be administered for sublingual absorption through sublingual films (thin film dosage form) ([0162]).
NEBULONI does not specifically disclose that the time between the traumatic event and the commencement of treatment with the pharmaceutical composition is between about 1 year and about 9 years.
However, NEBULONI already discloses the use of the composition comprising cyclobenzaprine HCl for treating PTSD during the perpetuation phase which encompasses 3 months or longer after the traumatic event. Thus, one of ordinary skill in the art would have recognized that the patient population of NEBULONI would encompass any patients who experienced the traumatic event any period before the commencement of treatment, including those who experienced the traumatic events one to nine years before the commencement of treatment. As such, the target patient population of the prior art substantially overlap those claimed. Also, it was known in the art that delays in initiating mental health treatment for PTSD would negatively impact on the treatment response as evidenced by Maguen et al. (title and abstract). Maguen et al. disclose that veterans who waited longer to initiate mental health outpatient treatment were less likely to have a negative screen result (no PTSD symptoms) and the decreasing probability of a negative screen result with each year that passed after the end of the last deployment. (p1417, col 1, para 3-col 2, para 1 and Figure 1). Figure 1 shows that probability of a negative screen result at follow-up decreases as a function of the time (1 year to beyond 6 years) to initiation of mental health treatment wherein time to initiation of treatment was defined as the period between the end of the veterans’ last deployment (traumatic event) and the first mental health visit (Fig. 1). Maguen et al. specifically teach that veterans who waited longer to get mental health treatment were less likely than veterans who sought treatment sooner to experience PTSD symptom improvement during the study period (p1417, col 2, para 3-col 3, para 1). Maguen et al. suggest that intervening early when mental health problems are first detected should be a priority (p1417, col 3, para 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to initiate the treatment with the composition comprising cyclobenzaprine HCl for PTSD taught by NEBULONI before too late, for example about 1 year or within 6 years after the traumatic event because the skilled artisan would have expected that the probability of PTSD symptom improvement in response to a treatment would decrease as a function of years that passed after the traumatic event as taught by Maguen et al. The skilled artisan would have been motivated to begin the treatment of PTSD with the cyclobenzaprine HCl composition of NEBULONI for those who would benefit from the treatment before the treatment would not work. Since Maguen et al. shows that the positive response to the treatment would be very low beyond 6 years after the traumatic event, the skilled artisan would have been motivated to find out the maximum year when the treatment would work.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over WO2014/145156 (hereafter, NEBULONI) in view of Maguen et al. (Psychiatric Services, 65 (12): 1414-1419, Dec. 2014) in further view of US 2011/0124656 (hereafter, LEDERMAN, cited in the IDS filed on 8/13/2021).
The teachings of NEBULONI and Maguen et al. as applied supra are herein applied for the same teachings in their entirety.
NEBULONI does not specifically teaches the amount of the cyclobenzaprine HCl that is administered to the subject.
However, LEDERMAN teaches pharmaceutical compositions comprising a very low dose of cyclobenzaprine, alone, or in combination with an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor. and a method of using the composition for treating or preventing symptoms associated with post-traumatic stress disorder (PTSD) (abstract). LEDERMAN also teaches that the amount of cyclobenzaprine administered is between 0.1 mg and 50 mg/day, between 0.5 mg and 30 mg/day, or between 1 mg and 20 mg/day (claims 1-4). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the same or similar amount of cyclobenzaprine HCl for treating the same disorder (PTSD) as taught by LEDERMAN because the salt form of cyclobenzaprine would have the same or similar effective amount for the same disorder. The skilled artisan would have been motivated to do so with a reasonable expectation of success.
Claims 1, 4, 9-12, 14, 20, 23, 25, and 76-77 are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0124656 (hereafter, LEDERMAN, cited in the IDS filed on 8/13/2021) in view of Maguen et al. (Psychiatric Services, 65 (12): 1414-1419, Dec. 2014) and WO2014/145156 (hereafter, NEBULONI).
LEDERMAN teaches pharmaceutical compositions comprising a very low dose of cyclobenzaprine, alone, or in combination with an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor. and a method of using the composition for treating or preventing symptoms associated with post-traumatic stress disorder (PTSD) (abstract).
LEDERMAN discloses that the compositions may be used to treat different phases of PTSD development at different time intervals after a traumatic event: For example, to treat the initiation phase of PTSD, cyclobenzaprine needs to be administered to a subject in need soon after the traumatic event, for example within the first week, within the second week, within the third week or within the fourth week or longer. Whereas to treat the consolidation phase of PTSD cyclobenzaprine has to be administered later after the traumatic event and later during the development of the symptoms, for example within the first month, within the second month or within the third month or longer. Typically to treat the perpetuation phase of PTSD the cyclobenzaprine is administered 3 months or longer after the traumatic event, for example within the third month, within the fourth month, within the fifth month or longer ([0019]). LEDERMAN teaches that as a result of cyclobenzaprine treatment at the initiation, consolidation, or perpetuation phase, PTSD symptoms will be ameliorated or be eliminated ([0019]).
As to claim 4, LEDERMAN teaches that cyclobenzaprine is administered once daily at bedtime ([0040] and [0041]).
As to claim 9-10, LEDERMAN teaches that any suitable route of administration may be employed for providing the patient with an effective dosage of cyclobenzaprine, including buccal, oral, rectal, parenteral, transdermal, subcutaneous, sublingual, intranasal, intramuscular, intrathecal administration ([0022]) and the pharmaceutical composition is administered as an orally dissolving tablet or as a thin film formulation (claim 10).
LEDERMAN teaches that the initiation of a PTSD symptom typically occurs immediately following the traumatic event, during which the symptoms of PTSD appear and become increasingly severe and one theory of how PTSD develops is that there is a type of "learning" or reinforcement process during which the memories of the trauma are engrained in the mind ([0018]). As these memories become more fixed (a process called consolidation), symptoms such as flashbacks and nightmares grow in severity and frequency and interventions during this critical time may prevent some patients from developing full-blown PTSD ([0018]). The consolidation of a PTSD symptom typically occurs during the weeks and months following a traumatic event. A person's memories of that event become consolidated into highly vivid and concrete memories that are re-experienced with increasing frequency either as flashbacks or nightmares. During this time, hyperarousal symptoms and avoidant behavior can become increasingly severe and disabling. The perpetuation of a PTSD symptom occurs once traumatic memories are consolidated, and the re- experienced symptoms (flashbacks and nightmares) and hyperarousal symptoms become persistent and remain at a level that is functionally disabling to the patient ([0018]). These teachings implicitly disclose that the efficacy of the treatment increases with decreasing time between experience of the traumatic event and the commencement of treatment recited in claim 13.
As to claim 14, LEDERMAN teaches that the amount of cyclobenzaprine administered is between 0.1 mg and 50 mg/day, between 0.5 mg and 30 mg/day, or between 1 mg and 20 mg/day (claims 1-4).
As to claim 20, LEDERMAN teaches that the method may further entail 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 or a serotonin-norepinephrine reuptake inhibitor ([0007]).
As to claims 23, LEDERMAN teaches the treatment may be combined with a psychotherapeutic intervention ([0006]).
As to claim 25, LEDERMAN teaches that the symptom may be a sleep disturbance or a non-sleep disturbance wherein "sleep disturbance" covers symptoms including difficulty falling asleep, early morning awakening, nightmares, and sleep of poor quality and non-sleep disturbance convers irritability or outbursts of anger, difficulty concentrating, hypervigilance, and exaggerated startle response ([0012]).
As to new claim 77, LEDERMAN teaches that the dosage form is an orally dissolving tablet or a thin film ([0022] and claim 10).
LEDERMAN does not specifically disclose that the time between the traumatic event and the commencement of treatment with the pharmaceutical composition is between about 1 year and about 9 years.
However, LEDERMAN already discloses the use of the composition comprising cyclobenzaprine for treating PTSD during the perpetuation phase which encompasses 3 months or longer after the traumatic event. Thus, one of ordinary skill in the art would have recognized that the patient population of LEDERMAN would encompass any patients who experienced the traumatic event any period before the commencement of treatment, including those who experienced the traumatic events one to nine years before the commencement of treatment. As such, the target patient population of the prior art substantially overlap those claimed. Also, it was known in the art that delays in initiating mental health treatment for PTSD would negatively impact on the treatment response as evidenced by Maguen et al. (title and abstract). Maguen et al. disclose that veterans who waited longer to initiate mental health outpatient treatment were less likely to have a negative screen result (no PTSD symptoms) and the decreasing probability of a negative screen result with each year that passed after the end of the last deployment. (p1417, col 1, para 3-col 2, para 1 and Figure 1). Figure 1 shows that probability of a negative screen result at follow-up decreases as a function of the time (1 year to beyond 6 years) to initiation of mental health treatment wherein time to initiation of treatment was defined as the period between the end of the veterans’ last deployment (traumatic event) and the first mental health visit (Fig. 1). Maguen et al. specifically teach that veterans who waited longer to get mental health treatment were less likely than veterans who sought treatment sooner to experience PTSD symptom improvement during the study period (p1417, col 2, para 3-col 3, para 1). Maguen et al. suggest that intervening early when mental health problems are first detected should be a priority (p1417, col 3, para 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to initiate the treatment with the composition comprising cyclobenzaprine HCl for PTSD taught by LEDERMAN before too late, for example about 1 year after the traumatic event within because the skilled artisan would have expected that the probability of PTSD symptom improvement in response to a treatment would decrease as a function of years that passed after the traumatic event as taught by Maguen et al. The skilled artisan would have been motivated to begin the treatment of PTSD with the cyclobenzaprine HCl composition of LEDERMAN for those who would benefit from the treatment. Since Maguen et al. shows that the positive response to the treatment would be very low beyond 6 years after the traumatic event, the skilled artisan would have been motivated to find out the maximum year when the treatment would work.
Also, LEDERMAN does not specifically disclose a specific salt form of cyclobenzaprine such as cyclobenzaprine HCl in claim 1. However, NEBULONI teaches pharmaceutical compositions comprising cyclobenzaprine HCl and a method of using the composition for treating or preventing the development (either the initiation, consolidation or perpetuation) of a PTSD symptom following a traumatic event (abstract and [0166]). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use cyclobenzaprine in a salt form such as HCl salt because NEBULONI already teach the use of cyclobenzaprine HCl in the treatment of PTSD. One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the salt form would have the same efficacy for treating PTSD.
As to claim 11-12, LEDERMAN does not specifically disclose adding a basifying agent.
However, it was known in the art that the presence of a basifying agent in a formulation comprising cyclobenzaprine HC1 increases stability of cyclobenzaprine HC1 as evidenced by NEBULONI ([0004]). NEBULONI further teaches that the basifying agent includes potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2H PO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (mono sodium phosphate, monobasic sodium phosphate, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), trisodium citrate anhydrous, bicarbonate or carbonate salts, borate, hydroxide, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids (including bicarbonate), and sulfide), that raises the pH of a solution containing Cyclobenzaprine HCl ( [0171]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add a basifying agent for stabilizing cyclobenzaprine HCl in the formulation as taught by NEBULONI. One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the resulting formulation would be similarly efficient for treating PTSD with improved stability.
As to claim 75, LEDERMAN does not specifically disclose a eutectic composition 75%12% cyclobenzaprine HCl by weight and 25%12% 3-mannitol by weight or 65%±2% cyclobenzaprine HCl by weight and 35%12% 6-mannitol by weight. However, NEBULONI teaches a pharmaceutical composition comprising a eutectic of mannitol and Cyclobenzaprine HC1 wherein 75%+2% Cyclobenzaprine HCl or 65%+2% Cyclobenzaprine HCl and 35%+2% mannitol, wherein the mannitol is β mannitol or δ mannitol and specifically discloses a eutectic composition comprising 75%+2% Cyclobenzaprine HCl and 25%+2% β-mannitol by weight (claims 1, 4, 11, 50, 52 and [0260]). NEBULONI further teaches that the eutectic formed with mannitol provides protection of the cyclobenzaprine HCl from hydration and other chemical interactions ([0141]). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the eutectic composition of NEBULONI because it would provide a stable cyclobenzaprine HCl formulation for treating PTSD. One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the eutectic formulation would be similarly efficient for treating PTSD with improved stability.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, it is concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Double Patenting Rejections
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, 4, 9-12, 14, 20, 23, 25, and 76-77 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-11 of US Patent 9918948 in view of Maguen et al. (Psychiatric Services, 65 (12): 1414-1419, Dec. 2014) and WO2014/145156 (hereafter, NEBULONI).
Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of ‘948 patent are also drawn to a method for treating PTSD following a traumatic event, comprising: administering to a human in need of such treatment a pharmaceutical composition comprising cyclobenzaprine in the same therapeutically effective amount as claimed and a therapeutically effective carrier, wherein such treatment eliminates or ameliorates the PTSD. The claims of the patents further recite that 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 and the pharmaceutical composition is administered as an orally dissolving tablet or as a thin film formulation and administered in combination with psychotherapeutic intervention.
The claims of the patent do not specifically disclose that the time between the traumatic event and the commencement of treatment with the pharmaceutical composition is between about 1 year and about 9 years.
However, the patient population of the patent encompasses any patients who experienced the traumatic event any period before the commencement of treatment including those who experienced the traumatic events one to nine years before the commencement of treatment. Thus, the target patient population of the patent substantially overlap those claimed. Also, it was known in the art that delays in initiating mental health treatment for PTSD would negatively impact on the treatment response as evidenced by Maguen et al. (title and abstract). Maguen et al. disclose that veterans who waited longer to initiate mental health outpatient treatment were less likely to have a negative screen result (no PTSD symptoms) and the decreasing probability of a negative screen result with each year that passed after the end of the last deployment. (p1417, col 1, para 3-col 2, para 1 and Figure 1). Figure 1 shows that probability of a negative screen result at follow-up decreases as a function of the time (1 year to beyond 6 years) to initiation of mental health treatment wherein time to initiation of treatment was defined as the period between the end of the veterans’ last deployment (traumatic event) and the first mental health visit (Fig. 1). Maguen et al. specifically teach that veterans who waited longer to get mental health treatment were less likely than veterans who sought treatment sooner to experience PTSD symptom improvement during the study period (p1417, col 2, para 3-col 3, para 1). Maguen et al. suggest that intervening early when mental health problems are first detected should be a priority (p1417, col 3, para 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to initiate the treatment with the composition comprising cyclobenzaprine HCl for PTSD before too late, for example about 1 year after the traumatic event within because the skilled artisan would have recognized that the probability of PTSD symptom improvement in response to a treatment would decrease as a function of years that passed after the traumatic event as taught by Maguen et al. The skilled artisan would have been motivated to initiate the treatment of PTSD with the cyclobenzaprine HCl composition for those who would benefit from the treatment.
As to sublingual administration and basifying agent, it was known in the art that cyclobenzaprine HCl have slow absorption when ingested by mouth (per oral, or po) and to speed absorption, tablets containing cyclobenzaprine HCl have been formulated in various sublingual (SL) preparations as evidenced by NEBULONI ([0004]). Also, NEBULONI teaches that the presence of a basifying agent in a formulation increases stability of cyclobenzaprine HCl ([0004]). NEBULONI further teaches that the basifying agent includes potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2H PO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (mono sodium phosphate, monobasic sodium phosphate, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), trisodium citrate anhydrous, bicarbonate or carbonate salts, borate, hydroxide, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids (including bicarbonate), and sulfide), that raises the pH of a solution containing Cyclobenzaprine HCl (p3, 12-13 and [0171]). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare cyclobenzaprine HCl in a sublingual formulation for improving the speed of absorption and to add a basifying agent for stabilizing cyclobenzaprine HCl in the formulation as taught by NEBULONI. One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the resulting sublingual formulation would be similarly efficient for treating PTSD with improved absorption and stability.
As to claim 76, NEBULONI teaches a pharmaceutical composition comprising a eutectic of mannitol and Cyclobenzaprine HC1 wherein 75%+2% Cyclobenzaprine HCl or 65%+2% Cyclobenzaprine HCl and 35%+2% mannitol, wherein the mannitol is β mannitol or δ mannitol and specifically discloses a eutectic composition comprising 75%+2% Cyclobenzaprine HCl and 25%+2% β-mannitol by weight (claims 1, 4, 11, 50, 52 and [0260]). NEBULONI further teaches that the eutectic formed with mannitol provides protection of the cyclobenzaprine HCl from hydration and other chemical interactions ([0141]). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the eutectic composition of NEBULONI because it would provide a stable cyclobenzaprine HCl formulation for treating PTSD. One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the eutectic formulation would be similarly efficient for treating PTSD with improved stability. As to claim 77, the claim of the patent recites that that the dosage form is an orally dissolving tablet or a thin film (see claim 10).
As such, the instant claims would have been obvious over the claims of the patent in view of Maguen et al. and NEBULONI.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BONG-SOOK BAEK whose telephone number is 571-270-5863. The examiner can normally be reached 9:00AM-6:00PM Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611