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
Status of claims
The amendment filed on April 28, 2026 is acknowledged. Claims 2-3, 5-8, 11, 13-19, 21-22, 24, and 26-76 have been canceled. New claims 78 has been added. Claims 1, 4, 9-10, 12, 20, 23, 25, and 77-78 are under examination in the instant office action.
Applicants' arguments, filed on April 28, 2026, have been fully considered but they are not found to be persuasive or moot in view of a new ground of rejection necessitated by the amendments (newly added limitations in claim 1 and new claim 78). Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
Claim Interpretation
Claim 1 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.
Applicant did not argue about the above claim interpretation; and thus it is considered acknowledged.
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, 9-10, 12, 20, 23, 25, and 77-78 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) in further view of US 2011/0124656 (hereafter, LEDERMAN, cited in the IDS filed on 8/13/2021).
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 specifically discloses a pharmaceutical composition a eutectic of 75%+2% Cyclobenzaprine HCl and 25%+2% β-mannitol by weight, which further comprises a basifying agent and at least one pharmaceutically acceptable carrier (claims 1, 4, 7, 50, [0172], and [0260]). NEBULONI further teaches that the eutectic formed with mannitol provides protection of the cyclobenzaprine HCl from hydration and other chemical interactions ([0141]).
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 ([0167]). 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 further teaches that a composition of the invention can be administered 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 claim 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] and claim 8).
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 77, NEBULONI teaches that the composition may be administered for sublingual absorption through sublingual films (thin film dosage form) ([0162]).
As to new claim 78, NEBULONI teaches that the basifying agent includes dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2H PO4) ([0171] and claims 7-8).
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 same eutectic composition comprising cyclobenzaprine HCl and mannitol 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 a eutectic of cyclobenzaprine HCl and mannitol 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.
As to the amount of the cyclobenzaprine HCl that is administered to the subject (5.6 mg/day) in amended claim 1, LEDERMAN teaches pharmaceutical compositions comprising a very low dose of cyclobenzaprine and a method of using the composition for treating or preventing symptoms associated with post-traumatic stress disorder (PTSD) (abstract). LEDERMAN further teaches a "therapeutically effective amount" of cyclobenzaprine for the purposes refers to the amount of the compound that prevents or alleviates or eliminates or interferes with one of the symptoms associated with PTSD ([0014]). Also, LEDERMAN teaches that one skilled in the art can readily determine an effective amount of a cyclobenzaprine to be administered, by taking into account factors such as the size, weight, age and sex of the subject, the extent of disease penetration or persistence and severity of symptoms, and the route of administration ([0014]). In addition, LEDERMAN specifically 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. One skilled in the art can readily determine an effective amount of a cyclobenzaprine HCl to be administered depending on the size, weight, age and sex of the subject, the extent of disease penetration or persistence and severity of symptoms, and the route of administration as taught by LEDERMAN. In addition, the claimed dose amount falls within the range of a "therapeutically effective amount" of cyclobenzaprine for treating PTSD taught by LEDERMAN. 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). Further, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
Response to Applicant’s arguments:
Applicant argued that the specification provides provide specific and statistically validated evidence of the efficacy of the claimed composition comprising a cyclobenzaprine HCl and mannitol eutectic in treating PTSD when administered within the recited range (between about 1 year and about 9 years after the traumatic event) while NEBULONI teaches “lifetime range”. Also, Applicant further argued that NEBULONI makes no mention or suggestion of the specific dosage of cyclobenzaprine HCI to be used in treating PTSD and rather, NEBULONI refers to a formulation comprising 2.40 mg cyclobenzaprine HCl, 31.55 mg mannitol and maize starch, 2.00 crospovidone, 0.50 mg colloidal silica, 0.050 mg sodium stearyl fumarate, and 1.05 potassium hydrogen phosphate used to assess the stability and compatibility of a drug product containing cyclobenzaprine HCl as the active pharmaceutical ingredient (API). In addition Applicant argued that Maguen does not remedy the defects of Nebuloni because Maguen broadly correlates the probability of veteran receiving a negative PTSD screen at a follow-up screen following an initial positive PTSD screen and Maguen makes no mention or suggestion of any pharmaceutical treatment for treating PTSD, much less the claimed pharmaceutical composition comprising a cyclobenzaprine HCI and mannitol eutectic, and specifically not the recited dose of 5.6 mg of cyclobenzaprine HCl per day.
The following responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is important to note that in an obvious rejection, it is not necessary that one reference addresses any limitation in a particular claim but that the references, when combined, do so. “[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.” See MPEP 2144.01
In this case, 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 as stated above. For example, the target patient population of the claimed method includes subjects who experienced traumatic event about 1 year or 6 years before the commencement of the treatment. NEBULONI already discloses the use of the same composition comprising a eutectic of cyclobenzaprine HCl and mannitol and a basifying agent 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 those who experienced the traumatic events from 3 months to several years, for example, one year before the commencement of treatment. As such, the target patient population of the prior art substantially overlap those claimed. In addition, the skilled artisan would have reasonable expectation that the same composition comprising a eutectic of cyclobenzaprine HCl and mannitol and a basifying agent would be effective for those who initiated the treatment about one year after the traumatic event in the same way for the patient population disclosed in NEBULONI in the absence of evidence to the contrary. Also, Maguen et al. was cited to evidence a general knowledge that delays in initiating mental health treatment for PTSD would negatively impact on the treatment response and the positive response to the treatment would be very low beyond 6 years after the traumatic event while Maguen et al. do not teach cyclobenzaprine HCl.
“[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649. “[A]n implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal-and even common-sensical-we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves. In such situations, the proper question is whether the ordinary artisan possesses knowledge and skills rendering him capable of combining the prior art references.” Id. at 1368, 80 USPQ2d at 1651.
Consistent with this reasoning, the skilled artisan, who is aware of teachings of NEBULONI and Maguen et al. would have been motivated to initiate the treatment with the composition comprising cyclobenzaprine HCl for PTSD 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 with cyclobenzaprine HCl would similarly 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. In addition, the skilled artisan would have reasonable expectation that those who initiates the treatment beyond 6 years after the traumatic event would not show a significant treatment effect and the alleged better effects during the claimed specific and advantageous time period (median time between the time the trauma was experienced and commencement of the treatment being 6 years) would have been expected in view of Maguen et al.
As to Applicant’s argument regarding the specific dose (5.6 mg/day), the newly added dose limitation in amended claim 1 has been addressed in the above rejection which has been modified and reiterated as necessitated by amendments. Also, while NEBULONI discloses an exemplary formulation comprising 2.40 mg cyclobenzaprine HCl, a reference is not limited to its working examples, but must be evaluated for what it teaches those of ordinary skill in the art. In re Boe, 355 F.2d 961, 148 USPQ 507 (C.C.P.A 1966). In re Chapman, 357 F.2d 418, 148 USPQ 711 (C.C.P.A. 1966). In addition, 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 (see [0163]).
For the foregoing reasons, Applicant’s arguments have not been found to be persuasive.
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, 9-10, 12, 20, 23, 25, and 77-78 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 a eutectic of 75%+2% Cyclobenzaprine HCl and 25%+2% β-mannitol by weight, NEBULONI teaches a pharmaceutical composition comprising a eutectic of 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 to new claim 78, the claims of the patents also recite that the amount of cyclobenzaprine administered is 1 mg and 20 mg/day, which overlaps the claimed dose. 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). Further, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
As to sublingual administration and basifying agent such as dipotassium hydrogen phosphate, 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 such, the instant claims would have been obvious over the claims of the patent in view of Maguen et al. and NEBULONI.
Response to Applicant’s arguments
Applicant submitted the same arguments regarding NEBULONI and Maguen et al. stated above. Thus, the same responses as stated above are applied. Also, as to Applicant’s argument regarding the specific dose (5.6 mg/day), the newly added dose limitation in amended claim 1 has been addressed in the above rejection which has been modified and reiterated as necessitated by amendments.
Conclusion
No claims are 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 extension fee 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 date of this final action.
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