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 .
DETAILED ACTION
Applicant’s amendment dated 24 March 2026, in which claims 1, 9, 10 have been amended, claims 3-8, 15-18 have been cancelled, and new claims 20, 21 have been added, is acknowledged.
Claims 1-2, 9-14, 19-21 are pending in the instant application.
Claims 1-2, 9-14, 19-21 are examined herein.
Response to arguments of 24 March 2026
In view of Applicant’s amendment of 24 March 2026, all the rejections to claims 3-8, 15-18 are herein withdrawn. Claims 3-8, 15-18 have been cancelled.
Applicant has relied on the exception under 35 U.S.C. 102(b)(1)(B) to overcome the rejection under 35 U.S.C. 102(a)(1) by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference Tonix Press Release (“Tonix Pharmaceuticals Completes Pre-IND Meeting with FDA for TNX-102 SL as a Clinical Candidate for Alcohol Use Disorder, FDA Official Meeting Minutes Support Tonix’s Plan to file an IND Application in the First Quarter of 2020 for a Phase 2 Proof-of-Concept Study”, November 20, 2019, 3 pages, cited in IDS)
was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1).
Applicant’s Declaration under 37 CFR 1.130(a), submitted on 24 March 2026, is acknowledged. Based on said Declaration, the rejection of claims 1, 3, 4, 5, 6, 8, 12-17 under 35 U.S.C. 102(a)(1) as being anticipated by Tonix Press Release, as evidenced by Lederman, is herein withdrawn.
On 24 March 2026, Applicant has amended independent claim 1 to recite a method for treating alcohol use disorder (AUD) and associated symptoms comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of eutectic of cyclobenzaprine HCl and mannitol and a pharmaceutically acceptable carrier, wherein the eutectic comprises 75% +/_2% cyclobenzaprine HCl by weight of the eutectic and 25% +/_2% b-mannitol by weight of the eutectic, wherein the composition comprises a basifying agent, and wherein the composition comprises 2.8 or 5.6 mg of cyclobenzaprine HCl.
A new/modified rejection is made below, based on Applicant’s amendment of 24 March 2026.
Applicant’s arguments (Remarks of 24 March 2026, pages 6-8) against the rejection of claims 1-19 under 35 U.S.C. 103 over Nebuloni, have been considered.
Applicant argues (page 7, third paragraph) that only one of the many disorders taught by Nebuloni is alcohol-dependent sleep disorder. Applicant argues that the instant claims are directed to the treatment of alcohol use disorder AUD and its associated symptoms. Applicant argues (page 7, last line, page 8, first paragraph) that the symptoms of AUD are limited to the ones specifically enumerated in [0041] of the Specification. Applicant argues that "problem sleeping" is a withdrawal symptom, and not an "alcohol-dependent sleep disorder" as recited in Nebuloni.
This argument is not found persuasive. Applicant’s Specification discloses [0026] a method for treating alcohol use disorder and associated symptoms thereof. The symptom may be, but is not limited to, a sleep disturbance.
Nebuloni teaches [0137] that the compositions of the invention are used to treat sleep disturbances or sleep disorders such as, for example, alcohol-dependent sleep disorder, or nocturnal drinking syndrome. As such, the conditions disclosed by Nebuloni are, based on Applicant’s Specification [0026], symptoms of AUD.
Applicant argues (page 8, second paragraph) that Nebuloni does not teach a composition comprising 2.8 or 5.6 mg cyclobenzaprine HCl, used to treat AUD. In response, Nebuloni teaches a eutectic comprising 75% cyclobenzaprine HCl and 25% mannitol, as in the instant claims, Nebuloni exemplifies the preparation of a composition comprising 2.4 mg cyclobenzaprine HCl, mannitol and basifying agent, and Nebuloni prepares the eutectic by mixing appropriate amounts of cyclobenzaprine HCl and mannitol. Weighing 2.4 mg of cyclobenzaprine HCl, or another amount close to 2.4 mg, in order to prepare a composition/tablet comprising a eutectic 75% cyclobenzaprine HCl and 25% mannitol, is routine, well within the skill of the artisan.
For these reasons, the rejection of the claims under 35 U.S.C. 103 over Nebuloni is maintained, and a modified rejection is made below, based on Applicant’s amendment of 24 March 2026.
Applicant’s arguments (pages 8-11) against the rejection of claims 1-19 under 35 U.S.C. 103 over Lederman, in view of Altintoprak, in further view of Nebuloni, have been considered.
Applicant argues (page 9, last paragraph, page 10, first paragraph) that Lederman does not teach a eutectic of cyclobenzaprine HCl and mannitol, and that Lederman’s cyclobenzaprine composition is not interchangeable with Nebuloni’s eutectic.
This argument is not persuasive. Nebuloni teaches the very composition in the instant claims, namely a eutectic comprising active pharmaceutical ingredient (API) cyclobenzaprine HCl 75% and mannitol 25%, and Nebuloni teaches the advantages of formulating API cyclobenzaprine HCl as a eutectic with mannitol. Thus, Nebuloni provides the motivation to formulate API cyclobenzaprine HCl in the form of a eutectic 75% with 25% mannitol, with the expectation that such eutectic retains the therapeutic effect of API cyclobenzaprine HCl, with the additional benefit of having higher stability and/or dissolution rates than the non-eutectic counterparts.
Applicant argues (page 10, second paragraph) that Lederman and Nebuloni are both silent regarding treating AUD. Applicant argues that the term “hangover” in Lederman is related to fatigue, somnolence or cognitive impairment, and not to alcohol consumption. In response, Applicant’s interpretation of the term “hangover” in Lederman is not supported by the teachings in Lederman. Hangover is defined in the Merriam-Webster dictionary as disagreeable physical effects following heavy consumption of alcohol or the use of drugs. Lederman does not provide an alternative definition for the term, and clearly does not provide a new meaning for the term to be limited to fatigue, somnolence or cognitive impairment, as Applicant asserts.
Applicant argues (page 10, last paragraph, page 11, first paragraph) that Altintoprak does not teach cyclobenzaprine. Applicant argues that a POSITA would not have been motivated to substitute amitriptyline with cyclobenzaprine in a method of treating alcohol dependence co-morbid with depression, because more side effects are seen with amitriptyline than with another antidepressant, mirtazapine. This is not persuasive, the rejection is based on the structural similarity between amitriptyline and cyclobenzaprine; a comparison between side effects seen with amitriptyline vs. other antidepressant drug(s) is not relevant to the rejection.
The point of the rejection is that a person of ordinary skill in the art would have been motivated to administer a composition comprising cyclobenzaprine to a subject suffering from depression and comorbid alcohol use disorder, because Lederman teaches that cyclobenzaprine is effective to treat depression, Altintoprak teaches that depressive symptoms frequently coexist with alcoholism, and Altintoprak teaches that structurally similar antidepressant amitriptyline is effective to treat alcohol dependence comorbid with depressive disorder. Thus, the person of ordinary skill in the art would have administered cyclobenzaprine to a subpopulation of patients suffering from depressive disorder, namely patients suffering from depression and comorbid alcohol use disorder, with the expectation of seeing therapeutic effect.
For these reasons, the rejection of the claims under 35 U.S.C. 103 over Lederman, in view of Altintoprak, in further view of Nebuloni, is herein maintained, and a modified rejection is made below, based on Applicant’s amendment of 24 March 2026.
In view of Applicant’s amendment of 24 March 2026, the rejections of claims 1-19 on the ground of nonstatutory obviousness-type double patenting over claims 1-2 of U.S. patent 10,357,465, is herein withdrawn. Claims 1-2 of U.S. patent 10,357,465 are drawn to a eutectic comprising 65% cyclobenzaprine HCl and 35% delta-mannitol by weight; the amended claims in the instant application recite a eutectic comprising 75% cyclobenzaprine HCl and 25% beta-mannitol by weight.
For the same reason, the rejection of the instant claims on the ground of nonstatutory obviousness-type double patenting over claims of U.S. patent 11,026,898, is herein withdrawn.
The rejections of the instant claims on the ground of nonstatutory obviousness-type double patenting over claims of U.S. patents over claims of U.S. patents 9,636,408; 10,322,094; 9,956,188; 10,117,936; 10,864,175; and the provisional rejection over claims of co-pending U.S. Patent application 19/230,858, are herein maintained. The claims of the reference patents/patent application recite a eutectic comprising 75% cyclobenzaprine HCl and 25% beta-mannitol by weight, as in the instant claims. The Specifications of the cited U.S. patents/patent application teach that pharmaceutical compositions comprising eutectics of the invention are effective to treat, for example, alcohol dependent sleep disorder or nocturnal drinking syndrome.
Applicant’s argument that the claims of the reference patents do not recite 2.8 mg or 5.6 mg, and do not recite treatment of AUD or symptoms, is not persuasive.
MPEP 804.II.B.1 states: In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.
In this case, the claims of reference patents are drawn to a eutectic comprising 75% cyclobenzaprine HCl and 25% beta-mannitol by weight, as in the instant claims; the reference patent’s specification is used in the rejection for teaching the utility of such eutectics to treat, for example, alcohol dependent sleep disorder or nocturnal drinking syndrome.
With respect to 2.8 mg or 5.6 mg, preparing a composition comprising a mg amount of cyclobenzaprine HCl in a eutectic with mannitol, by weighing the appropriate amounts, is routine, well within the skill of the artisan.
The rejection of claims 1-19 on the ground of nonstatutory obviousness-type double patenting over claims of co-pending U.S. patent application 13/918,692, is herein withdrawn. U.S. patent application 13/918,692 is now abandoned.
Applicant’s amendment of 24 March 2026 necessitated the following new/modified rejections.
Claim Rejections- 35 USC 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 9-14, 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Nebuloni et al. (US 2014/0336264, cited in IDS).
Nebuloni et al. (US 2014/0336264) teach [0005] a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, wherein the eutectic comprises 75% +/- 2% cyclobenzaprine HCl (as active pharmaceutical ingredient API) by weight of the eutectic and 25% +/- 2% mannitol by weight of the eutectic ([0205], [0210], claim 5), wherein the composition comprises a basifying agent (claim 8, [0138]), Thus, Nebuloni teaches the very composition of the instant claims.
Nebuloni teaches [0205] that the eutectic composition formed at approximately 75% Cyclobenzaprine HCl (API) and 25% mannitol (Fig. 61); under 75%, two distinct melting peaks (Fig. 55-60, [0060]-[0065]) were observed from the melting of the eutectic fraction and the excess of the individual components. Nebuloni teaches [0059], Fig. 54 the DSC heating curve of mannitol, beta form, as individual component.
Nebuloni [0208]-[0210] compares (by stacking) the XRPD pattern of the eutectic comprising 75% cyclobenzaprine HCl and 25% mannitol, to the XRPD of pure mannitol ([0074], [0075], Fig. 69, 70), which is mannitol form beta.
Thus, based on the DSC heating curve data presented, and based on the XRPD data presented for the eutectic and the individual components, the eutectic comprising 75% cyclobenzaprine HCl and 25% mannitol taught by Nebuloni contains mannitol as beta-mannitol, as in the instant claims.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed method. In the absence of evidence to the contrary, the burden is on the applicant to prove that the function of the product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Nebuloni teaches that the composition of the invention is administered orally [0127], as in instant claim 12, or sublingually [0129], as in instant claims 12, 14, or is administered for transmucosal absorption [0127], as in instant claim 13, and the composition can be administered on a daily basis [0130], which includes once daily administration, as in instant claims 2, 11.
Nebuloni teaches (claim 9) that the compositions of the invention comprise dipotassium hydrogen phosphate as basifying agent, as in instant claims 20, 21.
Nebuloni teaches [0137] that the compositions of the invention are used to treat sleep disturbances or sleep disorders such as, for example, alcohol-dependent sleep disorder, or nocturnal drinking syndrome.
Nebuloni exemplifies [0156] a formulation mixture comprising 2.40 mg cyclobenzaprine HCl and mannitol, where the amount of cyclobenzaprine is close to the amount in instant claim 1, 9.
It would have been obvious to a person of ordinary skill in the art to use the teachings of Nebuloni to arrive at the instant invention. The person of ordinary skill in the art would have been motivated to administer a pharmaceutical composition comprising a eutectic comprising 75% +/- 2% cyclobenzaprine HCl by weight of the eutectic and 25% +/- 2% beta-mannitol by weight of the eutectic taught by Nebuloni, to a subject in need thereof to treat alcohol use disorder or associated symptoms, because Nebuloni teaches that the compositions of the invention are used to treat, for example, alcohol-dependent sleep disorder, or nocturnal drinking syndrome. Thus, the person of ordinary skill in the art would have administered a pharmaceutical composition comprising a eutectic of 25% beta-mannitol and 75% cyclobenzaprine HCl, taught by Nebuloni, to a subject suffering from alcohol-dependent sleep disorder, or nocturnal drinking syndrome, with the expectation of seeing therapeutic effect.
Further, regarding claims 9-10, the person of ordinary skill in the art would have optimized the dose/amount of cyclobenzaprine HCl active ingredient administered in the method of treatment, and the frequency of administration, because determining the therapeutically effective amount and the dosing frequency in order to achieve optimum efficacy in treating a disease is well within the skill of the physician, and is a routine step in any method of treatment.
Regarding claim 19, the person of ordinary skill in the art would have administered a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, taught by Nebuloni, to a subject suffering from alcohol-dependent sleep disorder, or nocturnal drinking syndrome, during detoxification, with the expectation that said composition has therapeutic effect.
As such, claims 1-2, 9-14, 19-21 are rejected as prima facie obvious.
Claims 1-2, 9-14, 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Lederman, S. (US 2012/0232159, cited in IDS), in view of Altintoprak et al. (Hum. Psychopharmacol Clin Exp 2008, 23, 313-319, cited in PTO-892 of 24 September 2025), in further view of Nebuloni et al. (US 2014/0336264, cited in IDS).
Lederman (US 2012/0232159) teaches (claim 1) a method for treating depression comprising administering to a human in need of such treatment a pharmaceutical composition comprising cyclobenzaprine
PNG
media_image1.png
310
242
media_image1.png
Greyscale
in a therapeutically effective amount and a carrier, wherein such treatment ameliorates or eliminates the depression.
Claim 7 recites that the pharmaceutical composition is administered at bedtime, which is consistent with once daily administration, as in instant claims 2, 11.
Claim 2 recites that the amount of cyclobenzaprine administered in the method is less than 5 mg/day, which is within or overlaps with the range in instant claims 1, 9.
Lederman teaches [0009] that a therapeutically effective amount of cyclobenzaprine administered to a subject in the method of treatment is between 0.5 to about 10 mg/day, between 1 mg and 5 mg/day, or between 1 and 4 mg/day; these ranges encompass the amounts in instant claims 1, 9-10.
Lederman teaches [0012] that the amount of cyclobenzaprine in the pharmaceutical composition is between 0.5 to about 30 mg, or between 1 mg and 20 mg, which encompasses the amount in instant claims 1, 9, 10. Lederman teaches [0012] that the amount of cyclobenzaprine is very low to minimize side effects observed with higher amounts; the very low amounts are of less than 10 mg, which encompasses the amounts in instant claims 1, 9-10.
Lederman teaches [0013] buccal, oral, rectal, parenteral, transdermal, subcutaneous, sublingual administration, as in instant claims 12, 14, where sublingual administration is for transmucosal absorption, as in instant claim 13.
Claim 5 recites that the pharmaceutical composition is administered as an orally dissolving tablet or as a thin film formulation, which is consistent with buccal or sublingual administration, as in instant claims 12, 14, for transmucosal absorption, as in instant claim 13.
Lederman teaches (Example 2, page 4) a gelcap formulation of cyclobenzaprine with decreased potential for morning hangover.
Lederman does not teach a method of treating alcohol use disorder with cyclobenzaprine, where cyclobenzaprine is administered before, during or after detoxification, as in instant claim 19.
Lederman does not teach that the composition comprises a eutectic comprising 75% +/- 2% cyclobenzaprine HCl (as active pharmaceutical ingredient API) by weight of the eutectic and 25% +/- 2% mannitol by weight of the eutectic, further comprising a basifying agent, as in the instant claims.
Altintoprak (Hum. Psychopharmacol Clin Exp 2008, 23, 313-319) teaches (page 313, left column) that depressive symptoms frequently coexist with alcoholism. Most of the patients with alcohol dependence who consume alcohol heavily and on long term may lead to depression or the patients with depressive disorder may consume alcohol for self-medication.
Altintoprak teaches (page 324, left column, second paragraph) that the prevalence of depressive disorders in alcohol abusing-dependent individuals ranges from 15 to 70%.
Altintoprak teaches (Abstract, Table 2) that treatment with amitriptyline
PNG
media_image2.png
254
204
media_image2.png
Greyscale
resulted in the reduction of 17-item Hamilton Depression Rating Scale (HDRS) and alcohol craving scores, in patients suffering from alcohol dependence comorbid with depressive disorder, which is consistent with amitriptyline being effective to treat both depression and alcohol use disorder in said patients.
Altintoprak teaches (page 314, left column, third paragraph) that studies indicated that serotonergic and noradrenergic dysfunction have an important role in the development of alcohol abuse/dependence; several antidepressants, including tricyclics (TCA), have been investigated in depressive and non-depressive alcoholics either to reduce craving and alcohol intake or for the treatment of co-morbid depressive or anxiety symptoms.
Altintoprak teaches (page 314, left column, 5th paragraph) that amitriptyline
is a TCA that works as a noradrenergic and serotonergic reuptake inhibitor. The efficacy of amitriptyline in the severely depressed patients is well established and the maximizing clinical efficacy is not disputed.
Altintoprak teaches (page 314, left column, last paragraph) that experimental and clinical studies support the hypothesis that serotonergic and noradrenergic dysfunction are important in the development of both alcohol abuse/dependence and depression.
Altintoprak teaches (page 317, right column, last paragraph) that alcoholism is a complex disorder, several neurotransmitter systems, such as dopaminergic, GABAergic, noradrenergic, and serotonergic systems have been implicated in the pathophysiology of alcoholism. Serotonergic and noradrenergic systems also play a role in depression. In this context several antidepressant drugs have been used to reduce both alcohol craving and depressive symptoms in patients with alcohol dependence with co-morbid depressive disorder.
Altintoprak teaches (page 318, left column, second paragraph) that the efficacy of amitriptyline among patients withdrawn from alcohol and presenting depressive symptoms or major depression has been evaluated; amitriptyline was efficient in the treatment of severely depressive symptoms and also in anxiety, sleep disturbances, psychomotor retardation, and vegetative symptoms in said patients.
Altintoprak does not teach a method of treating alcohol use disorder with cyclobenzaprine, as in the instant claims.
Nebuloni et al. (US 2014/0336264) teach the advantages of formulating cyclobenzaprine HCl as eutectic with mannitol. Nebuloni teaches ([0110], [0119], [0120]) that eutectic compositions have higher stability and/or dissolution rates than their non-eutectic counterparts.
Nebuloni teaches a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, wherein the eutectic comprises 75% +/- 2% cyclobenzaprine HCl (as active pharmaceutical ingredient API) by weight of the eutectic and 25% +/- 2% beta-mannitol by weight of the eutectic ([0205], [0210], claim 5), wherein the composition comprises a basifying agent (claim 8, [0138]), Thus, Nebuloni teaches the very composition of the instant claims.
Nebuloni teaches [0205] that the eutectic composition formed at approximately 75% Cyclobenzaprine HCl (API) and 25% mannitol (Fig. 61); under 75%, two distinct melting peaks (Fig. 55-60, [0060]-[0065]) were observed from the melting of the eutectic fraction and the excess of the individual components. Nebuloni teaches [0059], Fig. 54 the DSC heating curve of mannitol, beta form, as individual component.
Nebuloni [0208]-[0210] compares (by stacking) the XRPD pattern of the eutectic comprising 75% cyclobenzaprine HCl and 25% mannitol, to the XRPD of pure mannitol ([0074], [0075], Fig. 69, 70), which is mannitol form beta.
Thus, based on the DSC heating curve data presented, and based on the XRPD data presented for the eutectic and the individual components, the eutectic comprising 75% cyclobenzaprine HCl and 25% mannitol taught by Nebuloni contains mannitol as beta-mannitol, as in the instant claims.
Nebuloni teaches that the composition is administered orally [0127], as in instant claim 12, or sublingually [0129], as in instant claims 12, 14, or is administered for transmucosal absorption [0127], as in instant claim 13, and the composition can be administered on a daily basis [0130], which includes once daily administration, as in instant claims 2, 11.
Nebuloni teaches (claim 9) that the compositions of the invention comprise dipotassium hydrogen phosphate as basifying agent, as in instant claims 20, 21.
It would have been obvious for a person of ordinary skill in the art to combine the teachings of Lederman, Altintoprak and Nebuloni to arrive at the instant invention. The person of ordinary skill in the art would have been motivated to administer a composition comprising cyclobenzaprine to a subject suffering from depression and comorbid alcohol use disorder, because Lederman teaches that cyclobenzaprine is effective to treat depression, Altintoprak teaches that depressive symptoms frequently coexist with alcoholism, with the prevalence of depressive disorders in alcohol abusing-dependent individuals ranging from 15 to 70%, and Altintoprak teaches that several antidepressant drugs have been used to reduce both alcohol craving and depressive symptoms in patients with alcohol dependence with co-morbid depressive disorder. Thus, the person of ordinary skill in the art would have administered cyclobenzaprine to a subpopulation of patients suffering from depressive disorder, namely patients suffering from depression and comorbid alcohol use disorder, with the expectation of seeing therapeutic effect.
Further, the person of ordinary skill in the art would have been motivated to replace amitriptyline
PNG
media_image2.png
254
204
media_image2.png
Greyscale
with
PNG
media_image1.png
310
242
media_image1.png
Greyscale
, in a method of treating patients suffering from alcohol dependence comorbid with depressive disorder taught by Altintoprak, with the expectation that cyclobenzaprine will be effective to treat both depression and alcohol use disorder in said patients. Obviousness based on similarity of structure and function entails motivation to make claimed compound in expectation that compounds similar in structure will have similar properties. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979) In the cited case law, the claimed and prior art compounds were both directed to heterocyclic carbamoyloximino compounds having pesticidal activity. The only structural difference between the claimed and prior art compounds was that the ring structures of the claimed compounds had two carbon atoms between two sulfur atoms whereas the prior art ring structures had either one or three carbon atoms between two sulfur atoms. The court held that although the prior art compounds were not true homologs or isomers of the claimed compounds, the similarity between the chemical structures and properties is sufficiently close that one of ordinary skill in the art would have been motivated to make the claimed compounds in searching for new pesticides.
In this case, amitriptyline and cyclobenzaprine display similar structure; both are tricyclic structures, the only difference is the presence of a double bond -CH=CH- in the central ring in cyclobenzaprine, versus a -CH2-CH2- bond in amitriptyline. As such, the similarity between the chemical structures and properties is sufficiently close that one of ordinary skill in the art would have been motivated to replace amitriptyline with cyclobenzaprine, with the expectation that cyclobenzaprine will be effective to treat both depression and alcohol use disorder in patients suffering from alcohol use disorder and comorbid depression.
Further, since Altintoprak teaches that amitriptyline is efficient in the treatment of severely depressive symptoms in patients withdrawn from alcohol and presenting depressive symptoms or major depression, and Lederman teaches that cyclobenzaprine is an effective antidepressant, the person of ordinary skill in the art would have administered cyclobenzaprine to patients after alcohol detoxification/withdrawn from alcohol, and suffering from depression, with a reasonable expectation of achieving therapeutic effect in said patients.
Further, the person of ordinary skill in the art would have formulated cyclobenzaprine as a eutectic comprising 75% +/- 2% cyclobenzaprine HCl (as active pharmaceutical ingredient API) and 25% +/- 2% beta-mannitol by weight of the eutectic, to administered in the method of treatment, because Nebuloni teaches the advantages of such eutectic compositions of cyclobenzaprine HCl and mannitol, namely have higher stability and/or dissolution rates than their non-eutectic counterparts.
Further, the person of ordinary skill in the art would have optimized the dose/amount of cyclobenzaprine HCl active ingredient administered in the method of treatment, and the frequency of administration, because determining the therapeutically effective amount and the dosing frequency in order to achieve optimum efficacy in treating a disease is well within the skill of the physician, and is a routine step in any method of treatment.
Regarding claim 19, the person of ordinary skill in the art would have administered a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, taught by Nebuloni, to a subject suffering from alcohol use disorder and comorbid depression, during detoxification, with the expectation that said composition has therapeutic effect.
As such, claims 1-2, 9-14, 19-21 are rejected as prima facie obvious.
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 1-2, 9-14, 19-21 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3 of U.S. patent 9,636,408 (cited in IDS). Although the conflicting claims are not identical, they are not patentably distinct from each other because claims 1-3 of U.S. patent 9,636,408 render obvious instant claims.
Claims 1-3 of U.S. patent 9,636,408 are drawn to a eutectic comprising 65% cyclobenzaprine HCl and 35% mannitol by weight.
The Specification of U.S. patent 9,636,408 teaches that pharmaceutical compositions comprising eutectics of the invention are effective to treat, for example, alcohol dependent sleep disorder or nocturnal drinking syndrome.
It would have been obvious to a person of ordinary skill in the art to use the teachings of claims 1-3 of U.S. patent 9,636,408 to arrive at the instant invention. The person of ordinary skill in the art would have been motivated to administer a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, taught by claims 1-3 of U.S. patent 9,636,408, to a subject in need thereof to treat alcohol use disorder or associated symptoms, because the Specification of U.S. patent 9,636,408 teaches that the compositions of the invention are used to treat, for example, alcohol-dependent sleep disorder, or nocturnal drinking syndrome. Thus, the person of ordinary skill in the art would have administered a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, taught by claims 1-3 of U.S. patent 9,636,408, to a subject suffering from alcohol-dependent sleep disorder, or nocturnal drinking syndrome, with the expectation of seeing therapeutic effect.
Further, regarding claims 1, 9, 10, the person of ordinary skill in the art would have optimized the dose/amount of cyclobenzaprine HCl active ingredient administered in the method of treatment, the frequency of administration, as in instant claims 2, 11, and route of administration, because determining the therapeutically effective amount and the dosing frequency in order to achieve optimum efficacy in treating a disease is well within the skill of the physician, and is a routine step in any method of treatment.
Regarding claim 19, the person of ordinary skill in the art would have administered a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, taught by claims 1-3 of U.S. patent 9,636,408, to a subject suffering from alcohol-dependent sleep disorder, or nocturnal drinking syndrome, during detoxification, with the expectation that said composition has therapeutic effect.
As such, claims 1-2, 9-14, 19-21 are rejected as prima facie obvious.
For similar reasons, claims 1-2, 9-14, 19-21 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable
over claims 1-4 of U.S. Patent 10,322,094;
over claims 1-2 of U.S. Patent 9,956,188 (cited in IDS);
over claims 1-6, 19-22 of U.S. Patent 10,117,936 (cited in IDS);
over claims 1-4 of U.S. Patent 10,864,175 (cited in IDS);
and are provisionally rejected over claims 1-10, 54, 55 of co-pending U.S. Patent application 19/230,858 (cited in PTO-892 of 09/24/2025).
Conclusion
Claims 1-2, 9-14, 19-21 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IRINA NEAGU/Primary Examiner, Art Unit 1629
Prosecution Insights