DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage entry of PCT/GB2022/051609 filed on 06/23/2022. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in UNITED KINGDOM on 06/23/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of (1). Naltrexone as a species of a naltrexone compound selected from: a naltrexone metabolite, or a naltrexone analogue selected from the group consisting of methylnaltrexone, nalmefene and nalorphine; (2). Cannabinol as a species of cannabinoid, flavonoid or terpene; (3). Serotonin hydrochloride as a species of a 5-hydroxytryptamine (5-HT) agonist compound; (4). Psoriasis as a species of an autoimmune disease; and (5). Calcitriol as a species of a Vitamin D compound, in the reply filed on April 8, 2026 is acknowledged.
Claims 1-7, 9, 11-12, 14-17, 19, 21-22 and 25-38 are being examined as they read on the elected species.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11, 14, 15, 29, 31, 32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The cited claims of the instant application are indefinite because they recite wherein the subject is administered vitamin D before, during or following the treatment of claim 1 or 2. However, claims 1 and 2 refer to multiple treatments, including a first treatment phase and a second treatment phase, and thus it is unclear which treatment claims 11, 14, 15, 29, 31, 32 refer to.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 9, 11-12, 14-17, 19, 21-22 and 25-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,029,737 in view of Callahan et al. WO 2019/144191 A1; Thorslund et al. (Drug News & Perspectives v. 20, n. 8 (2007) : 521); Chen U.S. Publication No. 2009/0286760 A1; Lebwohl et al. (J Am Acad Dermatol 2004;50:416-30.); and Magilavy WO 2005/077018 A2.
The cited claims of the instant application claim a method of treating an autoimmune disease within a subject, comprising administering a pharmaceutical composition comprising naltrexone, wherein a therapeutically effective amount of the naltrexone is to be administered to the subject in a first treatment phase, wherein after the first treatment phase the subject is administered a therapeutically effective amount of the cannabinoid cannabidiol in a second treatment phase, and wherein an agonist of a 5-hydroxytryptamine (5-HT) receptor such as serotonin hydrochloride is to be administered to the subject either simultaneously, sequentially or separately with naltrexone, and further administering vitamin D during the first or second treatment phase.
The cited claims of ‘737 claim a method for the treatment of an autoimmune disease, comprising administering a subject in need thereof, a therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof, and vitamin D or a pharmaceutically acceptable salt thereof, wherein said naltrexone or pharmaceutically acceptable salt thereof and said vitamin D or pharmaceutically acceptable salt thereof are administered simultaneously, wherein the autoimmune disease is psoriasis, Systemic Lupus Erythematosus (SLE) or thyroiditis, wherein the naltrexone or pharmaceutically acceptable salt thereof is administered at a dose less than 0.5 mg/kg.
The claims of ‘737 do not claim that the treatment regimen for psoriasis includes a cannabinoid such as cannabidiol. The claims of ‘737 do not claim that the treatment regimen for psoriasis includes an agonist of a 5-hydroxytryptamine (5-HT) receptor such as serotonin hydrochloride. The claims of ‘737 do not claim the specific treatment regimen including a recovery period in between drug administration phases.
Callahan et al. teaches a treatment regime for use in the treatment or prevention of psoriasis, said regime comprises the administration of: a) between 50 mg and 3000 mg of a topical liquid or gel composition comprising between 1% w/w and 15% w/w cannabinoid, wherein the cannabinoid is dissolved in the liquid or gel composition (abstract). Callahan et al. teaches methods of treating or preventing psoriasis using topical cannabinoids, including cannabidiol [0076]. Callahan et al. teaches that a topical composition containing cannabinoids such as cannabidiol, is preferably applied topically to an area which is affected by the psoriasis, wherein the application of cannabinoid results in reduction in redness, itch, pain or irritation, a reduction in blisters or pustules, a reduction in infection, less breakdown and loss of collagen and elastin in the skin, a reduction of swelling, cracking, weeping, crusting, and scaling and/or a general decrease in inflammation [0076]. Callahan et al. teaches a highly preferred composition contains 5 % w/w, 10 % w/w or 20 % w/w cannabidiol ([0026]-[0032] page 22).
Thus Callahan et al. teaches that cannabinoids including cannabidiol are useful for the treatment of psoriasis.
Thorslund et al. teaches that psoriasis is a chronic inflammatory skin disease, where specific immunity and/or innate immunity may be of importance in the disease pathogenesis (abstract). Thorslund et al. teaches that psoriasis may be worsened by stress, which suggests that a neuroimmune interaction is contributing to the disease (abstract). Thorslund et al. teaches that Serotonin (5-HT) is a monoamine which has an impact on cell proliferation, migration and apoptosis and 5-HT has a role in inflammation, and 5-HT receptors as well as its transporter protein have been found in psoriatic skin (abstract). Thorslund et al. teaches that there are several target structures/cells in psoriasis that might be affected by serotonergic drugs, with focus on the 5-HT1A and 5-HT2A receptors, and SERT and also, pruritus might be affected by serotonergic compounds, especially the ones modulating the 5 HT2A or 5-HT3 receptors (page 524). Thus Thorslund et al. teaches that psoriasis is a chronic inflammatory disease with an impact by the specific and/or innate immune systems, and there might be a role for serotonergic compounds in the treatment of this disease, also during the possible worsening of stress (page 524).
In addition, Chen teaches a combination for the treatment of hyperproliferative diseases including an anti-inflammatory agent; an oxidative phosphorylation inhibitor and a compound possessing or maintaining at least one of the serotonin's activities including serotonin such as serotonin sulfate, serotonin creatinine sulfate complex, or serotonin hydrochloride or a serotonin re-uptake inhibitor [0004]-[0008]. Chen teaches the use of serotonin and its functional equivalents such as psilocybin, psilocin, and other serotonergic agents [0025]-[0048]. Chen specifically teaches the serotonin agent is serotonin hydrochloride (claims 24 and 26). Chen teaches that an example of a hyperproliferative disease that can be treated is psoriasis [0120].
Thus Chen teaches that serotonin and its functional equivalents, in particular serotonin hydrochloride can be administered for the treatment of hyperproliferative diseases such as psoriasis.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of the claims of ‘737 which claim the combination of naltrexone and vitamin D for the treatment of autoimmune diseases including psoriasis, with the teachings of Callahan et al. which teaches that cannabinoids including cannabidiol are useful for the treatment of psoriasis, and both Thorslund et al. and Chen which teaches a role for serotonergic compounds in the treatment of psoriasis, in particular serotonin and its functional equivalents, such as serotonin hydrochloride can be administered for the treatment of hyperproliferative diseases such as psoriasis. Thus since the cited prior art teaches that cannabidiol and serotonin agonists are useful in the treatment of psoriasis, an ordinary skilled artisan would have been motivated to combine cannabidiol and serotonin hydrochloride as a suitable serotonergic compound with the treatment combination of ‘737 with a reasonable expectation of improving the treatment of psoriasis by combining known treatments. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Although the cited prior art do not teach the specific treatment regimen as claimed including a recovery period in between drug administration phases, it would be within the skill of an ordinary skilled artisan to determine an appropriate treatment regimen such that optimal treatment is achieved. Thus, said limitations as claimed reciting a first and second treatment phases as well as a recovery period are interpreted as optimization which is within the skill of an ordinary artisan. Thus in the absence of secondary considerations such as unexpected results or a demonstration of criticality, said limitations as claimed are rendered obvious. "[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).
In addition, Lebwohl et al. teaches that in patients with moderate-to-severe psoriasis, remission can be difficult to achieve and sustain and both acutely acting and long-term maintenance agents are needed (abstract). Lebwohl et al. teaches that combination, rotational, and sequential approaches are often more effective and safer than single-agent therapy (abstract). For any number of reasons, including loss of efficacy, adverse effects, or cumulative or acute toxicity—and especially the inability to clear resistant lesions—a single modality will not be adequate and using two or more therapies is thus the rule rather than the exception for most patients with moderate-to-severe psoriasis (abstract). Lebwohl et al. teaches in conventional combination therapy, two or more agents with synergistic or complementary action are used concomitantly, allowing lower-dose, toxicity-sparing regimens of each of the agents (page 417). Lebwohl et al. teaches that rotational therapy is another strategy for combining treatments wherein patients are moved from one mono therapy agent to another in an effort to minimize cumulative dosage and forestall toxicities (page 417). Sequential therapy is a strategy designed to optimize initial efficacy and then lead to a safe maintenance regimen by the use of specific combinations in a deliberate sequence (page 417). The three-step treatment strategy optimizes outcome through the scheduled use of topical agents (for mild to moderate psoriasis) or systemic and/or photo-therapeutic agents (for moderate to severe disease) (pages 417-418). Lebwohl et al. teaches that the sequential strategy consists of (1) the clearing phase, involving the use of a powerful, rapid-acting agent, often at the maximum dermatologic dose; (2) the transitional phase, in which a well-tolerated, safe maintenance agent is introduced and administered concurrently with the clearing agent, which is gradually tapered; and (3) the maintenance phase, in which the patient remains on the maintenance drug with additional therapy, if needed (page 418).
Furthermore, Magilavy teaches cycle therapy for the treatment of psoriasis (page 2). Magilavy teaches that a "cycle" of treatment includes (a) an administration period during which a therapeutic agent is administered at least twice (the interval between administrations is referred to as the IA), followed by (b) a rest period during which the therapeutic agent is not administered. The rest period is preferably at least as long as the administration period. During the administration period of the cycle, the agent can be administered at least 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 times at (preferably regular) intervals. Typically, the administration period is sufficiently long for a patient to exhibit a pre-selected level of amelioration of disease. The rest period can include monitoring the patient for a response to the therapeutic agent (e.g., a therapeutic effect or a side-effect) (page 5). The administration period of the cycle can vary with regard to dosing strategy. For example, if the administration period is measured in weeks or months, the administration period can include monthly, weekly, bi-weekly, semi-weekly, or daily administration of the agent for a specified number of weeks, as determined by a heath care practitioner for a particular patient (pages 5-6).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to develop a treatment regimen based on procedures well-known in the art for the treatment of psoriasis. Since Lebwohl et al. teaches that combination, rotational, and sequential approaches are often more effective and safer than single-agent therapy and that a single modality is usually not adequate and using two or more therapies is thus the rule rather than the exception for most patients with moderate-to-severe psoriasis, a person of ordinary skill in the art would have been motivated to use a combination with multiple agents and optimize the treatment regimen based on combination, rotational, and sequential approaches. Furthermore, based on the teachings of Magilavy which teaches "cycle" treatment for psoriasis that includes (a) an administration period during which a therapeutic agent is administered at least twice, followed by (b) a rest period during which the therapeutic agent is not administered, wherein the rest period can include monitoring the patient for a response to the therapeutic agent (e.g., a therapeutic effect or a side-effect), a person of ordinary skill in the art would have been motivated to optimize the psoriasis treatment regimen by incorporating a rest period such that monitoring the patient’s response to the therapy can be achieved with a reasonable expectation of success.
Thus based on the prior art teachings, it would have been obvious to optimize the administration of the combination of ‘737 including naltrexone and vitamin D in combination with serotonin hydrochloride as taught by Thorslund et al. and Chen and cannabinoids including cannabidiol as taught by Callahan et al. by simultaneous, sequential or separate administration and further incorporating a rest period between treatment agents in order to monitor the patient’s response to the treatment. With respect to the specific order of administration as claimed, it has been held that merely changing the order of steps in a multi-step process is not a patentable modification absent a showing of unexpected results. Ex parte Rubin 128 USPQ 440 (POBA 1959. Thus, in the absence of a demonstration of criticality, the cited claims of the instant application are rendered obvious.
Claims 1-2, 7, 9, 11-12, 14-17, 19, 21-22, 25, and 27-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/572,637 (U.S. Publication No. 2025/0281481 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of copending ‘637 are substantially overlapping in scope and mutually obvious.
The cited claims of the instant application claim a method of treating an autoimmune disease within a subject, comprising administering a pharmaceutical composition comprising naltrexone, wherein a therapeutically effective amount of the naltrexone is to be administered to the subject in a first treatment phase, wherein after the first treatment phase the subject is administered a therapeutically effective amount of the cannabinoid cannabidiol in a second treatment phase, and wherein an agonist of a 5-hydroxytryptamine (5-HT) receptor such as serotonin hydrochloride is to be administered to the subject either simultaneously, sequentially or separately with naltrexone, and further administering vitamin D during the first or second treatment phase.
Claims 1-19 of copending ‘637 claim a single unit oral dose pharmaceutical composition for use as a medicament for separate, sequential or simultaneous administration with an agonist of a 5-hydroxytryptamine (5-HT) receptor; wherein the single unit oral dose pharmaceutical composition comprises a first active ingredient and a second active ingredient; wherein the first active ingredient is for absorption in the gastrointestinal tract from the oesophagus onwards and the second active ingredient is for absorption in the oral cavity; and wherein the first active ingredient is naltrexone in an amount of 0.01 to 10 mg and the second active ingredient is calcitriol in an amount of 80 to 200 mg. Claim 13 of copending ‘637 claims the pharmaceutical composition is for use in the treatment of an autoimmune disease. Claim 14 of copending ‘637 claims the single unit oral dose pharmaceutical composition is to be administered to the subject in a first treatment phase, and wherein after the first treatment phase, the subject is administered the agonist of a 5-HT receptor in a subsequent second treatment phase. Claim 16 of copending ‘637 claims the single unit dose pharmaceutical composition further comprising a cannabinoid, flavonoid or terpene.
Thus copending ‘637 specifically claims the combination of naltrexone and vitamin D for administration, wherein an agonist of a 5-hydroxytryptamine (5-HT) receptor is to be administered to the subject either simultaneously, sequentially or separately with naltrexone and vitamin D, and further administering a cannabinoid. The use for the combination of copending ‘637 is for the treatment of an autoimmune disease. Therefore the cited claims of the instant application are mutually obvious and thus not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 1-7, 9, 11-12, 14-17, 19, 21-22 and 25-38 are rejected under 35 U.S.C. 103 as being unpatentable over Wai et al. WO 2019/186207 A1 (provided on IDS dated 12/21/2023) in view of Callahan et al. WO 2019/144191 A1; Thorslund et al. (Drug News & Perspectives v. 20, n. 8 (2007) : 521); Chen U.S. Publication No. 2009/0286760 A1; Lebwohl et al. (J Am Acad Dermatol 2004;50:416-30.); and Magilavy WO 2005/077018 A2.
The cited claims of the instant application claim a method of treating an autoimmune disease within a subject, comprising administering a pharmaceutical composition comprising naltrexone, wherein a therapeutically effective amount of the naltrexone is to be administered to the subject in a first treatment phase, wherein after the first treatment phase the subject is administered a therapeutically effective amount of the cannabinoid cannabidiol in a second treatment phase, and wherein an agonist of a 5-hydroxytryptamine (5-HT) receptor such as serotonin hydrochloride is to be administered to the subject either simultaneously, sequentially or separately with naltrexone. The claims further recite the oral administration of vitamin D such as calcitriol during the first or second treatment phase.
Wai et al. teaches naltrexone or an analogue thereof, wherein the analogue is methylnaltrexone, naloxone, nalmefene and nalorphine and vitamin D or an active metabolite, or a pharmaceutically acceptable salt of either for separate, sequential or simultaneous administration, for use in the therapy of an autoimmune disease (abstract). Wai et al. teaches an example of an autoimmune disease is psoriasis which is a condition characterized by localized inflamed pruritic patches on the skin that cause significant discomfort to the subject (page 2).
Wai et al. teaches that naltrexone together with vitamin D has a synergistic effect in the treatment of autoimmune diseases (page 3). Wai et al. teaches that the therapeutic pathways of naltrexone and vitamin D interact in such a way that enhances the therapeutic effect when used in combination and thus provides an effective treatment to alleviate symptoms associated with autoimmune diseases, in particular psoriasis (page 3).
Wai et al. teaches preferably the naltrexone is to be administered in a low dose regime, i.e. as “low dose naltrexone”, (LDN) where the naltrexone, analogue or metabolite is administered at a dose less than 0.5 mg/kg, preferably less than 0.2 mg/kg, more preferably between 0.01 mg/kg and 0.08 mg/kg (page 4).
Wai et al. teaches the use of vitamin D, an active metabolite such as any intermediate or product derived from a vitamin D metabolic pathway including a vitamin D precursor wherein non-limiting examples of vitamin D metabolites include ergocalciferol, cholecalciferol, calcidiol, and calcitriol, 1 a-hydroxycholecalciferol, 25- hydroxycholecalciferol, 1 a,25-hydroxycholecalciferol, 24,25hydroxycholecalciferol (page 5).
Wai et al. teaches that the vitamin D may be administered as part of the same treatment regimen preferably simultaneously (page 5). In certain embodiments, the vitamin D product is to be administered to the patient in an amount sufficient to bring the subject’s blood vitamin D concentration to at least 40 ng/ml, more preferable at least 50 ng/ml (page 6). Preferably, the blood vitamin D concentration is raised to within a range of from 40 to 120 ng/ml, more preferably the blood vitamin D concentration is raised to within a range of from 40 to 90 ng/ml (page 6).
Wai et al. teach that the naltrexone product and the vitamin D product are for simultaneous administration and may be provided as a combined preparation, where the combined preparation may be formulated in an oral solution, a caplet, a capsule, an injectable, an infusible, a suppository, a lozenge, a tablet, a cream or salve or an alternative topical ointment and the like (page 7).
Wai et al. teaches the naltrexone or an analogue thereof, wherein the analogue is methylnaltrexone, naloxone, nalmefene and nalorphine or a pharmaceutically acceptable salt is administered as low dose naltrexone, i.e. at a dose less than 0.5 mg/kg, preferably less than 0.2 mg/kg, more preferably between 0.01 mg/kg and 0.08 mg/kg (pages 7-8). Wai et al. teaches, the naltrexone product is in a solid oral dosage form which contains a therapeutically effective amount of naltrexone, which may be, for example, from about 0.01 mg to up to 50 mg, preferably from about 0.01 mg to about 40 mg, most preferably from about 0.01 to about 20 mg of the naltrexone product per tablet; e.g. about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg or about 50 mg of the naltrexone product per tablet (page 10). In certain embodiments the composition comprises from 3 mg to 4.5 mg (page 10).
Wai et al. teaches the vitamin D or analogue thereof, or pharmaceutically acceptable salt of either is administered at a daily dose in the range of about 400 IU to about 10,000 IU per dosage form, preferably in the range of about 2,000 to about 8,000, more preferably in the range of about 3,000 to 7,000 (page 8 and 9).
Wai et al. teaches that preferably the autoimmune disease is psoriasis, SLE or thyroiditis (page 8). Wai et al. teaches that the naltrexone and vitamin D may be administered in combination with other known therapies for autoimmune diseases and that introducing this combination of naltrexone and vitamin D is shown to increase the therapeutic effect of the known therapy (page 8)
Thus Wai et al. teaches the combination of naltrexone and an active metabolite of vitamin D such as calcitriol for the treatment of autoimmune diseases, preferably psoriasis and further teaches combining the combination with other known therapies for autoimmune diseases. With respect to claim 32 which claims the calcitriol is administered and absorbed in the oral cavity of the patient, said limitation is rendered obvious since Wai et al. teaches the form of the composition may be a lozenge which is administered in the oral cavity and will achieve absorption in the oral cavity (page 7).
Wai et al. does not teach that the treatment regimen for psoriasis includes a cannabinoid such as cannabidiol. Wai et al. does not teach that the treatment regimen for psoriasis includes an agonist of a 5-hydroxytryptamine (5-HT) receptor such as serotonin hydrochloride. Wai et al. does not teach the specific treatment regimen including a recovery period in between drug administration phases.
Callahan et al. teaches a treatment regime for use in the treatment or prevention of psoriasis, said regime comprises the administration of: a) between 50 mg and 3000 mg of a topical liquid or gel composition comprising between 1% w/w and 15% w/w cannabinoid, wherein the cannabinoid is dissolved in the liquid or gel composition (abstract). Callahan et al. teaches methods of treating or preventing psoriasis using topical cannabinoids, including cannabidiol [0076]. Callahan et al. teaches that a topical composition containing cannabinoids such as cannabidiol, is preferably applied topically to an area which is affected by the psoriasis, wherein the application of cannabinoid results in reduction in redness, itch, pain or irritation, a reduction in blisters or pustules, a reduction in infection, less breakdown and loss of collagen and elastin in the skin, a reduction of swelling, cracking, weeping, crusting, and scaling and/or a general decrease in inflammation [0076]. Callahan et al. teaches a highly preferred composition contains 5 % w/w, 10 % w/w or 20 % w/w cannabidiol ([0026]-[0032] page 22).
Thus Callahan et al. teaches that cannabinoids including cannabidiol are useful for the treatment of psoriasis.
Thorslund et al. teaches that psoriasis is a chronic inflammatory skin disease, where specific immunity and/or innate immunity may be of importance in the disease pathogenesis (abstract). Thorslund et al. teaches that psoriasis may be worsened by stress, which suggests that a neuroimmune interaction is contributing to the disease (abstract). Thorslund et al. teaches that Serotonin (5-HT) is a monoamine which has an impact on cell proliferation, migration and apoptosis and 5-HT has a role in inflammation, and 5-HT receptors as well as its transporter protein have been found in psoriatic skin (abstract). Thorslund et al. teaches that there are several target structures/cells in psoriasis that might be affected by serotonergic drugs, with focus on the 5-HT1A and 5-HT2A receptors, and SERT and also, pruritus might be affected by serotonergic compounds, especially the ones modulating the 5 HT2A or 5-HT3 receptors (page 524). Thus Thorslund et al. teaches that psoriasis is a chronic inflammatory disease with an impact by the specific and/or innate immune systems, and there might be a role for serotonergic compounds in the treatment of this disease, also during the possible worsening of stress (page 524).
In addition, Chen teaches a combination for the treatment of hyperproliferative diseases including an anti-inflammatory agent; an oxidative phosphorylation inhibitor and a compound possessing or maintaining at least one of the serotonin's activities including serotonin such as serotonin sulfate, serotonin creatinine sulfate complex, or serotonin hydrochloride or a serotonin re-uptake inhibitor [0004]-[0008]. Chen teaches the use of serotonin and its functional equivalents such as psilocybin, psilocin, and other serotonergic agents [0025]-[0048]. Chen specifically teaches the serotonin agent is serotonin hydrochloride (claims 24 and 26). Chen teaches that an example of a hyperproliferative disease that can be treated is psoriasis [0120].
Thus Chen teaches that serotonin and its functional equivalents, in particular serotonin hydrochloride can be administered for the treatment of hyperproliferative diseases such as psoriasis.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Wai et al. which teaches the combination of naltrexone and an active metabolite of vitamin D such as calcitriol for the treatment of autoimmune diseases, preferably psoriasis and further teaches combining the combination with other known therapies for autoimmune diseases, with the teachings of Callahan et al. which teaches that cannabinoids including cannabidiol are useful for the treatment of psoriasis, and both Thorslund et al. and Chen which teaches a role for serotonergic compounds in the treatment of psoriasis, in particular serotonin and its functional equivalents, such as serotonin hydrochloride can be administered for the treatment of hyperproliferative diseases such as psoriasis. Thus since the cited prior art teaches that cannabidiol and serotonin agonists are useful in the treatment of psoriasis, an ordinary skilled artisan would have been motivated to combine cannabidiol and serotonin hydrochloride as a suitable serotonergic compound with the treatment combination of Wai et al. with a reasonable expectation of improving the treatment of psoriasis by combining known treatments. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Although the cited prior art do not teach the specific treatment regimen including a recovery period in between drug administration phases, it would be within the skill of an ordinary skilled artisan to determine an appropriate treatment regimen such that optimal treatment is achieved. Thus, said limitations as claimed reciting first and second treatment phases as well as a recovery period are interpreted as optimization which is within the skill of an ordinary artisan. Thus in the absence of secondary considerations such as unexpected results or a demonstration of criticality, said limitations as claimed are rendered obvious. "[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).
In addition, Lebwohl et al. teaches that in patients with moderate-to-severe psoriasis, remission can be difficult to achieve and sustain and both acutely acting and long-term maintenance agents are needed (abstract). Lebwohl et al. teaches that combination, rotational, and sequential approaches are often more effective and safer than single-agent therapy (abstract). For any number of reasons, including loss of efficacy, adverse effects, or cumulative or acute toxicity—and especially the inability to clear resistant lesions—a single modality will not be adequate and using two or more therapies is thus the rule rather than the exception for most patients with moderate-to-severe psoriasis (abstract). Lebwohl et al. teaches in conventional combination therapy, two or more agents with synergistic or complementary action are used concomitantly, allowing lower-dose, toxicity-sparing regimens of each of the agents (page 417). Lebwohl et al. teaches that rotational therapy is another strategy for combining treatments wherein patients are moved from one mono therapy agent to another in an effort to minimize cumulative dosage and forestall toxicities (page 417). Sequential therapy is a strategy designed to optimize initial efficacy and then lead to a safe maintenance regimen by the use of specific combinations in a deliberate sequence (page 417). The three-step treatment strategy optimizes outcome through the scheduled use of topical agents (for mild to moderate psoriasis) or systemic and/or photo-therapeutic agents (for moderate to severe disease) (pages 417-418). Lebwohl et al. teaches that the sequential strategy consists of (1) the clearing phase, involving the use of a powerful, rapid-acting agent, often at the maximum dermatologic dose; (2) the transitional phase, in which a well-tolerated, safe maintenance agent is introduced and administered concurrently with the clearing agent, which is gradually tapered; and (3) the maintenance phase, in which the patient remains on the maintenance drug with additional therapy, if needed (page 418).
Furthermore, Magilavy teaches cycle therapy for the treatment of psoriasis (page 2). Magilavy teaches that a "cycle" of treatment includes (a) an administration period during which a therapeutic agent is administered at least twice (the interval between administrations is referred to as the IA), followed by (b) a rest period during which the therapeutic agent is not administered. The rest period is preferably at least as long as the administration period. During the administration period of the cycle, the agent can be administered at least 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 times at (preferably regular) intervals. Typically, the administration period is sufficiently long for a patient to exhibit a pre-selected level of amelioration of disease. The rest period can include monitoring the patient for a response to the therapeutic agent (e.g., a therapeutic effect or a side-effect) (page 5). The administration period of the cycle can vary with regard to dosing strategy. For example, if the administration period is measured in weeks or months, the administration period can include monthly, weekly, bi-weekly, semi-weekly, or daily administration of the agent for a specified number of weeks, as determined by a heath care practitioner for a particular patient (pages 5-6).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to develop a treatment regimen based on procedures well-known in the art for the treatment of psoriasis. Since Lebwohl et al. teaches that combination, rotational, and sequential approaches are often more effective and safer than single-agent therapy and that a single modality is usually not adequate and using two or more therapies is thus the rule rather than the exception for most patients with moderate-to-severe psoriasis, a person of ordinary skill in the art would have been motivated to use a combination with multiple agents and optimize the treatment regimen based on combination, rotational, and sequential approaches. Furthermore, based on the teachings of Magilavy which teaches "cycle" treatment for psoriasis that includes (a) an administration period during which a therapeutic agent is administered at least twice, followed by (b) a rest period during which the therapeutic agent is not administered, wherein the rest period can include monitoring the patient for a response to the therapeutic agent (e.g., a therapeutic effect or a side-effect), a person or ordinary skill in the art would have been motivated to optimize the psoriasis treatment regimen by incorporating a rest period such that monitoring the patient’s response to the therapy can be achieved with a reasonable expectation of success.
Thus based on the prior art teachings, it would have been obvious to optimize the administration of the combination of Wai et al. including naltrexone and calcitriol in combination with serotonin hydrochloride as taught by Thorslund et al. and Chen and cannabinoids including cannabidiol as taught by Callahan et al. by simultaneous, sequential or separate administration and further incorporating a rest period between treatment agents in order to monitor the patient’s response to the treatment. With respect to the specific order of administration as claimed, it has been held that merely changing the order of steps in a multi-step process is not a patentable modification absent a showing of unexpected results. Ex parte Rubin 128 USPQ 440 (POBA 1959. Thus, in the absence of a demonstration of criticality, the cited claims of the instant application are rendered obvious.
Conclusion
Claims 1-7, 9, 11-12, 14-17, 19, 21-22 and 25-38 are rejected. Claims 8, 10, 13, 18, 20, 23 and 24 are cancelled. No claims are allowed.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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