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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/2/26 has been entered.
Claim Status
Claims 3, 4, 6, 7, 9 and 12 are cancelled.
Claim 19 is new.
Claims 11, 2, 5, 8, 10, 11 and 13-19 are pending and under examination.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 4/9/26 and 7/2/26 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn rejections
Applicant's amendments and arguments filed 7/2/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 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 1-2, 5, 8, 10, 11 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Wai et al. (WO2019186207) and Dulieu et al. (WO2008127669) and Battaglia, A. (US20140371210) and The Compounder ([online] retrieved on 8/6/26 from: https:// thecompounder.com/2015/06/28/sublingual-ldn-drops/; 2015: 4 pages) and Flashner-Barak et al. (WO2007036802; of record).
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical formulation research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from pharmaceutical formulation compositions, methods of making pharmaceutical dosage forms, pharmaceutical active ingredients and the conditions treated by said pharmaceutical active ingredients— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1, 2, 5, 11 and 19, Wai et al. teach a combined preparation of naltrexone and vitamin D products in the form of a tablet where: “Numerous pharmaceutical forms and formulations for biologically active agents are known in the art, and any and all of these are contemplated by the present invention.” (Page 7, 2nd paragraph; claims 1-4). Wai et al. teach a combined preparation (Claim 4) such as a tablet (Claims 9-13; page 9, 3rd paragraph). A tablet is a single unit dosage form. Wai et al. teach combined preparations (Page 6, 2nd paragraph) and suggest: “The combined preparation will be provided in a form that is acceptable, tolerable, and effective for the subject.” (Page 7, 2nd paragraph). Wai et al. teach that the combined preparation can b formulated as a lozenge or tablet (Page 7, 2nd paragraph) and “the pharmaceutical composition is provided in oral dosage forms, particularly as a tablet.” (Page 8, 5th paragraph). The vitamin D or analogue thereof is administered at a daily dose in the range of about 400 IU to about 10000 IU per dosage form (Page 8, 2nd paragraph), which is about 400/40 = 10 mcg to about 10000/40 = 250 mcg and overlaps the claimed range of 80-200 mcg, or the composition may comprise from 0.01-25% by weight of the vitamin D product (Page 8, last paragraph). The naltrexone is employed in a therapeutically effective amount from about 0.01 to 50 mg (Page 10, 1st paragraph; claims 10-13), which overlaps the claimed range of 0.01 to 10 mg or from 0.01 to 6 mg with excipients (Page 10, 3rd and 4th paragraphs). See MPEP 2144.05(I): 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). Wai et al. teach employing vitamin D or an active metabolite (Page 6, 2nd paragraph).
Regarding claims 1 and 5, Battaglia teaches pharmaceutical compositions for the rapid transbuccal delivery of calcitriol (Claims 19 and 22), thereby bypassing first-pass liver metabolism and gastric/intestinal degradation [0002]. Battaglia also teaches sublingual dosage delivery forms are known to the artisan [0004].
Regarding claims 1, 11 and 19, Dulieu et al. teach bilayer dosage forms designed to adhere to the oral mucosa (Abstract; Figure 1; claims 1-39) where the bilayer dosage form allows release of APIs with different rates such as fast and sustained release of the one or more APIs (Page 4, lines 9-12) and contain a mixture of coated and non-coated APIs where the non-coated API enters the blood stream by transmucosal absorption and the coated API enters the blood stream much later by systemic absorption (Page 4, lines 26-31; page 27, lines 15-24). The API can be in the form of grains, granules, pellets, beads powders, mini-tablets (Page 17, line 32 through page 18, line 2). The APIs are without limitation and include anti-cancers (Page 18, lines 3-7) and vitamin D (page 18, line 32) and 1, 25-dihydroxycholecalciferol (Page 19, lines 4-5), which is calcitriol. Dulieu et al. teach: “Sublingual, gingival and/or buccal medications are administered by placing them in the mouth, either under the tongue (sublingual), on gum tissue (gingival) or between the gum and the cheek (buccal).” (Page 3, lines 1-12), which can help avoid first pass metabolism (Page 13, lines 4-8). Dulieu et al. teach adding carotenes (Page 18, lines 5-6), which is a type of terpene. Dulieu et al. teach an embodiment where the lyophilized layer (a) is for immediate release while lozenge/tablet (b) is for extended release (Example 9). Dulieu et al. teach that the bilayer dosage form is prepared by providing a suspension suitable for preparing the lyophilized layer (a), providing layer (b) in the form of a tablet or lozenge suitable for preparing the lyophilized mucoadhesive layer (b), adding the suspension layer (a) on said layer (b), freezing the system and lyophilizing (Page 10, lines 4-14; page 32, lines 4-11), which attaches the lyophilized and frozen liquid solution/suspension/emulsion to the tablet/lozenge. Dulieu et al. teach an embodiment where the lyophilized layer (a) is for immediate release while lozenge/tablet (b) is for extended release (Example 9), hence (b) is for release and/or absorption after the other formulation (a) is released and/or absorbed. Dulieu et al. expressly teach: “The base line layer (b) of the bilayer dosage form of the invention may be a standard tablet or lozenge” (Page 6, lines 16-17).
The tablet/lozenge can be placed in a mould container such as a blister prior to adding the other component (Page 11, lines 25-32).
Regarding claims 1 and 19, The Compounder teaches that naltrexone tastes terrible (Page 2).
Regarding claims 1 and 19, Flashner-Barak et al. teach an oral bioavailabilty of calcitriol of about 70% due to incomplete absorption, local intestinal degradation and/or hepatic metabolism of enterally absorbed calcitriol (Page 2, lines 7-13). Flashner-Barak et al. teach sublingual delivery of calcitriol to avoid hepatic first pass effect (Page 4, lines 10-20). Flashner-Barak et al. report: “We have surprisingly found that if one doses sublingually the high dose calcitriol or other vitamin D analogue in a very small volume in a suitable formulation one can obtain results that are significantly lower in patient-to-patient variability in bioavailability than in other forms of dosing.” Flashner-Barak et al. also teach that: “drug characteristics such as taste, irritancy, and allergenicity must be taken into account when positing sub lingual administration. Thus, not all drugs are suitable for administration via the sublingual route.” (Page 5, lines 25-27).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Wai et al. is that Wai et al. do not expressly teach calcitriol formulated for sublingual absorption in an amount of 80-200 micrograms in a ratio to naltrexone of 1:1 to 10:1; wherein the first formulation comprising naltrexone is in the form of a tablet and wherein the second formulation comprising calcitriol is a lyophilized and frozen liquid solution, suspension or emulsion which is attached to the tablet where the naltrexone is formulated for delayed release/absorption after the calcitriol is released/absorbed. This deficiency in Wai et al. is cured by the teachings of Dulieu et al., Battaglia, The Compounder and Flashner-Barak et al.
1. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate the tablet of Wai et al. with calcitriol formulated for sublingual absorption in an amount of 80-200 micrograms in a ratio to naltrexone of 1:1 to 10:1 wherein the first formulation comprising naltrexone is in the form of a tablet and wherein the second formulation comprising calcitriol is a lyophilized and frozen liquid solution, suspension or emulsion which is attached to the tablet where the naltrexone is formulated for delayed release/absorption after the calcitriol is released/absorbed, as suggested by Dulieu et al. and Battaglia, and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because of the following rationale. Wai et al. suggest an active metabolite of vitamin D, and in this art, the ordinary artisan is aware that calcitriol is the active form of vitamin D and thus obvious over the disclosure of an active metabolite of vitamin D by Wai et al. It is then merely routine optimization to have a 1:1 to 10:1 ratio of the calcitriol to naltrexone in the single unit dosage form of Wai et al. Wai et al. suggest employing known pharmaceutical formulations and Dulieu et al. provides a bilayer tablet for sublingual administration that can contain more than 1 API including calcitriol where the bilayer dosage form is prepared by providing a suspension suitable for preparing the lyophilized layer (a), providing layer (b) in the form of a tablet or lozenge suitable for preparing the lyophilized mucoadhesive layer (b), adding the suspension layer (a) on said layer (b), freezing the system and lyophilizing, which attaches the lyophilized and frozen liquid solution/suspension/emulsion to the tablet/lozenge. Battaglia suggests calcitriol for transmucosal administration as well. It is known through Flashner-Barak et al. the artisan understands to formulate calcitriol as a sublingual dosage form to obtain the desirable characteristic of significantly lower patient-to-patient variability in bioavailability and that not all drugs are suitable for sublingual administration due to organoleptic properties such as taste. It is known through the art of The Compounder that naltrexone tastes terrible. Accordingly, in order to provide a combined preparation that is acceptable, tolerable and effective for the subject, as suggested by Wai et al., the artisan would formulate a single unit oral dose pharmaceutical tablet composition with calcitriol formulated in a composition for sublingual absorption and the terrible tasting naltrexone formulated in a separate delayed release formulation for absorption in the GI tract from the esophagus onwards, which avoids the terrible taste of naltrexone, after the calcitriol is released/absorbed. Sublingual is just the position the bilayer tablet is placed in the oral cavity. In view of the combined references, the ordinary artisan would have a reasonable expectation of success.
The difference between the instant application and Wai et al. is that Wai et al. do not expressly teach adding a terpene. This deficiency in Wai et al. is cured by the teachings of Dulieu et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate the tablet of Wai et al. with a terpene, as suggested by Dulieu et al. and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because of the following rationale. Dulieu et al. teach a terpene, carotenes, as discussed above and teach the API is without limitation. The ordinary artisan would add the terpene carotenes for the desirable properties provided by carotenes as suggested by Dulieu et al. to the single unit dosage form with a reasonable expectation of success in the absence of evidence to the contrary.
Response to Arguments:
Applicant’s arguments filed 7/2/26 have been carefully considered but are not persuasive.
On pages 5-6 of remarks, Applicant argues that Wai et al. makes reference to a combined formulation, it is evident that the disclosure favors separate administration of the actives to allow for differing doses of each active to be given, depending on the profile of the patient. In response, the Examiner notes that Wai et al. do more than just make reference to a combined formulation and expressly teach combined preparations (Page 6, 2nd paragraph) and suggest: “The combined preparation will be provided in a form that is acceptable, tolerable, and effective for the subject.” (Page 7, 2nd paragraph). Wai et al. teach that the combined preparation can b formulated as a lozenge or tablet (Page 7, 2nd paragraph) and “the pharmaceutical composition is provided in oral dosage forms, particularly as a tablet.” (Page 8, 5th paragraph).
On page 6 of remarks, Applicant argues: “Where Wai et al. references a combined formulation, the description is of a unitary form, i.e., the actives present in admixture in a single form. This is quite distinct from the present claims which relate to a single dosage form with the actives in separate formulations each with different release properlies. It is not therefore clear why the skilled person would seek to modify the Wai et al. disclosure in the way proposed by the Examiner when to do so would be contrary to the examples in Wai et al.” Respectfully, the Examiner has a different perspective. Wai et al. provide the express teaching of calcitriol and naltrexone in a single dosage form such as a lozenge or tablet. But Wai et al. is not read in a vacuum. The secondary references provide motivation and guidance on dosage forms with a first aspect for sublingual absorption and a second aspect formulated for absorption in the GI tract. The secondary references teach calcitriol for sublingual administration for the desirable characteristic of significantly lower patient-to-patient variability in bioavailability and the terrible tasting naltrexone for the GI tract. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). Here, the combined references render obvious a single unit oral dosage form comprising calcitriol for sublingual absorption and naltrexone for absorption in the GI tract. Respectfully, Applicant’s arguments are not persuasive.
On page 6 of remarks, Applicant contends: “There is nothing in Wai et al. that suggest the formulation of Wai et al. is insufficient for its intended purpose or suggest that a better formulation may be obtained.” Respectfully, the Examiner has a different interpretation. Wai et al. state: “The combined preparation will be provided in a form that is acceptable, tolerable, and effective for the subject.” (Page 7, 2nd paragraph). Through the teachings of Flashner-Barak et al., it is known to administer calcitriol sublingually for the desirable bioavailability characteristic as discussed above. Thus, the most effective combination would be the one with calcitriol formulated in sublingual form and naltrexone formulated for absorption in the GI tract. The artisan would do so with a reasonable expectation of success. From MPEP 2143.02: The prior art can be modified or combined to reject claims as prima facie obvious as long as there is a reasonable expectation of success. In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On pages 6-7 of remarks, Applicant argues that the invention is based on the discovery that calcitriol, when administered at a constant level to the bloodstream of a patient, may be used to boost the priming effects of naltrexone on cancer cells for subsequent treatment by a chemotherapeutic agent… the inventors discovered and developed a method of obtaining consistent and higher levels of calcitriol prior to naltrexone entering the blood stream using a single unit oral dose formulation to achieve an enhanced therapeutic effect. Applicant relies upon Rassnick for teaching: “High inter-patient variability as demonstrated here can lead to inconsistent clinical responses” and “From Rassnick et al., it can be concluded that calcitriol is delivered into the bloodstream in an inconsistent manner when administered as a tablet.” However, as Applicant is well-aware because Applicant supplied the reference on the IDS filed 7/21/23, Flashner-Barak et al. already note the high inter-patient variability and instruct the artisan to the sublingual route of administration for calcitriol to avoid that problem as well as bypassing hepatic first-pass metabolism to provide more reliable and predictable systemic exposure to calcitriol. That would also be true for any cancer patients and allow for the calcitriol to be delivered consistently into the bloodstream before the naltrexone.
On pages 8-9, Applicant points to Example 2 for the benefits of the single unit oral dose of the invention where calcitriol is able to enhance the effects of naltrexone. The Examiner reviewed Example 2. Example 2 is not probative. All Applicant did was treat cancer cell lines with naltrexone and calcitriol. A single unit oral dosage form as claimed was not employed at all in Example 2. There is nothing there about enhancing the effects of naltrexone. In fact the inventor’s state (Examiner added emphasis): “The experiments show that the combination of naltrexone and calcitriol is more effective in boosting the effect of chemotherapeutic agents gemcitabine and oxaliplatin, than naltrexone alone”. Consequently, there is no basis to determine if the claimed single unit dosage form has any unexpected or surprising characteristics. Furthermore, the data in the Figures appears merely a difference in degree and not in kind. Consequently, Applicant’s assertion that: “The formulation is designed such that the calcitriol is delivered at a consistent and predictable level and is therefore able to enhance the effects of naltrexone” does not appear to have any basis in fact.
Respectfully, Applicant’s arguments are not persuasive.
On pages 9-10, Applicant discusses the references of Battaglia and Dulieu et al. The Examiner is relying upon these references as characterized in the rejection and not as characterized by Applicant. It is impermissible to attack references singly when the Examiner relies upon the combined teachings of the references, nor may they attack a reference for not teaching a limitation of the claim when the Examiner has explicitly relied upon another reference as teaching that limitation. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
On page 11 of remarks, Applicant asserts: “There is no disclosure in Dulieu et al. of a formulation of layer (b) which is intended to be swallowed. Contrary to established law, we submit that the Examiner has picked and chosen from Dulieu et al. only so much of it as will support their position”. Respectfully, the Examiner does not agree. Dulieu et al. expressly teach: “The base line layer (b) of the bilayer dosage form of the invention may be a standard tablet or lozenge” (Page 6, lines 16-17). Dulieu et al. also teach that lyophilized layer (a) is added to tablet layer (b) (Page 10, lines 4-14). Dulieu et al. expressly teach release in the stomach or intestines (Page 15, lines 14-20; page 27, lines 17-22). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 807 (Fed. Cir. 1989). In the present case, Dulieu et al. reasonably teach and suggest a bi-layer dosage form with one layer being lyophilized and the other layer is a tablet where the API can be orally/transmucosally absorbed and another API released in the GI tract.
Applicant’s arguments are not persuasive.
On pages 11-12 of remarks, Applicant asserts: “there is no reasoning provided by the Examiner to explain why it would be obvious for naltrexone to be placed in a part of a combined preparation such that it will be swallowed in combination with calcitriol in a form to be absorbed in the oral cavity…Applicant further submits that references alone or in combination also fail to explain "why" one of skill in the art would wish to deliver the active ingredients (calcitriol and naltrexone) into different locations and thus there is absolutely no motivation to modify any one of the cited references to do so. Respectfully, the Examiner has provided a rationale above where Flashner-Barak et al. teaches that sublingual calcitriol has significantly lower patient to patient variability in bioavailability, which is a desirable characteristic, and that not all drugs are suitable for sublingual administration where drug characteristics such as taste must be taken into account. The Compounder teaches that naltrexone tastes terrible. Thus, it is obvious to formulate the calcitriol for sublingual administration, a first location, but have the terrible tasting naltrexone as a tablet for the esophagus or lower GI, a second location, to avoid the bad taste.
Respectfully, Applicant’s arguments have been carefully considered but are not persuasive.
Claims 11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wai et al. (WO2019186207) and Dulieu et al. (WO2008127669) and Battaglia, A. (US20140371210) and The Compounder ([online] retrieved on 8/6/26 from: https:// thecompounder.com/2015/06/28/sublingual-ldn-drops/; 2015: 4 pages) and Flashner-Barak et al. (WO2007036802; of record), as applied to claims 1-2, 5, 8, 10 and 11 above, in further view of Maleki et al. (Food Chemistry 2019;299:11 pages) and Toledano (US20140275142) and Wendschuh et al. (US20160250270).
Applicant claims a single unit dose pharmaceutical composition according to claim 1 further comprising a cannabinoid or flavonoid or terpene.
The references of Wai et al., Dulieu et al., Battaglia, Flashner-Barak et al. and The Compounder are discussed in detail above.
Maleki et al. teach that flavonoids are anti-inflammatory and include kaempferol, luteolin and catechin (Title; Abstract; Tables 1-2; page 3, 4. Anti-inflammatory effects of flavonoids: Mechanisms of action).
Toledano teaches the compositions for the treatment of pain comprising the combination of naltrexone (Claims 1-2) and calcitriol (Claim 6) for treating migraine (Claim 17) and cancer pain [0021]. Toledano adding one or more pharmacologically active agents such as anti-inflammatory drugs, muscle relaxants and tetrahydrocannabinol derivatives [0049] and NSAIDs [0025-0026].
Regarding claim 18, Wendschuh et al. teach compositions of cannabinoids with flavonoids and terpenes (Abstract; claim 1) where: the cannabinoids include, for example, cannabigerol, cannabidolic acid, cannabidiol, cannabivarin and tetrahydrocannabivarin (Claims 8-10; [0365-0368]) as well as cannabinoids within the context of this disclosure include compounds belonging to any of the following classes of molecules, their derivatives, salts, or analogs: Tetrahydrocannabinol (THC), Tetrahydrocannabivarin (THCV), Cannabichromene (CBC), Cannabichromanon (CBCN), Cannabidiol (CBD), Cannabielsoin (CBE), Cannabidivarin (CBDV), Cannbifuran (CBF), Cannabigerol (CBG), Cannabicyclol (CBL), Cannabinol (CBN), Cannabinodiol (CBND), Cannabitriol (CBT), Cannabivarin (CBV), and Isocanabinoids [0018]; the terpenes include, for example, limonene, myrcene, camphene, bisabolol, humulene and pinene (Claims 6-7, 15-20) as well as terpenoids in their forms ofhemiterpenoids, monoterpenoids, sesquiterpenoids, sesterterpenoid, sesquarterpenoids, tetraterpenoids, Triterpenoids, tetraterpenoids, Polyterpenoids, isoprenoids, and steroids [0022, 0364]; and the flavonoids include, for example, apigenin, catechin and quercetin (Claim 13-14) as well as flavonoids chosen from phenolic acids, stilbenoids, dihydroflavonols, anthocyanins, anthocyanidins, polyphenols, tannins, flavones, flavan-3-ols, Flavan-4-ol, Flavan-3,4-diol flavonols, phytochemicals, antioxidants, homoisoflavonoids, phenylpropanoids, Phloroglucinols coumarins, Naphthodianthrones, Steroid glycosides, bioflavonoids, isoflavonoids, and neoflavonoids [0370].
The difference between the instant application and Wai et al. as modified by Dulieu et al., Battaglia, Flashner-Barak et al. and The Compounder, is that Wai et al. as modified by Dulieu et al., Battaglia, Flashner-Barak et al. and The Compounder, do not expressly teach adding the cannabinoids, flavonoids or terpenes claimed. The deficiency in Wai et al. as modified by the secondary references, is cured by the teachings of Toledano, Maleki et al. and Wendschuh et al. It would have been obvious to one of ordinary skill in the art before to the effective filing date of the claimed invention to formulate the tablet of Wai et al. as modified by as modified by the secondary references with a cannabinoid or flavonoid, as suggested by Dulieu et al., Toldedano, Maleki et al. and Wendschuh et al., and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because of the following rationale. Dulieu et al. teach that APIs include those for treatment of pain and migraine (Page 18, lines 13 and 15) as well as anti-inflammatories (Page 18, line 4). Toledano teach synergistic action from the combination of naltrexone and calcitriol [0027] and to add the cannabinoid tetrahydrocannabinol as well as anti-inflammatory drugs. The artisan in this art is well-aware through the teachings of Maleki et al. that flavonoids are anti-inflammatory compounds. The types of cannabinoid derivatives to employ in combination with flavonoids and terpenes is taught by Wendschuh et al. Consequently, it is obvious to add the cannabinoids, flavonoids and terpenes claimed to the single unit dose pharmaceutical composition of Wai et al. as modified by Dulieu et al. and Battaglia for at least an additive effect of the combined materials with a reasonable expectation of success.
Response to Arguments:
Applicant asserts that: “The addition of Maleki et al., Toledano, and Wendschuh et al. do not remedy the deficiencies of Wai et al., Dulieu et al. and Battaglia as applied to claim 1 and thus claim 1 is still novel and inventive over the combination of references.” Respectfully, the Examiner has a different perspective because at this time claim 1 remains obvious over the combined references. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). The Examiner has shown that the prior art teaches and suggests the subject matter of claims 1, 11 and 18. Applicant’s arguments are not persuasive. No unexpected results have been presented or asserted by Applicant that could be probative of non-obviousness. Consequently, the combined references render the claimed subject matter obvious to the ordinary artisan in this art.
Claims 1 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wai et al. (WO2019186207) and Dulieu et al. (WO2008127669) and Battaglia, A. (US20140371210) and The Compounder ([online] retrieved on 8/6/26 from: https:// thecompounder.com/2015/06/28/sublingual-ldn-drops/; 2015: 4 pages) and Flashner-Barak et al. (WO2007036802; of record), as applied to claim 1 above, in further view of Dalgleish et al. (WO2014181131).
Applicant claims:
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The references of Wai et al., Dulieu et al., Battaglia, The Compounder and Flashner-Barak et al. are discussed in detail above and those discussions are incorporated by reference.
The ordinary artisan in this art for cancer treatment methods is a pharmaceutical/medical cancer research scientist aware of cancer treatment formulations, cancer treatment protocols and cancer treatment regimens.
Regarding claim 13, Dalgleish et al. teach the treatment of cancer with the combination of naltrexone and vitamin D3 (Claims 14, 17, 18, 34) where low dose naltrexone in combination with vitamin D3 had a marked clinical response against metastatic melanoma (Example 2). Dalgleish et al. also teach hepatocellular melanoma (Claim 18), which is a form of liver cancer, and liver cancer and kidney cancer (Page 11, lines 20 and 22).
The difference between the instant application and Wai et al. as modified by the secondary references, is that Wai et al. as modified by the secondary references, do not expressly teach treating cancer in a subject by administering the single unit oral dose pharmaceutical composition wherein the subject is undergoing or is selected to undergo treatment with an anti-cancer agent wherein the subject has liver cancer and/or kidney cancer and/or wherein the subject has a reduced ability to metabolize vitamin D wherein the single unit 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 to be administered a therapeutically effective amount of an anti-cancer agent in a second treatment wherein the dosage regime is daily administration of a single unit dose. This deficiency in Wai et al. as modified by the secondary references, is cured by the teachings of Dalgleish et al.
It would have been obvious to one of ordinary skill in the art before to the effective filing date of the claimed invention to administer the tablet of Wai et al. as modified by the secondary references, to treat liver or kidney cancer or the subject has a reduced ability to metabolize vitamin D, as suggested by Dalgleish et al., and produce the instant invention. The ordinary artisan is motivated do so because the combination of naltrexone and vitamin D3 is already known for treating cancers, which reasonably extends to include kidney and liver cancer, as suggested by Dalgleish et al., and such a patient would have reduced ability to metabolize vitamin D into its active form calcitriol. Thus, directly administering the active form of vitamin D calcitriol to the cancer patient is an obvious variation of the prior art. The treatment regimen for the cancer patient is determined by the medical artisan and whether or not the patient is undergoing or is selected to undergo treatment with an anti-cancer agent is at the discretion of the ordinary artisan. Consequently, administration of a single unit dose daily in a first treatment phase followed by a second treatment with an anti-cancer agent is entirely within the purview of the medical artisan seeking to treat the patient with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicant asserts that the combination of Wai et al. Dulieu et al. and Battaglia fail to teach and suggest the invention of claim 1 and the addition of Dalgleish et al. does not remedy the deficiencies. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). As stated previously, the Examiner does not agree because the combination of references renders obvious the single unit oral dose pharmaceutical composition arranged as claimed in independent claim 1. Furthermore, while Wai et al. teach that the composition is for use in the treatment of an autoimmune disease (Claims 16-17), the ordinary artisan also understands from the combined references that the combination of vitamin D3 and naltrexone is known for treating cancer as taught by Dalgleish et al. Moreover, the ordinary artisan understands that vitamin D3 is the inactive form made by the body from sunlight while calcitriol is the body’s active form of vitamin D made from conversion of vitamin D3 in the liver. Dalgleish et al. provide the guidance to employ the single unit oral dose pharmaceutical composition of the combined reference to treat the same patient populations as claimed. Consequently, it is obvious to administer the active from calcitriol for immediate action in combination with the naltrexone with a reasonable expectation of success in treating cancer in a subject. Especially when Wai et al. teach and suggest overlapping amounts of vitamin D active metabolite, which is calcitriol, and naltrexone with what is claimed by Applicant. Respectfully, none of Applicant’s arguments are persuasive.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after review of all the facts, Applicant’s arguments are not persuasive. The Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts, which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
No claims are allowed.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
1 The status of claim 1 is “Currently Amended”. However, no amendments can be found. Rather than sending a Notice of Non-Compliant Claim Amendment, the Examiner is alerting Applicant to the issue in the interest of compact prosecution and stakeholder interaction with the understanding that this is merely an inadvertent oversight by Applicant.
Prosecution Insights