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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/17/2026 has been entered.
Applicants' arguments, filed 02/02/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1, 3-9, and 12-41 are pending.
Claims 15-41 are withdrawn.
Specification
The abstract of the disclosure is objected to because in line 4, following inflammatory, the typographical error of the inclusion of “7” should be removed. Further, in ln 2, following “containing gelatin”, “and” should be removed and replaced by a comma. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
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, 3-9, 13, and 14, are rejected under 35 U.S.C. 103 as being unpatentable over Ridall et al (US 20150133504 A1, cited on IDS dated 05/12/2023), in view of Rock et al (US 20120196819 A1, hereinafter “Rock”), as evidenced by El-Badry et al (J. Drug. Del. Sci. Tech. 2009, 19(5), pp. 347-351, hereinafter "El-Badry").
Ridall et al teach pharmaceutical compositions comprising about 5-20 mass% bovine gelatin, about 5-20 mass% mannitol, about 60-90 mass% of an active pharmaceutical ingredient, about 0-0.5 mass% of a flavorant, etc. (abs, ¶ 11). The compositions are lyophilized (¶ 51). The pharmaceutical composition disintegrates quickly, having a disintegration time of 7 seconds or less in deionized water maintained at 37.0° C ± 0.5° C (abs, ¶ 26). In other embodiments, the disintegration time is 5 seconds or less (¶ 12). In one embodiment, the active pharmaceutical ingredient (omeprazole) is micronized, having an average particle diameter of about 1 to about 10 microns (¶ 33). Example 3 discloses stability studies of omeprazole with varying pH levels, where under certain aqueous conditions, the omeprazole is unstable (¶ 95). Additionally, the active agents may be unstable due to pH (¶ 3). As evidenced by El-Badry, omeprazole is very unstable under acidic aqueous conditions, where drug degradation was reduced especially above pH 8 (abs, pg. 350 2nd col 2nd ¶). The formulations may be in the form of solutions or suspensions prior to lyophilizing (¶ 71). Sweeteners can be included (¶ 71).
Ridall et al do not teach methotrexate.
Rock teaches immediate release compositions comprising an active agent and excipients including gelatin, mannitol or other sugar alcohols, together with sweetening agents, flavoring agents, and flavors, where the composition dissolves in a short period of time, including about 30 seconds or less (abs, ¶¶ 13, 23). The compositions are formulated for direct systemic introduction (DSI), which means administering one or more therapeutically active agent(s) directly to the circulatory system of an animal via a formulation administered and absorbed in the oral cavity and/or the non-gastric mucosa (¶ 21). Administering therapeutic agents via the oral cavity, where the majority is absorbed prior to the gastric mucosa, i.e., under the tongue (sublingual), on the top of the tongue, and/or between the cheek (buccal), to animals, results in rapid onset of activity, more accurate and lowered dosing, an absence of diminishment of side-effects, and greater safety to both the animal and the administrator of the formulation (¶ 17). Therapeutic agents which can be utilized in DSI formulations and administered via the described methods include, but are not limited to omeprazole, methotrexate, etc. (¶ 28). The compositions may comprise from about 0.5 to 50 wt% of the active ingredient (abs). The actives and excipients are freeze-dried to prove immediate release compositions in which the active ingredient is relatively stable, and which can provide, upon administration, therapeutically useful levels of the active ingredient (¶ 14).
Regarding claim 1, it would have been obvious to modify the lyophilized compositions of Ridall et al by including known active agents suitable for fast-disintegrating compositions that can comprise gelatin and mannitol, such as methotrexate, as the active pharmaceutical ingredient, for desired treatments and applications.
Further, the skilled artisan would have had a reasonable expectation of success in formulating the compositions with methotrexate, where fast-disintegrating compositions comprising gelatin, mannitol, and methotrexate were known, and where methotrexate was known to be suitable for oral dosage forms for direct administration and absorption in the oral cavity and/or the non-gastric mucosa, as taught by Rock, which appears to be the preferred absorption route of Ridall et al. The skilled artisan would have motivation to administer methotrexate via the oral mucosa where Rock teaches it results in rapid onset of activity, more accurate and lowered dosing, an absence of diminishing side effects, and greater safety.
Regarding the limitation of a solid form of methotrexate, where the exemplified embodiments of Ridall et al comprise micronized active agent (omeprazole), suggesting solid forms of active ingredients are to be used, it would have been obvious to include other active agents, including methotrexate, in solid form. Purely arguendo, even if not, the compositions are lyophilized and therefore the final dosage form necessarily comprises a solid form of methotrexate.
Regarding the amount of methotrexate of claim 1, it would have been obvious to include methotrexate, an active pharmaceutical ingredient, within those ranges taught to be suitable for active pharmaceutical ingredients taught by Ridall et al, such as from about 60-90 mass%, or from about 0.5 to 50 wt% of the active ingredient, as taught by Rock, overlapping the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Further, where the compositions of Ridall et al are taught to be lyophilized, it appears the mass% is the dry mass.
Note, since mass and weight are directly proportional under normal Earth gravity, the numerical values for mass% and wt% are the same.
Further, it would have been well within the relative skills of the skilled artisan to routinely optimize the amount methotrexate in order to achieve optimal therapeutic activity for desired applications and treatments. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See MPEP 2144(II)(A).
Regarding claims 3 and 4, it would have been obvious to formulate the compositions made obvious by the combination above with a disintegration time of less than 7 seconds, such as less than 5 seconds in deionized water maintained at 37.0° C ± 0.5° C, as taught by Ridall et al. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 5, it would have been obvious to formulate the composition made obvious by the combination above with gelatin in an amount of about 5-20 mass%, as taught by Ridall et al, overlapping the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Further, where the compositions of Ridall et al are taught to be lyophilized, it appears the mass% is the dry mass.
Note, since mass and weight are directly proportional under normal Earth gravity, the numerical values for mass% and wt% are the same.
Regarding claims 6 and 7, the composition made obvious by the combination of Ridall et al and Rock comprises bovine gelatin.
Regarding claim 8, it would have been obvious to formulate the composition made obvious above with mannitol (sugar alcohol) in an amount of about 5-20 mass%, as taught by Ridall et al, overlapping the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Further, where the compositions of Ridall et al are taught to be lyophilized, it appears the mass% is the dry mass.
Note, since mass and weight are directly proportional under normal Earth gravity, the numerical values for mass% and wt% are the same.
Regarding claim 9, the composition made obvious by the combination of Ridall et al and Rock above comprises mannitol.
Regarding claim 13, it would have been obvious to micronize the methotrexate made obvious above, such as to an average particle diameter (i.e., D50) of about 1 to about 10 microns, where Ridall et al teaches the active agents in the exemplified embodiments are micronized.
Regarding claim 14, it would have been obvious to further include a flavorant or sweetener, as taught by Ridall et al.
Response to Arguments
First, Applicants assert Ridall et al explicitly relies on basic pH adjustment to solubilize/process omeprazole in the aqueous pre-formulation prior to freeze-drying and fails to disclose a solid form of methotrexate.
Second, Applicants assert Murray et al fails to cure the deficiencies of Ridall et al, by again arguing that Murray et al teaches away from mammalian gelatin for rapid dispersion where the fish gelatin exhibited fast disintegration time of 0.85 seconds compared to bovine gelatin at 4.28 seconds, which also had a gummy mouth-feel. Therefore, Applicants assert Murray et al teaches away from mammalian gelatin for rapid dispersion.
Third, Applicants assert that Giri teaches methotrexate has a fundamentally different solubility and permeability than omeprazole and asserts that Giri’s data indicate methotrexate will not be readily processed via such simple pH-based dissolution in water.
Fourth, Applicants assert that replacing omeprazole with methotrexate would render Ridall et al unsatisfactory for its intended purpose and inoperable in the manner taught. Applicants assert the substitution would frustrate Ridall et al’s processing and rapid disintegration objectives rather than achieve them. Applicants assert that DSI compositions provide no increased oral mucosal uptake for insoluble drugs, such as methotrexate, and some soluble drugs administered through rapidly dissolving tablets could get some pre-gastric uptake and improved bioavailability. Applicants assert insoluble drugs are not introduced to the oral mucosa, but rather though the gastrointestinal tract and have the same bioavailability of standard tablets/capsules. Applicants assert this would render Ridall et al inoperable for its intended purpose of a “formulation [that] may be absorbed prior to reaching the gastric mucosa.”
Fifth, Applicants assert the skilled artisan would not have had a reasonable expectation of success that mammalian gelatin would deliver methotrexate with Ridall-like rapid dispersion, where Murray et al teach mammalian gelatin had a slower disintegration than fish gelatin.
Sixth, Applicants assert absent methotrexate-specific solubility/dissolution strategies, a skilled artisan would not be motivated to substitute Murray et al’s methotrexate with Ridall et al’s mammalian gelatin-mannitol, high API, pH adjust lyophilized system.
First, respectfully, this argument is not persuasive. It appears that the pH adjustment in the compositions of Ridall et al are to ensure chemical stability of omeprazole, where Ridall et al teaches stability of omeprazole was tested under varying pH and that omeprazole was known to have poor stability under certain aqueous conditions and pH. Further, as evidenced by El-Badry above, omeprazole chemically degrades under acidic and neutral pH, and degradation was reduced at pH at 8 or above. Therefore, it appears that the pH adjustment to 8.3 was to ensure that the omeprazole did not chemically degrade during formulation, rather than for purposes of solubilizing the active agent. Additionally, Ridall et al teaches the pharmaceutical compositions are formulated with and comprise micronized active agent, thereby suggesting the active agent was not solubilized. Finally, from the working examples of Ridall et al, 200 mg of omeprazole was added to 732 mg of water, and the skilled artisan would not reasonably expect omeprazole, having low aqueous solubility, to be solubilized at this concentration under any pH.
Second, this argument is not persuasive. While not agreeing to the arguments, the examiner notes that Murray et al is no longer cited, and Applicants’ arguments with respect to Murray et al are moot.
Third, respectfully, this argument is not persuasive. While the examiner recognizes that omeprazole and methotrexate have different solubilities and permeabilities, as discussed above, it appears that the pH adjustment in the working examples of Ridall et al were done so in order to ensure chemical stability during the processing steps, for the same reasons discussed above. Accordingly, it would have been well within the relative skills of the skilled artisan to routinely optimize the processing conditions for optimal stability of methotrexate. As discussed above, it appears the active agent of Ridall et al are in the form of suspended particles, prior to lyophilization. Further, it was known from Rock that active agents, including methotrexate, can be added as a suspension prior to being lyophilized, and it would have been obvious to formulate them as such with a reasonable expectation of success. Additionally, the examiner notes that Giri et al is no longer cited for evidence.
Fourth, respectfully, this argument is not persuasive. Simply substituting an active agent known to be suitable for fast disintegrating oral dosage forms comprising gelatin and mannitol, would not appear to frustrate the processing, nor the rapid disintegration objectives of Ridall et al. The skilled artisan is that of an M.D., PhD., or pharmacist, and it would be well within the relative skills of the skilled artisan to formulate a rapid disintegrating dosage form with methotrexate as the active, where these dosage forms with methotrexate were already known.
Regarding the oral mucosal uptake arguments, Rock is newly cited above for teaching that it was known that methotrexate, when formulated in a rapid disintegrating dosage form, can be administered and absorbed via oral mucosa and/or pre-gastric mucosa from rapidly infusing compositions as instantly claimed. Accordingly, contrary to applicants’ assertion, it appears that the rapid disintegrating compositions made obvious above would be capable of being absorbed via the oral mucosa and non GI routes, which aligns with the goals of Ridall et al, and would therefore not render Ridall et al inoperable for its intended purpose.
Fifth, respectfully, this argument is not persuasive. While not agreeing to applicants’ arguments, the examiner notes that Murray et al are no longer cited, and applicants’ arguments with respect to Murray et al are moot. It appears that the disintegration time is tied to the components of the carrier composition, rather than the particular active to be released from the rapidly disintegrating carrier. A simple substitution of one active agent for another would not be expected to have a significant impact on the disintegration rate of the carrier itself.
Sixth, respectfully, this argument is not persuasive. While not agreeing to applicants’ arguments, the examiner notes that Murray et al are no longer cited, and applicants’ arguments with respect to Murray et al are moot. As discussed above, it does not appear that the compositions of Ridall et al require the drug to be solubilized where the pre-formulations appear to be in the form of suspensions, for the same reasons discussed above, and it appears that the pH adjusting step of Ridall et al were to ensure chemical stability, rather than to solubilize the active agent. Additionally, methotrexate was known to be suitable for gelatin-mannitol rapid disintegrating formulations, as taught by Rock, where methotrexate was known to be capable of absorption via the oral and/or non-gastric mucosa. Therefore, it appears that the skilled artisan would have had motivation to include other known actives suitable for rapid disintegrating dosage forms, such as methotrexate, with a reasonable expectation of success, for the same reasons discussed above and of record.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Ridall et al (US 20150133504 A1) and Rock et al (US 20120196819 A1, hereinafter “Rock”), as applied to claims 1, 3-9, 13, and 14 above, and further in view of United States Pharmacopeial Convention (Methotrexate, 2020, pp. 1-2, hereinafter “USP”).
Ridall et al and Rock are discussed above but do not teach the purity of methotrexate.
USP discloses purity requirements for methotrexate for pharmaceuticals, where methotrexate contains not less than 98.0% methotrexate (Definition).
When formulating the composition made obvious by the combination above, it would have been obvious to use methotrexate with a purity of not less than 98.0%, as required for pharmaceutical formulations by USP.
Response to Arguments
Applicants assert USP fails to cure the deficiencies of Ridall et al, and is silent regarding a solid form of methotrexate in rapidly infusing composition as recited in instant claim 1, and therefore the combination of Ridall et al, Murray et al, and USP, alone or in combination, fail to render obvious the instant claim.
Respectfully, this argument is not persuasive. The rapidly infusing composition as recited in instant claim 1 is made obvious by the combination of Ridall et al and Rock (newly cited), for the same reasons discussed above and of record. The examiner notes that applicants’ argument with respect to Murray et al are moot for the same reasons discussed above.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ridall et al (US 20150133504 A1) and Rock et al (US 20120196819 A1, hereinafter “Rock”), as applied to claims 1, 3-9, 13, and 14 above, and further in view of Vemula et al (Int Jour Pharm Sci Rev Res, 2010, vol 5, issue 1, pp. 41-51).
Ridall et al and Rock are discussed above and additional motivation for including micronized methotrexate is provided by Vemula et al.
Vemula et al teach micronization of poorly water soluble drugs was a known technique for increasing solubility, dissolution, and bioavailability of the drugs (pg. 42 last ¶ - pg. 43 2nd ¶).
Regarding claim 13, where the inclusion of micronized methotrexate falling within the claimed range is made obvious above, additional motivation for including micronized methotrexate is provided by Vemula et al, where it would have been obvious for the skilled artisan to include micronized methotrexate, such as with an average diameter (i.e., D50) of about 1 to about 10 microns, as taught by Ridall et al, where micronization of poorly soluble drugs was known to increase their dissolution, bioavailability, etc., as taught by Vemula et al.
Response to Arguments
Applicants assert Vemula et al provide no teachings of lyophilization in a gelatin-mannitol aqueous system, no guidance on formulating methotrexate into a mammalian-gelatin matrix, and no disclosure of achieving a disintegration time as required by the instant claims. Applicants assert Vemula et al are silent regarding a solid form of methotrexate in rapidly infusing composition as recited in instant claim 1, and therefore the combination of Ridall et al, Murray et al, and Vemula, alone or in combination, fail to render obvious the instant claim.
Respectfully, this argument is not persuasive. Vemula et al were not cited for teaching lyophilization in gelatin-mannitol aqueous systems, formulating methotrexate into a mammalian-gelatin matrix, nor disintegration times. Rather, Vemula et al were simply cited for teaching that micronization was a known technique of improving various properties of drugs. The rapidly infusing composition as recited in instant claim 1 is made obvious by the combination of Ridall et al and Rock (newly cited), for the same reasons discussed above and of record. The examiner notes that applicants’ argument with respect to Murray et al are moot for the same reasons discussed above.
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, 3-9, and 12-14, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/252,707 (reference application), hereinafter ‘707, in view of Rock et al (US 20120196819 A1, hereinafter “Rock”) and United States Pharmacopeial Convention (Methotrexate, 2020, pp. 1-2, hereinafter “USP”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘707 disclose a rapidly infusing composition comprising a pharmaceutically acceptable binder and/or excipient system comprising gelatin and a sugar alcohol, and tetrahydrocannabinol (active) (claim 1). The composition is lyophilized (claim 2). The composition has a disintegration time of approximately 1-30 seconds, and 1-5 seconds in deionized water maintained at 37° C ± 2° C (claims 3, 4). The gelatin is 10-50 wt% based on the total dry weight (claim 5). The gelatin is bovine gelatin (claim 6). The sugar alcohol is 5-45 wt% based on the total dry weight (claim 7). The sugar alcohol is mannitol (claim 8). The active is in an amount of 0.3-25 wt% (claim 9). The active is in the form of a solid (claim 11). The active is micronized having a D50 between 1-50 microns (claim 12). The composition further comprises at least one of a sweetener, a flavorant, and a colorant (claim 15).
The claims of ‘707 do not disclose methotrexate, nor the purity of methotrexate.
Rock and USP are discussed above.
It would have been obvious to substitute methotrexate of Rock for tetrahydrocannabinol of ‘707, where methotrexate was a known active agent suitable for fast disintegrating formulations comprising gelatin and mannitol, in order to formulate the compositions for desired treatments and applications. Further, it would have been obvious to use the solid form of methotrexate, where solid forms of actives are suitable, as disclosed by the claims of ‘707.
It would have been obvious to use methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons discussed above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The following also stand rejected for the same reasons in view of Rock and USP:
Copending Application No. 18/252,693. The claims of ‘693 disclose a method of treating an autoimmune disease with a rapidly infusing composition comprising gelatin, a sugar alcohol, and cannabidiol. The claims do not disclose methotrexate nor its purity. It would have been obvious to substitute solid methotrexate for the active of ‘741 for the same reasons discussed above by Rock. Further, it would have been obvious to include methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons above.
Copending Application No. 18/252,676. The claims of ‘676 disclose a rapidly infusing composition comprising gelatin, a sugar alcohol, and a PDE5 inhibitor. The claims do not disclose methotrexate nor its purity. It would have been obvious to substitute solid methotrexate for the active of ‘741 for the same reasons discussed above by Rock. Further, it would have been obvious to include methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons above.
Copending Application No. 18/307,228. The claims of ‘228 disclose a rapidly infusing composition comprising gelatin, a sugar alcohol, and solid form of cannabinoid. The claims do not disclose methotrexate nor its purity. It would have been obvious to substitute solid methotrexate for the active of ‘228 for the same reasons discussed above by Rock. Further, it would have been obvious to include methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons above.
Response to Arguments
Applicants assert a terminal disclaimer for copending application no. 18/252,707 was submitted in their response, however, no terminal disclaimer appears to have been filed. Further, Applicants have not provided arguments with respect to copending application nos. 18/252,707, 18/252,693 and 18/252,676. Accordingly, the claims stand rejected for the same reasons above and of record.
Claims 1, 3-9, and 12-14, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/252,681 (reference application), hereinafter ‘681, in view of Ridall et al (US 20150133504 A1), Rock et al (US 20120196819 A1, hereinafter “Rock”), Vemula et al (Int Jour Pharm Sci Rev Res, 2010, vol 5, issue 1, pp. 41-51), and United States Pharmacopeial Convention (Methotrexate, 2020, pp. 1-2, hereinafter “USP”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘681 disclose a rapidly infusing composition comprising gelatin, a sugar alcohol, and at least one supplement selected from a vitamin D compounds, etc. (claim 1). The composition is lyophilized (claim 2). The composition has a disintegration time of approximately 1-30 seconds, and 1-5 seconds in deionized water maintained at 37° C ± 2° C (claims 3, 4). The gelatin is 10-50 wt% based on the total dry weight (claim 5). The gelatin is bovine gelatin (claim 6). The sugar alcohol is 5-45 wt% based on the total dry weight (claim 7). The sugar alcohol is mannitol (claim 8). The active is in an amount of 0.3-25 wt% (claim 9). The active is in the form of a solid (claim 11). The active is micronized having a D50 between 1-50 microns (claim 12). The composition further comprises at least one of a sweetener, a flavorant, and a colorant (claim 15).
The claims of ‘681 do not disclose methotrexate, the purity of methotrexate, nor wherein the methotrexate has a D50 between 1-50 microns.
Ridall et al, Rock, Vemula et al, and USP are discussed above.
It would have been obvious to substitute methotrexate of Rock for the compounds of ‘681, where methotrexate was a known active agent suitable for fast disintegrating formulations comprising gelatin and mannitol, in order to formulate the compositions for desired treatments and applications. Further, it would have been obvious to use the solid form of methotrexate, where solid forms of actives are suitable, as disclosed by the claims of ‘707.
It would have been obvious to use methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons discussed above.
It would have been obvious to include micronized methotrexate having a particle size of about 1 to about 10 microns, for the same reasons discussed above by Ridall et al and Vemula et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants assert a terminal disclaimer for copending application no. 18/252,681 was submitted in their response, however, no terminal disclaimer appears to have been filed. Applicants have not provided arguments with respect to copending application no. 18/252,681. Accordingly, the claims stand rejected for the same reasons above and of record.
Claims 1, 3-9, and 12-14, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/510,165 (reference application), hereinafter ‘165, in view of Ridall et al (US 20150133504 A1), Rock et al (US 20120196819 A1, hereinafter “Rock”), Vemula et al (Int Jour Pharm Sci Rev Res, 2010, vol 5, issue 1, pp. 41-51), and United States Pharmacopeial Convention (Methotrexate, 2020, pp. 1-2, hereinafter “USP”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘165 disclose compositions and methods comprising a freeze-dried direct systemic induction composition comprising an effective dose of detomidine adapted to be absorbed via pre-gastric mucosa of the animal, wherein the oral dissolution time is less than about 30 seconds. The excipients include at least one of gelatin, mannitol, etc. The compositions further comprise sweetening agent and/or a flavoring agent.
The claims of ‘165 do not disclose solid methotrexate, the amount of methotrexate, the purity of methotrexate, nor the particle size of the methotrexate.
The references are discussed above.
It would have been obvious to formulate a composition comprising bovine gelatin, mannitol, and a sweetener/flavoring agent, where these formulations were known by Ridall et al be to suitable for fast disintegrating oral compositions that are capable of pre-gastric absorption.
It would have been obvious to substitute the methotrexate of Rock for the compounds of ‘681, where methotrexate was a known active agent suitable for fast disintegrating formulations comprising gelatin and mannitol, in order to formulate the compositions for desired treatments and applications, and for the same reasons discussed above. The skilled artisan would have had a reasonable expectation of success where Rock teaches methotrexate was suitable for oral mucosa absorption in rapidly disintegrating compositions. Further, where the compositions made obvious above comprise methotrexate, and Rock teaches direct systemic induction compositions can be formulated by suspensions of active agent, it would have been obvious to include the methotrexate in a solid form. Nevertheless, where the compositions are lyophilized, the methotrexate would necessarily be in solid form.
It would have been obvious to include methotrexate, an active pharmaceutical ingredient, within those ranges taught to be suitable for active pharmaceutical ingredients taught by Ridall et al, such as from about 60-90 mass%, for the same reasons discussed above.
It would have been obvious to use methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons discussed above.
It would have been obvious to include micronized methotrexate having a particle size of about 1 to about 10 microns, for the same reasons discussed above by Ridall et al and Vemula et al.
Claims 1, 3-9, and 12-14, are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,672,761 B2, hereinafter ‘761, in view of Ridall et al (US 20150133504 A1), Rock et al (US 20120196819 A1, hereinafter “Rock”), Vemula et al (Int Jour Pharm Sci Rev Res, 2010, vol 5, issue 1, pp. 41-51), and United States Pharmacopeial Convention (Methotrexate, 2020, pp. 1-2, hereinafter “USP”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘761 disclose a compositions and methods comprising a rapidly infusing composition comprising bovine gelatin at 10-35 wt%, a sugar alcohol at 5-35 wt%. The compositions have a disintegration time of 1-5 seconds in deionized water maintained at 37 deg C +/- 2 deg C. The compositions further comprise a sweetener, a flavorant, and a colorant.
The claims of ‘761 do not disclose a solid form of methotrexate, the amount of methotrexate, the purity of methotrexate, mannitol as the sugar alcohol specifically, nor the particle size of the methotrexate.
The references are discussed above.
It would have been obvious to substitute the methotrexate of Rock for the compounds of ‘681, where methotrexate was a known active agent suitable for fast disintegrating formulations comprising gelatin and mannitol, in order to formulate the compositions for desired treatments and applications, and for the same reasons discussed above. Further, it would have been obvious to use the solid form of methotrexate, where solid forms of actives are suitable, as disclosed by the claims.
It would have been obvious to include methotrexate, an active pharmaceutical ingredient, within those ranges taught to be suitable for active pharmaceutical ingredients taught by Ridall et al, such as from about 60-90 mass%, for the same reasons discussed above.
It would have been obvious to use methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons discussed above.
It would have been obvious to include known sugar alcohols suitable for rapidly infusing compositions, such as mannitol, as taught by Ridall et al above.
It would have been obvious to include micronized methotrexate having a particle size of about 1 to about 10 microns, for the same reasons discussed above by Ridall et al and Vemula et al.
Claims 1, 3-9, and 12-14, are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10,064,849 B2, hereinafter ‘849, in view of Rock et al (US 20120196819 A1, hereinafter “Rock”), Ridall et al (WO 2013165468 A1, hereinafter “Ridall ‘468”), Vemula et al (Int Jour Pharm Sci Rev Res, 2010, vol 5, issue 1, pp. 41-51), and United States Pharmacopeial Convention (Methotrexate, 2020, pp. 1-2, hereinafter “USP”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘849 disclose a pharmaceutical composition for direct systemic introduction comprising bovine gelatin, about 12-15 dry mass% mannitol, a flavorant, and about 65-80 dry mass% active agent (omeprazole), etc. The disintegration time is 7 seconds or less in deionized water maintained at 37.0 deg C +/- 0.5 deg C. The active agent is delivered to an animal via non-keratinous tissues in a mucosal cavity. The mucosal cavity includes oral cavity, etc.
The claims of ‘849 do not disclose solid methotrexate, wherein the compositions are lyophilized, the particle size of methotrexate, nor the purity of methotrexate.
Ridall ‘468 teaches pharmaceutical compositions for direct systemic introduction, where it was known to micronize the actives with an average sized of about 1 to about 10 microns (¶ 35).
It would have been obvious to substitute methotrexate for the omeprazole of ‘849, for the same reasons discussed above by Rock.
Regarding solid methotrexate, where the compositions made obvious above comprise methotrexate, and Rock teaches direct systemic induction compositions can be formulated by suspensions of active agent, it would have been obvious to include the methotrexate in a solid form. Nevertheless, where the compositions are lyophilized, the methotrexate would necessarily be in solid form.
It would have been obvious to lyophilize the compositions of ‘849, where direct system introduction compositions comprising gelatin, mannitol, etc., were known to be lyophilized, as taught by Rock.
Regarding the particle size of methotrexate, it would have been obvious to micronize the methotrexate particles, where micronizing active agents were known to be suitable for direct systemic introduction compositions, as taught by Ridall ‘468, and where Vemula et al teaches micronization was known to improve bioavailability, etc. Further, it would have been well within the relative skills of the skilled artisan to routinely optimize the particle size for desired bioavailability, etc.
It would have been obvious to use methotrexate with a purity of at least 98.0%, as taught by USP for the same reasons discussed above.
Conclusion
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612