DETAILED ACTION
Claims 1-20 are pending and under consideration on the merits.
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 .
Status of the Rejections
The claim objection is withdrawn in view of the amendment.
The 112(b) rejections are withdrawn in part in view of the amendment and maintained in part, and a new rejection of claim 6 was necessitated by the amendment.
The 103 rejection is maintained and expanded to include newly added claims.
The statutory double patenting rejection is withdrawn in view of the amendment and replaced with a nonstatutory rejection.
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 5 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as 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.
Claim 5 is newly rejected because it has been amended to recite a Markush group, but at the end of the claim “mixtures thereof” is preceded by “or,” and it is unclear if this limitation is part of the Markush group or an alternative to the Markush group. Clarification is required. It is suggested that “mixtures thereof” be preceded by “and” instead of “or.”
Claim 12 recites “film-forming polymers,” which is indefinite because claim 12 is a method for producing the composition of claim 1, but claim 1 does not recite “film-forming polymers,” but rather only “hydrophilic polymers,” one of which is a “structure forming polymer” and one of which is a “binding and/or intercalating polymer.” Are the film-forming polymers of claim 12 the same as the hydrophilic polymers of claim 1? Clarification is required. For the purpose of examination in view of the prior art, claim 12 has been given its broadest reasonable interpretation, which is that the film-forming polymers of claim 12 are the hydrophilic polymers of claim 1.
Response to Applicant’s Arguments
Regarding claim 12, Applicant argues that paragraphs 109-110 clearly define the phrase “film-forming polymers.”
In response, this argument is not persuasive because paragraphs 109-110 only provide an exemplary list of film forming polymers and does not formally define “film forming polymers” as being equivalent to “hydrophilic polymers” when used in the claims. Therefore, the rejection is maintained. It is suggested that claim 12 recite “the hydrophilic polymers” instead of “film forming polymers.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-6, 9-15, and 18-20 are rejected under 35 U.S.C. 103 as unpatentable over Schaneville (US Pat. Pub. 2020/0390837; of record in IDS) in view of Schultz et al. (US Pat. No. 6,194,395; of record in IDS) and Macphail et al. (US Pat. Pub. 2021/0267934; of record in IDS).
As to claims 1, 3-6, 9-15, and 18-20, Schaneville discloses sublingual orally dissolvable films for transmucosal delivery of an active (paragraphs 2, 28-29). The film comprises one or more film-forming agents (paragraph 41) such as pullulan and a starch polymer (paragraph 42)(“hydrophilic polymers” of claim 1). The composition further may comprise cyclodextrin as a taste masking agent (paragraph 40).
Regarding claim 5, the composition further may comprise a surfactant (paragraph 13), a plasticizer (paragraphs 41-42), as well as a flavorant, antioxidant, solubilizer, thickener, vitamin, or pH modifying agent (paragraph 13).
Regarding claim 6, the starch may be a corn or potato starch or a pregelatinized starch (paragraph 61).
As to claims 9 and 18-19, Schaneville teaches that the active may be present in the amount of up to about 50 wt% (paragraph 87), which encompasses the claimed range.
Regarding claim 11, the recitation that the composition is formulated for treating multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optical spectrum disorder (NMOSD) is merely an intended use of the composition and as such is not granted additional patentable weight.
As to claim 12, Schanevill teaches forming the film by mixing the film forming agents with the active ingredient at a temperature of 90 degrees Celsius with stirring at 300 rpm (paragraphs 95-96, 99).
As to claims 1, 3-6, 9-15, and 18-20, Schaneville does not further expressly disclose that the two hydrophilic polymers represent at least 20 wt% of the total composition as recited by claims 1 and 13 or 25 wt% as recited by claims 14 and 20, nor that the active is cladribine as recited by claims 1 and 12-13 and which is the sole effective ingredient (claim 10), and wherein the active and film-forming polymers are mixed for at least 10 minutes as recited by claim 12, nor a method of treating MS, MG, or NMOSD comprising administering the composition as recited by claim 13. Nor does Schaneville expressly teach that the cyclodextrin is one of the types recited by claim 3 such as beta-cyclodextrins in hydroxypropyl, dimethyl, or sulfobutyl forms or carboxymethyl forms (claim 3), or that the cladribine/cyclodextrin complex is within the molar ratio recited by claims 4 and 15.
Schultz teaches that cladribine is a pharmaceutical active known to be effective in the treatment of multiple sclerosis (column 1, 2nd paragraph). Schultz teaches that cladribine to date has been administered by intraveneous injection of saline solutions, but that cladribine is only slightly soluble in water and has limited stability in saline solutions, and that use of the compound orally has been limited since it would not be stable in the gastrointestinal system (column 1, 3rd paragraph). Schultz states that there is therefore a need for oral formulations that are stable against hydrolysis, and discloses compositions comprising cladribine in a complex with a cyclodextrin as a stabilizing/solubilizing agent to solve the foregoing issues (column 2, 1st and 2nd full paragraphs and Summary of the Invention at column 2). Schultz teaches that the composition is a solid oral dosage form that may be in the form of a fast-dissolving wafer (column 5, 5th full paragraph). Schultz teaches that particularly useful cyclodextrins are beta-cyclodextrins in hydroxypropyl, dimethyl, or sulfobutyl forms forms (column 3,5th full paragraph and column 6, 1st full paragraph) or carboxymethyl forms (column 3, 1st full paragraph), and further teaches an embodiment wherein the cladribine/cyclodextrin complex is formed at a 1:1.5 molar ratio, which is within the recited range of claim 4 (see Example 3). The Schultz compositions comprise cladribine as the sole active ingredient. Schultz also expressly teaches that the cladribine/cyclodextrin complexes can be used to treat multiple sclerosis (column 6, lines 43-59).
Macphail discloses an oral dispersible film comprising an active for delivery along with a film former such as pullulan or starch in the amount of 40-65 wt%, which is within the range of claims 1, 13, 14, and 20(paragraphs 1, 27, 30).
As to claims 1, 3-6, 9-15, and 18-20, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the composition of Schaneville by selecting cladribine in complex with a hydroxypropyl, dimethyl, or sulfobutyl beta-cyclodextrin as recited by claim 3, and in a molar ratio within the range of claim 4, as the sole active ingredient (claim 10), because Schaneville does not limit the identity of the active to any particular compound and Schultz teaches that cladribine may be delivering using a fast dissolving dosage form and further that complexing the cladribine with the foregoing cyclodextrins and in such molar ratios stabilizes the compound and allows the cladribine to be delivered orally such that the skilled artisan reasonably would have expected that the oral sublingual dispersible film of Schaneville could be used to deliver cladribine to a subject orally when it is complexed with a cyclodextrin. Such a modification is merely the combining of known prior art elements according to known methods to yield predictable results, which is prima facie obvious. MPEP 2143. The skilled artisan would have been motivated to select an oral delivery dosage form for cladribine such as the Schaneville dosage form because oral dosage forms are more convenient and have higher patient acceptance than injectable formulations.
It further would have been prima facie obvious to select amounts of the two hydrophilic polymers (i.e., pullulan and starch), such that they represent at least 20 wt% of the total composition as recited by claims 1 and 13 or 25 wt% (claims 14, 20), because MacPhail teaches that oral dispersible films comprising an active for delivery suitably comprise pullulan or starch in the amount of 40-65 wt%, which is within the claimed ranges, such that the skilled artisan reasonably would have expected that such amounts would be suitable for use in the Schaneville oral dispersible film.
As to claim 12, it further would have been prima facie obvious to arrive at a mixing time of at least 10 minutes, because it is well within the purview of the skilled artisan to select a mixing time that is sufficient to produce a homogeneous mixture. Schaneville teaches mixing amounts for other steps of the film forming process, e.g., a 5-45 minute period for mixing the active with an aqueous solution (Figure 4), which reads on the “at least 10 minute” range of claim 12 and would provide a starting point for the skilled artisan to determine the optimal period for the mixing step for the active with the film forming polymers. “Where 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).
Regarding claim 13, it further would have been prima facie obvious to administer an effective amount of the transmucosal delivery composition to a subject to treat multiple sclerosis, because Schultz expressly teaches that cladribine/cyclodextrin complexes are useful for treating multiple sclerosis.
Regarding claim 15, given that Schultz teaches in Example 3 an embodiment wherein the cladribine/cyclodextrin complex is formed at a 1:1.5 molar ratio, it further would have been prima facie obvious to vary the amount of cyclodextrin to arrive at a molar ratio within the claimed range of 1:1 to 1:3, because said amount is a result effective variable that will affect the stability of the cladribine and with a reasonable expectation of success because the cyclodextrin is serving the same purpose in the presently claimed composition as in the Schultz composition, i.e., to stabilize the cladribine by forming a complex with it. 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. “[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).
Claims 2, 7-8, and 16-17 are rejected under 35 U.S.C. 103 as unpatentable over Schaneville (US Pat. Pub. 2020/0390837; of record in IDS) in view of Schultz et al. (US Pat. No. 6,194,395; of record in IDS) and Macphail et al. (US Pat. Pub. 2021/0267934; of record in IDS) as applied to claims 1, 3-6, 9-15, and 18-20 above, and further in view of Borges et al. (Journal of Controlled Release 206 (2015) 1-19).
The teachings of Schaneville, Schultz, and Macphail are relied upon as discussed above. Schaneville further teaches that the film may comprise glycerol as a carrier/softening agent (paragraph 102), but the cited references do not further expressly disclose that the molecular weight of the structure forming polymer is above 100,000 g/mol and the binding and/or intercalating polymer has a molecular weight of 100,000 g/mol or below (claim 2), that the first and second hydrophilic polymers are used in a weight ratio of 95:5 to 5:95 as recited by claim 7 or the narrower ratios of claims 16-17, or that the starch polymer is hydroxypropyl pea starch as recited by claim 8.
Borges is a review of oral films useful for delivery of pharmaceutical actives (Title and Abstract), and teaches that hydroxypropyl pea starch is a suitable type of starch for use as a film former in oral films, and that it possesses fast dissolution time and satisfactory mechanical properties (see Table 1). Borges further teaches that pullulan is also a suitable polymer for use in oral film and that it advantageously produces smooth, transparent, and stable films (see Table 1). Borge teaches that hydrophilic polymers having a molecular weight of below 200,000 g/mol or between 1000 and 9000 g/mol are known to be useful as film formers in orally dissolving films (Section 2.1 on page 2). Borges further teaches that pullulan is a suitable hydrophilic polymer but is expensive, which can be solved by replacing 50-80% of it with starch (see starch row of Table 1 on page 5).
Regarding claim 2, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to select molecular weights for the two hydrophilic polymers that are within the recited ranges, because Borge expressly teaches that hydrophilic polymers used as film formers for orally dissolving films typically possess molecular weights that fit within the recited ranges. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
As to claims 7 and 16-17, since Schaneville teaches that the film can comprise more than one film-forming agent in combination such as pullulan and a starch polymer (paragraphs 41-42) it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to vary the weight ratio of the starch and pullulan to arrive at a weight ratio within the 95:5 to 5:95 ratio range recited by claim 7 or the narrower ranges recited by claims 16-17, because Borges teaches that pullulan is a suitable hydrophilic polymer for oral films but is expensive, which can be solved by replacing 50-80% of it with starch, such that the skilled artisan would have been motivated to use pullulan in the amount of 20-50% and use starch for the remaining 50-80% for reasons of economy, which would results in ratios within the scope of claims 7 and 16-17, for example, the use of 50:50 as recited by claim 16 or 60:40 as recited by claim 17. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 8, it further would have been prima facie obvious to select hydroxypropyl pea starch as the type of starch polymer in light of Borge’s teaching that is a suitable starch polymer for use as a film former in orally dissolving films, such that the skilled artisan reasonably would have expected that it could serve as the type of starch polymer in the Goldstein orally dissolving film.
Response to Applicant’s Arguments
Applicant argues that the claims recite a specific combination of at least two hydrophilic polymers in a combined amount of at least 20 wt%, which is said to be critical to achieving rapid disintegration and improved bioavailability that is not predictable, and that the prior art does not suggest that the claimed combination would result in rapid disintegration, improved viscosity, enhanced flexibility, and improved film homogeneity. Applicant cites to paragraphs 153 and 157 as showing that a total polymer content of 19.1 wt% showed markedly inferior performance, which was not predictable to the skilled artisan.
In response, the rejection relies upon MacPhail for its disclosure that oral films comprising hydrophilic starch or pullulan polymers should comprise these polymers in the amount of 40-65 wt%, which is within the presently claimed range of more than 20 wt%, to provide a motivation to utilize the hydrophilic polymers in these amounts in the Schaneville oral film, and there is no evidence of record that the higher amounts taught by MacPhail would show markedly inferior performance. In fact, the amounts disclosed by MacPhail are within the presently claimed range of more than 20 wt% and so would exhibit the same performance as the claimed composition.
Applicant, however, argues that MacPhail teaches polymer contents of 40-65 wt% which is nearly double the critical threshold identified by the present invention, and concludes that the skilled artisan would not have had motivation to reduce the polymer content towards the claimed lower boundary of 20 wt%.
In response, this is not persuasive because the claims are not limited to the lower boundary of 20 wt%, but rather also encompass any amounts above 20 wt% as well. The prima facie case of obviousness over the cited references therefore does not require a motivation to reduce the polymer content towards the claimed lower boundary of 20 wt%.
Applicant also argues that Schaneville does not teach or suggest cladribine or the challenges associated with integrating cladribine-cyclodextrin complexes into oral films, nor the specific polymer combination in an amount of at least 20 wt% as recited by the claims. Shultz is said not to discloses sublingual films nor adapting cladribine cyclodextrin complexes to a thin film format, nor the use of pullulan and starch as structure forming polymers.
In response, the references must be considered not individually but rather for what they suggest as a whole. Both Schaneville and MacPhail expressly teach that pullulan and starch are suitable polymers for use in film formers for oral dispersible films and Schaneville also teaches that more than one of the disclosed film forming polymers may be used in combination, and MacPhail teaches the use of amounts of the hydrophilic polymers within the recited range. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." (325 U.S. at 335, 65 USPQ at 301). MPEP § 2144.07.
Applicant’s argument regarding the challenges associated with integrating cladribine-cyclodextrin complexes into oral films is conclusory without any supporting evidence. Arguments of counsel cannot take the place of actual evidence of record. MPEP 2145 I.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as unpatentable over all claims of US Pat. Appl. No. 18/873,809.
Although the reference claims are not identical to the present claims, they are not patentably distinct because they recite a transmucosal delivery composition in the form of a sublingual orally dispersible film comprising cladribine as the sole active in the same amounts recited by the claims, and which is present in a complex with a cyclodextrin such as hydroxypropyl-beta-cyclodextrin, the composition further comprising at least two hydrophilic polymer in a total amount of at least 20 wt%, one being a structure forming polymer that is a starch polymer and the other being a binding and/or intercalating polymer that is pullulan, wherein each polymer has a molecular weight within the recited ranges, the complex comprising cladribine and cyclodextrin in the same molar ratio recited by the claims, wherein the starch may be the same starch recited by the present claims such as a hydroxypropyl pea starch, the two hydrophilic polymers being used in the same ratios recited by the claims, the composition further comprising a surfactant and plasticizer, the composition further comprising glycerol, the composition being formulated for use in a method of treating MS, MG, or NMOSD, the composition being formed by mixing the cladribine-cyclodextrin complex with film forming polymers by stirring with at least 100 rpm for at least 10 minutes at a temperature of at least 30 degrees Celsius.
Response to Applicant’s Arguments
Applicant argues that the amended claims are no longer the same as the reference claims, such that the statutory double patenting rejection is overcome.
In response, this argument is moot as the statutory rejection has been withdrawn and replaced with a nonstatutory rejection in view of the amendment.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GAREN GOTFREDSON whose telephone number is (571)270-3468. The examiner can normally be reached on M-F 9AM-6PM.
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/GAREN GOTFREDSON/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/ Primary Examiner, Art Unit 1600