DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-15 are pending.
Priority
This application is filed 11/27/2023 and no claims the benefit of domestic priority. Foreign priority claimed with Application as following:
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The priority foreign documents are in English and are present in the file.
Information Disclosure Statements
An Information Disclosure Statement (IDS) has not been filed in this application. See MPEP 609 as to requirements for the filing of IDS’s.
Claim Interpretation
Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard
consistent with the specification (See MPEP 2111). Claims 1-15 are drawn to a pharmaceutical mixture comprising pitolisant free base or a pharmaceutically acceptable salt thereof combined with pharmaceutically acceptable excipients and formulated into oral dosage forms are interpreted as follows:
The phrase “at least one pharmaceutically acceptable excipient” is interpreted as selection of any one or more excipients without requiring any specific combination, proportion, or interaction among them.
The phases “prepared by hot-melt extrusion” and “prepared by spray granulation” are interpreted as product-by-process. The claimed “the solid dispersion” is defended by its structural characteristics, and is limited to solid dispersion prepared by either hot-melt extrusion or spray granulation.
The dissolution limitation in claim 13 is interpreted as a result-based performance characteristic, rather than a process limitation or structural feature of the dosage form.
Claim Objections
Claims 3 and 13 are objected to because of the following informalities:
Claim 3, “polyethylene oxide/propylene oxide)” should read “polyethylene oxide/propylene oxide”, and “gelatin” is duplicated as “gelatin/gelatins”
Claim 13 is objected to under 35 USC § 112(b) as being indefinite because the claim includes a parenthetical expression, “(apparatus 2; paddle, 1000 ml of 0.1 N HCl and 37°C, 75 rpm)”, the scope and limiting effect of which are unclear. (See MPEP 2173)
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The use of a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as superscripted ™, SM , or ® following the term.
There are missing opening/closing parentheses in the paragraph [0033] and [00108].
The phrase “Polyols also include cyclodextrins and maltodextrins” in the paragraph [0034], maltodextrins are starch, not polyols.
In the paragraph [0050], “80170°C” should read “80-170°C
In the paragraph [00123], “Fischer” should read “Fisher”.
In the paragraph [00139] and [00149], “optionally sieving the granules of step (iii)” is not correct referencing. The granules of step are (iv).
In the paragraph [00159] and [00168], “the solvent of step (iii)” should read “the solvent of step (ii)”.
In the paragraph [00162], “tetrahydrofurane” should read “tetrahydrofuran”.
In the paragraph [00195], “microcristalline” should read “microcrystalline”.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 6, 12, 14 and 15 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Venkatragavan et al. in US 11,623,920 B2 (filed on 05/24/2022).
With respect to Claims 1-3, 6, 12, 14 and 15, Venkatragavan teaches a pharmaceutically acceptable pitolisant salt thereof (i.e., HCl salt, formula I) in amorphous form with use of pharmaceutically acceptable excipients, as required instant claim 1 (claim 1). Venkatragavan further teaches (1) pharmaceutically acceptable excipient comprises a diluent, a binder, a plasticizer or a disintegrant, as required instant claim 2 (column 17, line 26-32); (2) the diluent is selected including hydroxyethyl cellulose, hypromellose phthalate, and polyethylene glycol, as required instant claim 3 (claim 15, 20 and 25); (3) forming such compositions as amorphous solid dispersions using hot-melt extrusion, as required instant claim 6 (column 9, line 16-23); (4) oral tablet dosage forms optionally comprising additional pharmaceutical excipient(s) and more preferred forms are coated tablets, and a therapeutically effective amount of pitolisant ( e.g., about 4.45 mg or about 17 .8 mg), as required instant claims 12, 14 and 15. The teaching of Venkatragavan meets all limitations of claims 1-3, 6, 12, 14 and 15.
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 1-6, 11, 12, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Manuel et al. (US 8,207,197 B2, pub’d 06/26/2012), in view of Venkatragavan et al. in US 11,623,920 B2 (filed on 05/24/2022).
With respect to independent claim 1, Manuel teaches pitolisant free base or a pharmaceutically acceptable salt thereof (column 1, lines 32-35) with use of pharmaceutically acceptable excipients (claim 10). Manuel further teaches formulation of known active pharmaceutical ingredients into oral dosage forms using pharmaceutically acceptable excipients.
However, Manuel fails to teach that the pharmaceutical composition is in amorphous form, as required by instant claim 1.
Venkatragavan teaches pharmaceutical compositions comprising pitolisant hydrochloride in the form of amorphous solid dispersions with one or more pharmaceutically acceptable excipients (claim 1). Venkatragavan further teaches hot-melt extrusion processes for preparing such amorphous solid dispersions (column 9, lines 16-23). Venkatragavan continuous teaches that amorphous solid dispersions prepared by hot-melt extrusion show improved physicochemical stability under thermal, humid, and stress conditions, as well as enhanced dissolution performance and bioavailability (column 10, lines 5-11).
It would have been obvious to a PHOSITA at the time of the invention to combine and/or substitute the pitolisant free base or a pharmaceutically acceptable salt composition of Manuel and applying amorphous solid dispersion preparation for the pitolisant hydrochloride, as taught by Venkatragavan. Such combinations show improved physicochemical stability under thermal, humid, and stress conditions. For example, Manuel teaches pitolisant and excipient compositions suitable for oral administration in the treatment of narcolepsy, and applying the amorphous solid dispersion skills of Venkatragavan would allow those compositions to further benefit from the enhanced stability and dissolution performance taught by Venkatragavan.
The combination of these references is directed to the same field of endeavor and address related to the application of known formulation technique to a known drug substance to obtain a predictable improvement in performance. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A) or (B) in the claim 1, it would have been prima facie obvious to combine and/or substitute the amorphous solid dispersion form taught by Venkatragavan into the pitolisant composition of Manuel, as such combination shows a predictable variation using known elements according to the established functions and yields predictable results, yielding predictable results. (see MPEP 2141)
With respect to claims 2-6, as discussed above, Manuel teaches the base pharmaceutical composition comprising pitolisant and pharmaceutically acceptable excipients in the solid premix. Manuel specifically further teaches including (1) use of pharmaceutically acceptable excipients as suitable carriers including (1) diluents, binders, disintegrants, lubricants and glidants, as required instant claim 2 (column 4, lines 10-11); (2) the diluent is selected including starch, microcrystalline cellulose and magnesium carbonate, as required instant claims 3, and 5 (column 4, lines 13-21); (3) colloidal silicon dioxide is used as mesoporous inorganic hygroscopic-stability increasing substances, as required instant claim 4 (column 21, example 14).
Manuel fail to teaches that the pharmaceutical mixture is a solid dispersion prepared by hot-melt extrusion, as required by claim 6.
As discussed above with respect to independent claim 1, Venkatragavan teaches hot-melt extrusion for amorphous solid dispersions of pitolisant hydrochloride, which provide improved physicochemical performance. (column 9, lines 16-23, and column 10, lines 5-11). Further, Venkatragavan reiterates the diluent is selected including hydroxyethyl cellulose, hypromellose phthalate, and polyethylene glycol, as required instant claim 3 (claim 15, 20 and 25), and the diluent is selected including hydroxyethyl cellulose, hypromellose phthalate, and polyethylene glycol, as required instant claim 3 (claim 15, 20 and 25).
Applying KSR example rationale (A), it would have been prima facie obvious to combine the known pharmaceutical ingredients (e.g., pitolisant, and excipients) using known formulation methods, to achieve predictable results, rending the claims obvious to one of ordinary skill in the art at the time of the invention. (see MPEP 2141)
Applying KSR example rationale (B), it would have been prima facie obvious to certain simple substitution of one known excipient for another, including suitable carries, diluents, and the mesoporous inorganic hygroscopic-stability increasing substances, in the amorphous solid dispersion formulations taught by Manuel and Bhujbal, as such substitutions yielding predictable results. (see MPEP 2141)
With respect to claims 11, 12, 14 and 15, the claims are directed to conventional oral dosage forms. Manuel teaches including (1) a solid pharmaceutical mixture, as required by instant claim 11 (column 3, lines 48-50); (2) oral tablet dosage forms optionally comprising additional pharmaceutical excipient(s), as required by instant claim 12 (column 3, lines 48-50, and column 21, examples 14-17); (3) the sufficient dose ranges to counteract side effects of the psychotropic medication is about 5 to about 80 mg, as required by instant claim 14 (column 3, lines 61 - column 4, lines 6); (4) oral tablet dosage forms, including coated tablets, as required by instant claim 15 (column 3, lines 48-51).
Venkatragavan teaches encompassing the claimed 4.45 mg and 17.8 mg of pitolisant, as required by instant claim 14 (column 17, lines 33–36). Further, Venkatragavan reiterates the oral tablet dosage forms optionally comprising additional pharmaceutical excipient(s) and more preferred forms are coated tablets (claim 12).
Applying KSR example rationale (B), it would have been prima facie obvious to substitute one known tablet dosage strength or conventional excipient form for another in the oral dosage forms taught by Manuel and Venkatragavan, as such substitution shows predictable variations yielding predictable results. (see MPEP 2141)
Claims 1, 7-10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Manuel et al. (US 8,207,197 B2, pub’d 06/26/2012), in view of Bhujbal et al. (“Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies” Acta Pharmaceutica Sinica B, 2021, 11(8), 2505-2536, pub’d 06/05/2021).
With respect to claims 1, 7-10 and 12, Manuel teaches the pharmaceutical mixture of pitolisant free base or a pharmaceutically acceptable salt thereof (column 1, lines 32-35) with use of pharmaceutically acceptable excipients (claim 10) in the respect to independent claim 1, and generally teaches preparing solid oral dosage forms using conventional pharmaceutical formulation techniques, as mentioned above. Manuel further teaches oral tablet dosage forms optionally comprising additional pharmaceutical excipient(s), as required by instant claim 12 (column 3, lines 48-50, and column 21, examples 14-17), as mentioned above.
Manuel fails to teach that preparing the pharmaceutical composition as amorphous solid dispersions by hot-melt extrusion at a temperature from 120 to 170°C or spray granulation, and the weight ratio of pitolisant free base or a pharmaceutically acceptable salt thereof to pharmaceutically acceptable excipient is 10:1 to 1:10.
Bhujbal teaches forming such compositions as amorphous solid dispersions using known hot-melt extrusion or spray granulation techniques for the pharmaceutical composition as an amorphous solid dispersion, as required instant claim 9 (section 1.1, and section 2.3.1). Bhujbal further discloses the several different examples of the processing parameters and manufacturing formulation techniques such as temperatures (e.g., 110 to 180°C), speeds, drug content, spray-based processes and drug to excipient weight ratios (e.g., 1:10, 2:10 and 5:10), as required instant claims 7, 8, and 10 (section 2.1.1, section 2.1.2, section 2.1.4, section 2.2.2, section 2.3.1, and table 2). The combined teaching of Manuel and Bhujbal meet all limitations of claims.
It would have been obvious to a PHOSITA at the time of the invention to apply hot-melt extrusion or spray granulation techniques taught by Bhujbal to the pitolisant compositions of Manuel. Such substitution shows improved solubility and enhanced bioavailability for pitolisant, which is formulated as a solid oral dosage form. Such a substitution (e.g., hot-melt extrusion or spray granulation techniques) constitutes a predictable variation, yielding predictable results, consistent with KSR example rationale (B). (see MPEP 2141)
As discussed above, Bhujbal teaches overlapping ranges at claims 7, 8, and 10 for hot-melt extrusion carrying out temperature, and drug to excipient weight ratios for the same purpose and use. Adjusting component proportions to arrive at the claimed ranges constitutes routine optimization of result-effective variables and overlapping range, consistent with MPEP 2144.05.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Manuel et al. (US 8,207,197 B2, pub’d 06/26/2012), in view of Bhujbal et al. (“Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies” Acta Pharmaceutica Sinica B, 2021, 11(8), 2505-2536, pub’d 06/05/2021) and further in view of Reddy et al. (“In Vitro Dissolution of Generic Immediate-Release Solid Oral Dosage Forms Containing BCS Class I Drugs: Comparative Assessment of Metronidazole, Zidovudine, and Amoxicillin Versus Relevant Comparator Pharmaceutical Products in South Africa and India” American Association of Pharmaceutical Scientists Pharmaceutical Sciences and Technology, 2014, 15(5), 1076-1086, pub’d 05/22/2014).
With respect to claim 13, the claims recite a dissolution performance using US Pharmacopeia (USP) apparatus 2 (paddle) method. As discussed above, Manuel and Bhujbal fail to explicitly teach evaluation dissolution performance using USP methods.
Manuel and Bhujbal fail to teach a dissolution performance using USP method.
Reddy teaches dissolution performances of solid oral dosage forms using USP apparatus 2 (paddle) operated at 75 rpm in multiple dissolution media (pH 1.2, 4.5, and 6.8), and further teaches dissolution quantitation in accordance with the USP general chapter Validation of Compendial Procedures <1225> (abstract, and analytical quantitation section).
Applying KSR example rationale (D), it would have been prima facie obvious to evaluate the dissolution performances of the pitolisant amorphous solid dispersions prepared according to Manuel and Bhujbal using known USP method as taught by Reddy, as such testing represents a routine and predictable technique for assessing oral dosage form performance. (see MPEP 2141).
Conclusion
Claims 1-15 are rejected.
Claims 3 and 13 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571) 270-7679. The examiner can normally be reached on 7:00am-3:30pm.
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/SEONG JONG KIM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621