DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, filed 04/14/2023, is a 371 filing of PCT/IB2020/059683, filed 10/15/2020.
Preliminary Amendments and Claim Status
The preliminary amendment filed on 04/14/2023 is acknowledged and entered.
Claim 16 is amended;
Claims 1-16 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 04/14/2023 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statement is considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (page 2 and 3). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to because of the use of the foreign language in multiple instances throughout the specification (see page 3 lines 10 and 11, page 10 line 21). According to 37 CFR. § 1.52 (b) (1) (ii),
(b) The application (specification, including the claims, drawings, and the inventor’s oath or declaration) or reexamination or supplemental examination proceeding, any amendments to the application or reexamination proceeding, or any corrections to the application, or reexamination or supplemental examination proceeding.
(1) The application or proceeding and any amendments or corrections to the application (including any translation submitted pursuant to paragraph (d) of this section) or proceeding, except as provided for in § 1.69 and paragraph (d) of this section, must:
(ii) Be in the English language or be accompanied by a translation of the application and a translation of any corrections or amendments into the English language together with a statement that the translation is accurate.
As such, Applicant is required to remove all hyperlinks and provide a proper translation of the foreign language text used in the specification.
Appropriate correction is required.
Drawings
The drawings filed on 04/14/2023 are objected to under 37 CFR § 1.83(a) for the following reasons:
Due to the low resolution used in the images, the figure legends are very difficult to distinguish in Figures 1:
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and Figure 3:
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. The figures must be remade with a higher-quality representation of the key denoting the data type used to describe the data.
Due to the low resolution used in the images, the y-axis
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, as well as the numerical values on the plots
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are very difficult to read in Figure 2. The figure must be remade with higher resolution text that is readable.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR § 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR § 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 16 is objected to for reciting “according to any of claim 1.” It is recommended that the language “any of” is stricken from the claim in order for the claimed to be proper grammatical form.
Claim Rejections - 35 U.S.C. § 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 2, 5, 7-14 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance,
Claim 2 recites the broad recitation “salts of nontoxic organic and nonorganic acids”, and the claim also recites “for example, acetic acid, benzoic acid, citric acid, fumaric acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid,” which is the narrower statement of the range/limitation.
Claim 5 recites the broad recitation “pH regulators”, and the claim also recites “ethylenediamine (THPE), potassium carbonate, potassium hydroxide, sodium carbonate, sodium citrate, and sodium lactate,” which is the narrower statement of the range/limitation
Claim 7 recites the broad recitation “solubilizer,” and the claim also recites “monoethyl ether of diethylene glycol, cyclodextrins, glyceryl monostearate, lecithin, poloxamer, polyvinyl pyrrolidone, polyethylene alkyl ethers, hydrogenated castor oil derivatives, polyoxyethylene stearates, citric acid and ascorbic acid, polysorbates, sorbitan esters, polyvinyl alcohol, benzalkonium chloride and lauryl sulphate,” which is the narrower statement of the range/limitation
Claim 8 recites the broad recitation “surfactants,” and the claim also recites “polysorbates and macrogols,” which is the narrower statement of the range/limitation
Claim 8 recites the broad recitation “solubilizers,” and the claim also recites “polysorbates and macrogols,” which is the narrower statement of the range/limitation
Claim 9 recites the broad recitation “microbiological stability preservative”, and the claim also recites “methylparaben, propylparaben, sodium benzoate, benzyl alcohol, benzalkonium chloride, and chlorobutanol,” which is the narrower statement of the range/limitation
Claim 10 recites the broad recitation “organic co-solvents,” and the claim also recites “ethanol, propylene glycol, glycerol, and polyethylene glycols,” which is the narrower statement of the range/limitation
Claim 11 recites the broad recitation “a viscosity regulator,” and the claim also recites “hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxylmethylcellulose, and polyvinyl pyrrolidones of various grades, such as K15, K30, K60, and K90,” which is the narrower statement of the range/limitation
Claim 12 recites the broad recitation “osmolarity regulator,” and the claim also recites “sodium metabisulfite, sodium bisulfite, ethylenediaminetetraacetic acid (EDTA) disodium salt, and ascorbic acid,” which is the narrower statement of the range/limitation
Claim 14 recites the broad recitation “antimicrobial agent,” and the claim also recites “benzyl alcohol, benzoic acid and/or salts thereof, sorbates,benzalkonium chloride, phenylethyl alcohol, methylparaben, ethylparaben, propylparaben, and butylparaben,“ which is the narrower statement of the range/limitation
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claims 2, 5, 7, 8-14, and 16, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 16 and the recitation of, "at a dose rate of between 3 and 20mg." However, "3 and 20 mg" are not rates, since there is no other variable listed aside from the mass. Rates are defined as an amount per unit time. Without the variable of time as a unit of measure, a rate cannot be claimed. Therefore, the metes and bounds of the claim are unclear because it cannot be determined what other variable accounts for the claimed "rate," as recited. Accordingly, the scope of the claimed method cannot be determined with reasonable certainty, rendering the claim indefinite.
Claim 13 depends on a claim rejected as being indefinite (claim 12), and does not remedy the indefiniteness of the claim on which it depends, and is therefore also rejected as indefinite.
Claim Rejections - 35 U.S.C. § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 4, 6-14, and 16 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Khanna et al. (Ind J Pha Ed Res, Vol 54, Iss 2, published March 2020).
The instant claims are directed to a pharmaceutical composition for nasal administration comprising nalbuphine in combination with specific formulation excipients that enhance solubility, absorption, stability, viscosity, isotonicity, and preservation. The claims collectively define a mucoadhesive intranasal nalbuphine dosage form designed to achieve rapid systemic absorption and enhance bioavailability through the nasal mucosa.
Khanna discloses a pain relieving intranasal pharmaceutical composition comprising nalbuphine and chitosan as a mucoadhesive/absorption enhancer, formulated with PEG-400, ethanol, water, sodium chloride, and benzalkonium chloride, adjusted to pH ≈ 5.5-6.5, with an osmolarity of 288 ± 18 mOsm/L, for administration to animal models for rapid management (Abstract, Tables 1, 3-7).
Regarding claim 1, Khanna anticipates the instant claims by expressly teaching a pharmaceutical composition for nasal administration comprising nalbuphine base and chitosan (0.25-2.5& as a mucoadhesive/absorption enhancer, dissolved in a PEG-400, ethanol, water solvent system (page 312). The weight ratio of nalbuphine base (0.5%) to chitosan (0.25-0.5%) corresponds approximately to 1:0.5 to 1:1, which overlaps with the instantly claimed range of 1:0.1 through 1:1. With regard to anticipation of ranges, MPEP § 2131.03 (I),
"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (citing In re Petering, 301 F.2d 676, 682, 133 USPQ 275, 280 (CCPA 1962)) (emphasis in original)
As such, the specific example taught in the prior art falls within the claimed range, and thus anticipates the range claimed.
Regarding claim 3, Khanna reports that the intranasal nalbuphine formulation delivered drug to the brain within 10 minutes and remained localized up to 240 minutes (Abstract, page 319). Although the metric is not specifically disclosed within the prior art, such rapid and sustained absorption inherently results in bioavailability
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≥ 40%. According to MPEP § 2112 (III),
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. "There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102." In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims
Therefore, the instantly claimed property is deemed to be anticipated when the prior art product seems to be identical, except in that the prior art is silent to an inherent characteristic. Thus, the composition as taught by Khanna, because it overlaps with the instantly claimed subject matter, is inherently capable of achieving bioavailability
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≥ 40%.
Regarding claim 4, Khanna discloses that the pH of the nasal formulation is adjusted between 5.5 and 6.5, which lies within the instantly claimed range of 4.0-7.0 (see anticipation of ranges in MPEP § 2131.03 (I), as referenced earlier).
Regarding claims 6 and 7, Khanna teaches that the composition includes solubility enhancers in the form of PEG-400 (10-60%), which is a poly ethylene alkyl ether (Table 1, page 312), and anticipates the instantly claimed subject matter.
Regarding claims 8, 9, and 14, Khanna teaches the inclusion of benzalkonium chloride (0.01%), a cationic surfactant (Table 1, page 312), anticipating the instantly claimed surfactant, which is taught to be a microbiological preservative (page 320).
Regarding claim 10, the pharmaceutical composition comprises ethanol (5%) and propylene glycol (5-60%) (Table 1, page 312), anticipating the instantly claimed cosolvents.
Regarding claim 11, Khanna reports the viscosity of the nasal drop increases with increasing concentration of PEG and chitosan, demonstrating the presence of a viscosity regulator within the composition.
Regarding claim 12, Khanna includes sodium chloride (0.9%) to achieve isotonicity and to regulate osmolarity (Table 1, page 312), satisfying the limitation of claim 12.
Regarding claim 13, Khanna reports an osmotic pressure of 288 ± 18 mOsm/L for the optimized formulation (Abstract, Table 3, page 317), which lies within the instantly claimed range of 300-700 mOsm/L (see anticipation of ranges in MPEP § 2131.03 (I), as referenced earlier).
Regarding claim 16, Khanna discloses nasal administration of the composition to animals (pages 314 and 315), and reports dosing of 0.2-0.6mg/kg which corresponds to a human equivalent dose of approximately 12-36mg for a 60 kg subject—falling within the instantly claimed range of 3-20mg. Accordingly, the instant claims are anticipated by the teachings of Khannah, and thus, stand rejected.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claims 1-16 are rejected under 35 U.S.C. § 103 as being unpatentable over Khanna (see earlier citation) as applied to claims 1, 3, 4, 6-14, and 16 above, and further in view of Hariharan (U.S. 10,493,027 B5, published December 3, 2019).
In the interest of brevity, the teachings of Khanna are as applied supra, and are herein incorporated by reference in their entirety.
The instant are drawn to a nasal nalbuphine formulation encompassing conventional excipients to enhance solubility, stability, isotonicity, preservation, viscosity, and organoleptic qualities beyond the base composition and teach specific formulation refinements and excipient selections applied to the composition of claim 1.
Although Khanna anticipates the composition of claim 1, Khanna fails to describe the use of pharmaceutically acceptable salts of nalbuphine to improve solubility (claim 2); incorporation of defined pH regulators and buffers to maintain a nasal compatible pH range (claim 5); addition of solubility enhancers and surfactants to increase in drug dissolution and permeability (claims 6-8); inclusion of viscosity regulating polymers to control residence time and space performance (claim 11); addition of osmolarity regulating and stabilizing agents to maintain isotonicity and chemical stability (claim 12); use of broader set of antimicrobial preservatives to prevent microbial growth (claim 14); and finally, incorporation of taste, color, or order corrective additives for patient acceptability (claim 15).
The deficiencies of Khanna are remedied by Hariharan, who provides the full excipient system and stabilization strategy that Khanna’s intranasal nalbuphine formulation lacks. Hariharan teaches intranasal formulations of nalbuphine (see instant claim 1) (Table 22), which include nalbuphine hydrochloride in an amount of 3.1% (column 11 lines 16-33, column 19, lines 29-39, column 52 table 24, see instant claim 2). Hariharan discloses that converting a drug into a salt through this process can increase its chemical stability, rendering the complex easier to administer, and allowing manipulation of the pharmaceutically active agent's equilibrium solubility and pharmacokinetic profile (column 3, lines 15-18). Hariharan teaches wherein the pharmaceutical composition containing nalbuphine hydrochloride has high bioavailability and is used for the treatment (relief) of pain. Specifically Hariharan teaches wherein the absolute bioavailability of the component is 200% (column 53, lines 9-50, column 7, lines 59-65, see instant claim 3). Khanna further teaches that the composition may contain chitosan (column 21, lines 45-49, see instant claim 1). Hariharan discloses wherein the pH regulator may be citric, lactic, and phosphoric acids (column 9, lines 34-45 , see instant claim 5). Hariharan further discloses that the composition can contain a solvent, such as diethylene glycol monoethyl ether (column 23 lines 53-58, see instant claims 6 and 7). Hariharan teaches wherein the composition may contain polysorbates as surfactants (column 21 lines 5-15), and that the composition may contain poloxamer (column 51 table 22, see instant claims 7 and 8). Hariharan teaches wherein the composition may contain a preservative of microbiological stability, such as methylparaben (column 18 lines 45-49, see instant claim 9). Hariharan teaches wherein the composition contains water as a solvent, hydroxypropyl cellulose, and disodium salt of ethylenediaminetetraacetic acid (EDTA) (column 52, table 24, see claims 10-12). Hariharan teaches wherein color, taste and odor correctors may be used in the composition (column 12 lines 37-40, column 24 lines 1-4, see instant claim 15) Finally, Hariharan teaches a method of using the pharmaceutical composition, wherein the dose for nasal use is 20 mg. (Table 23, see instant claim 16).
Both Hariharan and Khanna teach compositions related to nasal formulations of nalbuphine and share the same objective—to treat pain by rapid systemic absorption. Following the teachings of Hariharan, which states that converting a drug into a salt through this process can increase its chemical stability, rendering the complex easier to administer, and allowing manipulation of the pharmaceutically active agent's equilibrium solubility and pharmacokinetic profile (column 3, lines 15-18), a person of ordinary skill in the art prior to the filing date of the instant claims would have been directly motivated to incorporate nalbuphine HCl into the composition taught by Khannah, in order to achieve greater solubility and stability, yielding predictable results with a reasonable expectation of success. In addition, a person of ordinary skill in the art would have found it obvious to incorporate both buffering and surfactant systems as taught by Khanna, in order to improve drug permeability and shelf stability. Finally, a person of ordinary skill would have found it obvious to include taste and odor correctors in order to make the composition more palatable, arriving at the instant claims. One of ordinary skill in the art would be directly motivated to do so in order to induce a pleasing aroma, or to mask flavors in the case of any product reaching the mouth, as taught by Hariharan (column 29 lines 63-65).
Correspondence
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5am-5pm EST, Mon-Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623