Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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.
DETAILED ACTION
Applicant’s Request for Reconsideration dated October 22, 2025 is acknowledged.
Claims 46, 47, 53, 61, 63-67, 81, 83-85, 89, 90, 93, 96, 98, 99 and 101-103 are pending.
Claims 1-45, 48-52, 54-60, 62, 68-80, 82, 86-88, 91, 92, 94, 95, 97 and 100 are cancelled.
Claims 46, 66, 93 and 96 are currently amended.
Claims 46, 47, 53, 61, 63-67, 81, 83-85, 89, 90, 93, 96, 98, 99 and 101-103 as filed on October 22, 2025 are under consideration.
This action is made FINAL.
Withdrawn Objections / Rejections
In view of the amendment of the claims, all previous claim rejections under 35 USC 112(b) are withdrawn.
Applicant’s arguments 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Objections
Claims 47, 53, 61, 63-65 and 89 are objected to because of the following informalities: the preamble should recite “The pharmaceutical formulation according to claim” in view of the amendment of claim 46 to recite another formulation and for consistency with claims 96, 98, 99 and 101-103. Appropriate correction is required.
Maintained Grounds of Rejection / New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 46, 47, 53, 61, 63-67, 81, 83-85, 93, 96, 98, 102 and 103 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Constantinides (WO 93/02664, published February 18, 1993, of record) as evidenced by the Captex® 300 product information sheet of ABITEC, July 13, 2007, of record, in view of Lacy et al. (US 5,645,856, published July 8, 1997, of record); Iyer et al. (US 2004/0033257, published February 19, 2004, IDS reference filed July 19, 2012); Rouffer (US 6,221,391, published April 24, 2001, of record); Chen (US 2003/0235595, published December 25, 2003, IDS reference filed July 7, 15, 2014); and Lin (US 6,720,002, published April 13, 2004, IDS reference filed July 19, 2012).
Constantinides teaches pharmaceutically acceptable, stable, self-emulsifying w/o microemulsions (liquid formulations) comprising (i) a lipophilic phase comprising a medium-chain fatty acid triglyceride and a low HLB surfactant, (ii) an aqueous-based hydrophilic phase containing a water-soluble therapeutic agent, and (iii) a high HLB surfactant having improved drug-delivery characteristics (abstract). Lipid-based microemulsions have already been proposed to enhance the bioavailability of different drugs, such as the highly hydrophobic cyclosporine peptides (page 2, lines 25-29; see also page 9, lines 4 and 10). Microemulsions intended for oral administration may be presented in soft gelatin capsules (page 16, lines 28-35). The microemulsions without a drug are novel and useful as precursors to drug-containing microemulsions (paragraph bridging pages 16 and 17; claim 10).
Suitable medium-chain fatty acid triglycerides having from 6 to 12, preferably 8 to 10 carbon atoms include those available under the tradenames CAPTEX 355 (glycerol caprylate caprate as evidenced by page 6, lines 20-30 of the instant specification), CAPTEX 300 (glyceryl tricaprylate/caprate as evidenced by page 6, lines 20-30 of the instant specification), MIGLYOL 810 and MIGLYOL 812 (caprylic/capric triglyceride as evidenced by page 6, lines 20-30 of the instant specification) (page 5, lines 9-29). As evidenced by the Captex® 300 product information sheet, the required HLB of Captex® 300 is 11 using surfactant blends of sorbitan laurate and polysorbate 20, as required by instant claims 64 and 84.
Suitable low HLB surfactants include medium-chain fatty acid monoglycerides and diglycerides formed from caprylic and capric acids inclusive of those available under the tradename CAPMUL MCM (glyceryl mono- & dicaprate as evidenced by page 6, lines 10-19 of the instant specification) (page 5, line 31 through page 6, line 9). Suitably the low HLB surfactant has an HLB from about 3 to 6; CAPMUL MCM has an HLB of about 5.5 to 6 (page 6, lines 9-12), as required by instant claims 61, 63, 81 and 83. The low HLB surfactant provides for reduced droplet size and this is believed to aid in the absorption of the therapeutic agent (page 6, lines 14-19).
Suitable high HLB surfactants having a HLB in the range of 13 to 20 include non-ionic surfactants such as polyoxyethylene sorbitan fatty acid esters (polysorbates) available under the tradename TWEEN such as TWEEN 20 and TWEEN 80 of which TWEEN 80 is especially preferred (paragraph bridging pages 6 and 7), as required by instant claims 65, 85 and 96. The high HLB surfactant (dispersant) is present from about 5 to about 75%, 5 to 50%, 7.5 to 30% (page 13, lines 25-28). "In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists.” In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05 I.
The hydrophilic phase comprises water (page 10, lines 13-15), as required by instant claims 47 and 67. The hydrophilic phase comprises just greater than 0 to about 40%, 0.1 to 20%, 0.1 to 10%, 1 to 5% (page 13, lines 29-31), as required by instant claim 53.
Suitably, the medium-chain fatty acid triglyceride plus the low HLB surfactant (includes medium-chain fatty acid monoglycerides and diglycerides as elaborated supra) together comprise about 8 to about 95%, 10 to 90%, 40 to 90%, 60 to 90% of the microemulsion; the triglyceride and the low HLB surfactant may be combined and mixed at various ratios such as about 5:1 to about 1.5:1 (broadly and reasonably interpreted as about 1:1 because the qualifier about permits some tolerance), 4:1 to 2:1 for low viscosity microemulsions (page 13, lines 11-23; see also paragraph bridging pages 16 and 17). With regard to the instantly claimed amount of the triglyceride / glycerol caprylate caprate, Constantinides therefore renders obvious a broad range of about 6.7 to 79 wt% at a ratio of 5:1 ((5/6)* 8 to 95) and a broad range of about 4.8 to 57 wt% at a ratio of 1.5:1 ((1.5/2.5)* 8 to 95), as required by instant claim 98. With regard to the instantly claimed amount of the mono-/di-glyceride / glyceryl mono- and dicaprate, Constantinides therefore renders obvious a broad range of about 1.3 to 15.8 wt% at a ratio of 5:1 ((1/6)* 8 to 95) and a broad range of about 3.2 to 38 wt% at a ratio of 1.5:1 ((1/2.5)* 8 to 95). A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). See MPEP 2144.05. In addition, Constantinides teaches appropriate ratios may be readily determined by the skilled man with the aid of a phase diagram because not all blends will yield stable, self-emulsifying microemulsions (page 10, lines 28-33; see also pages 11-12 and Figures). As per MPEP 2144.05 II, it is prima facie obvious to optimize result effective parameters within prior art conditions or through routine experimentation. And as elaborated supra, the low HLB surfactant (includes medium-chain fatty acid monoglycerides and diglycerides) provides for reduced droplet size and this is believed to aid in the absorption of the therapeutic agent (page 6, lines 14-19), providing further motivation to optimize the content thereof.
The various phases may optionally contain further ingredients such as for example stabilizers (paragraph bridging pages 14 and 15).
Regarding the desired result of immediate release of claims 46, 66 and 93, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. See MPEP 2111.04. However, Constantinides, as a whole, is drawn to microemulsions which may be presented in soft gelatin (soft gel) capsules. Therefore, it is presumed that the soft gelatin capsules of Constantinides are also capable of immediate release as instantly claimed, absent evidence to the contrary.
Regarding the “consisting essentially of” transitional phrases of claim 93, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355. See MPEP 2111.03.
Constantinides does not teach about 3 to about 7 wt% loratadine, wherein the loratadine is dissolved, does not teach povidone / povidone K-12, does not teach the weight ratio of dispersant / povidone / povidone K-12 to surfactant is about 1.75:1 to about 2.5:1, and does not teach the formulation has a HLB from 3 to 6 as required by claims 46, 66 and 93.
Constantinides does not teach 10 mg loratadine as required by claim 102.
Constantinides does not teach a plasticizer as required by claim 103.
These deficiencies are made up for in the teachings of Lacy, Iyer, Rouffer, Chen and Lin.
Lacy teaches oral drug delivery systems for improving the bioavailability of hydrophobic drugs inclusive of loratadine (abstract; column 1, lines 4-7; column 12, line 20). The concentration of the drug will be that which is required to provide the desired therapeutic effect, usually 0.1 to 50 wt% (column 12, lines 44-53). The drug delivery system or carrier comprises a digestible oil, preferably medium chain C8-C12 triglycerides inclusive of capric and/or caprylic triglyceride oils such as Miglyol 810, Miglyol 812, Captex 300 or Captex 355 (abstract; column 8, lines 55-64; column 9, lines 20-28). The drug delivery system or carrier comprises a hydrophilic surfactant for dispersing the digestible oil in vivo, preferably Tween 80 (abstract; column 1, lines 27-43; column 7, line 9). The drug delivery system or carrier further comprises a lipophilic surfactant, preferably mono- and/or di-glycerides of capric/caprylic acid inclusive of Capmul MCM (column 1, lines 27-43; column 4, lines 42-60; column 6, lines 11-14). The drug carrier systems may be prepared by mixing the oil and the lipophilic surfactant, adding the hydrophilic surfactant and if required hydrophilic solvent, and adding the hydrophobic drug until either a homogeneous solution or suspension is prepared (column 14, lines 13-33).
Iyer teaches a pharmaceutical formulation of a water insoluble drug that is loratadine encapsulated in a soft gelatin capsule; the loratadine is blended with a self-emulsifying drug delivery vehicle (abstract; paragraphs [0010] and [0020]). Usual recommended strength of loratadine is 10 mg/dosage unit although the strength may vary from 10 mg to 40 mg/dosage unit; the size and shape of the capsules may vary depending on the loratadine content and may be oval, oblong or round in shape (paragraph [0019]). The loratadine may be solved or suspended (paragraphs [0021]-[0022]). Polyvinyl pyrrolidone (PVP) K30 (povidone) was used as a solubility enhancer as it is known to form a complex with insoluble molecules and those are difficult to solubilize and hence to give good dissolution and enhanced bioavailability (paragraph [0030]). Iyer further teaches the vehicle may optionally contain PVP or povidone that is Kollidon® as a viscosity modifier (paragraph [0029]-[0030]). Iyer further teaches the usual recommended strength of loratadine is 10 mg/dosage unit (paragraph [0019]), as required by instant claim 102. Iyer further teaches gelatin capsule formulations for soft gelatin capsules comprise gelatin and one or more plasticizers to adjust the hardness (paragraph [0031]), as required by instant claim 103.
Rouffer teaches a self-emulsifying oil-based solution of ibuprofen suitable for encapsulation into a soft gelatin capsule (abstract; column 1, lines 53-56). Low molecular weight PVPs such as PVP K-12 and PVP K-17, typically used as solubilizers or crystallization inhibitors, have the capacity or property of forming water-soluble complexes with water insoluble drug substances like ibuprofen (paragraph bridging columns 2 and 3). The amount of PVP can range from approximately 15 to 20% in order to prevent recrystallization (paragraph bridging pages 2 and 3). Higher molecular weight PVPs are used as thickeners (paragraph bridging pages 2 and 3).
Chen teaches oral pharmaceutical compositions, preferably gelatin capsules, comprising a therapeutic, preferably hydrophobic, agent and a carrier comprising a triglyceride such as glyceryl tricaprylate/caprate and at least two surfactants, at least one of which is hydrophilic such as Tween-80 and optionally at least one of which is hydrophobic such as glyceryl caprylate/caprate (abstract; paragraphs [0017]-[0018], [0022], [0042], [0056], [0072], [0074], [0094], [0101], [0152] and [0210]). The therapeutic agent may include loratadine (paragraphs [0103], [0115] and [0126]). The compositions may further comprise additional compounds to enhance the solubility of the therapeutic active; solubilizers preferably include polyvinylpyrrolidone (povidone) (paragraphs [0115], [0128], [0131] and [0135]). The amount of solubilizer is not particularly limited; the solubilizer can be present in a concentration of 200% or up to 400 wt% based on the amount of surfactant or in very small amounts such as 25%, or 1 wt% or less (paragraph [0136]).
Lin teaches soft capsule dosage forms of loratadine in a solvent system having a HLB value from about 3 to 7 (title; abstract; claims; column 3, lines 62-67). Lin further teaches a 10 mg loratadine dose can be accommodated by a 5 minim or less size oval soft capsule; a minim is a pharmaceutical volumetric unit of measure wherein 1 minim = 0.0616 cc (paragraph bridging columns 5 and 6), as required by instant claim 102. Lin further teaches dosage forms comprising about 6.3 wt% loratadine and about 6.3 wt% povidone (claim 1; column 2, line 56 through column 3, line 25; column 4, lines 13-27).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the microemulsion of Constantinides either comprising a hydrophilic drug or formulated without a drug to further comprise 0.1 to 50 wt% of a hydrophobic drug inclusive of loratadine as taught by Lacy because drug delivery systems comprising inter alia medium chain C8-C12 triglycerides, Tween 80 and mono- and/or di-glycerides of capric/caprylic acid improve the bioavailability of hydrophobic drugs inclusive of loratadine. There would be a reasonable expectation of success because the microemulsion of Constantinides having improved drug-delivery characteristics comprises medium-chain C6-C12 fatty acid triglycerides, medium-chain fatty acid monoglycerides and diglycerides formed from caprylic and capric acids and TWEEN 80. It would have been obvious to one of ordinary skill in the art at the time the invention was made that the loratadine would dissolve or disperse in the microemulsion of Constantinides in view of Lacy because Lacy teaches drug carrier systems are prepared by mixing the oil and the lipophilic surfactant, adding the hydrophilic surfactant and if required hydrophilic solvent, and adding the hydrophobic drug until either a homogeneous solution or suspension is prepared.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the microemulsion of Constantinides in view of Lacy comprising a dissolved / dispersed hydrophobic drug inclusive of loratadine to further comprise polyvinyl pyrrolidone (PVP) K30 (povidone dispersant) as taught by Iyer because PVP K30 is a solubility enhancer known to form a complex with insoluble molecules like loratadine and hence improve dissolution and enhance bioavailability in the context of a self-emulsifying drug delivery vehicle. There would be a reasonable expectation of success because the microemulsion of Constantinides may comprise further ingredients and because Constantinides as a whole is drawn to microemulsions having improved drug-delivery characteristics and which self-emulsify.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to optimize the amount of PVP K30 in the microemulsion of Constantinides in view of Lacy and Iyer because Iyer teach PVP is a solubility enhancer which improves dissolution and enhances bioavailability when complexed with insoluble drug molecules inclusive of loratadine. As per MPEP 2144.05 II, it is prima facie obvious to optimize result-effective variables within prior art conditions or through routine experimentation.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the PVP K30 solubility enhancer of Constantinides in view of Lacy and Iyer to comprise other low molecular weight PVP solubility enhancers such as K12 or/and K17 as taught by Rouffer because it is prima facie obvious to substitute or/and combine equivalents known in the art for the same purpose. See MPEP 2144.06. Because Rouffer teaches about 15 to 20% PVP is suitable for inhibiting crystallization of ibuprofen, which is an art-recognized hydrophobic drug as evidenced by Lacy (column 10, line 57), and Lin teaches dosage forms comprising about 6.3 wt% povidone in combination with about 6.3 wt% loratadine, it would have been obvious to one of ordinary skill in the art at the time the invention was made to optimize within this range.
With regard to the instantly claimed ratio of povidone / K-12 dispersant to surfactants selected from the group consisting of polyoxyethylene sorbitan fatty acid esters (polysorbates or Tweens), ethoxylated aliphatic alcohols and propylene glycol monolaurate, it would have been obvious to one of ordinary skill in the art at the time the invention was made that the optimized amount of the PVP solubility enhancer of Iyer in the microemulsion of Constantinides in view of Lacy, Iyer and Lin would fall within conventional amounts as taught by Chen. Chen teaches solubilizers inclusive of PVP are included in triglyceride-based drug delivery vehicles in amounts of 200% or up to 400 wt% based on the amount of surfactant or in very small amounts such as 25%, or 1 wt% or less, where the surfactant according to Chen includes both the Tween 80 and the mono- and di-glycerides. Chen therefore render obvious a ratio of less than 4:1 to less than 0.01 on a basis of only one of the surfactants, e.g., the Tween 80. And as elaborated supra, the PVP solubility enhancer is a result-effective parameter that would be prima facie obvious to optimize.
With regard to the instantly claimed HLB of the formulation, because the combined teachings of the prior art render obvious formulations as instantly claimed, comprising overlapping amounts of the same ingredients as instantly claimed, the formulations of the prior art must also be characterized by an HLB as instantly claimed, absent evidence to the contrary. Additionally or/and alternatively, it would have been obvious to one of ordinary skill in the art at the time the invention was made to formulate the microemulsion of modified Constantinides to possess a HLB of about 3 to 7 as taught by Lin because this value is optimal for loratadine.
Regarding claim 102, it would have been obvious to one of ordinary skill in the art at the time the invention was made to formulate the microemulsion of modified Constantinides comprising 0.1 to 50 wt% loratadine in 10 mg dosage forms because Iyer teaches this to be the usual recommended strength of loratadine and that the size and shape of the capsules may vary depending on the loratadine content.
Regarding claim 103, it would have been obvious to one of ordinary skill in the art at the time the invention was made that the soft gelatin capsules of modified Constantinides comprise one or more plasticizers as taught by Iyer in order to adjust the hardness.
Claims 89, 90, 99 and 101 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Constantinides (WO 93/02664, published February 18, 1993, of record) as evidenced by the Captex® 300 product information sheet of ABITEC, July 13, 2007, of record, in view of Lacy et al. (US 5,645,856, published July 8, 1997, of record); Iyer et al. (US 2004/0033257, published February 19, 2004, IDS reference filed July 19, 2012); Rouffer (US 6,221,391, published April 24, 2001, of record); Chen (US 2003/0235595, published December 25, 2003, IDS reference filed July 7, 15, 2014); and Lin (US 6,720,002, published April 13, 2004, IDS reference filed July 19, 2012) as applied to claims 46, 47, 53, 61, 63-67, 81, 83-85, 93, 96, 98, 102 and 103 above, and further in view of Legen et al. (WO 2008/077823, published July 3, 2008, of record).
The teachings of Constantinides, Lacy, Iyer, Rouffer, Chen and Lin have been described supra.
They render obvious compositions comprising about 0.1 to 50 wt% of a hydrophobic drug inclusive of loratadine, compositions comprising about 6.3 wt% povidone in combination with about 6.3 wt% loratadine, and compositions comprising solubilizers inclusive of PVP in amounts of 200% based on the amount of surfactant (e.g., ratio of 2:1).
They do not teach about 41 to 45.3 wt% glyceryl mono- and dicaprate and about 41 to 45.3 wt% triglyceride as required by claims 89 and 90.
They do not teach about 41 to 50 wt% triglyceride as required by claim 99.
They do not teach about 41 to 45 wt% of each of the mono- and di- glycerides and the triglycerides as required by claim 101.
These deficiencies are made up for in the teachings of Legen.
Legen teaches self-microemulsifying drug delivery systems and a microemulsion comprising a POE sorbitan fatty acid emulsifier that is preferably polysorbate 80, a fatty acid ester co-emulsifier selected from glyceryl mono- or di- fatty acid esters of C6-C18 fatty acids, and an oil selected from C6-C12 fatty acid triglycerides that is a caprylic or capric triglyceride oil and optionally further comprising a drug having an aqueous solubility of less than 0.1 g/mL either dissolved or dispersed therein (title; abstract; claims, in particular 1, 2, 5, 6, 8-11, 16-18, 20, 21). The ratio of the co-emulsifier to the triglyceride oil is at least 1.5:1, preferably 2:1, more preferably at least 3:1 (claim 9).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the mixing ratios of the triglyceride and the low HLB surfactant of the compositions of modified Constantinides to extend to the ratios encompassed by Legen because the ratios of Legen also provide a self-microemulsifying drug delivery systems and because these ratios are suitable for delivering drugs having low aqueous solubility. The combined teachings of the prior art therefore render obvious ratios of about 5:1 to about 1.5:1 (e.g., Constantinides) through ratios of less than about 1:1.5 to 1:3 (e.g., Legen) and at a ratio of 1:1 the combined teachings of the prior art therefore render obvious amounts of about 4 to 47.5 wt% ((1/2)* 8 to 95) for the amount of the mono- and di-glyceride and for the amount of the triglyceride.
Claims 46, 47, 53, 61, 63-67, 81, 83-85, 89, 90, 93, 96, 98, 99, 101 and 102 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lacy et al. (US 5,645,856, published July 8, 1997, of record) as evidenced by Ottinger (US 2007/0082016, of record) in view of Shojaei et al. (US 7,011,846, published March 14, 2006, of record); Agarwal et al. (WO 2010/030667, published March 18, 2010, of record); Liu et al. (US 2001/0025046, published September 27, 2001, of record); and Lin (US 6,720,002, published April 13, 2004, IDS reference filed July 19, 2012).
Lacy teaches drug delivery systems comprising a carrier for hydrophobic drugs inclusive of inter alia loratadine, the carrier comprises a digestible oil and a surfactant for dispersing the oil in vivo, and the surfactant comprises a hydrophilic surfactant having an HLB greater than 10 and a lipophilic surfactant having an HLB value below 10 (title; abstract; column 1, lines 4-7 and 27-43; column 3, lines 56-67; column 4, lines 20-25; column 10, lines 33-54; column 12, lines 18-21; claims), as required by instant claims 65 and 85. Digestible oils include medium chain triglycerides; triglycerides include capric and/or caprylic triglyceride oils such as Miglyol, Neobee, Captex 300 (glyceryl tricaprylate / caprate, HLB of about 11 as evidenced by page 6 of the instant specification), Captex 355 (glycerol caprylate caprate, HLB of about 11 as evidenced by page 6 of the instant specification) and Captex 8000 (column 8, lines 45-64; column 9, lines 20-28), as required by instant claims 64 and 84. Lipophilic surfactants include inter alia mono- and/or di-glycerides of fatty acids, e.g., Capmul MCM (glyceryl mono & dicaprate as evidenced by page 6 of the instant specification; HLB of about 5.5 as evidenced by paragraph [0035] of Ottinger) (column 4, lines 33-38 and 42-60; column 6, lines 11-14; claims 3-4), as required by instant claims 61, 63, 81 and 83. Hydrophilic surfactants include inter alia polyoxyethylene sorbitan fatty acid derivatives, e.g., Tween or/and alcohol ethoxylates (dispersant) (column 6, lines 63-65; column 7, lines 1-9 and 31-38; column 8, lines 12-13), as required by instant claims 65, 85 and 96. The relative proportions of the digestible oil, the hydrophilic surfactant and the lipophilic surfactant are not critical, however, the relative concentrations (based on the total amount of the digestible oil, the hydrophilic surfactant and the lipophilic surfactant) are (column 9, line 62 through column 10, line 32; claims 7 and 14):
PNG
media_image1.png
287
759
media_image1.png
Greyscale
, as required by instant claims 89, 90, 98, 99 and 101. Regarding the amount of surfactant (hydrophilic) of about 3.1 wt% required by claim 101, Lacy teaches a generally preferred range of 10 to 60 wt% which is broadly and reasonably construed as about 3.1 wt% because the qualifier about permits some tolerance and because the ranges of Lacy will shift to lower values based on the total composition further comprising inter alia hydrophobic drugs. The concentration of drug will be that which provides therapeutic effect, generally 0.1 to 50 wt% (column 12, lines 44-53; claim 1), as required by instant claim 101. The compositions may further comprise a hydrophilic solvent from 0.1 to 20 wt% (column 13, lines 47-57; claims 8-9). The compositions are liquid oral dosage forms, more preferably filled into hard or soft capsules, e.g., gelatin capsules (column 14, lines 4-12; claims 15-16). Lacy further teaches the carrier may be prepared by conventional techniques; typically the addition of the hydrophobic drug forms a homogenous solution (column 14, lines 13-33).
Regarding the desired result of immediate release of claims 46, 66 and 93, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. See MPEP 2111.04. However, Lacy, as a whole, is drawn to drug delivery systems which may be filled into hard or soft (soft gel) capsules. Therefore, it is presumed that the soft capsules of Lacy are also capable of immediate release as instantly claimed, absent evidence to the contrary.
Regarding the “consisting essentially of” transitional phrases of claim 93, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). See MPEP 2111.03 Transitional Phrases
Lacy does not teach povidone, wherein the weight ratio of the dispersant / povidone to surfactant(s) is about 1.75:1 to 2.5:1, wherein the formulation has a HLB from 3 to 6 as required by claims 46, 66.
Lacy does not teach povidone K-12, water in an amount from about 1 to 4 wt%, wherein the weight ratio of the povidone K-12 to surfactant(s) is about 1.75:1 to 2.5:1, wherein the formulation has a HLB from 3 to 6 as required by claim 93.
Lacy does not teach water as required by claims 47, 53, 67.
Lacy does not teach about 1 to 4 wt% water as required by claim 53.
Lacy does not teach about 6.3 wt% povidone as required by claim 101.
Lacy does not teach 10 mg loratadine as required by claim 102.
These deficiencies are made up for in the teachings of Shojaei, Agarwal, Liu and Lin.
Shojaei teaches a liquid formulation for a stabilized capsule for oral administration comprising a hydrophobic active agent inclusive of inter alia loratadine solubilized in a non-aqueous solubilizer inclusive of inter alia polyvinylpyrrolidone (povidone, dispersant) and at least one stabilizing agent selected from C8-C10 fatty acids, Labrasol®, Capmul MCM®, Captex 200®, Captex 300® or/and Miglyol® (title; abstract; column 2, lines 26-35 and 51-56; column 4, lines 9-14; column 7, lines 2 and 55-63; claims). The hydrophobic active is present from about 1 to 200 wt%, about 100 wt% with respect to the solubilizer (column 8, lines 7-17). The amount of solubilizer is not limited (column 3, lines 3-10). The solubilizer dissolves the hydrophobic active (paragraph bridging columns 2 and 3).
Agarwal teaches a drug-containing (micro)emulsion or a self-(micro)emulsifying oil composition comprising about 1 to 50 wt% drug and an oil phase comprising oils inclusive of mono-, di- and triglycerides inclusive of CAPTEX® and CAPMUL® (title; abstract; pages 2-3; page 11, lines 16-25; page 12, line 19 through page 13, line 3; page 13, line 26 through page 14, line 11; page 16, lines 23-32; claims). The (micro)emulsions require an emulsifying agent inclusive of Tween (page 13, lines 6-20; page 24, lines 10-15). Agarwal further teaches CAPTEX®, CAPMUL® and Tween as co-solvents; alternative co-solvents include inter alia PVP (polyvinylpyrrolidone) K12, K17, K30 or/and K90 (paragraph bridging pages 23-24). In an embodiment, the co-solvent is selected from Captex 355®, Capmul MCM®, PVP K12®, propylene glycol, and mixtures thereof (page 24, lines 5-7).
Liu teaches about 1 to 15 wt% water as a stabilizing component of a stabilized self-emulsifying system comprising a carrier comprising an oily component selected from the group inclusive of medium chain mono-, di- and triglycerides and at least one surfactant (title; abstract; paragraphs [0013], [0021], [0024], [0027], [0033]; Example 1; claims), as required by instant claims 47, 53 and 67. The presence of water will form reverse micelles with surfactants, for example, Tween 80 or Capmul MCM; hydrophilic impurities will be solubilized or portioned into the micelles (paragraph [0027]). The formulation of Example 1a comprises Captex 200, Capmul MCM and Tween 80 (paragraph [0043]).
Lin teaches soft gelatin capsule dosage forms comprising about 6.3 wt% loratadine and a solvent system having a HLB value of about 3 to 7 comprising a mixture of medium chain fatty acids; the soft capsule has a size of 5 minim or less and can accommodate 10 mg loratadine (title; abstract; column 3, lines 62-67; column 4, lines 34-40; paragraph bridging columns 5 and 6; claims, in particular, claims 15, 19), as required by instant claim 102. The composition may further comprise a dispersant comprising about 6.3 wt% povidone and comprising polysorbate 80 (column 2, line 56 through column 3, line 25; column 4, lines 13-27). The dispersant may further comprise polysorbate 80 (Tween); the mixtures of povidone and polysorbate can be present in a weight ratio of about 10:1 to 15:1 (column 2, lines 59-63; column 4, lines 12-27).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the drug / loratadine delivery systems of Lacy to further comprise a non-aqueous solubilizer inclusive of polyvinylpyrrolidone as taught by Shojaei in order to dissolve hydrophobic actives inclusive of loratadine in the carrier. There would be a reasonable expectation of success because the carrier of Lacy comprises oils inclusive of Captex and surfactants inclusive of Capmul and the solubilizer of Shojaei is taught to dissolve hydrophobic actives inclusive of loratadine in Capmul or/and Captex. Because Shojaei teach the hydrophobic active is present from about 1 to 200 wt%, about 100 wt% with respect to the solubilizer, it would have been obvious to one of ordinary skill in the art that the amount of the solubilizer is related to the amount of drug and one of ordinary skill in the art would be motivated to optimize within this range in order to achieve the expected result of drug dissolution. There would be a reasonable expectation of success because Lin teaches loratadine dosage forms comprising about 6.3 wt% loratadine and about 6.3 wt% povidone (polyvinylpyrrolidone) which means the loratadine is present at about 100 wt% with respect to the solubilizer. Regarding the ratio of the dispersant / povidone to surfactant, because the drug / loratadine delivery systems of Lacy may comprise 0.1 to 50 wt% drug / loratadine which means the polyvinylpyrrolidone solubilizer should also be present at 0.1 to 50 wt% when the loratadine is present at about 100 wt% with respect to the solubilizer as taught by Shojaei, the combined teachings of Lacy and Shojaei generally suggest the amount of hydrophilic surfactant will exceed the amount of polyvinylpyrrolidone, however, Lin teaches the amount of hydrophilic surfactant / Tween is generally less than the amount of povidone. Therefore, the prior art renders obvious a broad range for the relative amounts into which the instantly claimed amounts fall.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the PVP solubilizer of the drug / loratadine delivery systems of Lacy in view of Shojaei to comprise PVP K12, K17, K30 or/and K90 as taught by Agarwal because these species of PVP are art-recognized co-solvents for drugs in combination with inter alia Captex or/and Capmul.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the drug / loratadine delivery systems of Lacy in view of Shojaei, Agarwal and Lin to further comprise about 1 to 15 wt% water as taught by Liu as a stabilizing component. There would be reasonable expectation of success because the delivery systems of Lacy may further comprise a hydrophilic solvent in amounts from 0.1 to 20 wt% and water is a species falling within this genus.
With regard to the instantly claimed HLB of the formulation, because the combined teachings of the prior art render obvious formulations as instantly claimed, comprising overlapping amounts of the same ingredients as instantly claimed, the formulations of the prior art must also be characterized by an HLB as instantly claimed, absent evidence to the contrary. Additionally or/and alternatively, it would have been obvious to one of ordinary skill in the art at the time the invention was made to formulate the drug delivery system of modified Lacy to possess a HLB of about 3 to 7 as taught by Lin because this value is optimal for loratadine.
Regarding claim 102, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the amount of loratadine in the drug / loratadine delivery systems of Lacy in view of Shojaei, Agarwal, Lin and Liu to comprise about 10 mg as taught by Lin because this is the usual dosage for loratadine.
Claim 103 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lacy et al. (US 5,645,856, published July 8, 1997, of record) as evidenced by Ottinger (US 2007/0082016, of record) in view of Shojaei et al. (US 7,011,846, published March 14, 2006, of record); Agarwal et al. (WO 2010/030667, published March 18, 2010, of record); Liu et al. (US 2001/0025046, published September 27, 2001, of record); and Lin (US 6,720,002, published April 13, 2004, IDS reference filed July 19, 2012) as applied to claims 46, 47, 53, 61, 63-67, 81, 83-85, 89, 90, 93, 96, 98, 99, 101 and 102 above, and further in view of Iyer et al. (US 2004/0033257, published February 19, 2004, IDS reference filed July 19, 2012).
The teachings of Lacy, Shojaei, Agarwal, Lu and Lin have been described supra.
They do not teach a plasticizer as required by claim 103.
This deficiency is made up for in the teachings of Iyer.
The teachings of Iyer have been described supra. Iyer teaches a pharmaceutical formulation of a water insoluble drug that is loratadine encapsulated in a soft gelatin capsule; the loratadine is blended with a self-emulsifying drug delivery vehicle (abstract; paragraphs [0010] and [0020]). Iyer further teaches gelatin capsule formulations for soft gelatin capsules comprise gelatin and one or more plasticizers to adjust the hardness (paragraph [0031]), as required by instant claim 103.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the soft gelatin capsules of modified Lacy to further comprise one or more plasticizers as taught by Iyer in order to adjust the hardness of the capsules.
Response to Arguments: Claim Rejections - 35 USC § 103
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant’s statements at page 8 of the Remarks that there is no motivation to modify the compositions of Constantinides to have a HLB from 3 to 6 because Constantinides teaches the blend of low and high HLB surfactants will have an HLB of about 7 to about 15 at page 7, lines 9-10 has been carefully considered but is ultimately not found persuasive because (1) the qualifier about as employed by Constantinides permits some tolerance permitting values below 7 and (2) the w/o microemulsions of Constantinides further comprise at least medium-chain fatty acid triglyceride(s) and a hydrophilic phase. That is, the w/o microemulsions of Constantinides, to the limited extent a microemulsion per se can be characterized as having an HLB, have a HLB reflective of all of the ingredients thereof. This is important because the instantly claimed compositions also require at least medium-chain fatty acid triglyceride, PVP and optionally a hydrophilic phase (e.g., claim 47) and it is unorthodox to characterize such “complex” systems in accordance with the hydrophile-lipophile balance systems known to describe the disparate “parts” of surfactant molecules.
Applicant’s statements at pages 8-9 of the Remarks that there is no motivation to modify Constantinides to comprise loratadine remains unpersuasive for reasons of record. Applicant’s statements at page 9 that Constantinides discourages a hydrophobic drug because Constantinides wants to ensure the hydrophilic drug is dissolved in the hydrophilic phase is unpersuasive because it is expected that a hydrophilic drug will partition into the hydrophilic phase just as it is expected that a hydrophobic drug will partition into the hydrophobic phase. Please see at least Legen for the disclosure of hydrophobic drugs within microemulsions consistent with those of Constantinides. Applicant’s statements at pages 9-10 citing to MPEP 2141.02 remain unpersuasive because Constantinides does not in fact state anywhere within the four corners of the document that the w/o microemulsions cannot comprise a hydrophobic drug and because Constantinides very plainly discloses an embodiment of composition without the hydrophilic drug.
Applicant’s statements at page 10 that the modification of Constantinides to comprise hydrophobic loratadine render Constantinides inoperable remain unpersuasive for reasons of record because the entire purpose of the microemulsions of Constantinides is improved drug delivery (e.g., abstract). The principle of operation is not changed by the modification to include a drug.
Applicant’s statements at pages 10-11 that there is no motivation to modify Lacy to have a HLB from 3 to 6 are acknowledged but ultimately not found persuasive because the drug delivery systems of Lacy comprise overlapping amounts of the same ingredients as instantly claimed.
Applicant’s statements at pages 11-12 that Lacy fails to recognize problems associated with soft gel formulations and recrystallization and citation to Leo Pharmaceutical Products, Lt. v. Rae is unpersuasive because (1) the drug delivery systems of Lacy are intended to be filled into hard and soft capsules, (2) the instant specification at page 2 discloses recrystallization to be a potential problem caused by hydrophilic solvents and is not expected to be a problem associated with the hydrophobic solvents of the drug delivery systems of Lacy and (3) Lin evidences the combination of loratadine with a solvent system comprising a mixture of medium chain fatty acids solves the problem of “recrystallization and precipitation of loratadine” (Lin, column 2, lines 44-55). The citation to Leo is inapt because the prior art has already recognized and solved the problems identified by Applicant. Applicant’s further citation to a PTAB decision at page 12 is unpersuasive because Lacy expressly teaches loratadine. It does not matter that Lacy discloses long lists of actives because there is no need for motivation to select loratadine out the list. Rather, Lacy is in possession of a multitude of embodiments inclusive of those comprising loratadine.
Applicant’s statement at page 15 that the secondary references fail to recognize the problem of the present Application is unpersuasive because Lin recognizes the same problems.
Therefore, the rejections are properly maintained in modified form as necessitated by Applicant’s amendments.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Peresypkin et al. (US 2007/0298099) teaches improved solubility and bioavailability in a lipophilic vehicle comprising a surfactant having an HLB of 1 to 8, a surfactant having an HLB of 8 to 20 and optionally a digestible oil (title; abstract; claims; paragraph [0046]).
Gumkowski et al. (US 2006/0014788) teaches improved solubility and bioavailability in a lipophilic vehicle comprising a cosolvent, a surfactant having an HLB of 1 to 8, a surfactant having an HLB of 8 to 20 and optionally a digestible oil (title; abstract; claims; paragraphs [0064]-[0069]).
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 ALISSA PROSSER whose telephone number is (571)272-5164. The examiner can normally be reached M - Th, 10 am - 6 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, DAVID BLANCHARD can be reached on (571)272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALISSA PROSSER/
Examiner, Art Unit 1619
/BENNETT M CELSA/Primary Examiner, Art Unit 1600