DETAILED ACTION
Claim Status
Claims 1-20 are under current Examination.
Notice of Pre-AIA or AIA Status
The present application is examined under the pre-AIA first to invent provisions.
Information Disclosure Statements
Information Disclosure Statement (IDS) filed on 01/19/2024 has been considered by the Examiner. A signed copy of the IDS is included with the present Office Action.
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, 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.
Claims 1-5 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Barcomb (EP0722720-IDS filed 1/19/24) in view of Irie et al. (WO 92/04888-IDS filed 1/19), Loftsson et al. (WO2003033025-see IDS filed 1/19) and Pitha et al. (United States Patent 4,877,774-see IDS filed 1/19/24)
Claim 1 is to a tablet for sublingual administration of a first active ingredient said tablet comprising a core, and an outer coating on the exterior surface of said tablet and optionally a separation coating that separates said outer coating from said core, wherein said outer coating comprises a mixture of - said first active ingredient in amorphous form in an amount of between about 0.1-10 mg; - a coating polymer in an amount of between about 0.25-25 mg; and - water in an amount of between about 0.0-10% w/w of the outer coating.
Barcomb teaches tablet compositions having a core the tablet comprises a sugar (i.e. sucrose sweetener) outer coating composition, in which the coating comprises a hormonal steroid and microcrystalline cellulose and polyvinyl pyrrolidone, see claims 1-3. The tablet core also comprises a medicinal agent that is conventionally used in conjunction with steroid hormones (i.e. second agent). The steroid hormone is present in an amount from 1-50 milligrams, see claim 9 and paragraph [0009]. The core can comprise conventional excipients including cellulose, see paragraph [0006]. The tablet can be formulated as an immediate release, see paragraph [0004]. The polyvinylpyrrolidone can comprise 0-5% by weight of the sugar coating, see claim 5. The range for steroid hormone is from 0.1-20% which Barcomb also teaches that 1-50mg of steroid is present. Therefore, since the polyvinylpyrrolidone encompasses about 0-5% by weight (i.e. weight=grams) of the coating (encompassing a weight of 0-5g which is a range from 0mg to 5000mg) the milligram amount is overlapping and thus renders obvious the claimed amounts. It is further obvious to adjust the amount of the polyvinylpyrrolidone coating because polyvinylpyrrolidone is suggested to contribute to the rate controlling properties of the sugar coating, see paragraph [0007]. The core can comprise calcium phosphate (inorganic salt), see paragraph [0006]. The hormonal steroid of Barcomb comprises testosterone, see claim 3. In embodiments where rapid administration is desired Barcomb suggests that the sugar coatings are absent microcrystalline cellulose, per examples 1-3.
Barcomb does not expressly teach that the active agent testosterone is in amorphous form, the inclusion of about 0.25-25mg of cyclodextrin with the outer coating, or sublingual administration.
However, Irie et al. teach that amorphous complexes of lipophilic substances with cyclodextrin provide improved water solubility and enhanced stability, see page 5, lines 1-25 and page 6 at lines 31-33 to page 7, lines 1-3. Examples of the lipophilic substance include testosterone, see page 9, lines 8-18.
Irie does not expressly teach that the cyclodextrin is from 0.25-25mg.
Loftsson et al. tech that combining cyclodextrin with poorly soluble drugs at 0.1-80% w/v cyclodextrin, see abstract and page 7, lines 21-28 and page 8, lines 1-25 . A 1% w/v is equal to 10mg per L. The drug includes testosterone, see page 20, line 11. According to Loftsson, amorphous complexes of poorly soluble drugs with cyclodextrin provides improved water stability, see pages 1-9 and 25-26
Pitha suggests that providing amorphous forms of the testosterone was known to an ordinary skilled artisan to provide absorption of steroid hormones from the oral cavity as the amorphous form enables direct absorption in the oral cavity, see column 60-68. According to Pitha, direct absorption is desirable since the hormone is less subject to rapid metabolism by the portal vein-liver system and relatively long periods of hormone levels in circulation may be obtained in this manner. By sublingual administration, rapid dissolution of steroid hormones permits efficient absorption in the bloodstream and permits bypassing of the portal vein system which is highly desirable to provide long periods of hormone levels in circulation, see column 2, lines 56-68 to column 3, lines 1-6. The use of amorphous hydrophilic cyclodextrins gives good results for solubilization of steroid hormones, a step which appears to be crucial for their absorption by tissues. Oral administration of steroids is complicated by their lack of solubility which delays absorption until they reach the lower GI tract. Thus Pita teaches it is advantageous to complex poorly soluble steroids with cyclodextrin to avoid the first pass effect, see column 2, lines 56-68 to column 3, lines 1-15.
Accordingly, it would have been prima facie obvious to administer the steroid hormone of Barcomb’s disclosed coating composition sublingually as an amorphous form complexed to cyclodextrin to improve solubility and stability of the formulation and provide direct absorption in the oral cavity of the steroid hormone while permitting efficient absorption in the bloodstream and bypassing of the portal vein system which is highly desirable to provide long periods of hormone levels in circulation. Loftsson teaches that such as complex of poorly soluble drugs to cyclodextrin can be achieved at a range which is about 0.1-80% w/v and is inclusive of 10mg cyclodextrin and an ordinary skilled artisan would have been motivated to adjust the concentration of cyclodextrin to achieve the desired dissolution and absorption of the testosterone.
There would have been a reasonable expectation of success given Irie, Pitha and Barcomb teach the administration of steroid hormones.
Claims 7-14 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Barcomb (EP0722720B1) in view of Irie et al. (WO 92/04888), Loftsson et al. (WO2003033025) and Pitha et al. (United States Patent 4,877,774) as applied to claims 1-5 above and further in view of Penhasi et al. (United States Patent Publication 20020110593-see IDS filed 1/19) as evidenced by Dharmadhikari et al. (United States Patent Publication 2008/0213381-see IDS filed 1/19).
The teachings of the modified Barcomb are discussed above.
The modified Barcomb does not expressly teach a separation coating that comprises an enteric coating or a hydrophilic and hydrophobic polymer, and that the second active is selected from the group consisting of a phosphodiesterase type 5 (PDE5) inhibitor, a 5- hydroxytryptamine lA (5HT1A} receptor agonist, and a neutral endopeptidase (NEP) inhibitor (per instant claims 6 and 8-15).
However, Penhasi discloses: two pulse gastrointestinal drug delivery systems:
The system comprises a desired agent in combination with a swellable core material, the core being surrounded by an inner coat of a water-insoluble or relatively water-insoluble coating material in which particulate water-insoluble material is embedded. The inner coat is additionally surrounded by an outer coat that contains additional amounts of the desired agent. When the delivery device enters the gastrointestinal tract, the outer coat releases the desired agent contained therein and disintegrates, exposing the inner coat. The particulate matter in the inner coat takes up liquid, thus forming channels interconnecting the drug-containing core with the outside of the delivery device. Through these channels liquid enters the core which then swells to the point at which the inner coat is broken. When the integrity of the inner coat is destroyed, the core then disintegrates, immediately releasing all or most of the drug at a specific site. By controlling parameters in the device, such as the core material, carrier material in the coating, and particulate matter, the location of release of both pulses of the drug can be carefully controlled. (see abstract).
Penhasi also discloses [0152] the composition can further contain menthol (flavor, instant claims 6 ), 5HT1A 5-hydroxytryptamine 1A receptor agonist (ie, gepiron), and steroid hormone, see paragraphs [0069], [0136], [0152] and claim 54. Penhasi discloses the outer coating can mask the taste, see paragraph [0027]. Penhasi discloses in pulsatile delivery systems the pulses are separated by a film layer of an enteric coating at 4-15% weight percent of the core, see paragraph [0015]. Eudragit is used as a preferable enteric coat, see paragraph [0124]. The inner (i.e. separation) coating can comprise a hydrophobic polymer and hydrophilic substance, see paragraph [0095]. The combination allows the entry of liquid into the core in a controlled fashion by means of channels, see paragraphs [0095]-[0099]. The polymers which are useful in the inner coating can comprise Eudragit RL, see paragraph [0096] which as evidenced by Dharmadhikari et al. it is a pH independent polymer, see paragraph [0080] of Dharmadhikari et al. Examples of the therapeutic agents of the dosage form includes steroid hormones, see claim 28 and paragraph [0152].
It would have been prima facie obvious to one of ordinary skill in the art to modify the tablet of Barcomb by utilizing a polymer providing an inner (i.e. separation) enteric coating as suggested by Penhasi in order to delay release of the drug from the core. Such delayed release can be accomplished with various coatings (i.e. pH independent, enteric and hydrophobic polymer/hydrophilic substances) as suggested by Penhasi.
There would have been a reasonable expectation of success given both Barcomb and Penhasi teach dosage forms comprising steroid hormones.
Regarding the fact the core and the separation volume is between 50-1000m3, since the separation (i.e. inner coatings) are taught by Penhasi function to delay the release of the drug from the core, it would have been obvious to an ordinary skilled artisan to adjust the core and separation coating volume such that increasing the volume would result in longer delayed release of the compounds located in the core, and a smaller volume and separation layer would result in a faster delayed release of the compounds located in the core.
In light of the foregoing discussion, the claimed subject matter would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of skill in the art at the time the claimed invention was made, as evidenced by the references.
Claims 15-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Barcomb (EP0722720-IDS filed 1/19) in view of Irie et al. (WO 92/04888-IDS filed 1/19), Loftsson et al. (WO2003033025-see IDS) and Pitha et al. (United States Patent 4,877,774-see IDS) and Penhasi et al. (United States Patent Publication 20020110593-see IDS) as evidenced by Dharmadhikari et al. (United States Patent Publication 2008/0213381-see IDS).
Barcomb teaches tablet compositions having a core the tablet comprises a sugar (i.e. sucrose sweetener) outer coating composition, in which the coating comprises a hormonal steroid and microcrystalline cellulose and polyvinyl pyrrolidone, see claims 1-3. The tablet core also comprises a medicinal agent that is conventionally used in conjunction with steroid hormones (i.e. second agent). The steroid hormone is present in an amount from 1-50 milligrams, see claim 9 and paragraph [0009]. The core can comprise conventional excipients including cellulose, see paragraph [0006]. The tablet can be formulated as an immediate release, see paragraph [0004]. The polyvinylpyrrolidone can comprise 0-5% by weight of the sugar coating, see claim 5. The range for steroid hormone is from 0.1-20% which Barcomb also teaches that 1-50mg of steroid is present. Therefore, since the polyvinylpyrrolidone encompasses about 0-5% by weight (i.e. weight=grams) of the coating (encompassing a weight of 0-5g which is a range from 0mg to 5000mg) the milligram amount is overlapping the claimed range. It is further obvious to adjust the amount of the polyvinylpyrrolidone coating because polyvinylpyrrolidone is suggested to contribute to the rate controlling properties of the sugar coating, see paragraph [0007]. The core can comprise calcium phosphate (inorganic salt), see paragraph [0006]. The hormonal steroid of Barcomb comprises testosterone, see claim 3. In embodiments where rapid administration is desired Barcomb suggests that the sugar coatings are absent microcrystalline cellulose, per examples 1-3.
Barcomb does not expressly teach that the active agent testosterone is in amorphous form, the inclusion of about 0.25-25mg of cyclodextrin with the outer coating, or sublingual administration.
However, Irie et al. teach that amorphous complexes of lipophilic substances with cyclodextrin provide improved water solubility and enhanced stability, see page 5, lines 1-25 and page 6 at lines 31-33 to page 7, lines 1-3. Examples of the lipophilic substance include testosterone, see page 9, lines 8-18.
Irie does not expressly teach that the cyclodextrin is from 0.25-25mg.
Loftsson et al. tech that combining cyclodextrin with poorly soluble drugs at 0.1-80% w/v cyclodextrin, see abstract and page 7, lines 21-28 and page 8, lines 1-25 . A 1% w/v is equal to 10mg per L. The drug includes testosterone, see page 20, line 11. According to Loftsson, amorphous complexes of poorly soluble drugs with cyclodextrin provides improved water stability, see pages 1-9 and 25-26
Pitha suggests that providing amorphous forms of the testosterone was known to an ordinary skilled artisan to provide absorption of steroid hormones from the oral cavity as the amorphous form enables direct absorption in the oral cavity, see column 60-68. According to Pitha, direct absorption is desirable since the hormone is less subject to rapid metabolism by the portal vein-liver system and relatively long periods of hormone levels in circulation may be obtained in this manner. By sublingual administration, rapid dissolution of steroid hormones permits efficient absorption in the bloodstream and permits bypassing of the portal vein system which is highly desirable to provide long periods of hormone levels in circulation, see column 2, lines 56-68 to column 3, lines 1-6. The use of amorphous hydrophilic cyclodextrins gives good results for solubilization of steroid hormones, a step which appears to be crucial for their absorption by tissues. Oral administration of steroids is complicated by their lack of solubility which delays absorption until they reach the lower GI tract. Thus Pita teaches it is advantageous to complex poorly soluble steroids with cyclodextrin to avoid the first pass effect, see column 2, lines 56-68 to column 3, lines 1-15.
Accordingly, it would have been prima facie obvious to administer the steroid hormone of Barcomb’s disclosed coating composition sublingually as an amorphous form complexed to cyclodextrin to improve solubility and stability of the formulation and provide direct absorption in the oral cavity of the steroid hormone while permitting efficient absorption in the bloodstream and bypassing of the portal vein system which is highly desirable to provide long periods of hormone levels in circulation. Loftsson teaches that such as complex of poorly soluble drugs to cyclodextrin can be achieved at a range which is about 0.1-80% w/v and is inclusive of 10mg cyclodextrin and an ordinary skilled artisan would have been motivated to adjust the concentration of cyclodextrin to achieve the desired dissolution and absorption of the testosterone.
There would have been a reasonable expectation of success given Irie, Pitha and Barcomb teach the administration of steroid hormones.
Neither Barcomb, Irie et al. nor Loftsson et al. expressly teach a separation coating that comprises an enteric coating or a hydrophilic and hydrophobic polymer, and that the second active is selected from the group consisting of a phosphodiesterase type 5 (PDE5) inhibitor, a 5- hydroxytryptamine lA (5HT1A} receptor agonist, and a neutral endopeptidase (NEP) inhibitor (per instant claims 6 and 8-15).
However, Penhasi discloses: two pulse gastrointestinal drug delivery systems:
The system comprises a desired agent in combination with a swellable core material, the core being surrounded by an inner coat of a water-insoluble or relatively water-insoluble coating material in which particulate water-insoluble material is embedded. The inner coat is additionally surrounded by an outer coat that contains additional amounts of the desired agent. When the delivery device enters the gastrointestinal tract, the outer coat releases the desired agent contained therein and disintegrates, exposing the inner coat. The particulate matter in the inner coat takes up liquid, thus forming channels interconnecting the drug-containing core with the outside of the delivery device. Through these channels liquid enters the core which then swells to the point at which the inner coat is broken. When the integrity of the inner coat is destroyed, the core then disintegrates, immediately releasing all or most of the drug at a specific site. By controlling parameters in the device, such as the core material, carrier material in the coating, and particulate matter, the location of release of both pulses of the drug can be carefully controlled. (see abstract).
Penhasi also discloses [0152] the composition can further contain menthol (flavor, instant claims 6 ), 5HT1A 5-hydroxytryptamine 1A receptor agonist (ie, gepiron), and steroid hormone, see paragraphs [0069], [0136], [0152] and claim 54. Penhasi discloses the outer coating can mask the taste, see paragraph [0027]. Penhasi discloses in pulsatile delivery systems the pulses are separated by a film layer of an enteric coating at 4-15% weight percent of the core, see paragraph [0015]. Eudragit is used as a preferable enteric coat, see paragraph [0124]. The inner (i.e. separation) coating can comprise a hydrophobic polymer and hydrophilic substance, see paragraph [0095]. The combination allows the entry of liquid into the core in a controlled fashion by means of channels, see paragraphs [0095]-[0099]. The polymers which are useful in the inner coating can comprise Eudragit RL, see paragraph [0096] which as evidenced by Dharmadhikari et al. it is a pH independent polymer, see paragraph [0080] of Dharmadhikari et al. Examples of the therapeutic agents of the dosage form includes steroid hormones, see claim 28 and paragraph [0152].
It would have been prima facie obvious to one of ordinary skill in the art to modify the tablet of Barcomb by utilizing a polymer providing an inner (i.e. separation) enteric coating as suggested by Penhasi in order to delay release of the drug from the core. Such delayed release can be accomplished with various coatings (i.e. pH independent, enteric and hydrophobic polymer/hydrophilic substances) as suggested by Penhasi.
There would have been a reasonable expectation of success given both Barcomb and Penhasi teach dosage forms comprising steroid hormones.
Regarding the fact the core and the separation volume is between 50-1000m3, since the separation (i.e. inner coatings) are taught by Penhasi function to delay the release of the drug from the core, it would have been obvious to an ordinary skilled artisan to adjust the core and separation coating volume such that increasing the volume would result in longer delayed release of the compounds located in the core, and a smaller volume and separation layer would result in a faster delayed release of the compounds located in the core.
In light of the foregoing discussion, the claimed subject matter would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of skill in the art at the time the claimed invention was made, as evidenced by the references.
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 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No.10,966,933 (hereafter Patent ‘933).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Both the instant claims and that of U.S. Patent ‘933 claim tablets for sublingual administration having a first active ingredient including testosterone, a core, and an outer coating with optionally a separation coating. The outer coating contains a mixture of a first active ingredient in amorphous form in an amount between 0.1-10mg, a coating polymer in an amount of from 0.25-25mg and water present from 0-10% by weight. The outer coating can comprise cyclodextrin or polyvinylpyrrolidone present between 0.25-25mg. The outer coating in both the instant claims and that of Patent ‘933 includes 1.34mg of hydroxypropylmethylcelluose, 2.66mg of hydroxypropyl beta-cyclodextrin, 1mg of aspartame and 0.6mg menthol. The separation coating of both the instant claims and that of Patent ‘933 is present from 50-1000mm3 and is an acid soluble, pH independent or enteric coating. The core of both the instant claims and that of Patent ‘933 contains cellulose, inorganic salt filler and a second active agent wherein the second agent is a PDE5 inhibitor, SHTIA receptor agonist or neutral endopeptidase inhibitor. The difference between the instant claims and that of Patent ‘933 is that the instant claims are broader, however Patent ‘933 claims render obvious and arrive at the instantly claimed formulation, and thus the instant claims are obvious over the claims of Patent ‘933.
Accordingly, claims 1-20 are rejected on the ground of nonstatutory double patenting.
Claims 1-5 and 7-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 U.S. Patent No. 9763884 (hereafter ‘3884) in view Barcomb (EP0722720) in view of Irie et al. (WO 92/04888), Loftsson et al. (WO2003033025), Pitha et al. (United States Patent 4,877,774) and Penhasi et al. (United States Patent Publication 20020110593) as evidenced by Dharmadhikari et al. (United States Patent Publication 2008/0213381).
The instant claims are directed to a tablet comprising a core, outer coating, optionally a separation coating where the outer coating comprises testosterone in amorphous form from 0.1-10mg, a coating polymer from 0.25-25mg, water inclusive of 0-10% of the outer coating and a cyclodextrin from 0.25-25mg.
Patent ‘3884 recites a sublingual drug delivery comprising a core , and a second coating that is the outer coating of testosterone and cyclodextrin. The second coating polymer of HPMC can comprise 1-2mg with the cyclodextrin at 2-3.5mg and 0.1-1mg of testosterone, see claim 2. The coating that surrounds the core can comprise cellulose and the core can comprise a PDE5 inhibitor, see claim 7.
The difference between the instant claims and that of Patent ‘3884 is that the outer coating can further comprise flavor or sweetener and that the testosterone is amorphous form wherein the separation coating (i.e. second layer) has a volume from 50-1000mm, wherein the separation layer is enteric or acid soluble and wherein the formulation is a tablet.
Barcomb teaches tablet compositions having a core the tablet comprises a sugar (i.e. sucrose sweetener) outer coating composition, in which the coating comprises a hormonal steroid and microcrystalline cellulose and polyvinyl pyrrolidone, see claims 1-3. The tablet core also comprises a medicinal agent that is conventionally used in conjunction with steroid hormones (i.e. second agent). The steroid hormone is present in an amount from 1-50 milligrams, see claim 9 and paragraph [0009]. The core can comprise conventional excipients including cellulose, see paragraph [0006]. The tablet can be formulated as an immediate release, see paragraph [0004]. The polyvinylpyrrolidone can comprise 0-5% by weight of the sugar coating, see claim 5. The range for steroid hormone is from 0.1-20% which Barcomb also teaches that 1-50mg of steroid is present. Therefore, since the polyvinylpyrrolidone encompasses about 0-5% by weight (i.e. weight=grams) of the coating (encompassing a weight of 0-5g which is a range from 0mg to 5000mg) the milligram amount is overlapping the claimed range. It is further obvious to adjust the amount of the polyvinylpyrrolidone coating because polyvinylpyrrolidone is suggested to contribute to the rate controlling properties of the sugar coating, see paragraph [0007]. The core can comprise calcium phosphate (inorganic salt), see paragraph [0006]. The hormonal steroid of Barcomb comprises testosterone, see claim 3. In embodiments where rapid administration is desired Barcomb suggests that the sugar coatings are absent microcrystalline cellulose, per examples 1-3.
Irie et al. teach that amorphous complexes of lipophilic substances with cyclodextrin provide improved water solubility and enhanced stability, see page 5, lines 1-25 and page 6 at lines 31-33 to page 7, lines 1-3. Examples of the lipophilic substance include testosterone, see page 9, lines 8-18.
Irie does not expressly teach that the cyclodextrin is from 0.25-25mg.
Loftsson et al. tech that combining cyclodextrin with poorly soluble drugs at 0.1-80% w/v cyclodextrin, see abstract and page 7, lines 21-28 and page 8, lines 1-25 . A 1% w/v is equal to 10mg per L. The drug includes testosterone, see page 20, line 11. According to Loftsson, amorphous complexes of poorly soluble drugs with cyclodextrin provides improved water stability, see pages 1-9 and 25-26
Pitha suggests that providing amorphous forms of the testosterone was known to an ordinary skilled artisan to provide absorption of steroid hormones from the oral cavity as the amorphous form enables direct absorption in the oral cavity, see column 60-68. According to Pitha, direct absorption is desirable since the hormone is less subject to rapid metabolism by the portal vein-liver system and relatively long periods of hormone levels in circulation may be obtained in this manner. By sublingual administration, rapid dissolution of steroid hormones permits efficient absorption in the bloodstream and permits bypassing of the portal vein system which is highly desirable to provide long periods of hormone levels in circulation, see column 2, lines 56-68 to column 3, lines 1-6. The use of amorphous hydrophilic cyclodextrins gives good results for solubilization of steroid hormones, a step which appears to be crucial for their absorption by tissues. Oral administration of steroids is complicated by their lack of solubility which delays absorption until they reach the lower GI tract. Thus Pita teaches it is advantageous to complex poorly soluble steroids with cyclodextrin to avoid the first pass effect, see column 2, lines 56-68 to column 3, lines 1-15.
Penhasi also discloses [0152] the composition can further contain menthol (flavor, instant claims 6 ), 5HT1A 5-hydroxytryptamine 1A receptor agonist (ie, gepiron), and steroid hormone, see paragraphs [0069], [0136], [0152] and claim 54. Penhasi discloses the outer coating can mask the taste, see paragraph [0027]. Penhasi discloses in pulsatile delivery systems the pulses are separated by a film layer of an enteric coating at 4-15% weight percent of the core, see paragraph [0015]. Eudragit is used as a preferable enteric coat, see paragraph [0124]. The inner (i.e. separation) coating can comprise a hydrophobic polymer and hydrophilic substance, see paragraph [0095]. The combination allows the entry of liquid into the core in a controlled fashion by means of channels, see paragraphs [0095]-[0099]. The polymers which are useful in the inner coating can comprise Eudragit RL, see paragraph [0096] which as evidenced by Dharmadhikari et al. is a pH independent polymer, see paragraph [0080] of Dharmadhikari et al. Examples of the therapeutic agents of the dosage form includes steroid hormones, see claim 28 and paragraph [0152].
Accordingly, it would have been obvious to administer the steroid hormone of the instantly claimed coating composition sublingually for Patent ‘3884 as an amorphous form complexed to cyclodextrin to improve solubility and stability of the formulation and provide direct absorption in the oral cavity of the steroid hormone while permitting efficient absorption in the bloodstream and bypassing of the portal vein system which is highly desirable to provide long periods of hormone levels in circulation. Loftsson teaches that such as complex of poorly soluble drugs to cyclodextrin can be achieved at a range which is about 0.1-80% w/v and is inclusive of 10mg cyclodextrin and an ordinary skilled artisan would have been motivated to adjust the concentration of cyclodextrin to achieve the desired dissolution and absorption of the testosterone. Furthermore, it would have been obvious to administer a sucrose sweetener with the table in order in improve the sweet taste of the tablet. It would have further been obvious to provide the claims of Patent ‘3884 with a sweetener to impart the desired sweetness to a tablet formulation.
Regarding the fact the core and the separation volume is between 50-1000m3, since the separation (i.e. inner coatings) are taught by Penhasi function to delay the release of the drug from the core, it would have been obvious to an ordinary skilled artisan to adjust the core and separation coating volume of the first layer of Patent ‘3884 such that increasing the volume would result in longer delayed release of the compounds located in the core, and a smaller volume and separation layer would result in a faster delayed release of the compounds located in the core.
It would have been prima facie obvious to one of ordinary skill in the art to modify the drug formulation of Patent ‘3884 by utilizing a polymer providing an inner (i.e. separation) enteric coating as suggested by Penhasi in order to delay release of the drug from the core. Such delayed release can be accomplished with various coatings (i.e. pH independent, enteric and hydrophobic polymer/hydrophilic substances) as suggested by Penhasi.
Conclusion
Currently, no claims are allowed and all claims are rejected.
Correspondence
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/SARAH ALAWADI/Primary Examiner, Art Unit 1619