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Patent Application 17338747 - DOSAGE FORM FOR NICOTINE REPLACEMENT THERAPY - Rejection

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Patent Application 17338747 - DOSAGE FORM FOR NICOTINE REPLACEMENT THERAPY

Title: DOSAGE FORM FOR NICOTINE REPLACEMENT THERAPY

Application Information

  • Invention Title: DOSAGE FORM FOR NICOTINE REPLACEMENT THERAPY
  • Application Number: 17338747
  • Submission Date: 2025-05-21T00:00:00.000Z
  • Effective Filing Date: 2021-06-04T00:00:00.000Z
  • Filing Date: 2021-06-04T00:00:00.000Z
  • National Class: 424
  • National Sub-Class: 465000
  • Examiner Employee Number: 85369
  • Art Unit: 1619
  • Tech Center: 1600

Rejection Summary

  • 102 Rejections: 0
  • 103 Rejections: 1

Cited Patents

No patents were cited in this rejection.

Office Action Text


    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 .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on May 09, 2024 are acknowledged and have been fully considered due to the entered request for continued examination. Claims 1-20 are pending. Claims 1-16 and 19-20 are under consideration in the instant office action. Claims 17-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Applicant’s claim amendments and arguments did not overcome the rejections under 35 USC 103 for reasons set forth in the previous office action and herein below.
Withdrawn Objection/Rejection
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.

The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary.  Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-16 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bunick et al. (EP2480215, previously cited), Al Husban et al. (US20190117577, previously cited), Chen (US 20130289079, previously cited).
Applicants’ claims
Applicant claims a tablet for intra-oral delivery of nicotine.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Bunick et al. teach in certain embodiments, the chewing includes at least two layers, e.g., with different types and/or concentrations of amorphous carbohydrate polymers and/or other ingredients or different concentrations of pharmaceutically active agents. Such an embodiment is shown in FIGS. 2A-2D. In one embodiment, the lozenge is a bilayer form; wherein the first layer is a lozenge form and the second layer is a orally disintegrating form. In one embodiment the first layer is a lozenge form and the second layer is a lozenge form. In one embodiment the lozenge form layer is free of a material that reacts to RF heating. In one embodiment, the lozenge form layer or the orally disintegrating form layer is first compressed as a layer, then the powder blend is added to the compressed lozenge or compressed orally disintegrating form layer and the entire form is energized utilizing the RF apparatus (paragraph 0093). In another embodiment, the lozenge product further includes a second layer which is not a lozenge layer (e.g., a layer having orally disintegrating properties). In such an embodiment, upon administration of such a lozenge product having an additional orally disintegrating layer, the orally disintegrating layer quickly disintegrates in the mouth of the user, leaving the lozenge product to be sucked on by the user. In one such embodiment, the orally disintegrating layer contains one pharmaceutically active agent (e.g., an analgesic, antihistamine, decongestant, cough suppressant, or expectorant) and the lozenge product either does not contain a pharmaceutically active agent or contains a different pharmaceutically active agent (e.g., menthol) (paragraph 0096). As discussed above, the lozenge shape is manufactured by forming a powder blend containing an amorphous carbohydrate polymer and optionally nicotine and/or other pharmaceutically active agent(s) and/or excipients. Examples of such excipients include, but are not limited to, glidants, lubricants, sweeteners, flavors and aromatics, enhancers, coloring agents, preservatives, vitamins, minerals, fluoride, and tooth whitening agents, and mixtures thereof. One or more of the above ingredients may be present on the same particle of the powder blend (paragraph 0010). Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof (paragraph 0011). Suitable glidants include, but are not limited to, colloidal silicon dioxide. Examples of sweeteners include, but are not limited to, synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, and stevside; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called laevulose), and lactose (also called milk sugar); isomalt, salts thereof, and mixtures thereof. Examples of flavors and aromatics include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit comprising mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, peppermint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana, in amounts not contributing significantly to the level of nicotine, and ginger (paragraphs 0012-0014). In one embodiment, the amount of amorphous carbohydrate polymer in the powder blend/lozenge shape/lozenge product is from about 50 percent to about 99.9 percent, by weight, such as from about 80 percent to about 95 percent by weight (paragraph 0017). In one embodiment, the powder blend/lozenge shape/lozenge product contains a smoking cessation compound(s) such as: nicotine and/or metabolites thereof, such as cotinine, etc., (paragraph 0019). In one embodiment, lozenge product includes the nicotine compound in an amount of from about 0.05 to about 12 mg calculated as the free base form of nicotine per lozenge product, such as from about 0.2-6 mg, such as from about 0.5-5 mg. This may in different embodiments include 0.05, 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 6, 7, 8, 9, 10, or 12 mg calculated as the free base form of nicotine per lozenge product (paragraph 0024). In one embodiment, the lozenge/powder blend/coating contains both nicotine and a buffering agent. In one embodiment, the lozenge is buffered such that upon administration of the lozenge, the pH of the saliva is transiently increased from about 0.2 to about 4 pH units, preferably from about 0.4 to about 2 pH units. The buffering is designed so as to achieve a transient buffering of the saliva of a subject during use of the lozenge product. As the change is transient, the pH will return to its normal value after a certain period of time (paragraph 0025). Examples of buffering agents include, but are not limited to, carbonates including carbonate, bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium or sodium, or ammonium such as trisodium or tripotassium citrate, trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, calcium hydroxide, sodium glycinate, and trometamol (TRIS). Alkali metal carbonates, glycinates and phosphates are preferred buffering agents (paragraph 0026). The pharmaceutically active agent may be present in various forms. For example, the pharmaceutically active agent may be dispersed at the molecular level, e.g. melted, within the lozenge product, or may be in the form of particles, which in turn may be coated or uncoated. If the pharmaceutically active agent is in form of particles, the particles (whether coated or uncoated) typically have an average particle size of from about 1 to about 2000 microns. In one embodiment, such particles are crystals having an average particle size of from about 1 to about 300 microns. In another embodiment, the particles are granules or pellets having an average particle size of from about 50 to about 2000 microns, such as from about 50 to about 1000 microns, such as from about 100 to about 800 microns (paragraph 0047). The pharmaceutically active agent may be present in pure crystal form or in a granulated form prior to the addition of the taste masking coating. Granulation techniques may be used to improve the flow characteristics or particle size of the pharmaceutically active agents to make it more suitable for compaction or subsequent coating. Suitable binders for making the granulation include but are not limited to starch, polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose (which is Hypromellose), and hydroxypropylcellulose. The particles including pharmaceutically active agent(s) may be made by cogranulating the pharmaceutically active agent(s) with suitable substrate particles via any of the granulation methods known in the art. Examples of such granulation method include, but are not limited to, high sheer wet granulation and fluid bed granulation such as rotary fluid bed granulation (paragraph 0048). In one embodiment, a lubricant is added to forming cavity prior to the addition of the flowable powder blend. This lubricant may be a liquid or solid. Suitable lubricants include but are not limited to solid lubricants such as magnesium stearate, starch, calcium stearate, aluminum stearate and stearic acid; or liquid lubricants such as but not limited to simethicone, lecithin, vegetable oil, olive oil, or mineral oil. In certain embodiments, the lubricant is added at a percentage by weight of the lozenge of less than 5 percent, e.g. less than 2 percent, e.g. less than 0.5 percent (paragraph 0076). In one embodiment, the nicotine compound and/or the pharmaceutically active agent is in the form of a gel bead, which is liquid filled or semi-solid filled. The gel bead(s) are added as a portion of the powder blend. In one embodiment, the lozenge product of this invention has the added advantage of not requiring a strong compaction step, allowing for the use of liquid or semisolid filled particles or beads which are deformable since they will not rupture following the reduced pressure compaction step. These bead walls may contain gelling substances such as: gelatin; gellan gum; xanthan gum; agar; locust bean gum; carrageenan; polymers or polysaccharides such as but not limited to sodium alginate, calcium alginate, hypromellose, hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches. The bead walls may further contain a plasticizer such as glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate and tributyl citrate. The pharmaceutically active agent may be dissolved, suspended or dispersed in a filler material such as but not limited to high fructose com syrup, sugars, glycerin, polyethylene glycol, propylene glycol, or oils such as but not limited to vegetable oil, olive oil, or mineral oil (paragraph 0091). Different bilayer tablet examples containing disintegrating layer and lozenge layer in mgs are taught in the examples.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Bunick et al.do not specifically teach the disintegration promoting excipients as recited in claim 5. This deficiency is cured by the teachings of Al Husban et al.
Al Husban et al. teach rapidly disintegrating oral dosage forms, more particularly to rapidly disintegrating tablets containing (1S ,2S ,3R,5S)-3-[7-{[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-55-(2-hydroxyethoxy)cyclopentane-1,2-diol and a disintegrating excipient, wherein the tablet has a hardness of from about 50 to about 150N and a disintegration time of less than about 3 minutes (see claim 1). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises a fast oral disintegrating excipient (claim 3). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises at least one carbohydrate filler and at least one disintegrant (claim 4). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose (claim 7).  The tablet according to claim 1, wherein the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet (claim 8). F-melt type C is the most preferred disintegrating excipient for use in the tablets of the invention. Thus, in one embodiment the at least one disintegrating excipient is a disintegrating excipient pre-mix comprising mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose. In a further embodiment, the at least one disintegrating excipient pre-mix comprises F-melt type C (paragraph 0027). The tablets of the invention should contain a sufficient amount of the at least one disintegrating excipient in order for the tablet to disintegrate within a sufficiently short time. However, the amount of the at least one disintegrating excipient must not be so high as to cause difficulties in the manufacture of the tablet in view of the adhesiveness and/or cohesiveness of ticagrelor. It has been surprisingly found that tablets of the invention in which the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet have an acceptable disintegration time (e.g. less than 3 minutes) while simultaneously allowing the adhesiveness and/or cohesiveness of ticagrelor to be adequately countered during the manufacture of the tablets. Thus, in a further embodiment, the at least one disintegrating excipient is a disintegrating excipient pre-mix present in an amount ranging from about 50% to about 80% by weight of the tablet (paragraph 0028).

Bunick et al. do not specifically teach the buffering agents and polymer matrix ratios as recited in claim 1 by amendment and do not teach nicotine polacrilex. These deficiencies cured by the teachings of Chen.
Chen teaches nicotine lozenge compositions comprising reduced levels of buffering agents from traditional nicotine lozenges and which provide optimal oral pH and prompt nicotine absorption in a smaller, more convenient dosage form (abstract).  An oral lozenge composition comprising: a) a master granule component comprising: at least one an alkaline buffering agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof; at least one dissolution modifier; and at least one diluent; and b) an extragranular component blended with the master granule component comprising nicotine polacrilex and at least one alkaline buffering agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof (claim 1). Alkaline buffering agents suitable for use in the present invention include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate. In one embodiment, the buffering agents are selected from potassium bicarbonate, sodium carbonate and mixtures thereof. The buffering agents are incorporated within the master granules as well as incorporated within the extra-granular space between said master granules. The total amount of buffer present in the compositions of the present invention is from about 5 mg to about 20 mg. In one embodiment the total amount of buffer present in the compositions of the present invention is from about 8 mg to about 12 mg. In one embodiment the ratio of nicotine polacrilex to total buffer is from about 3:1 to about 1:3 by total weight (paragraph 0025). As indicated above the alkaline buffering agents are incorporated both within the master granules (intragranular) and within the extragranular space between said master granules (extragranular). In general, the amount of buffering agent present in the compositions of the present invention, expressed as a ratio of intragranular buffering agent to extragranular buffering agent is from about 5:1 to about 1:5. In one embodiment, the ratio of intragranular buffering agent to extragranular buffering agent is about 1:1 (paragraph 0026). Dissolution modifiers suitable for use in the present invention include, but are not limited to, acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum and mixtures thereof. In one embodiment, the dissolution modifiers included within the formulations of the present invention are selected from the group consisting of alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum and mixtures thereof. In one embodiment, sodium alginate, calcium polycarbophil and xanthan gum are incorporated within the master granules of the present invention. The amount of dissolution modifier present in the master granules of the present invention is from about 10 mg to about 30 mg per lozenge, in another embodiment from about 15 mg to about 25 mg per lozenge (paragraph 0031). With regard to the amount of Hypromellose and xanthan gum one of ordinary skill in the art can easily calculate various ratios, for instance assuming Hypromellose is added in amount of about 10 mg to about 30 mg and xanthan gum is added in amounts of about 15 mg to about 25 mg, one can calculate 30/15 to 10/25 which is equivalent to 2:1 to 1:2.5 which will overlap with claimed amounts.

Finding of Prima Facie Obviousness Rational and Motivation 
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the before the effective filing date of the instant invention to modify the teachings of Bunick et al. by utilizing the disintegrating agent pre-mix as recited in claim 5 because Al Husban et al. teach rapidly disintegrating oral dosage forms, more particularly to rapidly disintegrating tablets containing (1S ,2S ,3R,5S)-3-[7-{[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-55-(2-hydroxyethoxy)cyclopentane-1,2-diol and a disintegrating excipient, wherein the tablet has a hardness of from about 50 to about 150N and a disintegration time of less than about 3 minutes (see claim 1). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises a fast oral disintegrating excipient (claim 3). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises at least one carbohydrate filler and at least one disintegrant (claim 4). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose (claim 7).  The tablet according to claim 1, wherein the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet (claim 8). F-melt type C is the most preferred disintegrating excipient for use in the tablets of the invention. Thus, in one embodiment the at least one disintegrating excipient is a disintegrating excipient pre-mix comprising mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose. In a further embodiment, the at least one disintegrating excipient pre-mix comprises F-melt type C (paragraph 0027). One of ordinary skill in the art would have been motivated to do so because Al Husban et al. teach that the tablets of the invention should contain a sufficient amount of the at least one disintegrating excipient in order for the tablet to disintegrate within a sufficiently short time. However, the amount of the at least one disintegrating excipient must not be so high as to cause difficulties in the manufacture of the tablet in view of the adhesiveness and/or cohesiveness of ticagrelor. It has been surprisingly found that tablets of the invention in which the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet have an acceptable disintegration time (e.g. less than 3 minutes) while simultaneously allowing the adhesiveness and/or cohesiveness of ticagrelor to be adequately countered during the manufacture of the tablets. Thus, in a further embodiment, the at least one disintegrating excipient is a disintegrating excipient pre-mix present in an amount ranging from about 50% to about 80% by weight of the tablet (paragraph 0028). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Bunick et al. and Al Husban et al. because both references teach orally fast disintegrating layers.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant inventionto modify the teachings of Bunick et al. by utilizing the buffering agents and polymeric matrixes in ratios as recited in claim 6 because Chen teaches nicotine lozenge compositions comprising reduced levels of buffering agents from traditional nicotine lozenges and which provide optimal oral pH and prompt nicotine absorption in a smaller, more convenient dosage form (abstract).  An oral lozenge composition comprising: a) a master granule component comprising: at least one an alkaline buffering agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof; at least one dissolution modifier; and at least one diluent; and b) an extragranular component blended with the master granule component comprising nicotine polacrilex and at least one alkaline buffering agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof (claim 1). Alkaline buffering agents suitable for use in the present invention include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate. In one embodiment, the buffering agents are selected from potassium bicarbonate, sodium carbonate and mixtures thereof. The buffering agents are incorporated within the master granules as well as incorporated within the extra-granular space between said master granules. The total amount of buffer present in the compositions of the present invention is from about 5 mg to about 20 mg. In one embodiment the total amount of buffer present in the compositions of the present invention is from about 8 mg to about 12 mg. In one embodiment the ratio of nicotine polacrilex to total buffer is from about 3:1 to about 1:3 by total weight (paragraph 0025). As indicated above the alkaline buffering agents are incorporated both within the master granules (intragranular) and within the extragranular space between said master granules (extragranular). In general, the amount of buffering agent present in the compositions of the present invention, expressed as a ratio of intragranular buffering agent to extragranular buffering agent is from about 5:1 to about 1:5. In one embodiment, the ratio of intragranular buffering agent to extragranular buffering agent is about 1:1 (paragraph 0026). Dissolution modifiers suitable for use in the present invention include, but are not limited to, acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum and mixtures thereof. In one embodiment, the dissolution modifiers included within the formulations of the present invention are selected from the group consisting of alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum and mixtures thereof. In one embodiment, sodium alginate, calcium polycarbophil and xanthan gum are incorporated within the master granules of the present invention. The amount of dissolution modifier present in the master granules of the present invention is from about 10 mg to about 30 mg per lozenge, in another embodiment from about 15 mg to about 25 mg per lozenge (paragraph 0031). It is within the purview of one of ordinary skill in the art to optimize any amounts or ratios as they are result effective parameters. If applicants resort to argue the reference does not provide any motivation to select this specific combination, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.”  KSR v.  Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.”  (Id.).  Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.”  KSR at 1741.  The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.”  Id. at 1742.  With regard to the amount of Hypromellose and xanthan gum one of ordinary skill in the art can easily calculate various ratios, for instance assuming Hypromellose is added in amount of about 10 mg to about 30 mg and xanthan gum is added in amounts of about 15 mg to about 25 mg, one can calculate 30/15 to 10/25 which is equivalent to 2:1 to 1:2.5 which will overlap with claimed amounts. Furthermore, in the case where the amount of ingredients, ratios, etc., "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). Similarly, 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)  Furthermore, differences in concentration or size will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Bunick et al. and Chen because both references teach lozenge compositions containing nicotine based compounds.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.  Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Applicant’s Arguments
Applicant argues the current Office Action merely summarizes the disclosures of Bunick and Chen and provides no analysis regarding motivation to combine to arrive at applicant’s claim. The Office Action provides no clear articulation of the reason(s) why the claimed invention would have been obvious. The Office Action fails to provide articulated reasoning with some rational underpinning to support the legal conclusion of obviousness. In view of the foregoing, Applicant respectfully submits that the Office Action does not establish a prima facie case of obviousness for claim 1. Applicant further submits that the subject matter of claim 1 is not obvious in view of the art of record and respectfully requests an indication that claim 115 1n condition for allowance.
The above assertions are not found persuasive in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.  See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).  In this case, the examiner indeed provided proper motivations and rationales why one of ordinary skill in the art would have been motivated to combine the references. Applicant failed to articulate or provide any reasons why those motivations and rationales provided by the examiner are not proper.
It would have been prima facie obvious to a person of ordinary skill in the before the effective filing date of the instant invention to modify the teachings of Bunick et al. by utilizing the disintegrating agent pre-mix as recited in claim 5 because Al Husban et al. teach rapidly disintegrating oral dosage forms, more particularly to rapidly disintegrating tablets containing (1S ,2S ,3R,5S)-3-[7-{[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-55-(2-hydroxyethoxy)cyclopentane-1,2-diol and a disintegrating excipient, wherein the tablet has a hardness of from about 50 to about 150N and a disintegration time of less than about 3 minutes (see claim 1). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises a fast oral disintegrating excipient (claim 3). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises at least one carbohydrate filler and at least one disintegrant (claim 4). The tablet according to claim 1, wherein the at least one disintegrating excipient comprises mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose (claim 7).  The tablet according to claim 1, wherein the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet (claim 8). F-melt type C is the most preferred disintegrating excipient for use in the tablets of the invention. Thus, in one embodiment the at least one disintegrating excipient is a disintegrating excipient pre-mix comprising mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose. In a further embodiment, the at least one disintegrating excipient pre-mix comprises F-melt type C (paragraph 0027). One of ordinary skill in the art would have been motivated to do so because Al Husban et al. teach that the tablets of the invention should contain a sufficient amount of the at least one disintegrating excipient in order for the tablet to disintegrate within a sufficiently short time. However, the amount of the at least one disintegrating excipient must not be so high as to cause difficulties in the manufacture of the tablet in view of the adhesiveness and/or cohesiveness of ticagrelor. It has been surprisingly found that tablets of the invention in which the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet have an acceptable disintegration time (e.g. less than 3 minutes) while simultaneously allowing the adhesiveness and/or cohesiveness of ticagrelor to be adequately countered during the manufacture of the tablets. Thus, in a further embodiment, the at least one disintegrating excipient is a disintegrating excipient pre-mix present in an amount ranging from about 50% to about 80% by weight of the tablet (paragraph 0028). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Bunick et al. and Al Husban et al. because both references teach orally fast disintegrating layers.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant inventionto modify the teachings of Bunick et al. by utilizing the buffering agents and polymeric matrixes in ratios as recited in claim 6 because Chen teaches nicotine lozenge compositions comprising reduced levels of buffering agents from traditional nicotine lozenges and which provide optimal oral pH and prompt nicotine absorption in a smaller, more convenient dosage form (abstract).  An oral lozenge composition comprising: a) a master granule component comprising: at least one an alkaline buffering agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof; at least one dissolution modifier; and at least one diluent; and b) an extragranular component blended with the master granule component comprising nicotine polacrilex and at least one alkaline buffering agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof (claim 1). Alkaline buffering agents suitable for use in the present invention include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate. In one embodiment, the buffering agents are selected from potassium bicarbonate, sodium carbonate and mixtures thereof. The buffering agents are incorporated within the master granules as well as incorporated within the extra-granular space between said master granules. The total amount of buffer present in the compositions of the present invention is from about 5 mg to about 20 mg. In one embodiment the total amount of buffer present in the compositions of the present invention is from about 8 mg to about 12 mg. In one embodiment the ratio of nicotine polacrilex to total buffer is from about 3:1 to about 1:3 by total weight (paragraph 0025). As indicated above the alkaline buffering agents are incorporated both within the master granules (intragranular) and within the extragranular space between said master granules (extragranular). In general, the amount of buffering agent present in the compositions of the present invention, expressed as a ratio of intragranular buffering agent to extragranular buffering agent is from about 5:1 to about 1:5. In one embodiment, the ratio of intragranular buffering agent to extragranular buffering agent is about 1:1 (paragraph 0026). Dissolution modifiers suitable for use in the present invention include, but are not limited to, acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum and mixtures thereof. In one embodiment, the dissolution modifiers included within the formulations of the present invention are selected from the group consisting of alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum and mixtures thereof. In one embodiment, sodium alginate, calcium polycarbophil and xanthan gum are incorporated within the master granules of the present invention. The amount of dissolution modifier present in the master granules of the present invention is from about 10 mg to about 30 mg per lozenge, in another embodiment from about 15 mg to about 25 mg per lozenge (paragraph 0031). With regard to the amount of Hypromellose and xanthan gum one of ordinary skill in the art can easily calculate various ratios, for instance assuming Hypromellose is added in amount of about 10 mg to about 30 mg and xanthan gum is added in amounts of about 15 mg to about 25 mg, one can calculate 30/15 to 10/25 which is equivalent to 2:1 to 1:2.5 which will overlap with claimed amounts. It is within the purview of one of ordinary skill in the art to optimize any amounts or ratios as they are result effective parameters. If applicants resort to argue the reference does not provide any motivation to select this specific combination, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.”  KSR v.  Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.”  (Id.).  Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.”  KSR at 1741.  The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.”  Id. at 1742.  Furthermore, in the case where the amount of ingredients, ratios, etc., "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). Similarly, 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)  Furthermore, differences in concentration or size will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Bunick et al. and Chen because both references teach lozenge compositions containing nicotine based compounds. 
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.

Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 TIGABU KASSA whose telephone number is (571)270-5867.  The examiner can normally be reached on 8 AM-5 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.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619


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