DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 18 November 2025 has been entered.
Formal Matters
Applicant’s claim amendments and arguments filed on 18 November 2025 are acknowledged and have been fully considered due to the entered request for continued examination. Claims 42-51, 53, 55-57, 59, 62, and 64-69 are pending. Claims 42-51, 53, 55-57, 59, 62, and 64-69 are under consideration in the instant office action. Claims 1-41, 52, 54, 58, 60-61, 6and 63 are canceled. Applicant amended claims 42, 51, 53, and 55-57. Applicant’s claim amendments and arguments did not overcome the rejections under 35 USC 103 (a) as set forth in the previous office action for reasons set forth in the previous office action and herein below.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections-Maintained and Restructured with the same references
Claim Rejections - 35 USC § 103
The following is a quotation of 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 through 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 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 42-51, 53, 55-57, 59, 62, and 64-69 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Pfeffer et al. (US 2006/0210627, IDS reference), Thomas et al. (The Journal of Pharmacology and Experimental Therapeutics, 325(1), 175-182, 2008, IDS reference), Manuchehri (WO 2008/055940, IDS reference), Dugi et al. (US 20070281940, IDS reference), and Kohlrausch et al. (US 2008/0107731, IDS reference).
Note: All references have been provided by the examiner in the prosecution history of the parent application 15/846,897 and are cited in the instant application in the IDSs of June 20, 2024.
Note: Claims are examined with respect to the elected species only.
Applicant Claims
Applicant claims a solid pharmaceutical dosage form for oral administration comprising the components as recited in claim 42 and other dependent claims.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Pfeffer et al. teach tablets formed by direct compression of a dipeptidylpeptidase IV (DPP-IV) inhibitor compound, a process for the preparation thereof, to new pharmaceutical formulations, and new tableting powders comprising DPP-IV inhibitor formulations capable of being directly compressed into tablets. Pfeffer et al. teach further to a process for preparing the tablets by blending the active ingredient and specific excipients into the new formulations and then directly compressing the formulations into the direct compression tablets. Pfeffer et al. teach also vildagliptin particle size distribution and a new crystal form of vildagliptin particularly adapted for the preparation of improved tablets and other pharmaceutical compositions (see abstract). Pfeffer et al. teach in a first embodiment, a pharmaceutical composition comprising a DPP-IV inhibitor in free form or in acid addition salt form, preferably LAF237 a pharmaceutically acceptable diluent, wherein in the unit dosage form, the weight of DPP-IV inhibitor preferably LAF237 (also known as vildagliptin) (see paragraph 0014) on a dry weight basis to tablet weight of diluent ratio is of 0.5 to 0.25, preferably 0.4 to 0.28 (paragraph 0101-0103). One, two, three or more diluents can be selected. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc (paragraph 0094).
Pfeffer et al. teach on paragraphs 0118-0122 that in a further embodiment, a pharmaceutical composition comprising; (a) 5-60% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form, preferably LAF237; (b) 40-95% by weight on a dry weight basis of a pharmaceutically acceptable diluent; (c) 0-20% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant; and optionally (d) 0.1-10% by weight on a dry weight basis of a pharmaceutically acceptable lubricant. A pharmaceutical composition comprising; (a) 5-60% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form; (b) 40-95% by weight on a dry weight basis of a pharmaceutically acceptable diluent; (c) 0-20% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant; and optionally (d) 0.1-10% by weight on a dry weight basis of a pharmaceutically acceptable lubricant (see claim 1). Other conventional solid fillers or carriers, such as, cornstarch, calcium phosphate, calcium sulfate, calcium stearate, magnesium stearate, stearic acid, glyceryl mono- and distearate, sorbitol, mannitol, gelatin, natural or synthetic gums, such as carboxymethyl cellulose, methyl cellulose, alginate, dextran, acacia gum, karaya gum, locust bean gum, tragacanth and the like, diluents, binders, lubricants, disintegrators, coloring and flavoring agents could optionally be employed (paragraph 0098). Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, e.g., microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder, e.g., may be present in an amount from about 10% to about 40% by weight of the composition (paragraph 0099). In addition to the active ingredient, the tableting powder contains a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet. The primary composition includes fillers, binders or diluents, lubricants, disintegrants and glidants (paragraph 0092). One, two, three or more diluents can be selected. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc (paragraph 0094). One, two, three or more disintegrants can be selected. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose; soy polysaccharides; and guar gum. The disintegrant, e.g., may be present in an amount from about 2% to about 20%, e.g., from about 5% to about 10%, e.g., about 7% about by weight of the composition (paragraph 0096). One, two, three or more lubricants can be selected. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant, e.g., may be present in an amount from about 0.1% to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0.1% to about 10% by weight. The lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants include stearic acid, talc and magnesium stearate (paragraph 0097). Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, e.g., microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder, e.g., may be present in an amount from about 10% to about 40% by weight of the composition (paragraph 0099). Other conventional solid fillers or carriers, such as, cornstarch, calcium phosphate, calcium sulfate, calcium stearate, magnesium stearate, stearic acid, glyceryl mono- and distearate, sorbitol, mannitol, gelatin, natural or synthetic gums, such as carboxymethyl cellulose, methyl cellulose, alginate, dextran, acacia gum, karaya gum, locust bean gum, tragacanth and the like, diluents, binders, lubricants, disintegrators, coloring and flavoring agents could optionally be employed (paragraph 0098). Tablets may be coated or uncoated and are made from powdered, crystalline materials (paragraph 0060). Tablets may be plain, film or sugar coated bisected, embossed, layered or sustained-release (paragraph 0062).
Pfeffer et al. teach in a first embodiment (a), compressed tablets preferably direct compressed pharmaceutical tablets, wherein the dispersion contains particles comprising DPP-IV inhibitor preferably LAF237, in free form or in acid addition salt form, and wherein at least 40%, preferably 60%, most preferably 80% even more preferably 90% of the particle size distribution in the tablet is less than 250 microns or preferably between 10 to 250 microns (paragraph 0228). The vildagliptin crystal or the pharmaceutical compositions comprising the vildagliptin crystal, can be administered either alone or in a combination with another (e.g. one or two) therapeutic agent (in the same or in different dosage unit), e.g., each at an effective therapeutic dose as reported in the art (paragraph 0463). The vildagliptin crystal is preferably administered in combination with one or two compounds selected from mefformin, a glitazone (such as pioglitazone or rosiglitazone), insulin, sulfonylureas, nateglinide, or valsartan (paragraph 0464).
The DPP-IV inhibitor compounds e.g. those of formula (I), and their corresponding pharmaceutically acceptable acid addition salts, may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered enterally, e.g., orally, in the form of tablets, capsules, caplets, etc. or parenterally, e.g., intravenously, in the form of sterile injectable solutions or suspensions (paragraph 0055). With regard to the new amendments Pfeffer et al. clearly teach The DPP-IV inhibitor compounds especially compounds of formula I, IA or IB, useful in this invention are hygroscopic, presents stability problems, and are not inherently compressible. Consequently, there is a need to provide a free-flowing and cohesive composition capable of being directly compressed into strong tablets with an acceptable in vitro dissolution profile. Tablets may be defined as solid dosage pharmaceutical forms containing drug substances with or without suitable fillers. They are produced by compression or compaction of a formulation containing the active ingredient and certain excipients selected to aid in the processing and to improve the properties of the product. Tablets may be coated or uncoated and are made from powdered, crystalline materials. They may include various diluents, binders, disintegrants, lubricants, glidants and in many cases, colorants. Excipients used are classified according to the function they perform. For example, a glidant may be used to improve the flow of powder blend in the hopper and into the tablet die (paragraph 0060). Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight (paragraph 0064). One, two, three or more lubricants can be selected. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant, e.g., may be present in an amount from about 0.1% to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0.1% to about 10% by weight. Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight. The lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die. It has a particle size range of 450-550 microns and a density range of 1.00-1.80 g/mL. It is stable and does not polymerize within the tableting mix. The preferred lubricant, magnesium stearate is also employed in the formulation. Preferably, the lubricant is present in the tablet formulation in an amount of from about 0.25% to about 6%; also preferred is a level of about 0.5% to about 4% by weight; and most preferably from about 0.1% to about 2% by weight. Other possible lubricants include talc, polyethylene glycol, silica and hardened vegetable oils. In an optional embodiment of the invention, the lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather than being added directly to the formulation (paragraph 0097).
Ascertainment of the Difference between Scope the Prior Art and the Claims
(MPEP §2141.012)
Although Pfeffer et al. generically teaches DPP-IV inhibitors, Pfeffer et al. do not specifically teach linagliptin. This deficiency is cured by the teachings of Thomas et al.
Thomas et al. teach in the abstract that BI 1356 [proposed trade name ONDERO; (R)-8-(3-aminopiperidin 1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] (which is linagliptin) is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. Thomas et al. teach in the abstract that in their study investigated the potency, selectivity, mechanism, and duration of action of BI 1356 in vitro and in vivo and compared it with other DPP-4 inhibitors. BI 1356 inhibited DPP-4 activity in vitro with an IC50 of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a Ki of 1 nM. The calculated koff rate for BI 1356 was 3.0x10-5/s (versus 2.1x10-4/s for vildagliptin). BI 1356 was ≥ 10,000- fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidases trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 greater than (sitagliptin/saxagliptin) greater than vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once a-day DPP-4 inhibitor for the treatment of type 2 diabetes. Thomas et al. teach during in vivo studies, compound administration was by oral gavage using 0.5% aqueous hyroxyethylcellulose as vehicle (page 176 see materials and methods).
Although Pfeffer et al. teach the vildagliptin crystal or the pharmaceutical compositions comprising the vildagliptin crystal, can be administered either alone or in a combination with another (e.g. one or two) therapeutic agent (in the same or in different dosage unit), e.g., each at an effective therapeutic dose as reported in the art (paragraph 0463). The vildagliptin crystal is preferably administered in combination with one or two compounds selected from mefformin, a glitazone (such as pioglitazone or rosiglitazone), insulin, sulfonylureas, nateglinide, or valsartan (paragraph 0464) and Thomas et al. teach linagliptin being more potent than vildagliptin, neither Pfeffer et al. nor Thomas et al. teach (1.3), 1- chloro-4-(beta- D-glucopyranos-1-yl)- 2-[ 4-( ( S )-tetrahydrofuran- 3- yloxy)-benzyl]-benzene wherein R1 denotes chloro and R3 denotes (S)-tetrahydrofuran-3-yloxy as the second active as recited in claim 42. This deficiency is cured by the teachings of Manuchehri and Dugi et al.
Manuchehri teaches a pharmaceutical composition comprised of one or more SGLT-2 inhibitor compound(s) in combination with one or more therapeutic agents which is suitable for the treatment of metabolic disorders including type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia, overweight, obesity, including class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity, and metabolic syndrome (see abstract). Manuchehri teaches the Active Ingredients can be administered in a single pharmaceutical composition or administered individually. In one embodiment, a pharmaceutical composition according to the invention is suitable for combined or simultaneous or sequential use of the one or more SGLT-2 inhibitor compound(s) and the one or more second therapeutic agent(s). In one embodiment, the one or more SGLT-2 inhibitor compound(s) and the one or more second therapeutic agent(s) are present in a single dosage form. In another embodiment, the one or more SGLT-2 inhibitor compound(s) and the one or more second therapeutic agent(s) are present each in a separate dosage form (page 5, lines 7-14). Manuchehri teaches a composition comprising a Glucopyranosyl-substituted phenyl derivatives selected from the group of compounds 1-17: 1-chloro-4-(-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy- )-benzyl]-benzene (applicant’s elected compound) etc., in combination with at least one second therapeutic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia (pages 5-6). Expediently, the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day (paragraph 0135) which overlaps with range recited in claim 13.
Dugi et al. teach DPP IV inhibitors for the treatment of physiological functional disorders and for reducing the risk of the occurrence of such functional disorders in at-risk patient groups. In addition, the use of DPP IV inhibitors in conjunction with other active substances is described, by means of which improved treatment outcomes can be achieved (see abstract). Examples of antidiabetic combination partners are SGLT2-inhibitors such as KGT-1251 (paragraph 0061). The dosage required of the DPP IV inhibitors when administered intravenously is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and when administered orally 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg, in each case 1 to 4 times a day (paragraph 0046). Manuchehri teaches a pharmaceutical composition comprised of one or more SGLT-2 inhibitor compound(s) (in which applicant's elected compound belong to) in combination with one or more therapeutic agents which is suitable for the treatment of metabolic disorders including type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia, overweight, obesity, including class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity, and metabolic syndrome (see abstract).
Pfeffer et al., Thomas et al., Manuchehri, and Dugi et al. do not explicitly teach copovidone as binder and also do not teach linagliptin in amount of 2.8% by weight of the total weight of the composition. These deficiencies are cured by the teachings of Kohlrausch et al.
Kohlrausch et al. pharmaceutical compositions of DPP IV inhibitors with an amino group, their preparation and their use to treat diabetes mellitus (see abstract). A pharmaceutical composition according to the present invention is intended for the treatment of to achieve glycemic control in a type 1 or type 2 diabetes mellitus patient and comprises a DPP-IV inhibitor with an amino group, especially a free or primary amino group, as an active ingredient, a first and second diluent, a binder, a disintegrant and a lubricant (paragraph 0007). Binders suitable for a pharmaceutical composition according to the invention are copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, low-substituted hydroxypropylcellulose (L-HPC), copovidone and pregelatinized starch being preferred. Kohlrausch et al. A pharmaceutical composition comprising as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant (see claim 1). The pharmaceutical composition of claim 1 comprising 0.5-20% active ingredient 40-88% diluent 1, 3-40% diluent 2, 1-5% binder, 5-15% disintegrant, and 0.1-4% lubricant (see claim 11). The pharmaceutical composition of claim 1 comprising 0.5-7% active ingredient 50-75% diluent 1, 5-15% diluent 2, 2-4% binder, 8-12% disintegrant, and 0.5-2% lubricant (see claim 12). The pharmaceutical composition according to claim 1 in the dosage form of a capsule, a tablet, or a film-coated tablet (see claim 13).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one or ordinary skill in the art at the time the invention was made to modify the teachings of Pfeffer et al. by incorporating linagliptin as a DPP-IV inhibitor in the composition because Thomas et al. teach in the abstract that BI 1356 [proposed trade name ONDERO; (R)-8-(3-aminopiperidin 1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] (which is linagliptin) is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. One of ordinary skill in the art would have been motivated to incorporate linagliptin because Thomas et al. teach that BI 1356 inhibited DPP-4 activity in vitro with an IC50 of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a Ki of 1 nM. The calculated koff rate for BI 1356 was 3.0x10-5/s (versus 2.1x10-4/s for vildagliptin). BI 1356 was ≥ 10,000- fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidases trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 greater than (sitagliptin/saxagliptin) greater than vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once a-day DPP-4 inhibitor for the treatment of type 2 diabetes. Thomas et al. teach during in vivo studies, compound administration was by oral gavage using 0.5% aqueous hyroxyethylcellulose as vehicle (page 176 see materials and methods). In the alternative, one of ordinary skill in the art would have been motivated to substitute vildagliptin wherein the composition of it is exemplified by Pfeffer et al. with linagliptin because Thomas et al. teach that BI 1356 inhibited DPP-4 activity in vitro with an IC50 of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a Ki of 1 nM. The calculated koff rate for BI 1356 was 3.0x10-5/s (versus 2.1x10-4/s for vildagliptin). BI 1356 was ≥ 10,000- fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidases trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 greater than (sitagliptin/saxagliptin) greater than vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once a-day DPP-4 inhibitor for the treatment of type 2 diabetes. Thomas et al. teach during in vivo studies, compound administration was by oral gavage using 0.5% aqueous hyroxyethylcellulose as vehicle (page 176 see materials and methods). Furthermore, in the case where the claimed ranges of the amount of drugs, ingredients, and particle size distributions in the composition "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). Moreover, differences in concentration 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). 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). One of ordinary skilled in the art would have had a reasonable expectation of success in combining the teachings of Pfeffer et al. and Thomas et al. because both references teach similar compositions containing DPP-IV inhibitors. With regard to the limitations drawn to the pharmacokinetic release profile of the composition that since the combination teachings by Pfeffer et al., Thomas et al., Manuchehri, and Dugi et al. render the claimed structure obvious, the pharmacokinetic profile would necessarily be substantially similar or there. Additionally, it is noticed that specific release profiles recited are highly dependent on the type of polymers and other ingredients used in the composition and how the composition is metabolized in an individual. As such, the specific release profiles recited are a testable limitation. Because the instantly clamed product and the product taught by the combination teachings of the references are substantially similar, one of ordinary skill in the art would expect the prior art product, to show the recited release profile values since these values are innate within the product. Additionally, with regard to specific release profiles recited because the Patent Office does not have the facilities to determine whether the specific release profiles recited of the composition are the same as that of the prior art, absent evidence to the contrary, the burden is on applicant to show a novel and unobvious difference between the specific release profiles recited of the claimed composition and that of the prior art. See In re Brown, 59 CCPA 1036, 459 F.2d. 531, 173 USPQ 685 (CCPA 1972) (holding at 1041, “[a]s a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith”) and Ex parte Gray, 10 USPQ 2d 1922, 1924-25 (PTO Bd. Pat. App. & Int.). "[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979). Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
It would have been prima facie obvious to one or ordinary skill in the art at the time the invention was made to modify the teachings of Pfeffer et al. and Thomas et al. via incorporating 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy- )-benzyl]-benzene (applicant’s elected compound of the second active) in combination with either with the generic DPP IV inhibitors taught by Pfeffer et al. or linagliptin taught by Thomas et al. because Manuchehri teaches a pharmaceutical composition comprised of one or more SGLT-2 inhibitor compound(s) in combination with one or more therapeutic agents which is suitable for the treatment of metabolic disorders including type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia, overweight, obesity, including class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity, and metabolic syndrome (see abstract). One of ordinary skill in the art would have been motivated to combine either the generic DPP IV inhibitors which certainly encompass linagliptin as taught by Pfeffer et al. or linagliptin taught by Thomas et al. because Dugi et al. teach that when DPP IV inhibitors in conjunction with other active substances such as SGLT 2 inhibitors is utilized, by means of which improved treatment outcomes can be achieved (see abstract). Furthermore, in the case where the claimed ranges of the amount of DPP IV inhibitors or the second active "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). Moreover, differences in concentration 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 skilled in the art would have had a reasonable expectation of success in combining the teachings of Pfeffer et al., Thomas et al., Manuchehri, and Dugi et al. because Pfeffer et al., Thomas et al., and Dugi et al. teach similar compositions comprising DPP IV inhibitors for the treatment of diabetes while Manuchehri teaches the second active agent which can be combined with the DPP IV inhibitors based on the teachings of Dugi et al. for treatment of diabetes as well.
It would have been prima facie obvious to one or ordinary skill in the art at the time the invention was made to substitute binders that are taught by Pfeffer et al. with copovidone because the binders are functional equivalents. The use of copovidone as binder in formulating compositions that contain DPP-IV inhibitors is clearly demonstrated by Kohlrausch et al. as set forth above. It would have been prima facie obvious to one or ordinary skill in the art at the time the invention was made to incorporate or include linagliptin in amount of 2.8% by weight of the composition because Kohlrausch et al teach a pharmaceutical composition comprising as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant (see claim 1). The pharmaceutical composition of claim 1 comprising 0.5-20% active ingredient 40-88% diluent 1, 3-40% diluent 2, 1-5% binder, 5-15% disintegrant, and 0.1-4% lubricant (see claim 11). The pharmaceutical composition of claim 1 comprising 0.5-7% active ingredient 50-75% diluent 1, 5-15% diluent 2, 2-4% binder, 8-12% disintegrant, and 0.5-2% lubricant (see claim 12). The pharmaceutical composition according to claim 1 in the dosage form of a capsule, a tablet, or a film-coated tablet (see claim 13). The amount clearly overlaps with the claimed 2.8% by weight of the total weight of the composition and also overlaps with the teachings of Pfeffer et al. 5-60% of the total weight of the composition. It should be known that Kohlrausch et al. teach as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof which covers linagliptin as linagliptin is a DPP IV inhibitor compound with an amino group. Furthermore, in the case where the claimed ranges of the amount of DPP IV inhibitor "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). Moreover, differences in concentration 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 expectation of success in combining the teachings of Pfeffer et al., Thomas et al., Manuchehri, Dugi et al., and Kohlrausch et al. because all of the references teach compositions for treatment of diabetes.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues claim 42 has been amended to recite a solid pharmaceutical dosage form comprising 2.8 % by weight of linagliptin. Such content of a DPP-IV inhibitor is not described or suggested by Pfeffer et al.’s teaching of a compositions containing 5-60% by weight on a dry weight basis of a DPP-IV inhibitor. Pfeffer further relates to solving problems encountered preparing a compressed tablet where “[a] solid dosage form containing a high-dose drug, i.e., the drug itself comprises a substantial portion of the total compressed tablet weight.” ({ [0080].) According to Pfeffer et al., “It is an object of the invention to provide a DPP-IV inhibitor formulation in the form of a free-flowing, cohesive tableting powder, capable of being directly compressed into a tablet.” ({| [0088].) Additionally, the Examiner concedes that Pfeffer et al. does not specifically teach linagliptin. In summary, Pfeffer relates to preparation of a compressed tablet where “the drug itself comprises a substantial portion of the total compressed tablet weight.” Pfeffer et al. does not teach or suggest a solid dosage form containing 2.8 wt % of a DPP-IV inhibitor, let alone linagliptin as recited in amended claim 42. his deficiency of Pfeffer et al. is not overcome in view of the other combination of Thomas et al., Manuchehri et al. Dugi et al, and Kohlrausch et al. The Examiner relies on of Kohlrausch et al. for teaching “pharmaceutical compositions of DPP IV inhibitors with an amino group.” According to the Examiner, the pharmaceutical composition “comprises a DPP-IV inhibitor with an amino group, especially a free or primary amino group, as an active ingredient” and may include copovidone as a binder.” Applicant submits that Kohlrausch et al. is focused solely on pharmaceutical compositions containing a single DPP IV inhibitor with a primary or secondary amino group as the sole active ingredient. The formulations of Kohlrausch et al. are designed to address compatibility and stability issues between the DPP IV inhibitors and various excipients, especially in low-dose applications due to the high potency of the compounds. In contrast, Pfeffer et al. relates to solving problems when preparing tablet formulation where the “drug itself comprises a substantial portion of the total compressed tablet weight.”
The above assertions are not found persuasive because Kohlrausch et al. indeed teach pharmaceutical compositions of DPP IV inhibitors with an amino group, their preparation and their use to treat diabetes mellitus (see abstract). A pharmaceutical composition according to the present invention is intended for the treatment of to achieve glycemic control in a type 1 or type 2 diabetes mellitus patient and comprises a DPP-IV inhibitor with an amino group, especially a free or primary amino group, as an active ingredient, a first and second diluent, a binder, a disintegrant and a lubricant (paragraph 0007). Binders suitable for a pharmaceutical composition according to the invention are copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, low-substituted hydroxypropylcellulose (L-HPC), copovidone and pregelatinized starch being preferred. Kohlrausch et al. A pharmaceutical composition comprising as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant (see claim 1). The pharmaceutical composition of claim 1 comprising 0.5-20% active ingredient 40-88% diluent 1, 3-40% diluent 2, 1-5% binder, 5-15% disintegrant, and 0.1-4% lubricant (see claim 11). The pharmaceutical composition of claim 1 comprising 0.5-7% active ingredient 50-75% diluent 1, 5-15% diluent 2, 2-4% binder, 8-12% disintegrant, and 0.5-2% lubricant (see claim 12). The pharmaceutical composition according to claim 1 in the dosage form of a capsule, a tablet, or a film-coated tablet (see claim 13). The examiner reminds Applicant that it would have been prima facie obvious to one or ordinary skill in the art at the time the invention was made to incorporate or include linagliptin in amount of 2.8% by weight of the composition because Kohlrausch et al teach a pharmaceutical composition comprising as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant (see claim 1). The pharmaceutical composition of claim 1 comprising 0.5-20% active ingredient 40-88% diluent 1, 3-40% diluent 2, 1-5% binder, 5-15% disintegrant, and 0.1-4% lubricant (see claim 11). The pharmaceutical composition of claim 1 comprising 0.5-7% active ingredient 50-75% diluent 1, 5-15% diluent 2, 2-4% binder, 8-12% disintegrant, and 0.5-2% lubricant (see claim 12). The pharmaceutical composition according to claim 1 in the dosage form of a capsule, a tablet, or a film-coated tablet (see claim 13). The amount clearly overlaps with the claimed 2.8% by weight of the total weight of the composition and also overlaps with the teachings of Pfeffer et al. 5-60% of the total weight of the composition. It should be known that Kohlrausch et al. teach as an active ingredient a DPP IV inhibitor compound with an amino group or a salt thereof which covers linagliptin as linagliptin is a DPP IV inhibitor compound with an amino group. Furthermore, in the case where the claimed ranges of the amount of DPP IV inhibitor "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). Moreover, differences in concentration 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 expectation of success in combining the teachings of Pfeffer et al., Thomas et al., Manuchehri, Dugi et al., and Kohlrausch et al. because all of the references teach compositions for treatment of diabetes.
Conclusion
No claims are allowed.
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