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 19 September 2025 are acknowledged and have been fully considered. Claims 1, 3-25, and 28-33 are pending. Claims 1, 3-25, and 28-31 are under consideration in the instant office action. Claims 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Claims 2 and 26-27 are canceled. 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.
Election/Restriction
Newly submitted claims 32-33 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: Inventions I (claims 1, 3-25, and 28-31) and II (new claims 32-33) are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, a method for treating and/or preventing pain can be accomplished using pharmaceutical compositions containing opioid agonists..
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 32-33 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Withdrawn Objections/Rejections
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, 3-25, and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over TSUBIO et al. (US 2011/0294804, IDS reference) in view of MATSUI et al. (WO2019/230937 using for English translation its equivalent US20210369624, IDS reference).
Applicant Claims
Applicant claims an oral dosage form containing the active recited, disintegrant comprising pregelatinized starches, and a binder.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of TSUBIO et al. are described in detail above and are herein incorporated by reference.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
TSUBIO et al. do not specifically teach pregelatinized starches 2-4, 7-8, and 13-14 and their amounts. Additionally, TSUBIO et al. do not specifically teach low substituted hydroxypropyl cellulose as disintegrant type as recited in claims 6-7. TSUBIO et al. also do not specifically teach the inclusion of mannitol as the water soluble excipient. TSUBIO et al. also do not specifically teach sodium stearyl fumarate as lubricant type. These deficiencies are cured by the teachings of MATSUI et al.
MATSUI et al. teach a solid oral dosage form comprising: (i) (S)-4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl)methyl]-2-morpholinyl}methyl]-2-methoxybenzamide, a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the same; (ii) a disintegrating agent; and (iii) a water-soluble polymer binder. The present disclosure also relates to a medicinal composition, a therapeutic agent and/or a preventive agent, which comprise the medicine according to the present disclosure, for treating and/or preventing digestive diseases, digestive symptoms, psychoneurological diseases or urinary diseases, a preferable example thereof being a solid oral dosage form (see abstract). “Disintegrant” refers to an agent added for the purpose of inducing disintegration or dispersion of a solid formulation such as a tablet or granule into particles (paragraph 0182). Still more preferred examples of “disintegrant” include croscarmellose sodium, pregelatinized starch, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone (paragraph 0193). Still more preferred examples of “cellulose-based disintegrant” include croscarmellose sodium and low substituted hydroxypropyl cellulose. The most preferred example of “cellulose-based disintegrant” include croscarmellose sodium (paragraphs 0197-0198). The disintegrant content is generally 0.1 to 80% by weight, preferably 0.5 to 70% by weight, more preferably 0.5 to 60% by weight, still more preferably 1 to 50% by weight, and most preferably 1 to 40% by weight, per 100% by weight of formulation. In another preferred embodiment, the disintegrant content is generally 1 to 50% by weight, preferably 1 to 40% by weight, more preferably 5 to 35% by weight, still more preferably 10 to 30% by weight, and most preferably 15 to 25% by weight, per 100% by weight of formulation (paragraph 0202-0203). Regarding content of the disintegrant, when two or more disintegrants are used, the combined content of two or more disintegrants is in the range described above. Content of a disintegrant other than pregelatinized starch (e.g., cellulose-based disintegrant such as croscarmellose sodium or low substituted hydroxypropyl cellulose) is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation (paragraph 0204-0205). The “pregelatinized starch” described above is prepared by pregelatinizing various starches such as corn starch, potato starch, wheat starch, rice starch, and tapioca starch. Specific examples of “pregelatinized starch” include the “Pregelatinized starch” and “Partly pregelatinized starch” in the Japanese Pharmaceutical Excipients, “Pregelatinized starch” in USP/NF, “Starch, pregelatinized” in Ph. Eur., and the like. “pregelatinized starch” is preferably “partly pregelatinized starch”. Specific examples of commercially available pregelatinized starch or partly pregelatinized starch include PCS (product name, distributor: Asahi Kasei Corporation), SWELSTAR (product name, distributor: Asahi Kasei Corporation), Starch 1500 and Starch 1500G (product name, distributor: Colorcon), LYCATAB C (product name, distributor: Roquette), and the like. The pregelatinized starch content is generally 0.1 to 96% by weight, preferably 1 to 70% by weight, more preferably 5 to 50% by weight, still more preferably 10 to 50% by weight, even more preferably 10 to 30%, still even more preferably 15 to 30% by weight, and most preferably 15 to 25% by weight, per 100% by weight of formulation (paragraph 0210-0212). One or two or more water soluble macromolecular binding agents described above can be used simultaneously. Specifically, a water soluble macromolecular binding agent can be one selected from those described above or a mixture of two or more thereof, or a combination of two or more thereof (paragraph 0224). More preferred examples of water soluble macromolecular binding agents include hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolyvidone, and polyvinyl alcohol. (paragraph 0225). The water soluble macromolecular binding agent content is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation. When two or more water soluble macromolecular binding agents are used, the combined content of two or more water soluble macromolecular binding agents is in the range described above (paragraph 0229-0230). Excipient” refers to an agent that is added to shape the form, increase the amount, or dilute and improve the usability of a drug when the “bulk” is not sufficient with just the base component upon preparation of a dosage form, where the excipient has a function of not just simply increasing the amount, but also improving the mixability of powder, improving granulating property upon preparation of particles in granules or the like, improving the fillability into a mortar, adherence, and fluidity upon tableting for tablets, improving the fillability into a capsule for capsule agents or the like. Examples of “excipient” include water soluble excipients and non-water soluble excipients. An excipient is preferably a water soluble excipient. While a water soluble excipient that is generally used in formulation can be used as the water soluble excipient, preferred examples thereof include sugars and sugar alcohol. The type of sugars and sugar alcohol is not particularly limited. Examples thereof include D-mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, white sugar, trehalose, and the like. Sugars or sugar alcohol are preferably D-mannitol, erythritol, lactose, or trehalose, more preferably D-mannitol or lactose. Sugars or sugar alcohol are most preferably D-mannitol. In this regard, one or two or more water soluble excipients described above can be used. Specifically, a water soluble excipient can be one selected from those described above or a mixture of two or more thereof, or a combination of two or more thereof. The excipient content is generally 0.1 to 96% by weight, preferably 1 to 90% by weight, more preferably 10 to 80% by weight, still more preferably 30 to 80% by weight, and most preferably 50 to 80% by weight, per 100% by weight of formulation (see paragraphs 0232-0236). “Lubricant” refers to an agent added for the purpose of improving fluidity or fillability, prevent adhesion, or the like of powder when filling a capsule or tableting in the manufacturing process of a capsule or tablet. Examples of lubricants include magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like. A lubricant is more preferably magnesium stearate or sodium stearyl fumarate, and still more preferably sodium stearyl fumarate. The lubricant content is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 0.1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation (see paragraphs 0238-0240). The preparation of the compound of the present invention can be prepared according to a conventional method. For example, a tablet can be prepared by mixing the compound of Example 1 (20 mg), lactose (100 mg), crystalline cellulose (25 mg) and magnesium stearate (1 mg), and tableting the obtained mixture (paragraph 0282). The dose is 10 μg-2 g, preferably 1 mg-1 g, more preferably 10-100 mg, in the amount of the active ingredient for an adult patient per single administration, which can be administered at once or in several portions a day. For parenteral administration, the dose can be 0.1-100 mg/day, more preferably 0.3-50 mg/day, for an adult patient, which can be administered at once or in several portions a day. To reduce administration frequency, a sustained-release preparation can also be used (see paragraph 0284).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to substitute one disintegrant, binder, water soluble excipient, and lubricant respectively taught by TSUBIO et al. with another disintegrant, binder, water soluble excipient, and lubricant respectively because MATSUI et al. teach a solid oral dosage form comprising: (i) (S)-4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl)methyl]-2-morpholinyl}methyl]-2-methoxybenzamide, a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the same; (ii) a disintegrating agent; and (iii) a water-soluble polymer binder. The present disclosure also relates to a medicinal composition, a therapeutic agent and/or a preventive agent, which comprise the medicine according to the present disclosure, for treating and/or preventing digestive diseases, digestive symptoms, psychoneurological diseases or urinary diseases, a preferable example thereof being a solid oral dosage form (see abstract). “Disintegrant” refers to an agent added for the purpose of inducing disintegration or dispersion of a solid formulation such as a tablet or granule into particles (paragraph 0182). Still more preferred examples of “disintegrant” include croscarmellose sodium, pregelatinized starch, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone (paragraph 0193). Still more preferred examples of “cellulose-based disintegrant” include croscarmellose sodium and low substituted hydroxypropyl cellulose. The most preferred example of “cellulose-based disintegrant” include croscarmellose sodium (paragraphs 0197-0198). The disintegrant content is generally 0.1 to 80% by weight, preferably 0.5 to 70% by weight, more preferably 0.5 to 60% by weight, still more preferably 1 to 50% by weight, and most preferably 1 to 40% by weight, per 100% by weight of formulation. In another preferred embodiment, the disintegrant content is generally 1 to 50% by weight, preferably 1 to 40% by weight, more preferably 5 to 35% by weight, still more preferably 10 to 30% by weight, and most preferably 15 to 25% by weight, per 100% by weight of formulation (paragraph 0202-0203). Regarding content of the disintegrant, when two or more disintegrants are used, the combined content of two or more disintegrants is in the range described above. Content of a disintegrant other than pregelatinized starch (e.g., cellulose-based disintegrant such as croscarmellose sodium or low substituted hydroxypropyl cellulose) is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation (paragraph 0204-0205). The “pregelatinized starch” described above is prepared by pregelatinizing various starches such as corn starch, potato starch, wheat starch, rice starch, and tapioca starch. Specific examples of “pregelatinized starch” include the “Pregelatinized starch” and “Partly pregelatinized starch” in the Japanese Pharmaceutical Excipients, “Pregelatinized starch” in USP/NF, “Starch, pregelatinized” in Ph. Eur., and the like. “pregelatinized starch” is preferably “partly pregelatinized starch”. Specific examples of commercially available pregelatinized starch or partly pregelatinized starch include PCS (product name, distributor: Asahi Kasei Corporation), SWELSTAR (product name, distributor: Asahi Kasei Corporation), Starch 1500 and Starch 1500G (product name, distributor: Colorcon), LYCATAB C (product name, distributor: Roquette), and the like. The pregelatinized starch content is generally 0.1 to 96% by weight, preferably 1 to 70% by weight, more preferably 5 to 50% by weight, still more preferably 10 to 50% by weight, even more preferably 10 to 30%, still even more preferably 15 to 30% by weight, and most preferably 15 to 25% by weight, per 100% by weight of formulation (paragraph 0210-0212). One or two or more water soluble macromolecular binding agents described above can be used simultaneously. Specifically, a water soluble macromolecular binding agent can be one selected from those described above or a mixture of two or more thereof, or a combination of two or more thereof (paragraph 0224). More preferred examples of water soluble macromolecular binding agents include hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolyvidone, and polyvinyl alcohol. (paragraph 0225). The water soluble macromolecular binding agent content is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation. When two or more water soluble macromolecular binding agents are used, the combined content of two or more water soluble macromolecular binding agents is in the range described above (paragraph 0229-0230). Excipient” refers to an agent that is added to shape the form, increase the amount, or dilute and improve the usability of a drug when the “bulk” is not sufficient with just the base component upon preparation of a dosage form, where the excipient has a function of not just simply increasing the amount, but also improving the mixability of powder, improving granulating property upon preparation of particles in granules or the like, improving the fillability into a mortar, adherence, and fluidity upon tableting for tablets, improving the fillability into a capsule for capsule agents or the like. Examples of “excipient” include water soluble excipients and non-water soluble excipients. An excipient is preferably a water soluble excipient. While a water soluble excipient that is generally used in formulation can be used as the water soluble excipient, preferred examples thereof include sugars and sugar alcohol. The type of sugars and sugar alcohol is not particularly limited. Examples thereof include D-mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, white sugar, trehalose, and the like. Sugars or sugar alcohol are preferably D-mannitol, erythritol, lactose, or trehalose, more preferably D-mannitol or lactose. Sugars or sugar alcohol are most preferably D-mannitol. In this regard, one or two or more water soluble excipients described above can be used. Specifically, a water soluble excipient can be one selected from those described above or a mixture of two or more thereof, or a combination of two or more thereof. The excipient content is generally 0.1 to 96% by weight, preferably 1 to 90% by weight, more preferably 10 to 80% by weight, still more preferably 30 to 80% by weight, and most preferably 50 to 80% by weight, per 100% by weight of formulation (see paragraphs 0232-0236). “Lubricant” refers to an agent added for the purpose of improving fluidity or fillability, prevent adhesion, or the like of powder when filling a capsule or tableting in the manufacturing process of a capsule or tablet. Examples of lubricants include magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like. A lubricant is more preferably magnesium stearate or sodium stearyl fumarate, and still more preferably sodium stearyl fumarate. The lubricant content is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 0.1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation (see paragraphs 0238-0240). The preparation of the compound of the present invention can be prepared according to a conventional method. For example, a tablet can be prepared by mixing the compound of Example 1 (20 mg), lactose (100 mg), crystalline cellulose (25 mg) and magnesium stearate (1 mg), and tableting the obtained mixture (paragraph 0282). The dose is 10 μg-2 g, preferably 1 mg-1 g, more preferably 10-100 mg, in the amount of the active ingredient for an adult patient per single administration, which can be administered at once or in several portions a day. For parenteral administration, the dose can be 0.1-100 mg/day, more preferably 0.3-50 mg/day, for an adult patient, which can be administered at once or in several portions a day. To reduce administration frequency, a sustained-release preparation can also be used (see paragraph 0284). Substituting one disintegrant, binder, water soluble excipient, and lubricant respectively with another disintegrant, binder, water soluble excipient, and lubricant is prima facie obvious as they all are functionally equivalent ingredients respectively. It should be noticed that TSUBIO et al. teach the inclusion of disintegrant, binder, water soluble excipient, and lubricant respectively in its dosage form in overlapping manner with regard to type and amount. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) In the case where the amount of ingredients such as disintegrant, binder, water soluble excipient, and lubricant respectively "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 amount 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 TSUBIO et al. and MATSUI et al. because both references are drawn to the preparation of solid oral dosage form compositions.
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. 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 Arguments
Applicant's arguments filed 19 September 2025 have been fully considered but they are not persuasive.
Applicant argues Tsubio et al. do not disclose any formulation example containing the present compound, and merely disclose the present compound in isolation. The reference briefly mentions a list of common formulation ingredients in para. [0280]. However, this is a very limited list and does not include "pregelatinized starches", according to claim 1. The oral solid dosage form of claim 1 prevents tableting troubles from low content to high content of the present compound, and provides excellent storage stability while maintaining good dissolution properties, as shown in the Examples. Additionally, para. [0282] of Tsubio et al. discloses a single example of preparing a tablet that comprises the reference's Example 1, lactose, crystalline cellulose and magnesium stearate. However, the reference's tablet is quite different from the oral solid dosage form of claim 1 comprising the present compound and "pregelatinized starches" and "a binder" The reference's Example 1 clearly has a different structure than its Example 96 (the present compound), as shown below. A person having ordinary skill in the art would recognize that the properties of formulations comprising different active ingredients having different chemical structures have different problems when manufacturing solid dosage forms.
The above assertions are not found persuasive because first the examiner reminds Applicant that the rejection is based on the combination teachings of Tsubio et al. and Matsui et al. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, for Tsubio et al. to be a proper reference combinable with Matsui et al., Tsubio et al. do not have to teach all the claimed elements in a specific example or embodiment. The examiner indeed acknowledged that TSUBIO et al. do not specifically teach pregelatinized starches 3-4 and 13-14 and their amounts. Additionally, TSUBIO et al. do not specifically teach low substituted hydroxypropyl cellulose as disintegrant type as recited in claims 6-7. TSUBIO et al. also do not specifically teach the inclusion of mannitol as the water soluble excipient. TSUBIO et al. also do not specifically teach sodium stearyl fumarate as lubricant type. These deficiencies are cured by the teachings of MATSUI et al. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989).
Applicant further argues Matsui et al. teach oral solid dosage forms. However, the active ingredient in this reference is clearly different from the present compound and the compounds taught by Tsubio et al., as shown below. As previously mentioned, the dosage form of claim 1 can suppress the increase in the amount of impurities. As is known in the art, impurities originate from an active ingredient, different active ingredients have different impurities, and the generation of the impurities have different mechanisms. Thus, the teachings in Matsui et al. of its active ingredient in combination with a disintegrant, such as pregelatinized starches, provides no suggestion or teaching that pregelatinized starches has the potential to suppress impurities. In addition, Matsui et al. do not study the suppression of impurities or inhibition of tableting troubles. The reference performs dissolution tests, but the amount of the active ingredient is smaller than the amounts recited in the present claims.
The above assertions are not found persuasive because first the examiner reminds Applicant that the rejection is based on the combination teachings of Tsubio et al. and Matsui et al. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, for Matsui et al., to be a proper reference combinable with Tsubio et al., Matsui et al., do not have to teach the same active agents as Tsubio et al. The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below). It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to substitute one disintegrant, binder, water soluble excipient, and lubricant respectively taught by TSUBIO et al. with another disintegrant, binder, water soluble excipient, and lubricant respectively because MATSUI et al. teach a solid oral dosage form comprising: (i) (S)-4-amino-5-chloro-N-[{4-[(1-hydroxyacetyl-4-piperidinyl)methyl]-2-morpholinyl}methyl]-2-methoxybenzamide, a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the same; (ii) a disintegrating agent; and (iii) a water-soluble polymer binder. The present disclosure also relates to a medicinal composition, a therapeutic agent and/or a preventive agent, which comprise the medicine according to the present disclosure, for treating and/or preventing digestive diseases, digestive symptoms, psychoneurological diseases or urinary diseases, a preferable example thereof being a solid oral dosage form (see abstract). “Disintegrant” refers to an agent added for the purpose of inducing disintegration or dispersion of a solid formulation such as a tablet or granule into particles (paragraph 0182). Still more preferred examples of “disintegrant” include croscarmellose sodium, pregelatinized starch, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone (paragraph 0193). Still more preferred examples of “cellulose-based disintegrant” include croscarmellose sodium and low substituted hydroxypropyl cellulose. The most preferred example of “cellulose-based disintegrant” include croscarmellose sodium (paragraphs 0197-0198). The disintegrant content is generally 0.1 to 80% by weight, preferably 0.5 to 70% by weight, more preferably 0.5 to 60% by weight, still more preferably 1 to 50% by weight, and most preferably 1 to 40% by weight, per 100% by weight of formulation. In another preferred embodiment, the disintegrant content is generally 1 to 50% by weight, preferably 1 to 40% by weight, more preferably 5 to 35% by weight, still more preferably 10 to 30% by weight, and most preferably 15 to 25% by weight, per 100% by weight of formulation (paragraph 0202-0203). Regarding content of the disintegrant, when two or more disintegrants are used, the combined content of two or more disintegrants is in the range described above. Content of a disintegrant other than pregelatinized starch (e.g., cellulose-based disintegrant such as croscarmellose sodium or low substituted hydroxypropyl cellulose) is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation (paragraph 0204-0205). The “pregelatinized starch” described above is prepared by pregelatinizing various starches such as corn starch, potato starch, wheat starch, rice starch, and tapioca starch. Specific examples of “pregelatinized starch” include the “Pregelatinized starch” and “Partly pregelatinized starch” in the Japanese Pharmaceutical Excipients, “Pregelatinized starch” in USP/NF, “Starch, pregelatinized” in Ph. Eur., and the like. “pregelatinized starch” is preferably “partly pregelatinized starch”. Specific examples of commercially available pregelatinized starch or partly pregelatinized starch include PCS (product name, distributor: Asahi Kasei Corporation), SWELSTAR (product name, distributor: Asahi Kasei Corporation), Starch 1500 and Starch 1500G (product name, distributor: Colorcon), LYCATAB C (product name, distributor: Roquette), and the like. The pregelatinized starch content is generally 0.1 to 96% by weight, preferably 1 to 70% by weight, more preferably 5 to 50% by weight, still more preferably 10 to 50% by weight, even more preferably 10 to 30%, still even more preferably 15 to 30% by weight, and most preferably 15 to 25% by weight, per 100% by weight of formulation (paragraph 0210-0212). One or two or more water soluble macromolecular binding agents described above can be used simultaneously. Specifically, a water soluble macromolecular binding agent can be one selected from those described above or a mixture of two or more thereof, or a combination of two or more thereof (paragraph 0224). More preferred examples of water soluble macromolecular binding agents include hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolyvidone, and polyvinyl alcohol. (paragraph 0225). The water soluble macromolecular binding agent content is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation. When two or more water soluble macromolecular binding agents are used, the combined content of two or more water soluble macromolecular binding agents is in the range described above (paragraph 0229-0230). Excipient” refers to an agent that is added to shape the form, increase the amount, or dilute and improve the usability of a drug when the “bulk” is not sufficient with just the base component upon preparation of a dosage form, where the excipient has a function of not just simply increasing the amount, but also improving the mixability of powder, improving granulating property upon preparation of particles in granules or the like, improving the fillability into a mortar, adherence, and fluidity upon tableting for tablets, improving the fillability into a capsule for capsule agents or the like. Examples of “excipient” include water soluble excipients and non-water soluble excipients. An excipient is preferably a water soluble excipient. While a water soluble excipient that is generally used in formulation can be used as the water soluble excipient, preferred examples thereof include sugars and sugar alcohol. The type of sugars and sugar alcohol is not particularly limited. Examples thereof include D-mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, white sugar, trehalose, and the like. Sugars or sugar alcohol are preferably D-mannitol, erythritol, lactose, or trehalose, more preferably D-mannitol or lactose. Sugars or sugar alcohol are most preferably D-mannitol. In this regard, one or two or more water soluble excipients described above can be used. Specifically, a water soluble excipient can be one selected from those described above or a mixture of two or more thereof, or a combination of two or more thereof. The excipient content is generally 0.1 to 96% by weight, preferably 1 to 90% by weight, more preferably 10 to 80% by weight, still more preferably 30 to 80% by weight, and most preferably 50 to 80% by weight, per 100% by weight of formulation (see paragraphs 0232-0236). “Lubricant” refers to an agent added for the purpose of improving fluidity or fillability, prevent adhesion, or the like of powder when filling a capsule or tableting in the manufacturing process of a capsule or tablet. Examples of lubricants include magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like. A lubricant is more preferably magnesium stearate or sodium stearyl fumarate, and still more preferably sodium stearyl fumarate. The lubricant content is generally 0.1 to 50% by weight, preferably 0.5 to 40% by weight, more preferably 0.1 to 20% by weight, still more preferably 1 to 10% by weight, and most preferably 1 to 5% by weight, per 100% by weight of formulation (see paragraphs 0238-0240). Substituting one disintegrant, binder, water soluble excipient, and lubricant respectively with another disintegrant, binder, water soluble excipient, and lubricant is prima facie obvious as they all are functionally equivalent ingredients respectively. It should be noticed that TSUBIO et al. teach the inclusion of disintegrant, binder, water soluble excipient, and lubricant respectively in its dosage form in overlapping manner with regard to type and amount. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) In the case where the amount of ingredients such as disintegrant, binder, water soluble excipient, and lubricant respectively "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 amount 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 TSUBIO et al. and MATSUI et al. because both references are drawn to the preparation of solid oral dosage form compositions. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989).
Applicant further argues the Examples in the present application demonstrate that the tableting problems have been solved irrespective of the present compound's concentration in a solid dosage form. For instance, the tablets of Examples 2, 4 and 8 have similar compositions, but their drug concentrations are largely different (see Tables 2, 5 and 8 of the specification). The drug concentrations and the results of Examples 2, 4 and 8 are reproduced in the table below, which shows that there was no tableting problem even when the content ratio of the present compound changed.
The above assertions are not found persuasive because whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Examples 2, 4 and 8 are narrower data points that are not commensurate in scope with the claim in terms of ingredient types and amounts. Claim 1 is broader in scope comparing to Examples 2, 4 and 8. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
Conclusions
No claims are allowed.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619