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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29 April 2026 has been entered.
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 29 April 2026 are acknowledged and have been fully considered due to the entered request for continued examination. Claims 1, 5-8, 12-13, , 15-17, 23-25, and 28-43 are pending. Claims 1, 5-8, 12-13, , 15-17, 23-25, 28-31, and 34-43 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 Claims 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species, there being no allowable generic or linking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 2-4, 9-11, 14, 18-22, and 26-27 are canceled. Claims 34-43 are newly added. Applicant’s claim amendments, arguments, and new claims did not overcome the rejections under 35 USC 103 for reasons set forth in the previous office action and herein below.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.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, 5-8, 12-13, , 15-17, 23-25, 28-31, and 34-43 are rejected under 35 U.S.C. 103 as being unpatentable over TSUBIO et al. (US 2011/0294804, IDS reference, reference of record) in view of MATSUI et al. (WO2019/230937 using for English translation its equivalent US20210369624, IDS reference, reference of record).
Applicant Claims
Applicant claims an oral solid dosage form comprising:
() N²-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl)methyl}-L-alaninamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (ii) a disintegrant comprising partly pregelatinized starch, (iii) hydroxypropylcellulose as a binder, (iv) mannitol, and (v) sodium stearyl fumarate. Dependent claims thereof recite different features limiting the independent claim.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
TSUBIO et al. teach in the abstract a compound for the treatment or prophylaxis of pathology involving SNS, specifically diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like. The compound is represented by formula (1) or a pharmaceutically acceptable salt thereof wherein R1 is a hydrogen atom or the like, L is a single bond, —O— or the like, R2 is a phenyl group or the like, X is a carbon atom or a nitrogen atom, and R3, R4, R5a, R5b, R6 and R7 are each independently a substituted or unsubstituted alkyl group or the like:
PNG
media_image1.png
321
780
media_image1.png
Greyscale
The compound of any one of [1] to [10], wherein L is —CH2O—, or a pharmaceutically acceptable salt thereof (paragraph 0013). N2-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl}-L-alaninamide or a pharmaceutically acceptable salt thereof (see paragraph 0014 and claim 14). The therapeutic or prophylactic drug of the present invention for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis can contain various additional components for preparation such as conventional carrier, binder, stabilizer, excipient, diluent, pH buffering agent, disintegrant, solubilizer, dissolution aid, isotonic agent and the like, which are pharmaceutically acceptable. In addition, these therapeutic or prophylactic drugs can be orally or parenterally administered. That is, for oral administration, the drug can be orally administered in the form generally employed, for example, in dosage forms such as tablet, pill, powder, granule, capsule, syrup, emulsion, suspension and the like. For parenteral administration, the drug can be formulated as a preparation in the form of, for example, intravenous injection (drip infusion), intramuscular injection, subcutaneous injection, embrocation, eye drop, ophthalmic ointment and the like (paragraph 0279). A solid preparation such as tablet is prepared by mixing the active ingredient with generally pharmacologically acceptable carrier or excipient such as lactose, sucrose, cornstarch and the like, binder such as crystalline cellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like, disintegrant such as carboxymethylcellulose sodium, starch sodium glycolate and the like, lubricant such as stearic acid, magnesium stearate and the like, preservative and the like (see paragraph 0280).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
TSUBIO et al. do not specifically teach partly pregelatinized starch and its amounts as recited in claims 13 and 34-35. 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 and its amounts as recited in claims 38-39 and 42-43. TSUBIO et al. also do not specifically teach sodium stearyl fumarate as lubricant type and its amounts as recited in claim 40-43. 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.
With regard to the limitations of claim 24 the claim is written in product-by-process format. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1370 n. 14, 92 USPQ2d 1289, 1312, n. 14 (Fed. Cir. 2009). See also Biogen MA Inc. v. EMD Serono, Inc., 976 F.3d 1326, 1334, 2020 USPQ2d 11129 (Fed. Cir. 2020) ("Biogen is certainly correct that the scope of composition and method of treatment claims is generally subject to distinctly different analyses. But where, as here, the novelty of the method of administration rests wholly on the novelty of the composition administered, which in turn rests on the novelty of the source limitation, the Amgen analysis will necessarily result in the same conclusion on anticipation for both forms of claims."); United Therapeutics Corp. v Liquidia Techs., Inc., 74 F.4th 1360, 1373, 2023 USPQ2d 862 (Fed. Cir. 2023) (the court held that product-by-process claims were properly rejected as "anticipated by a disclosure of the same product irrespective of the processes by which they are made."); and Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). However, in the context of an infringement analysis, a product-by-process claim is only infringed by a product made by the process recited in the claim. Id. at 1370 ("a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim"). 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 (see paragraph 0282). The examiner calculates (20/146)x100 which is equivalent to 13.7 wt% of active which reads on the limitations of claims 16-17 and 42-43. While the dose and frequency of administration vary depending on the administration method, and age, body weight, the disease state and the like of patients, a method of topical administration to a disease-injury lesion part is preferable. It is also preferable to administer the drug once or twice or more per day. When administering twice or more, consecutive administration or repeat administration at suitable intervals is desirable. 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. In addition, the therapeutic or prophylactic drug of the present invention for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis can also be utilized as an animal drug (see paragraphs 0283-0285).
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 as explained in the Amendment filed September 19, 2025, Examples 2, 4 and 8 demonstrate that tableting problems in the art have been solved irrespective of the present compound's concentration in a solid dosage form (the "present compound" is "N²-{[1-ethy1-6-(4-methylphenoxy)-1H-benzimidazol-2-yl]methyl]-L-alaninamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof"). 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.
PNG
media_image2.png
168
717
media_image2.png
Greyscale
Tsubio and Matsui are silent about the preparation of formulations with various drug concentrations. As a result, it would not have been obvious from these references that the oral dosage form of claim 1 can be prepared while inhibiting tableting problems irrespective of the concentration of the present compound. The references disclose compounds and formulations that are different from the present compound. In general, it is common technical knowledge that even slight differences in the chemical structure of small molecule pharmaceutical compounds result in differences in physicochemical properties, such as crystal form, melting point, solubility and stability, and the technical issues involved in the preparation of formulations may also differ depending on the compounds. The formulations disclosed in Tsubio and Matsui do not contain a disintegrant comprising "pregelatinized starch" or "sodium stearyl fumarate" as a lubricant, according to amended claim 1. On the other hand, Examples 1-10 of the present application, including Examples 2, 4 and 8, have both pregelatinized starch and sodium stearyl fumarate, and these Examples have excellent properties and manufacturing characteristics (i.e., no tableting trouble, high dissolution rates, and good storage stability). See Tables 2, 3, 5, 6, 8-12 and paras. [0182]-[0183] of the specification.
The above assertions are not found persuasive because the examiner maintains that 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. Claim 1 recites “An oral solid dosage form comprising: (i) N²-{[1-ethyl-6-(4-methylphenoxy)-1H-benzimidazol-2-yl)methyl}-L-alaninamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (ii) a disintegrant comprising partly pregelatinized starch, (iii) hydroxypropylcellulose as a binder, (iv) mannitol, and (v) sodium stearyl fumarate.” The amount of each of the ingredients (i)-(v) in the composition can be any amount whereas Examples 2, 4, 8 contain single point data. Furthermore, 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 8 AM-5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIGABU KASSA/
Primary Examiner, Art Unit 1619
Prosecution Insights