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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07 July 2026 has been entered.
Formal Matters
Applicant’s claim amendments and remarks in the reply filed on 07 July 2026 are acknowledged and have been fully considered. Claims 1, 3-22 and 33-38 are pending. Claims 1, 3-22 and 33-38 are under consideration in the instant office action. Claims 2 and 23-32 are canceled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07 July 2026 is noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. A signed copy is attached herein.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-22 and 33-38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a NACA-acceptable, biocompatible excipient” (singular). The subsequent limitations then refer to “the biocompatible excipient” (singular) in the clause “wherein the biocompatible excipient does not degrade the NACA in the tablet.” However, the next wherein clause recites “wherein the biocompatible excipients are microcrystalline cellulose, lactose, croscarmellose sodium, and stearic acid” (plural). There is no proper antecedent basis for the plural “the biocompatible excipients.” It is unclear whether the plural term is intended to refer back to the singular “a…excipient,” whether multiple distinct excipients from the list are required, or whether the list is merely exemplary. This inconsistency renders the scope of the claim unclear.
Claim 1 also recites the limitation “wherein the biocompatible excipient does not degrade the NACA in the tablet” which is a functional limitation that fails to clearly delineate the metes and bounds of the claim. It is unclear:
-What degree or amount of degradation is encompassed by “does not degrade” (e.g., zero degradation, or some acceptable threshold?).
-Under what conditions or over what time period the stability must be maintained (e.g., during manufacturing, storage at 25 C/60% RH, accelerated conditions, or in vivo?).
-How one of ordinary skill in the art would determine whether a given excipient meets this limitation without undue experimentation, particularly since the claim lists specific excipients but provides no objective criteria or test methodology.
Claims 1, 33, and 38 also recite the term “NACA-acceptable” (modifying the biocompatible excipient) which lack a clear definition in the claims or specification (assuming standard prosecution context). It is unclear what criteria make an excipient “NACA-acceptable” versus merely biocompatible or pharmaceutically acceptable. This subjective or undefined term leaves one of ordinary skill in the art in doubt as to the scope of the claims.
Claims 1 and 33 recite “a NACA-acceptable, biocompatible excipient and one or more pharmaceutically acceptable additives, binders, or fillers.” The claim then states that “the biocompatible excipients are “the four named substances. It is unclear whether the listed substances (microcrystalline cellulose, lactose, croscarmellose sodium, and stearic acid) are intended to be the only biocompatible excipient(s), or whether they can overlap with the separately recited “additives, binders, or fillers.” Many of listed items are conventionally used as binders, fillers, or disintegrants. This creates ambiguity as to whether the claim requires distinct categories or allows overlap, rendering the claim indefinite.
Claims 6-9 and 34-37 depend from canceled claim 2, respectively. A dependent claim cannot properly depend from non-existent canceled claim. See MPEP 608.01(n). This renders the claims improper and indefinite to their scope.
Claims 6-9 and 34-37 recite the phrase “with corresponding adjustments to other component”, which is a relative and subjective phrase that fails to specific how the other components (e.g., NACA, microcrystalline cellulose, lactose, stearic acid, fillers, binders, etc.) are to be adjusted when each of the components recited in the respective claims are present at any given level. The phrase does not define the quantitative relationships, ranges, or total mass balance required to maintain a complete tablet formulation. One of ordinary skill in the art would not be able to determine the metes and bounds of the claim without undue speculation. The phrase does not delineate whether the percentages are weight percent of the total tablet or of some other component, nor does it account for whether the adjustments must preserve the “does not degrade the NACA” functional limitation or other properties. Furthermore, the inclusion of 0 wt. % in claims 6-8 creates further ambiguity when combined with “corresponding adjustments,”.
Claims 6-8 recite “0…wt.%” for each of the respective ingredients recited in each claim. These recitation render the claims indefinite when read in light of the specification and the base claim. Specifically, when each of the respective ingredients are present at 0 wt.%, the claims encompass tablets that do not contain each of the respective excipients at all. However, assuming Applicant is intending to make claims 6-8 to depend from base claim 1, claim 1 recites “a NACA-acceptable, biocompatible excipient and one or more pharmaceutically acceptable additives, binders, or fillers, wherein the biocompatible excipient does not degrade NACA in the tablet, wherein the biocompatible excipients are microcrystalline cellulose, lactose, croscarmellose sodium, and stearic acid.” Claim 1 requires the incorporation of lactose, microcrystalline cellulose, and croscarmellose sodium respectively. The 0 wt.% recitation is in contradiction with the base claim recitation rendering the claims indefinite and ambiguous.
Claim 38 recites “a NACA-acceptable, biocompatible excipient consisting essentially of microcrystalline cellulose, lactose, croscarmellose sodium, crospovidone, and colloidal silicon dioxide.” This “consisting essentially of” language is immediately followed by the limitation “wherein the biocompatible excipient comprises stearic acid.” The “consisting essentially of” is a closed transitional phrase that generally excludes additional ingredients that materially affect the basic and novel characteristics of the invention. However, the subsequent “wherein” clause affirmatively requires the presence of stearic acid (an additional component not listed in the “consisting essentially of” group). This creates a direct contradiction: the excipient cannot both consist essentially of only the five named substances and comprise an unlisted sixth substance (stearic acid). The scope of the claim is therefore unclear. One of ordinary skill in the art would not be able to ascertain whether stearic acid is permitted, required, or excluded.
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.
Claim(s) 1, 3-22, and 33-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rosenfeld (US20150209310, previously cited) in view of ALEKSENKO et al. (RU 2611411, published on February 21, 2017, machine English translation provided, previously cited) and further in view of De Lazzari et al. (US 20160113876, previously cited).
Note: The claims are examined with respect to the elected species only wherein microcrystalline cellulose as the specific biocompatible excipient; at least one of lactose, croscarmellose sodium and/or stearic acid as the specific one of more pharmaceutically acceptable additives, binders, or fillers.
Applicant Claims
Applicant claims a tablet comprising N-acetylcysteine amide (NACA) and a NACA-acceptable, biocompatible excipient and optionally one or more pharmaceutically acceptable additives, binders, or fillers, wherein the biocompatible excipient does not degrade the NACA in the tablet, wherein the biocompatible excipients are microcrystalline cellulose, lactose, croscarmellose sodium, and stearic acid. Dependent claims thereof recite further features.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Rosenfeld teaches compositions and methods for treating a human subject in need of treatment for traumatic brain injury or neurological damage resulting from exposure to one or more low-energy impacts, comprising administering to the human subject an effective dose of N-acetylcysteine amide (NACA), or a pharmaceutically acceptable salt or ester thereof, thereby treating the human subject in need of treatment for traumatic brain injury or spinal cord injury resulting from exposure to one or more chronic or low-energy impacts (see abstract). A method of treating a human subject in need of treatment for traumatic brain injury or neurological damage resulting from exposure to one or more low-energy impacts, comprising administering to the human subject an effective dose of N-acetylcysteine amide (NACA), or a pharmaceutically acceptable salt or ester thereof, thereby treating the human subject in need of treatment for traumatic brain injury or spinal cord injury resulting from exposure to one or more low-energy impacts (see claim 1). The method of claim 1, wherein the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid (see claim 5). The present invention includes methods and compositions for treating a human subject in need of treatment for traumatic brain injury or neurological damage resulting from exposure to one or more low-energy impacts, comprising administering to the human subject an effective dose of N-acetylcysteine amide (NACA or NAC Amide), or a pharmaceutically acceptable salt or ester thereof, thereby treating the human subject in need of treatment for traumatic brain injury or spinal cord injury resulting from exposure to one or more low-energy impacts. In one aspect, the NACA is administered prophylactically before the one or more low-energy impacts. In another aspect, the dose for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose. In another aspect, the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per day. In another aspect, the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid. In another aspect, the NACA is administered orally, subcutaneously, intravenously, intramuscularly, intrasternally, or intraperitoneally. In another aspect, the NACA is administered for immediate release orally, via inhalation, topically, or intranasally (paragraph 0008). Effervescent pharmaceutical compositions may be in the form of a tablet for dissolving in water or a dispersible powder for sprinkling onto water, prior to administration. The components of the couple are blended together during manufacture of the composition. Suitable pharmaceutical formulations include effervescent tablets and sachets containing water dispersible powders. Effervescent pharmaceutical formulations according to the present invention may be prepared by blending together the granulates formed by roller compaction with other components prior to processing into, e.g., beads. Roller compaction may also be extended to include other components, such as one or more active ingredients and non-active ingredients or excipients such as lubricants, disintegrants, flavors and sweeteners. For capsule, final processing may include introducing the beads into the capsules using an encapsulation machine (paragraph 0026). The pharmaceutical composition and/or the solid carrier particles can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings may be applied for desired performance. Further, NACA may be provided for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release. For release/absorption control, solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a desired performance. The compositions may be formulated for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery, although oral delivery is used mostly (paragraph 0030). The coating may also contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include: triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate (see paragraph 0034). The examiner notes that the composition does not comprise D-NACA.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Rosenfeld does not specifically teach microcrystalline cellulose and lactose monohydrate as excipient types; amounts of NACA, microcrystalline cellulose, lactose monohydrate; hardness of the tablet; the thickness and width of the tablets (which the examiner equates to dimeter and width of the tablet); and the features recited in claims 20-22. These deficiencies are cured by the teachings of ALEKSENKO et al.
ALEKSENKO et al. teach dispersible in water acetylcysteine tablet, which contains from 100 to 600 mg of said substance and auxiliary components, taken in ratio 1:1 to the total weight from 200 to 1200 mg. Active and auxiliary substances are used in the following weight ratio, %: acetylcysteine - 50.0; microcrystalline cellulose - 34.1; lactose monohydrate - 5.0; crospovidone - 5.0; povidone - 25-2.0; lemon flavour - 1.0; sodium saccharinate - 0.825; aspartame - 0.675; citric acid monohydrate - 0.325; colloidal silicon dioxide - 0.75; magnesium stearate - 0.75. Tablet is capable of dispersing in water at temperature 15-25°C within 3 minutes with formation of dispersion, consisting of particles with size smaller than 710 mm (see abstract). The technical result of the invention is the creation of a water-dispersible solid dosage form of acetylcysteine, which disintegrates in water at a temperature of 15-25 °C over a 3-minute period of time with the formation of a dispersion that is able to pass through a sieve with a hole size of 710 microns. In this case, the content of active substance in the obtained tablet should be from 100 to 600 mg, with a total tablet weight of 200 to 1200 mg, respectively, and the ratio of active and auxiliary substances should be equal to 1: 1. The resulting water-dispersible solid dosage form of acetylcysteine should have sufficient strength to maintain integrity and appearance during the process and during consumer handling, and also be stable during storage. The hardness or crushing resistance of tablets according to the present invention can be determined using standard tests. The hardness of the tablets is usually determined according to standard test 2.9.8. European Pharmacopoeia 7.0 Vol. 1 (2011). A tablet testing device, such as, for example, Kremer® 3S, can be used. This test determines the resistance of tablets to crushing, measured by the force necessary to break them by crushing. The hardness of the tablets of the present invention varies according to the weight and diameter of the tablets and the compressive strength. For a tablet weighing 200 mg with a diameter of about 8.0 mm, the hardness is preferably from 40 to 80 N (which is 4 to 8 kp). To achieve such a hardness, a compressive force of 4000 to 7000 N is preferably used. For a tablet weighing 400 mg with a diameter of about 10.0 mm, hardness it is preferably 60 to 120 N and can be achieved by applying a compression force of 6000 to 1000 N. For a tablet weighing 1200 mg of an oval biconvex shape of 20.5 × 11 mm, the hardness is preferably not less than 140 N and can be achieved with application of compression force from 6000 N. ALEKSENKO et al. teach Oval biconvex tablets of size 20.5 × 11 mm, height of about 3.2 mm and average weight of 1200 mg, compressive strength of 200-240 N and disintegration in water of room temperature 50-70 are pressed from the resulting mixture on an industrial press KTR-400 from. A combination of lactose monohydrate and microcrystalline cellulose is used as a filler in this solid dosage form. Lactose, as a crystalline substance, improves flowability and increases the bulk density of the mixture. Microcrystalline cellulose contains sections of fibers that increase the area of contact surfaces during pressing, thereby increasing the strength of the tablets. However, microcrystalline cellulose fibers quickly conduct water inside the tablet when it is dispersed in water, which is necessary to achieve a minimum disintegration time. Preferably, but not limited to, use microcrystalline cellulose types MKC-101, MKC-102, MKC-105, for example, manufactured by JRS Pharma, Germany. Crospovidone is a typical disintegrant that can swell in water, increasing the particle size several times, and in such an amount provides the mixture with sufficient disintegration. It is preferable, but not limited, to use crospovidone sold under the trade name Collidon CL, manufactured by BASF, Germany. In the production, in order to increase the fluidity of the tableted masses, to prevent them from sticking to the punches and the walls of the holes of the matrix, magnesium stearate is used as a lubricant, in an amount of 0.325% by mass, and colloidal silicon dioxide, preferably 0.75% by mass, is used as a sliding substance.
Rosenfeld and ALEKSENKO et al. do not specifically teach croscarmellose sodium as excipient type and its amounts; and friability of the tablet and the new limitations recited in new claims 34-38. These deficiencies are cured by the teachings of De Lazzari et al.
De Lazzari et al. teach swallowable tablets containing at least 80% by weight of N-acetylcysteine (NAC) and at least one pharmaceutically acceptable excipient, in particular tablets in which the sulfurous odor is absent, characterized in that the said tablets are assembled using a granulate prepared by means of a process of dry granulating the active ingredient alone, with which the excipients are mixed before compression (see abstract). Preferably the tablets according to the invention comprise at least one pharmaceutically acceptable excipient selected from the group comprising binding agents, diluents, disintegrating agents, lubricating agents and glidants (paragraph 0035). Advantageously the tablets according to the invention comprise at least one binder in a quantity of 5% or more by weight with respect to the total weight of the tablet (paragraph 0036). Advantageously the tablets according to the invention comprise at least one diluent in a quantity of 5% or more by weight with respect to the total weight of the tablet (paragraph 0037). Advantageously the tablets according to the invention comprise at least one disintegrating agent in a quantity of 5% or more by weight with respect to the total weight of the tablet (paragraph 0038). Advantageously the tablets according to the invention comprise at least one lubricant in a quantity of 1% or less by weight with respect to the total weight of the tablet (paragraph 0039). Advantageously the tablets according to the invention comprise at least one glidant in a quantity of 1% or less by weight with respect to the total weight of the tablet (paragraph 0040). Advantageously the tablets formulated and produced according to the invention are quickly disintegrating and dissolving tablets with suitable physical properties (paragraph 0041). Pharmaceutically acceptable excipients which may be included in the tablets according to this invention comprise:
binders such as for example: hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyethylene glycol (PEG), methyl cellulose (MC), povidone (PVP), modified starches and others;
diluents such as for example: microcrystalline cellulose (MCC), anhydrous lactose or lactose monohydrate, pregelatinized starch, mannitol, isomaltose, sorbitol and similar carbohydrates, anhydrous dicalcium phosphate or dicalcium phosphate dihydrate, maltodextrin and others;
disintegrating agents such as for example: crospovidone, sodium croscarmellose, sodium starch glycolate, partly pregelatinized starch and others;
lubricants such as for example: Ca stearate, Mg stearate, sodium stearyl fumarate, stearic acid and others; and
glidants such as for example: anhydrous colloidal silica, talc and others.
The tablets according to this invention have physical characteristics which satisfy the requirements imposed by official Pharmacopoeias. For example the hardness of the tablets is between 7.5 and 12.5 KP, and/or their friability is between 0.10-0.70%, and/or their disintegration time is less than 4 minutes (paragraph 0063).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Rosenfeld by utilizing microcrystalline cellulose as NACA-acceptable biocompatible excipient and lactose monohydrate, croscarmellose sodium, and/or stearic acid as one or more pharmaceutically acceptable additives, binders, or fillers because ALEKSENKO et al. teach dispersible in water acetylcysteine tablet, which contains from 100 to 600 mg of said substance and auxiliary components, taken in ratio 1:1 to the total weight from 200 to 1200 mg. Active and auxiliary substances are used in the following weight ratio, %: acetylcysteine - 50.0; microcrystalline cellulose - 34.1; lactose monohydrate - 5.0; crospovidone - 5.0; povidone - 25-2.0; lemon flavour - 1.0; sodium saccharinate - 0.825; aspartame - 0.675; citric acid monohydrate - 0.325; colloidal silicon dioxide - 0.75; magnesium stearate - 0.75. Tablet is capable of dispersing in water at temperature 15-25°C within 3 minutes with formation of dispersion, consisting of particles with size smaller than 710 mm (see abstract). The technical result of the invention is the creation of a water-dispersible solid dosage form of acetylcysteine, which disintegrates in water at a temperature of 15-25 °C over a 3-minute period of time with the formation of a dispersion that is able to pass through a sieve with a hole size of 710 microns. In this case, the content of active substance in the obtained tablet should be from 100 to 600 mg, with a total tablet weight of 200 to 1200 mg, respectively, and the ratio of active and auxiliary substances should be equal to 1: 1. The resulting water-dispersible solid dosage form of acetylcysteine should have sufficient strength to maintain integrity and appearance during the process and during consumer handling, and also be stable during storage. The hardness or crushing resistance of tablets according to the present invention can be determined using standard tests. The hardness of the tablets is usually determined according to standard test 2.9.8. European Pharmacopoeia 7.0 Vol. 1 (2011). A tablet testing device, such as, for example, Kremer® 3S, can be used. This test determines the resistance of tablets to crushing, measured by the force necessary to break them by crushing. The hardness of the tablets of the present invention varies according to the weight and diameter of the tablets and the compressive strength. For a tablet weighing 200 mg with a diameter of about 8.0 mm, the hardness is preferably from 40 to 80 N. To achieve such a hardness, a compressive force of 4000 to 7000 N is preferably used. For a tablet weighing 400 mg with a diameter of about 10.0 mm, hardness it is preferably 60 to 120 N and can be achieved by applying a compression force of 6000 to 1000 N. For a tablet weighing 1200 mg of an oval biconvex shape of 20.5 × 11 mm, the hardness is preferably not less than 140 N and can be achieved with application of compression force from 6000 N. ALEKSENKO et al. teach Oval biconvex tablets of size 20.5 × 11 mm, height of about 3.2 mm and average weight of 1200 mg, compressive strength of 200-240 N and disintegration in water of room temperature 50-70 are pressed from the resulting mixture on an industrial press KTR-400 from. One of ordinary skill in the art would have been motivated to utilize lactose monohydrate and microcrystalline cellulose because ALEKSENKO et al. teach a combination of lactose monohydrate and microcrystalline cellulose is used as a filler in this solid dosage form. Lactose, as a crystalline substance, improves flowability and increases the bulk density of the mixture. Microcrystalline cellulose contains sections of fibers that increase the area of contact surfaces during pressing, thereby increasing the strength of the tablets. However, microcrystalline cellulose fibers quickly conduct water inside the tablet when it is dispersed in water, which is necessary to achieve a minimum disintegration time. Preferably, but not limited to, use microcrystalline cellulose types MKC-101, MKC-102, MKC-105, for example, manufactured by JRS Pharma, Germany. Crospovidone is a typical disintegrant that can swell in water, increasing the particle size several times, and in such an amount provides the mixture with sufficient disintegration. It is preferable, but not limited, to use crospovidone sold under the trade name Collidon CL, manufactured by BASF, Germany. In the production, in order to increase the fluidity of the tableted masses, to prevent them from sticking to the punches and the walls of the holes of the matrix, magnesium stearate is used as a lubricant, in an amount of 0.325% by mass, and colloidal silicon dioxide, preferably 0.75% by mass, is used as a sliding substance. Furthermore, in the case where the claimed ranges for the amounts, concentrations of active agent and other ingredients 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 and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). It is within the purview of the skilled artisan to optimize result effective parameters such as amounts and concentrations of active and inactive ingredients. The skilled artisan would have had a reasonable expectation of success in combining the teachings of Rosenfeld and ALEKSENKO et al. because both references teach N-acetylcysteine based tablet compositions. With regard to the limitations of claims 10-11 the claims are 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"). With regard to the new limitation reciting “wherein the biocompatible excipient does not degrade the NACA in the tablet” the combination teaching of Rosenfeld and ALEKSENKO et al. clearly met the inclusion of diluents such as microcrystalline cellulose as a conventional pharmaceutically acceptable additive and the microcrystalline cellulose provides stabilization of the formulation and there is no indication of microcrystalline cellulose degrading the active in the tablet composition absent evidence to the contrary.
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Rosenfeld and ALEKSENKO et al. by utilizing croscarmellose sodium as one or more pharmaceutically acceptable additives, binders, or fillers and also incorporate the different one or more pharmaceutically acceptable additives and their amounts as recited in claims 34-38 with tablet hardness and friability as recited in the current claims because De Lazzari et al. teach swallowable tablets containing at least 80% by weight of N-acetylcysteine (NAC) and at least one pharmaceutically acceptable excipient, in particular tablets in which the sulfurous odor is absent, characterized in that the said tablets are assembled using a granulate prepared by means of a process of dry granulating the active ingredient alone, with which the excipients are mixed before compression (see abstract). Preferably the tablets according to the invention comprise at least one pharmaceutically acceptable excipient selected from the group comprising binding agents, diluents, disintegrating agents, lubricating agents and glidants (paragraph 0035). Advantageously the tablets according to the invention comprise at least one binder in a quantity of 5% or more by weight with respect to the total weight of the tablet (paragraph 0036). Advantageously the tablets according to the invention comprise at least one diluent in a quantity of 5% or more by weight with respect to the total weight of the tablet (paragraph 0037). Advantageously the tablets according to the invention comprise at least one disintegrating agent in a quantity of 5% or more by weight with respect to the total weight of the tablet (paragraph 0038). Advantageously the tablets according to the invention comprise at least one lubricant in a quantity of 1% or less by weight with respect to the total weight of the tablet (paragraph 0039). Advantageously the tablets according to the invention comprise at least one glidant in a quantity of 1% or less by weight with respect to the total weight of the tablet (paragraph 0040). Advantageously the tablets formulated and produced according to the invention are quickly disintegrating and dissolving tablets with suitable physical properties (paragraph 0041). Pharmaceutically acceptable excipients which may be included in the tablets according to this invention comprise:
binders such as for example: hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyethylene glycol (PEG), methyl cellulose (MC), povidone (PVP), modified starches and others;
diluents such as for example: microcrystalline cellulose (MCC), anhydrous lactose or lactose monohydrate, pregelatinized starch, mannitol, isomaltose, sorbitol and similar carbohydrates, anhydrous dicalcium phosphate or dicalcium phosphate dihydrate, maltodextrin and others;
disintegrating agents such as for example: crospovidone, sodium croscarmellose, sodium starch glycolate, partly pregelatinized starch and others;
lubricants such as for example: Ca stearate, Mg stearate, sodium stearyl fumarate, stearic acid and others; and
glidants such as for example: anhydrous colloidal silica, talc and others.
The tablets according to this invention have physical characteristics which satisfy the requirements imposed by official Pharmacopoeias. For example the hardness of the tablets is between 7.5 and 12.5 KP, and/or their friability is between 0.10-0.70%, and/or their disintegration time is less than 4 minutes (paragraph 0063). It should be noticed that Rosenfeld and ALEKSENKO et al. do teach the inclusion of fillers, disintegrants, lubricants, binders, etc. It would have been prima facie obvious substituting one disintegrant with another as they are functionally equivalent. 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.) Furthermore, in the case where the claimed ranges for the amounts, concentrations of active agent and other ingredients 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 and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). It is within the purview of the skilled artisan to optimize result effective parameters such as amounts and concentrations of active and inactive ingredients such as croscarmellose sodium and hardness and friability of a tablet. The skilled artisan would have had a reasonable expectation of success in combining the teachings of Rosenfeld, ALEKSENKO et al., and De Lazzari et al. because all of the references teach N-acetylcysteine based tablet compositions.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 07 July 2026 have been fully considered but they are not persuasive.
Applicant argues the combination of Rosenfeld and Aleksenko fails to teach each and every element or limitation of the present invention because neither reference recognizes that N-acetylcysteine amide (NACA) is easily degraded including by normal pharmaceutically acceptable agents typically included in tablet and other formulations. Both Rosenfeld and Aleksenko are completely silent with regard to the degradation of formulations including NACA. Each active agent must be individually tested for degradation, and molecules such as acetylcysteine (Aleksenko), would be expected to have a completely different degradation profile than NACA. N-acetylcystine is known to have the problem that it is highly acidic (pH ~2) and has a strong and unpleasant aftertaste and a strong smell of rotten eggs due to the presence of a thiol group (-SH) thus, making it very unpleasant to drink a solution of NAC in water. By contrast, NACA has significantly less acidity but is highly degraded, and, the skilled artisan in possession of Aleksenko would not have selected to use stearic acid because of the known, highly acidic nature of NAC, which would have increased the acidity of the formulation. By contrast, the invention as claimed uses stearic acid as a NACA biocompatible excipient, which is not taught by Aleksenko. At best, Aleksenko teaches magnesium stearate, which the skilled artisan will recognize is not the same. Stearic acid is a naturally occurring saturated fatty acid, while magnesium stearate is an artificial salt compound created by binding stearic acid to magnesium. They differ significantly in their chemical makeup, regulatory status, and practical applications. Surprisingly, stearic acid was found to be NACA-compatible. As such, for at least these reasons, the prima facie case of obviousness fails.
The above assertions are not found persuasive because first 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). The examiner reminds Applicant that the rejection is based on the combination teachings of Rosenfeld, Aleksenko, and De Lazzari as described above. Furthermore, Applicant’s assertions are not supported by objective evidence. Contrary to Applicant’s assertions Rosenfeld who teaches N-acetylcysteine amide (NACA), describes that Roller compaction may also be extended to include other components, such as one or more active ingredients and non-active ingredients or excipients such as lubricants, disintegrants, flavors and sweeteners. For capsule, final processing may include introducing the beads into the capsules using an encapsulation machine (paragraph 0026). A method of treating a human subject in need of treatment for traumatic brain injury or neurological damage resulting from exposure to one or more low-energy impacts, comprising administering to the human subject an effective dose of N-acetylcysteine amide (NACA), or a pharmaceutically acceptable salt or ester thereof, thereby treating the human subject in need of treatment for traumatic brain injury or spinal cord injury resulting from exposure to one or more low-energy impacts (see claim 1). The method of claim 1, wherein the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid (see claim 5). The inclusion of microcrystalline cellulose and the other inactive ingredients are addressed by the combination teachings of Rosenfeld, Aleksenko, and De Lazzari et al. as described above. If Applicant alleges the N-acetylcysteine amide (NACA) tablet composition which is taught by the combination teachings of Rosenfeld, Aleksenko, and De Lazzari et al. is degraded by the presence of the pharmaceutically acceptable ingredients such as microcrystalline cellulose and the others, Applicant should support the argument by objective evidence or experimental data. Even based on the teachings of Aleksenko, and De Lazzari et al. there is no evidence that the inclusion of the pharmaceutically inactive ingredients with N-acetylcysteine degraded the active. The evidence is the pharmaceutically inactive ingredients such as microcrystalline cellulose and others help formulate a stable dosage forms as described above. The examiner takes the position that the structure as claimed is met by the combination teachings of Rosenfeld, Aleksenko, and De Lazzari as described above. Therefore, the any property or functional limitations recited by the claim are necessarily present are innate within the tablet formulation.
Applicant then further argues Applicants traverse the rejection and incorporate herein by reference in its entirety their response to the combination of Rosenfeld and Aleksenko hereinabove. By contrast, the invention as claimed uses stearic acid as a NACA biocompatible excipient, which is not taught by Aleksenko. At best, Aleksenko teaches magnesium stearate, which the skilled artisan will recognize are not the same. Stearic acid is a naturally occurring saturated fatty acid, while magnesium stearate is a salt compound created by binding stearic acid to magnesium. Nothing in De Lazzari teaches that which is missing from Rosenfeld and Aleksenko, namely, a recognition of the problem solved by the present invention. The combination of Rosenfeld, Aleksenko, and De Lazzari fails to recognize that certain excipients are not compatible with NACA, and further, fail to teach the combination of microcrystalline cellulose, lactose, croscarmellose sodium, and stearic acid, or the inclusion of stearic acid as a biocompatible excipient. De Lazzari is merely cumulative with Aleksenko, as both are limited to NAC. Moreover, De Lazzari also fails to recognize the lack of compatibility of certain excipients with NACA, or teach that stearic acid would be incompatible with a substance that is highly acidic (NAC), because it would increase the acidity of the formulation. De Lazzari provides, at best, various lists of ingredients from which the skilled artisan would have to guess which to include without any recognition that many of these excipients would not be compatible with NACA. As such, for at least these reasons, the prima facie case of obviousness fails.
The above assertions are not found persuasive because both magnesium stearate and stearic acid are conventionally known lubricants in the pharmaceutical art as recognized by De Lazzari et al. It is prima facie obvious to substitute one lubricant with the other absent evidence to the contrary.
Conclusion
No claim is allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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