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 response in the reply filed on 13 November 2025 are acknowledged and have been fully considered. Claims 1, 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, 34-36, 43, 57, and 60 are pending. Claims 1, 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, 34-35, and 60 are under consideration in the instant office action. Claims 36, 43, and 57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 19 January 2022, 01 August 2023, 31 January 2024, 27 September 2024, and 16 June 2025, are noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. Signed copies are attached herein.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1, 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, 34-35, and 60) in the reply filed on 13 November 2025 is acknowledged. The traversal is on the ground(s) that with the presently claimed invention, a combination of (i) a bulk density of the granulate of less than about 0.52 g/mL and (ii) the granulate having a particle size distribution such that no more than about 30 wt.% of the granulate is retained on an ASTM #60 (250µm) sieve, unexpectedly and desirably provides both improved disintegration and improved dissolution. Attention is directed to Example 1, Table 2, Example 2, Table 3, and paragraph [00165] of the Examples of the specification.
This is not found persuasive because the amended claim 1 still lack inventive step based on the teachings of Mdluli (US 20180280401, IDS reference) in view of Metta et al. (International Journal of Pharmaceutics 549 (2018) 271–282) because the results provided in Example 1, Table 2, Example 2, Table 3 are based on specific compositions comprising specific ingredients at specific amounts while claim 1 is drawn to a broader claim that is not limited to Examples 1 and 2. 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.).
The requirement is still deemed proper and is therefore made FINAL.
Claim Objections
Claim 1 is objected to because of the following informalities: Independent claim 1 in the preamble recites “An oral pharmaceutical composition”. Claim 1 on lines 8 and 9 recites “composition”, and “the pharmaceutical composition”. For consistency and clarity reasons claim 1on those specific recitations should recite “the oral pharmaceutical composition”. Appropriate correction is required.
Claims 11, 13, 15-16, 18, 21, 24, 28, and 30 are objected to as being of improper dependent form because claim 11 depends from canceled claim 10. Claims 13, 15-16, 18, 21, 24, 28, and 30 depend from claim 11. See 37 CFR § 1.75(c) and MPEP § 608.01(n). Appropriate correction is required.
Claims 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, and 34-35 are objected to because of the following informalities: Independent claim 1 in the preamble recites “An oral pharmaceutical composition”. Claims 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, and 34-35 which depends from claim 1 directly or indirectly recite in their preambles and in some cases in the recitations of the claims “The pharmaceutical composition” or “the pharmaceutical composition”. For consistency and clarity reasons claims 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, and 34-35 should recite in the preamble “The oral pharmaceutical composition” or in the body of the claims “the pharmaceutical composition”. Appropriate correction is required.
Claim 60 is objected to because of the following informalities: claim 60 recites "An oral pharmaceutical composition prepared according to the process of claim 43." Claim 60 depends from a withdrawn process for preparing an oral pharmaceutical composition. Claim 60 should be written in independent form, for example in product-by-process format including the process steps as recited in claim 43. Appropriate correction is required.
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 11, 13, 15, 18, 21, 24, 28, 30-31, and 34-35 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 11 recites “The pharmaceutical composition of claim 10, wherein each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” However, claim 10 has been canceled. Therefore, there is no proper antecedent basis for the phrase “The pharmaceutical composition of claim 10” nor for the term “each excipient”. Because claim 10 no longer exists, the metes and bounds of claim 11 cannot be determined with reasonable certainty by one of ordinary skill in the art. Furthermore, claims 13, 15-16, 18, 21, 24, 28, and 30 also carry the same lack of antecedent basis since claims 13, 15-16, 18, 21, 24, 28, and 30 depend from claim 11. See MPEP § 608.01(n) (If the base claim has been canceled, a claim which is directly or indirectly dependent thereon should be rejected as incomplete).
Claim 11 recites “The pharmaceutical composition of claim 10, wherein each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” Independent claim 1 recites “one or more pharmaceutically acceptable intragranular excipients” and “one or more pharmaceutically acceptable extragranular excipients” without limiting them to any particular category or function. The phrase “each excipient” in claim 11 therefore lacks clear antecedent basis and renders the scope of the claim unclear for the following reasons: it is ambiguous whether “each excipient” refers only to the intragranular excipients, only to the extragranular excipients, or to all excipients present in the entire composition; it is unclear whether the Markush group is intended to be closed (i.e., the composition can contain only excipients from that list) or open (i.e., other unrecited excipient types are still permitted), particularly given the “comprising” nature of the independent claim; or the phrase “independently selected” does not resolve whether multiple excipients of the same type (e.g., two different diluents) are permitted or whether every excipient in the formulation must fall within one of the six listed functional categories. Because one of ordinary skill in the art cannot determine the metes and bounds of claim 11 with reasonable certainty, the claim is indefinite. See MPEP§§ 2173.05(a, d, and e) regarding lack of antecedent basis, Markush Groups, and functional/relative terminology. To overcome the rejection, Applicant may amend claim 11 to clearly specify which excipients (intragranular, extragranular, or both) are being limited by the Markush group and to resolve any ambiguity regarding the open/closed nature of the group and the meaning of “each.”
Claim 11 recites “The pharmaceutical composition of claim 10, wherein each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” Then claim 15 recites “The pharmaceutical composition of claim 11, wherein the diluent comprises lactose monohydrate (e.g. spray-dried lactose monohydrate) and microcrystalline cellulose.
Claim 13 recites “The pharmaceutical composition of claim 11, wherein each diluent is selected from the group consisting of a saccharide, a disaccharide, a sugar alcohol, a polysaccharide, and a polysaccharide derivative.” Claim 13 is indefinite for at least the following reasons: claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any diluent. Therefore, the definite article “each diluent” in claim 13 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 13 affirmatively requires a diluent or merely provides an optional further limitation if a diluent is present. See MPEP 2173.05(e).
Regarding claim 15, the phrase "e.g.," renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 15 recites the broad recitation lactose monohydrate, and the claim also recites spray dried lactose monohydrate, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, claim 15 is indefinite because claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any diluent. Therefore, the definite article “the diluent” in claim 15 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 13 affirmatively requires a diluent or merely provides an optional further limitation if a diluent is present. See MPEP 2173.05(e).
Claim 16 recites “The pharmaceutical composition of claim 11, wherein the binder comprises a polymeric binder.” Claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any binder. Therefore, the definite article “the binder” in claim 16 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 16 affirmatively requires a binder or merely provides an optional further limitation if a binder is present. See MPEP 2173.05(e).
Claim 18 recites “The pharmaceutical composition of claim 11, wherein the surfactant comprises sodium lauryl sulfate, ammonium lauryl sulfate, docusate sodium, ammonium dinonyl sulfosuccinate, diamyl sulfosuccinate sodium, dicapryl sulfosuccinate sodium, diheptyl sulfosuccinate sodium, dihexyl sulfosuccinate sodium, diisobutyl sulfosuccinate sodium, ditridecyl sulfosuccinate sodium, sodium dodecylbenzenesulfonate or a mixture thereof.” Claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any surfactant. Therefore, the definite article “the surfactant” in claim 18 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 18 affirmatively requires a surfactant or merely provides an optional further limitation if a surfactant is present. See MPEP 2173.05(e).
Claim 21 recites “The pharmaceutical composition of claim 11, wherein the disintegrant comprises low substituted hydroxypropyl cellulose, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, and sodium starch glycolate, or a mixture thereof.” Claim 21 is indefinite for at least the following reasons: claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any disintegrant. Therefore, the definite article “the disintegrant” in claim 21 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 21 affirmatively requires a disintegrant or merely provides an optional further limitation if a disintegrant is present. See MPEP 2173.05(e). Furthermore, the phrase “wherein the disintegrant comprises low substituted hydroxypropyl cellulose, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, and sodium starch glycolate, or a mixture thereof.” is grammatically and substantively unclear. It is ambiguous whether, all five listed disintegrants are required to be present together, or any one or more of them (i.e., a mixture of any subset) is permitted. The placement of “or a mixture thereof” at the end of the list creates confusion as to the intended closed versus open nature of the limitation. This leaves the metes and bounds of the claim unclear. See MPEP 2173.05(d) and 2173.05(e).
Claim 24 recites “The pharmaceutical composition of claim 11, wherein the lubricant comprises lauric acid, myristic acid, palmitic acid, stearic acid or pharmaceutically acceptable salts or esters thereof, such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or zinc stearate or a mixture thereof.” Claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any surfactant. Therefore, the definite article “the lubricant” in claim 24 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 24 affirmatively requires a lubricant or merely provides an optional further limitation if a lubricant is present. See MPEP 2173.05(e).
Regarding claim 24, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 24 recites the broad recitation “wherein the lubricant comprises lauric acid, myristic acid, palmitic acid, stearic acid or pharmaceutically acceptable salts or esters thereof” and the claim also recites “such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or zinc stearate or a mixture thereof.” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 28 recites “The pharmaceutical composition of claim 11, wherein the glidant comprises talc, calcium phosphate, calcium silicate, magnesium silicate, magnesium trisilicate, silicon dioxide, colloidal silicon dioxide, magnesium aluminosilicate, or a mixture thereof.” Claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any surfactant. Therefore, the definite article “the lubricant” in claim 28 lacks proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 28 affirmatively requires a glidant or merely provides an optional further limitation if a glidant is present. See MPEP 2173.05(e).
Claim 30 recites “The pharmaceutical composition of claim 11, wherein the composition comprises: a) from 10 wt.% to 30 wt.% of the pretomanid, b) from 60 wt.% to 85 wt.% of the diluent, c) from 1 wt.% to 10 wt.% of the disintegrant, d) from 0.1 wt.% to 1 wt.% of the surfactant, e) from 1 wt.% to 5 wt.% of the binder, f) from 0.1 wt.% to 1 wt.% of the glidant, and g) from 0.1 wt.% to 3 wt.% of the lubricant.” Claim 11 recites only that “each excipient is independently selected from the group consisting of a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant.” The Markush group is permissive and does not require the presence of any diluent, disintegrant, surfactant, binder, glidant or lubricant. Therefore, the definite articles, “the diluent”, “the disintegrant”, “the surfactant”, “the binder”, “the glidant”, and “the lubricant” respectively in claim 30 lack proper antecedent basis in claim 11. A person of ordinary skill in the art cannot reasonably determine whether claim 30 affirmatively requires a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant respectively or merely provides an optional further limitation if a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant respectively are present. See MPEP 2173.05(e).
Claim 30 recites the limitation "the composition" on line 2 in claim 11. There is insufficient antecedent basis for this limitation in the claim. For clarity reasons, claim 30 should recite “the oral pharmaceutical composition”.
Claim 31 recites the limitation "the composition" on line 2 in claim 1. There is insufficient antecedent basis for this limitation in the claim. For clarity reasons, claim 31 should recite “the oral pharmaceutical composition”.
Claim 34 recites the limitation "the composition" on line 2 in claim 1. There is insufficient antecedent basis for this limitation in the claim. For clarity reasons, claim 34 should recite “the oral pharmaceutical composition”. Claim 35 which depends from claim 34 does not clarify the issue.
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.
Note: The claims are examined with respect to the elected species wherein sodium stearyl fumarate as the binder; sodium starch glycolate as the disintegrant; and colloidal silicon dioxide as the excipient.
Claims 1, 3-4, 6, 9, 11, 13, 15, 18, 21, 24, 28, 30-31, 34-35, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over the pretomanid tablet formulation and manufacturing process taught in the EMA Assessment Report for pretomanid FGK (published and publicly available/referenced as of March 11, 2019, prior to the July 19, 2019 priority date; see also consistent details in the FDA NDA 212862 chemistry review, with submissions and reviews occurring in 2018 and early 2019), herein after “FDA Report” in view of Swinney et al. (US 2016/0354316)
Applicants’ claims
Applicants claim an oral pharmaceutical composition comprising a granulate and a pharmaceutically effective amount of pretomanid or a pharmaceutically acceptable solvate thereof. Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
FDA Report Pretomanid is an oral nitroimidazooxazine antimycobacterial drug. Pretomanid is a white to off-white to yellow colored powder. The chemical name for pretomanid is (6S)-2-Nitro-6-{[4-(trifluoromethoxy)phenyl]methoxy}-6,7-dihydro-5H imidazo[2,1-b][1,3]oxazine. The molecular formula for pretomanid is C14H12F3N3O5, and the molecular weight is 359.26. The structural formula of pretomanid is as follows:
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Each pretomanid tablet contains 200 mg of pretomanid. The inactive ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, sodium lauryl sulfate, and povidone (see section 11 description).
FDA Report teach oral immediate release tablet (200 mg pretomanid) comprising a granulate made by wet granulation (high-shear granulation with intragranular excipients including pretomanid, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and povidone as a binder) followed by the addition of excipients (magnesium stearate, colloidal anhydrous silica, sodium lauryl sulfate, which the examiner equates as extragranular), blending, lubrication, and compression. This directly reads on “the oral pharmaceutical composition comprising the granulate and one or more pharmaceutically acceptable extragrnular excipients, wherein the granulate comprises the pretomanid and one or more pharmaceutically acceptable intragranular excipients” and “an oral pharmaceutical composition comprising a pharmaceutically effective amount of pretomanid”. FDA Report teach micronized pretomanid was specifically chosen to improve dissolution and blend uniformity for this poorly soluble compound. The manufacturing process (dry sifting/blending-high shear wet granulation-wet milling-fluid bed drying-dry milling/sifting-extragranular excipients addition) produces a granulate suitable for tableting. Regarding the release profile of the composition FDA Report teach dissolution method utilizing USP Apparatus 2 (paddle) at 37 ±0.5 ºC in 0.1 N HCl is surfactant (optimized amount; the FDA chem review explicitly confirms 0.5% w/v hexadecyltrimethylammonium bromide (HDTMA) in 0.1 N HCl, 1000 mL, 75 rpm-identical to the claim). The formulation provides rapid release (Q value met in 30 minutes; development data and discriminatory power confirm fast dissolution consistent with ≥ 40 wt.% dissolved in 20 minutes) (see page 2).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
FDA Report do not specifically teach the specific granulate bulk density (0.47-0.53 g/mL); granulate PSD (≤30 wt.%, about 5 wt.% to about 30 wt.% retained on ASTM#60/250 mm sieve) as claimed in claims 1 and 3 and at least 80% wt.% of the granulate is retained on ASTM#200/75 mm sieve as recited in claim 4; tablet disintegration time (≤5 minutes); the amounts of active and ingredients as recited in claim 11 and the tablet strength as recited in claim 35. These deficiencies are cured by the teachings of Swinney et al.
Swinney et al. teach processes of preparing pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) in Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2), methods of treating, lessening the severity of or symptomatically treating CFTR mediated diseases, such as cystic fibrosis, methods of administering, and kits thereof are disclosed (see abstract). A continuous process for preparing a tablet comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 comprising the steps of: a) mixing Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, a filler, and a disintegrant in a blender to form a blend; b) preparing a granulation solution with water, a binder, and a surfactant; c) feeding the blend from step a) into a continuous twin screw granulator while adding the granulation solution from step b) to produce granules; d) drying the granules from step c) and milling them; e) blending the milled granules from step d) with a filler, disintegrant, and lubricant to form a blend; and f) compressing the blend from step e) into a tablet; wherein at least one of the above steps comprises process analytical technology (see claim 1). It will also be appreciated that the compound and pharmaceutically acceptable compositions and formulations of the invention can be employed in combination therapies; that is, Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2 and pharmaceutically acceptable compositions thereof can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures (paragraph 0340). In one embodiment, the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a compound that induces CFTR activity other than Compound 1 Form I and substantially amorphous Compound 2, or a nutritional agent (see paragraph 0341). In another embodiment, the admixture comprises a composition of Compound 1 Form I, a solid dispersion of substantially amorphous Compound 2, and any one or more of the excipients; a binder, a surfactant, a diluent, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in a powder form (e.g., provided as particles having a mean or average diameter, measured by light scattering, of 250 μm or less (e.g., 150 μm or less, 100 μm or less, 50 μm or less, 45 μm or less, 40 μm or less, or 35 μm or less)) (paragraph 0330). In some embodiments, the particle size distribution of D90 is about 82 μm or less for Compound 1 Form I. In some embodiments, the particle size distribution of D50 is about 30 μm or less for Compound 1 Form I (see paragraph 0297). Compound 1 Form I, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be dispensed in separate intermediate bin containers (IBCs). These materials may be screened using a “bin-to-bin” screening operation. Appropriate screen sizes are mesh 20, mesh 40, or mesh 60 (see paragraph 0474). As used herein, “bulk density” is the mass of particles of material divided by the total volume the particles occupy. The total volume includes particle volume, inter-particle void volume and internal pore volume. Bulk density is not an intrinsic property of a material; it can change depending on how the material is processed. In one embodiment, the granules used to prepare the pharmaceutical compositions provided by the invention have a bulk density of about 0.5-0.7 g/cc (which is equivalent to g/mL) (paragraph 0139). In another embodiment, compressing the admixture into a tablet is accomplished by filling a form (e.g., a mold) with the admixture and applying pressure to admixture. This can be accomplished using a die press or other similar apparatus. In some embodiments, the admixture of Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and excipients can be first processed into granular form. The granules can then be sized and compressed into tablets or formulated for encapsulation according to known methods in the pharmaceutical art. It is also noted that the application of pressure to the admixture in the form can be repeated using the same pressure during each compression or using different pressures during the compressions. In another example, the admixture of powdered ingredients or granules can be compressed using a die press that applies sufficient pressure to form a tablet having a dissolution of about 50% or more at about 30 minutes (e.g., about 55% or more at about 30 minutes or about 60% or more at about 30 minutes). For instance, the admixture is compressed using a die press to produce a tablet hardness of at least about 5 kP (at least about 5.5 kP, at least about 6 kP, at least about 7 kP, at least about 10 kP, or at least 15 kP). In some instances, the admixture is compressed to produce a tablet hardness of between about 5 and 20 kP (paragraph 0331). As indicated, in addition to Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2, in some embodiments of the invention, the pharmaceutical compositions which are oral formulations also comprise one or more excipients such as fillers, disintegrants, surfactants, diluents, binders, glidants, lubricants, colorants, or fragrances and any combination thereof (paragraph 0159). Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol) lactose, sucrose, or the like), or any combination thereof (paragraph 0160). Thus, in one embodiment, the pharmaceutical composition comprises at least one filler in an amount of at least 5 wt % (e.g., at least about 20 wt %, at least about 30 wt %, or at least about 40 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt %, from about 25 wt % to about 50 wt %, or from about 27 wt % to about 45 wt %) of filler, by weight of the composition. (paragraph 0161). Disintegrants suitable for the invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof (paragraph 0162). Thus, in one embodiment, the pharmaceutical composition comprises disintegrant in an amount of about 10 wt % or less (e.g., about 7 wt % or less, about 6 wt % or less, or about 5 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 1 wt % to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of disintegrant, by weight of the composition (paragraph 0163). Surfactants suitable for the invention enhance the wettability of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., Tween™), any combination thereof, or the like (paragraph 0164). Thus, in one embodiment, the pharmaceutical composition comprises a surfactant in an amount of about 10 wt % or less (e.g., about 5 wt % or less, about 2 wt % or less, about 1 wt % or less, about 0.8 wt % or less, or about 0.6 wt % or less) by weight of the composition. For example, the pharmaceutical composition includes from about 10 wt % to about 0.1 wt % (e.g., from about 5 wt % to about 0.2 wt % or from about 2 wt % to about 0.3 wt %) of surfactant, by weight of the composition. In another example, the pharmaceutical composition comprises 10 wt % or less (e.g., about 5 wt % or less, about 2 wt % or less, about 1 wt % or less, about 0.8 wt % or less, or about 0.6 wt % or less) of sodium lauryl sulfate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 10 wt % to about 0.1 wt % (e.g., from about 5 wt % to about 0.2 wt % or from about 2 wt % to about 0.3 wt %) of sodium lauryl sulfate, by weight of the composition (paragraph 0165). Binders suitable for the invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof (paragraph 0166). Thus, in one embodiment, the pharmaceutical composition comprises a binder in an amount of at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 3 wt %, at least about 4 wt %, or at least about 5 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 10 wt % or from about 2 wt % to about 7 wt %) of binder, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 2 wt %, at least about 3 wt %, or at least about 4 wt %) of polyvinylpyrrolidone, by weight of the composition. In yet another example, the pharmaceutical composition comprises a glidant in an amount ranging from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 8 wt % or from about 2 wt % to about 5 wt %) of polyvinylpyrrolidone, by weight of the composition (paragraph 0167). Diluents suitable for the invention may add necessary bulk to a formulation to prepare tablets of the desired size and are generally compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary diluents include: sugars, for example, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, and modified celluloses, for example, powdered cellulose, talc, calcium phosphate, starch, or any combination thereof (paragraph 0168). Thus, in one embodiment, the pharmaceutical composition comprises a diluent in an amount of 40 wt % or less (e.g., 35 wt % or less, 30 wt % or less, or 25 wt % or less, or 20 wt % or less, or 15 wt % or less, or 10 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 40 wt % to about 1 wt % (e.g., from about 35 wt % to about 5 wt % or from about 30 wt % to about 7 wt %, from about 25 wt % to about 10 wt %, from about 20 wt % to about 15 wt %) of diluent, by weight of the composition. In another example, the pharmaceutical composition comprises 40 wt % or less (e.g., 35 wt % or less, 25 wt % or less, or 15 wt % or less) of mannitol, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 35 wt % to about 1 wt % (e.g., from about 30 wt % to about 5 wt % or from about 25 wt % to about 10 wt %) of mannitol, by weight of the composition (paragraph 0169). Glidants suitable for the invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof (paragraph 0170). Thus, in one embodiment, the pharmaceutical composition comprises a glidant in an amount of 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of glidant, by weight of the composition. In another example, the pharmaceutical composition comprises 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) of colloidal silicon dioxide, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of colloidal silicon dioxide, by weight of the composition (paragraph 0171). In some embodiments, the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press. The lubricant is also compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition. Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In one embodiment, the pharmaceutical composition comprises a lubricant in an amount of 5 wt % or less (e.g., 4.75 wt %, 4.0 wt % or less, or 3.00 wt % or less, or 2.0 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.5 wt % or from about 3 wt % to about 1 wt %) of lubricant, by weight of the composition. In another example, the pharmaceutical composition comprises 5 wt % or less (e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) of magnesium stearate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.15 wt % or from about 3.0 wt % to about 0.50 wt %) of magnesium stearate, by weight of the composition (paragraph 0172).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of FDA Report by preparing an oral pharmaceutical composition comprising granulate with specific granulate bulk density (0.47-0.53 g/mL); granulate PSD (≤30 wt.%, about 5 wt.% to about 30 wt.% retained on ASTM#60/250 mm sieve) as claimed in claims 1 and 3 and at least 80% wt.% of the granulate is retained on ASTM#200/75 mm sieve as recited in claim 4; tablet disintegration time (≤5 minutes); the amounts of active and ingredients as recited in claim 11; and tablet strength as recited in claim 35 because Swinney et al. teach processes of preparing pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) in Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2), methods of treating, lessening the severity of or symptomatically treating CFTR mediated diseases, such as cystic fibrosis, methods of administering, and kits thereof are disclosed (see abstract). A continuous process for preparing a tablet comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 comprising the steps of: a) mixing Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, a filler, and a disintegrant in a blender to form a blend; b) preparing a granulation solution with water, a binder, and a surfactant; c) feeding the blend from step a) into a continuous twin screw granulator while adding the granulation solution from step b) to produce granules; d) drying the granules from step c) and milling them; e) blending the milled granules from step d) with a filler, disintegrant, and lubricant to form a blend; and f) compressing the blend from step e) into a tablet; wherein at least one of the above steps comprises process analytical technology (see claim 1). It will also be appreciated that the compound and pharmaceutically acceptable compositions and formulations of the invention can be employed in combination therapies; that is, Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2 and pharmaceutically acceptable compositions thereof can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures (paragraph 0340). In one embodiment, the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a compound that induces CFTR activity other than Compound 1 Form I and substantially amorphous Compound 2, or a nutritional agent (see paragraph 0341). In another embodiment, the admixture comprises a composition of Compound 1 Form I, a solid dispersion of substantially amorphous Compound 2, and any one or more of the excipients; a binder, a surfactant, a diluent, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in a powder form (e.g., provided as particles having a mean or average diameter, measured by light scattering, of 250 μm or less (e.g., 150 μm or less, 100 μm or less, 50 μm or less, 45 μm or less, 40 μm or less, or 35 μm or less)) (paragraph 0330). In some embodiments, the particle size distribution of D90 is about 82 μm or less for Compound 1 Form I. In some embodiments, the particle size distribution of D50 is about 30 μm or less for Compound 1 Form I (see paragraph 0297). Compound 1 Form I, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be dispensed in separate intermediate bin containers (IBCs). These materials may be screened using a “bin-to-bin” screening operation. Appropriate screen sizes are mesh 20, mesh 40, or mesh 60 (see paragraph 0474). As used herein, “bulk density” is the mass of particles of material divided by the total volume the particles occupy. The total volume includes particle volume, inter-particle void volume and internal pore volume. Bulk density is not an intrinsic property of a material; it can change depending on how the material is processed. In one embodiment, the granules used to prepare the pharmaceutical compositions provided by the invention have a bulk density of about 0.5-0.7 g/cc (which is equivalent to g/mL) (paragraph 0139). In another embodiment, compressing the admixture into a tablet is accomplished by filling a form (e.g., a mold) with the admixture and applying pressure to admixture. This can be accomplished using a die press or other similar apparatus. In some embodiments, the admixture of Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and excipients can be first processed into granular form. The granules can then be sized and compressed into tablets or formulated for encapsulation according to known methods in the pharmaceutical art. It is also noted that the application of pressure to the admixture in the form can be repeated using the same pressure during each compression or using different pressures during the compressions. In another example, the admixture of powdered ingredients or granules can be compressed using a die press that applies sufficient pressure to form a tablet having a dissolution of about 50% or more at about 30 minutes (e.g., about 55% or more at about 30 minutes or about 60% or more at about 30 minutes). For instance, the admixture is compressed using a die press to produce a tablet hardness of at least about 5 kP (at least about 5.5 kP, at least about 6 kP, at least about 7 kP, at least about 10 kP, or at least 15 kP). In some instances, the admixture is compressed to produce a tablet hardness of between about 5 and 20 kP (paragraph 0331). As indicated, in addition to Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2, in some embodiments of the invention, the pharmaceutical compositions which are oral formulations also comprise one or more excipients such as fillers, disintegrants, surfactants, diluents, binders, glidants, lubricants, colorants, or fragrances and any combination thereof (paragraph 0159). Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol) lactose, sucrose, or the like), or any combination thereof (paragraph 0160). Thus, in one embodiment, the pharmaceutical composition comprises at least one filler in an amount of at least 5 wt % (e.g., at least about 20 wt %, at least about 30 wt %, or at least about 40 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt %, from about 25 wt % to about 50 wt %, or from about 27 wt % to about 45 wt %) of filler, by weight of the composition. (paragraph 0161). Disintegrants suitable for the invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof (paragraph 0162). Thus, in one embodiment, the pharmaceutical composition comprises disintegrant in an amount of about 10 wt % or less (e.g., about 7 wt % or less, about 6 wt % or less, or about 5 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 1 wt % to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of disintegrant, by weight of the composition (paragraph 0163). Surfactants suitable for the invention enhance the wettability of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., Tween™), any combination thereof, or the like (paragraph 0164). Thus, in one embodiment, the pharmaceutical composition comprises a surfactant in an amount of about 10 wt % or less (e.g., about 5 wt % or less, about 2 wt % or less, about 1 wt % or less, about 0.8 wt % or less, or about 0.6 wt % or less) by weight of the composition. For example, the pharmaceutical composition includes from about 10 wt % to about 0.1 wt % (e.g., from about 5 wt % to about 0.2 wt % or from about 2 wt % to about 0.3 wt %) of surfactant, by weight of the composition. In another example, the pharmaceutical composition comprises 10 wt % or less (e.g., about 5 wt % or less, about 2 wt % or less, about 1 wt % or less, about 0.8 wt % or less, or about 0.6 wt % or less) of sodium lauryl sulfate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 10 wt % to about 0.1 wt % (e.g., from about 5 wt % to about 0.2 wt % or from about 2 wt % to about 0.3 wt %) of sodium lauryl sulfate, by weight of the composition (paragraph 0165). Binders suitable for the invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof (paragraph 0166). Thus, in one embodiment, the pharmaceutical composition comprises a binder in an amount of at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 3 wt %, at least about 4 wt %, or at least about 5 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 10 wt % or from about 2 wt % to about 7 wt %) of binder, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 2 wt %, at least about 3 wt %, or at least about 4 wt %) of polyvinylpyrrolidone, by weight of the composition. In yet another example, the pharmaceutical composition comprises a glidant in an amount ranging from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 8 wt % or from about 2 wt % to about 5 wt %) of polyvinylpyrrolidone, by weight of the composition (paragraph 0167). Diluents suitable for the invention may add necessary bulk to a formulation to prepare tablets of the desired size and are generally compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary diluents include: sugars, for example, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, and modified celluloses, for example, powdered cellulose, talc, calcium phosphate, starch, or any combination thereof (paragraph 0168). Thus, in one embodiment, the pharmaceutical composition comprises a diluent in an amount of 40 wt % or less (e.g., 35 wt % or less, 30 wt % or less, or 25 wt % or less, or 20 wt % or less, or 15 wt % or less, or 10 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 40 wt % to about 1 wt % (e.g., from about 35 wt % to about 5 wt % or from about 30 wt % to about 7 wt %, from about 25 wt % to about 10 wt %, from about 20 wt % to about 15 wt %) of diluent, by weight of the composition. In another example, the pharmaceutical composition comprises 40 wt % or less (e.g., 35 wt % or less, 25 wt % or less, or 15 wt % or less) of mannitol, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 35 wt % to about 1 wt % (e.g., from about 30 wt % to about 5 wt % or from about 25 wt % to about 10 wt %) of mannitol, by weight of the composition (paragraph 0169). Glidants suitable for the invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof (paragraph 0170). Thus, in one embodiment, the pharmaceutical composition comprises a glidant in an amount of 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of glidant, by weight of the composition. In another example, the pharmaceutical composition comprises 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) of colloidal silicon dioxide, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of colloidal silicon dioxide, by weight of the composition (paragraph 0171). In some embodiments, the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press. The lubricant is also compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition. Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In one embodiment, the pharmaceutical composition comprises a lubricant in an amount of 5 wt % or less (e.g., 4.75 wt %, 4.0 wt % or less, or 3.00 wt % or less, or 2.0 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.5 wt % or from about 3 wt % to about 1 wt %) of lubricant, by weight of the composition. In another example, the pharmaceutical composition comprises 5 wt % or less (e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) of magnesium stearate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.15 wt % or from about 3.0 wt % to about 0.50 wt %) of magnesium stearate, by weight of the composition (paragraph 0172). The examiner notes that the deficient parameters of the FDA Report are classic result effective variables that a person of ordinary skill in the art in formulation science would routinely utilize and adjust by varying granulation parameters (ingredients addition rate, impeller/chopper speed, wet massing time, drying conditions, milling screen size, optimizing amount of active and ingredients, varying types of ingredients used etc.,) as demonstrated by Swinney et al. to achieve the known benefits of improved flow, compressibility, content uniformity, rapid disintegration, and fast dissolution already exhibited by the FDA Report’s pretomanid wet granulated tablet. 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.). The examiner reminds Applicant that all of the ingredients and their amounts are known in the art as clearly shown by the FDA Report and Swinney et al. Furthermore, in the case where the claimed amounts of active and other ingredients, particle size, bulk density, tablet hardness etc.,"overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Furthermore, differences in concentration or any measurable parameters 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 FDA Report and Swinney et al. because both references are drawn to an oral pharmaceutical composition comprising substantially similar ingredients and an antibiotic.
With regard to the limitation of claim 60, 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").
With regard to the release profile recitations in claims 1 and 6 since the combination teachings of the FDA Report and Swinney et al. met the claimed structure the release profile would necessarily be substantially similar and would necessary be there. “[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979). Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
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.
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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