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 .
DETAILED ACTION
Status of Claims
Claims 1-10 are pending and under examination in this office action.
Priority
The instant application 18/249,344 filed on 04/17/2023, is a 371 of PCT/IN2021/050984 filed 10/14/2021, which claims the benefit of foreign application INDIA 202021044873 filed 10/15/2020.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of foreign Application INDIA 202021044873 is filed on 04/17/2023.
Information Disclosure Statement
The information disclosure statement filed 04/14/2023 is in compliance with the provisions of 37 CFR1.97. Accordingly, the reference listed in IDS are being considered by the Examiner.
Claim Objections
Claims 1-10 are objected to because of the following informalities:
Claims 1-10 recite “An oral pharmaceutical formulation comprising of oily dispersion”. An article is missing between “comprising of” and “oily” in all claims 1-10. An article is missing before “pharmaceutically acceptable salt thereof” in claims 1-7.
Claim 1 recites limitation “oily dispersion which consisting essentially of” should read an oily dispersion
Claim 1, 5 and 6 recite “after stability study of 9 months at (40 ± 2) °C and (75 ± 5) % RH”. It’s not clear what abbreviation “RH” is. It’s not clear what “stability study” is referring to at what conditions. An article is missing between “after” and “stability”.
Claims 5 also recites “in 900 ml volume of 0.1 N HCl dissolution media in USP apparatus type II (paddle) at 100 RPM at 37ºC”. An article is missing from between “in” and “USP”.
Claims 8 and 9 are objected to for reciting table in the claims. In utility patents, the claims should be written as a sentence and not contain figures or drawings. The claims lack a period at the end. The abbreviation “Qty” should be Quantity.
Claim 10 is objected to: “melting of” in step a) should be melting; step b): “mixing of” should be mixing “Lbrafac” in step b) is misspelled. An article is missing between “form” and “homogenous”.
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Specification
Instant specification does not disclose CROSS-REFERENCE TO RELATED APPLICATIONS.
35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, requires the specification to be written in “full, clear, concise, and exact terms.” The specification is replete with terms which are not clear, concise and exact. The specification should be revised carefully in order to comply with 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112. Examples of some unclear, inexact or verbose terms used in the specification are:
Page 6, line 25, “ Nintedanib salt used in Nintedanib esylate as active ingredient” should be Nintedanib esylate is used as active ingredient.
Numerous articles are missing in instant specification, for example, page 5,line 18, an article is missing before “formulation”; page 6, line 27, the article is missing from “ active ingredient is present in amorphous form”. Please check all the articles missing in instant specification.
Numerous “prior-arts” in instant specification should be singular prior art, e.g. page 4, lines 19, 33; page 5, line 17, 20, etc..
Numerous capitalized “Lauroyl macrogol (or polyoxyl) 6 glyceride”, “Lecithin”, “Soybean Oil”, “Olive Oil”, “Sesame Oil” ,etc. in the middle of sentence should be lower case, for example, page 5, lines 2,19, 21; page 8, line 4, etc; Page 7, “Lecithin derived from the source of Soya like Soya-Lecithin may provide an immune response to the patients”. “Soya” should be soy.
Page 11, the process for preparation: “step-1” at line 10 should be step a); “step-2” at line 12 should be step b).
Instant specification use trade names without proper symbol following the terms, for example, page 11, lines 8-10; Examples 1-5, etc.
The use of the term Labrafil® M 2130 CS, Labrafac® lipofile WL 1349, Lauroglycol® , etc. which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claims 1-10 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.
Independent claim 1 recites “an oral pharmaceutical formulation comprising of oily dispersion which consisting essentially of: a) Nintedanib or pharmaceutically acceptable salt thereof; b) Medium chain fatty acid glycerides; wherein the above formulation, i) does not contain Lecithin… iii) shows total impurities content less than 0.2% after stability study of 9 months at (40 ± 2) °C and (75 ± 5) % RH”. Independent claims 8 and 9 recite “an oral pharmaceutical formulation comprising of oily dispersion of Nintedanib Esylate…” Dependent claims 2-7 recite “The oral pharmaceutical formulation comprising of oily dispersion of Nintedanib or pharmaceutically acceptable salt thereof as claimed in claim 1”. The transitional phrase “comprising of” is indefinite. It’s not clear “comprising of” is open-ended “comprising” or close-ended “consisting of”. All claims having the language “comprising of” are rejected under 112(b) because it is not clear if the formulation itself comprises the oily dispersion or if the oily dispersion itself (e.g. claims 8-10) is the formulation and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The limitation “oily dispersion which consisting essentially of” in claim 1 also renders the claim indefinite. According to MPEP 2111.03 III, the transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original) …The term “consisting essentially of ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite components that do not materially affect the basic and novel characteristic(s) of the oily dispersion. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It’s not clear what other component at what amount, e.g. 1% , 0.5% or 0.05% are excluded from instantly claimed oily dispersion which consisting essentially of nintedanib or salt thereof and medium chain fatty acid glycerides.
Claims 2, 4 and 8 recite ratio or percentage of ingredients, it is not clear if the ratio/percentage is in relation to the combination of ingredients or the formulation as a whole. It’s noted instant claimed formulation comprises other ingredients that are NOT within the oily dispersion.
Claim 6 recites “wherein the formulation shows % assay not less than 99% after the stability study …” It’s not clear what is a “% assay”. Claims 9 and 10 contain the trademark/trade name Labrafil® and Labrafac®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name Labrafil® M2130 CS is used to identify/describe lauroyl macrogol-6 glycerides/lauroyl polyoxyl-6 glycerides comprising PEG-esters and a glycerides fraction that is a water dispersible surfactant /solubilizer for lipid-based formulation to improve solubility of active ingredients (See instant Example 5 on page 14, Labrafil® M2130 CS product information retrieved from https://www.pharmamanufacturingdirectory.com/company/120304/products/204227/labrafil-m2130-cs). Labrafac® lipofile WL1349 is used to identify/describe caprylic capric triglyceride, medium chain fatty acid triglyceride (retrieved from https://materie-prime.farmalabor.it/sds_completa/23212_en.pdf). Accordingly, the identification/description of surfactant/solubilizer and medium chain fatty acid triglyceride are indefinite.
Claim 10 recites “wherein the process for the preparation of the said formulation is prepared by following steps: a) melting of Labrafil M 2130 CS at the temperature around 45±5°C;b) mixing of Lbrafac Lipofile WL1349 along with above melted solution and Nintedanib Esylate to form homogeneous dispersion; c) encapsulating above homogeneous dispersion to provide the final formulation”. “the process” in claim 10 lacks antecedent basis. The temperature of claim 10 in step a) also lacks antecedent basis. It is not clear what the phrase “melted solution” at step b) is. Step 2) recites melting Labrafil but nothing about a solution or that this a solution itself. The phrase “above homogenous dispersion” at step c) is also unclear. It is not clear if Applicant is referring to the whole oily dispersion or the dispersion of step b).
Claim Interpretation
As disclosed by instant specification (pages 1 and 2 ), instant claimed active ingredient, nintendanib esylate having structure of Formula (I), is originally developed by Boehringer Ingelheim with brandname OFEV® for oral capsule available in multiple strength ( 100mg, 150mg) that was first approved by FDA in 2014 for treatment of idiopathic pulmonary fibrosis.
Independent claim 1 recites “an oral pharmaceutical formulation comprising of oily dispersion which consisting essentially of: a) Nintedanib or pharmaceutically acceptable salt thereof; b) Medium chain fatty acid glycerides; wherein the above formulation, i) does not contain Lecithin; ii) shows more than 90% of drug dissolution within 15 minutes; and, iii) shows total impurities content less than 0.2% after stability study of 9 months at (40 ± 2) °C and (75 ± 5) % RH”. Dependent claim 3 recites “[t]he oral pharmaceutical formulation comprising of oily dispersion of Nintedanib or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the formulation further comprises Lauroyl polyoxyl-6-glycerides”. The lauroyl polyoxyl-6-glycerides is considered as component of the oral pharmaceutical formulation, but NOT component of “oily dispersion of Nintedanib consisting essentially of: a) Nintedanib or pharmaceutically acceptable salt thereof; b) Medium chain fatty acid glycerides”. Thus, the transitional phrase “comprising of” in claim 1 and its dependent claims 2-7 are considered as open-ended “comprising” which might further comprise other component that are not within the “oily dispersion”.
As noted in preceding 35 USC § 112 section, absent of clear definition by instant specification. instantly claimed “oily dispersion which consisting essentially nintedanib or salt thereof and medium chain fatty acid glycerides” is indefinite. According to MPEP 2111.03 III, the transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original) …For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising" See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). See also AK Steel Corp. v. Sollac, 344 F.3d 1234, 1240-41, 68 USPQ2d 1280, 1283-84 (Fed. Cir. 2003).
The limitation “shows more than 90% of drug dissolution within 15 minutes” and “shows total impurities content less than 0.2% after stability study of 9 months at (40 ± 2) °C and (75 ± 5) % RH ”recited in independent claim 1 and its dependent claims 2-7 are construed as property and/or intended result of instantly claimed nintedanib formulation which do not necessarily contribute to the structural limitation of formulation product. Stability and dissolution profile are the property/direct result of nintedanib formulation once it is prepared/processed and could be measured through routine experiment by a skilled artisan in the art of formulation industry.
Independent claims 8 and 9 do not recite exclusion of lecithin, and/or other components that might be included or exclude in instantly claimed formulation, and dissolution and stability profile thereof. The transitional phrase “comprising of” in claims 8-10 are also considered as open-ended “comprising” which might further comprise other component that’s not within the “oily dispersion”. As such, claims 8-10 are construed as encompassing embodiments of oral pharmaceutical formulation comprising oily dispersion of nintedanib esylate having instantly claimed formula and other component (including lecithin) that are NOT within the oily dispersion.
Regarding the process recited in claim 10, instant claims are product claims. "[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). See MPEP 2113.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over XU et al. (CN107184549A, Applicant’s IDS 04/14/2023, machine translated copy by Google/EPO).
Xu teaches a pharmaceutical formulation of nintedanib (e.g. soft capsule) comprising nintedanib (2%-3%), oil phase (10% -30%), emulsifier (20-40% by mass), co-emulsifier, etc. (See abstract, [0014] of machine translated Description, claims 1-7).
Regarding the oil dispersion comprising medium chain triglyceride MCT, Xu teaches embodiments wherein the oil phase is one of medium chain triglyceride (MCT), propylene glycol monocaprylate, castor oil, etc. (See [0015], [0045], claim 4)(which reads on instant claimed MCT).
Regarding the emulsifier, Xu teaches embodiments wherein the emulsifier is one or a mixture of caprylic/capric macrogol glycerides (LABRASOl®), polyethylene glycol 40 hydrogenated castor oil (e.g. RH 40), etc. (See [0016]), claim 3). As disclosed by instant specification (page 9, lines 5-8), LABRASOl® is similar/equivalent of instantly claimed lauroyl macrogol-6 glycerides/lauroyl polyoxyl-6 glycerides) as the pharmaceutical vehicle.
Xu teaches embodiments comprising nintedanib and medium chain triglyceride (MCT) without lecithin (See [0045], [0057], [0062], [0075], Examples 1-9)(which is considered read on instant claims 1-4).
Xu teaches amount of nintedanib is 2%-3% by mass, oil phase is 10%-30% (w/w) and emulsifier in the nintedanib preparation is 20%-40% (w/w)(See [0014], [0022]-[0024] of machine translated Description, claims 1). The ratio of nintedanib to the oil phase (e.g. MCT), would not be more than 1:1(which reads on instant claim 2). The ratio of nintedanib to the emulsifier (e.g. macrogol glycerides) would not be more than 1:0.5 (which reads on instant claim 4).
Xu is silent about the crystalline form or amorphous form of claim 7. Xu teaches embodiments without crystal precipitation, indicating nintedanib in amorphous form (See [0046] of machine translated Description). A skilled artisan would have known to explore crystalline form or amorphous form of nintedanib for desired
Xu is silent about the dissolution and stability profile of embodiments comprising nintedanib, oil phase (e.g. MCT) and emulsifier (e.g. RH 40, macrogol glycerides). However, stability and dissolution profile are property of nintedanib formulation. Once nintedanib formulation in oil phase (MCT) and emulsifier (e.g. macrogol glycerides) is prepared, the stability profile and dissolution could be measured through routine experiment by a skilled artisan in the art of formulation industry.
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to further explore/optimize dosage form of nintedanib comprising nintedanib, oil phase (e.g. MCT) and emulsifier taught by Xu, together with exploration/optimization based on general knowledge of oral formulation, and arrive at the instantly claimed invention with reasonable expectation of success. Before the effective filing date of instant claimed invention, it was already known oral dosage form (e.g. capsule) comprising nintedanib, oil phase (e.g. MCT) and emulsifier (RH 40, macrogol glycerides) could be made as taught by Xu. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further explore/optimize pharmaceutical formulation comprising nintedanib and variety of oily phase (e.g. MCT ) and emulsifier (e.g. macrogol glycerides ) since Xu further teaches variety of emulsifier (e.g. macrogol glycerides, caprylic/capric macrogol glycerides (LABRASOl® ) could be used in the formulation. Where 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. MPEP 2144.05.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of and oral formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Messerschmid et al.(WO2009/147212, hereafter “Messerschmid’ 212”, Applicant’s IDS dated 04/17/2023).
Messerschmid’ 212 by Boehringer Ingelheim disclosed a pharmaceutical composition comprising compound of Formula I, 3-Z-[1-( 4-(N-(( 4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino )-anilino )-1-phenyl-methylene ]-6-methoxycarbonyl-2-indo linone-monoethanesulphonate (i.e. nitendanib eyslate), lipid carrier (e.g. medium chain triglyceride) , a thickener (e.g. hard fat, etc.) and optionally a glidant/solubilizing agent (See abstract, page 4, lines 21-26; claims 1- 20).
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Messerschmid’ 212 teaches various amount of active ingredient (i.e. nitendanib eyslate) from 60mg -240mg (e.g.180.6mg ) and concentration ranging from 10-50% (e.g. 43%), wherein the amount of ethanesulfonate salt /esylate ( dry basis) equivalent to the labeled amount of the free base ( See page 10, line Examples 1-7).
Regarding limitation of medium chain triglyceride MCT, Messerschmid’ 212 teaches variety of suitable carrier, e, g. caprylic-capric triglycerides, medium chain triglycerides, medium chain partial glycerides, macrogolglycerols, etc. (page 10, lines 29-35; page 11, lines 1-5 ; claim 3). Messerschmid’ 212 teaches most preferred lipid carrier is medium chain triglycerides ranging from 1 to 90 weight% of the lipid suspension formulation, preferably within 10 and 70 %(See page 11, lines 11-15; Examples 1-2 and 4-10). The ratio of nintedanib esylate (e.g. 20% ) and medium chain triglycerides (e.g. 30%) could be calculated as no more that 1:1 (which reads on instant claim 2).
Regarding Lauroyl polyoxyl-6-glycerides ( i.e. lauroyl macrogol-6 glycerides) , Labrafil M 2130 CS) of instant claims 3-4 and 8-10, Messerschmid’ 212 disclosed embodiments further comprising one or more macrogolglycerols as lipid (lipophilic) carrier and/or solubilizing agents, e.g. lauroyl macrogolglycerides, linoleoyl macrogolglycerides, macrogolglycerol caprylocaprate, macrogolglycerol linolate, oleoyl macrogolglycerides, polyoxyl castor oil, polyoxyl hydrogenated castor oil, etc. ( See page 5, lines 28-34; page 5, lines 9-17; page 6, lines 10-18; page 12, lines 23; claims 3 and 9-10). Please note lauroyl macrogolglycerides read on instantly recited Lauroyl polyoxyl-6-glycerides ( i.e. lauroyl macrogol-6 glycerides/Labrafil M 2130 CS). Messerschmid’ 212 teaches embodiments comprising one or more macrogolglycerols (e.g. macrogolglycerol hydroxystearate or macrogolglycerol ricinoleate) and/or solubilizing agents (See page 6, lines 16-18; claims 9-10). Please note macrogolglycerols ( lauroyl macrogolglyceride) taught by Messerschmid’ 212 are considered as both lipid (lipophilic ) carrier, thickener (lipophilic excipients of high viscosity) and/or solubilizing agents for the active ingredient. Messerschmid’ 212 teaches embodiments comprising active ingredient, medium chain triglycerides and one or more macrogolglycerols (e.g. macrogolglycerol hydroxystearate or macrogolglycerol ricinoleate) and various amount of macrogolglycerols ranging from 0.1 to 50 weight% of the lipid formulation (See page 12, lines 17-31). The ratio of nintedanib esylate (e.g. 40% ) and medium macrogolglycerols (e.g. 40%) could be calculated as not more that 1:0.5 (which reads on instant claim 4). Regarding limitation of lecithin, Messerschmid’ 212 teaches embodiments comprising Macrogol without lecithin (See P3 on page 13; Example 3, page 17) and other embodiments without lecithin (See page 8, lines 15-20; Figure 2). It’s noted the bioavailability of P3 comprising Macrogol without lecithin is comparable with P1 and P2 comprising MCT, hard fat and lecithin indicating lecithin is only optionally inactive ingredient (See page 14, liens 14-15; Figure 4).
Regarding instantly claimed formulation recited in claims 8 and 9, Messerschmid’ 212 teaches Example 7/formulation C (See page 20) ,wherein the active nitendanib esylate amount is 180.60 mg ( , the amount of thickener( hard fat) is 76.5mg (which reads on instant recited Labrafil M2130 CS), and medium chain triglyceride at 162.90mg. It’s noted is the additive amount of medium chain triglyceride 160.20mg + 2.70mg of lecithin taught by Messerschmid’ 212 is calculated to be 162.90 mg (which reads on instantly recited amount of medium chain triglyceride). Where 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. MPEP 2144.05.
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Regarding the process of claim 10, Messerschmid’ 212 teaches Experiment 10, wherein the basic ingredients are mixed, homogenized/ dissolved at elevated temperature(See page 21 and 22), For example, melting range of 33 to 40ºC or 40 °C - 44 °C (See Figure 3). The instant claims are product claims. Thus, irrespective of how they were produced, they are examined based the on the structural limitations claimed. See M.P.E.P. § 2113. 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.
Although Messerschmid’ 212 teaches embodiments comprising lecithin, lecithin is only one optionally glidant/solubilizing agent disclosed/ taught by Messerschmid’ 212 (See page4, line 26). For example, Messerschmid’ 212 teaches embodiments comprising Macrogol without lecithin (See P3 on page 13; Example 3, page 17) and other embodiments without lecithin (See page 8, lines 15-20; Figure 2).
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to further explore/optimize dosage form of nitendanib and salt thereof (e.g. esylate ) taught by Messerschmid’ 212, together with optimization based on general knowledge of oral formulation, and arrive at the instantly claimed invention with reasonable expectation of success. Before the effective filing date of instant claimed invention, it was already known oral dosage form (e.g. capsule) of nitendanib esylate comprising various pharmaceutical carrier/vehicle, e.g. medium chain triglycerides and one or more macrogolglycerols could be made as taught by Messerschmid’ 212. Messerschmid’ 212 teaches most preferred lipid carrier is medium chain triglycerides. Messerschmid’ 212 further teaches variety of lipid (lipophilic) carrier/solubilizing agent (e.g. lauroyl
macrogolglycerides, linoleoyl macrogolglycerides) that could be used in the formulation.
A skilled artisan would be motivated to further explore formulation comprising of oily dispersion consisting essentially nintedanib esylate and medium chain fatty acid glycerides because Messerschmid’ 212 teaches most preferred lipid carrier is medium chain triglycerides. A skilled artisan would be motivated to further explore macrogolglycerols in combination with medium chain triglyceride as lipophilic carrier and/or thickening agent of nitendanib esylate for better dissolution and bioavailability profile, because macrogolglycerols (e.g. lauroyl macrogolglycerides) could be used as lipophilic carrier and/or thickening agent as substitute for hard fat and solubilizing agent based on collective teachings of Messerschmid’ 212. Exploration different carrier/solubilizing agent, and combination and ratio thereof is the routine practice in the art of formulation and within general knowledge of an ordinarily skilled in the art. Where 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. MPEP 2144.05. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of oral formulation (e.g. lipophilic carrier/solubilizing agent). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary. Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over TELI et al. (WO2019/197961A1, hereafter “ TELI’ 961”, Applicant’s IDS 04/14/2023), in view of Rowe et al. (Handbook of Pharmaceutical Excipients, 6th edition, 2009, page 557-561, Polyoxylglycerides )
TELI’ 961 by Intas Pharmaceuticals discloses a pharmaceutical composition (e.g. soft gelatin capsules) comprising suspension of Nintedanib esylate and lauroyI polyoxyl-6 glyceride or hydrogenated vegetable oil, and preparation process of aforementioned pharmaceutical composition of Nintedanib esylate (See abstract, Examples 1-6; claims 1-8).
TELI’ 961 reviews development of OFEV® ( Nintedanib esylate) soft gelatin capsule by Boehringer Ingelheim and optimization of nintedanib esylate capsule composition comprising medium chain triglyceride as a carrier and lauroyl polyoxyl-6 glyceride as a thickener (See page 1-3). TELI’ 961 teaches soft gelatin capsules comprising suspension of nintedanib esylate comprising 5-25 % w/w Lauroyl polyoxyl-6 glyceride of the total suspension composition (See page 12, lines 25-27; claim 1), nintedanib esylate is present in an amount ranging from 30-60 % w/w of the total suspension (See page 12, lines 16-19; claim 3), medium chain triglyceride present in an amount ranging from 35-65 % w/w (See page 12, lines 21-24; claim 4) and lecithin present in an amount ranging from 0.1-5 % (See page 12, lines 1-3; claim 5).
TELI’ 961 teaches embodiments comprising nintedanib esylate, medium chain triglyceride and lauroyl polyoxyl-6 glyceride at very similar amount of instantly claimed amount and stability and dissolution profile thereof (See Examples 1-6, page 19).
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TELI’ 961 teaches working examples comprising nintedanib esylate at 180.60mg (See Example 5 and 6, which is also the amount of nintedanib esylate in commercial 150mg OFEV® capsule) and/or 43% ( See Example 3). TELI’ 961 teaches various amount of nintedanib esylate (30-60 %), Lauroyl polyoxyl-6 glyceride (5 - 25 % w/w ) and medium chain triglyceride (35-65 % w/w) within the suspension composition (See page 12, lines 16-31; Examples 1-6; claims 1-3). TELI’ 961 explicitly teaches LABRAFIL® M 2130 CS (i.e. Lauroyl polyoxyl-6 glyceride) by Gattefosse which is a suitable thickener as compared to hard fat and stabilizes the suspension system, ensures optimal processing and guarantees an adequate capsule quality, especially as far as content uniformity or dissolution behavior is concerned (See page 11, lines 4-12). Where 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. MPEP 2144.05.
Instant claims 8-10 do not recite limitation that excludes lecithin, thus are construed as encompassing embodiments of oral pharmaceutical formulation comprising oily dispersion of nintedanib esylate having instantly claimed formula and other component (including lecithin) that are NOT within the oily dispersion. As such, TELI’ 961 is considered as read on instant claims 8 and 9. TELI’ 961 teaches preparation /manufacturing process of working examples (See page 13, lines 6-15; page 18, lines 8-16) (which reads on instant claim 10).
Although instantly claims 1-7 recites limitation to exclude lecithin, the difference between instant claimed invention and prior art TELI’ 961 is about 0.1 to 0.43% of lecithin as solubilizer which are so slight, an ordinary skilled in the art would consider the difference within the meaning of obviousness under 35 USC §103. It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to further explore/optimize capsule composition comprising nitendanib esylate (30-60 %), medium chain triglyceride (35-65 % w/w) and Lauroyl polyoxyl-6 glyceride (5-25 % w/w ) within the suspension composition taught by TELI’ 961, together with optimization based on general knowledge of oral formulation, and arrive at the instantly claimed invention with reasonable expectation of success. For example, embodiments comprising 43% of nintedanib esylate, 45% of medium chain triglyceride and 25% of lauroyl polyoxyl-6 glyceride encompassed by TELI’ 961 would have read on the ratio limitation of instant claims 2 and 4.
TELI’ 961 is silent about lauroyl polyoxyl-6 glyceride as solubilizing agent/surfactant for nintedanib esylate. As evidenced by Rowe Handbook of Pharmaceutical Excipients (page 557-561, Table IV, IX, X), lauroyl polyoxyl-6 glyceride (polyoxylglyceride) is self-emulsifying, solubilizing agent/dissolution enhancer/ surfactant that is commonly used in oral pharmaceutical formulation. As such, a skilled artisan would have known lauroyl polyoxyl-6 glyceride is multiple-functional excipient as thickener, solubilizing agent/surfactant/ dissolution enhancer for nintedanib esylate. During exploration/optimization for alternative combination of lauroyl polyoxyl-6 glyceride and medium chain triglyceride as the carrier/vehicle for nitendanib esylate, a skilled artisan would be motivated to optimize/use higher amount of multifunctional lauroyl polyoxyl-6 glyceride which is also a solubilizer/surfactant that could have substituted/omitted the function of lecithin as solubilizer/surfactant. A skilled artisan would have reasonably expectation to arrive at minimal amount of lecithin (<0.1%) or omitting lecithin completely in presence of optimized amount of lauroyl polyoxyl-6 glyceride as instantly claimed.
As stated MPEP 2144.04 II, “omission of an element and its function is obvious if the function of the element is not desired or required”. Ex parte Wu, 10 USPQ 2031 (Bd. Pat. App. & Inter. 1989). In instant case, a skilled artisan would have known both lauroyl polyoxyl-6 glyceride and lecithin are solubilizer/surfactant, and composition comprising optimized amount of multiple-functional lauroyl polyoxyl-6 glyceride as carrier/thickener/solubilizer/surfactant for nitendanib would not require additional solubilizer (lecithin). It would have been obvious for a skilled artisan to omit lecithin, since it has been held that omission of an element and its function in combination where the remaining elements perform the same functions as before involves only routine skill in the art. The omission of additional solubilizer/surfactant ( lecithin) would simplify the inactive component to multifunctional lauroyl polyoxyl-6 glyceride and medium chain triglyceride, reduce the variation of multiple components and provide lecithin-free nitendanib composition to patients who are allergic to lecithin.
It’s noted instant application cites Example 3 of TELI’ 961 as control. As stated in MPEP 2144.05, " It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of oral formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jadhav et al. (WO2019106692A1, hereafter “Jadhav’ 692”, Applicant’s IDS 04/14/2023), in view of Rowe et al. (Handbook of Pharmaceutical Excipients, 6th edition, 2009, page 557-561, Polyoxylglycerides ).
Jadhav’ 692 by Sun Pharmaceutical teaches optimization of OFEV® ( Nintedanib esylate) soft gelatin capsules developed by Boehringer Ingelheim. Jadhav’ 692 disclosed gelatin capsules comprising oral suspension comprising: a) nintedanib esylate in an amount ranging from 25% to 50% by weight of the suspension; b) medium chain triglycerides in an amount ranging from about 25% to 55% w/w; c) surfactant having hydrophilic-lipophilic balance value ranging from 8 to 10 and a melting point in the range of 33 °C to 38 °C in an amount ranging from about 4 % to 25 %, preparation process and dissolution profile thereof (See abstract, page 1-3; Examples 1-3, Tables 1-4; claims 1-9).
Jadhav’ 692 explicitly teaches Lauroyl polyoxyl-6 glyceride as preferred surfactant, available under brand name Labrafil® M 2130CS in an amount from about 4 % to 25 %, preferably within 15 % to 25 % by weight of the oral suspension (See page 5, lines 11-14; Examples 1-3). Jadhav’ 692 teaches effect of lauroyl polyoxyl-6 glycerides on the particle size, content uniformity and in-vitro dissolution of the suspension in soft gelatin capsule, wherein 18.2% and 23.8% concentration of lauroyl polyoxyl-6 glycerides, satisfactory results were achieved for capsule dissolution (See page 6, lines 1-10; page 10, lines 20-28).
Jadhav’ 692 teaches embodiments that are very similar to instant claim 8 except lecithin (See page 8, line 20; Examples 1-3). It’s noted Jadhav’ 692 Example 2 comprising the same amount/ concentration of nintedanib esylate and lauroyl polyoxyl-6 glycerides as instant claim 8, wherein the additive amount of medium chain triglyceride (38.36%) and lecithin(0.43%) is calculated to be 38.79% which also reads on instant claim 8.
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Jadhav’ 692 teaches embodiments comprising nintedanib esylate as crystalline or amorphous form at amount from 120 mg to about 180 mg per soft gelatin capsule, which corresponds to 100 mg to about 150 mg of nintedanib base (See page 4, lines 21-27 ) and examples comprising nintedanib esylate 180 mg (equivalent to 150 mg nintedanib base used in OFEV® )(See page 9, lines 9-10). Where 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. MPEP 2144.05.
Instant claims 8-10 do not recite limitation that excludes lecithin, thus are construed as encompassing embodiments of oral pharmaceutical formulation comprising oily dispersion of nintedanib esylate having instantly claimed formula and other component (including lecithin) that are NOT within the oily dispersion. As such, Jadhav’ 692 is considered as read on instant claims 8 and 9. Jadhav’ 692 teaches preparation /manufacturing process of working examples (See page 6, lines 15-30; page 7, lines 1-15; page 9, lines ) (which reads on instant claim 10). The instant claims are product claims. Thus, irrespective of how they were produced, they are examined based the on the structural limitations claimed. See M.P.E.P. § 2113. 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.
Although instantly claims 1-7 reciting limitation to exclude lecithin, the difference between instant claimed invention and prior art Jadhav’ 692 is about 0.1 to 0.43% of lecithin as surfactant which are so slight, an ordinary skilled in the art would consider the difference within the meaning of obviousness under 35 USC §103. It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to further explore/optimize capsule composition comprising nitendanib esylate, medium chain triglyceride and Lauroyl polyoxyl-6 glyceride within the suspension composition taught by Jadhav’ 692, together with optimization based on general knowledge of oral formulation, and arrive at the instantly claimed invention with reasonable expectation of success. For example, embodiments comprising 43% of nintedanib esylate, 45% of medium chain triglyceride and 25% of lauroyl polyoxyl-6 glyceride encompassed by Jadhav’ 692 would have read on the ratio limitation of instant claims 2 and 4.
As evidenced by Rowe Handbook of Pharmaceutical Excipients (page 557-561, Table IV, IX, X), lauroyl polyoxyl-6 glyceride (polyoxylglyceride) is self-emulsifying, solubilizing agent/dissolution enhancer/ surfactant that is commonly used in oral pharmaceutical formulation. As such, a skilled artisan would have known lauroyl polyoxyl-6 glyceride is multiple-functional excipient as carrier/ solubilizing agent/surfactant/ dissolution enhancer for nintedanib esylate that offers more benefit than lecithin as surfactant. During exploration/optimization for alternative combination of lauroyl polyoxyl-6 glyceride and medium chain triglyceride as the carrier/vehicle for nitendanib esylate taught by Jadhav’ 692, a skilled artisan would be motivated to further optimize amount of multifunctional lauroyl polyoxyl-6 glyceride in combination with medium chain triglycerides that could have substituted/omitted the function of lecithin as surfactant. A skilled artisan would have reasonably expectation to arrive at minimal amount of lecithin (<0.1%) or omitting lecithin completely in presence of optimized amount of lauroyl polyoxyl-6 glyceride.
As stated MPEP 2144.04 II, “omission of an element and its function is obvious if the function of the element is not desired or required”. Ex parte Wu, 10 USPQ 2031 (Bd. Pat. App. & Inter. 1989). In instant case, a skilled artisan would have known both lauroyl polyoxyl-6 glyceride and lecithin are surfactant, and lauroyl polyoxyl-6 glyceride is multiple-functional excipient that have beneficial effect to particle size, content uniformity, dissolution profile of nintedanib esylate formulation as taught by Jadhav’ 692. Composition comprising optimized amount of multiple-functional lauroyl polyoxyl-6 glyceride as carrier/solubilizer/surfactant and medium chain triglycerides for nitendanib would not require additional surfactant (lecithin). It would have been obvious for a skilled artisan to omit lecithin since it has been held that omission of an element and its function in combination where the remaining elements perform the same functions as before involves only routine skill in the art. The omission of additional surfactant ( lecithin) would simplify the inactive component to multifunctional lauroyl polyoxyl-6 glyceride and medium chain triglyceride, reduce the variation of multiple components and provide lecithin-free nitendanib compositions to patients who are allergic to lecithin.
As stated in MPEP 2144.05, " It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of oral formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/LIYUAN MOU/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628