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
Claims 76-95 are pending and are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/09/2023 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application claims benefit to European patent application no. 21 180 485.1 that was filed on June 19, 2021.
Claim Objections
Claims 77-95 are objected to because of the following informalities: Claim 77-89 and 95 depends on the cancelled claim 1. Claim 90-91 depends on cancelled claim 14, claim 92 depends on cancelled claim 16 and claim 93 and 94 depends on cancelled claim 16, Appropriate correction is required.
In the instant office action, Claims 77-89 and 95 will be examined as reading on instant claim 76 and claims 90-93 will be read on dependent and reading on instant claim 89 and claim 94 depending on claim 88, Applicant is however required to correct the dependency.
Claim Rejections - 35 USC § 112
The following is a quotation of the second paragraph of 35 U.S.C. 112:
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 77-95 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 77-95 are vague and indefinite in that there is no clear and positive prior antecedent basis for claim limitations as these claims are depending on the cancelled claims, Absence of what was recited in the cancelled claims it is unclear as to what elements or limitations these claims are based on. It would be remedial to amend the claim to provide a clear antecedent basis for the limitations of each of these claims.
Claims 77-95 are vague and indefinite in that it is impossible to ascertain the metes and bounds of these claims limitations as these claims are depending on the cancelled claims, Absence of what was recited in the cancelled claims it is unclear if these claims are limiting the independent claims in anyway or what is the new limitation it adds to the independent claim. It would be remedial to amend the claim to correct for this issue.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 76, 77, 80, 81, 82, 83, 84 and 85 are rejected under 35 U.S.C. 102 (a) (1) and under 35 U.S.C 102(a)(2) as being anticipated by Bruneau (US 8,293,756)
Instant claims are drawn to a pharmaceutical composition comprising:(i) granules comprising Nilotinib or a physiologically acceptable salt and/or solvate thereof; and (ii) an extragranular phase; wherein the pharmaceutical composition comprises a surfactant which is contained in the extragranular phase, the granules, or both.
Note: It is noted that the instant claims except for claim 76 is dependent on cancelled claims. Please see the claim objection above as to how the examiner is interpreting them.
Bruneau discloses a pharmaceutical composition, especially capsules, comprising granules containing nilotinib or a salt thereof with at least one pharmaceutically acceptable excipient (abstract). Bruneau discloses that their compositions are in the form of solid oral dosage forms such as capsules which are filled with granules of Nilotinib blended with an external phase comprising at least one pharmaceutically acceptable excipient. They further disclose inclusion of a surfactant to the mixture and an example of a particularly useful surfactant, is a poloxamer such as poloxamer 188. They further disclose that It has been found that the use of a surfactant allows for a decrease in concentration of other excipients (such as lubricants) (col.1, lines 44-59). Bruneau discloses that the particularly useful salt of Nilotinib is Nilotinib hydrochloride monohydrate (col. 7, lines 20-25) and discloses in their example in Table 1, Nilotinib hydrochloride monohydrate concentration of 55.2% (col.12, line 11).
Bruneau discloses that their formulation comprises of other excipients such as binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents. They disclose that One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granule and/or solid oral dosage form by routine experimentation and without any undue burden and the amount of each excipient used may vary within ranges conventional in the art (Col.8, lines 12-29). Bruneau discloses surfactants include, but are not limited to, polyoxyethylene-polyoxypropylene block copolymers (also known as poloxamers), alkyl sulfates (e.g., sodium lauryl sulfate, sodium stearyl sulfate, sodium oleyl sulfate and sodium cetyl sulfate), alkyl aryl sulfonates (e.g., sodium dodecylbenzene sulfonate and dialkyl sodium sulfosuccinates), polyethylene glycols and polysorbates. Particularly useful is poloxamer 188 which has an a and b value of 75 and 30 respectively. The surfactant may be present in a concentration of 0 to about 1% by weight of the composition (e.g., by the weight of the capsule fill weight) (col.8, line 57-col.9 line 4) and teaches . Bruneau discloses examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or copovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, N.J.); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum and that the disintegrant may be present in a concentration from about 0 to about 50% by weight of the composition (e.g., by the capsule fill weight) (co.9, lines 5-15). Binders include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA.), hydroxypropyl cellulose hydroxyethyl cellulose and hydroxypropyl methyl cellulose, e.g. METHOCEL from Dow Chemical Corp. (Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides; povidone and gelatin and the binder may be present in a concentration from about 0 to about 50% by weight of the composition (e.g., by the capsule fill weight) (col.9, lines 16-25). Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, and sucrose and the filler may be present in a concentration from about 0 to about 80% by weight of the composition (e.g., by the capsule fill weight. (col.9, lines 26-32). Bruneau discloses that glidant. facilitates the flow of the blended mixture in the processing equipment and teaches examples of pharmaceutically acceptable glidants are disclosed which include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, magnesium carbonate, magnesium oxide and powdered cellulose and the glidant may be present in a concentration from about 0 to 10%, e.g. from 0 to 10%, alternatively about 1%, e.g. 1%, by weight of the total weight of the pharmaceutical composition (col..11, lines 10-17). He discloses that lubricant helps to avoid any sticking in the processing equipment and discloses examples of lubricants, e.g. pharmaceutically acceptable lubricants include, but are not limited to, talc, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, polyethylene glycol, glyceryl behenate, stearic acid, hydrogenated castoril, glyceryl monostearate and sodium stearyl fumarate and the lubricant may be present in a concentration form about 0 to 10%, e.g. 0 to 10%, alternatively about 2%, e.g. 2%, by weight of the total weight of the pharmaceutical composition.(col. 11, lines 19-49).
Therefore the composition disclosed by Bruneau fully anticipates instant claims 76, 77, 80, 81, 82, 83, 84 and 85.
Claims 76, 77, 80- 85, 89 and 95 are rejected under 35 U.S.C. 102 (a) (1) and under 35 U.S.C 102(a)(2) as being anticipated by Reddy et al. (WO 2012/164578) (reference cited in the instant IDS).
Note: It is noted that the instant claims except for claim 76 is dependent on cancelled claims. Please see the claim objection above as to how the examiner is interpreting them.
Instant claims are drawn to a pharmaceutical composition comprising:(i) granules comprising Nilotinib or a physiologically acceptable salt and/or solvate thereof; and (ii) an extragranular phase; wherein the pharmaceutical composition comprises a surfactant which is contained in the extragranular phase, the granules, or both and a process for the preparation of the said pharmaceutical composition comprising the steps of:(a) providing a formulation comprising: Nilotinib or a physiologically acceptable salt and/or solvate thereof, and optionally one or more of the following: - a diluent, - a disintegrant, - a fraction of glidant, - a fraction of lubricant; and - a surfactant or a fraction of surfactant; (b) dry granulating the formulation to obtain granules; (c) optionally, sieving the granules such that during the step of sieving the granules removes large granules not passing a sieve of size 1.60 mm as well as small granules passing a sieve of size 0.80 mm; (d) optionally, providing a surfactant formulation comprising the surfactant or the remainder of surfactant; and(e) optionally, blending the surfactant formulation and the granules.
Reddy et al. discloses a dry granulated pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof and at least one excipient selected from a diluent, binder, disintegrant, surfactant a glidant and a lubricant. (page 3, para 3-4 and page 5 para 6-7). Reddy et al. discloses Diluents, fillers, or bulking agents in addition to the particulate product of their invention may be added in order to increase the bulk weight of the material to be tableted or filled into capsules to make a practical size and they exemplify fillers to lactose, microcrystalline cellulose, dibasic calcium phosphate, calcium phosphate, powdered cellulose, dextrates, isomalt, calcium carbonate, magnesium carbonate, starch, pre-gelatinized starch, and mixtures thereof. They disclose that a binder also sometimes called an adhesive, can be added to a drug-filler mixture to increase the mechanical strength of the granules and tablets during formation and exemplify binders to include starch, microcrystalline cellulose, gelatin, polyvinylpyrrolidone, and sugars such as sucrose, glucose, dextrose, lactose, polyvinyl alcohol and mixtures thereof. They teach one or more disintegrants are included in the compositions to ensure that the formulation has an acceptable dissolution rate in an environment of use such as the gastrointestinal tract and disclose examples of disintegrants suitable for use herein include croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Reddy et al. disclose Suitable surfactants to include polyoxyethylene-polyoxypropylene block copolymers (also known as poloxamers), soluplus (a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate), sodium lauryl sulfate, sodium stearyl sulfate, sodium oleyl sulfate, sodium cetyl sulfate, sodium dodecylbenzene sulfonate, dialkyl sodium sulfosuccinates, polyethylene glycols and polysorbates and teach that their composition has 0.1 to 2 % of surfactant based on total weight of the composition. They disclose use of one or more glidants may be used in compositions to improve flow in low concentrations and suitable glidants for example include silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, tale, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica. Reddy et al. disclose the use of Lubricants to decrease any friction that occurs between the solid and the die wall during manufacturing of formulations and include but not limited to fatty acids, fatty acid salts,
and fatty acid esters such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like (pages 6-7). Reddy et al. further disclose wherein the composition is in the form of capsules and is used in the method of treating Philadelphia chromosome positive chronic myeloid leukemia (reference claims 6-7 and 10). Another embodiment provides composition comprising nilotinib hydrochloride, microcrystalline cellulose, poloxamer, hydrophobic colloidal silica and magnesium stearate which in the form of amorphous nilotinib hydrochloride, anhydrous crystalline nilotinib hydrochloride, crystalline nilotinib hydrochloride monohydrate, crystalline nilotinib hydrochloride dihydrate or combinations thereof. (page 8, para 4-8). They disclose dry granulation process by slugging or roller compaction, method. Reddy et al. further disclose a process of preparing the composition using dry granulation process, Mixing process includes: (i) sifting and blending of nilotinib hydrochloride with one or more pharmaceutically acceptable excipients to form a dry mixture; (ii) followed by filling the dry mixture of step (i) into capsules (page 8, para 1-6)
They further disclose in their examples 1 preparation of the dry granulation of nilotinib with the following compositions, with Nilotinib at 53.45%, Poloxamer at 1.5%, Lactose (diluent, filler) at 39%, Colloidal silicon dioxide (glidant ) at 0.5%, Magnesium stearate (lubricant) at 0.63%, Crospovidone (disintegrant) at 5%. This process reads on claim 89-90 since the steps d and e in the instant claim are optional. The formulation below excludes microcrystalline cellulose (reads on instant claim 85)
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Therefore the composition disclosed by Reddy fully anticipates instant claims 76, 77, 80- 85, 89 and 95 ..
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 78-79, 87-88 and 90-95 are rejected under 35 U.S.C. 103(a) as being unpatentable over by Reddy et al. (WO 2012/164578) (reference cited in the instant IDS) as applied to claims 76, 77, 80- 85 and 89 (in 102 rejection above) further in view of Li et al. (WO 2012/174084)
Note: It is noted that the instant claims except for claim 76 is dependent on cancelled claims. Please see the claim objection above as to how the examiner is interpreting them.
Instant claims are drawn to a pharmaceutical composition comprising:(i) granules comprising Nilotinib or a physiologically acceptable salt and/or solvate thereof; and (ii) an extragranular phase; wherein the pharmaceutical composition comprises a surfactant which is contained in the extragranular phase, the granules, or both and a process for the preparation of the said pharmaceutical composition comprising the steps of:(a) providing a formulation comprising: Nilotinib or a physiologically acceptable salt and/or solvate thereof, and optionally one or more of the following: - a diluent, - a disintegrant, - a fraction of glidant, - a fraction of lubricant; and - a surfactant or a fraction of surfactant; (b) dry granulating the formulation to obtain granules; (c) optionally, sieving the granules such that during the step of sieving the granules removes large granules not passing a sieve of size 1.60 mm as well as small granules passing a sieve of size 0.80 mm; (d) optionally, providing a surfactant formulation comprising the surfactant or the remainder of surfactant; and(e) optionally, blending the surfactant formulation and the granules.
Reddy et al teaches as supra and is applied here in the same manner.
Reddy et al fails to teach the following :
1. Limitations of the surfactant being in the extra granular phase or the first fraction in the granules and the second fraction in the extragranular phase and the relative weight ration of the surfactant in the granular vs extra granular phase, The HLB value of the surfactant and average particle size as measured by sieve analysis and the distribution of the surfactant with the standard deviation between 8.8% and 10.9)% as recited in instant claims 78-79 and 87.
2. Process of dry granulation of the composition performed by roller compaction with the average roller gap and pressure as recited in instant claim 90, and the process as recited in instant claims 91-93
However Li et al. discloses (see example 2 on page 19 - page 21) Nilotinib intermediate A granules which are obtained by spray-drying Nilotinib HCI, citric acid anhydrate, PVP K30, Vitamin E TPGS (surfactant).
Intermediate A was mixed with additional external phase excipients and compressed into tablets.
For example, modified release tablets B (fast release) are then produced by:
a) sieving and blending said Nilotinib intermediate A granules, poloxamer 407
(surfactant), Eudragit L100-55 (diluent), Aerosil (glidant, lubricant),
b) adding magnesium stearate (lubricant) and blending and
c) compressing the blend into tablets.
Modified release tablets C (slow release) are also produced by:
a) sieving and blending said Nilotinib intermediate A granules, poloxamer
407 (surfactant), Eudragit L100-55 (diluent), HPMC K100 LV CR (diluent), Aerosil
(glidant),
b) adding magnesium stearate (lubricant) and blending and
c) compressing the blend into tablets.
An IR (immediate release) capsule is also used as a reference and is produced by:
a) sieving and blending said Nilotinib intermediate A granules, poloxamer 407,
crospovidone (disintegrant), Aerosil (glidant),
b) adding magnesium stearate (lubricant) and blending,
c) roller compacting the blend
d) milling the ribbon and sieving
c) filling into capsules.
As such it would have been prima facia obvious to a person of ordinary skill in Reddy et al and Li et al. to arrive at the instant claims. Reddy et al. discloses dry granulation method for Nilotinib, and Li et al. suggests to use "dry granulation" as an alternative process, as it discloses (see page 16, lines 23-27) "a process of making the composition comprising the steps of blending the pharmaceutically active ingredient, the compound or the small molecule respectively, with the polymer of the invention. The blend can be further processed to form granules by roller compaction, wet granulation, dry granulation etc. The granules may be further processed to form capsules, compressed into tablets or pills. As such the dry granulation method to produce Nilotinib granules to be filled into capsules is a method which is very well known in the pharmaceutical arts including the excipients used in the dry granulation process. In terms of varying the excipients and their amounts in the granulation process, it is well within the purview of a person of ordinary skill in the art to modify these by routine optimization to achieve the most optimal product. Both these references teach poloxamer-188 as being used as a surfactant, as such the surfactant properties instantly claimed will be inherent to the poloxamer used by the references. Further an ordinary skilled artisan would be motivated to include the surfactant in the extra granular phase to improve the properties of the final product, through routing optimization. Further the applicants have not shown any specific advantage with the instantly claimed method or the differences in the granules they have produced with that of those shown in the references. So absence of evidence to the contrary, the instantly claimed process of preparation will yield the same product as those taught by the references which will function in the similary way upon administration to the cancer patient. . As such a person of ordinary skill in the art would be imbued with a reasonable expectation of a reasonable expectation of success with minor variations within the excipient usage in the process of producing granules comprising Nilitinib to be used in a formulation.
Conclusion
76-95 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/ Primary Examiner, Art Unit 1691 .