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 17 November 2025 are acknowledged and have been fully considered. Claims 1-13 are pending. Claims 1-13 are under consideration in the instant office action. Claims 14-23 are canceled.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 11 November 2024 and 18 September 2023 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 of Group I (claims 1-13) in the reply filed on 17 November 2025 is acknowledged. Additionally, Applicant’s election of microcrystalline cellulose as diluent type; silicon dioxide as the glidant type; croscarmellose sodium as the disintegrant type; and magnesium stearate as the lubricant type in the reply filed on 17 November 2025 is also acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
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 microcrystalline cellulose as diluent type; silicon dioxide as the glidant type; croscarmellose sodium as the disintegrant type; and magnesium stearate as the lubricant type.
Claims 1-10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Schwab et al. (US 2016/0145216, previously provided) in view of Rumondor et al. (American Pharmaceutical Review, July 30, 2016, newly cited).
Applicants’ claims
Applicants claim a mini-tablet comprising (a) about 1 to about 5 mg of letermovir; and (b) a pharmaceutically acceptable carrier; wherein the mini-tablet has a diameter of from about 1 to about 4 mm, and a total weight of from about 2 to about 15 mg. Dependent claims thereof recite further limitations defining amounts of active, diameter of the mini-tablet, total weight of the mini-tablet, and types of ingredients and their amounts.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Schwab et al. teach amorphous Letermovir and orally administrable solid pharmaceutical formulations thereof (immediate release formulation) (see abstract). Schwab et al. teach an improved isolation of the amorphous API Letermovir and chemically stable galenic formulations thereof having sufficient dissolution properties for oral administration. Further, the present invention relates to oral dosage forms such as tablets or capsules that contain the solid amorphous API Letermovir or pharmaceutically acceptable salts, solvates or hydrates thereof and exhibit sufficient bioavailability thereof. Moreover, the present invention relates to orally applicable pharmaceutical formulations of the solid amorphous API Letermovir or pharmaceutically acceptable salts, solvates or hydrates thereof for use in methods of treatment of viral diseases, in particular in methods of treatment for HCMV infections (paragraph 0036). In another aspect, subject matter of the invention are film-coated tablets containing the amorphous Letermovir in different dose strengths, i.e. 5 mg, or 20 mg, or 30 mg, or 60 mg, or 120 mg, or 240 mg of Letermovir, or >240 mg of Letermovir. Said distinct dose strengths should be not understood as limiting dose strengths. Any other dose strength reasonably administrable to a subject is also comprised by the scope of the present invention (paragraph 0132). In accordance with the invention the “excipients” applied in the solid pharmaceutical formulations do have the function as outlined in table 1 below (paragraph 0318):
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A tablet with diameter of 5.4-5.5 mm with a total weight of 75 mg is disclosed in paragraphs 0409-0410).
It should be noticed that Table 1 teach microcrystalline cellulose, colloidal anhydrous silicon dioxide, polyvinylpyrrolidone (povidone), croscarmellose sodium, and magnesium stearate.
Schwab et al. teach exemplary formulations in table 19 as follows and the tablets can be film coated or non-film coated:
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Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Schwab et al. do not specifically teach a mini-tablet wherein the mini-tablet has a diameter of from about 1 to about 4 mm, and a total weight of from about 2 to about 15 mg as recited in claim 1. Additionally, Schwab et al. do not specifically teach a mini-tablet having 2.5 mg or 2.0 mg of letermovir as recited in claims 2-3; the 2 mm diameter of the mini-tablet as recited in claims 5 and 8; and the total weight of the mini-tablets as recited in claims 6-8. These deficiencies are cured by the teachings of Rumondor et al.
Rumondor et al. teach multiparticulate formulation technology can be beneficial in designing a patient-centric dosage form. One such dosage form is minitablets, which are compressed tablets with typical diameters of one to four millimeters. Minitablets can offer versatile applications, including as a pediatric dosage form, for patients with dysphagia, and uses where rapid or flexible dose adjustments are needed. Variations of the tablet formulation and coating systems can achieve specific functionalities such as orally disintegrating tablets (ODTs), extended release formulations, or gastrointestinal-targeted delivery. Many of the manufacturing unit operations used to produce minitablet-based dosage forms are the same as those employed in manufacturing of larger tablet images. However, due their unique size, some adjustments to the manufacturing processes and testing approaches may be required. These considerations are discussed in this paper, along with perspectives of the challenges and opportunities of designing a minitablet-based dosage forms (abstract). The term “minitablets” commonly refers to compressed tablets with size smaller than typical tablets. Although there are currently no regulatory guidelines that define minitablets (sometimes referred to as microtablets), the term has been used to describe tablets with diameters between one to four millimeters (mm). Since oral dosage forms smaller than 2.5 mm can be considered as oral granules, many minitablet products are focused at this size range, to take advantage of the potential flexibility in dosage form administration (e.g. mixed with soft foods) (see background section). The approximate compression weights for round minitablets with 2, 3, and 4-mm diameters are 7, 20, and 40 mg, respectively. Minitablets with height-to-width ratios close to one are desirable, as this will aid in packaging and dispensing. A deeper cup design may be beneficial for packaging, since it leads to more spherical minitablets. However, minitablets compressed with deeply concaved tooling can have larger tablet density gradients compared to standard or shallow concave designs. Such gradients can lead to tablet attrition during coating, packaging, or other handling steps. The use of tapered die designs can aid in decreasing residual stresses, resulting in smaller or fewer microdefects and more robust minitablets (see Manufacturing and Packaging of Minitablets, Compression of Minitablets section).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Schwab et al. by preparing minitablets with a diameter of from about 1 to about 4 mm or 2 mm as recited in claims 5 and 8 with a total weight of from about 2 to about 15 mg or the total weights as recited in claims 6-8 having 2.5 mg or 2.0 mg of letermovir as recited in claims 2-3 because Rumondor et al. teach multiparticulate formulation technology can be beneficial in designing a patient-centric dosage form. One such dosage form is minitablets, which are compressed tablets with typical diameters of one to four millimeters. One of ordinary skill in the art would have been motivated to split the dosage amount recommended by Schwab et al. into multiple minitblets because Rumondor et al. teach Minitablets can offer versatile applications, including as a pediatric dosage form, for patients with dysphagia, and uses where rapid or flexible dose adjustments are needed. Variations of the tablet formulation and coating systems can achieve specific functionalities such as orally disintegrating tablets (ODTs), extended release formulations, or gastrointestinal-targeted delivery. Many of the manufacturing unit operations used to produce minitablet-based dosage forms are the same as those employed in manufacturing of larger tablet images. However, due their unique size, some adjustments to the manufacturing processes and testing approaches may be required. These considerations are discussed in this paper, along with perspectives of the challenges and opportunities of designing a minitablet-based dosage forms (abstract). The term “minitablets” commonly refers to compressed tablets with size smaller than typical tablets. Although there are currently no regulatory guidelines that define minitablets (sometimes referred to as microtablets), the term has been used to describe tablets with diameters between one to four millimeters (mm). Since oral dosage forms smaller than 2.5 mm can be considered as oral granules, many minitablet products are focused at this size range, to take advantage of the potential flexibility in dosage form administration (e.g. mixed with soft foods) (see background section). With regard to the total weight of the minitablet and the diameter of the minitablet, Rumondor et al. teach that the approximate compression weights for round minitablets with 2, 3, and 4-mm diameters are 7, 20, and 40 mg, respectively. Minitablets with height-to-width ratios close to one are desirable, as this will aid in packaging and dispensing. A deeper cup design may be beneficial for packaging, since it leads to more spherical minitablets. However, minitablets compressed with deeply concaved tooling can have larger tablet density gradients compared to standard or shallow concave designs. Such gradients can lead to tablet attrition during coating, packaging, or other handling steps. The use of tapered die designs can aid in decreasing residual stresses, resulting in smaller or fewer microdefects and more robust minitablets (see Manufacturing and Packaging of Minitablets, Compression of Minitablets section). Furthermore, in the case where the claimed amounts of active agent, diameter of the minitablet, and total weight of the minitablet" 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 measurable parmeters 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 Schwab et al. and Rumondor et al. because both references are drawn to pharmaceutical compositions for the delivery of active agents.
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.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwab et al. (US 2016/0145216, previously provided) in view of Rumondor et al. (American Pharmaceutical Review, July 30, 2016, newly cited) as applied to claims 1-10 and 12-13 above, and further in view of TÜRKYILMAZ et al. (WO 2019/190433, newly cited)
Applicants’ claims
Applicants claim a table formulation composition for the treatment of hyper proliferative disorders comprising a triazolopyrazine derivative and the components as recited in claim 1. Dependent claim 11 recites a composition and the other ingredients with specific amounts.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Schwab et al. and Rumondor et al. are described above in detail and are incorporated herein by reference. Furthermore, Schwab et al. teach a granulate for a tablet in table 19 comprising dosage strength 30 mg of letermovir for which the tablet weight is 75.00 mg, the amount of microcrystalline cellulose is 16.500 mg, the amount of povidone is 2.500 mg, the amount of silica is 0.500 mg, the about of croscarmellose sodium is 1.500 mg, magnesium stearate is 0.300 mg. The examiner calculates that a 7 mg mini-tablet comprising the same weight percentages both active and excipients would result in a tablet with the following amounts: 2.8 mg of letermovir (30 x 7 ÷ 75 = 2.8), 1.54 mg of microcrystalline cellulose (16.5 x 7 ÷ 75 = 1.54), 0.047 mg of silica (0.5 x 7 ÷ 75 = 0.047), 0.23 mg of povidone (2.5 x 7 ÷ 75 = 0.23), 0.14 mg of croscarmellose sodium (1.5 x 7 ÷ 75 = 0.14), and 0.028 mg of magnesium stearate (0.3 x 7 ÷ 75 = 0.028). The tablet after coating is 77.30 mg versus 75.000 mg before coating which means the weight of the coating is 2.30 mg which is 2.97% of the coated tablet weight. 2.97% of 7 mg is 0.208 mg of coating.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Schwab et al. and Rumondor et al. do not specifically teach the specific amounts of each of the ingredients recited in claim 11. These deficiencies are cured by the teachings of TÜRKYILMAZ et al.
TÜRKYILMAZ et al. teach a pharmaceutical composition comprising flurbiprofen or a pharmaceutically acceptable salt thereof in combination with one 5-HT 1 -receptor agonist or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (see claim 1). The pharmaceutical composition according to any preceding claims, wherein the pharmaceutical composition is formulated as tablets, comprising compressed tablets, coated or uncoated tablets, tablet-in-tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets; capsule-in-capsules, pellets, effervescent compositions, pills, capsules, hard or soft gelatin capsules, powders, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions, suspensions, aerosols, sprays, drops, ampoules, suppositories, parenteral systems, creams, gels, ointments, dragees, sachets, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, syrups, colloidal dispersions or emulsions (see claim 10). The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is in the form of a tablet or a coated tablet or a bilayer tablet or a trilayer tablet or a multilayer tablet or a capsule or encapsulated mini tablets or a capsule-in-capsule or tablet-in-tablet (claim 11). The pharmaceutical composition according to claim 1 1 , wherein said flurbiprofen or a pharmaceutically acceptable salt thereof and the 5-HT1 -receptor agonist or a pharmaceutically acceptable salt thereof are in the different forms in one dosage form (see claim 12). The pharmaceutically composition according to claim 12, the different forms are powders, mini tablets, granules, pellets, capsules or beads (see claim 13). TÜRKYILMAZ et al. teach in example 1 tablet that contains ingredients as follows:
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Based on a 7mg, 2mm mini-tablet as taught by Rumondor et al. and the weight percentages taught by TÜRKYILMAZ et al. as shown above, the examiner calculates 10.00-80.00% active in a 7mg mini-tablet is 0.7-5.6 mg of active, 10.00-90.00% of microcrystalline cellulose in a 7mg mini-tablet is 0.7-6.3 mg, 0.10-20% of croscarmellose sodium in a 7mg mini-tablet is 0.007-1.4 mg, 0.01-10% silicone dioxide in a 7mg mini-tablet is 0.007-0.7mg, 0.01-10% magnesium stearate in a 7mg mini-tablet is 0.007-0.7 mg. Given the total coated tablet weight is 100.00-105.00% versus 100.00% for the tablet without the coating the percentage of coating ranges from 0-5% which, based on 7mg tablet is 0-0.35mg. However, one would reasonably expect the weight percentage for the coating on a mini-tablet to be higher than larger size tablets given the surface area to volume ratio increases as the size of a 3-dimensional object decreases one would reasonably expect weight percent of coating to be higher on a mini-tablet compared to a larger size tablet.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Schwab et al. and Rumondor et al. by incorporating letermovir, microcrystalline cellulose, povidone, silica, croscarmellose sodium, and coatings in amounts as recited in claim 11 because TÜRKYILMAZ et al. teach a pharmaceutical composition comprising flurbiprofen or a pharmaceutically acceptable salt thereof in combination with one 5-HT 1 -receptor agonist or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (see claim 1). The pharmaceutical composition according to any preceding claims, wherein the pharmaceutical composition is formulated as tablets, comprising compressed tablets, coated or uncoated tablets, tablet-in-tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets; capsule-in-capsules, pellets, effervescent compositions, pills, capsules, hard or soft gelatin capsules, powders, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions, suspensions, aerosols, sprays, drops, ampoules, suppositories, parenteral systems, creams, gels, ointments, dragees, sachets, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, syrups, colloidal dispersions or emulsions (see claim 10). The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is in the form of a tablet or a coated tablet or a bilayer tablet or a trilayer tablet or a multilayer tablet or a capsule or encapsulated mini tablets or a capsule-in-capsule or tablet-in-tablet (claim 11). The pharmaceutical composition according to claim 1 1 , wherein said flurbiprofen or a pharmaceutically acceptable salt thereof and the 5-HT1 -receptor agonist or a pharmaceutically acceptable salt thereof are in the different forms in one dosage form (see claim 12). The pharmaceutically composition according to claim 12, the different forms are powders, mini tablets, granules, pellets, capsules or beads (see claim 13). TÜRKYILMAZ et al. teach in example 1 tablet that contains ingredients as follows:
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Based on a 7mg, 2mm mini-tablet as taught by Rumondor et al. and the weight percentages taught by TÜRKYILMAZ et al. as shown above, the examiner calculates 10.00-80.00% active in a 7mg mini-tablet is 0.7-5.6 mg of active, 10.00-90.00% of microcrystalline cellulose in a 7mg mini-tablet is 0.7-6.3 mg, 0.10-20% of croscarmellose sodium in a 7mg mini-tablet is 0.007-1.4 mg, 0.01-10% silicone dioxide in a 7mg mini-tablet is 0.007-0.7mg, 0.01-10% magnesium stearate in a 7mg mini-tablet is 0.007-0.7 mg. Given the total coated tablet weight is 100.00-105.00% versus 100.00% for the tablet without the coating the percentage of coating ranges from 0-5% which, based on 7mg tablet is 0-0.35mg. However, one would reasonably expect the weight percentage for the coating on a mini-tablet to be higher than larger size tablets given the surface area to volume ratio increases as the size of a 3-dimensional object decreases one would reasonably expect weight percent of coating to be higher on a mini-tablet compared to a larger size tablet. Furthermore, differences in concentration or amount of active and ingredients 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). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Schwab et al., Rumondor et al., TÜRKYILMAZ et al. because all of the references are drawn to pharmaceutical compositions for the delivery of active agents comprising similar inactive ingredients as described above.
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