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 .
Request for Continued Examination (RCE)
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/17/26 has been entered.
Priority
This application is a 371 of PCT/EP2021/066629 (06/18/2021),
PCT/EP2021/066629 has PRO 63/041,197 (06/19/2020).
Status
Claims 1-3, 5-7, 12, 15-28 are pending. Claims 26-28 were newly presented.
Rejections not reiterated in this action are withdrawn.
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.
Claims 1-3, 5-7, 12, 15-28 are rejected under 35 U.S.C. 103 as obvious over Blatter et al. (WO2017002095).
Blatter teaches acalabrutinib maleate ([0093]: “the invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a] pyrazin-1-yl)-N-(pyridin-2-yl)benzamide maleate.”, “Formula (1) … maleate Form A”; [00223] Example 6; [00239] Example 6.2: “Crystalline Form A maleate salt (sample SP221-MLE-P9)”).
Blatter also teaches a solid dosage form comprising 100 mg ([0059]: “FIG. 32 shows trends in the AUC, Cmax, and for conditioned dogs treated with a formulation of Formula (1) with acidulant and four salt forms of Formula (1). Liquid capsules ("liq cap") (100 mg) were administered for comparison with the solid forms. Solid capsules of 100 mg strength in the clinical formulation of Form I of Formula (1) were administered to dogs prior to or following daily treatment with omeprazole to reduce stomach acidity. The subsequent study phases followed 4 days of dosing with omeprazole (10 mg/day); omeprazole treatment continued throughout the study. An acidulant formulation of Form I of Formula (1) ("FA-3") was compared with the F-l maleate, F-l phosphate, F-l fumarate, F-l tartrate salts, as well as control formulations (F-l free base and F-2) and administered as 100 mg equivalent of free base in capsules.”) including formulations with excipients (Fig. 32, [00341]-[00356]). Blatter teaches formulations of acalabrutinib maleate wherein the amount present is 25-35% w/w (Example 11; Table 21; [0351]-[0356]).
Blatter teaches the significance of solubility for the composition as affected by pH (Example 7; Fig. 24-33), for example due to acid-reducing agents ([00337]-[00338]). Blatter addressed the solubility concerns via formulation including utilizing solubilizers such as mannitol ([00128]-[00131]), disinegrants such as micro-crystalline cellulose ([00116]), excipients including low substituted hydroxypropylcellulose ([00154]) and lubricants such as sodium stearyl fumarate ([00117]).
Although Blatter teaches all of the elements of the claims, Blatter does not teach all of the elements in a single embodiment – i.e., selection of the particle combinations of excipients in the formulation.
One of ordinary skill in the art following the teaching of Blatter and would have considered optimization of the formulation with respect to dissolution rates through routine experimentation using the technique taught by Blatter ([00109]-[00155]; Example 7.2 maleate salt dissolution study; [00342] 0-12h study, Figures 30-32), including the use of the well-known dissolution test system ([0353]: “a U.S. Pharmacopeia Type II apparatus equipped with paddles (at 50 rpm) and 900 mL vessels equilibrated at 37 °C”). One of ordinary skill in the art would have been motivated to vary the solid dosage form composition to improve dissolution characteristics to facilitate bioavailability. Such optimization is well within the level of skill of one of ordinary skill in the art and within their technical grasp such that they would arrive at the claimed invention with a reasonable expectation of success.
Regarding the functional claim limitations such as following “wherein the dosage form satisfies the following conditions: …” these are considered inherent properties of the product and as per MPEP 2112.01:
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
…
“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
are necessarily present in the obvious composition because they have substantially identical composition as the instant invention as claimed. The technical reasoning supporting the conclusion of inherency includes the fact that the prior art discloses the identical chemical formula and solid form formulated in the same manner for the same purpose. Furthermore, one of ordinary skill in the art would have considered optimization of the dissolution profile as taught by Blatter and arrived at the claimed invention in the same manner when screening for solubility (i.e., Example 7).
Regarding claims 5-6 specifying storage stability, Blatter teaches the importance of optimization of the parameter to ensure long-term shelf-life of the compositions ([00112]) and one of ordinary skill in the art performing routine optimization of the formulation as suggested by Blatter would have had a reasonable expectation of success in arriving at the claimed invention.
Regarding claim 7, Blatter teaches AUC and Cmax in vivo studies of the formulations to ensure clinically relevant bioavailable doses with the composition ([0059]-[0060], Figs. 32-33) and one of ordinary skill in the art performing routine optimization of the formulation as suggested by Blatter would have had a reasonable expectation of success in arriving at the claimed invention.
Regarding claims 12, 15-17 specifying the particular ratios of ingredients, Blatter teaches these limitations ([00341]-[00356]) and further any alleged differences would be routinely optimized in the course of formulation as was done by Blatter. One of ordinary skill in the art would need to select from the components and using their high level of experience in the art would arrive at the claimed values in the course of routine experimentation. “[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); MPEP 2144.05.
Regarding claim 18 specifying the particle size, Blatter teaches the same particle size range ([00232]-[00235], Table 8).
Regarding claim 19, Blatter teaches “These formulations, and all of the foregoing formulations, may be prepared as capsules or tablets, with or without coating” ([00355]).
Regarding claims 20-21 specifying the tensile strength of the tablet over time under certain conditions, Blatter teaches tablets that are formed in the same manner as disclosed in the instant specification (Example 11-21) such that one of ordinary skill in the art following the teaching of Blatter would arrive at the invention as claimed using the same process.
Regarding the method of claim 22, Blatter teaches treating mantle cell lymphoma by administration once daily ([0022]; [00141]; [00157]; [00161]).
Regarding claims 23-25 specifying the particular ratios of ingredients, Blatter teaches these limitations ([00116]-[00117], [00131], [00148]-[00152], [00341]-[00356]) and further any alleged differences would be routinely optimized in the course of formulation as was done by Blatter. One of ordinary skill in the art would need to select from the components and using their high level of experience in the art would arrive at the claimed values in the course of routine experimentation. “[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); MPEP 2144.05.
Regarding new claims 26-28 relating to stability and steady states after administration of the product, these functional claim limitations are considered inherent properties of the product and as per MPEP 2112.01 are considered necessarily present in the obvious composition because they have substantially identical composition as the instant invention as claimed. The technical reasoning supporting the conclusion of inherency includes the fact that the prior art discloses the identical chemical formula and solid form formulated in the same manner for the same purpose.
With each of the above claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art in the same field of endeavor. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed with a reasonable expectation of success.
Response to Remarks / Amendment - 35 USC § 103
Applicant argues 1) “the Examiner has not identified a teaching, suggestion, or motivation to modify Blatter to arrive at the recited solid pharmaceutical tablet, and no reasonable expectation of success associated with the proposed modification has been established”; 2) “the Examiner has not explained why a person of skill in the art would specifically select the maleate salt of acalabrutinib for modification over all other salt forms”; 3) “the Examiner has not explained why a person of skill in the art would specifically select both mannitol and microcrystalline cellulose as diluents”, “low substituted hydroxypropyl cellulose as a disintegrant”, “sodium stearyl fumarate as a lubricant”, formulated as a tablet, a dose of 100 mg, and at 15 to 55% by weight over all of the options disclosed by Blatter.
Applicant’s arguments are not persuasive because Blatter specifically teaches formulations of acalabrutinib maleate ([0093]: “the invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a] pyrazin-1-yl)-N-(pyridin-2-yl)benzamide maleate.”, “Formula (1) … maleate Form A”; [00223] Example 6; [00239] Example 6.2: “Crystalline Form A maleate salt (sample SP221-MLE-P9)”) that one of ordinary skill in the art following the teaching of Blatter and would have considered from among the components that Blatter specifically described and employed routine experimentation to optimize dissolution rates through using the technique taught by Blatter ([00109]-[00155]; Example 7.2 maleate salt dissolution study; [00342] 0-12h study, Figures 30-32), including the use of the well-known dissolution test system ([0353]: “a U.S. Pharmacopeia Type II apparatus equipped with paddles (at 50 rpm) and 900 mL vessels equilibrated at 37 °C”) as a tablet ([00351]: “compressed into a tablet (in the case of FA-4)”). One of ordinary skill in the art would have been motivated to vary the solid dosage form formulation to improve dissolution characteristics to facilitate bioavailability. Blatter teaches the significance of solubility for the composition as affected by pH (Example 7; Fig. 24-33), for example due to acid-reducing agents ([00337]-[00338]). Blatter addressed the solubility concerns via formulation including utilizing solubilizers such as mannitol ([00128]-[00131]), disinegrants such as micro-crystalline cellulose ([00116]), excipients including low substituted hydroxypropylcellulose ([00154]) and lubricants such as sodium stearyl fumarate ([00117]). Such optimization to improve therapeutic utility is routine in the art and well within the level of skill of one of ordinary skill in the art. Through following Blatter’s guidance regarding formulation and dissolution experiments one of ordinary skill in the art would arrive at the claimed invention with a reasonable expectation of success. “[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); MPEP 2144.05. Thus, a prima facie case of obviousness of the claimed solid pharmaceutical tablet has been established.
Applicant argues the claimed solid pharmaceutical tablet provides unexpected results compared to the prior art. Applicant further argues that “Examiner has not identified where Blatter provides, e.g., for the pH-dependent dissolution profiles recited in instant claims 1, 2, and 5, the stability profiles recited in instant claims 6, 26, and 27, the bioequivalence properties recited in instant claim 7, and the tablet potency recited in instant claim 28.”
This argument remains unpersuasive. Regarding the claim limitations of dissolution, stability, bioequivalence, and potency, as detailed above, these are considered inherent properties of the product and would necessarily be present in the same obvious product.
Regarding the alleged unexpected results, Applicant argument and data focuses on acalabrutinib free base capsule (C3) compared to the claimed invention. However, Blatter specifically teaches formulations with acalabrutinib maleate that represents the closest prior art for comparison. The data presented in the Specification was fully considered, including Examples 1, 5, 6, 10, 11, and 14 and is not persuasive because the examples do not clearly demonstrate how the results are unexpected given that Blatter teaches studies of the maleate salt, including pharmacokinetics following omeprazole treatment ([00343] “Study 2219-061”) which one of ordinary skill in the art following the teaching would have considered formulation to address the concern of pH dependent solubility as specifically taught by Blatter ([00338]-[00340]: “The bioavailability of Formula (1) may therefore be modified by factors that improve its dissolution. Alternate forms of Formula (1), and acidification of the formulation of Form 1 of Formula (1) were tested in dogs treated with omeprazole 10 mg/day to evaluate the extent to which an alternate form of Formula (1) can overcome the effects of acid-reducing agents.”) and had a reasonable expectation of success in arriving at the invention as claimed. One of ordinary skill in the art following the teachings of Blatter and performing routine optimization of the formulation to address the concerns regarding pH dependent solubility would have utilized the same components suggested by Blatter and performed the suggested optimization and arrived at the claimed invention with an expectation of success.
Double Patenting Rejections
Claims 1-3, 5-7, 12, 15-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of U.S. Patent No. 11059829 in view of Blatter et al. (WO2017002095) as detailed supra and incorporated herein. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims the same compound and maleate salt for use as a pharmaceutical including for treating mantle cell lymphoma.
Claims 1-3, 5-7, 12, 15-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10899770 in view of Blatter et al. (WO2017002095) as detailed supra and incorporated herein. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims the same compound and maleate salt with a disclosed utility for use as a pharmaceutical including for treating mantle cell lymphoma.
Claims 1-3, 5-7, 12, 15-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of U.S. Patent No. 9290504 in view of Blatter et al. (WO2017002095) as detailed supra and incorporated herein. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims the same compound and maleate salt (claim 32) with a disclosed utility for use as a pharmaceutical including for treating mantle cell lymphoma.
Response to Remarks / Amendment - Double Patenting
Applicant argues that the instant claims are distinct from the patents “[f]or similar reasons to those provided above”.
This argument is not persuasive in view of the same reasoning provided above. Furthermore, ordinary skill in the art would consider formulating the pharmaceutical in view of the teaching of Blatter and consider a tablet in the same manner, to address the pH dependent dissolution, and arrive at the claimed invention.
Conclusion
No claims allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626