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 .
Status of the Application
This Office Action is in response to applicant’s arguments filed on 4/24/26. Claims 1-21 have been cancelled. Claims 42-43 have been added. Claims 22-43 are pending. Claims 22-23, 29 have been amended. Claims 22-43 examined herein.
The claim amendments have rendered the 112 rejection of the last Office Action moot, therefore hereby withdrawn.
Applicant’s arguments with regard to the remaining rejections have been fully considered but found not persuasive, therefore maintained for reasons of record and modified below due to the claim amendments.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 22-31, 33-38, 40-41 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1 and 46 of U.S. Patent No. 9,499,553 in view of Ohtani et al. (WO 2014142273, of record) and Dalvi et al. (WO 2019/060604, of record).
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims recite 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide. However, the referenced claims fail to disclose a disintegrant, a lubricant, an excipient, p-toluenesulfonate salt, and a volume-based particle size.
Ohtake et al. teach a method for preventing or treating a disease, such as hyperphosphatemia (claim 29), by administering a compound of formula I (claim 1). A preferred compound of formula I is 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (same structure as the claimed compound of formula I) (claim 46) or a salt thereof (col. 88, lines 40-48). The compositions may be produced by a well-known method using additives such as excipients, lubricants, and disintegrants, such as croscarmellose sodium (col. 91, lines 8-26). The compositions may be administered as a powder via inhalation (col. 90, lines 61-66).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have formulated a composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (same structure as the claimed compound of formula I) (claim 46) or a salt thereof with 12 wt% or more for the disintegrant, 5.3 wt% or more for the lubricant, and 25 wt% or more of the excipient.
A person of ordinary skill in the art would have been motivated to formulate a composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (same structure as the claimed compound of formula I) (claim 46) or a salt thereof with 12 wt% or more for the disintegrant, 5.3 wt% or more for the lubricant, and 25 wt% or more of the excipient because Ohtake et al. already teaches that disintegrants, lubricants, and excipients can be formulated into the compositions. Furthermore, one of ordinary skill in the art would know how to optimize the amounts of disintegrants, lubricants, and excipients based on how much the breakdown into smaller fragments is desired, or how much reduced friction is desired, or how much help towards manufacturing and stability is desired.
Generally, mere optimization of ranges will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “When the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimal or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F. 3d at 1330, 65 USPQ 2d at 1382; lt has been held that it is within the skills in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. In re Boesch, 205 USPQ 215 (CCPA 1980) MPEP 2114.04
Dalvi et al. teach an inhalable dry powder medicament (title and abstract). A dry powder medicament typically contains a micronized active ingredient with a mass median aerodynamic diameter of 1-10 µm. The size of the particle is able to penetrate into the lung on inhalation (page 3, lines 15-21). Preferably, the particle size is d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, d90 = 2.5-9.0 µm (page 11, lines 20-21).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have modified the composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, as taught by Ohtake et al., into a dry powder having a particle size of d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, and d90 = 2.5-9.0 µm, as taught by Dalvi et al.
A person of ordinary skill in the art would have been motivated to formulate the composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, as taught by Ohtake et al., into a dry powder having a particle size of d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, and d90 = 2.5-9.0 µm because both Ohtake and Dalvi et al. teach an inhalable powder formulation, and Dalvi et al. teach the claimed particle size is well-suited for penetration into the lung on inhalation. Therefore, the skilled artisan would have had a reasonable expectation of success in formulating a composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, as taught by Ohtake et al., into a dry powder having a particle size of d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, and d90 = 2.5-9.0 µm.
Response to Arguments
Applicant argues that the referenced claims do not recite the limitations regarding disintegrant at 12 wt%, particle sizes, lubricant, excipient, the p-toluenesulfonate salt, type 1 crystal form, and particle size distributions. Furthermore, combination with Dalvi is improper because the reference teaches an inhalable dry powder medicament, whereas the present claims are drawn to an oral dosage form.
This is not persuasive because the limitation regarding “oral dosage form” is given little patentable weight since the present claims are drawn to a composition. Furthermore, the present composition also recites particle sizes that encompass those described by the cited prior art. Whether the prior art teaches these particles for oral or inhalation administration matters little as it pertains to intended use, just as long as the particle sizes are taught.
Applicant also argues that it would not be obvious to optimize the excipient amounts since no amounts are taught to optimize.
This is not persuasive because even though general ranges may not be disclosed, one of ordinary skill would know how to optimize an excipient in this field of study. Furthermore, one of ordinary skill in the art would know how to optimize the amounts of disintegrants, lubricants, and excipients based on how much the breakdown into smaller fragments is desired, or how much reduced friction is desired, or how much help towards manufacturing and stability is desired.
, 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 of this title, 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.
Claims 22, 25-31, 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Ohtake et al. (US Patent 9,499,553, of record).
The instant claims are directed to a pharmaceutical composition and methods of making a pharmaceutical composition comprising a compound of formula I.
Ohtake et al. teach a method for preventing or treating a disease, such as hyperphosphatemia (claim 29), by administering a compound of formula I (claim 1). A preferred compound of formula I is 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (same structure as the claimed compound of formula I) (claim 46) or a salt thereof (col. 88, lines 40-48). The compositions may be produced by a well-known method using additives such as excipients, lubricants, and disintegrants, such as croscarmellose sodium (col. 91, lines 8-26). The compositions may be administered as a powder via inhalation (col. 90, lines 61-66).
However, Ohtake et al. fail to disclose 12 wt% or more for the disintegrant, 5.3 wt% or more for the lubricant, and 25 wt% or more of the excipient.
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have formulated a composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (same structure as the claimed compound of formula I) (claim 46) or a salt thereof with 12 wt% or more for the disintegrant, 5.3 wt% or more for the lubricant, and 25 wt% or more of the excipient.
A person of ordinary skill in the art would have been motivated to formulate a composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (same structure as the claimed compound of formula I) (claim 46) or a salt thereof with 12 wt% or more for the disintegrant, 5.3 wt% or more for the lubricant, and 25 wt% or more of the excipient because Ohtake et al. already teaches that disintegrants, lubricants, and excipients can be formulated into the compositions. Furthermore, one of ordinary skill in the art would know how to optimize the amounts of disintegrants, lubricants, and excipients based on how much the breakdown into smaller fragments is desired, or how much reduced friction is desired, or how much help towards manufacturing and stability is desired.
Generally, mere optimization of ranges will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “When the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimal or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F. 3d at 1330, 65 USPQ 2d at 1382; lt has been held that it is within the skills in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. In re Boesch, 205 USPQ 215 (CCPA 1980) MPEP 2114.04
Response to Arguments
Applicant argues that Ohtake is a compound patent, not a formulation patent, therefore does not identify any formation problem to solve and provides no guidance on optimizing excipient amounts for this particular compound.
This is not persuasive because Applicant’s interpretation of Ohtake is not correct. The reference clearly teaches a method for preventing or treating a disease, such as hyperphosphatemia (claim 29), by administering a compound of formula I (claim 1). Furthermore, compositions may be produced by a well-known method using additives such as excipients, lubricants, and disintegrants, such as croscarmellose sodium (col. 91, lines 8-26).
Applicant argues unexpected results in terms of a unique formulation challenge due to the low solubility of the active ingredient. The present invention enables the claimed compound to have improved solubility in the gastrointestinal tract by formulation. Furthermore, the present invention enables stable production of formulations having uniformity of or above a certain level in the production of formulations of the claimed compounds.
This is not persuasive because unexpected results must be presented in a declaration format under the following guidelines. It appears there is no support presented in the art with regard to the formulation challenge as well as no hard data with regard to the present invention having stable formulations.
Regarding the establishment of unexpected results or synergism, a few notable principles are well settled. The Applicant has the initial burden to explain any proffered data and establish how any results therein should be taken to be unexpected and significant. See MPEP 716.02 (b). It is applicant’s burden to present clear and convincing factual evidence of nonobviousness or unexpected results, i.e., side-by-side comparison with the closest prior art in support of nonobviousness for the instant claimed invention over the prior art. The claims must be commensurate in the scope with any evidence of unexpected results. See MPEP 716.02 (d). With regard to synergism, a prima facie case of synergism has not been established if the data or result is not obvious. The synergism should be sufficient to overcome the obviousness, but must also be commensurate with the scope of the claims. Further, if the Applicant provides a DECLARATION UNDER 37 CFR 1.132, it must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See MPEP 716.02 (e).
Claims 23-24, 33, 36-38, 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Ohtake et al. (US Patent 9,499,553, of record), as applied to claims 22, 25-31, 34-35, in view of Dalvi et al. (WO 2019/060604, of record).
The instant claims are directed to a pharmaceutical composition and methods of making a pharmaceutical composition comprising a compound of formula I.
Ohtake et al. teach as discussed above, however, fail to disclose a volume-based particle size.
Dalvi et al. teach an inhalable dry powder medicament (title and abstract). A dry powder medicament typically contains a micronized active ingredient with a mass median aerodynamic diameter of 1-10 µm. The size of the particle is able to penetrate into the lung on inhalation (page 3, lines 15-21). Preferably, the particle size is d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, d90 = 2.5-9.0 µm (page 11, lines 20-21).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have modified the composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, as taught by Ohtake et al., into a dry powder having a particle size of d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, and d90 = 2.5-9.0 µm, as taught by Dalvi et al.
A person of ordinary skill in the art would have been motivated to formulate the composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, as taught by Ohtake et al., into a dry powder having a particle size of d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, and d90 = 2.5-9.0 µm because both Ohtake and Dalvi et al. teach an inhalable powder formulation, and Dalvi et al. teach the claimed particle size is well-suited for penetration into the lung on inhalation. Therefore, the skilled artisan would have had a reasonable expectation of success in formulating a composition comprising 7-[[2,3-difluoro-4-[2-[-2-methoxyethyl(methyl)amino]-ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, as taught by Ohtake et al., into a dry powder having a particle size of d10 = 0.4-1.0 µm, d50 = 1.0-3.0 µm, and d90 = 2.5-9.0 µm.
Response to Arguments
Applicant argues that both Ohtake and Dalvi teach an inhalable powder formulation, whereas the present invention is drawn to an oral dosage form.
This is not persuasive because the limitation regarding “oral dosage form” is given little patentable weight since the present claims are drawn to a composition. Furthermore, the present composition also recites particle sizes that encompass those described by the cited prior art. Whether the prior art teaches these particles for oral or inhalation administration matters little as it pertains to intended use, just as long as the particle sizes are taught.
Applicant also argues unexpected results in the form of particle sizes. Specifically, the particle size has a direct and unexpected effect on dissolution property of the claimed compound when compared to a non-pulverized product.
This is not persuasive because Applicant has not provided any reasoning or data as to why this result is unexpected. Furthermore, Applicant is reminded that any showing of unexpected results must be presented in a 132 declaration to rebut a prima facie case of obviousness.
Claim Objections
Claims 32, 39, 42-43 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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 Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623
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