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 .
Current Status of 18/035,905
This Office Action is responsive to the amended claims and Applicant remarks of 01/23/2026. Claims 1-9 and 11-30 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2021/059139, international filing date 11/12/2021, which claims priority to U.S. Provisional Application No. 63/255,745, filed 10/14/2021, U.S. Provisional Application No. 63/261,945, filed 09/22/2021, U.S. Provisional Application No. 63/216,467, filed 09/21/2021, U.S. Provisional Application No. 63/245,927, filed 09/19/2021, and U.S. Provisional Application No. 63/113,826 , filed 11/13/2020.
The claims largely find support in PRO 63/113,826 and the claims are given the effective filing date of 11/13/2020, with the exception of the following: Provisional applications ‘826 and ‘927 disclose Compound 1 in a range from 1 mg to 100 mg. Amounts over 100 mg find support in ‘467 and are given the effective filing date of 09/21/2021, reading on instant claims 4, 5, 26, and 27. The earliest disclosure of once daily administration is found in [0244] of ‘467. Claim 30 is given the effective filing date of 09/21/2021.
Response to Applicant Remarks and Amendments
Amendments to the Specification
Applicants have made amendments at the following paragraphs of the specification: [0037], [0043], [0044], [0366], [0368], [0045], [0046], [0369], and [0108-0110].
The original disclosure expressly recites "wet granulating the extragranular excipients." While Applicants argue that this is inconsistent with the definition of "extragranular," the specification as filed nonetheless affirmatively uses this language. Given the repeated inconsistencies between process steps and definitions, the artisan would not conclude that only "intragranular" could have been intended. The amendment therefore resolves an ambiguity rather than correcting an unmistakable error.
The originally filed disclosure describes both dry and wet granulation as distinct and well-known processes and associates them with specific formulations and batches. The amendments replacing "dry granulation" with "wet granulation" and vice versa, alter these originally disclosed process designations. Because both processes are technically plausible and disclosed in the application, the original disclosure does not compel one interpretation over the other. These changes therefore constitute substantive revisions rather than correction of obvious errors.
The amendments revising batch numbers and formulation identifiers rely on other portions of the specification to assert correctness. However, the originally filed disclosure presents conflicting batch identifiers and associations. Selecting one set of identifiers over another based on later interpretation does not reflect an obvious clerical error, but instead resolves inconsistencies in the original disclosure. Accordingly, these revisions are not clearly and unambiguously supported.
In each instance discussed above, the originally filed specification contains internally inconsistent disclosures and supports more than one plausible interpretation. Accordingly, Applicants' assertion that "nothing else could have been intended" is not persuasive. The amendments do not merely recite correct typographical or clerical errors, but instead resolve ambiguities and substitute one of multiple possible interpretations. Because the originally filed disclosure does not clearly and unambiguously support the amended language, the amendments introduce new matter.
Regarding the amendments to [0108-0110]. The amendment deleting reference to SEQ ID NO: 22 appears to remove a reference to a sequence listing to present in the originally filed application. This change is understood as a correction of an obvious error and does not introduce new matter.
35 U.S.C. §112
Applicants have corrected an antecedent issue with the limitations “the disintegrant” of claim 1. The amendment to “a disintegrant” resolves this issue and renders the previous rejection moot. The rejection over this issue for claims 1, 13, and 20 are withdrawn.
Applicants have amended claim 1 to include the phrase "a granulation fluid composed of povidone" to correct an antecedent basis issue. Applicants cite Example 4, [0350] as support of "a granulation fluid composed of povidone." However [0350] explicitly discloses that povidone K30 is dissolved in water to obtain the granulation fluid. The disclosed granulation fluid comprises povidone and water, not povidone alone. The specification does not disclose a granulation fluid composed of povidone as now claimed. The amended limitation lacks adequate written description support and is new matter.
Applicants have amended claim 1 to remove the indefinite phrase “an additional amount” with specific percentages of diluent from claim 10. These amendments render the previous rejection moot, and the rejection is withdrawn.
Claim 23 was previously rejected under 35 U.S.C. §112(b) for reciting “wet granulating the extragranular excipients.” Applicants have amended the claim to recite “wet granulating the intragranular excipients,” asserting that no other interpretation could have been intended. This argument is not persuasive. The originally filed application contains internally inconsistent disclosures regarding intragranular and extragranular excipients and their roles in the granulation process. Applicants argue that intragranular excipients are, by definition, added prior to granulation, the originally filed claim and specification expressly recited wet granulation of extragranular excipients. Because both extragranular and intragranular excipients are described in the application and the original language is not facially impossible, the artisan would not conclude that only “intragranular” could have been intended. Rather, the amendment resolves an ambiguity in the original disclosure by selecting one of multiple plausible interpretations. Accordingly, the amendment does not merely correct an obvious error and is not persuasive to overcome the rejection.
35 U.S.C. §103
Applicants allege that the teachings of references Sydorenko, Shotton, and Turkyilmaz fail to teach the instantly claimed tablet compositions. Applicants support their position by highlighting the experimental results of Examples 1-10 of the disclosure. Applicants further allege that the teachings of Sydorenko, which disclose compositions containing the claimed active compound of formula I as part of a tablet including pharmaceutically acceptable excipients, would not have provided a reasonable expectation of success in developing the claimed compositions without undue experimentation.
These arguments are not persuasive. The applied references collectively teach tablet compositions comprising the same active compound and pharmaceutically acceptable excipients, and further teach that excipient selection and the relative amounts of intragranular and extragranular excipients may be adjusted to achieve desired tablet properties. The references additionally establish that such formulation parameters are results-effective variables that can be optimized through routine experimentation.
Examples 1-10 describe iterative formulation development processes involving known techniques, including direct compression, dry granulation, and wet granulation, as well as the use of conventional excipients to address known issues such as flowability, sticking, and dissolution. Such optimizations are within the skill of the artisan and reflect routine optimization of known formulation variables, rather than evidence of non-obviousness.
Specification
The amendment filed 01/23/2026 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: [0037] “wet granulating the intragranular excipients”; [0043] and [0044] “wet granulation Batch 15”; [0045], [0046], and [0366] “dry granulation Batch 20”; [0368] second line “wet granulation Batch 15”, line 4 “dry granulation Batch 20”, line 9 “formulation Batch 15”, line 10 “formulation Batch 20”; [0369] line 1 “Batch 15”.
The reasons why these phrases constitute new matter are discussed above in the response to arguments section.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 112(a) because the amendment adding “a granulation fluid composed of povidone” lacks written description support and introduces new matter. The originally filed specification does not clearly and unambiguously disclose this limitation. The detailed reasons supporting this determination are set forth in the Response to Applicant Remarks and Amendments section, which are incorporated by reference into this rejection.
Claim 23 is rejected under 35 U.S.C. 112(a) because the amendment adding “wet granulating the intragranular excipients” lacks written description support and introduces new matter. The originally filed specification does not clearly and unambiguously disclose this limitation. The detailed reasons supporting this determination are set forth in the Response to Applicant Remarks and Amendments section, which are incorporated by reference into this rejection.
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.
Claims 1-7, 9, 11, 13-18, and 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over Sydorenko (WO 2020/005873 A1, found in IDS filed 05/08/2023) in view of Shotton (Shotton, E, and G S Leonard. “Effect of intragranular and extragranular disintegrating agents on particle size of disintegrated tablets.” Journal of pharmaceutical sciences vol. 65,8 (1976): 1170-4. doi:10.1002/jps.2600650810) and Turkyilmaz (EP 3329908 A1).
Sydorenko teaches pharmaceutical compositions, including tablets, for treating Huntington’s disease (HD) (see abstract, pg. 89, lines 16-21). The reference teaches compounds of Formula (I) as active ingredients in the claimed compositions, and include 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol (Claim 6, Claim 7, Compound 163 pg. 50). The reference teaches target plasma concentrations can be achieved in doses of the compounds varying from 0.1 ng to 10,000 mg (Pg. 83, lines 11-17). The reference provides the following teachings regarding dose administration:
PNG
media_image1.png
298
643
media_image1.png
Greyscale
PNG
media_image2.png
496
631
media_image2.png
Greyscale
(pg 84 line 20 to pg. 85 line 18). The reference teaches the use of one or more pharmaceutically acceptable excipients (pg. 88, lines 15-18) and teaches that pharmaceutically acceptable excipients can be determined by the route of administration (pg. 89, lines 1-2). Exemplary excipients are found beginning on line 4 of pg. 89 and continue through line 29 of pg. 90. Exemplary excipients include inert diluents (celluloses and lactose, pg. 89, line 30), disintegrating agents (croscarmellose sodium pg. 89, line 31), binding agents (povidone pg. 90, line 1), pharmaceutically acceptable surfactants (pg. 92, line 3) and lubricating agents (magnesium stearate, steric acid, or talc pg. 90, line 2).
Sydorenko generally teaches cellulose and lactose as excipients, but does not explicitly disclose microcrystalline cellulose (MCC) or lactose monohydrate. The reference is silent on poloxamers, glidants, and silicon dioxide as acceptable excipients. The reference does not explicitly disclose the claimed ratios of MCC:diluent, the range of MCC present in the tablet, the range of disintegrant present, or the range of povidone (binder present). The reference does not explicitly disclose that the excipients are intragranular or extragranular.
Shotton teaches that using different ratios of intra- and extragranular excipients, or different excipients intra- and extragranularly, can formulate a tablet with improved properties. For drugs absorbed from the GI tract, the particle size of the disintegrated tablet and the disintegration time are both important to obtain the desired dissolution characteristics (pg. 1174, left Col. Final para). These teachings highlight that intra- and extragranular excipients are routinely employed in tablet formulation and that their compositions and placement are results-effective variables that can be optimized to tune the desired tablet properties.
Turkyilmaz teaches orally disintegrating tablets comprising a water soluble and water swellable diluents such as MCC present in ranges from 5-50% by weight [0027-0029], superdisintegrants such as croscarmellose sodium present in ranges from 4-20% by weight [0022-0023], and glidants and lubricants such as magnesium stearate and colloidal silicone dioxide present in ranges from 0.25-5% by weight [003-0035]. The reference teaches that polyvinylpyrrolidone, also known and povidone, is a suitable binder or filler and provides a range of 5-50% by weight for similar excipients [0028-0029].
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
Regarding the ratios of the instant claims, it is the position of the Examiner that such limitations do not distinguish over the prior art. The prior art combination provides a tablet comprising the same drug, excipients and similar concentration ranges. The general conditions of the claims have been met. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See in re Aller, 220 F.2d 454 105 USPQ 233, 235 (CCPA 1955).
Considering these teachings, it would have been obvious to the artisan to formulate Compound 1 as an oral tablet for treating HD by relying on Sydorenko for the active pharmaceutical ingredient and therapeutic use, implementing the specific granulation/placement optimizations taught by Shotton, and employing the excipient set and proportions taught or suggested by Turkyilmaz to ensure tablet stability. The selection and distribution of excipients between intra- and extragranular phases, as well as their relative levels, are results-effective variables routinely optimized in the art. Their application here would merely combine familiar elements according to known methods to yield predictable results (a stable oral tablet for delivery of Compound 1). Thus, the artisan would have been motivated to combine Sydorenko, Shotton, and Turkyilmaz with a reasonable expectation of success.
Claims 1 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Sydorenko, Shotton, and Turkyilmaz in view of Handbook of Pharmaceutical Excipients (Handbook of Pharmaceutical excipients (2009). Pharmaceutical Press).
Sydorenko, Shotton, and Turkyilmaz teach claim 1. The above discussion is incorporated by reference into this rejection. Sydorenko generally teaches lactose as an excipient, but does not explicitly disclose the monohydrate form.
The Handbook of Pharmaceutical Excipients treats lactose monohydrate under the non-proprietary entry lactose, that supports the propositions that a POSITA reading “lactose” in a reference would understand it to encompass the routine pharmaceutical forms/grades, including monohydrate.
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
The artisan would have been motivated to use lactose as part of the tablet composition as taught by Sydorenko. In standard pharmaceutical usage, “lactose” encompasses its recognized forms/grades, including lactose monohydrate, and the artisan would have understood it as such. Accordingly, selecting the monohydrate form is a routine choice from a finite set of known alternatives expected to yield predictable results, and would have been obvious absent evidence of criticality or unexpected results.
Claims 1, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Sydorenko, Shotton, and Turkyilmaz in view of Kaul (Kaul, Goldi et al. “Quality-by-design case study: investigation of the role of poloxamer in immediate-release tablets by experimental design and multivariate data analysis.” AAPS PharmSciTech vol. 12,4 (2011): 1064-76. doi:10.1208/s12249-011-9676-0).
Sydorenko, Shotton, and Turkyilmaz teach claims 1 and 11. The above discussion is incorporated by reference into this rejection. Sydorenko generally teaches surfactants, but does not explicitly disclose poloxamer as a surfactant.
Kaul teaches poloxamer in tablets either acts as a binder by itself or promotes binder action of the binder povidone resulting in increased intragranular cohesion. Additionally, poloxamer was found to mediate tablet dissolution on stability as well (Abstract).
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
The artisan would have been motivated by Sydorenko to formulate a tablet that includes a surfactant excipient. Poloxamers are well known, viable surfactants in tablet formulations. Incorporating a poloxamer would have been a routine selection from recognized alternatives, made with a reasonable expectation of predictable improvements in granulation robustness and dissolution.
Claims 1 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Sydorenko, Shotton, and Turkyilmaz in view of Parikh (Parikh, D. M. (2005a). Handbook of Pharmaceutical Granulation Technology, Second Edition. CRC Press).
Sydorenko, Shotton, and Turkyilmaz teach claim 1. The above discussion is incorporated by reference into this rejection. The references are silent on wet granulation of intragranular excipients.
Parikh teaches that the classical granulation process using either wet or dry methods is employed in the process industries. Pharmaceutical granulation process is used for tablet and sometimes capsule dosage forms. In some applications the process is used to produce spherical granules for the modified release indication or to prepare granules as sprinkles for pediatric patients. The reasons for granulation a pharmaceutical compound are listed as follows 1. To increase the uniformity of drug distribution in the product; 2. To densify the material; 3. To enhance the flow rates and rate uniformity; 4. To facilitate metering or volumetric dispensing; 5. To reduce dust; and 6. To improve the appearance of the product (pg. 2 final para to first para pg. 3).
The artisan would have been motivated to wet granulate the intragranular excipients 1. To increase the uniformity of drug distribution in the product; 2. To densify the material; 3. To enhance the flow rates and rate uniformity; 4. To facilitate metering or volumetric dispensing; 5. To reduce dust; and 6. To improve the appearance of the product. These are well-established, regulatory recognized benefits of wet granulation. The artisan would have reasonably expected that at least one of these advantages would apply to the formulation at issue and would have selected wet granulation with a reasonable expectation of success.
Claims 1 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Sydorenko, Shotton, and Turkyilmaz in view of Handbook of Pharmaceutical Excipients.
Sydorenko, Shotton, and Turkyilmaz teach claim 1. The above discussion is incorporated by reference into this rejection. The references do not explicitly disclose all the claimed ratios and weight percentages of all claimed excipients.
The Handbook of Pharmaceutical Excipients teaches that colloidal silicon dioxide is widely used in pharmaceuticals and teaches that when used as a glidant that its typical concentration range is between 0.1-1.0% (pg. 186 Section 7, Table 1). The reference teaches that magnesium stearate is widely used in pharmaceutical formulations, primarily as a lubricant in tablet manufacture at concentrations between 0.25-5% by weight. The reference also teaches that lactose monohydrate and MCC can be used in tablets for direct compression and that lactose monohydrate and MCC occur as a white powder containing about 73-77% lactose monohydrate to about 23-27% MCC. This range gives a range of the ratio of MCC:lactose monohydrate of 1:2.7 to 1:3.35. This ratio falls within the ±20% tolerance of “about” which yields an MCC range of 25-42%. MCC is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation and direct-compression processes. In addition to its use as a binder/diluent, MMC also has some lubricant and disintegrant properties that make it useful in tableting (pg. 130, section 7). The reference gives the following ranges of MCC for its common uses
PNG
media_image3.png
201
505
media_image3.png
Greyscale
(pg. 131, section 8). The reference teaches that povidone is used in a variety of pharmaceutical formulations, primarily in solid-dosage forms. In tableting, povidone solutions are used as binders in wet-granulation processes (pg. 581, section 7). The reference gives the following ranges of povidone for its common uses
PNG
media_image4.png
178
375
media_image4.png
Greyscale
(pg. 582).
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
Regarding the ratios of the instant claims, it is the position of the Examiner that such limitations do not distinguish over the prior art. The prior art combination provides a tablet comprising the same drug, excipients and similar concentration ranges. The general conditions of the claims have been met. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See in re Aller, 220 F.2d 454 105 USPQ 233, 235 (CCPA 1955).
Considering these teachings, it would have been obvious to the artisan to formulate Compound 1 as an oral tablet for treating HD by relying on Sydorenko for the active pharmaceutical ingredient and theraputic use, implementing the specific granulation/placement optimizations taught by Shotton, and employing the excipients and proportions taught or suggested by Turkyilmaz and the Handbook of Pharmaceutical Excipients to ensure tablet stability. The selection and distribution of excipients between intra- and extragranular phases, as well as their relative levels, are results-effective variables routinely optimized in the art. Their application here would merely combine familiar elements according to known methods to yield predictable results (a stable oral tablet for delivery of Compound 1). Thus, the artisan would have been motivated to combine Sydorenko, Shotton, Turkyilmaz, and the Handbook of Pharmaceutical Excipients with a reasonable expectation of success
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
Prosecution Insights