Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of 17/641,705
Claims 1, 3-4, 8, 13, 15, 19-20, 22-23, 25-26, 28-31, 33-43, 45, and 106 are currently pending.
Priority
Instant application 17/641,705, filed 3/9/2022, claims priority as follows:
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Support for the instant claims is found in the provisional application.
Information Disclosure Statement
All references from the IDS’s submitted on 1/5/2023, 3/2/2023, 10/22/2024, 3/27/2025, 10/21/2025, and 2/5/2026 have been considered unless marked with a strikethrough.
Response to Arguments/Amendments
The amendment filed 2/5/2026 has been entered. Claims 1, 13, 15, 19, 20, 22, and 23 have been amended. Claims 12 and 18 have been cancelled, and claim 106 has been added, but is not considered new matter.
Claims 1, 13, 20, 26, 28, 30-31, 36, and 43 were rejected under 35 U.S.C. 112(b) in the Non-Final dated 11/5/2025. In response, Applicant has struck through the term “comprising” in reference to the solvents of the reaction in claim 1, but not in claims 13, 20, 26, 28, 30-31, 36, and 43. However, the Examiner has reassessed and considers the term broad, but not indefinite. Thus, the rejection is withdrawn.
In the Non-Final dated 11/5/2025, claim 12 was rejected under 35 U.S.C. 102(a)(1). In response, Applicant has cancelled claim 12, which overcomes the rejection. Thus, the rejection is withdrawn.
Claims 1, 3-4, and 8 were rejected under 35 U.S.C. 103 in the Non-Final dated 11/5/2025. In response, Applicant has amended instant claim 1 to incorporate the subject matter of claims 12 and 18, which overcomes the rejection. Thus, the rejection is withdrawn.
During the search, additional prior art was identified that teaches claims previously indicated as allowable. See the 103 rejection below. Therefore, this Office Action is considered a second Non-Final.
Claim Interpretation
Claims 3, 4, 8, 22, 25, 28, 33, 35, 37, 39, 40, and 106 recite the term, “about” in reference to numerical values limiting the process of preparing a compound of Formula I. The instant specification defines the term “about” as an acceptable error for a particular value as determined by one of ordinary skill in the art (page 62, lines 17-21). Examples of the interpretation of “about” disclosed in the instant specification include within 1, 2, 3, or 4 standard deviations and within 0.05%-30% of a given value range. The term “about” is considered a relative term, and because the term limits different numerical values in the process of the instant claims, one of ordinary skill would not immediately know the acceptable error for each particular value. Thus, the term “about” is currently being interpreted in the broadest sense as defined by Applicant as ±30%.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 3, 4, 8, 13, 15, 19, 20, 22, 23, 25, 26, 28, and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Neurocrine Biosciences, Inc. (WO 2017/112857 A1, cited in the IDS of 1/5/2023, herein after “Neurocrine”) in view of Haj (WO 2019/104141 A1, cited in the IDS of 1/5/2023) and Wang (US 2010/0184814 A1). Though the Neurocrine reference shares a common Applicant and common inventors, it was published more than a year before the effective filing date of the instant application and thus qualifies under 102(a)(1) prior art.
Determining the scope and contents of the prior art
The reference Neurocrine teaches the synthesis of valbenazine ditosylate (abstract), also known as (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), which is the same compound as instant Formula I recited in claim 1. Specifically, Neurocrine teaches the following synthesis (page 60):
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In which the camphorsulfonate salt compound is the same compound as instant Formula F6-CSA, the compound with the Boc-protected valine attached to the benzo[α]quinolizine core is the same compound as instant Formula F8, and the ditosylate salt product is the same as instant Formula I. Though not explicitly depicted in the scheme, Neurocrine teaches that the camphorsulfonate salt is converted to the free base in situ after addition of 1N sodium hydroxide to a mixture of the camphorsulfonate salt and dichloromethane at 25±5°C (page 56), which is the same as the conversion of instant Formula F6-CSA to instant Formula F6, respectively. This also helps teach instant claims 19, 20, and 22. Additionally, Neurocrine teaches the conversion of Formula F6 and F7 to F8 in dichloromethane with EDC·HCl and DMAP (page 56), which also helps teach claims 13 and 15. Finally, Neurocrine teaches the production of instant Formula F8 after free basing from the HCl salt (page 61, para [00171] and page 58, para [00167]), which then undergoes the final product formation with 2.0 molar equivalents of p-toluenesulfonic acid in acetonitrile at 50°C, and cooled to 25°C before product isolation, which helps teach claims 3, 4, 8, and 106. The Examiner notes the equivalency and temperature disclosed by Neurocrine currently satisfies the limitations of “about 2.1:1 molar equivalents”, “about 50°C”, and “about °C” in accordance with Applicant’s definition of “about” on page 62, lines 17-21 in the instant specification. See the claim interpretation section above.
Regarding claims 23, 25, 26, and 28, Neurocrine teaches the resolution of 3-isobutyl-9, 10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-α]isoquinolin-2-ol:
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also known as instant Formula F5, to Formula F6-CSA with 1 equivalent of (1S)-(+)-camphorsulfonic acid in 19:1 ethanol:water (page 55). The Examiner notes the ratios of CSA to compound and ethanol to water of Neurocrine currently satisfy the limitations of the instant claims in accordance with the definition of “about” as disclosed above.
The reference Haj teaches the direct conversion of Compound 2, known as instant Formula F8, to VLB ditosylate, known as instant Formula I with p-toluenesulfonic acid (page 7):
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The reference Wang teaches the deprotection of a Boc-Valine moiety on a different skeleton with p-toluenesulfonic acid in acetonitrile (page 13, page [0255]):
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Depicted with more clarity on SciFinder:
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Ascertaining the differences between the prior art and the claims at issue
The reference Neurocrine fails to teach the conversion of instant Formula F8 to instant Formula I without going through the HCl salt or the free base, and thus fails to teach the p-toluenesulfonic acid deprotection in acetonitrile.
The reference Haj fails to teach the additional steps of the synthesis to Formula I recited in the instant claims.
The reference Wang fails to teach the synthesis of valbenazine ditosylate.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of synthetic routes of valbenazine salts. An artisan possess the technical knowledge necessary to make adjustments to the valbenazine salts to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said synthetic routes of valbenazine salts and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (A), it would have been prima facie obvious to one of ordinary skill in the art to combine the processes of Neurocrine, Haj, and Wang to improve known syntheses of instant Formula I, also known as valbenazine ditosylate. A skilled artisan would be motivated before the effective filing date to combine the references to discover additional methods of synthesis and to optimize the current synthesis of instant Formula F1. Additionally, one skilled in the art would have reasonably predicted that such a combination would result in a successful, improved process for producing the compound in light of the teachings of Neurocrine, Haj, and Wang.
Claim Objections
Claims 29-31, 33-43, and 45 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
Claims 1, 3-4, 8, 13, 15, 19-20, 22-23, 25-26, 28, and 106 are rejected. Claims 29-31, 33-43, and 45 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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