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 .
Priority
The present Application, filed March 3, 2023, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2021/071366, filed September 3, 2021, which claims priority to U.S. Provisional Patent Application No. 63/075,019, filed September 4, 2020.
Status of the Claims
In the amendment filed March 3, 2023, claims 3, 5-9, 11-12, and 15-17 are canceled, and new claims 18-24 are added. Claims 1, 3, and 10 are amended. Claims 1-2, 4, 10, 13-14, and 18-24 are currently pending.
Information Disclosure Statement
The two information disclosure statements (IDSs) submitted on November 7, 2025 are acknowledged.
Previous Rejections and/or Objections
Any objections and/or rejections raised in the previous Office Action but not reiterated below are considered to have been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim Rejections - 35 USC § 103 – Maintained – Modified in View of Amendment
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 1-2, 4, 10, and 13-14, and 18-24 are obvious over Yao and Tomesch:
Claims 1-2, 4, 10, and 13-14, and 18-24 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. 2019/0231780 to Yao et al. (hereinafter, “Yao”), in view of U.S. Patent No. 8,648,077 to Tomesch et al. (hereinafter, “Tomesch”).
In its Remarks of November 7, 2025, Applicant argues that the Non-Final Office Action of August 7, 2025 does not address the limitation of claim 1 that the recited salt is a crystalline solid (pg. 7 of Applicant’s Remarks, last full paragraph). This argument has been fully considered, but is not found persuasive.
The Office Action notes that the lumateperone tosylate of Tomesch is a solid and, and further notes further notes the crystalline nature of the solid in discussing a number of the claims (see mentions in the previous discussions of claims 12 and 14, for example). Furthermore, as noted more explicitly in the present rejections, which are modified in response to Applicant’s amendments, Tomesch discloses XRD peaks of the solid, crystalline lumateperone monotosylate (see the rejection of amended claims 4 and 18-19, below).
Applicant next argues that Yao and Tomesch do not create a reasonable expectation of success that solid, crystalline salts of d2-lumateperone could be successfully prepared (paragraph spanning the bottom of pg. 7 to the top of pg. 8 of Applicant’s Remarks). To this point, Applicant asserts that forming solid, crystalline salts of (non-deuterated) lumateperone) is difficult and unpredictable, and that d2-lumateperone fails to form several crystalline solid salts that have been formed with non-deuterated lumateperone. This argument has been fully considered but is not found persuasive.
Regarding the assertion that forming solid, crystalline salts of (non-deuterated) lumateperone) is difficult and unpredictable, it may be the case that it was difficult and unpredictable prior to being explored, but it was explored and elucidated in the prior art, such as Tomesch. In particular, Tomesch teaches a method for forming the solid, crystalline tosylate salt of non-deuterated lumateperone, and so the formation of this salt, with the non-deuterated drug, cannot be considered unpredictable nor difficult as of the time of filing.
Regarding the assertion that one would not have had a reasonable expectation of success in forming d2-lumateperone salts because d2-lumateperone salts unexpectedly fail to form several crystalline solid salts that have been formed with non-deuterated lumateperone, this argument seems self-contradicting. Indeed, Applicant acknowledges that Applicant expected d2-lumateperone to form salts in essentially the same manner as does non-deuterated lumateperone (“it was unexpected that d2-lumateperone would not form the same crystalline salts and co-crystals as lumateperone did”). As such, Applicant’s argument arising from this allegedly unexpected observation appears to be more suited to a rebuttal of the prima facie case of obviousness, based on unexpected results, rather than an argument that the prima facie case is lacking because one of skill in the art would not have had a reasonable expectation of success in making the claimed solid, crystalline d2-lumateperone salts.
Considering Applicant’s argument as an asserted rebuttal of the prima facie case of obviousness, based on the allegedly unexpected result that d2-lumateperone has markedly different crystallization properties than does non-deuterated lumateperone, the evidence of record is found insufficient to support such a rebuttal. On this point, the present record includes a generalized description in the specification regarding an inability to form certain salts with d2-lumateperone (e.g. cyclamate and 4-aminosalicylate salts) that had previously been produced with non-deuterated lumateperone. There is, however, no specific statements regarding conditions used and whether, for example, exact conditions known in the art to produce a given non-deuterated lumateperone salt crystal have been found incapable of producing the equivalent d2-lumateperone salt crystal.
The present record supports that one of skill in the art would, as of the priority date of the present Application, have known of the benefits of d2-lumateperone and of lumateperone tosylate, and would have reasonably expected success in applying the method of Tomesch to free base d2-lumateperone to combine these benefits. While a showing that d2-lumateperone does not form salt crystals under conditions in which non-deuterated lumateperone does might be considered a surprising result, If Applicant wishes to rebut the prima facie case of obviousness based on such a surprising result, a more detailed showing of the evidence is needed.
The rejections for obviousness, as modified in view of the amendments are maintained.
Reiterated, albeit modified, rejection:
Claim 1 recites 2,2-d2-l-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (d2-lumateperone), in the form of a salt selected from a mono-tosylate salt, and specifies that the salt is a crystalline solid. Claim 10 recites a method of making a salt according to claim 1, comprising
reacting free base d2-lumateperone with an acid selected from hydrochloric acid and
toluenesulfonic acid, and
recovering the salt thus formed
Yao teaches deuterated heterocycle fused gamma-carbolines (Abstract). In particular, Yao teaches a compound of Formula II
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in free or salt form. The compound of Formula II is d2-lumateperone. Moreover, Yao explicitly describes the tosylate salt as a disclosed form of d2-lumateperone (paragraph [0017]). Yao further teaches that the compound of d2-lumateperone (Example 2) has superior metabolic stability in mice than does non-deuterated lumateperone (see Example 5). While Yao provides a working example of a tosylate salt of an alternative deuterated lumateperone (paragraph [0217]), Yao does not disclose a working example of a tosylate salt, or any other salt, of the compound of Formula II (d2-lumateperone), but merely discloses it in concept.
Tomesch teaches toluenesulfonic acid (tosylate) salts of non-deuterated lumateperone and methods of making and using the salts (Abstract), and further teaches that these salts have improved stability (col. 2, lines 35-39). In particular, Tomesch teaches a method of forming lumateperone tosylate involving dissolving lumateperone free base, which is a liquid (paragraph [col. 1, lines 59-61]) in isopropanol and adding p-toluenesulfonic acid monohydrate (col. 9, lines 24-36). Tomesch further teaches collecting, by filtration, the solid lumateperone tosylate that forms, confirmed to be a monotosylate by mass spectrometry and NMR (col. 9, lines 42-48). This is the method of instant claim 10, applied to non-deuterated lumateperone, rather than to d2-lumateperone, and it produces lumateperone tosylate rather than the claimed d2-lumateperone tosylate. In addition to describing the monotosylate salt of non-deuterated lumateperone as a solid, Tomesch teaches it is crystalline by disclosing XRD peaks for the salt (also referred to as Form A, see Table 4, beginning at col. 13, line 37).
It would have been obvious to apply the method of forming lumateperone tosylate, as taught by Tomesch, to the d2-lumateperone free base of Yao; in order to take advantage of the metabolic stability of d2-lumateperone and the chemical stability of lumateperone tosylate. Furthermore, one would have had a reasonable expectation of success in obtaining the corresponding tosylate salt, d2-lumateperone tosylate, by applying the method of forming lumateperone tosylate to its deuterated analog, d2-lumateperone. As such, claims 1 and 10 are obvious over Yao and Tomesch.
With respect to claim 2, Tomesch teaches the lumateperone tosylate is 93.2% pure as evaluated by HPLC (col 9, lines 45-47), i.e. substantially free of other forms of lumateperone. One would have had a reasonable expectation of success in obtaining a similar result when applying the method of Tomesch to the d2-lumateperone of Yao.
With respect to claim 4, Tomesch discloses a table (Table 4, beginning at col. 13, line 37) of diffraction peaks that indicates the diffraction pattern of the non-deuterated lumateperone monotosylate of Tomesch is substantially the same as the diffraction pattern of the d2-lumateperone monotosylate of instant Figure 2, and further discloses several images of diffraction patterns (e.g. Tomesch Figure 7a, see below) that confirm the diffraction pattern is substantially the same as that of instant Figure 2.
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Above: Instant Figure 2 (top) and Figure 7 of Tomesch (bottom).
With respect to claim 12, as noted above with respect to claim 10, Tomesch teaches reacting lumateperone with toluenesulfonic acid and recovering the salt thus formed. Because the purpose of “purifying” is not afforded patentable weight, as discussed above, claim 12 is obvious over Yao and Tomesch for the same reasons that claim 10 is obvious over Yao and Tomesch. With respect to claim 13, Yao teaches a method of treatment or prophylaxis of a central nervous system disorder, comprising administering to a patient in need thereof. The method of treatment of Yao comprises administering a therapeutically effective amount of, for example d2-lumateperone (paragraph [0046]). Yao further teaches the central nervous system disorder can be a disorder involving serotonin 5-HT2A, dopamine D1/D2 receptor system and/or serotonin reuptake transporter (SERT) pathways (paragraph [0047], 7.5). It therefore would have been obvious to utilize the crystal of Yao/Tomesch in such a method.
With respect to claims 18 and 19, Figure 7 of Tomesch (see above) as well as Table 4 of Tomesch indicates that the non-deuterated lumateperone monotosylate of Tomesch has substantially the same XRD peaks as does the d2-lumateperone monotosylate of the instant claims.
With respect to claim 20, Yao teaches wherein the compound has greater than 90% incorporation of deuterium at the indicated deuterated positions of the structure (paragraph [0023], 1.5 and 1.8). With respect to claim 21, Tomesch teaches a pharmaceutical composition comprising a salt crystal disclosed by Tomesch (e.g. lumateperone tosylate) together with a pharmaceutically acceptable diluent or carrier (col 5, line 66 to col. 6, line 2). With respect to claims 22-24, Yao teaches that, in the disclosed method for the treatment or prophylaxis of a central nervous system disorder, the disorder can suitably be selected from a wide variety, such as depression or anxiety (paragraph [0047], 7.1).
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 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 ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629