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 instant application, filed 12/17/2021, is a 371 filing of PCT/EP2020/067070, filed 06/12/2020, which claims foreign priority to EP19183622.0, filed 07/01/2019, and claims domestic priority to U.S. provisional application 62/863,487, filed 06/19/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Continued Examination Under 37 CFR § 1.114
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and the fee set forth in 37 CFR § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR § 1.114.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 03/13/2026 has been entered.
Amendments and Claim Status
The supplemental amendment filed on 06/11/2026 is acknowledged and entered.
Claims 1 2, 4, 5, 7, 8, 10, 11, 12, 14-17, and 19 are amended;
Claim 13 is cancelled;
Claims 1-12 and 14-20 are pending
Claims 3, 6, 9, 14-18, and 20 remain withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species.
Claim 21 is added;
Claims 1, 2, 4, 5, 7, 8, 10-12, 19, and 21 read on an elected invention and species and are being examined on the merits.
Information Disclosure Statement
The Information Disclosure Statement filed on 08/25/2025 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statement is considered.
Response to arguments
Applicant’s arguments filed 01/10/2026 with respect to the claim rejection under 35 U.S.C. § 103 have been fully considered.
With respect to the rejection of claim 1, 2, 4, 5, 7, 8, 10-13, and 19 under 35 U.S.C. § 103 as being unpatentable over Stadler et al. (J Med Chem 2019, 62, 317−341, published October 5, 2018), hereinafter Stadler, in view of Meanwell (J Med Chem 2011, 54, 2529–2591, published March 17, 2011), the cancellation of claim 13 has rendered the rejection against said claim moot. The relevant claim amendments and arguments made by Applicant, filed on both 01/20/2026 and 06/11/2026, are herein addressed as follows.
In the remarks filed on 01/20/2026, Applicant argues that a person of ordinary skill in the art would lack of reasonable expectation of success in resolving the (S)-enantiomer of compound 37 because Stadler disparages or deemphasizes the phenylether series.
Applicant’s argument is found unpersuasive because a person of ordinary skill in the art would be precisely motivated to modify the compound which does not work well, using well-known substitutions, as outlined by Meanwell, in order to develop novel therapeutics. The relative low activity of compound 37, serves as a perfect starting point for a person seeking to improve the compound’s potency, which is well-recognized by those who use bioisosteric replacements to develop novel therapeutics.
In the remarks filed on 01/20/2026, Applicant argues that Meanwell’s disclosure is not focused on the design of novel GABAAR receptors, and is thus, not considered analogous art.
Applicant’s argument is found unpersuasive because Meanwell’s disclosure does not necessarily focus on the development any particular type of receptors, but rather, general guidelines of developing novel therapeutics using common bioisosteric replacements, independent of the intended target. The mere fact that Applicant is seeking to develop novel compounds makes this art directly analogous and reasonably pertinent to that of the instant disclosure.
In the remarks filed on 06/11/2026, Applicant argues that Stadler’s stated objective was to find GABAAR receptors combining valerenic acid (VA) with the loreclezole (LOR), and that the racemic compound 37 fell well short of the goal, with only compounds 12 and 15 advanced for further study.
Applicant’s argument is unconvincing because a compound need not be a lead compound in order to be prioritized for modification. As stated earlier, poor performance of a compound provides a person of ordinary skill in the art ample motivation to modify the compound so as to improve the compound’s performance. Stadler still discloses compound 37 as a functional, structurally defined GABAAR modulator, which provides basis for an obviousness analysis, regardless of relative activity ranking as compared to other compounds within the same disclosure.
In the remarks filed on 06/11/2026, Applicant argues that under MPEP § 2143.01 (V) and (VI), resolving compound 37 from a racemic mixture into the claimed >90% enantiomeric excess (S)-enantiomer would render it unsatisfactory for its intended purpose, or change its principle of operation. As such, there is no motivation to make the modification.
Applicant’s argument is unconvincing because the cited doctrine addresses modification to defeat a reference’s stated mechanism, and are not centered on several chemical purification of an already disclosed molecule. The more appropriate citation is the enantiomer/racemate doctrine of MPEP § 2144.09 (II), which states that stereoisomers are presumed to have similar properties because they are close in structure. The courts have found,
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) .. are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Absent unexpected results of superior activity of the (S)-enantiomer over the (R)-enantiomer, or the racemic mixture, resolving a racemic mixture into its enantiomers to an enantiomeric excess is considered prima facie obvious—because enantiomers are well-known to commonly differ in potency from each other and the racemate. With only two possible enantiomers, the resolution of S or R to enantiomeric excess is a finite and predictable scenario.
In the remarks filed on 06/11/2026, Applicant argues that under MPEP § 2143.02, there is no reasonable expectation of success, because the final office action never explains why a person of ordinary skill in the art would expect the isolated (S)-enantiomer to be potent, when Stadler disparages the racemate’s potency.
Applicant’s argument is found unconvincing because under MPEP § 2144.09 (II), routine enantiomer resolution is established as prima facie obvious. The burden then shifts to Applicant to show with comparative examples that the instantly claimed (S)-enantiomer composition behaves unexpectedly relative to the racemate or (R)-enantiomer. Applicant has submitted no such data. There is no side-by-side testing of the isolated (S)-enantiomer of compound 37, the (R)-enantiomer, or the racemic mixture of the prior art compound for the instantly claimed elected species. Absent unexpected results, the prima facie case of obviousness as outlined by MPEP § 2144.09 (II) stands.
In the remarks filed on 06/11/2026, Applicant argues that Meanwell fails to disclose anything suggesting the (S)-enantiomer of compound 37 specifically would be potent, so the combined references lack a reasonable expectation of success and motivation to modify.
Applicant’s argument is unconvincing because, the standard doesn’t require a secondary reference to predict the specific outcome for this exact compound. Furthermore, Meanwell is relied upon for the substitution of halogens as bioisosteric replacements. The general state of the art, along with MPEP 2144.09 (II), establishes enantiomer resolution as a routine technique with a reasonably predictable expectation of success.
As such, without comparative data showing that the instantly claimed >90% enantiomeric excess (S) enantiomer composition has unexpectedly superior, or otherwise different properties relative to the racemic mixture or the R enantiomer, Applicant has not met the burden needed to rebut the prima facie case of obviousness. Accordingly, the rejection is maintained.
Thus, all arguments presented by Applicants have been addressed and are found unpersuasive for the reasons presented herein and in the previous Final rejection, filed 10/17/2025. Applicants are again reminded that “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Drawings
The drawings filed on 12/17/2021 objected to under 37 CFR § 1.83(a) for the following reasons:
The different data types are indistinguishable in Figures 4 and 5. The figures lack a figure key to describe the different data types. The figures must be remade with a figure key describing the different types of data found in the figures.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR § 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR § 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 U.S.C. § 112 (a)
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, 2, 4, 5, 7, 8, 11, 12, and 19 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.
Claims 1, 2, 4, 5, 7, 8, 11, 12, and 19 of the instant application are drawn to compounds having following substituents:
R2 is H, F, Cl, Br, I, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R9, and 5-6 membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;
R3 is deuterium and F;
R4 is C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl and C3-5 cycloalkyl each of which may be optionally substituted with one or more, identical or different, substituents R7;
R6 is C3-5 cycloalkyl, —O—C1-5 alkyl, —O—C3-5 cycloalkyl, —S—C1-5 alkyl and —S—C3-5 cycloalkyl each of which may optionally substituted with one or more, identical or different, substituents R8, deuterium, F and —CN;
R7 is C3-5 cycloalkyl, —O—C1-5 alkyl, —O—C3-5 cycloalkyl, —S—C1-5 alkyl and —S—C3-5 cycloalkyl each of which may optionally substituted with one or more, identical or different, substituents R8, deuterium, F and —CN;
R8 is OH, OMe and F;
R9 is deuterium, methoxy, nitro, cyano, CF3, Cl, Br, I and F;
R10 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(═O)—C3-5 cycloalkyl;
R11 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8 and phenyl optionally substituted with one or more, identical or different, substituents R9; and phenyl optionally substituted with one or more, identical or different, substituents R9;
R13 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C3-5 alkyl optionally substituted with one or more, identical or different, substituents R3 and —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R14 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R17, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R15 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R16, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R16, phenyl optionally substituted with one or more, identical or different, substituents R9, and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R17 with the proviso that when R15 is H then R14 is not H;
R16 is F, Cl, Br, I, —CN, =O, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —O—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —O—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —S—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —S—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —SO—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —SO—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —SO2—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —SO2—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different substituents R8, —C(=O)-OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C (=O)-OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C1-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-NH—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R9, —C(=O)-NH—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, phenyl optionally substituted with one or more, identical or different, substituents R9, pyrrolidin-1-yl optionally substituted with one or more, identical or different, substituents R17 and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R17;
R17 is independently selected from the group consisting of F, Cl, Br, I, —CN, =O, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-NH—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(=O)-NH—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R18 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R19 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8 and phenyl optionally substituted with one or more, identical or different, substituents R9;
R20 is H, NH2, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)C1-5, alkyl optionally substituted with one or more, identical or different, substituents R8 and —NH—SO2-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R;
n is an integer 0, 1, 2 or 3;
35 U.S.C. § 112 (a) and the first paragraph of pre-AIA 35 U.S.C. § 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the absence of any working example of the invention as claimed, and the lack of predictability in the art.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
R2 as Cl, I, C3-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R9, and 6 membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;
R3 as deuterium;
R4 as C2-5 alkenyl, C2-5 alkynyl and C3-5 cycloalkyl each of which may be optionally substituted with one or more, identical or different, substituents R7;
R6 as C3-5 cycloalkyl, —O—C3-5 cycloalkyl, —S—C1-5 alkyl and —S—C3-5 cycloalkyl each of which may optionally substituted with one or more, identical or different, substituents R8, deuterium, and —CN;
R7 as C3-5 cycloalkyl,—O—C3-5 cycloalkyl, —S—C1-5 alkyl and —S—C3-5 cycloalkyl each of which may optionally substituted with one or more, identical or different, substituents R8, deuterium, and —CN;
R8 as OH;
R9 as deuterium, methoxy, nitro, cyano, Cl, Br, and I ;
R10 as C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(═O)—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R11 as C2-5 alkyl optionally substituted with one or more, identical or different, substituents R8, and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8 ;
R13 as C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C3-5 alkyl optionally substituted with one or more, identical or different, substituents R3 and —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R14 as C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, and —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R15 as phenyl optionally substituted with one or more, identical or different, substituents R9
R16 as Cl, Br, I, —CN, —O—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —S—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —SO—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —SO—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8,—SO2—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C1-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-NH—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R9, or pyrrolidin-1-yl optionally substituted with one or more, identical or different, substituents R17;
R17 as F, Cl, Br, I, —CN, —C(=O)-OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-NH—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(=O)-NH—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R18 as C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8 and —C(=O)-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8;
R19 as C2-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C4-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8 and phenyl optionally substituted with one or more, identical or different, substituents R9;
R20 as C2-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —OC2-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C(=O)C1-5, alkyl optionally substituted with one or more, identical or different, substituents R8 and —NH—SO2-C2-5 alkyl optionally substituted with one or more, identical or different, substituents R;
n as 2 or 3
The instant specification (pages 48-65, 73-75, 132-164) teaches compounds which are characterized as having only the following substituents:
R2 is H, F, Br, C1-2 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, and 5 membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;
R3 is F
R4 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R7;
R6 is —O—C1-5 alkyl, substituted with F
R7 is —O—C1-5 alkyl, substituted with F
R8 is OMe and F
R9 is CF3 and F;
R10 is H
R11 is CH3 and phenyl optionally substituted with one or more, identical or different, substituents R9;
R13 is H
R14 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R17, and—C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8
R15 is H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R16, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R16, and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R17
R16 is F, =O, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, —O—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —S—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —SO2—C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different substituents R8, —NH—C (=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, —NH—C (=O)-OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R8,—C(=O)-NH—C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, phenyl optionally substituted with one or more, identical or different, substituents R9, and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R17
R17 is =O, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, and —C(=O)-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8,
R18 is H
R19 is CH3 and C3 cycloalkyl
R20 is H, NH2, CH3, CF3, —OCH3 and —NH—SO2-CH3
n is 0 or 1
Therefore, the compounds described in the instant specification detail only a limited number of the total substituents claimed (see substituents 1-18, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 37-54, above).
There are no working examples in the instant specification for the wide range of substituents claimed, but for which evidence of possession has not been provided (see substituents 19-36). Thus the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 1, 2, 4, 5, 7, 8, 11, 12, and 19 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claim Rejections - 35 U.S.C. § 112 (d)
The following is a quotation of 35 U.S.C. § 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. § 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. § 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. § 112(d) or pre-AIA 35 U.S.C. § 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
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Regarding claim 10, the claim recites a compound (found on pages 48-65 and 73-75 of the instant specification) in which R6 is F—such as in (2S)-2-[4-chloro-2-(trifluoromethyl)phenoxy]-N-(cyclopropylmethoxy)propanamide (top right). This is also true for (2S)-2-[4-chloro-2-(trifluoroethylphenoxy]-N-methoxypropanamide (middle left) , and (2S)-2-[4-chloro-2-(trifluoromethyl)phenoxy]-N-(cyclopropylmethoxy)propanamide (bottom right). These limitations contain subject matter that is not within the scope of the claim on which it depends. This determination is based on the definition of R2 and R6 in claim 1, on which claim 10 is based. Specifically, R2 is defined as being C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, and R6 is defined only as being C3-5 cycloalkyl, —O—C1-5 alkyl, —O—C3-5 cycloalkyl, —S—C1-5 alkyl and —S—C3-5 cycloalkyl and not as being F. For all the reasons set forth above, a compound wherein R6 is F is not encompassed by the limitations of instant claim 1, nor is it encompassed by any special definition found within the instant specification. As such, it has been determined that this claim limitation contains subject matter that is not within the scope of the claim on which it depends.
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Further regarding claim 10, the claim recites several compounds (found on pages N-M of the instant specification) in which R15 is alkenyl—such as in (2S)-2-(4-chlorophenoxy)-N-{[(2E)-2-methyl-3-phenylprop-2-en-1-yl]oxy}propanamide (right). This is also the case for (2S)-2-(4-chlorophenoxy)-N-[(3-methylbut-2-en-1-yl)oxy]propanamide (left). These limitations contain subject matter that is not within the scope of the claim on which it depends. This determination is based on the definition of R15 in claim 1, on which claim 10 is based. Specifically, R15 is defined only as being C1-5 alkyl, C3-6 cycloalkyl, phenyl and 4-6 membered heterocycle, and not as being alkenyl. For all the reasons set forth above, a compound wherein R15 is alkenyl is not encompassed by the limitations of instant claim 1, nor is it encompassed by any special definition found within the instant specification. As such, it has been determined that this claim limitation contains subject matter that is not within the scope of the claim on which it depends.
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Further regarding claim 10, the claim recites several compounds (in which R16 is imidazole —such as in (2S)-2-(4-chlorophenoxy)-N-[(2-methyl-1H-imidazol-4-yl)methoxy]propanamide (top right). This is also the case for tert-butyl 4-({[(2S)-2-(4-chlorophenoxy)propanamido]oxy}methyl)-2-methyl-1H-imidazole-1-carboxylate (bottom right). These limitations contain subject matter that is not within the scope of the claim on which it depends. This determination is based on the definition of R16 in claim 1, on which claim 10 is based. Specifically, R16 is not defined as being a heteroaryl or imidazole. For all the reasons set forth above, a compound wherein R16 is imidazole is not encompassed by the limitations of instant claim 1, nor is it encompassed by any special definition found within the instant specification. As such, it has been determined that this claim limitation contains subject matter that is not within the scope of the claim on which it depends.
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Further regarding claim 10, the claim recites several compounds (in which R16 is NH2—such as in (2S)-N-(2-aminoethoxy)-2-(4-chlorophenoxy)propanamide. This limitation contains subject matter that is not within the scope of the claim on which it depends. This determination is based on the definition of R16 in claim 1, on which claim 10 is based. Specifically, R16 is not defined as being amino. For all the reasons set forth above, a compound wherein R16 is amino is not encompassed by the limitations of instant claim 1, nor is it encompassed by any special definition found within the instant specification. As such, it has been determined that this claim limitation contains subject matter that is not within the scope of the claim on which it depends.
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Further regarding claim 10, the claim recites several compounds (in which R16 is OH—such as in (2S)-N-(2-aminoethoxy)-2-(4-chlorophenoxy)propanamide (left). This limitation contains subject matter that is not within the scope of the claim on which it depends. This determination is based on the definition of R16 in claim 1, on which claim 10 is based. Specifically, R16 is not defined as being hydroxyl. For all the reasons set forth above, a compound wherein R16 is hydroxyl is not encompassed by the limitations of instant claim 1, nor is it encompassed by any special definition found within the instant specification. As such, it has been determined that this claim limitation contains subject matter that is not within the scope of the claim on which it depends.
With respect to the example compounds included within the above rejections based on subject matter that is not within the scope of the claim on which it depends: the exemplary compounds are in no way a complete listing of the compounds within the claim. Over 120 unique compounds have been listed in claim 10. In the interest of brevity, only singular examples of the various substituents which contain subject matter that is not within the scope of claim 1 have been included so as to guide Applicant. To make the record clear, many more compounds listed in claim 6 are identified as including subject matter beyond that which is defined by claim 1. Applicant is expected to properly address every instance in which unsupported subject matter is included in all compounds in any forthcoming amendments to claim 10 based on the substituents identified herein. Particular attention should be paid to MPEP § 608.04, regarding new matter upon amendment of the instant dependent claim, as well as the independent claim.
Claim Rejections – 35 U.S.C. § 103
The text of those sections of title 35, U.S. Code not included in this action can be found in the prior Office action.
Claims 1, 2, 4, 5, 7, 8, 10-12, 19, and 21 are rejected under 35 U.S.C. § 103 as being unpatentable over Stadler (see earlier citation), in view of Meanwell (see earlier citation).
The cited claims are drawn to a composition comprising a compound of Formula (I) (see Figure 1a, below) such as 5-[(S)-1-(4-bromo-2-fluorophenoxy)ethyl]-2H-1,2,3,4-tetrazole, which is Applicant’s elected species (see Figure 1c, below).
Regarding claim 1, Stadler teaches a racemic mixture of CAPlus Registry Number: RN 2263970-56-3 [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 2263970-56-3 Entered STN: 31 Jan 2019]. On page 319, scheme 1, compound 37, Stadler teaches an obvious variant of the elected compound, (see Figure 1b). Stadler teaches wherein the compound 37 was derived from a liquid suspension of Et2AlN3 and tetrazole, worked up with sodium nitrite and sodium hydroxide (page 337), thereby teaching a composition comprising said compound.
Figure 1. Prior art compound compared to the elected species of the instant application
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Figure 1. a) Compound 37 taught by Stadler; b) RN 2263970-56-3 as taught by Stadler; b) The elected species 5-[(S)-1-(4-bromo-2-fluorophenoxy)ethyl]-2H-1,2,3,4-tetrazole
R1 is Cl
R2 is Cl
R5 is tetrazole
R4 is methyl
n is 0
the compound is a racemic mixture
Regarding wherein R1 of the prior art compound 37 is Chlorine and R1 of the elected species is Bromine (see claim 21); R2 of the prior art compound 37 is Chlorine and R2 of the elected species is Fluorine, Stadler fails to teach these substitutions explicitly in the disclosure.
The deficiencies of Stadler are remedied by Meanwell, who teaches rational approaches in drug design, which encompass substitutions used by those skilled in the art to develop novel and more potent therapeutics. Specifically, Meanwell teaches that Halogen substitutions are classical bioisosteres in drug design (page 2529-2530, Table 1). More specifically, Fluorine, Chlorine, and Bromine are well-known monovalent bioisosteres. Aside from their designations as classical bioisosteres, Fluorine, Chlorine, and Bromine are all halogens, having the same number of valence electrons and general electron configurations. Any substitution within the group of halogens would result in compounds of similar properties and electronic structure. The courts have determined that such substitutions are considered obvious variants of each other, stating
similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close' structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP § 2144.08(d)).
Thus, substitutions for Fluorine and Bromine in the instant application by Chlorine found in the prior art are considered to be obvious variants. In Ex parte Wiseman, 98 USPQ 277 (1953), it was held that compounds are rejected over prior art when the difference between the claimed compounds and the compounds of the prior art is Fluorine atoms versus Chlorine atoms. The basis of this reasoning is that Fluorine and Chlorine are both halogen elements from the seventh group of the periodic system and the claimed compound is thus an analogue or an isologue of that disclosed in the prior art. The compounds are expected to possess similar properties differing only in degree. Therefore, an ordinary artisan would be motivated to make the halogen substitutions, as the resulting compounds would have similar chemical properties, and the substitutions are known in the art to be modulators of chemical affinity to a drug target.
Regarding the limitation of enantiomeric excess of the (S) enantiomer, this is found to be prima facie obvious. According to MPEP § 2144.09 (II), stereoisomers are presumed to have similar properties because they are close in structure. The courts have found,
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) .. are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Thus, absent unexpected results of the activity of the (S)-enantiomer over the (R)-enantiomer, or the racemic mixture, resolving a racemic mixture into its enantiomers to and enantiomeric excess is considered prima facie obvious—because enantiomers are well-known to commonly differ in potency from each other and the racemate. With only two possible enantiomers, the resolution of S or R to enantiomeric excess is a finite and predictable scenario.
Regarding claim 2, the compound detailed by Stadler in Scheme 1 of the referenced document (page 319) meets the limitations of Formula (II) as described above. In the interest of brevity, all applicable rejections of claim 1 are fully incorporated herein.
Regarding claim 4, R1 is Cl.
Regarding claim 5, R2 is Cl.
Regarding claim 7, R4 is CH3.
Regarding claim 8, the elected species describes a positional isomer of tetrazole. With regard to positional isomers, the courts have stated:
[c]ompounds which are position isomers or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious) (see MPEP § 2144.09). See also In re Ex Parte Ullyot, 103 USPQ 185.
Therefore, the tetrazole of the prior art meets the limitations of the instantly claimed substituent, despite the connectivity position in the ring.
Regarding claim 11, the ability to inhibit the CIC-1 ion channel is an inherent property of the compound. Regarding inherent properties, the courts have stated,
In re Reynolds, 443 F.2d 384, 170 USPQ 94 (CCPA 1971); In re Smythe, 480 F. 2d 1376, 178 USPQ 279 (CCPA 1973); Yeda Research and Dev. Co. v. Abbott GMBH & Co., 837 F.3d 1341, 120 USPQ2d 1299 (Fed. Cir. 2016) ("Under the doctrine of inherent disclosure, when a specification describes an invention that has certain undisclosed yet inherent properties, that specification serves as adequate written description to support a subsequent patent application that explicitly recites the invention’s inherent properties." See MPEP § 2163.07 (a).
Thus, all compounds within Formula (II) are presumed to share the same properties. Therefore, the compound detailed by Stadler can reasonably be used for the purposes of inhibiting the CIC-1 ion channel, although not explicitly taught in the reference.
Regarding claims 12 and 19, Stadler teaches pharmacological testing of the compounds detailed in the manuscript (page 320). Despite not being explicitly taught by the reference, it would be obvious for an ordinary artisan to combine the claimed compounds with a pharmaceutically acceptable carrier, as this is a technique well known in the art.
Correspondence
No claim is allowed.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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