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 .
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.
Current Status of 17/771,391
This Office Action is responsive to the amended claims received 1 May 2026.
Claims 1-14 and 20-23 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent application PCT/US2020/056797 (filed 22 October 2020) and 62/925,395 (filed 24 October 2019) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Response to Amendments
The 35 U.S.C. 102(a)(1) rejections to the claims, present in the previous office action, are partially maintained herein, but they have been altered as necessitated by Applicant’s amendments.
The 35 U.S.C. 103 rejections to the claims, present in the previous office action, are partially maintained herein, but altered as necessitated by Applicant’s amendments. New rejections under 35 USC 103 are presented herein, as necessitated by Applicant’s amendments.
Response to Arguments
Applicant's arguments received 1 May 2026 have been fully considered.
Applicant argues that because claims 1 and 9 now require the serine/threonine kinase-dependent disease to be specifically a casein kinase 1-dependent disease, the Examiner’s rejections of these claims should be withdrawn. The Examiner has provided evidence, through several references, that all of the diseases discussed by the Examiner’s earlier cited references do, in fact, depend upon casein kinase-1.
Applicant argues that PALOMA does not teach a compound that falls within the scope of claim 7 or claim 14, as currently amended. The Examiner has withdrawn the 35 USC 102 rejections of instant claims 7 and 14, and the claims that depend thereupon, based upon PALOMA.
Applicant argues that neither MOSTERT nor SHERIDAN teach or suggest a neurodegenerative disease from the narrow list of such diseases in claim 7. The Examiner has withdrawn the rejection of instant claim 7 based upon MOSTERT and SHERIDAN, due to Applicant’s amendments.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 6, 9, and 12-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
KIM (Kim, H.J.; Kang, S.K.; Mun, J.Y.; et al. “Involvement of Akt in mitochondria-dependent apoptosis induced by a cdc25 phosphatase inhibitor naphthoquinone analog” FEBS Letters 555 (2003) 217-222)
as evidenced by:
EBERT (Ebert, B.L.; Kronke, J. “Inhibition of Casein Kinase 1 Alpha in Acute Myeloid Leukemia” N ENGL J MED 379;19; November 8, 2018).
KIM teaches the use of 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (referred to as DDN therein, shown below) to induce apoptosis in human promyelocytic leukemia HL-60 cells (abstract). The DDN compound of KIM, which is identical to Formula (IX) of instant claim 9, can be shown to fall within the scope of instant claim 1. Defining the variables of instant claim 1 as follows produces the DDN compound of KIM: X, Y, and Z are each direct bonds; R2 and R3 are each H; R1 is chloro; F is OH; D is –C(=O)-; and E is chloro.
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EBERT teaches that acute myeloid leukemia cells were shown to be more sensitive to pharmacologic casein kinase 1 alpha (CK1α) inhibition as compared to normal hematopoietic cells (2nd paragraph of Pg. 1873). Therefore, EBERT teaches that leukemia has been shown to be a casein kinase 1-dependent disease, as is instantly claimed.
Regarding claims 6 and 12-13: Whether the compounds of formulae VIII-X are inhibitors of particular kinases is based entirely upon the structure of these compounds. In other words, the inhibitory ability of these compounds cannot be separated from their structure. As described above, KIM anticipates the method of claim 9. Therefore, claims 12-13 are also rendered anticipated.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
PALOMA (Bermejo-Bescos, P.; Martin-Aragon, S.; Jimenez-Aliaga, K.L.; et al. “In vitro antiamyloidogenic properties of 1,4-naphthoquinones” Biochemical and Biophysical Research Communications 400 (2010) 169–174)
as evidenced by:
SUNDARAM (Sundaram, S.; Nagaraj, S.; Mahoney, H.; et al. “Inhibition of casein kinase 1δ/ε improves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s disease” Scientific Reports | (2019) 9:13743 | https://doi.org/10.1038/s41598-019-50197-x).
PALOMA teaches the use of 1,4-naphthoquinones to inhibit Beta-secretase (BACE) (abstract). PALOMA teaches 3-Phenyl-5-hydroxy-1,4-naphthoquinone, drawn below, as compound 14 therein (Table 2). Compound 14 of PALOMA can be shown to fall within the scope of instant claim 1. Defining the variables of instant claim 1 as follows produces compound 14 of PALOMA: X, Y, and Z are each direct bonds; R2 and R3 are each H; R1 is a phenyl ring; F is H; D is –C(=O)-; and E is H. PALOMA teaches that the compounds therein that inhibit BACE activity can be used for the treatment of Alzheimer’s disease (conclusion section).
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SUNDARAM provides evidence that casein kinase 1 (CK1) isoforms ε and δ “are significantly upregulated in [Alzheimer’s disease]”. SUNDARAM also provides evidence that inhibition of CK1 with a small molecule improved cognition and decreased the amyloid burden in a mouse model of Alzheimer’s disease (abstract). Therefore, SUNDARAM provides evidence that Alzheimer’s disease is a casein kinase 1-dependent disease.
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.
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, 7-8, 14, and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over:
PALOMA (Bermejo-Bescos, P.; Martin-Aragon, S.; Jimenez-Aliaga, K.L.; et al. “In vitro antiamyloidogenic properties of 1,4-naphthoquinones” Biochemical and Biophysical Research Communications 400 (2010) 169–174)
in view of:
PATANI (Patani, G. A.; LaVoie, E. J. “Bioisosterism: A Rational Approach in Drug Design” Chem. Rev. 1996, 96, 3147-3176.)
as evidenced by:
SUNDARAM (Sundaram, S.; Nagaraj, S.; Mahoney, H.; et al. “Inhibition of casein kinase 1δ/ε improves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s disease” Scientific Reports | (2019) 9:13743 | https://doi.org/10.1038/s41598-019-50197-x).
Teachings of PALOMA and evidence provided by SUNDARAM are discussed in the rejections above. SUNDARAM provides evidence that Alzheimer’s disease is a casein kinase 1-dependent disease.
PALOMA teaches the use of 1,4-naphthoquinones to inhibit Beta-secretase (BACE) (abstract). PALOMA teaches 3-Phenyl-5-hydroxy-1,4-naphthoquinone, drawn below, as compound 14 therein (Table 1). PALOMA teaches that the compounds therein that inhibit BACE activity, including compound 14, can be used for the treatment of Alzheimer’s disease (conclusion section).
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Compound 14 of PALOMA does not fall within the scope of instant claims 7 or 14 because those claims do not allow R1 to be a phenyl ring. PATANI teaches, within the “Ring Equivalents” section on page 3158, that benzene and pyridine are “classical bioisosteres” for each other. Figure 31 of PATANI provides an example of an antihistamine compound, wherein the potency was tuned by replacing a phenyl moiety with a pyridyl moiety.
It would have been obvious to one of ordinary skill in the art to replace the phenyl ring of compound 14 of PALOMA with a pyridyl ring (as taught to be a classical isosteric replacement by PATANI), for the purpose of tuning the BACE inhibitory activity of compound 14. The artisan would have expected success in this replacement, because PATANI teaches that this replacement is well known in the literature and provides specific examples of using this replacement to tune the biological effect of small molecules. Defining the variables of instant claim 7 as follows produces the obvious pyridyl derivative of compound 14 of PALOMA: X, Y, and Z are each direct bonds; R2 and R3 are each H; R1 is a pyridyl ring; F is H; D is –C(=O)-; and E is H.
Regarding claims 20-23: PALOMA teaches, within section 2.4, the details of the BACE enzyme assay discussed therein. The assay was carried out in sodium acetate buffer with the BACE enzyme and each of the 1,4-naphthoquinone compounds investigated therein (section 2.4 and Table 1). This aqueous buffered solution of each of the compounds of PALOMA reads on the instantly claimed pharmaceutical compositions of claims 20-23.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over:
MOSTERT (Mostert, S.; Petzer, A.; Petzer, J. “Evaluation of Natural and Synthetic 1,4-naphthoquinones as Inhibitors of Monoamine Oxidase” Chem Biol Drug Des 2016; 87: 737–746)
in view of:
SHERIDAN (Sheridan, R.P. “The Most Common Chemical Replacements in Drug-Like Compounds” J. Chem. Inf. Comput. Sci. 2002, 42, 103-108)
as evidenced by:
CHIA (Chia, R.; Haddock, S.; Beilina, A.; et al. “Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7” NATURE COMMUNICATIONS; 5:5827; 2014).
CHIA provides evidence that casein kinase 1α is responsible for the phosphorylation of LRRK2, which then plays a role in Parkinson’s disease (abstract). Therefore, CHIA teaches that Parkinson’s disease is a casein kinase 1-dependent disease.
MOSTERT teaches a structure activity relationship among 1,4-naphthoquinone compounds when using these compounds to inhibit monoamine oxidase enzymes (abstract). MOSTERT specifically states that the compounds therein may be useful in the treatment of Parkinson’s disease (abstract). MOSTERT teaches the compound shown below as compound 7b in Table 1 therein, also referred to as shikonin. The compound of MOSTERT does not fall within the scope of instant claim 1, because it contains an alkenyl group at the instantly defined R1 position of claim 1.
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SHERIDAN teaches an algorithmic manner of identifying pairs of chemical moieties that are frequently replaced with one another within the chemical literature (abstract). If a high rank is given by the algorithm to a particular chemical moiety pair, it indicates that a database of reported therapeutic molecules frequently describes very similar molecules having both moieties of the pair in the analogous location within multiple molecules. This high rank would also indicate that replacing a chemical moiety for the other moiety of the pair is well known within the chemical arts (Pages 104-105). Figure 5 of SHERIDAN shows that replacing a tertiary olefin with its fully saturated alkyl equivalent (replacement A18) is well known within the chemical arts.
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to replace the isopentenyl moiety within compound 7b of MOSTERT with an isopentyl moiety (in other words, the fully saturated version of the moiety), as is taught by SHERIDAN, for the purpose of producing derivatives to increase the efficacy of compound 7b of MOSTERT, for the treatment of the conditions described therein. The artisan would have expected success in this moiety replacement, because SHERIDAN teaches that this type of replacement is one of the most common bioisostere replacements known in the chemical arts.
The isopentyl version of compound 7b of MOSTERT can be shown to fall within the scope of instant claim 1. Defining the variables of instant claim 1 as follows produces this isopentyl version: Y and Z are each direct bonds; X is –CH(OH)-; R2 and R3 are each H; R1 is a C5 alkyl group; F is -OH; D is –C(=O)-; and E is H.
Allowable Subject Matter
Claims 1-9, 12-14, and 20-23 are currently rejected. Claims 10-11 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.
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art is that of KIM (Kim, H.J.; Kang, S.K.; Mun, J.Y.; et al. “Involvement of Akt in mitochondria-dependent apoptosis induced by a cdc25 phosphatase inhibitor naphthoquinone analog” FEBS Letters 555 (2003) 217-222). KIM teaches the compound 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (referred to as DDN therein, shown below) to induce apoptosis in human promyelocytic leukemia HL-60 cells (abstract). KIM teaches the treatment of these cancerous cells, which cause a serine/threonine kinase-dependent disease, as described in the 35 USC 102 rejection above. However, KIM does not teach the use of the DDN compound therein in the treatment of a neurodegenerative disease or Alzheimer’s disease. The Examiner has not found any additional prior art that would have rendered the use of the compound of KIM for one of those purposes obvious.
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Conclusions
Claims 1-9, 12-14, and 20-23 are currently rejected. Claims 10-11 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.
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 JOHN D MCANANY whose telephone number is (571)270-0850. The examiner can normally be reached 8:30 AM - 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ANDREW D 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.
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/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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