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
This Application is a 371 of PCT/US2020/034193, filed 05/22/2020 and claims priority to U.S. provisional application no. 62852548, filed 05/24/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/06/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1, 4-20 and 21 are currently pending and subject to examination.
Withdrawn Rejections – Overcome by Amendment
The rejection of claims 1, 4, 13 and 20-21 under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (Nature Communications, 8, Article No. 14740 (2017), Published March 27, 2017) is withdrawn.
Claim Rejections – 35 USC § 103 – Previously Presented
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.
The rejection of claim(s) 1, 4-20 and 22 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Nature Communications, 8, Article No. 14740 (2017), Published March 27, 2017) and further in view of Ye et al. (US 20170166569 A1) (U.S. counterpart to WO2015/157376 (of record)) is maintained.
Response to Arguments
The declaration under 37 CFR 1.132 filed Dec. 29, 2025 is insufficient to overcome the rejection of claims 1, 4-20 and 22 based upon 35 USC 103 as set forth in the last Office action because: the declaration fails to demonstrate that the compounds have unexpectedly superior properties as compared to the prior art compounds.
The declaration asserts that the claimed compounds are non-obvious because R5 can impact the activity of the compounds. These arguments were fully considered but are not persuasive. It is established in the art that differences in structure can impact the activity of compounds. In order to find compounds with similar activity to the prior art compound, 5-((7-morpholinobenzo[c][1,2,5]oxadiazol-4-yl)amino)-1,3,4-thiadiazole-2-thiol (11d23) of Zhang, one of ordinary skill in the art would rationally screen structurally similar compounds based on the teachings of Ye, and would expect to find compounds with similar activity. The fact that some related compounds have worse activity does not undermine the reasonable expectation that structurally similar compounds would have similar properties. The Applicants declaration indeed establishes that these structurally related compounds do inhibit AEP in the nanomolar range, similar to the compounds tested by Zhang. The Applicant has failed to demonstrate that any of the claimed compounds have unexpectedly greater activity than the prior art compound. In fact, the prior art compound has better activity than the claimed compounds as shown in Fig. 1. The Applicant has failed to demonstrate unexpectedly superior properties which is the secondary consideration material to the patentability of the claimed compounds (see MPEP § 2141.II).
The Applicant argues that a personal of ordinary skill in the art would have lacked motivation to modify the substituents on the thiadiazolyl ring to achieve better AEP inhibitory activity because Zhang provides no structure activity relationship data or other teaching regarding the substituents on the thiadiazolyl ring (Remarks, p. 10). These arguments were fully considered but are not persuasive. Zhang teaches the compound 11d23 has the best AEP inhibitory activity of the compounds in the series. One of ordinary skill in the art would select this compound for modification and modify this compound on the expectation that structurally similar compounds would have similar properties (see MPEP § 2144.09). Indeed, Ye provides a roadmap to do just that because Ye teaches that the thiadiazolyl on AEP inhibitor compounds can be modified with different groups.
The Applicant argues that Ye does not provide guidance on how to obtain novel compounds with better AEP inhibitory activity (Remarks, p. 10-11). These arguments are fully considered but are not persuasive. Zhang teaches a compound 11d23 which is very similar to the claimed compounds. One of ordinary skill in the art would modify 11d23 to create structurally similar compounds under the expectation that they would have similar properties to 11d23. Ye teaches that the thiadiazolyl can be modified with different groups to produce AEP inhibitors as in the instant invention.
The Applicant argues that similar compounds can have inferior activity to 11d23 (Remarks, p. 13). These arguments were fully considered but are not persuasive. It is established in the art that differences in structure can impact the activity of compounds. In order to find compounds with similar activity to the prior art compound, 5-((7-morpholinobenzo[c][1,2,5]oxadiazol-4-yl)amino)-1,3,4-thiadiazole-2-thiol (11d23) of Zhang, one of ordinary skill in the art would rationally screen structurally similar compounds based on the teachings of Ye, and would expect to find compounds with similar activity. The fact that some related compounds have worse activity does not undermine the reasonable expectation that structurally similar compounds would have similar properties. The Applicants declaration indeed establishes that these structurally related compounds do inhibit AEP in the nanomolar range, similar to the compounds tested by Zhang. The Applicant has failed to demonstrate that any of the claimed compounds have unexpectedly greater activity than the prior art compound. In fact, the prior art compound has better activity than the claimed compounds as shown in Fig. 1. The Applicant has failed to demonstrate unexpectedly superior properties which is the secondary consideration material to the patentability of the claimed compounds (see MPEP § 2141.II).
Reiterated Rejection
Claim(s) 1, 4-20 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Nature Communications, 8, Article No. 14740 (2017), Published March 27, 2017), as applied to claims 1, 4, 13 and 20-21 above, and further in view of Ye et al. (US 20170166569 A1) (U.S. counterpart to WO2015/157376 (of record)).
The rejection of claims 1, 4, 13 and 20-21 above is incorporated herein by reference.
Claim 1 is directed towards AEP inhibitor compounds having formula I: . For example, claim 5 is directed towards the compound (7-((5-(methylamino)-1,3,4-thiadiazol-2- yl)amino)-4-morpholinobenzo [c][1,2,5]oxadiazol-5-yl)methanol, having the following structure
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(Specification, page 53); and claim 20 is directed towards the compound:
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(Fig. 6).
Zhang teaches the compound:
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(representation drawn by examiner). Zhang discloses this compound (11d23) as a potent AEP (δ-secretase) inhibitor for the treatment of Alzheimer’s disease:
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer’s disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.
Zhang, Abstract;
[W]e focused on the thiol free compound 11 for activity studies. Although, this compound contains some susceptible PAINS motifs (benzofurazan), the SAR assays (Supplementary Fig. 5a–e) demonstrate that this compound might not act as PAINS but rather specifically blocks δ-secretase protease activity. A nitro group in place of the primary amine (11d15) fully inactivated compound 11. Amide conjugation on the primary amine (derivative #1-14 but not #7) weakened compound 11’s activity, whereas alkylation (derivative #16-23) somehow escalated its effect. On the other hand, replacing the morpholino group with pyrrolidine (#24) or piperidine (#25) greatly reduced compound 11’s inhibitory activity. Noticeably, elimination of the furazan group in #26 substantially diminished compound 11’s activity, but replacing it with another morpholino group in #27 (compound 11b) augmented its activity (Supplementary Fig. 5d,e).
Zhang, p. 4 (emphasis added);
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Zhang, Supplementary Fig 5(a) and 5(d).
This compound differs from the claimed compound in having methylamino instead of mercapto off the thiadiazol and in that there is a hydroxymethyl from the core structure. One of ordinary skill in the art would have a reasonable expectation of success to modify the compound of Zheng with methylamino instead of mercapto and with an additional hydroxymethyl substituent because Ye teaches AEP inhibitors of general formula
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wherein R1 is heterocyclyl, R2 is hydrogen or alkyl substituted with hydroxy (R20), R3 is hydrogen, R4 is amino substituted with heterocyclyl (R40) substituted with mercapto or methylamino (R41) (Ye, Specification, paragraphs 0080-94). Ye thus teaches one of ordinary skill in the art how to modify the compound of Zhang to arrive at the instantly claimed compound. Therefore, claims 1, 5 and 20 were prima facie obvious at the time of filing.
Claim 4 is directed towards the compound of claim 1, wherein R1 is morpholinyl, piperidinyl, piperazinyl, or 4-alkylpiperazinyl. As shown above, Zhang teaches that R1 is morpholinyl. Therefore, claim 4 was prima facie obvious at the time of filing.
Claim 6 is directed towards a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient. Claim 17 is directed towards a pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable excipient. Zhang teaches pharmaceutical compositions comprising compound 11
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(Zhang, Supplementary Fig. 5(d)) as a representative compound: “The mice received gavage treatments with vehicle or compound 11 at a dose of 10 mg kg−1d−1.” (Zhang, p. 13). As shown in the rejection of claim 1, Zhang teaches that the compound of claim 1, 11d23, is a derivative of compound 11 with enhanced activity. The compound of claim 5 is a similar derivative that is obvious over the teachings of Ye. Therefore, one of ordinary skill in the art would have a reasonable expectation of success to substitute compound 11d23 or the compound of claim 5 for compound 11 in a pharmaceutical composition.
Thus, claims 6 and 17 were prima facie obvious at the time of filing.
Claim 7 recites: “The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, gel, gel capsule, or cream.” While Zhang does not teach these pharmaceutical forms, one of ordinary skill in the art would have a reasonable expectation of success to formulate the composition in these forms because Ye teaches such compositions: “In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline aqueous buffer.” (Ye, Specification, paragraph 0182). Therefore, claim 7 was prima facie obvious at the time of filing.
Claim 8 recites: “The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in the form of a sterilized pH buffered aqueous salt solution or a saline phosphate buffer between a pH of 6 to 10 or an isotonic phosphate buffered saline solution” While Zhang does not teach these pharmaceutical forms, one of ordinary skill in the art would have a reasonable expectation of success to formulate these compositions because Ye teaches such compositions such as those made with Ringer’s solution (a sterilized pH buffered aqueous salt solution for injection) (Ye, Specification, paragraph 0193). Therefore, claim 8 was prima facie obvious at the time of filing.
Claim 9 recites: “The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in solid form surrounded by an enteric coating.” Claim 10 recites: “The pharmaceutical composition of claim 9, wherein the enteric coating comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, or combinations thereof.” While Zhang does not teach these pharmaceutical forms, one of ordinary skill in the art would have a reasonable expectation of success to formulate these compositions because Ye teaches solid forms with enteric coatings containing methacrylate copolymers and cellulose ethers such as hydroxypropyl methyl cellulose:
In certain embodiments, it is contemplated that these compositions may be extended release formulations. Typical extended release formations utilize an enteric coating. Typically, a barrier is applied to oral medication that controls the location in the digestive system where it is absorbed. Enteric coatings prevent release of medication before it reaches the small intestine. Enteric coatings may contain polymers of polysaccharides, such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaloronic acid, chitin, chitosan and the like; other natural polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine; sodium poly(acrylic acid); poly(hydroxyalkylmethacrylates) (for example poly(hydroxyethyl methacrylate)); carboxypolymethylene (for example Carbopol™); carbomer; polyvinylpyrrolidone; gums, such as guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellan gum, gum tragacanth, agar, pectin, gluten and the like; poly(vinyl alcohol); ethylene vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers, such as hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethyl-cellulose (HPMC), hydroxypropylethylcellulose (HPEC) and sodium carboxymethylcellulose (Na CMC); as well as copolymers and/or (simple) mixtures of any of the above polymers.
Ye, Specification, paragraph 0194.
Therefore, claims 9-10 were prima facie obvious at the time of filing.
Claim 11 recites:
The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose, sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calciumstearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.
Claim 13 recites: “A method of treating a cognitive disorder, comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.” As shown above, Zhang teaches that AEP inhibitors such as compound 11d23 for the treatment of cognitive disorders. Therefore, claim 13 was prima facie obvious at the time of filing.
Claim 14 recites: “The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a saccharide or polysaccharide.” While Zhang does not teach these excipients, one of ordinary skill in the art would have a reasonable expectation of success to use these excipients because Ye teaches such excipients:
In certain embodiments, the pharmaceutically acceptable excipient is selected from a saccharide, disaccharide, sucrose, lactose, glucose, mannitol, sorbitol, polysaccharides, starch, cellulose, microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose (HPC), xylitol, sorbitol, maltito, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), crosslinked sodium carboxymethyl cellulose, dibasic calcium phosphate, calcium carbonate, stearic acid, magnesium stearate, talc, magnesium carbonate, silica, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, and sodium citrate, methyl paraben, propyl paraben, and combinations thereof.
Ye, Specification, paragraph 0182.
Therefore, claims 11 and 14 were prima facie obvious at the time of filing.
Claim 12 is directed towards a method of treating cancer comprising administering an effective amount of a compound of claim 1 to a subject in need thereof. Claim 15 is directed towards a method of treating cancer, comprising administering an effective amount of the pharmaceutical composition of claim 6 to a subject in need thereof. Claim 18 is directed towards a method of treating cancer, comprising administering an effective amount of the compound of claim 5 to a subject in need thereof. One of ordinary skill in the art would a have a reasonable expectation of success to treat cancer with the compounds and compositions of the instant invention because (1) Zhang suggests that AEP inhibitors are useful in the treatment of cancer:
Dysregulated δ-secretase activity has been implicated in various diseases, including cancers and neurodegenerative diseases… A DNA vaccine targeting δ -secretase was able to effectively inhibit the enzyme and suppress breast tumour growth and metastasis in mice18. However, an effective small molecule inhibitor of d-secretase has yet to be identified. Novel inhibitors of the enzyme might be useful as powerful therapeutic agents.
Zhang, p. 2;
and because Ye teaches that the AEP inhibitors of their invention and compositions thereof are effective for treating cancer:
This disclosure relates to asparagine endopeptidase inhibitors useful for treating or preventing metastasis, tumor growth, and/or cancer. In certain embodiments, the disclosure relates to methods of treating a cancer comprising administering an effective amount of pharmaceutical composition comprising a compound disclosed herein to a subject in need thereof.
Ye, Specification, paragraph 0197.
Therefore, claims 12, 15 and 18 were prima facie obvious at the time of filing.
Claim 16 recites: “A method of treating a cognitive disorder, comprising administering an effective amount of the pharmaceutical composition of claim 6 to a subject in need thereof.” Claim 19 recites: “A method of treating a cognitive disorder, comprising administering an effective of the compound of claim 5 to a subject in need thereof.” While Zhang does not specifically teach a composition comprising a compound of claim 1 or a compound of claim 5 for the treatment of cognitive disorders, one of ordinary skill in the art would have a reasonable expectation of success to treat a cognitive disorder with such a composition or compound because Zhang teaches similar compositions and compounds for the treatment of cognitive disorders, as shown above. Therefore, claims 16 and 19 were prima facie obvious at the time of filing.
Claim 22 is directed towards the compound:
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.
Zhang teaches the compound:
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(representation drawn by examiner). Zhang discloses this compound (11d23) as a potent AEP (δ-secretase) inhibitor for the treatment of Alzheimer’s disease.
While the prior art compound differs from the claimed compound in that the thiadiazolyl is substituted with mercapto instead of ethylamino, one of ordinary skill in the art would have a reasonable expectation of success to modify the prior art compound with ethylamino because it is known in the art that these substituents can produce AEP inhibitors with similar properties.
For example, Ye teaches AEP inhibitors of general formula
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wherein R1 is heterocyclyl, R2 is hydrogen, R3 is hydrogen, R4 is amino substituted with heterocyclyl (R40) substituted with mercapto, ethylamino or methylamino (R41) (Ye, Specification, paragraphs 0080-94). Ye thus teaches one of ordinary skill in the art how to modify the compound of Zhang to arrive at the instantly claimed compound.
Therefore, claim 22 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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 extension fee 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 HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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