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 .
Claims 1-25 have undergone amendments. Thus, Claims 1-25, submitted on 9 August 2026, represent all claims currently under consideration.
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.
Response to Arguments
The objection to Claims 1-8 is withdrawn. Applicant has amended the claims to correct the issues cited in the prior office action.
The objection to Claim 8 is withdrawn. Applicant has added commas between each claimed compound.
The objection to Claim 10 is withdrawn. Applicant has removed the superfluous “according to”.
The objection to Claims 10 and 11 are withdrawn. Applicant has amended the claims to include an “and” between R0 and R2 to R11.
The objection to Claim 12 is withdrawn. Applicant has amended the claims to include an “and” in between R0 and R5 to R11.
The objection to Claim 15 is withdrawn. Applicant has replaced “dihydroxylation” with “dihydroxylating”, and inserted an “are” and removed the superfluous “and”.
The objection to Claims 9-15 is withdrawn. Applicant has corrected the phrasing.
The objection to Claims 16 and 17 is withdrawn. Applicant has corrected the phrasing.
The objection to Claim 18 is withdrawn. Applicant has corrected the phrasing.
The objection to Claim 19 is withdrawn. Applicant has corrected the phrasing.
The objection to Claim 20 is withdrawn. Applicant has corrected the phrasing.
The objections of Claims 21-25 are each withdrawn. Applicant has corrected the phrasing.
The objection to Claim 25 is withdrawn. Applicant has removed the superfluous “of”.
The objection to Claims 9-16 are withdrawn. Applicant has replaced the images with those of higher quality.
The 35 U.S.C. § 112(a) rejection of Claims 21 and 23 is partially withdrawn. Applicant has amended Claim 21 to specify human lung cancer and human glioblastoma, which is enabled by the specification. However, the claims are still not fully enabled as the specification does not enable the treatment of all neurodegenerative or viral diseases using the compounds of the invention. The Examiner suggests amending the claims to specify that the neurodegenerative diseases or viral diseases involve activation of oxysterol binding protein to overcome this rejection.
The 35 U.S.C. § 112(a) rejection of Claims 1, 2, 9-16, and 18-25 is withdrawn. Applicant has amended the claims to remove “sugar radical” and to specify the specific radicals which are described in the specification.
The 35 U.S.C. § 112(b) rejection of Claims 1-25 is withdrawn. Applicant has amended the claims to correct the lack of antecedent basis.
The 35 U.S.C. § 112(b) rejection of Claim 9 is withdrawn. Applicant has amended Claim 9 to correct the lack of antecedent basis.
The 35 U.S.C. § 112(b) rejection of Claim 16 is withdrawn. Applicant has removed the limitation that states that Hal is defined in Claim 1.
The 35 U.S.C. § 102(a)(1) rejections of the previous office action are each withdrawn. Applicant has amended Claim 16 to have substituents which are not disclosed or suggested in the rejections of record.
The 35 U.S.C. § 103 rejection of Claims 1, 3, and 18-23 over Huang is withdrawn. Applicant argues that the inclusion of a hydroxyl at this location, which is not taught or suggested by Huang, provides an unexpected increase in metabolic stability while maintaining potency against the OBSP protein. The Examiner finds these arguments to be persuasive.
The 35 U.S.C. § 112(b) rejection of Claim 21 is maintained. The claims remain directed to the treatment of multiple cancers, neurodegenerative disorders, and/or viral disorders, causing indefiniteness issues as described in the previous office action.
Claim Rejections - 35 USC § 112(a)- REJECTIONS MAINTAINED
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.
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of certain conditions, including cancers, which dysregulated oxysterol-binding protein, it does not reasonably provide enablement for all forms of cancer, neurodegenerative diseases or viral diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating cancer, including several specific forms of cancer, neurodegenerative diseases, and viral diseases comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I) of Claim 1. The compounds of the invention are inhibitors of oxysterol-binding protein (OSBP). Thus, the claims are drawn to a method of treating human lung cancer, human glioblastoma, any neurodegenerative disease, and any viral disease by inhibition of OSBP.
The state of the prior art and the predictability or unpredictability of the art:
Lin (BBA- Molecular and Cell Biology of Lipids, 1868, 2023, 159365) provides an overview of OSBP in human diseases. It has been discovered that OSBP dysfunction is involved in many diseases, such as fatty liver disease, diabetes, lysosome-related diseases, cancer, and viral infections (3. OSBP and diseases). Table 1 (Page 4) provides an overview of conditions associated with OSBP, and this list includes Niemann-Pick disease type C, Hepatitis C virus infection, poliovirus infection, enterovirus infection, rhinovirus infection, Aichi virus infection, and Dengue virus infection. Infections caused by positive-sense single-stranded RNA virus are a widespread public health issue of great concern. These viruses replicate in the cytosol of the host cells, using membrane contact sites (MCSs) of the ER, Golgi, and endosomal membranes as a replication platform, while utilizing lipid droplets and lipid metabolism of host cells as replication energy. Closely involved in the formation of the viral replication organelle (RO) in infected cells, OSBP is considered to be involved in the viral replication process. Small-molecule antagonists targeting OSBP have been proposed as a new strategy against viral infections. The natural compound OSW-1 binds to the ORD of OSBP and blocks its exchange entry, inhibiting the replication of enteroviruses. Posaconazole also affects cholesterol homeostasis by targeting OSBP to inhibit dengue and Zika virus replication. OSBP has been hypothesized as a potential target for the treatment of COVID-19 (3.5. OSBP and virus infection). Thus, the treatment of certain viral infections which require OSBP for replication, as well as certain neurodegenerative conditions which involve OSBP, including conditions such as Alzhiemer’s (Delac, Current Opinion in Endocrine and Metabolic Research, 41, 2025, 100590), are known in the prior art to be treatable using inhibitors of OSBP. However, not all neurodegenerative conditions involve OSBP. For example, alcohol-induced dementia is a neurodegenerative condition which is caused by excessive alcohol consumption, and is only treatable by complete cessation of alcohol consumption.
Liu (World Journal of Clinical Cases, 2020 January 6, 8, 1, 1-10) provides an overview of oxysterol-binding proteins (OSBPs) in cancer. Current evidence indicates that certain members of the family of OSBPs can lead to cancers, with many studies revealing the putative roles of OSBPs in various cancer types. However, the exact effects and mechanisms of action of members of the OSBP family in cancer initiation and progression are currently unknown (Abstract). Oxysterols are oxygenated derivatives of cholesterol molecules that are formed in the body or ingested via the diet and oxygenated forms of plant sterols. Oxysterols are involved in certain human clinical pathologies and even influence the carcinogenesis and progression of malignant tumors, such as breast, prostate, colon, and bile duct cancers. However, the role of oxysterols in carcinogenesis and cancer progression needs to be further elucidated. Oxysterols exert a very sophisticated effect on miscellaneous cell lines. Various studies have noted that oxysterols can adjust inflammatory and signaling pathways or exert pro-cancerous and pro-proliferative activities through oxysterol-binding proteins (OSBPs). These proteins regulate the metabolism and trafficking of cholesterol and lipid molecules, particularly in the ER and Golgi apparatus. It is believed that OSBPs are associated with cell proliferation, cell migration, and carcinogenesis. Substantial lines of evidence indicate that certain members of the OSBP/ORP family can result in cancer development, however, the exact mechanism these members play in cancer cell initiation and progression and their effects on these processes are currently unclear (Introduction). ORP3 has the ability to regulate cell adhesion and migration. ORP4 can increase tumor cell invasion and metastasis, and ORP5 has the ability to increase tumor cell invasion and metastasis. In addition, ORP6 and ORP7 can regulate cell adhesion and migration, ORP8 can regulate apoptosis, ORP9 can maintain the functional integrity of the early secretory pathway, while ORP10 and ORP11 are involved in cardiovascular diseases. Further studies are required to confirm their important functions in tumor prevention, prognosis, or treatment and in carcinogenesis. There, the extraction of various samples from the human circulation and target tissues at different pathological states for genomic, proteomic, and metabolomic analyses is required for the clinical application of oxysterol in diagnosis and treatment. It is believed that future research will provide a more detailed information on the mechanism through which ORPs regulate the growth of tumor cells and will help us establish ORPs as new targets for the treatment of various cancers (Conclusion).
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various neurodegenerative or viral diseases; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of these conditions as not all neurodegenerative conditions have overexpression of OSBP, nor are all viruses sensitive to the inhibition of this enzyme.
The amount of direction or guidance presented and the presence or absence of working examples:
Example 5 (Page 101) provides demonstration of the biological activity of the compounds of the invention, and shows that they are capable of inhibiting OSBP in the low nanomolar range, and are also cytotoxic towards U87-MG (human glioblastoma cell line) and A549 (human lung cancer cell line) cell lines in vitro in the low µM concentrations. The specification does not demonstrate the treatment of all forms of cancer, all neurodegenerative diseases, or all viral infections. Thus, the specification enables the treatment of conditions wherein OSBP is implicated, and cancers wherein OBSP is overexpressed. However, not all cancers overexpress this enzyme, nor do all forms of neurodegenerative diseases overexpress this enzyme, nor are all viral infection sensitive to the inhibition of this enzyme. The specification does not provide any data demonstrating the treatment of a viral disease or a neurodegenerative condition.
The quantity of experimentation necessary:
Considering the state of the art as described above, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
Claim Rejections - 35 USC § 112(b)- REJECTIONS MAINTAINED
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim states a method for treating cancers, neurodegenerative disorders, dylipidemia, hypercholesterolemia, and/or viral diseases. The claim is indefinite as it claims the treatment of cancers, neurodegenerative disorders, and/or viral diseases. It is unclear from the use of “and/or” if the patient must have all conditions to be treated by this method. The claim is also indefinite due to the use of plural forms of cancer, neurodegenerative disorder, and viral disease. It is unclear if this method is used to treat multiple neurodegenerative disorders or viral diseases at once. Notwithstanding the 112(a) enablement rejection, the Examiner suggests amending the claim to read “A method for treating a cancer selected from human lung cancer and human glioblastoma, a neurodegenerative disease, dyslipidemia, hypercholesterolemia, or a viral disease…” to correct this issue.
Response to Amendment
Due to Applicant’s amendment of Claim 23, there is a new issue of indefiniteness. Claim 23 currently reads “a method of treating a cancer which is selected from human and human glioblastoma”. The Examiner believes that the claim should read “human lung cancer and human glioblastoma” as these are the forms of cancer enabled by the specification.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Claim Rejections - 35 USC § 112(b)- REJECTION NECESSITATED BY AMENDMENT
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 23 is indefinite because it reads “a method of treating a cancer which is selected from human and human glioblastoma”. The Examiner believes that the claim should read “human lung cancer and human glioblastoma” as these are the forms of cancer enabled by the specification.
Allowable Subject Matter
Claims 1-20, 22, and 24-25 are allowed.
Claim 23 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
The following is an examiner’s statement of reasons for allowance: There is no prior art which teaches, suggests, or provides the motivation for the compounds of Formula (I), their synthesis, or their intermediates (See STN Search, Search Notes). The closest prior art comes from Huang (US 2017/0348367; Publication Date: 7 December 2017). Huang discloses the use of Helminthostachys zeylanica, ugonins, or a compound of Formula (I) for the treatment or prevention of metabolic diseases selected from metabolic syndrome, excessive lipid accumulation, obesity, fatty liver, dyslipidemia, liver cancer, hypercholesterolemia, cardiovascular disease, insulin disorder, and a combination thereof (Abstract). Compounds of the invention are of the structure
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wherein variable R3 and R4 can form an oxygen-containing heterocyclic ring (Paragraph 0041). Disclosed compounds for use in the invention include (7aR,11 aS)-3-(3,4-dihydroxyphenyl)-6-hydroxy-8,8,11a-trimethyl-7a,8,9,10,11,11a-hexahydro-1H,7H-pyrano[2,3-c]xanthen-1-one
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, as well as different stereoisomers of this compound. This compound has variables R0 as O, R2, R3, and R4 each as CH3, variable R5 as methoxy, variables R6, R9, R10, and R11 each as hydrogen, and variables R7 and R11 as hydroxyl. The present disclosure relates to the use of a compound of formula (I) for the treatment of metabolic diseases such as metabolic syndrome, excessive lipid accumulation, fatty liver, liver cancer, dyslipidemia, hyperlipidemia, hypercholesterolemia, and a combination thereof (Paragraph 0040). However, Huang does not teach, nor provide a suggestion or motivation for a compound wherein the analogous variable R1 is hydroxyl. Applicant has provided data that the insertion of a hydroxyl group at this position unexpectedly results in a massive improvement in metabolic stability which would not be expected while retaining activity against the OSBP receptor. As these compounds are novel and non-obvious, methods of their use and synthesis are similarly novel and non-obvious.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 21 and 23 are rejected.
Claims 1-20, 22, and 24-25 are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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