Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application claims priority to the applications, CN 202110668715.4 and PCT/CN2022/099223, with effective filing dates of 16 June 2021 and 16 June 2023, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 7 July 2026.
Applicant’s election without traverse of Group 1 (claims 1-2 and 4) and species (
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) in the reply filed 7 July 2026 is acknowledged.
Additionally, the Examiner notes that claims 2-3 and 5-7 are canceled.
Accordingly, claims 1 and 4 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed 30 April 2024 and the references cited therein have been considered, unless indicated otherwise.
Claim Interpretation
For clarity, the Examiner interprets the phrase “[a] compound with coronavirus inhibitory activity” to be “a compound” as coronavirus inhibitory activity is an inherent property of the compound. Products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. See MPEP § 2112(II)-(III) and 2112.01(II).
Drawings
1. The drawings are objected to under 37 CFR 1.83(a) because they fail to show discernible features as described in the specification in Figures 2, 9, 12, and 14 due to the quality of the images. 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 USC § 103
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.
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.
2. Claim(s) 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Cuffie-Jackson (US 2009/0149480, published 11 Jun 2009) in view of Kayik (J. Enzyme Inhib. Med. Chem., 2017, 32(1), 311-330) and Wang (EBioMedicine, Feb 2020, 52(102650), 1-13, see IDS filed 30 April 2024).
Cuffie-Jackson teaches phosphodiesterase type (PDE) V inhibitors for treating congestive heart failure having general structure:
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(abstract; [0003]). Cuffie-Jackson teaches that congestive heart failure is a disorder in which the heart loses its ability to pump blood efficiently and that congestive heart failure may be caused by occurrence of a myocardial infarction or be secondary to other causes such as hypertension or cardiac malformations, such as valvular disease ([0006]-[0007]). Cuffie-Jackson teaches that current therapy for heart failure is insufficient and that PDE V inhibitor compounds have been used in treating a variety of physiological conditions and further apply PDE V inhibitors to congestive heart failure ([0010]; [0012]-[0013]). Cuffie-Jackson teaches Compound 133:
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(page 26, Table II). Cuffie-Jackson teaches all compounds had a PDE V IC50 within the range of <1 nM to >100 nM ([0139]). While Cuffie-Jackson does not explicitly teach n-butyl, compounds which are constitutional isomers (compounds having the same radicals in physically different positions on the same nucleus) 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 MPEP § 2144.09(II). Accordingly, n-butyl and t-butyl are constitutional isomers. Additionally, as the t-butyl analog performed well as a PDE V inhibitor, the more flexible n-butyl analog would reasonably be expected to perform better than the more sterically encumbered t-butyl. Thus, Cuffie-Jackson teaches
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.
Regarding claim 1, Cuffie-Jackson fails to teach the amino alcohol chain of
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.
Kayik teaches that phosphodiesterase (PDE) type enzymes regulate the cytoplasmic levels of intracellular second messengers and that PDE5 (also known as PDE V) is found in diverse tissues in the human body (abstract; page 311, column 1, paragraph 1). Kayik teaches that PDE5 inhibitors treat diseases such as pulmonary hypertension and that some PDE5 inhibitors are also PDE6 inhibitors due to amino acid sequence and secondary structure similarity of the catalytic domain (page 311, column 1, paragraph 1; page 311, column 2, paragraphs 1-2; page 312, column 1, paragraph 1). Kayik teaches structural background takeaways for high/low binding tendencies to PDE5, PDE6, and PDE11 in order to reduce cross-reactivity (page 312, column 1, paragraphs 1 and 3). Kayik teaches the PDE5 inhibitor, tadalafil, bound in PDE5:
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(Figure 1, page 314).
Wang teaches that increases in hepatic low-density lipoprotein receptor play a pivotal role in enhancing the clearance of plasma low-density lipoprotein cholesterol and are associated with reducing the risk of cardiovascular disorder (page 1, column 1, paragraph 1). Wang teaches that proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical player in low-density lipoprotein cholesterol metabolism through regulating the degradation of hepatic low-density lipoprotein receptors (page 1, column 1, paragraph 1; page 1, column 2, paragraph 1). Wang teaches that in human subjects, loss-of-function PCSK9 mutations are associated with hypocholesterolemia and protection against coronary artery disease (page 1, column 2, paragraph 1). Wang teaches that at the time of publication, PCSK9 inhibitors are novel therapeutics for the treatment of cardiovascular disease in addition to statins (page 2, column 1, paragraph 1). Wang teaches that previous PCSK9 treatments were monoclonal antibodies that were expensive and required subcutaneous administration, which limited widespread use (page 2, column 1, paragraph 1). Wang teaches Compound 7030B-C5:
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, which had PCSK9 inhibitory and anti-atherosclerosis activity (page 4, Figure 1d; page 2, column 1, paragraph 3). Wang teaches that small-molecule inhibitors of PCSK9 have attracted a great deal of attention for their cost-effectiveness and ease of administration (page 10, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify Compound 133 of Cuffie-Jackson to 1) change the t-butyl of Compound 133 to its constitutional isomer, n-butyl, which is more flexible and would be expected to bind better in PDE5 as taught by Kayik (Figure 1, page 314); and 2) incorporate the aminoalkyl alcohol of Compound 7030B-C5 of Wang to optimize potency for PCSK9 and reduce cross-reactivity to other PDE targets whilst designing a cost-effective and easy to administer therapeutic. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Cuffie-Jackson teaches phosphodiesterase type (PDE) V inhibitors for treating congestive heart failure having general structure:
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,
-Cuffie-Jackson teaches that congestive heart failure is a disorder in which the heart loses its ability to pump blood efficiently and that congestive heart failure may be caused by occurrence of a myocardial infarction or be secondary to other causes such as hypertension or cardiac malformations, such as valvular disease,
-Cuffie-Jackson teaches that current therapy for heart failure is insufficient and that PDE V inhibitor compounds have been used in treating a variety of physiological conditions and further apply PDE V inhibitors to congestive heart failure.
-Cuffie-Jackson teaches Compound 133:
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,
-Cuffie-Jackson teaches all compounds had a PDE V IC50 within the range of <1 nM to >100 nM,
-While Cuffie-Jackson does not explicitly teach n-butyl, compounds which are constitutional isomers (compounds having the same radicals in physically different positions on the same nucleus) 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 MPEP § 2144.09(II). Accordingly, n-butyl and t-butyl are constitutional isomers. Accordingly, n-butyl and t-butyl are constitutional isomers. Additionally, as the t-butyl analog performed well as a PDE V inhibitor, the more flexible n-butyl analog most likely would perform better than the more sterically encumbered t-butyl. Thus, Cuffie-Jackson teaches
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,
-Kayik teaches that phosphodiesterase (PDE) type enzymes regulate the cytoplasmic levels of intracellular second messengers and that PDE5 (also known as PDE V) is found in diverse tissues in the human body,
-Kayik teaches that PDE5 inhibitors treat diseases such as pulmonary hypertension and that some PDE5 inhibitors are also PDE6 inhibitors due to amino acid sequence and secondary structure similarity of the catalytic domain,
-Kayik teaches structural background takeaways for high/low binding tendencies to PDE5, PDE6, and PDE11,
-Kayik teaches the PDE5 inhibitor, tadalafil, bound in PDE5:
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,
-Wang teaches that increases in hepatic low-density lipoprotein receptor play a pivotal role in enhancing the clearance of plasma low-density lipoprotein cholesterol and are associated with reducing the risk of cardiovascular disorder,
-Wang teaches that proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical player in low-density lipoprotein cholesterol metabolism through regulating the degradation of hepatic low-density lipoprotein receptors,
-Wang teaches that in human subjects, loss-of-function PCSK9 mutations are associated with hypocholesterolemia and protection against coronary artery disease,
-Wang teaches that at the time of publication, PCSK9 inhibitors are novel therapeutics for the treatment of cardiovascular disease in addition to statins,
-Wang teaches that previous PCSK9 treatments were monoclonal antibodies that were expensive and required subcutaneous administration, which limited widespread use,
-Wang teaches Compound 7030B-C5:
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, which had PCSK9 inhibitory and anti-atherosclerosis activity, and
-Wang teaches that small-molecule inhibitors of PCSK9 have attracted a great deal of attention for their cost-effectiveness and ease of administration.
Accordingly, the combination of Cuffie-Jackson and Wang teaches
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.
Regarding claim 4, Cuffie-Jackson teaches pharmaceutical compositions comprising at least one subject compound and a pharmaceutically acceptable excipient ([0004]; [0064]; [0076]; [0080]; [0167]).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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