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
Applicant’s claim to priority from International Application No. PCT/US2021/027182 filed 04/14/2021 and from Provisional Application No. 63/013,963 filed 04/22/2020 is hereby acknowledged.
Election/Restrictions
Applicant's election with traverse of Invention Group I (claims 1-6, 12, 14 and
29-31, drawn to a method of treating a metabolic symptom, or a related disease or condition thereof) in the reply filed on 05/18/2026 is acknowledged. The traversal is on the ground(s) that the Patent Office has not established that it would pose an undue burden to examine the full scope of the claimed invention (See Applicant' s Response, “Remarks” dated 05/18/2026, page 7). This is not found persuasive because “undue search burden” is not a criteria for election/restriction purposes under 35 USC §121 and 35 USC § 372.
According to PCT Rule 13.1, and as indicated in the Requirement for Restriction dated 04/22/2026, unity of invention exists only when there is a technical relationship among the claimed inventions involving one or more of the same or corresponding special technical features. The expression "special technical features" is defined in PCT Rule 13.2 as meaning those technical features that define a contribution which each of the inventions, considered as a whole, makes over the prior art. PCT Rule 13.2 has clearly stated that ‘Where a group of inventions is claimed in one and the same international application, the requirement of unity of invention referred to in Rule 13.1 shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art”. Please refer MPEP §1850 for details.
In the present case, Inventions Groups I, II, III and IV lack unity of invention because even though the inventions of these groups require the technical feature of a PKD3 inhibitor, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Mayer (Mayer, A.E. et al. Science Signaling, Vol. 12 (2019), p: eaav9150).
The requirement is still deemed proper and is therefore made FINAL.
Claims 7-11, 13, 15, 27-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/18/2026.
Application Status
The instant Application is a National Stage entry under 35 U.S.C. §371 of the International Application No. PCT/US2021/027182 filed 04/14/2021.
Preliminary amendments to claims filed 05/18/2026 are hereby acknowledged.
Claim 4 is currently amended. Claims 16-26 and 32-33 are cancelled.
Claims 1-15 and 27-31 are pending. Claims 7-11, 13, 15, 27-28 are withdrawn from consideration. Therefore, claims 1-6, 12, 14 and 29-31 are under consideration in this Office Action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 04/30/2026 and 05/05/2026 were filed after the mailing date of the Office Action on 04/22/2026. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figures 1, 2, 3, 5 and 6 that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
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.
Claims 1-2, 5-6, 14 and 30-31 are rejected under 35 U.S.C. §103 as being unpatentable over McGee (McGee. WO 2021/113914 A1, published June 17, 2021, benefitting from Foreign Application with priority date of December 11, 2019), in view of Venardos (Venardos, K. et al. “The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice”. PLoS ONE, Vol. 10, No. 3 (2015), p: e0120934) and Mayer (Mayer, A.E. et al. “The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling”. Science Signaling, Vol. 12 (2019), p: eaav9150; previously cited).
Regarding claim 1, McGee teaches therapeutic compositions and methods for the prevention and treatment of diastolic dysfunction in obese, prediabetic, or diabetic or elderly individual, and more preferably in obese individuals (see title and Embodiment 1, page 5, lines 20-28). McGee teaches that adipocytes secrete elevated amount of Amyloid β42 (Aβ42) in plasma, therefore obese individuals present with elevated plasma Aβ42 requiring prevention or treatment of the metabolic complication Left Ventricular Diastolic Dysfunction (LVDD) (see page 5, lines 20-28, and page 14, lines 1-5). McGee also teaches compositions for the treatment of diabetic cardiomyopathy, hypertrophic cardiomyopathy, hypertensive cardiomyopathy in obese, pre-diabetic or diabetic individuals (see page 11, lines 1-11).
McGee teaches the use of a composition comprising mGluR5 negative allosteric modulators (mGluR5 NAM) for treating or preventing diastolic dysfunction associated with obesity (see page 4, lines 5-11; page 5, lines 20-28). Examples of mGluR5 NAM are presented in Tables 1, 2 and 3 (
McGee teaches that using Basimglurant (mGluR5 NAM) prevents the decline in cardiac performance associated with chronic Aβ42 exposure (see page 55, lines 4-20).
McGee teaches that chronic exposure to Aβ42 induces a cardiac inflammatory response regulated by Protein kinase D (PKD) in obesity (see page 14, lines 28-30; page 15, lines 1-2).
McGee teaches that Aβ42 is a ligand for mGluR5, and that mGLuR5 agonism increases PKD activity (see page 13, lines 22-28).
McGee teaches that PKD regulates cardiomyocyte metabolism (Figure 7; page 19, line 19). McGee teaches that reduced PKD activity preserves cardiac function in obesity (figure 8, page 19, line 20-21).
McGee also teaches that “Various (enumerated) embodiments of the present invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure” (see page 5, lines 16-19).
McGee teaches “Example 9 – Inactivation of PKD preserves cardiac function in obesity” (see page 54, lines 21-28 and page 55, lines 1-3). McGee uses a cardiac-specific Dominant Negative (DN) PKD mice fed either chow or a high fat diet, and assesses the systolic function, and teaches that the genetic inactivation of PKD ( DN-PKD) in mice fed high fat diet leads to a preserved/normal heart function (see page 54, lines 21-28 and page 55, lines 1-3; page 58, lines 25-31, and page 59, lines 1-3).
McGee also teaches that chronic administration of Aβ42 to mice increased phosphorylation of PKD, which activates PKD, and exposing the cardiomyocytes further with 10µM CID755673, a PKD inhibitor, prevented the Aβ42-induced increase in inflammatory gene expression (see page 54, lines 5-10, Figure 6B).
Therefore, McGee teaches using a PKD inhibitor for preventing inflammation induced by excess Aβ42, as in obesity condition, in cardiomyocytes.
Venardos teaches that diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes, and that a potential therapeutic target is protein kinase D (see title and abstract).
Venardos teaches chronic CID755673 administration to type 2 diabetic db/db mice for two weeks reduces the expression of the gene expression signature of PKD activation, and enhances diastolic and systolic left ventricular function, and a reduction in heart weight (see abstract; see Figure 3 and page 7, “The PKD inhibitor CID755673 reduces PKD activation in a time and dose-dependent manner in C57BL6 mice” paragraph; and page 8).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined a mGluR5 NAM taught by McGee, with the PDK inhibitor, CID755673, therefore combining two examples of preventing diastolic dysfunction taught both by McGee and by Venardos. One with ordinary skills in the art, motivated in applying a tighter control over adipocyte-secreted Aβ42’s negative effects in obese individuals, could have performed this modification with a reasonable expectation of success, and would have arrived at a method of treating a metabolic symptom, or a related disease or condition thereof, comprising administering to a subject in need thereof, a PKD inhibitor in combination with a mGluR5 NAM for the treatment of obese individuals and prevention of obesity’s metabolic complications.
McGee and Venardos do not teach an inhibitor of PKD having the formula (I).
According to instant Specification, an inhibitor of Formula (I) is a PKD3 inhibitor identified as CRT 0066101 (see [0008]-[0009]).
However, Mayer teaches that lipid accumulation increases PKD3 activity in the liver and insulin resistance, and that hepatic deletion of PKD3 promotes insulin sensitivity (see page 1, right column, “Results” section; and page 2, left column).
Mayer also teaches the use of a specific PKD3 inhibitor of formula (I), i.e., CRT 0066101 (see Figure 5).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the inhibitor CID755673 taught by McGee and Venardos, with the inhibitor CRT 0066101 taught by Mayer. It would have been a substitution of one inhibitor for another with equivalent function by one with ordinary skills in the art motivated in testing different known inhibitors in the art. One with ordinary skills in the art could have performed this substitution with a reasonable expectation of success and would arrived at the claimed invention.
Regarding claim 2, McGee teaches that the condition can be preferably a metabolic symptom related to obesity ( see page 17, lines 19-20; i.e., “more preferably an obesity-associated cardiomyopathy”).
Regarding claim 5, McGee teaches that the condition can be obesity-related diabetes, and diabetes related symptom (see page 20, lines 11-16). Venardos teaches type 2 diabetes (see title and abstract).
Regarding claim 6, Mayer teaches that that elevated activated PKD3 leads to insulin resistance (see page 7, right column, “Constitutive activation of PKD3 promotes insulin resistance” paragraph).
The obviousness of the combining the references McGee and Mayer is described above. The elements of the claims are rendered obvious by the combination of McGee and Mayer.
Regarding claim 12, McGee teaches pharmaceutical composition that can be salts, e.g., “stearic acids or its salts and the like” (see page 36, lines 1-4; page 37, lines 1-9). Venardos teaches a solution of 5% DMSO and PBS as a buffer for the PKD inhibitor (see page 3, “Animal experiments” paragraph). Mayer uses DMSO as a reference standard/blank/control, which indicates that Mayer uses DMSO as an excipient/diluent/carrier for inhibitors (see Figure 6).
It would have been obvious to one with ordinary skills before the effective filing date of the claimed invention to have substituted the DMSO used as excipient/diluent as taught by Venardos and Mayer with a pharmaceutically acceptable salt of the inhibitor within a pharmaceutically acceptable excipient/diluent/carrier as taught by McGee. One with ordinary skills in the art, motivated in administering a pharmaceutical composition comprising a biologically active agent in a form suitable for use in vivo, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding claim 14, McGee teaches pharmaceutical compositions that can be administered orally, parenterally and/or in the form of injections ( see page 36, lines 1-10). Venardos teaches intraperitoneal injections (see page 3, “Animal experiments” paragraph).
Regarding claims 29 and 30, McGee teaches administering a mGluR5 NAM (see title and abstract ). McGee also teaches using a PKD inhibitor CID755673 (see page 54, lines 5-10). Venardos teaches using CID755673 for treating diabetic cardiomyopathy (see title and abstract). Mayer also teaches the use of a specific PKD3 inhibitor of formula (I), i.e., CRT 0066101 (see Figure 5).
The obviousness of combining the compounds from McGee and Venardos in the method of treating a metabolic symptom of obesity is described above.
It would also have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined a PKD inhibitor CID755673 taught by McGee and Venardos, with a mGluR5 NAM as taught by McGee within the composition used for treating a diastolic dysfunction associated with obesity. It would also have been obvious to have substituted the inhibitor taught by McGee and Venardos within the mGluR5 NAM-containing composition, with the inhibitor CRT 0066101 taught by Mayer. It would have been a substitution of one inhibitor for another with equivalent function by one with ordinary skills in the art motivated in testing different known inhibitors in the art. One with ordinary skills in the art could have performed this substitution with a reasonable expectation of success and would arrived at the claimed invention, i.e., a method of treating a metabolic symptom associated with obesity using a composition comprising a first and a second therapeutic agents.
Regarding claim 31, McGee teaches obesity as a preferred embodiment ( see page 17, lines 19-20; i.e., “more preferably an obesity-associated cardiomyopathy”).
The obviousness of the combination of the references is described above.
Claims 3 and 4 are rejected under 35 U.S.C. §103 as being unpatentable over McGee (McGee. WO 2021/113914 A1, published June 17, 2021, benefitting from Foreign Application with priority date of December 11, 2019), in view of Venardos (Venardos, K. et al. “The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice”. PLoS ONE, Vol. 10, No. 3 (2015), p: e0120934) and Mayer (Mayer, A.E. et al. “The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling”. Science Signaling, Vol. 12 (2019), p: eaav9150; previously cited), as applied to claim 1 above and in further view of Samuel (Samuel, V.T. et al. “Non-alcoholic fatty liver disease as a nexus of metabolic and hepatic diseases”. Cell Metabolism, Vol. 27, No. 1 (2018), pp: 22-41).
The rejection of claim 1 is described above. The combination of references McGee, Venardos and Mayer renders elements of claim 1 obvious.
However, Mayer teaches about insulin resistance in the liver as a result of constitutive activation of PKD3 (see page 7, right column, “Constitutive activation of PKD3 promotes insulin resistance in the liver” paragraph), and suggests that inhibition of PKD3 with CRT 0066101 may partially ameliorate hepatic insulin resistance due to lipid overload (see page 7, right column, “Discussion” section, last line, and page 8, left column, lines 1-2).
Regarding claims 3 and 4, the combination of references does not render obvious a metabolic symptom or related condition that is nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
However, Samuel teaches that NAFLD is associated with obesity and encompasses a range of pathologies from steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Samuel also teaches that the presence of diabetes mellitus can also increase the risk of liver disease (see page 22, Introduction, second paragraph).
Samuel teaches that ectopic lipid accumulation in the liver leads to liver insulin resistance (see Figure 2 and page 26, “Cellular and Molecular mechanisms of hepatic insulin resistance” paragraph).
Therefore, according to Samuel’s teachings, ectopic lipid accumulation associated with obesity may be responsible for NAFLD, and NAFLD may be responsible for hepatic insulin resistance.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the method of treating obesity and associated ventricular dysfunction as taught by McGee and Venardos, with a method of treating NAFLD/NASH using the same therapeutic composition comprising a combination of mGluR35 NAM and PKD inhibitor as taught by McGee and Venardos modified with Mayer. Mayer’s teachings suggests that specifically inhibiting PKD3 with CRT 0066101 may improve hepatic insulin resistance, which is a component of NAFLD/NASH associated with obesity. One with ordinary skills in the art, motivated in treating obese and diabetic patients presenting with ectopic fat accumulation, and in preventing or treating NAFLD/NASH in these patients, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights