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 .
DETAILED ACTION
Claims 1-20 filed on 03/09/2023 are acknowledged. No preliminary amendment was filed.
Priority
This application is a continuation of National Stage Application of PCT/US2021/049851, filed on 09/10/2021 and claims benefit to 63/076,662 filed on 09/10/2020.
Information Disclosure Statement
The information disclosure statement (IDS) dated 03/09/2023 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the IDS document has been placed in the application file and the information therein has been considered as to the merits.
Claim Rejections - 35 USC § 112(b)
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.
Claims 9 and 18 are 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.
Claims 9 and 18 recite the NAE inhibitors Compound 1, Compound 13, ABP1, ABP A3, I-216, LZ3, M22; LP0040, and ZM223, but does not define the structures of the listed compounds and the specification does not further define the structures of the listed NAE inhibitors. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant' s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). (MPEP § 2173.05(s)). For the purposes of applying prior art, Compound 1, Compound #13, ABP1, ABP A3, LZ3 will be compounds #2, #4, #5, #6, and #7, respectively, from Figure 10. From Figure 11 compounds M22; LP0040, and ZM223 will be compounds # 17, #18, and #19, respectively.
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 1-6, 8, and 10-20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Rao et al. (WO 2019/227764 A1, published 12/05/2019, translation accessed 09/12/2025, see PTO-892 for English translation), as evidenced by Toth et al. (Cell Reports, published 04/19/2012, see PTO-892), as evidenced by Lan et al. (Scientific Reports, published 04/11/2016, see PTO-892), and as evidenced by Confettura et al. (Biochemistry Research International, published 11/11/2012, see IDS dated 03/09/2023).
Rao is drawn to the use of the inhibitor MLN4924 to treat diabetes and/or obesity (abstract). Rao teaches that MLN4924 is a potent and selective NEDD8-activating enzyme (NAE) inhibitor. Formation of the NAE-MLN4924 complex inhibits NAE activity and inhibits ubiquitinated degradation of a class of proteins that are partially dependent on Cullin-Ring E3 ligase (CRL). In HCT-116 cells, MLN4924 caused a reduction in Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, thereby inhibiting CRL-ubiquitination-mediated protein degradation (such as CDT1 protein) and CDT1 protein accumulation (page 2). Rao teaches that the MLN4924 inhibitor can target ubiquitin ligase and inhibit ubiquitin-like modification, thereby inhibiting insulin and achieving the treatment of diabetes and obesity (page 3). Rao teaches that attenuating insulin secretion can effectively reduce obesity-induced insulin resistance and hyperglycemia indicating that inhibition of protein ubiquitination can effectively inhibit insulin secretion and obesity, and the use of MLN4924 can achieve the effect of treating obesity and diabetes (page 3). Rao administered MLN4924 to the mice fed a normal diet (NCD) and mice fed a high fat diet (HFD) which was a diabetic mice model and found shows that a significant decrease in serum glucose levels between the HFD mice administered MLN4924 and the HFD administered the control (Figure 3). As the method of administering MLN4924 lowers the blood glucose level it necessarily treats hyperglycemia as described in the instant specification (instant specification page 15, paragraph 0103). Rao also claims that the MLN4924 may be used as a medicament that further comprises a pharmaceutically acceptable excipient and may include a diluent or a carrier (page 6).
Regarding claim 2 and 12, it is noted that Rao does not expressly teach that the subject has type II diabetes. Rao teaches that there are two main types of diabetes: type I diabetes is mainly due to genetic factors that prevent patients from producing
sufficient insulin; type II diabetes accounts for 90% of the total number of patients, mainly due to the inability of the body to effectively use insulin, which is often accompanied by obesity and insulin resistance (page 1). Rao uses a HFD mice model to test MLN4924 for use in inhibiting insulin secretion which can reduce obesity-induced insulin resistance and hyperglycemia achieving the effect of treating obesity and diabetes (page 2). Since Rao teaches that insulin resistance and hyperglycemia are related to type II diabetes, the HFD mice model meets the limitations of a type II diabetic subject.
Regarding claims 5 and 16, as evidenced by Toth, UBA3 contains the nucleotide binding pocket that accommodates MLN4924 and the catalytic cysteine necessary for formation of the inhibitory NEDD8-MLN4924 covalent adduct meeting the limitations of claims 5 and 15 (page 311, column 1).
Regarding claims 6 and 16, as evidenced by Lan, MLN4924 rapidly inhibited cullin1 neddylation, meeting the limitations of claims 6 and 16 (abstract).
Regarding claims 8 and 17, as evidenced by Confettura, MLN4924 is able to counteract the insulin resistance induced degradation of IRS1 and also partially rescue IRS2 levels (page 63). Confettura teaches that one of the most important hallmarks of IR (insulin resistance) in many cell types is the diminished phosphorylation of AKT (Ser473) with a subsequently reduced activation of several proteins involved in cell homeostasis (page 52). Further, MLN-4924 application prevented dephosphorylation of AKT (page 63).
Regarding claims 11 and 19, it is noted that Rao does not expressly teach that administration of an NAE to a subject having a hyperglycemic condition would result in increasing insulin secretion. However, since the teachings of the prior art suggests administration of the same active, an NAE inhibitor MLN4924, to the same population having hyperglycemia, the result that increasing insulin secretion would necessarily flow, thereby meeting the instant claim limitations. The recitation “causing an increase in insulin secretion followed by a subsequent decrease in blood glucose concentration” is merely a mechanism of action resulting from the administration step. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Furthermore, MPEP 2145 states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Applicant’s recitation of a new mechanism of action for the prior art method would not, by itself, distinguish the instant claims over the prior art teaching the same or nearly the same method steps.
Accordingly, the claims are anticipated by the art.
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.
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Rao et al. (WO 2019/227764 A1, published 12/05/2019, translation accessed 09/12/2025, see PTO-892 for English translation) and Confettura et al. (Biochemistry Research International, published 11/11/2012, see IDS dated 03/09/2023).
The teachings of Rao are discussed above.
Rao does not teach that the inhibitor causes an increase in insulin sensitization in the subject.
Confettura is drawn to the study of the neddylation-dependent protein degradation and its nexus between the metabolic syndrome, synaptic insulin resistance and Alzheimer’s Disease (title). Confettura teaches that MLN4924 potentially has effects as a glucose sensitizer in peripheral tissues (page 98) and that a pharmacological intervention that selectively blocks neddylation improves insulin sensitivity in neurons (page 7).
It would have been prima facie obvious to combine the teachings of Rao and Confettura before the effective filing date of the claimed invention by selecting MLN4924 as an NAE inhibitor that can be a glucose sensitizer and improve insulin sensitivity as taught by Confettura and administer the MLN4924 to a subject to treat hyperglycemia as taught by Rao to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select MLN4924 because Confettura teaches that MLN4924 can be a glucose sensitizer and that selectively blocking neddylation improves insulin sensitivity. One or ordinary skill in the art would have a reasonable expectation of success because Confettura teaches that MLN4924 can be a glucose sensitizer and selectively blocking neddylation improves insulin sensitivity and Rao exemplifies the method of reducing blood glucose levels by administering MLN4924.
Claims 1, 4 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Rao et al. (WO 2019/227764 A1, published 12/05/2019, translation accessed 09/12/2025, see PTO-892 for English translation) and Brownell et al. (Molecular Cell, published 01/15/2010, see PTO-892).
The teachings of Rao are discussed above.
Rao does not teach an NAE inhibitor compound listed in instant claim 9.
Brownell is drawn to the study of the NEDD8 EI inhibitor MLN4924 and the substrate-assisted inhibition of ubiquitin-like protein-activating enzymes (title). Brownell teaches that the stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924 and that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes (abstract). Brownell teaches that Compound 1 is an adenosine sulfamate analog of MNL4924 and is an equipotent inhibitor of NAE, UAE, and SAE-dependent transthiolation reactions with IC50 values of 5 nM (page 107, column 2).
It would have been prima facie obvious to combine the teachings of Rao and Brownell before the effective filing date of the claimed invention by substituting the MLN4924 with Compound 1 as taught by Brownell for the method of treating hyperglycemia with an NAE inhibitor such as MLN4924 taught by Rao to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to substitute MLN4924 with Compound 1 because Brownell teaches that Compound 1 is an adenosine sulfamate analog of MNL4924 and is an equipotent inhibitor of NAE. One of ordinary skill in the art would have a reasonable expectation of success because Brownell teaches that Compound 1 is an equipotent inhibitor of NAE and Rao teaches the method of treating hyperglycemia in a subject with an inhibitor of NAE such as MLN4924.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA LYNN SCHACHERMEYER whose telephone number is (703)756-5337. The examiner can normally be reached Monday thru Friday, alternate Fridays off, 7:30AM-5PM EST.
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, Scarlett Goon can be reached on (571) 270-5241. 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.
/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693