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
Status of Application, Amendments, and/or Claims
The Information Disclosure Statement (IDS) filed 20 March 2023 has been entered. Applicant’s amendment of the claims filed 12 November 2025 has been entered.
Election/Restriction
In the reply received on 12 November 2025, Applicant elected the species of:
A-a) wherein the compound is TAK-448, a conservative variant thereof, or any salt thereof;
B) wherein the subject suffers from the condition of non-alcoholic fatty liver disease (NAFLD); and
C) wherein the second compound is MGL-3196 (resmetirom).
Claims 1-6 are pending and under examination to the extent they read on the elected species.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The tables and drawings at pages 15-16 of the specification are unreadable or of insufficient clarity.
Appropriate correction is required.
Claim Objections
Claim 3 is objected to because of the following informalities:
In claim 3, the phrase “… selected from … or …” should be “… selected from … and …”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-6 are 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: a method of reducing fat in the liver of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from TAK-448 and any salt thereof, and kisspeptin-10 and any salt thereof, does not reasonably provide enablement for using the genus of compounds as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The instant claims are drawn to a method of reducing fat in the liver of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from TAK-448 and any salt thereof, a conservative variant of TAK-448 and any salt thereof, kisspeptin-10 and any salt thereof, and a conservative variant of kisspeptin-10 and any salt thereof. The claims encompass the use of a genus of compounds, including conservative variants of TAK-448 and kisspeptin-10, and their salts thereof, however, the specification does not show evidence that the genus of compounds, particularly the conservative variants of TAK-448 and kisspeptin-10 and their salts thereof, are enabled in the claimed method. The specification shows that administration of TAK-448 protects against NAFLD, lowers liver steatosis, and reduces circulating free fatty acid and white adipose tissue mass in a mouse model of NAFLD. The specification, however, does not show evidence that the genus of claimed compounds can exhibit the effects as TAK-448 and be useful in a method as claimed. The specification defines that “The term “conservative variant” with respect to a natural or synthetic peptide or peptide analog, refers to a sequence that is about 90% or more identical to the peptide, for example with one amino acid substituted, added, or deleted in the sequence. This term also includes chemical variants of the peptide, such as a chemical modification of the amino acid side chains, including addition of a methyl, ethyl, halo, tri-fluoro, hydroxyl, carboxylate, amino, methylamino, and the like to the structure of the compound.” The specification further lists a number of exemplary compound variants in Tables 2 and 3. However, Curtis et al. (Am. J. Physiol. Endocrinol. Metab., 2010, Vol. 298:E296–E303) teaches that variants of kisspeptin-10 (KP-10) having a single amino acid substitution may have dramatically reduced or impaired receptor binding in vitro; further, substitution with different amino acid residues at the same position also affected binding affinities (p. E297, Table 1). The compounds tested by Curtis et al. include those compounds disclosed in the instant application. It is unpredictable how a structural change in KP-10 would affect the function or activity of the molecule. Clearly, it would require a tremendous amount of experimentation to determine whether the variant compounds are useful in the treatment method as claimed. The scope of patent protection sought by Applicant as defined by the claims fails to correlate reasonably with the scope of enabling disclosure set forth in the specification.
Clearly, the instant specification does not enable one of skill in the art to use the genus of the compounds for treating a subject in need of reducing fat in the liver. See In re Wands', 858 F.2d at 737, 8 USPQ2d at 1404. The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue" include, but are not limited to: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Given the breadth of the claims, in light of the predictability of the art as determined by the number of working examples, the level of skill of the artisan, and the guidance provided in the instant specification and the prior art of record, it would require undue experimentation for one of ordinary skill in the art to make and use the claimed invention.
Claim Rejections - 35 USC § 102
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 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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov ID - NCT02369796 (Last Update Posted: 2017-03-31) (hereinafter “NCT02369796”).
NCT02369796 describes a study that evaluates the effects of administrating TAK-448 to overweight/obese males with hypogonadotropic hypogonadism (see “Brief Summary” under “Study Overview”). NCT02369796 describes that 10 out of 15 participates were alcohol drinkers (see “Baseline Characteristics” under “Results Posted Tab”). The patients participated in the NCT02369796 clinical trial meet the limitation as in need of reducing fat in liver.
Therefore, NCT02369796 anticipates the claimed invention.
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 1-4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Damon et al. (WO 03/080070 A2, Int’l. pub. Date: 2 October 2003), in view of Bowe et al. (Islets, 2012, Vol. 4(1), 20-23).
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.
Damon teaches a method for treatment of a disease and disorder which may be inhibited by the inhibition of HMG-Co-A reductase and/or by the enhancement of insulin secretion, the method comprising administering to a subject in need thereof a composition comprising at least two components: (i) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an insulin secretion enhancer or a pharmaceutical acceptable salt thereof (p. 2, 2nd paragraph). Damon teaches that the diseases and disorders include, e.g., non-alcoholic fatty liver disorders or non-alcoholic steatohepatitis (p. 4, last paragraph through p. 5, 2nd paragraph). Damon teaches that the composition can be administered by oral administration (bridging paragraph between p. 20-21).
Damon teaches as set forth above. Damon, however, does not teach using kisspeptin-10 as an insulin secretion enhancer.
Bowe teaches that kisspeptin-10 (which also meets the limitation as a conservative variant of TAK-448) is capable of stimulating insulin release in vivo (see Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use kisspeptin-10 in the method of Damon. One of ordinary skill in the art would have been motivated to do so, because Damon teaches a combination therapy for treatment of a disease and disorder, e.g., non-alcoholic fatty liver disorders or non-alcoholic steatohepatitis, by administering an HMG-CoA reductase inhibitor and an insulin secretion enhancer, and Bowe teaches that kisspeptin-10 is capable of stimulating insulin release in vivo. Therefore, the combined teachings provide a reasonable expectation of success in treating a patient in need thereof.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Damon et al. (WO 03/080070 A2), in view of Bowe et al., and further view of Madrigal’s News Release (May 31, 2018) (hereinafter “Madrigal”).
Damon and Bowe teach as set forth above. These references, however, do not teach further administering to the patient a second compound which is MGL-3196 (resmetirom) (claim 5).
Madrigal reports that its MGL-3196 achieved liver biopsy endpoints in patients with non-alcoholic steatohepatitis (NASH) in phase 2 clinical trial.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include MGL-3196 in the treatment method taught and suggested by Damon and Bowe for patients having non-alcoholic steatohepatitis (NASH). One of ordinary skill in the art would have been motivated to do so, because Damon teaches a combination therapy for treatment of a disease and disorder, e.g., non-alcoholic fatty liver disorders or non-alcoholic steatohepatitis, by administering an HMG-CoA reductase inhibitor and an insulin secretion enhancer, Bowe further teaches that kisspeptin-10 is an insulin secretion enhancer capable of stimulating insulin release in vivo, and Madrigal furthermore teaches that MGL-3196 is clinically effective for treating patients with non-alcoholic steatohepatitis (NASH). Therefore, the combined teachings provide a reasonable expectation of success in treating the patients.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674 November 28, 2025