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
This application is a 371 of PCT/JP2022/029655 08/02/2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. JP-2021-135496, filed on 08/23/2021. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Status of Claims
Claims 16-31 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 16-27, and 30-31 in the reply filed on 3/31/2026 is acknowledged. The traversal is on the ground(s) that Examiner’s cited reference is drawn to an alternative mechanism. Examiner finds this persuasive and withdraws restriction between groups. However, the requirement for species election is maintained, as the species of NF-kB inducing kinase inhibitors claimed by the Applicant span disparate categories of compounds, such as nucleic acids (claim 25) as well as small-molecule compounds of formula (I) (claim 23).
The elected species reads upon claims 16-24, and 26-27, 30-31.
Claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 3/31/2026.
Claims 16-24, and 26-31 are under examination.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract of the disclosure is objected to because the language is excessive and doesn’t clearly state what the invention is. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 16-24, and 26-31 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 suppressing transdifferentiation of a mature hepatocyte, as well as a method of treating cholangiocarcinoma, comprising administering a composition comprising the Applicant’s elected and exemplified compound,
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to a subject in need thereof, does not reasonably provide enablement for a method of suppressing transdifferentiation of a mature hepatocyte, or a method of treating cholangiocarcinoma, comprising administering a composition comprising any and all NF-kB inducing kinase inhibitors. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention: The nature of the invention is complex in that the claims are drawn to a method of suppressing transdifferentiation of a mature hepatocyte, and a method of treating cholangiocarcinoma, comprising administering a composition comprising any and all NF-kB inducing kinase inhibitors. However, Applicant has only demonstrated activity in one species of NF-kB inducing kinase inhibitor, yet claims any and all NF-kB inducing kinase inhibitors broadly to include all current and future NF-kB inducing kinase inhibitors.
Breadth of the Claims: The claims are broad in that the claims recite a method of suppressing transdifferentiation of a mature hepatocyte, and a method of treating cholangiocarcinoma, comprising administering a composition comprising any and all NF-kB inducing kinase inhibitors. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification describes utilizing the Applicant’s elected species of formula (I), showing efficacy against relevant cell lines. However, no working examples are given for any other species of compound other than the Applicant’s elected compound.
While it is noted that the applicant has shown some data for activity against relevant cell lines with the Applicant’s elected compound, the applicant is not enabled for the full-scope of NF-kB inducing kinase inhibitors.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that enablement of one species of a genus does not necessarily enable the full-scope of the genus (MPEP 2164.01)
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach a method of suppressing transdifferentiation of a mature hepatocyte, or a method of treating cholangiocarcinoma, comprising administering a composition comprising any and all NF-kB inducing kinase inhibitors. In order to carry out the claimed invention, one of ordinary skill in the art would have to determine the efficacy of the full-scope of NF-kB inducing kinase inhibitors in the context of treating cholangiocarcinoma and suppressing transdifferentiating of a mature hepatocyte.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 16-31 are not considered to be fully enabled by the instant specification.
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.
Claim(s) 16-24, and 26-31 are rejected under 35 U.S.C. 103 as being unpatentable over Seubwai, W. (“Aberrant Expression of NF-kB in Liver Fluke Associated Cholangiocarcinoma: Implications for Targeted Therapy”, PLOS ONE, Vol. 9, no. 8, 2014. Pp 1-10.) in view of
Wattanawongdon, W. (“Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness”, International Journal of Oncology, Vol. 47, no. 6, 2015, Pp. 398-410), in further view of
Blaquiere, N., et. al. (WIPO Publication No. WO 2015/025026 A1; Issued 07/21/2015) in further view of Pflug, K.M. (“Targeting NF-kB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer”, International Journal of Molecular Sciences, Vol. 21, no. 8470, 2020, Pp. 1-19.)
Seubwai teaches that NF-kB is implicated in progression of several malignancies, including intrahepatic cholangiocarcinoma (ICC) (reading on claim 26) (See Page 2; Materials and Methods; KKU-M139 cell line (ICC)) as evidenced by Wattanawongdon, W. (“Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness”, International Journal of Oncology, Vol. 47, no. 6, 2015, Pp. 398-410.) (See Page 399; Materials and Methods)
Seubwai further teaches that Inhibition of NF-kB action significantly reduced cell growth and enhanced cell apoptosis (See Page 1; Conclusions).
Seubwai does not directly teach NF-kB inducing kinase (NIK) inhibition.
However, Blaqiuere teaches that NIK inhibition results in lower NF-kB signaling (See Page 1; Lines 14-26).
Blaquiere also teaches the Applicant's elected compound of the formula (reading on claims 23 and 24) (See Page 64; Table 1 compound 90), and that it is known as a NIK inhibitor (page 299; Table 2 -compound 90).
Neither Seubwai nor Blaqiuere teach TRAF3.
Pflug teaches that TRAF3 is a relevant biomarker for NIK activity (reading on claim 27). Pflug teaches that NF-kB-inducing kinase (NIK; gene name Map3k14) is a key upstream regulator of the noncanonical NF-kB signaling pathway and that NIK was subsequently shown to be essential for activation of noncanonical NF-kB signaling (See Page 2 - 3; NIK and the Noncanonical NF-kB Pathway).
Pflug further teaches that NIK is a serine/threonine kinase with four binding domains in including an N-terminal region for TRAF3 binding, NIK is bound to tumor necrosis factor (TNF) receptor-associated factor 2 and 3 (TRAF2/3), that TRAF3 degradation allows accumulation of newly synthesized NIK within the cell (Figure 3), and that NIK stabilization and accumulation is critical for subsequent activation of the noncanonical NF-kB pathway (See Page 3; NIK and the Noncanonical NF-kB Pathway).
In the instant case, Seubwai, Blaquiere, and Pflug provide adequate teaching, suggestion, and motivation to one having ordinary skill in the art, before the Applicant’s filing date, to use the Applicant’s elected compound in a method of treating cholangiocarcinoma in which an amount of TRAF3 is lower than a specified value or cholangiocarcinoma in which an amount of NF-kB inducing kinase is higher than a specified value, comprising administering a composition comprising the Applicant’s elected compound to a subject in need thereof, as well as a method of suppressing transdifferentiation of a mature hepatocyte into a proliferative or intrahepatic cholangiocyte, comprising administering a composition comprising an NF-kB inducing kinase inhibitor which is the Applicant’s elected compound of formula (I), to a subject in need thereof, wherein the method is used to treat cholangiocarcinoma in which an amount of TRAF3 is lower than a specific value or cholangiocarcinoma in which an amount of NF-kB inducing kinase is higher than a specific value, as well as methods of screening a substance that suppresses transdifferentiation of a mature hepatocyte, and for treatment of cholangiocarcinoma, comprising a step of measuring activity of NF-kB inducing kinase.
Seubwai establishes the nexus between cholangiocarcinoma and reduced NF-kB signaling being shown to directly reduce the progression of cholangiocarcinoma, such that one having ordinary skill in the art, before the Applicant’s effective filing date, would have had motivation to treat cholangiocarcinoma by reducing NF-kB signaling.
Blaquiere provides a nexus between the Applicant’s elected compound, its activity as an NIK inhibitor and the effect of NIK inhibition in lowering NF-kB signaling, such that one having ordinary skill in the art, would have been motivated, before the Applicant’s effective filing date, to use the Applicant’s elected compound as a NIK inhibitor to reduce NF-kB signaling and treat cholangiocarcinoma (reads on claim 26).
Pflug teaches that TRAF3 suppresses NIK accumulation within cells, and that lower levels of TRAF3 would result in higher NIK accumulation and activity, resulting in increased NF-kB signaling. This provides motivation to one having ordinary skill in the art to optimize the treatment conditions to include low TRAF3 and high NIK levels so that the Applicant’s NIK inhibitor would have the most potential for effecting treatment (reads on claim 27), by screening for activity of these biomarkers before treatment to maximize treatment efficacy (reads on claim 31).
Seubwai, Blaquiere, and Pflug render obvious the Applicant’s claims drawn to a method of treating cholangiocarcinoma, and thus render obvious the method drawn to suppressing transdifferentiation of a mature hepatocyte (reads on claims 16-24 and 30), as this is the mechanism by which treatment of cholangiocarcinoma is achieved and both methods require administration of the same compound to the same subjects. Products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
One having ordinary skill in the art, before the Applicant’s effective filing date, would have been motivated and have had reasonable expectation of success to combine the teachings in these references to arrive at the Applicant’s invention.
Therefore, it would have been obvious to one having ordinary skill in the art, before the Applicant’s effective filing date, to combine these teachings and arrive at a method of using the Applicant’s elected compound in a method of treating cholangiocarcinoma in which an amount of TRAF3 is lower than a specified value or cholangiocarcinoma in which an amount of NF-kB inducing kinase is higher than a specified value, comprising administering a composition comprising the Applicant’s elected compound to a subject in need thereof, as well as a method of suppressing transdifferentiation of a mature hepatocyte into a proliferative or intrahepatic cholangiocyte, comprising administering a composition comprising an NF-kB inducing kinase inhibitor which is the Applicant’s elected compound of formula (I), to a subject in need thereof, wherein the method is used to treat cholangiocarcinoma in which an amount of TRAF3 is lower than a specific value or cholangiocarcinoma in which an amount of NF-kB inducing kinase is higher than a specific value.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OROD MOTEVALLI whose telephone number is (571)272-6026. The examiner can normally be reached Monday - Friday 10:00AM - 6:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/OROD MOTEVALLI/ Examiner, Art Unit 1628
/AMY L CLARK/ Supervisory Patent Examiner, Art Unit 1628
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