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 .
Current Status of 18/689,031
This Office Action is responsive to the amended claims of 03/04/2024 and the Applicant response of 07/17/2026.
Election/Restrictions
Applicant’s election without traverse of SIAIS630037 in the reply filed on 07/17/2026 is acknowledged. Applicants did not specify what each variable is in the elected species. The examiner has applied their own interpretation of the elected species to the following variables:
A is
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L1 is C3 alkylene
B is a 6 membered heterocyclylene group (piperidinyl)
C is a 6 membered arylene group (1,4-phenylene)
Y is a ring D, where n is 1
D is unsubstituted 6 membered heterocyclyl (piperazine)
LIN is the following linker
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ULM is the following E3 ligase ligand
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.
The elected species was searched using the structural definitions of the variables identified above, and no prior art was found describing the same structure. The search was expanded to encompass the broadest required structural features of the NAMPT-binding portion of the compound of claim 1. Ring A was searched broadly as a heterocyclic moiety, L1 was searched broadly as an alkyl moiety, and Ring B was searched broadly as a heterocyclic moiety. These features are the required structural elements of the NAMPT-binding portion of Formula (I) relevant to the elected species. This search was combined with a search of ULM structures corresponding to thalidomide-derived E3 ligase ligand moieties.
Claims 8-11, 14, and 18-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claims. Election was made without traverse in the reply filed on 07/17/2026. Claims 1-7, 12-13, 15-17, 23-28, and 32-39 have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/CN2022/114935, filed 08/25/2022, which claims the benefit of priority Chinese Patent Application No. CN 202111025519.1, filed 09/02/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/04/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: The specification is objected to because several of the ULM structures of [0075] contain a rectangular symbol along a bond
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. This is not a recognized conventional bond notation in organic chemistry and is not defined or explained in the specification. It is unclear what structural feature, bond type, attachment point, or other chemical significance is intended with these symbols. [0075] also depicts certain chemical structures bearing carbon-carbon triple bonds using inaccurate geometry
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. Each structure bearing a carbon-carbon triple bond should be amended to depict the accurate 180° bond angle of such bonds
Appropriate correction is required.
Claim Objections
Claim 13 is objected to because of the following informalities: Claim 13 is objected to because certain chemical structures depict carbon-carbon triple bonds using inaccurate geometry
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. Each structure bearing a carbon-carbon triple bond should be amended to depict the accurate 180° bond angle of such bonds. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-7, 12-13, 15-17, 23, 25-28, and 32-39 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.
Claim 1 recites a compound of Formula (I) comprising the groups LIN and ULM. The claim does not define the structural scope of either LIN or ULM. ULM is defined as “a E3 ligase ligand moiety,” and LIN is defined as “a linker moiety.” However, neither of these definitions provide sufficient structural guidance for the artisan to determine with reasonable certainty which moieties are encompassed by ULM or LIN. Accordingly, the claims fail to establish clear metes and bounds for the compounds encompassed by Formula (I) and are indefinite. Claims 2-7, 12-13, 15-17, 23, 25-28, and 32-39 depend directly or indirectly from claim 1 and fail to remedy these issues as the claims do not establish clear structural guidance for both the ULM and LIN moieties. Claims 12-13 provide clear structural limitations for the ULM moiety, but are indefinite in regard to LIN. Conversely, claims 15-17 provide clear structural limitations for the LIN moiety, but are indefinite in regard to ULM.
Claims 33-35 are further indefinite because claim 33 recites “[t]he compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, for use in the prevention and/or treatment of disease or disorder associated with NAMPT.” It is unclear whether claim 33 is directed to the compound of Formula (I), with the recited prevention and/or treatment constituting an intended use of the compound, or whether the claim is intended to define a method of using the compound of Formula (I) for the prevention and/or treatment of a disease or disorder associated with NAMPT. Accordingly, the scope of claim 33 cannot be determined with reasonable certainty. Claims 34 and 35 depend from claim 33 and fail to remedy this ambiguity.
Claims 35 and 38 are further indefinite because the claims recite the following parenthetical listings of specific diseases: “(including triple negative breast cancer, invasive breast cancer, infiltrating breast cancer);” “(such as acute myeloid leukemia, acute lymphocytic leukemia);” “(such as non-small cell lung cancer and small cell lung cancer);” “(such as diffuse large B-cell carcinoma, follicular B-cel lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma);” “(such as renal oncocytoma, clear cell renal cell carcinoma, renal urothelial carcinoma);” “(such as rheumatoid arthritis, autoimmune encephalitis);” “(including coronary atherosclerosis, acute myocardial infarction, myocardial ischemia-reperfusion injury, ischemic stroke).” It is unclear whether the diseases identified in the parenthetical phrases are required limitations of the claims or are merely exemplary species falling within the preceding disease genera. The scope of the claimed methods cannot be determined with reasonable certainty.
Claim 13 is further indefinite because several of the recited structures contain a rectangular symbol positioned along a bond
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. The claim does not define this symbol. Accordingly, it is unclear what the symbol represents.
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 36-39 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 while being enabling for the in vitro evaluation of certain compounds of Formula (I) for NAMPT-related activity, including the inhibition of tumor-cell proliferation and the degradation of NAMPT using compounds SIAIS630120 and SIAIS630121 in the specifically tested tumor cell lines, does not reasonably provide enablement for treating and/or preventing all forms of NAMPT associated disease comprising administering any compound of Formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating and/or preventing any disease or disorder associated with NAMPT in a subject comprising administering a therapeutically effective amount of any compound of Formula (I). Thus, the claims taken together with the specification imply that any compound of Formula (I) is capable of not only treating any NAMPT associated disease, but is also capable of preventing these diseases and disorder. Thus, the scope of the claims is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the prior art is that target protein binding alone is not predictive of PROTAC-mediated degradation. Bondeson et al. demonstrated that PROTACs capable of binding more than 100 kinases degraded only a small subset of the bound targets and further teaches that degradation is dependent on the protein-protein interactions and the stability of the ternary complex (see Summary pg. 78; Discussion, right col., second para, pg. 83; left col., fourth para, pg. 84; Significance, pg. 85).
Hsu et al. teaches that the biological and therapeutic effects associated with modulation of NAMPT are dependent upon the particular physiological and cellular context. The reference teaches that cardiac-specific overexpression of NAMPT protected the heart against ischemia/reperfusion injury and that extracellular NAMTP was likewise reported to reduce myocardial infarction and apoptosis (see Nampt protects the heart against ischemia/reperfusion (I/R) injury). The reference additionally teaches that extracellular NAMPT with FK866 was reported to reduce myocardial infract size through a distinct anti-inflammatory mechanism (see Nampt protects the heart against ischemia/reperfusion (I/R) injury). The reference therefore recognizes differing biological consequences resulting from NAMPT modulation and conclude that, although upregulation of NAMPT is generally protective in the heart, the role of NAMPT during cardiac stress requires further clarification because extracellular NAMPT may exert either beneficial or detrimental effects on cardiomyocyte survival (see Conclusions). The reference further underscores the uncertainty in the art regarding the role of NAMPT regulation in cardiac diseases.
Cho et al. teaches autoimmune diseases are heterogenous both between different autoimmune diseases and within a single disease (see Abstract and Within-disease heterogeneity). The reference teaches that although anti-TNF therapy is effective and the standard of care treatment across multiple autoimmune disease, it is ineffective in multiple sclerosis (MS) and may actually worsen MS (see Understand heterogeneity in autoimmune disease through therapy response). The reference further teaches that there is no clear-cut boundary between responders and nonresponders to anti-TNF treatment and that treatment is a continuum where the degree of response depends on the timing of the therapy (see Understand heterogeneity in autoimmune disease through therapy response). The reference further teaches that inhibition of IL-17 is effective in treating psoriasis but was ineffective in treating inflammatory bowel disease (see Table 2), demonstrating the tissue- and disease-specific consequences of targeting a common immune pathway.
Rybinkski et al. teaches that cancer treatment response is inherently heterogeneous and that a therapy effective against one tumor population cannot simply be extrapolated across all cancer, or even across all cells within the same tumor (see Abstract and Introduction). Ther reference teaches that malignant tumors exhibit substantial genetic, epigenetic, and microenvironmental heterogeneity, resulting in significant variability in therapeutic response and the development of treatment resistance (see Introduction; Genetic Heterogeneity; Epigenetic Heterogeneity; Microenvironmental Heterogeneity). The reference further teaches that genetically distinct subclones may exhibit sensitivities to targeted therapies and that even genetically identical cancer cells may respond differently to the same treatment depending upon their microenvironment (see Genetic Heterogeneity; Microenvironmental Heterogeneity). The reference concludes by teaching that effective cancer treatment strategies must account for the heterogenous characteristics of a particular tumor (see Towards personalized combination therapies that account for tumor heterogeneity).
(5) The relative skill of those in the art:
The relative skill of those in the art is high. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the synthesis, development, and biological evaluation of PROTACs for the targeted degradation of proteins.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for the synthesis of example compounds 1-91, which are compounds encompassed by Formula (I), as well as assays for determining the IC50 values of the disclosed compounds using Jurkat tumor cells ([00462]-[00465]). The specification further provides guidance for conducting in vitro cytotoxicity assays using MOLT4 and HL60 tumor cells with compounds SIAIS630120 and SIAIS630121 and for evaluating NAMPT degradation by Western blot in SW620, HT29, MCF-7, BEL7404, MOLT4, Jurkat and HL60 tumor cells ([00466]-[00475]; Figures 1-7).
However, the specification does not provide sufficient direction or guidance for treating or preventing the full scope of diseases and disorders associated with NAMPT using the full scope of compounds encompassed by Formula (I). In particular, the specification does not provide reasonably specific guidance regarding therapeutically effective compounds, dosages, routes of administration, treatment regimens, or other therapeutic parameters for the diverse diseases and disorders encompassed by the instant claims. The specification provides no experimental evidence demonstrating that the in vitro activity observed for the tested compounds in selected tumor cell lines can reasonably be extrapolated to the treatment or prevention of all diseases and disorders associated with NAMPT.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the unpredictability associated with PROTAC-mediated protein degradation, the substantial biological and therapeutic heterogeneity of the broadly claimed diseases and disorders, and the absence of a single common pathway or therapeutic mechanism form which efficacy could reasonably be extrapolated across the full scope of the claimed methods and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claims 1-7, 12-13, 15-17, and 23-25 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 making salts, stereoisomers, and prodrugs of the claimed compounds does not reasonably provide enablement for making analogs of every single compound encompassed by Formula (I) or for making solvates, polymorphs, or isotopically enriched analogs of the claimed compound of Formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
"The factors to be considered [in making an enablement rejection] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims",
In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Exparte Formal, 230 USPQ 546. a) Finding a solvate or a crystal such as a polymer is an empirical exercise. Predicting if a certain crystal , for example, is in fact a single entity crystal or a molecular adduct, that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science.
For a compound to be a solvate or polymorph and effectively work, it must meet three tests. It must be bioavailable and able to avoid drug interactions. It must be metabolized in such a way so that it is soluble and possess physiologically meaningful concentration. Thirdly, that polymorph must be physically and chemically stable in order to be clinically effective. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation.
b) The direction concerning analogues is lacking as nowhere in the specification did applicant indicate what is considered an analogue of NAMPT ligand and which NAMPT is the non-existent analogue compound is applicant referring to. Likewise, the direction concerning solvates and crystals such as polymorphs is also lacking in the instant invention as applicant failed to provide any information as to how these purported novel compounds of Formula (I) that are polymorphs are prepared and avoid disappearing polymorphism wherein the previously prepared form no longer appears after obtaining the more stable form. Moreover, applicant provided no thermodynamic and kinetic properties to ascertain dissolution rates or packing properties to predict the particle morphology. Given the purported novelty of such compounds the examiner maintains that applicant has not enabled the breadth of the claims.
c) There is no working example of a crystal form of the compounds of formula (I). While examples are not required and one can look to the prior art for enablement support, the examiner contends that formation of crystals such as solvates and hydrates of bifunctional compounds are unpredictable as stability at various temperatures can differ across structures or in the case of polymorphs wherein different polymorphs of the same compound can possess contrasting slip planes wherein a defined slip plane provides greater plasticity, compressibility and tabletability as taught by Datta et al. on pg. 43.
There is no working example of an isotopically enriched form of the compounds of formula (I). While examples are not required and one can look to the prior art for enablement support, the examiner contends that isotopic enrichment of bifunctional compounds are unpredictable and position-dependent rather than a universally routine modification (see Atzrodt et al discussion below).
d) The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body.
e) Datta et al. summarize the state of the crystal art. Datta et al. Crystal structures of drugs: Advances in determination, prediction, and engineering; 2004, Nature Reviews, Vol. 3, pgs. 42-57. The table on the left side of page 43 outlines all the differences that exists among polymorphs, many of which are important in drug performance. Datta et al. further teach that while polymorphism and solid-state solvation are common among chiral drugs, the existence of polymorphism of a dug will not only affect its pharmaceutically relevant properties but may also result in interconversion between different types of racemates (see pg. 45, right col.) and this would indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, solvents and polymorphism concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol or unpredictability within drugs discussed in the page of this paragraph is particularly relevant.
Atzrodt et al. teaches that the preparation of isotopically enriched organic compounds is highly dependent upon the particular molecular substrate, the desired site of isotopic incorporation, and the method of labeling. The reference explains that adjustment of reaction conditions for individual substrates are generally required and that isotopic incorporation represents a significant synthetic challenge (see 3. Heterogeneous Catalysis; 5. Conclusions and Outlook).
f) Datta et al. in the first paragraph on page 42 describes how the shape and particle size of a drug can affect its performance making Applicants' crystals which thus indicates the need of a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph. D. degree and several years of industrial experience.
Atzrodt et al.’s teachings demonstrate that preparation of an unspecified “isotopically enriched analog” of each compound encompassed by Formula (I) cannot reasonably be presumed to be achieved through a single synthetic process of the corresponding unlabeled compounds.
g) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See ln re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970).
h) The breadth of the claims includes all of the yet to be delineated compounds of formula (I) as well as the presently unknown list of potential solvates, polymorph derivatives, and isotopically enriched analogs embraced by claim 1. MPEP 2164.01 (a) states, "[a] conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here. Thus, undue experimentation will be required to determine if any particular compound can, in fact, be made as an analogue of NAMPT ligand or a solvate, a polymorph, or an isotopically enriched analog of Formula (I).
Close Art
The closest prior art of record is CN 111454327 (found in IDS filed 03/04/2024). ‘327 discloses bifunctional NAMPT protein degradation targeting chimeras. The disclosed species of the reference include the following species
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(pg 31, [0128]). The boxed portion of the species above corresponds to the NAMPT ligand of the instant application, but is excluded by the proviso of claim 1. The reference also discloses species with the following structures
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( pg. 32, [0129]) that possess NAMPT ligands similar to those of the instant claims. However, the instant claims do not allow for heteroaryl moieties at the indicated position. Although the prior art discloses NAMPT degraders that are structurally similar to the instantly claimed compounds, the reference, either alone or in combination with the other references of record, does not provide a teaching, suggestion, or motivation to modify the identified structural features in a manner required to arrive at the instantly claimed compounds.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.K.E./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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