DETAILED ACTION
This office action is in response to applicant’s filing dated August 25, 2025.
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 .
Status of Claims
Claims 21-39 are pending in the instant application. Acknowledgement is made of Applicant's remarks filed August 25, 2025. Claims 1-20 were previously canceled.
Election of Species
Applicant’s election without traverse of Compound 1:
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as the elected compound of Chemical Formula (1) species and atopic dermatitis as the elected inflammatory disease species in the reply filed on August 25, 2025 is acknowledged.
Compound 1 is a compound of Chemical Formula (1) wherein R1 is C2alkyoxy-C2alkyl, -CH2CH2OCH2CH3; R2 is halogen, Cl; R3 is H; R4- and R5 are independently H and C1alkyl, -CH3.
Compound 1 is a compound of Chemical Formula (2) wherein R1 is C2alkyoxy-C2alkyl, -CH2CH2OCH2CH3; R2 is halogen, Cl; R3a and R3b are both H; R4- is C1alkyl, -CH3; and R5 is H.
Claims 30, 32, 36, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 25, 2025.
Claims 21-28, 31, 33-35, 38, and 39 are presently under examination as they relate to the elected species:
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and atopic dermatitis.
Priority
The present application is a 371 of PCT/KR2021/009447 filed on July 21, 2021, which claims benefit of foreign priority to REPUBLIC OF KOREA 10-2020-0091182 filed on July 22, 2020 and REPUBLIC OF KOREA 10-2021-0004150 filed on January 12, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 20, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except where marked with a strikethrough.
Drawings
Acknowledgement is made of the drawings received on January 20, 2023. These drawings are accepted.
Specification
The abstract of the disclosure is objected to because:
The abstract recite the phrases “The present disclosure relates to…” and “compound according to the present disclosure…” These phrases can be implied and should be avoided.
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).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The disclosure is objected to because of the following informalities:
Table at paragraph [110] contains structures that are blurry and difficult to read, for example, compounds 4, 10, and 11.
Chemical Formula 2 at paragraph [113] contains blurry variables.
The preparation scheme at paragraph [343] is blurry and the structures contain difficult to read variables.
The structure at paragraph [425] is blurry and variables are difficult to read.
The structure at paragraph [429] is blurry and variables are difficult to read.
The structure at paragraph [433] is blurry and variables are difficult to read.
Appropriate correction is required.
Claim Objections
Claim 27 is objected to because of the following informalities:
Chemical Formula 2 is blurry.
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 21-29, 31, 33-35, 38, and 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 21 recites, “A method for treating an inflammatory disease, comprising administering a compound represented by the following Chemical Formula 1.” Claim 21 does not set forth a subject. It is not clear what the compound is administered to. Thus, the metes and bounds of the instant claims are not clear.
Claims 22-29, 31, 33-35, 38, and 39, which depend from and thus incorporate all the limitations of claim 21, do not clarify the ambiguity of claim 21. Thus, the rejection also applies to claims 22-29, 31, 33-35, 38, and 39.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
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 21-29, 31, 33-35, 38, and 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 a method of treating sepsis and inflammatory bowel disease comprising administering Compound 1, does not reasonably provide enablement for a method of treating any inflammatory disease comprising administering any compound of Chemical Formula (1). 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method of treating an inflammatory disease comprising administering a compound of Chemical Formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The relative skill of those in the art is high, generally that of a D.V.M. or Ph.D. The artisan using Applicant’s invention would generally be a veterinarian with a V.M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites Freire et al (Periodontol 2000, 2013; 63(1):149-164), Tabas et al (Science, 2013; 339(6116):166-172), Patil et al (Int. J. Mol. Sci., 2019; 20:4367 pp 1-38), and Prescott et al (Cells, 2018; 7:115 pp 1-34).
Freire, cited for evidentiary purposes, teaches inflammation is an essential mechanism in human health and disease (page 149, 1st paragraph); inflammation is initiated as a protective response to challenges or foreign bodies, or injury, experienced by host tissues. Thus, by broadest reasonable interpretation any injury or disease is a disease associated with an inflammatory response and thus would read on inflammatory disease.
Tabas, cited for evidentiary purposes, teaches a number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer’s disease, have a pathophysiologically important inflammatory component; in these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove; although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations; in particular, the inflammatory response is critical for survival; as a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs (Abstract).
Patil, cited for evidentiary purposes, teaches inflammatory diseases are globally identified as the major cause of morbidity across the population; inflammatory condition is associated with the activated immune system, including activated immune cells and the bio-molecules; inflammation is a defensive response of an organism against invasion by the foreign bodies like bacteria, parasites, and viruses; many chronic diseases manifest due to presence of low grade sustained inflammation; treatment of the chronic inflammatory diseases like rheumatoid arthritis and inflammatory bowel diseases is still a challenge due to lack of safe and effective drugs (page 2, 1st paragraph). Patil teaches finding a safe and effective drug to control inflammation has been a challenge and therefore, many animal models have been developed for the evaluation of drugs having anti-inflammatory properties; choosing the right animal model for the preclinical evaluation has been a challenge in establishing the efficacy and mechanism of action of drugs for translation as a therapeutic effect in humans; although numerous in-vivo and in-vitro models for anti-inflammatory drug development are available, the judicious selection of the animal model is always critical and brings a challenge for the inclusion in drug discovery and development; an inappropriate selection of animal models can lead to false positive or false negative results and may limit the discovery of promising drug molecules from a screening program (page 2, 2nd paragraph).
Prescott, cited for evidentiary purposes, teaches deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies; consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery; as the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines; thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease; however, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors (Abstract). Prescott teaches NF-κB signalling pathways are normally tightly controlled by multiple regulatory mechanisms to ensure minimal basal activation; however, given its critical role in regulating the expression of genes involved in cell-survival, proliferation, angiogenesis, metabolism, inflammation and cell adhesion/migration, it is unsurprising that a wide range of inflammatory diseases and cancers have been shown to exhibit deregulated NF-κB signalling that results in constitutive pathway activation; indeed, the ability of NF-κB to induce inflammation places it as one of the crucial links between chronic inflammation and cancer; however, aberrant NF-κB activation is also capable of promoting tumorigenesis in cancers whose early progression isn’t typically associated with inflammation through contributions of NF-κB target genes to almost all the hallmarks of cancer (page 4, last bridge paragraph). Prescott teaches the potential of IKKβ inhibition as a therapeutic strategy remains unrealized and previous optimism for IKKβ as a therapeutic target has significantly cooled; there are several plausible reasons for this lack of clinical success; the simplest is that IKKβ inhibitors developed to date may not exhibit the combination of properties required to achieve success during preclinical development, including but not limited to: nanomolar-range potency, high selectivity over IKKα/other kinases, and clinically relevant pharmacokinetics/pharmacodynamics; as mentioned earlier, several ‘selective’ IKKβ inhibitors that continue to be used by the research community have been shown to be anything but selective; IKKβ inhibitors described to date were identified following hit-to-lead development and characterization of structure–activity relationships in the absence of resolved crystal structures for the IKKs; however, the recent reports of human IKKβ X-ray crystal structures have revealed many new structural details at a sufficiently high resolution that will hopefully facilitate the structure-guided design of next-generation IKKβ inhibitors with enhanced potency and selectivity (page 8, last bridge paragraph).
Prescott further teaches another reason for the lack of success of IKKβ inhibitors in pre-clinical development may be their inappropriate therapeutic application. In the simplest sense this could reflect use of the wrong dosing strategy (drug concentration/dosing schedule, etc.) for effective target inhibition; more challenging is the appropriate selection of patient subgroups to achieve the desired therapeutic efficacy; for example, the proof of concept study for SAR113945 failed to show any effect in the overall group of recruited study participants for the primary endpoint; however, post-study analysis demonstrated a statistically significant difference in a patient subgroup that had presented with synovial effusion at baseline (page 10, 2nd paragraph).
These articles plainly demonstrate that the art of developing and testing drugs, particularly for use in treating any inflammatory conditions, including those mediated by NFκB and IKK, is extremely unpredictable.
2. The breadth of the claims
Claims 21-29, 31, 33-35, 38, and 39 are very broad in terms of the type of diseases being treated: all types of inflammatory diseases are claimed to be treated with any compound of Chemical Formula (1). Moreover, the instant claims do not require the composition to be administered to a subject in need thereof. Without a subject in need thereof, the method encompasses a healthy subject without the disease. Claim 33 while narrow in terms of compounds of Chemical Formula (1), is very broad in terms of the type of diseases being treated: all types of inflammatory diseases are claimed to be treated.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides examples wherein Compound 1 inhibits both canonical and non-canonical pathways of NF-κB inflammatory signaling pathway (Test Example 5); inhibits formation of hexamer IKKα and acted as a selective inhibitor for IKKα (Test Example 6); and reduced mortality in a sepsis model (Test Example 7). Thus, the specification provides evidence of a single compound of Chemical Formula (1) in an animal model of sepsis.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that any Chemical Formula (1) could be predictably used as treatment for all inflammatory disease other than sepsis comprising administering Compound 1.
Determining if a particular compound will treat any particular disease state would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the inventions of claims 21-29, 31, 33-35, 38, and 39 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
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 21-29, 31, 33, 34, 38, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al (US 2002/0128292 A1, cited in the IDS dated January 20, 2023).
Regarding claims 21-29, 31, 33, and 34, Cai teaches a method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering an effective amount of a compound of Formula (I):
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wherein X is O; R2-R6 are independently hydrogen or alkyl; R12 and Ar1 is an optionally substituted heteroaryl (claim 1); wherein the disorder is inflammatory bowel disease (claim 23). Inflammatory bowel disease reads on an inflammatory disease as evidenced by instant claim 34. Moreover, Cai teaches heteroaryl groups include indolyl [0149]. Cai teaches useful substituents on heteroaryl groups include halo and C1-C6- alkoxy [0136] and useful alkyl groups include straight-chained C1-10 alkyl groups. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to produce a compound of Formula (I) wherein X is O; R2, R3, R5, and R6 are hydrogen and R4 is methyl; and Ar1 is a substituted indolyl substituted with a halo, Cl and C4-alkoxy, -CH2CH2OCH2CH3 to arrive at the elected compound for use in a method of treating inflammatory bowel disease from the teachings of Cai.
Regarding claim 38, Cai teaches typically, the compounds may be administered to
animals, e.g., mammals, orally [0171].
Regarding claim 39, Cai teaches the pharmaceutical compositions of the present
invention may be administered by any means that achieve their intended purpose; for example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes [0177].
Taken together, all this would result in the practice of the method of claims 21-29, 31, 33, 34, 38, and 39 with a reasonable expectation of success.
Conclusion
Claims 21-29, 31, 33-35, 38, and 39 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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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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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628