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 .
Claim Status
Claims 1, 3-4, 6-7, 9-10, 12, 14, 20-22, 25, 29-31, and 49-64 are pending.
Claims 10, 12, 60, 63 and 64 are examined herein.
Claims 1, 3-4, 6-7, 9, 14, 20-22, 25, 29-31, 49-59, 61 and 62 are withdrawn (see restriction/election below).
Priority
This application is filed 02/27/2024, and claims the benefit of domestic priority as below:
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Information Disclosure Statements
One IDS(s) received on 10/03/2024 has been considered unless marked with a strikethrough.
Election/Restrictions
Applicants elect Group IV, claims 10, 12 and 60, drawn to a method of treating an inflammatory disease comprising administering a compound of formula (IV) in the reply field on 06/22/2026 is acknowledged. New claims 63 and 64 also fall within the selected group. Because applicants did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant further elects the “3-(5-bromo-2-methoxyphenyl)-1-(3,4-dimethoxyphenyl)-2-propen-1-one (Compound IV-1)” disclosed in claim 12 and 63 as the elected species in the reply filed on 1/9/2026 is acknowledged.
The applicant asserts that the claims 12, 60, 63 and 64 are readable on the elected species. However, the Examiner finds that the claims 10, 12, 60, 63 and 64 read on the elected species. Claims 1, 3-4, 6-7, 9, 14, 20-22, 25, 29-31, 49-59, 61 and 62 from Group I, II, III, V, and VI are withdrawn from consideration because these claims do not read on the elected species.
If the elected species is not identified in the prior arts, the elected species would be allowable if an independent claim was drafted with that species alone. (see MPEP 802.03)
However, the elected species was identified in the prior art. Accordingly, claims 10, 12, 60, 63 and 64 will be examined on their merits, and no further claims are withdrawn. With respect to the selected species, the art is rejected under 35 USC 103 below.
Claim Objections
Claim 10 is objected to because of the following informalities:
Claim 10 is objected to because the term “alkyloxy” should be “alkoxy” for consistency. Appropriate correction is required.
Claim Rejections - 35 USC § 112, 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 10, 12 and 63 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 identifying specific compounds having selective IL-12b inhibitory activity and using the compounds for treatment of specifically identified IL2b-associated inflammatory diseases, does not reasonably provide enablement for treating the full scope of inflammatory diseases encompassed by claims 10 and 63. 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.
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
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 the 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).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 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:
Nature of the invention:
The invention is drawn to a method of treating an inflammatory disease in a subject comprising administering a therapeutically effective dose of a selective IL-12b inhibitor of Formula (IV) or recited compounds in claims 12 and 63. The specification states that aberrant expression of IL-12p40 impacts several autoinflammatory diseases.
Breadth of the claims:
The claims 10 and 63 broadly encompass treatment of “an inflammatory disease”. The specification identifies psoriasis, chronic eczema, vitiligo, lichen planus, cutaneous lupus erythematosus, Behcet's disease, ulcerative colitis, Crohn' s disease, or alopecia as an inflammatory disease. However, the term "inflammatory disease" encompasses a heterogeneous group of diseases exhibiting distinct etiologies, pathophysiological mechanisms, and clinical manifestations. Furthermore, claim 10 broadly encompasses compounds of Formula (IV). However, the specification identifies and tests only a limited number of compounds falling within Formula (IV) for selective IL-12b inhibitory activity.
Level of ordinary skill in the art:
The artisans using applicants’ method would be a collaborative team of synthetic chemists, biologists, immunologists, pharmacologists, and/or health practitioners having advanced skills and experience in inflammatory diseases and drug development.
State of the prior art and predictability in the art:
Sandborn et al. (Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease, Gastroenterology, 135(4), 1130-41, pub’d 07/17/2008) teaches that Ustekinumab, a monoclonal antibody against the p40 subunit of inter leukin-12/23, included a clinical response in patients with moderate-to-severe Crohn’s disease (abstract, and discussion section). Thus, Sandborn supports therapeutic inhibition of the p40 subunit of inter leukin-12/23 for a particular inflammatory disease. In contrast, Segal et al. (Repeated subcutaneous injections of IL-12/23p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol., 7(9), 796-804, pub’d 08/07/2008) teaches inhibition of the same IL-12/IL-23p40 pathway with ustekinumab does not show efficacy in relapsing remitting multiple sclerosis (abstract and results). Multiple sclerosis is identified in the instant specification as an autoimmune disease within its disclosure of inflammatory disease (paragraph [0180]).
Thus, Sandborn and Segal demonstrate that the therapeutic efficacy of inhibiting the IL-12/IL-23 p40 pathway varies by disease and that findings from a specific inflammatory disease cannot be validly extrapolated to inflammatory diseases in general. Moreover, pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The amount of directions provided and working examples:
The specification provides 1) a dual fluorescence macrophage screening assay for identifying selective IL-12b inhibitors; 2) a treatment example that compound IV-1 is administered topically to a patient with Behcet’s disease; and 3) a treatment example that compound IV-1 with apremilast to a patient with alopecia. However, these limited examples do not demonstrate the therapeutic efficacy of the claimed compounds across the entire scope of "inflammatory diseases." Furthermore, the in vivo experimental data described in the specification do not pertain to compounds of Formula (IV) or the specifically mentioned compounds; rather, they relate to an imiquimod-induced psoriasis-like dermatitis model involving β-adrenergic signaling and the treatment of that model with clenbuterol.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The amount of experimentation required to practice the full scope of the claims amounts to undue experimentation. A person skilled in the art would need to determine, for each specific disease, whether the inhibition of IL-12b provides a therapeutic benefit and whether the specific claimed compounds provide effective dosages, routes of administration, and treatment regimens for the scope of the diseases in question.
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.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
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.
Claim 12 is 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 12 recites the limitation the specific compounds in the body of claim 12. There is insufficient antecedent basis for this limitation in the claim. Claim 10 defines that Formula (IV) has R1 is halo or alkyloxy; R2 and R3 are independently alkyloxy; and R4 is hydrogen, alkyl or alkoxy. The specific compounds in claim 12 including (E)-3-(5-bromo-2-methoxyphenyl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one (comp. 1); (E)-3-(2,5-dimethoxyphenyl)-1-( 4-methylphenyl)prop-2-en-1-one (comp. 2); (E)-3-(3-chlorophenyl)-1-(3,4-dimethoxyphenyl)prop-2-en-1-one (comp. 3); and (E)-3-(2,3-dimethoxyphenyl)-1-( 4-ethoxyphenyl)prop-2-en-1-one (comp. 4) do not fall within the limitations of Formula (IV) in claim 10. For example, R3 and R4 cannot be “1,4-dioxane” in comp. 1; R3 cannot be “H” in comp. 2; R2 cannot be “H” in comp. 3; and comp. 4 has substitution at a non-R position.
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Instant Formula (IV) compound 1 compound 2
compound 3 compound 4
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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) 10, 12, 60, 63 and 64 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (Licochalcone E reduces chronic allergic contact dermatitis and inhibits IL-12p40 production through down-regulation of NF-κB, Int. Immunopharmacol., 10(9), 1119-1126, pub’d 07/03/2010), in view of Kumar et al. (Synthesis and antimicrobial activity of 2,4-diaryl-2,3-dihydrobenzo[b][1,4] thiazepines, Res. Chem. Intermed. 39, 2555–2564, pub’d 09/11/2012), further in view of Ni et al. (US 6,608,101 B1, pub’d 08/19/2003).
With respect to independent claim 10, the claim recites that a method of treating an inflammatory disease in a subject comprising administering a therapeutically effective dose of a selective IL-12b inhibitor of Formula (IV).
Cho teaches that 1) licochalcone E, a chalcone compound, dose-dependently inhibits IL-12p40 production in LPS-stimulated macrophages (results); 2) licochalcone E reduces IL-12p40 expression and inflammatory swelling in a chronic allergic contact dermatitis model (results); and 3) the inhibitory effect involves down regulation of NF-kB activity at the IL-12 promoter (abstract and Fig. 4); and 4) licochalcone E has therapeutic potential for reducing skin inflammation (abstract). Therefore, Cho concludes that licochalcone E holds therapeutic potential for alleviating skin inflammation. Cho also explains that chronic allergic contact dermatitis serves as an experimental model for psoriasis, one of the most common Th1 cell-mediated inflammatory diseases in humans (discussion).
Cho fails to teach the disclosed Formula (IV) compound.
Kumar teaches that 3-(5-bromo-2-methoxyphenyl)-1-(3,4-dimethoxyphenyl)-2-propen-1-one, as an intermediate for synthesizing 2,4-diaryl-2,3-dihydrobenzo[b][1,4]thiazepines, falls in Formula (IV) (scheme 2). Kumar further teaches Chalcones, 1,3-diaryl-2-propen-1-ones, are promising bioactive molecules with wide ranges of biological activity, for example antibacterial, anticancer, antimicrobial, anti-tuberculostatic, anti-inflammatory, anti-infective, antiproliferative, antiangiogenic, and anti-allergic (introduction). Kumar is relied upon for disclosure of the claimed chalcone structure, not for therapeutic utility of the intermediate.
The combination of Cho and Kumar fails to teach that the Formula (IV) compound disclosed by Kumar possesses anti-inflammatory activity or is useful for treating an inflammatory disease.
Ni teaches that 1) structurally related chalcone compounds that inhibit the expression of inflammatory mediators and are useful for treating inflammatory diseases (abstract, column 10, lines 6-20, and table 4). The active compound taught by Ni and the compound taught by Kumar have the same chalcone core and the identical 5-bromo-2-methoxyphenyl ring. The two compounds differ only in that Ni’s compound contains one additional methoxy substituent on the other ring; such compound as an active chalcone derivative and reports that it inhibits VCAM-1 expression with an IC50 of ~1 µM (see table 2 and 4); 3) pharmaceutical compositions and methods comprising administering therapeutically effective amounts of the disclosed chalcone compounds to trat VCAM-1 mediated inflammatory disease (claim 49); 4) the inflammatory diseases are include psoriasis, dermatitis, systemic lupus erythematosus, and inflammatory bowel diseases (column 1, lines 34-44).
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instant elected spices/Kumar’s compound Ni’s compound
It would have been obvious to a PHOSITA at the time of the invention to substitute the chalcone disclosed by Kumar for the chalcone of Cho because Cho teaches that a chalcone compound inhibits macrophage IL-12p40 production and reduces inflammation in an in vivo psoriasis related disease model, Kumar teaches the structurally related Formula (IV) chalcone and Ni teaches that 1) potent anti-inflammatory activity for a chalcone having the identical 5-bromo-2-methoxyphenyl ring and differing from Kumar’s compound by only one methoxy substituent; and 2) Ni teaches administering therapeutically effective amounts of such chalcone compounds to treat inflammatory diseases, including psoriasis and dermatitis. A PHOSITA would have been motivated to make this substitution because Ni demonstrates that structurally related chalcones retain anti-inflammatory activity and are useful for treating inflammatory diseases, thereby, providing a reason to use the Kumar chalcone in place of the chalcone of Cho. A PHOSITA would have had a reasonably expectation that Kumar’s chalcone compound would retain anti-inflammatory activity to inhibit IL-12p40 production and treat an IL-12p40 associated inflammatory diseases taught by Cho.
To the extent that the recited “selective IL-12b inhibitor” reflects a pharmacological property that necessarily results from administration of the Formula (IV) compound under the claimed conditions, that property would be inherent in the otherwise obvious method. However, the rejection does not rely solely on "inherency," because the Cho discloses the IL-12p40 inhibitory effect of anti-inflammatory chalcones, and the Ni supports a reasonable expectation that the structurally similar Kumar chalcone would also retain the relevant anti-inflammatory activity.
With respect to claim 12, the claim recites that The method of claim 10, wherein the compound is 3-(5-bromo-2-methoxyphenyl)-1-(3,4-dimethoxyphenyl)-2-propen-1-one; (E)-3-(5-bromo-2 methoxyphenyl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one; (E)-3-(2,5-dimethoxyphenyl)-1-( 4-methylphenyl)prop-2-en-1-one; (E)-3-(3-chlorophenyl)-1-(3,4-dimethoxyphenyl)prop-2-en-1-one; and (E)-3-(2,3-dimethoxyphenyl)-1-(4-ethoxyphenyl)prop-2-en-1-one.
Kumar teaches 3-(5-bromo-2-methoxyphenyl)-1-(3,4-dimethoxyphenyl)-2-propen-1-one (scheme 2). Therefore, claim 12 would have been obvious for the reason stated above with respect to claim 10.
With respect to claim 60, the claim recites that the inflammatory disease is any of psoriasis, chronic eczema, vitiligo, lichen planus, cutaneous lupus erythematosus, Behest' s disease, ulcerative colitis, Crohn' s disease, or alopecia.
Ni teaches pharmaceutical compositions and methods comprising administering therapeutically effective amounts of the disclosed chalcone compounds to trat VCAM-1 mediated inflammatory disease (claim 49). Ni further teaches the inflammatory diseases include psoriasis, dermatitis, systemic lupus erythematosus, and inflammatory bowel diseases (column 1, lines 34-44). Therefore, claim 60 would have been obvious for the reasons stated above with respect to claim 10.
With respect to claims 63 and 64, the claim 63 recites that a method of treating an inflammatory disease in a subject comprising administering a therapeutically effective dose of a selective IL-12b inhibitor selected from 3-(5-bromo-2-methoxyphenyl)-1-(3,4-dimethoxyphenyl)-2-propen-1-one; (E)-3-(5-bromo-2 methoxyphenyl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one; (E)-3-(2,5-dimethoxyphenyl)-1-( 4-methylphenyl)prop-2-en-1-one; (E)-3-(3-chloropheny 1)-1-(3,4-dimethoxypheny l)prop-2-en-1-one; or (E)-3-(2,3-dimethoxypheny l)-1-( 4-ethoxyphenyl)prop-2-en-1-one; and the claim recites that the method of claim 63, wherein the inflammatory disease is any of psoriasis, chronic eczema, vitiligo, lichen planus, cutaneous lupus erythematosus, Behcet's disease, ulcerative coli tis, Crohn' s disease, or alopecia.
As discussed above with respect to claims 10, 12 and 60, claims 63 and 64 would have been obvious for these reasons with respect to claims 10, 12 and 60.
Conclusion
Claims 10, 12, 60, 63, 64 are rejected.
Claims 10 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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