Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
A request for continued examination under 37 C.F.R. 1.114, including the fee set forth in 37 C.F.R. 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. 1.114, and the fee set forth in 37 C.F.R. 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 C.F.R. 1.114. Applicant’s submission filed Feb. 17, 2026 has been received and entered into the present application.
Status of claims
The amendment filed on Fe. 17, 2026 is acknowledged. Claims 1-102, 104-111 and 117-120 have been canceled and claims 103 and 116 have been withdrawn. Claims 112-115 are under examination in the instant office action.
Applicants' arguments and declaration, filed on Fe. 17, 2026, have been fully considered but they are not found to be persuasive or moot in view of a new ground of rejection. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 112-115 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0014979 (hereafter, DENT) in view of Kerres et al. (cell Reports 20: 2860-2875, 2017; cited in the IDS filed on 2/17/2026).
DENT teaches a method for inhibiting or stopping abnormal T follicular helper (Tfh) activity in individuals suffering from an autoimmune disease, comprising administering to an individual in need of such treatment an effective amount of a BCL6 inhibitor ([0009] and claim 1). DENT teaches that there are two major stages of Tfh function: first, "pregerminal center" Tfh cells interact with antigen-activated B cells and promote the major phases of the initial B cell response: B cell clonal expansion, antibody isotype switch, plasma cell differentiation, and the induction of germinal centers; second, Tfh cells regulate the fate of B cells and the antibody response by interacting with B cells in the germinal center; and thus, Tfh cells are critical for memory B cell and plasma cell development and the key cytokine produced by Tfh cells is IL-21, which is a factor that potently promotes B cell activation and antibody secretion ([0006]). DENT further teaches that compounds that act as inhibitors of BCL6 can be useful in the treatment of autoimmune diseases because increased Tfh activity promoted by BCL6 can lead to non-specific antibody responses and eventually to autoimmunity, while blockade of BCL6 activity can block Tfh function and thus inhibit autoimmune disease progression ([0021]). DENT further teaches that the over-production of Tfh cells can lead to autoimmunity as Tfh cells help B cells to produce self-reactive antibodies ([0007]).
Thus, the patient population of DENT is those implicitly identified as having elevated numbers or activity of Tfh cells, B-cells, or germinal center, and elevated levels of autoantibodies or immune complexes in blood or tissue and who have been diagnosed with an autoimmune disease as claimed.
DENT further teaches that any BCL6 inhibitor can be used including BCL6 peptide inhibitors and non-peptide inhibitors ([0026] and [0032]).
Also, DENT teaches that the autoimmune disease is selected from lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohns Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, Wegener's granulomatosis, and combinations thereof (claim 18). In addition, DENT teaches that the autoimmune disease is lupus erythematosus (claim 19 and Example 2).
DENT does not specifically discloses 1-(5-Chloro-4-((8-methoxy-1-methyl-3-(2-(methylamino)- 2-oxoethoxy)-2-oxo-1 ,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide as BCL6 inhibitor.
Kerres et al. discloses the following compounds: BI-3812,
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(1-(5-Chloro-4-((8-methoxy-1-methyl-3-(2-(methylamino)- 2-oxoethoxy)-2-oxo-1 ,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide) and BI-3802 as BCL6 inhibitors. The compound BI-3812 is the same compound as claimed. Kerres et al. further discloses that BI-3812 inhibits interaction with transcriptional co-repressors of BCL6 such as BCOR, NCOR and SMRT, SMRT and thereby de-repression of target genes of BCL6 (Graphical abstract). Kerres et al. further teach that mutation of the co-repressor binding interface on BCL6 has been shown to prevent the formation of germinal centers and pharmacological inhibition of the interaction of BCL6 with corepressor proteins promises to block the oncogenic function of the protein with few or no side effects other than the lack of affinity maturation of B-cells (p2860, col 2, para 3). Kerres et al. teach that the BTB domain of BCL6 is highly druggable and allows the development of potent inhibitors (p2861, col 1, para 3). Kerres et al. disclose that BI-3812 inhibits the BTB domain of BCL6 in the low nanomolar range and inhibits the BCL6 co-repressor interaction in cellular LUMIER assays (p2863, Table 1 and Fig 2). In addition, Kerres et al. disclose that BCL6-regulated genes were induced by the non-degrader BI-3812 and the degrader BI-3802 (p2865, para 3-4 and Fig 6A-6D).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the BCL6 inhibitors of Kerres et al. including the claimed compound for inhibiting or stopping abnormal Tfh activity in individuals suffering from an autoimmune disease such as lupus erythematosus because DENT already teaches and suggest any BCL6 inhibitors can be used for their method and Kerres et al. specifically disclose the claimed compound (BI-3812) as BCL6 inhibitor. Thus, one of ordinary skill in the art, who was searching for alternative BCL6 inhibitors, would have been motivated to use BI-3812 on the reasonable expectation that BI-3812 as BCL6 inhibitors would be similarly effective for inhibiting Tfh activity promoted by BCL6 and thus blocking Tfh function and inhibiting autoimmune disease progression as taught by DENT.
Claims 112-115 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0014979 (hereafter, DENT) in view of WO2018/108704 (STEURER, cited in the IDS filed on 4/26/21).
DENT teaches a method for inhibiting or stopping abnormal T follicular helper (Tfh) activity in individuals suffering from an autoimmune disease, comprising administering to an individual in need of such treatment an effective amount of a BCL6 inhibitor ([0009] and claim 1). DENT teaches that there are two major stages of Tfh function: first, "pregerminal center" Tfh cells interact with antigen-activated B cells and promote the major phases of the initial B cell response: B cell clonal expansion, antibody isotype switch, plasma cell differentiation, and the induction of germinal centers; second, Tfh cells regulate the fate of B cells and the antibody response by interacting with B cells in the germinal center; and thus, Tfh cells are critical for memory B cell and plasma cell development and the key cytokine produced by Tfh cells is IL-21, which is a factor that potently promotes B cell activation and antibody secretion ([0006]).
DENT further teaches that compounds that act as inhibitors of BCL6 can be useful in the treatment of autoimmune diseases because increased Tfh activity promoted by BCL6 can lead to non-specific antibody responses and eventually to autoimmunity, while blockade of BCL6 activity can block Tfh function and thus inhibit autoimmune disease progression ([0021]). DENT further teaches that the over-production of Tfh cells can lead to autoimmunity as Tfh cells help B cells to produce self-reactive antibodies ([0007]).
Thus, the patient population of DENT is those implicitly identified as having elevated numbers or activity of Tfh cells, B-cells, or germinal center, and elevated levels of autoantibodies or immune complexes in blood or tissue and who have been diagnosed with an autoimmune disease as claimed.
DENT further teaches that any BCL6 inhibitor can be used including BCL6 peptide inhibitors and non-peptide inhibitors ([0026] and [0032]).
Also, DENT teaches that the autoimmune disease is selected from lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohns Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, Wegener's granulomatosis, and combinations thereof (claim 18). In addition, DENT teaches that the autoimmune disease is lupus erythematosus (claim 19 and Example 2).
DENT does not specifically discloses the claimed compound: 1-(5-Chloro-4-((8-methoxy-1-methyl-3-(2-(methylamino)- 2-oxoethoxy)-2-oxo-1 ,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide as BCL6 inhibitor.
STEURER teaches the use of compounds of the following formula (I):
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, wherein R1 is heterocyclyl or heteroaryl (e.g.,
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), as BCL6 inhibitors in the treatment and/or prevention of a disease and/or condition wherein the inhibition of BCL6 is of therapeutic benefit and the disease includes autoimmune diseases (abstract, p1, lines 4-10, p14, p23, lines 1-10, and Claims 1 and 15).
STEURER further teaches that "BCL6 inhibitor(s)" means those compounds which inhibit the BCL6 functions as a transcriptional repressor or those compounds which inhibit the BCL6 functions as transcriptional repressor and induce degradation of the BCL6 protein (p3, lines 13-16).
STEURER further teaches that BCL6 functions as a transcriptional repressor that binds specific DNA sequences via its Zn-fingers and recruits transcriptional co-repressor complexes by its BTB/POZ and the transcriptional co- repressors of BCL6 include NCOR1, SMRT and BCOR (p2, lines 11-22 and lines 23-33). STEURER further teaches that mutation of the co-repressor binding interface on BCL6 has been shown to prevent the formation of germinal centers and pharmacological inhibition of the interaction of BCL6 with corepressor proteins promises to block the oncogenic function of the protein with few or no side effects other than the lack of affinity maturation of B-cells (p2, lines 11-22).
STEURER specifically discloses the following compound:
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(P156, Table 9, I-148, p151, C.3.1), which is the claimed compound. STEURER further discloses the activity of the claimed compound on inhibiting interaction of BCL6 with co-repressor protein (BCOR) using the BCOR ULight TR-FRET assay and shows the claimed compound is one of those having the lowest IC50 (p171, line 3-p172, line 18 and p174-p180, Table).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the BCL6 inhibitors of STEURER including the claimed compound for inhibiting or stopping abnormal Tfh activity in individuals suffering from an autoimmune disease such as lupus erythematosus because DENT already teaches and suggest any BCL6 inhibitors can be used for their method and STEUTRER teaches the compounds of formula (I) including the claimed compound as BCL6 inhibitors in use for treating autoimmune diseases. Also, STEURER specifically discloses the activity of the claimed compound on inhibiting interaction of BCL6 with co-repressor protein (BCOR) using the BCOR ULight TR-FRET assay and shows the claimed compound is one of those having the lowest IC50. Thus, one of ordinary skill in the art, who was searching for alternative BCL6 inhibitors, would have been motivated to use the claimed compound taught by STEUTRER on the reasonable expectation that the compound of STEURER as BCL6 inhibitor would be similarly effective for inhibiting Tfh activity promoted by BCL6 and thus blocking Tfh function and inhibiting autoimmune disease progression as taught by DENT.
Response to Applicant’s arguments
Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
Applicants argued that the BCOR ULight TR-FRET assay disclosed in STEURER is not measuring BCL6 inhibitory activity because all that this assay demonstrates is an inhibition of binding of the 18-residue peptide to Bcl-6 in vitro. Also, Applicant argued that Kerres et al. reference, which includes the inventors of STEURER references, discloses that one of the compounds (I-4, also known as BI-3802) induces proteasome-dependent degradation of BCL-6 while the claimed compound (BI-3812) does not. In addition, Applicant argued that the failure to determine pharmacokinetics of BI-3812 indicates that the compound was not of interest as a pharmaceutical to Kerres et al./Steurer et al.
In response, STEUTRER explicitly identifies a compound of formula (I) including the claimed compound as BCL6 inhibitor and teaches and suggests the use of such compounds for treatment of autoimmune diseases. STEURER teaches that "BCL6 inhibitor(s)" means those compounds which inhibit the BCL6 functions as a transcriptional repressor or those compounds which inhibit the BCL6 functions as transcriptional repressor and induce degradation of the BCL6 protein (p3, lines 13-16). STEURER further teaches that BCL6 functions as a transcriptional repressor that binds specific DNA sequences via its Zn-fingers and recruits transcriptional co-repressor complexes by its BTB/POZ and the transcriptional co-repressors of BCL6 include NCOR1, SMRT and BCOR (p2, lines 11-22 and lines 23-33). STEURER also teaches that mutation of the co-repressor binding interface on BCL6 has been shown to prevent the formation of germinal centers and pharmacological inhibition of the interaction of BCL6 with corepressor proteins promises to block the oncogenic function of the protein with few or no side effects other than the lack of affinity maturation of B-cells (p2, lines 11-22). The BCOR ULight TR-FRET assay disclosed in STEURER actually shows the activity of the claimed compound (BI-3812) on inhibiting interaction of BCL6 with co-repressor protein (see p171, line 3-p172, line 18 and p174-p180, Table), which would result in inhibiting BCL6 functions as a transcriptional repressor.
As stated above, it should be noted that BCL6 inhibitors can inhibit BCL6 function via inhibiting interaction of BCL6 with co-repressor protein as well as inducing the degradation of BCL6. Thus, the finding that the claimed compound does not have the activity on degradation of BCL6 does not change the fact that the claimed compound is BCL6 inhibitor. Also, the fact that Kerres et al. did not further determine the pharmacokinetics of BI-3812 also does not change that BI-3812 is a BCL6-inhibitor. It may be simply because the primary focus of Kerres et al. is degradation of BCL6 and the treatment of lymphoma as shown in the title and abstract of the reference. It should be noted that the existence of a preferred embodiment alone normally cannot established a teaching away. In In re Fulton, the Federal Circuit explained that “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed . . . .” 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In fact, Kerres et al. disclose that both BI-3812 and BI-3802 inhibit the BTB domain of BCL6 in the low nanomolar range (Table 1) and clearly identify BI-3802 as atypical inhibitor and BI-3812 as a “BCL6 inhibitor”, which inhibits the interaction of BCL6 with corepressor proteins, thereby de-repression of target genes (see graphical abstract and Fig. 2). Thus, one of ordinary skill in the art would have recognized the claimed compound as a highly potent and efficacious BCL6 inhibitor in view of the teachings of STEURER and further evidenced by Kerres et al. and would have been motivated to use the claimed compound as BCL6 inhibitor.
As to the alleged unexpected results based on the direct comparison of BI-3902 and BI-3812 (claimed compound) in the declaration, it is noted that much lower amount of BI-3902 (10 or 30 mg/kg) was used when compared with that of BI-3912 (100 mg/kg). Since the much higher amount of BI-3912 was used, higher attenuation of the immune response with BI-3912-treatment would have been expected. Also, the effects on geminal center and IgG antibodies do not appears to be significantly different for both compounds even though lower amount of BI-3802 was used. Thus, it is unclear whether the difference in results is in fact unexpected and unobvious and of both statistical and practical significance.
The examiner notes that it is applicant's burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Moreover, evidence as to any unexpected benefits must be "clear and convincing" In re Lohr, 137 USPQ 548 (CCPA 1963), and be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972).
For the foregoing reasons, Applicant’s arguments have not found to be persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BONG-SOOK BAEK whose telephone number is 571-270-5863. The examiner can normally be reached 9:00AM-6:00PM Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
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