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
Status of claims
The amendment filed on Oct. 29, 2024 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 Claims 1-102, 104-111 and 117-120 have been canceled and claims 103 and 116 have been withdrawn.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, filed on Oct. 29, 2024, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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. Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
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 WO2018/108704 (STEURER, cited in the IDS filed on 4/26/21) in view of WO2018/219281 (hereafter, CHEN; its English translation cited) as evidenced by Blanco (Eur. J. Immunol. 2016. 46: 281–290).
STEURER teaches the use of compounds of the following formula (I):
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143
154
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, wherein R1 is heterocyclyl or heteroaryl (e.g.,
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163
90
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), as inhibitors of BCL6 in the treatment and/or prevention of a disease and/or condition wherein the inhibition of BCL6 is of therapeutic benefit, including autoimmune diseases (abstract, p1, lines 4-10, p14, p23, lines 1-10, and Claim 1)
STEURER specifically discloses the following compound:
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259
255
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(P156, Table 9, I-148, p151, C.3.1), which is the elected compound.
STEURER does not specifically disclose specific autoimmune diseases such as lupus erythematosus (elected species) and the step of identifying a patient as having one or more selected from the group consisting of: (i) elevated numbers or activity of plasmablasts in blood or tissue, (ii) a plasmablast signature as determined by RNA expression or protein expression analyses, (iii) elevated numbers or activity of Tfh cells or Tfh-like cells in blood or tissue, (iv) elevated numbers or activity of germinal centers or extra follicular T and B-cells; (v) presence of ectopic follicular structures or ectopic germinal centers or ectopic lymphoid aggregates in a tissue (vi) elevated levels of autoantibodies or immune complexes in blood or tissue.
CHEN teaches the use of an inhibitor of B cell lymphokine 6 (BCL6) for preventing and/or treating BCL6-mediated diseases such as autoimmune diseases, wherein the autoimmune diseases include lupus erythematosus (abstract, p10, para 11, and p21, para 5). CHEN further teaches that BCL6 plays an important role in autoimmune diseases and is an important regulator of germinal centers (GC) (p3, para 4). It has been confirmed that germinal-like (GC-like) structures are present in salivary glands, meninges, and synovium of autoimmune diseases such as systemic lupus erythematosus (SLE) (p3, para 4).
It was known in the art that elevated levels of autoantibodies or immune complexes in blood or tissue and elevated numbers or activity of Tfh cells or Tfh-like cells in blood or tissue are characteristics of autoimmune diseases such as systemic lupus erythematosus (SLE) as evidenced by Blanco (abstract, p281, col 1, para 1, p281, col 2, para 2-p282, col 1, para 1, Fig, 1, and p284, col 2, para 2)
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 inhibitor of STEURER for treating lupus erythematosus because STEUTRER already teaches the use of the BCL6 inhibitors for treating autoimmune diseases and lupus erythematosus is a well-known autoimmune disease treatable by inhibition of BCL6 as evidenced by CHEN. Thus, one of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the compound of STEURER as BCL6 inhibitor would be effective for treating lupus erythematosus as BCL6-mediated autoimmune diseases via inhibiting BCL6 as taught by CHEN.
As to the identifying step as claimed, implicitly in any disclosure of giving a treatment to a patient with a condition is first determining that the patient has the condition. Therefore, the subject under treatment has been identified prior to applying the treatment. A person of ordinary skill in the art is a healthcare provider which first identify patients with a condition and then treats them with an appropriate drug. This is what a person of ordinary skill in the corresponding art does. In this case, 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 identify a patient as having known characteristics/markers of the autoimmune diseases such as lupus erythematosus (e.g., elevated numbers or activity of Tfh cells or Tfh-like cells in blood or tissue, presence of ectopic follicular structures or ectopic germinal centers or ectopic lymphoid aggregates in a tissue, or elevated levels of autoantibodies or immune complexes in blood or tissue) as taught by CHEN and Blanco. The skilled artisan would have been motivated to do so because the presence of such known characteristics/markers would indicate the patient as having autoimmune diseases such as lupus erythematosus and thereby treatable by the BCL6-inhibitor.
Response to Applicant’s arguments
Applicant argued that no data is presented in the reference indicating which, if any, of the millions of compounds within the broad definition of formula (I) has any transcriptional repressor or degradation activity. Applicant further stated that STEUTRER only discloses in vitro assay based on a recombinant BCL6 protein binding to 1% of a BCL6 corepressor and the assay provide no information that enables a skilled artisan to identify which of millions possible compounds inhibit BCL6 function as transcription repressor and induce degradation of the BCL6 protein or which of millions of possible compounds can be used in treatment and/or prevention of a disease and/or condition wherein the inhibition of BCL6 is of therapeutic benefit.
In response to applicants’ argument that the prior art does not provide efficacy data for any transcriptional repressor or degradation activity or enabling disclosure, efficacy is not a requirement for prior art enablement. A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." ImpaxLabs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006). See also MPEP § 2122. In this case, STEUTRER explicitly teaches the use of the same compound for treatment of autoimmune diseases as claimed based on their BCL6 inhibitory activities and discloses the same dosage range (1 mg to 1000 mg) (p190, lines 6-9) as in the instant specification ([0180]). Also, the BCOR ULight TR-FRET assay disclosed in STEURER actually shows the activity of the claimed compound on inhibiting interaction of BCL6 with co-repressor protein (see p171, line 3-p172, line 18 and p174-p180, Table), which would results in inhibiting BCL6 functions. Thus, the prior art describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention. Furthermore, Applicants also do not show any evidence of in vivo efficacy of the claimed compounds in the treatment of claimed autoimmune disease or condition. If Applicants’ logical conclusion taken, Applicant's argument ultimately cast doubt on applicants’ own invention since Applicants contemplate the use of the same BCL6 inhibitor for the treatment of autoimmune disease or condition based on their BCL6 inhibitory activities as the prior art discloses. As stated above, STEURER as a whole provides sufficient enabling disclosure. Finally, when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). However, Applicants did not provide sufficient factual evidence why or how the reference is not enabled.
Also, the skilled artisan would not have to identify a BCL6 inhibitor from millions possible compounds of formula (I) because STEURER already disclose limited number of specific examples (178) which have been tested for BCL6 inhibitory activity and shown that the claimed compound (I-148) is one of those having the lowest IC50. Thus, one of ordinary skill in the art would have been motivated to select the claimed compound (I-148) for the method of treating autoimmune disease as taught by STEURER. This is further motived by CHEN which teach similar 4-pyrimidinediamine compounds as BCL6 inhibitors and its use for treating autoimmune disease treatable by inhibition of BCL6, including lupus erythematosus. It is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number in the thousands or more. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).
In addition, Applicant argued that the structure of the BCL-6 inhibitors of the secondary Chen et al. reference do not overlap with those of STEURER, thus Chen does not add anything to assist the skilled artisan in the research assignment offered by STEURER.
On the contrary to Applicant’s assertion, the BCL-6 inhibitors of Chen share the same 4-pyrimidinediamine core structure as the compound of STEURER. Also, Chen teaches the use of such compounds for treating autoimmune disease treatable by inhibition of BCL6. One having ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to combine these references and make the modification because they are drawn to the same technical fields (constituted with BCL6 inhibitors and share common utilities), and pertinent to the problem which applicant concerns about. MPEP 2141.01(a).
As to the argument based on Kerres et al. reference, it is noted that a copy of the reference has not been provided. Thus, the reference is not considered fully. To be considered fully, it should be filed in a form of IDS and its copy should be provided. Also, 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. See STEURER (p2, lines 20-23). The BCOR ULight TR-FRET assay disclosed in STEURER shows the activity of the claimed compound on inhibiting interaction of BCL6 with co-repressor protein (see p171, line 3-p172, line 18 and p174-p180, Table). 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 as evidenced by STEURER. This is further evidenced by Kerres et al. that applicant cited. Thus, it would have been obvious to use the BCL6 inhibitor such as Compound I-148 (also known as BI-3812) taught by STEURER for treating a disease and/or condition wherein the inhibition of BCL6 is of therapeutic benefit, including autoimmune disease as stated above.
For the foregoing reasons, Applicant’s arguments have not found to be persuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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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