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
Claims 1-12, 15, 16 and 22-24 are pending in the application. Claims 1-4, 6-12, 15, 16 and 22-24 are rejected. Claim 7 is objected to. Claim 5 is withdrawn.
Response to Amendments
Objections and rejections made in the Office Action mailed January 7, 2026 that do not appear below have been overcome by Applicant’s amendments to the claims and have been withdrawn.
Claim Objections
Claim 7 is objected to because of the following informalities:
Claim 7 should be amended to include a strike-through through the center of each canceled chemical structure and remove the currently shown underlinings for sake of clarity. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings.
Appropriate correction is required.
Response to Arguments - 35 USC § 103
In reply, Applicant traverses the claim rejections under 35 U.S.C. § 103 as presented in the Nonfinal Rejection mailed January 7, 2026. The newly applied claim rejections under 35 U.S.C. § 103 has been necessitated by Applicant’s amendment filed on April 6, 2026. The previously presented rejection under 35 U.S.C. § 103 in the Office Action mailed January 7, 2026 has been withdrawn and replaced with the rejection(s) below. Applicant’s remarks, dated April 6, 2026, relevant to the newly applied 35 U.S.C. § 103 are addressed below.
With respect to Wang (PCT Publication No. WO 2018/027097 A1; February 8, 2018) and Sharief (J Neuroimmunol. 2003, 134(1-2):158-166), Applicant argues that “[t]he Office does not identify any disclosure in Wang to teach or suggest treatment of multiple sclerosis, or to provide any guidance that its disclosed compounds would be effective in autoimmune or neuroinflammatory diseases” and that “Sharief merely reports dysregulation of Bcl-2 family protein expression in multiple sclerosis...[but] does not validate Bcl-2 as a therapeutic target for multiple sclerosis...[or] disclose any therapeutic success via Bcl-2 inhibition.” See page 29 of Response filed on April 6, 2026. Applicant then contends that “the Office did not provide any reason why a skilled artisan would have reasonably selected Wang’s compounds for multiple sclerosis treatment based on Sharief...supposing a skilled artisan were to combine Wang and Sharief.” See page 29 of Response filed on April 6, 2026. As discussed previously and below, Wang teaches the instantly claimed compound as an inhibitor of Bcl-2 proteins (e.g., Bcl-2 or Bcl-XL), whereas Sharief teaches “that [the] dysregulated expression of Bcl-2 family proteins in peripheral lymphocytes is a feature of clinically active multiple sclerosis.” See e.g., the abstract. Therefore, it would have been obvious to arrive at the instantly claimed invention based on the combined teaching of the prior art as discussed below in the rejection under 35 U.S.C. § 103, which is incorporated here by reference. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s position appears to be that the inventive feature of Sharief cannot be bodily incorporated into the structure of Wang. However, this is simply not the standard for obviousness. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art.” In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981). Furthermore, “[t]he rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law.” In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988). See MPEP § 2144. Additionally, “[c]onclusive proof of efficacy is not required to show a reasonable expectation of success.” OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).
Applicant further argues that “[t]he Office’s position [] relies on Applicant’s disclosure as a roadmap, which constitutes impermissible hindsight.” See page 29 of Response filed on April 6, 2026. However, “[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Furthermore, there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See MPEP § 2145(X)(A). It is further noted that the statutory criterion for “obviousness” requires that the subject matter was obvious to a person of ordinary skill at the time of the invention. In the instant case, at the time of the claimed invention, a person of ordinary skill would have had a reasonable expectation of success from combining Wang and Sharief to arrive at the instant invention. As the Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) explained, the standard for “obvious to try” is whether there was a “reasonable expectation of success” at the time.
Applicant also argues that “the claimed invention exhibits unexpected properties that rebut any prima facie case of obviousness...[because] the claimed compounds significantly reduce clinical scores for multiple sclerosis [], demyelination [], and inflammatory cell populations.” See page 30 of Response filed on April 6, 2026. It is noted that “[t]he arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.” See MPEP § 716.01(c). Notwithstanding, Applicant’s assertion for “unexpected results” with respect to the instantly claimed invention merely amounts to beneficial results which have not been shown to have a significance equal to or greater than the expected properties. “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Evidence of a greater than expected result may […] be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately. Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Therefore, the instant claims are prima facie obvious over the prior art.
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, 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.
Claims 1-4, 6-12, 15, 16 and 22-24 are rejected under 35 U.S.C. § 103 as being unpatentable over Wang et al. (PCT Publication No. WO 2018/027097 A1; February 8, 2018) in view of Sharief et al. (J Neuroimmunol. 2003, 134(1-2):158-166).
Determining the scope and contents of the prior art (See MPEP § 2141.01)
Wang et al. teach inhibitor compounds of “Bcl-2 proteins, e.g., Bcl-2 and/or Bcl-xL” such as Example 9 shown below. See e.g., paragraphs [0019] and [0301]).
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Wang et al. further teach methods of inhibiting Bcl-2 proteins comprising administering an effective amount of the disclosed prior art invention (e.g., Example 9) to a subject. See e.g., paragraph [0014].
Regarding instant claims 1-4 and 6, Example 9 as taught by Wang et al. is encompassed by variable definitions of the instantly claimed compound represented by Formula I, wherein A is “A-1”, further wherein R2 is -NO2, R2a is hydrogen and R3 is -N((heterocyclo)alkyl)(H); X1, X2, and X3 are each independently -CH; and Y is -CH2-. See e.g., paragraph [0301].
Regarding instant claim 7, Example 9 as taught by Wang et al. corresponds to the fourth/ninth compound as recited in the claim.
Regarding instant claim 8, Example 9 as taught by Wang et al. corresponds to the first/second compound as recited in the claim.
Regarding instant claim 9, Example 9 as taught by Wang et al. corresponds to the compound as recited in the claim.
Regarding instant claim 11, Wang et al. disclose a “unit oral dose.” See e.g., paragraph [0163].
Regarding instant claim 12, Example 9 as taught by Wang et al. is encompassed by variable definitions of the instantly claimed compound represented by Formula I, wherein A is “A-1”, further wherein R2 is -NO2, R2a is hydrogen and R3 is -N((heterocyclo)alkyl)(H); X1, X2, and X3 are each independently -CH; and Y is -CH2-. See e.g., paragraph [0301].
Regarding instant claim 23, Example 9 as taught by Wang et al. corresponds to the fourth/ninth compound as recited in the claim.
Regarding instant claim 24, Example 9 as taught by Wang et al. corresponds to the first/second compound as recited in the claim.
Ascertainment of the differences between the prior art and the claims (See MPEP § 2141.02)
Regarding instant claims 1, 10, 12, 15, 16 and 22, Wang et al. does not explicitly teach methods of treating multiple sclerosis/reducing neuroinflammation (i.e., caused by multiple sclerosis). Instead, Wang et al. mainly focus on methods for “selectively inhibit[ing] the activity of one type or a subset of Bcl-2 proteins for the treatment of hyperproliferative disease such as cancer.” See e.g., paragraph [0011]. However, it is noted that Wang et al. does not teach away from the instantly claimed methods of treating multiple sclerosis (MS) as evidenced by the disclosed combination therapy comprising “an agent for treating multiple sclerosis.” See e.g., paragraph [0210]. Notwithstanding, Sharief et al. teach “that [the] dysregulated expression of Bcl-2 family proteins in peripheral lymphocytes is a feature of clinically active multiple sclerosis.” See e.g., the abstract. Sharief et al. further teach “that failure of apoptosis (programmed cell death)...may be involved in the pathogenesis of multiple sclerosis” and that there is “a significant increase in Bcl-XL [apoptotic] protein expression...[and relatively lower] cellular expression of the [pro-apoptotic][]-protein Bax in active MS.” See e.g., the abstract and page 160. Note: “Bax” appears to have been mislabeled as an “anti-apoptosis protein” on page 160 of the prior art. For example, see pages 159 and 162 of the prior art where “Bax” is accurately described as being pro-apoptotic. With respect to the limitations of instant claims 10, 12, 15, 16 and 22, Sharief et al. teach the following:
Regarding instant claims 10 and 16: Sharief et al. teach data obtained from “28 patients with relapsing-remitting MS.” See e.g., page 159.
Regarding instant claims 12, 15 and 22: Sharief et al. associate multiple sclerosis (MS) with “a continuous cycle of inflammation within the CNS.” See e.g., page 158. Sharief et al. also provides support for “a role for Bcl-2 proteins in the pathogenesis of inflammation in MS.” See e.g., page 164. Therefore, a person of ordinary skill in the art would reasonably expect a method of treating MS to result in reduced neuroinflammation (e.g., inflammation within the CNS). Note: Instant claims 15 and 22 are drawn towards characteristics that would necessarily be present from administering the instantly claimed compound of Formula I, as recited in parent claim 12, to a MS patient population. Therefore, instant claims 15 and 22 do not further limit the scope of parent claim 1. See MPEP § 2112.01 which states: A chemical composition and its properties are inseparable; therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Considering that Wang et al. disclose the instantly claimed compound of Formula I as inhibitors of Bcl-2 proteins (e.g., Bcl-2 or Bcl-XL), it would have been obvious to a person of ordinary skill in the art to utilize the prior art Bcl-2 inhibitor compound (e.g., Example 9) in therapeutic methods deriving benefit from the inhibition of, for instance, anti-apoptotic Bcl-XL proteins. See e.g., paragraphs [0017] and [0018]. Therefore, in view of the teachings of Sharief et al. which teach “a significant reduction in the expression ratios of pro-apoptosis Bcl-2 proteins in patients with active MS when compared to patients with stable MS or the control group,” a skilled artisan would recognize the potential therapeutic benefit in increasing the expression ratios of pro-apoptotic Bcl-2 family proteins by decreasing (i.e., inhibiting) anti-apoptotic Bcl-2 proteins, such as Bcl-XL, in patients with active MS (e.g., relapsing-remitting MS). Therefore, at least in the interest of utilizing the Bcl-2 inhibitor compound of Wang et al. in methods of treating cancer or otherwise MS, a skilled artisan would be motivated to employ the instantly claimed methods.
Response to Arguments – Double Patenting
In reply, Applicant traverses the Double Patenting claim rejections as presented in the Nonfinal Rejection mailed January 7, 2026. The claims of copending U.S. Application No. 18/838,451 do not recite “multiple sclerosis.” Therefore, the Double Patenting rejection of claims 12, 13 (canceled), 15 and 22 is withdrawn as a result of Applicant’s amendment filed on April 6, 2026.
Conclusion
No claims are allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 mailing date of this final action.
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/D.M.S./Examiner, Art Unit 1626
/REBECCA L ANDERSON/Primary Examiner, Art Unit 1626
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