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 .
Continued Examination Under 37 CFR 1.114
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Election/Restrictions
Applicant’s election without traverse of bortezomib-induced neurotoxicity as the elected neurotoxicity species; CX-8998 as the elected T-type calcium channel modulator species; and human as the elected mammal species are maintained.
Claim 13 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on May 7, 2026, wherein claims 1 and 18 are amended; claims 2, 6, 7, 13, and 20 are unchanged; claims 3-5, 8-12, 14-17 and 19 are canceled.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 6-7, 13, 18 and 20 are pending.
Claim 13 is withdrawn.
Claims 1-2, 6-7, 18 and 20 are under examination in accordance with the elected species.
Priority
The instant application 17/766,113 filed on April 1, 2022 is a 371 of PCT/US2020/053944 filed
on October 2, 2020, which claims priority to, and the benefits of U.S. Provisional Application No.
62/909,694 filed on October 2, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 7, 2026 was filed after the mailing date of the Final Office Action on November 7, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Action Summary
Applicant’s amendment to the claims overcome each and every objection previously sets
forth in the Final Office Action mailed on November 7, 2025.
Claims 1-2 and 20 rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018; cited under “Non-Patent Literature Documents”, cited no. C16 in the IDS filed on July 12, 2024) in view of Barrow et al. (WO 2007/120729 A2), as evidenced by Carrington College Blog (Decoding Your Prescriptions: Understanding Pharmacy Abbreviations. Published on February 24, 2015), Cross (Chemical & Engineering News, Vol. 87, Issue 33. Published on August 24, 2019), and Jensen et al. (Lancet Neurol., 2014. Vol. 13(9): 924-935) are maintained.
Claims 1-2, 6-7 and 20 rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2) as applied to claims 1-2 and 20 above, and further in view of Mujtaba et al. (Discov Med., 2011. Vol. 12(67)) are maintained.
Claims 1-2, 18 and 20 rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2) as applied to claims 1-2 and 20 above, and further in view of Maricich (WO 2017/070680 A1) are maintained.
Claims 1-2 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 51 of copending Application No. 17/282,730 (referred to herein as ‘730 application) in view of Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018), as evidenced by Carrington College Blog (Decoding Your Prescriptions: Understanding Pharmacy Abbreviations. Published on February 24, 2015), Cross (Chemical & Engineering News, Vol. 87, Issue 33. Published on August 24, 2019), and Jensen et al. (Lancet Neurol., 2014. Vol. 13(9): 924-935) are maintained, but revisited and modified in light of the fact that the reference application is now an issued U.S. Patent No. 12,383,539 B2 published on August 12, 2025.
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 1-2 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018; cited under “Non Patent Literature Documents”, cited no. C16 in the IDS filed on July 12, 2024) in view of Barrow et al. (WO 2007/120729 A2), as evidenced by Carrington College Blog (Decoding Your Prescriptions: Understanding Pharmacy Abbreviations. Published on February 24, 2015), Cross (Chemical & Engineering News, Vol. 87, Issue 33. Published on August 24, 2019), and Jensen et al. (Lancet Neurol., 2014. Vol. 13(9): 924-935).
Lee et al. teaches CX-8998 is a potent, selective T-type calcium channel modulator, and Cav3 antagonist that demonstrates dose dependent efficacy in a model of chemotherapy-induced peripheral neurotoxicity (CIPN); and these results highlight the potential for selective Cav3 modulators as a therapeutic option in CIPN (see e.g., title; abstract, “conclusions” and “objective” section). Please note the CX-8998 of Lee et al. has a chemical structure of:
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, as evidenced by Cross; and the bortezomib-induced peripheral neurotoxicity is a bortezomib-induced neurotoxicity. Lee et al. further teaches the rats were treated with bortezomib (iv 0.2 mg/kg 3x/week for 4 weeks) to induce chemotherapy-induced peripheral neurotoxicity, and then CX-8998 (3, 10 and 30 mg/kg PO daily) administration was initiated for an additional 4 weeks (see e.g., title; abstract, “design/method” section). Please note the term “PO” is a medical abbreviation referring to oral administration, as evidenced by Carrington College Blog (see e.g., p. 2, “medical abbreviations that describe how to use your medication” section). Lee et al. further teaches CX-8998 dose-dependently reversed bortezomib-induced reduction of nerve conduction velocity and tactile allodynia after both 1 week and 4 weeks of co-administration without affecting bortezomib-induced proteasome inhibition (see e.g., “results” section). Please note the tactile allodynia taught by Lee et al. is a symptom of neurotoxicity induced by bortezomib according to page 26, line 18-20 of the instant specification; and allodynia is pain due to a stimulus that does not usually provoke pain, as evidenced by Jensen et al. (see e.g., abstract).
Lee et al. does not teach a human.
Barrow et al. teaches a compound of Example 16, 2-(4-isopropylphenyl)-N[(1R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl] acetamide, having the structure of:
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is an exemplary compound of formula I useful for antagonizing T-type calcium channel activity in a patient such as a mammal (see e.g., p. 47, line 17-20; p. 20, line 20-23; p. 20, line 18-20). Please note the compound of Example 16 taught by Barrows et al. is a CX-8998. Barrows et al. further teaches the subject treated in the method is generally a mammal, in particular, a human being, male or female (see e.g., p. 20, line 29-30). Barrow et al. further teaches a method for treating or controlling pain in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of the formula I or a pharmaceutically acceptable salt thereof; and generally, dosage levels of between 0.0001 to 10 mg/kg of body weight daily are administered to the patient, e.g., humans and elderly humans, to obtain effective antagonism of T-type calcium channel (see e.g., claims 1 and 28; p. 26, line 20-22). Barrows et al. further teaches pain includes, inter alia, neuropathic pain (see e.g., p. 25, line 29-34). Barrow et al. further teaches a pharmaceutical composition which comprises an inert carrier and the compound of formula I or pharmaceutically acceptable salt thereof (see e.g., claim 22).
The difference between the method of Lee et al. and the claimed method is that the prior art administers the CX-8998 orally to the rats having bortezomib-induced neurotoxicity and the claimed invention administers to the human having bortezomib-induced neurotoxicity. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Lee et al. by administering the CX-8998 orally at a therapeutically effective amount to a human having bortezomib-induced neurotoxicity. One would have been motivated to do so, because Lee et al. teaches oral administration of CX-8998 demonstrates dose dependent efficacy in reversing bortezomib-induced reduction of nerve conduction velocity and tactile allodynia without affecting bortezomib-induced proteasome inhibition in an animal model of bortezomib-induced peripheral neurotoxicity; and suggested the use of selective Cav3 modulators, such as CX-8998, as a therapeutic option in chemotherapy-induced peripheral neurotoxicity; and Barrow et al. teaches the compound of Example 16, which has identical chemical structure to the CX-8998, can administer to a human at a therapeutically effective amount for treating or controlling neuropathic pain. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the oral administration of CX-8998 at a therapeutically effective amount to a human having bortezomib-induced neurotoxicity would have successfully treat said bortezomib-induced neurotoxicity by antagonizing T-type calcium channel activity and reversing the bortezomib-induced reduction of nerve conduction velocity and tactile allodynia. Please note the fact that the human having bortezomib-induced neurotoxicity is being treated, the human having said bortezomib-induced neurotoxicity would necessarily be identified in the method of Lee et al. and Barrow et al., and that renders obvious the limitation in claim 2.
Regarding the limitation of “wherein said CX-8998, or a salt thereof, does not interfere with anti-tumor activity and tolerability of bortezomib in a human; and wherein said CX-8998, or a salt thereof, reduces bortezomib-induced [Symbol font/0x62]-tubulin polymerization” in claim 1, the claimed limitation simply expresses the intended outcome of the method step positively recited. In this case, although Lee et al. may not have recognized that the CX-8998 results no interference with the anti-tumor activity and tolerability of bortezomib and has a characteristic of reducing the bortezomib-induced [Symbol font/0x62]-tubulin polymerization, these characteristics of CX-8998 would have been prima facie obvious to one of ordinary skill in the art by practicing the method of Lee et al. and Barrow et al. set forth above, because products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. Therefore, the claimed limitation is made obvious by the prior arts. MPEP 2145 II states: "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 6-7 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2) as applied to claims 1-2 and 20 above, and further in view of Mujtaba et al. (Discov Med., 2011. Vol. 12(67)).
The teachings of Lee et al. and Barrow et al. are set forth above and applied as before.
Lee et al. and Barrow et al. does not teach said human having bortezomib-induced neurotoxicity has been administered said bortezomib to treat a cancer within said human as claimed in claim 6. Lee et al. and Barrow et al. also does not teach said cancer is selected from the group as claimed in claim 7.
Mujtaba et al. teaches bortezomib is the first U.S. Food and Drug Administration approved proteasome inhibitor used in the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma (see e.g., abstract).
Regarding the limitation of “wherein said human having bortezomib-induced neurotoxicity has been administered said bortezomib to treat a cancer within said human” in claim 6 and the limitation of “wherein said human having bortezomib-induced neurotoxicity has been administered said bortezomib to treat a cancer within said human” in claim 7, these limitations are drawn to the intended use of the bortezomib that induces neurotoxicity. In this case, Lee et al. clearly teaches bortezomib is the chemotherapy used to induce chemotherapy-induced peripheral neurotoxicity; However, Lee et al. does not expressly teach said chemotherapy is for treating a cancer, such as mantle cell lymphoma. It would have been prima facie obvious to one of ordinary skill in the art at the time the application as filed to modify the method of Lee et al. and Barrow et al. set forth above to incorporate a human that has been administered with bortezomib for the treatment of mantle cell lymphoma as the cancer. One would have been motivated to do so, because Lee et al. teaches bortezomib is a chemotherapy; and Mujtaba et al. teaches bortezomib is a selective inhibitor of the proteasome used for the treatment of mantle cell lymphoma. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the oral administration of CX-8998 at a therapeutically effective amount to the human having bortezomib-induced neurotoxicity would have successfully reversed bortezomib-induced neurotoxicity in the human who has been administered with the bortezomib for the treatment of mantle cell lymphoma.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2) as applied to claims 1-2 and 20 above, and further in view of Maricich (WO 2017/070680 A1).
The teachings of Lee et al. and Barrow et al. are set forth above and applied as before.
Lee et al. and Barrow et al. does not teach 10 nM to 1000 nM of said CX-8998 or salt thereof as claimed in claim 18.
Maricich teaches a T-type channel inhibitor that is effective may inhibit T-type calcium channels with an IC50 for inhibiting T-type calcium channels when the membrane potential is about -40 mV that is about 10 μΜ or lower, e.g., about 1 μΜ or lower, about 500 nM or lower, about 100 nM or lower, about 50 nM or lower, about 10 nM or lower, about 5 nM or lower, or about 1 nM or lower (see e.g., p. 23, line 21-25). Please note 1 μΜ is equivalent to 1000 nM. Maricich further teaches the T-type calcium channel antagonist is MK-8998 (also known as “CX-8998”) having the chemical structure shown as follows:
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(see e.g., p. 5, line 29; p. 15, line 7).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In this case, even though Lee et al. does not teach 10 nM to 1000 nM of the CX-8998, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Lee et al. and Barrow et al. set forth above to incorporate CX-8998 at 1000 nM as taught by Maricich. One would have been motivated to do so, because Maricich teaches an IC50 for inhibiting T-type calcium channels for the T-type calcium channel antagonist such as CX-8998 is about 10 μΜ or lower, and that includes about 1 μΜ (equivalent to 1000 nM) or lower. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of the CX-8998 at 1000 nM would successfully inhibit T-type calcium channels that results in the treatment of bortezomib-induced peripheral neurotoxicity.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on May 7, 2026 have been fully considered.
Applicant's arguments filed on May 7, 2026 with respect to the rejection of claims 1-2 and 20 under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2), as evidenced by Carrington College Blog (Decoding Your Prescriptions: Understanding Pharmacy Abbreviations. Published on February 24, 2015), Cross (Chemical & Engineering News, Vol. 87, Issue 33. Published on August 24, 2019), and Jensen et al. (Lancet Neurol., 2014. Vol. 13(9): 924-935) have been fully considered but they are not persuasive for the reasons set forth below.
Applicant's arguments filed on May 7, 2026 with respect to the rejection of claims 1-2, 6-7 and 20 under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2) as applied to claims 1-2 and 20 above, and further in view of Mujtaba et al. (Discov Med., 2011. Vol. 12(67)) have been fully considered but they are not persuasive for the reasons set forth below.
Applicant's arguments filed on May 7, 2026 with respect to the rejection of claims 1-2, 18 and 20 under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018) in view of Barrow et al. (WO 2007/120729 A2) as applied to claims 1-2 and 20 above, and further in view of Maricich (WO 2017/070680 A1) have been fully considered but they are not persuasive for the reasons set forth below.
In Summary, Applicant argues there were numerous examples of drug in the art that had failed to effectively treat chemotherapy-induced peripheral neurotoxicity (CIPN) without interfering with anti-tumor activity and tolerability. Applicant argues a substance that treats bortezomib(BTZ)-induced neurotoxicity will not inevitability do so by reducing BTZ-induced [Symbol font/0x62]-tubulin polymerization. Specifically, Applicant relies on the teachings of Ludman (cited in the IDS filed on May 7, 2026) and argues that the metformin of Ludman treats BTZ-induced neurotoxicity by alleviating neuropathic pain through blockade of H1F1A expression, which is a completely different mode of action compared to CX-8998 instantly claimed. Applicant further argues CX-8998 outperforms other substances reported by Meregalli and Ceresa et al. (both cited in the IDS filed on May 7, 2026), respectively, and argues the claimed CX-8998 demonstrate a clinically relevant outcome (effectively reduce BTZ-induced [Symbol font/0x62]-tubulin polymerization without negatively impacting BTZ's anti-tumor activity and tolerability in comparison to the substances of these cited references).
In response, applicant’s arguments are not found persuasive. First, Ludman, Meregalli and Ceresa et al., which are cited the information disclosure statement filed on May 7, 2026, have been considered by the Examiner. It is respectfully noted that the rejection(s) of record does not rely on any teachings of Ludman, Meregalli and Ceresa et al. specifically presented by the applicant; therefore, these arguments appear to be irrelevant. For instance, applicant argues one would not have a reasonable expectation of success to administer the claimed CX-8998 for treating bortezomib(BTZ)-induced neurotoxicity by reducing bortezomib-induced [Symbol font/0x62]-tubulin polymerization, because metformin is not known to do so; However, the metformin upon which applicant relies is not recited in the rejected claim(s). The mere fact that other drugs, e.g., metformin, are not known to reduce bortezomib-induced [Symbol font/0x62]-tubulin polymerization, or are known to interfere with anti-tumor activity and tolerability of bortezomib, it does not mean the CX-8998 of Lee et al. and Barrow et al. set forth in the rejection of record is incapable of reducing bortezomib-induced [Symbol font/0x62]-tubulin polymerization, and would, in fact, interfere with anti-tumor activity and tolerability of bortezomib. In addition, the mere fact that other drugs interfere with bortezomib’s anti-tumor activity and tolerability, does not make the claimed CX-8998 patentably distinct from the CX-8998 of Lee et al. and Barrow et al.
According to MPEP 2112.01, “’[p]roducts of identical chemical composition cannot have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). 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. Id.”. Same logic is applicable to instant process claims, by administering the same compound (CX-8998) for treating bortezomib-induced neurotoxicity, said compound would necessarily have the same properties of reducing “bortezomib-induced [Symbol font/0x62]-tubulin polymerization”, and would “not interfere with anti-tumor activity and tolerability of bortezomib”, even though the prior art does not expressly teach it.
According to MPEP 2145 II, "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f))”. In other words, the properties of CX-8998 (i.e., “wherein said CX-8998, or salt thereof, does not interfere with anti-tumor activity and tolerability of bortezomib in a human; and wherein said CX-8998, or salt thereof, reduces bortezomib-induced [Symbol font/0x62]-tubulin polymerization”) does not necessarily make the CX-8998 in the method patentability distinct. If applicant contends the compound CX-8998 in the method made obvious by Lee et al. and Barrow et al. does not have the same properties instantly claimed, said objective evidence is respectfully requested. MPEP 716.01(c), I states: “[o]bjective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of 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, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984)”.
Applicant further argues the unexpected results are commensurate in scope with the claimed invention. Applicant argues the claimed invention does not require an active step of administering bortezomib, but the human having bortezomib-induced neurotoxicity must have been administered bortezomib. Specifically, Applicant argues the in vivo experiment demonstrating the unexpected results is commensurate in scope by administering both BTZ and CX-8998 during the treatment period of 28 days. Applicant further argues that the in vitro experiment demonstrating the unexpected results specifically administer bortezomib and CX-8998 in combination, and not sequentially; and a person skilled in the art would readily determine the amount of bortezomib used therein from the IC50 concentrations (6 nM, 4 nM, and 2.5 nM) stated in Figure 1A.
In response, applicant’s arguments are not found persuasive. As stated in the previous Final Office Action mailed on November 7, 2025 , applicant argues the claimed invention demonstrates unexpected results (“does not interfere with anti-tumor activity and tolerability of bortezomib”) based on the results present in the in vitro or in vivo studies, which demonstrates the co-treatment of CX-8998 and bortezomib (BTZ) does not interfere with bortezomib activity against multiple myeloma cells in xenograft mouse model of multiple myeloma (see page 2, line 16-19 and page 25, line 27-29 of the specification); and said effect is also confirmed by an in vitro assay illustrated in Figure 1A (see p. 7-8 of the reply filed on August 27, 2025).
According to MPEP 716.02(d), "whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the 'objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.' In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289,296 (CCPA 1980)".
It is respectfully noted that the instant claim(s) are drawn to “[a] method for treating a human having bortezomib-induced neurotoxicity, comprising administering an effective amount of a composition comprising CX-8998, or a salt thereof to said human; wherein said CX-8998, or salt thereof, does not interfere with anti-tumor activity and tolerability of bortezomib in a human; and wherein said CX-8998, or salt thereof, reduces bortezomib-induced [Symbol font/0x62]-tubulin polymerization”. As stated by the applicant, the claimed invention does not require the active step of administering bortezomib, but the human having bortezomib-induced neurotoxicity must have been administered bortezomib (see page 9 line 4-6 in the reply). Based on the in vivo study applicant relied on for the unexpected results (see page 25, line 27-29 of the specification), the nude mice bearing multiple myeloma cells RPMI-8229 is a xenograft mouse model of multiple myeloma rather than a model of bortezomib-induced neurotoxicity. It may well be true that said mice were treated with bortezomib (1 mg/kg, intravenous injection twice weekly) in combination with CX-8998 (30 mg/kg, orally once daily) for a period of 28 days; However, said in vivo study does not established that the mice used therein had bortezomib-induced neurotoxicity instantly claimed, nor established said mice had received bortezomib prior to administering the claimed composition comprising CX-8998.
In other words, applicant only exemplified unexpected results using a single weight-based dosage of CX-8998 (30 mg/kg) in combination with bortezomib (1 mg/kg) in mice bearing multiple myeloma cells RPMI-8229, but broadly claims any effective amount of a composition comprising CX-8998 is contemplated for use for treating the entire scope of human having bortezomib-induced neurotoxicity, including those who do not have a cancer or those who received bortezomib for other purposes (e.g., autoimmune disease). Therefore, the in vitro study upon which applicant relies does not provide adequate basis for concluding that similar results would be obtained for the broad effective amount of any composition comprising CX-8998 for treating the entire scope of human having bortezomib-induced neurotoxicity. The in vivo study applicant relied on for the unexpected results appears to be conflicting with applicant’s assertion that the treated subject must have been administered bortezomib. In addition, applicant asserts the in vitro results presented by Figure 1A does not administer BTZ and CX-8998 sequentially (see page 8, list 2 in the reply); and the amount of bortezomib is explicitly supported by the molar concentrations of bortezomib (6 nM, 4 nM and 2.5 nM of bortezomib) used against the MM.1S, RPMI 8226 and U266B1 cell lines. However, the in vitro study applicant relied on for the unexpected results is not a model of bortezomib-induced neurotoxicity, and said study fails to establish the subject received bortezomib prior to administering the claimed composition comprising CX-8998; and therefore, the in vitro results also do not provide adequate basis for concluding that similar results would be obtained for the broad effective amount of genus composition comprising CX-8998 for treating the entire scope of human having bortezomib-induced neurotoxicity.
Solely to rebut applicant’s argument that the administration of CX-8998 “does not interfere with anti-tumor activity and tolerability of bortezomib in a human” is unexpected, said unexpected result would have been expected by one of ordinary skill in the art. As stated in the rejection of record, Lee et al. clearly teaches CX-8998 reverses bortezomib-induced peripheral neurotoxicity without affecting bortezomib-induced proteasome inhibition (see e.g., “results” section); and Mujtaba et al. (Discov Med., 2011. Vol. 12(67)) clearly teaches bortezomib is an approved proteasome inhibitor used for treating newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma (see e.g., abstract). In other words, one of ordinary skill in the art would have reasonably expected that the CX-8998 would successfully reversing bortezomib-induced peripheral neuropathy without affecting bortezomib from achieving its antitumor activity by inhibiting proteasome. If applicant contends the claimed CX-8998 exhibits mutually exclusive properties, the supporting evidence is respectfully requested.
Applicant further argues Lee fails to teach the treatment of human and the impact of CX-8998 against BTZ’s anti-tumor activity (reduce BTZ-induced [Symbol font/0x62]-tubulin polymerization without interfering with BTZ's anti-tumor activity and tolerability), because the study is performed using healthy rats with no tumor; and Barrow also fails to teach said impact of CX-8998. Applicant further argues even if Barrow teaches that CX-8998 was useful for treating neuropathic pain in humans, one would not have expected it would be useful in treating BTZ-induced neurotoxicity. Applicant argues Barrow provides no relevant experimental data relating to CX-8998; Mujtaba fails to teach CX-8998; Maricich fails to provide any teachings or motivation to use CX-8998.
In response, applicant’s arguments are not found persuasive. 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). In the present case, Applicant’s arguments improperly evaluate each reference individually rather than considering the combined teachings of the reference as a whole. For instance, applicant argues Barrow et al. fails to teach bortezomib-induced neurotoxicity when the rejection of record already established the treatment of said bortezomib-induced neurotoxicity using Lee et al. The rejection(s) of record also does not rely on Mujtaba and Maricich alone to teach the claimed invention. It is respectfully noted that the obviousness-type rejection under 35 U.S.C. 103 does not require that every claimed limitation be disclosed within a single reference. Rather, the issue is whether the collective teachings of the prior art(s) would have suggested the claimed invention to one of ordinary skill in the art with a reasonable expectation of success.
Specifically, the rejection of record is form on the basis that Lee et al. teaches the administration of CX-8998 (3, 10 and 30 mg/kg PO daily for 4 weeks), which is a potent, selective T-type calcium channel modulator and Cav3 antagonist, to rats for treating bortezomib-induced peripheral neurotoxicity, and further relies on Barrow et al. to teach said CX-8998 can administer to a human at a therapeutically effective amount for treating or controlling neuropathic pain by antagonizing T-type calcium channel activity. It may well be true Lee et al. fails to teach a human; However, the rejection of record does not rely on Lee et al. alone, but further relies on Barrow et al. to establish that one would have a reasonable expectation of success to translate the therapeutic effect of CX-8998 demonstrates effective in animal model of Lee et al. to a human for clinical application. One would have reasonably expected that the T-type calcium channel antagonizing effect of CX-8998 can also be found in a human based on the teachings of Barrow et al. If Applicant contends the therapeutic effect of CX-8998 against bortezomib-induced neurotoxicity cannot translate between human and rats, the supporting evidence is respectfully requested.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., tumor) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In this case, applicant’s argues the rats with bortezomib-induced peripheral neurotoxicity as taught by Lee et al. does not have tumor, said technical feature (i.e., tumor) is not recited in rejected claims 1-2 and 18-20. In other words, even though the claim recites “said CX-8998, or salt thereof, does not interfere with anti-tumor activity and tolerability of bortezomib in a human”, the rejected claim(s) does not require the human having bortezomib-induced neurotoxicity to have tumor or cancer. It is respectfully noted that the technical feature applicant relies on (“tumor”) is only found in claims 6-7, which claims the human having bortezomib-induced neurotoxicity has been administered said bortezomib to treat the claimed cancer within said human. For these claims (claims 6-7), said technical feature is further addressed in another rejection of record that uses the collective teachings of Lee et al., Barrow et al. and Mujtaba et al. (see rejection above). Specifically, in addition to the teachings of Lee et al. and Barrow et al. set forth above, Mujtaba et al. teaches bortezomib is known to treat mantle cell lymphoma as one of the cancers. Therefore, one of ordinary skill in the art would have reasonably expected that the administration of CX-8998 would have successfully reversed bortezomib-induced neurotoxicity in human who has been administered bortezomib for the treatment of mantle cell lymphoma.
If applicant contends the therapeutic effect of CX-8998 cannot translate between subject without cancer/tumor and subject with cancer/tumor, such an assertion undermines the allegation of unexpected results applicant relies on. It is noted that the disclosure specifically evaluates the effects of CX-8998 on reversal of bortezomib-induced neurotoxicity and bortezomib-induced [Symbol font/0x62]-tubulin polymerization using a rat model without tumor or cancer (see e.g., p. 26, line 1-16 of the specification; p. 21, line 20 to p. 22, line 19). Applicant cannot simultaneously rely on the results of an in vivo study that uses rats without tumor or cancer to assert that the claimed invention demonstrates unexpected results when comparing to the teachings of prior art that also uses the rats without tumor or cancer for reversing bortezomib-induced neurotoxicity.
In view of these foregoing, applicant’s arguments are not found persuasive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,383,539 B2 (reference patent) in view of Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018; cited under “Non Patent Literature Documents”, cited no. C16 in the IDS filed on July 12, 2024), as evidenced by Carrington College Blog (Decoding Your Prescriptions: Understanding Pharmacy Abbreviations. Published on February 24, 2015), Cross (Chemical & Engineering News, Vol. 87, Issue 33. Published on August 24, 2019), and Jensen et al. (Lancet Neurol., 2014. Vol. 13(9): 924-935).
Please note this nonstatutory double patenting rejection is the same as the provisional
nonstatutory double patenting rejection over copending Application No. 17/282,730 set forth in the
previous office action. Since the copending application is now an issued U.S. Patent No. 12,383,539 B2
published on August 12, 2025, and do not have the same claim numbers, this nonstatutory double
patenting rejection are revisited and modified in light of the issued patent; However, this rejection
should be interpretated as being the same as corresponding to the provisional nonstatutory double
patenting rejection.
The claim of reference patent is drawn to an oral dosage form comprising a Cav3 antagonist, wherein the Cav3 antagonist is CX-8998 or a pharmaceutically acceptable salt thereof, wherein said oral dosage form, when administered once daily to a human, is effective to maintain a
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from about 1.0 to about 4.0 (see claim 1).
The reference patent does not teach the human having bortezomib-induced neurotoxicity.
Lee et al. teaches CX-8998 is a potent, selective T-type calcium channel modulator, and Cav3 antagonist that demonstrates dose dependent efficacy in a model of chemotherapy-induced peripheral neurotoxicity (CIPN); and these results highlight the potential for selective Cav3 modulators as a therapeutic option in CIPN (see e.g., title; abstract, “conclusions” and “objective” section). Please note the CX-8998 of Lee et al. has a chemical structure of:
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, as evidenced by Cross. Lee et al. further teaches the rats were treated with bortezomib (iv 0.2 mg/kg 3x/week for 4 weeks) to induce chemotherapy-induced peripheral neurotoxicity, and then CX-8998 (3, 10 and 30 mg/kg PO daily) administration was initiated for an additional 4 weeks (see e.g., title; abstract, “design/method” section). Please note the term “PO” is a medical abbreviation referring to oral administration, as evidenced by Carrington College Blog (see e.g., p. 2, “medical abbreviations that describe how to use your medication” section). Lee et al. further teaches CX-8998 dose-dependently reversed bortezomib-induced reduction of nerve conduction velocity and tactile allodynia after both 1 week and 4 weeks of co-administration without affecting bortezomib-induced proteasome inhibition (see e.g., “results” section). Please note the tactile allodynia taught by Lee et al. is a symptom of neurotoxicity induced by bortezomib according to page 26, line 18-20 of the instant specification; and allodynia is pain due to a stimulus that does not usually provoke pain, as evidenced by Jensen et al. (see e.g., abstract).
The conflicting claim(s) of reference patent recites the oral dosage form comprising a Cav3 antagonist CX-8998 that can administer once daily to a human whereas the rejected claims cover a method of treating a human having bortezomib-induced neurotoxicity. The conflicting claims does not recite the human is a human having bortezomib-induced neurotoxicity. However, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer the oral dosage form of reference patent (comprising CX-8998) once daily to a human having bortezomib-induced neurotoxicity. One would have been motivated to do so, because Lee et al. teaches orally administer CX-8998 daily can reverse bortezomib-induced neurotoxicity, and suggested the use of selective Cav3 modulators, such as CX-8998, as a therapeutic option; and the claim(s) of reference patent teaches the oral dosage form comprising CX-8998 can administer to human. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the oral dosage form of reference patent comprising the same compound at a therapeutically effective amount to a human having bortezomib-induced neurotoxicity would successfully treat said neurotoxicity. Please note the fact that the human having bortezomib-induced neurotoxicity is being treated, the human having said bortezomib-induced neurotoxicity would necessarily be identified in the method of Lee et al. and Barrow et al., and that renders obvious the limitation in claim 2.
Regarding the limitation of “wherein said CX-8998, or a salt thereof, does not interfere with anti-tumor activity and tolerability of bortezomib in a human; and wherein said CX-8998, or a salt thereof, reduces bortezomib-induced [Symbol font/0x62]-tubulin polymerization” in claim 1, the claimed limitation simply expresses the intended outcome of the method step positively recited. In this case, although Lee et al. may not have recognized that the CX-8998 results no interference with the anti-tumor activity and tolerability of bortezomib and has a characteristic of reducing the bortezomib-induced [Symbol font/0x62]-tubulin polymerization, these characteristics of CX-8998 would have been prima facie obvious to one of ordinary skill in the art by practicing the method of the reference patent and Lee et al. set forth above, because products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. Therefore, the claimed limitation is made obvious by the prior arts. MPEP 2145 II states: "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Response to Arguments
Applicant's arguments filed on August 27, 2025 have been fully considered.
Applicant's arguments filed on May 7, 2026 with respect to the provisional rejection of claims 1-2 and 20 on the ground of nonstatutory double patenting as being unpatentable over claim 51 of copending Application No. 17/282,730 (referred to herein as ‘730 application) in view of Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018), as evidenced by Carrington College Blog (Decoding Your Prescriptions: Understanding Pharmacy Abbreviations. Published on February 24, 2015), Cross (Chemical & Engineering News, Vol. 87, Issue 33. Published on August 24, 2019), and Jensen et al. (Lancet Neurol., 2014. Vol. 13(9): 924-935) have been fully considered but they are not persuasive.
In Summary, Applicant present the same arguments. Specifically, applicant argues a substance that treats bortezomib(BTZ)-induced neurotoxicity will not inevitability do so by reducing BTZ-induced [Symbol font/0x62]-tubulin polymerization by citing the metformin taught by Ludman. Applicant further argues CX-8998 outperforms other substances reported by Meregalli and Ceresa et al. (both cited in the IDS filed on May 7, 2026), respectively, and argues the claimed CX-8998 demonstrate a clinically relevant outcome.
In response, applicant’s arguments are not found persuasive. First of all, the Examiner noted that the ‘730 application is now an issued U.S. Patent No. 12,383,539 B2 published on Aug. 12, 2025, which do not have the same claim numbers. Therefore, the previous rejection of record has been revisited and modified in view of the issued patent; However, the rejection should be interpretated as being the same as corresponding to the provisional nonstatutory double patenting rejection sets forth in the previous Office Action. In response to applicant’s argument(s), they have been addressed in the response to arguments with respect to the rejection(s) under 35 U.S.C. 103, and are also applicable to this nonstatutory double patenting rejection. In sum, the mere fact that other drugs, e.g., metformin, are not known to reduce bortezomib-induced [Symbol font/0x62]-tubulin polymerization, or are known to interfere with anti-tumor activity and tolerability of bortezomib, it does not mean the CX-8998 of reference patent and Lee et al. is incapable of reducing bortezomib-induced [Symbol font/0x62]-tubulin polymerization, and would, in fact, interfere with anti-tumor activity and tolerability of bortezomib. The fact that other drugs interfere with bortezomib’s anti-tumor activity and tolerability, does not make the claimed CX-8998 patentably distinct from the CX-8998 of reference patent and Lee et al.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
Prosecution Insights