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 .
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Claim 13 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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 August 27, 2025, wherein claims 1-2, 6, 13, and 18 are amended; claims 3-5, 8-12, 14-17 and 19 are cancelled; and claims 7 and 20 are unchanged.
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 Claim 13 is withdrawn.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.
Action Summary
Claims 18-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in view of the claim amendment.
Claims 1-2, 4-5, 8-12 and 19-20 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al. (Neurology, 2018. Vol. 90(15)), 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 Vol. 13(9): 924-935) are withdrawn in view of the claim amendment.
Claims 1-2, 4-12 and 19-20 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) as applied to claims 1-2, 4-5, 8-12 and 19-20 above, and further in view of Mujtaba et al. (Discov Med., 2011. Vol. 12(67)) are withdrawn in view of the claim amendment.
Claims 1-5, 8-12 and 19-20 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) as applied to claims 1-2, 4-5, 8-12 and 19-20 above, and further in view of Barrow et al. (WO 2007/120729 A2) are withdrawn in view of the claim amendment.
Claims 1-5, 8-12, and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 and 6-7 of U.S. Patent No. 11,324,733 B2 (referred to herein as ‘733 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) are withdrawn in view of the claim amendment.
Claims 1-5, 8-12, and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,273,218 B2 (referred to herein as ‘218 patent) and over claims 1 of U.S. Patent No. 11,311,522 B2 (referred to herein as ‘522 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) are withdrawn in view of the claim amendment.
Claims 1-5, 8-12, and 19-20 are 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; 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) are withdrawn in view of the claim amendment.
Claim Objections
Claims 1 and 18 are objected to because of the following informalities (newly reapplied as necessitated by amendment):
Regarding claim 1,
the recitation of “comprises administering an effective amount of a composition comprising CX-8998: …or a salt thereof; to said human;” does not appear to have a clear sentence structure, because a semicolon is often used to separates two closely related independent claims rather than connecting them. In this case, said recitation should read –comprises administering
the recitation of “wherein said CX-8998, or a salt thereof” in line 6-9 should read –wherein said CX-8998, or salt thereof–, such that the article “a” is deleted before the term “salt”. It is noted that the article “a” is often used to refer to something that is not previously introduced; therefore, when said article is used in the context of “a salt thereof” it is not clear if applicant is intending to refer to another salt form that is different than the salt form sets forth before.
Regarding claim 18, the recitation of “said CX-8998, or a salt thereof” should read –said CX-8998, or salt thereof–, such that the article “a” is deleted before the term “salt”. It is noted that the article “a” is often used to refer to something that is not previously introduced. therefore, when said article is used in the context of “a salt thereof” it is not clear if applicant is intending to refer to another salt form that is different than the salt form sets forth before.
Appropriate correction is required.
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)(newly reapplied as necessitated by amendment).
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))(newly reapplied as necessitated by amendment).
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)(newly reapplied as necessitated by amendment).
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 August 27, 2025 have been fully considered.
All rejections pertaining to claims 3-5, 8-12, and 19 are moot because the claims were cancelled in view of the claim amendment filed on August 27, 2025.
Applicant's arguments filed on August 27, 2025 with respect to the rejection of claims 1-2, 4-12 and 19-20 under 35 U.S.C. 103 as being unpatentable over Lee et al. (Neurology, 2018. Vol. 90(15). Published online on April 10, 2018; cited under “Non Patent Literature Documents”, cited no. C16 in the IDS filed on July 12, 2024) as applied to claims 1-2, 4-5, 8-12 and 19-20 above, and further in view of Mujtaba et al. (Discov Med., 2011. Vol. 12(67)) have been fully considered but they are not persuasive.
Applicant's arguments filed on August 27, 2025 with respect to the rejection of claims 1-5, 8-12 and 19-20 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) as applied to claims 1-2, 4-5, 8-12 and 19-20 above, and further in view of Barrow et al. (WO 2007/120729 A2) have been fully considered but they are not persuasive.
Applicant's arguments filed on August 27, 2025 with respect to the rejection of claims 1-2, 4-5, 8-12 and 18-20 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) as applied to claims 1-2, 4-5, 8-12 and 19-20 above, and further in view of Maricich (WO 2017/070680 A1) have been fully considered but they are not persuasive.
Applicant amends claim 1 from the recitation of “[a] method for treating a mammal having neurotoxicity” to the recitation of “[a] method for treating a human having bortezomib-induced neurotoxicity” in the preamble; amending the recitation of “a composition comprising a T-type calcium channel modulator or a salt thereof” to the recitation of “a composition comprising CX-8998:
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, or a salt thereof”; and added the new limitations 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”. Applicant further changes the dependency of claim 6. Each of these findings demonstrate that the amendment to the claims changes the scope of claims, and that necessitated a modification of the previous rejection on the record.
In Summary, Applicant argues “Lee does not teach administration of CX-8998 to a human having
bortezomib-induced neurotoxicity, nor does it teach the lack of interference with anti-tumor
activity and tolerability of bortezomib and/or reduction of bortezomib-induced [Symbol font/0x62]-tubulin
polymerization”. Applicant further argues the claimed invention demonstrates unexpected results. Specifically, applicant argues the co-treatment of CX-8998 and bortezomib (BTZ) does not interfere with bortezomib activity on human multiple myeloma cell lines in vitro or in vivo by directing attention to page 2, line 16-19 and page 25, line 27-29 of the specification. Applicant further argues the administration of CX-8998 does not interfere with the anti-tumor activity and tolerability of bortezomib by directing attention to Figure 1A that demonstrates the % survival of multiple myeloma cell lines (MM.1S, RPM1, and U266B1) when bortezomib is administered alone; bortezomib is administered in combination with CX-8998 at concentration between 10-1000 nM; CX-8998 is administered alone; and DMSO control is administered. Applicant further argues Mujtaba does not teach CX-8998; Barrow does not teach bortezomib; and Maricich does not teach bortezomib.
In response, applicant’s argument is not found persuasive for the following reasons:
First, 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. Therefore, by practicing the method made obvious by the prior arts, these outcome would necessarily be present because products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
Second, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. Applicant argues unexpected results are demonstrated in page 2, line 16-19 and page 25, line 27-29 of the specification, and Figure 1A. It is noted that the unexpected results (“the co-treatment of CX-8998 and BTZ does not interfere with bortezomib activity on human multiple myeloma cell lines in vitro or in vivo”) that applicant relies upon specifically administer 1 mg/kg of bortezomib (intravenous injection twice weekly for 28 days) in combination with 30 mg/kg CX-8998 (orally once daily for 28 days) to the mice bearing multiple myeloma cell RPMI-8229 until the tumor volume reached 125-250 mm2 (see e.g., page 25, “In Vivo Combination (BTZ and CX-8998) Anti-Tumor Interference Study” section; p. 21, lines 1-13). The specification does specify whether the combination recites therein is sequential or combinational, for instance, it is not clear if the bortezomib is administered before CX-8998 or bortezomib is administered together with CX-8998 on day 1. It is also noted that the unexpected results (“the administration of CX-8998 does not interfere with the anti-tumor activity and tolerability of bortezomib”) that applicant relies upon exposes the three multiple myeloma cells (MM.1S, RPM1, and U266B1) for 72 hours to IC50 concentration of BTZ alone in combination with 5 concentrations of CX-8998 (10, 30, 100, 300, 1000 nM) in an in vitro assay (see e.g., p. 25, “In Vitro BTZ Cytotoxicity Study and In Vitro Combination (BTZ and CX-8998) Cytotoxicity Interference Study”; p. 4, line 16-22; p. 20, line 10-19); However, the amount of bortezomib has not been disclosed and the specification also does not specify whether the combination recites therein is sequential or combinational.
In contrast, claim 1 recites “[a] method of treating a human having bortezomib-induced neurotoxicity, wherein said method comprises administering an effective amount of a composition
comprising CX-8998…, or salt thereof; to said human; 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”. It is noted that the claim does not positively recite the administration of bortezomib.
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)”. In this case, the in vivo study noted by the applicant only tested the combination of CX-8998 and bortezomib in a mice having multiple myeloma (RPMI-8229), and that is not commensurate in scope to encompass each and every human species having bortezomib-induced neurotoxicity, including those treated with bortezomib for other cancer species. It is further noted that the specification does not specify whether the mice with multiple myeloma in said in vitro assay has bortezomib-induced neurotoxicity prior to the administration of CX-8998, because the specification did not clearly set forth the CX-8998 was administer after the mice having bortezomib-induced neurotoxicity. In addition, the specification exemplifies the administration of 1 mg/kg of bortezomib (intravenous injection twice weekly for 28 days) in combination with 30 mg/kg CX-8998 (orally once daily for 28 days), and that is not commensurate in scope to encompass the admisnritation of any composition comprising CX-8998 or a salt thereof at any effective amount through any administration route. Each of these findings demonstrate that applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention, thus, the argument is not found persuasive.
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”, and “reduces bortezomib-induced [Symbol font/0x62]-tubulin polymerization” are unexpected, these unexpected results would have been expected for the following reasons. In this case, Lee et al. (Neurology, 2018. Vol. 90(15)) clearly teaches CX-8998 reverses bortezomib-induced peripheral neurotoxicity after both 1 week and 4 weeks of co-administration without affecting bortezomib-induced proteasome inhibition (see e.g., “results” section); and Mujtaba et al. (Discov Med., 2011. Vol. 12(67)) 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, CX-8998 has shown efficacy in reversing bortezomib-induced peripheral neuropathy without affecting bortezomib's antitumor activity in inhibiting proteasome. According to Staff et al. (NeuroToxicology, 2013. Vol. 39: 124–131), an in vitro model of bortezomib-induced peripheral neuropathy utilized to mechanistically understand bortezomib-induced peripheral neuropathy found out that bortezomib induces somatic aggregation of beta-tubulin, causes an increased tubulin polymerization, and impaired axonal transport (see e.g., p. 125, left column, 2nd paragraph; p. 127, right column, “3.2. Bortezomib induces somatic aggregation of beta-tubulin without altering microtubule ultrastructure” section; p. 129, left column, line 3 to right column, line 1). In other words, bortezomib-induced peripheral neuropathy is known to increase beta-tubulin polymerization; and therefore, by practicing the method made obvious by the prior arts, which administers CX-8998 at a therapeutically effective amount for treating bortezomib-induced peripheral neuropathy, the increased beta-tubulin polymerization induced by bortezomib would necessarily be reduced by reversing bortezomib-induced peripheral neuropathy.
In response to applicant's arguments against the references individually (Mujtaba does not teach CX-8998; Barrow does not teach bortezomib; and Maricich does not teach bortezomib), 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 this case, the rejection on the record does not rely on Mujtaba alone to teach CX-8998, nor on Barrow et al. alone to teach bortezomib, nor on Maricich alone to teach bortezomib. As noted in the rejection above, Lee et al. clearly teaches the administration of CX-8998 in a rat with bortezomib-induced neurotoxicity. 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 and the claimed invention administers to the human having bortezomib-induced peripheral neurotoxicity. Therefore, Barrow is applied to teach CX-8998 can be administer at a therapeutically effective amount to a human; Maricich is applied to teach the concentration of CX-8998 (about 10 μΜ or lower, including about 1000 nM or lower) that can inhibit T-type calcium channels; and Mujtaba et al. is applied to teach the intended use of bortezomib (e.g., treating mantle cell lymphoma). Given that applicant does not provide any showing that each of these teachings taught by the cited reference would lead to unexpected results, these arguments presented by the applicant are not found persuasive for the reasons set forth herein.
Therefore, the new ground of rejection has been applied in view of the claim amendments for the reasons set forth herein.
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 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; 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)(newly reapplied as necessitated by amendment).
The claims of ‘730 application 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 51).
The claims of ’730 application 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 claims of ‘730 application 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 ‘730 application (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 claims of ‘730 application 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 ‘730 application 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 ‘730 application 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).
Therefore, this is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed on August 27, 2025 have been fully considered.
All rejections pertaining to claims 3-5, 8-12, and 19 are moot because the claims were cancelled in view of the claim amendment filed on August 27, 2025.
Applicant's arguments filed on August 27, 2025 with respect to the provisional rejection of claims 1-5, 8-12, and 19-20 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; 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) have been fully considered but they are not persuasive.
Applicant amends claim 1 from the recitation of “[a] method for treating a mammal having neurotoxicity” to the recitation of “[a] method for treating a human having bortezomib-induced neurotoxicity” in the preamble; amending the recitation of “a composition comprising a T-type calcium channel modulator or a salt thereof” to the recitation of “a composition comprising CX-8998:…or a salt thereof”; and added the new limitations 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”. Applicant further changes the dependency of claim 6. Each of these findings demonstrate that the amendment to the claims changes the scope of claims, and that necessitated a modification of the previous rejection on the record.
In Summary, Applicant argues based on the text of the ‘730 claims, one would not motivate to administer the oral dosage form of ’730 claims to treat bortezomib-induced neurotoxicity. Applicant further argues Lee et al. does not teach a method for treating bortezomib-induced neurotoxicity without interfering with anti-tumor activity and tolerability of bortezomib.
In response, applicant’s argument is not found persuasive, because the provisional rejection on the record is based on the claims of ‘730 application in view of Lee et al. rather than the text of the ‘730 claims alone. Specifically, the claims of ‘730 application teaches a oral dosage form comprising a Cav3 antagonist CX-8998 that can administer once daily to a human, and Lee et al. provides the motivation to administer CX-8998 orally once daily for treating bortezomib-induced peripheral neurotoxicity. Therefore, the motivation to administer CX-8998 is not based upon the ‘730 application alone. Since applicant presents the same argument with respect to Lee et al. (“Lee et al. does not teach a method for treating bortezomib-induced neurotoxicity without interfering with anti-tumor activity and tolerability of bortezomib”), the same reasons addressed above are also applied as before.
Therefore, the new ground of rejection has been applied in view of the claim amendments for the reasons set forth herein.
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 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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