Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed April 8, 2026. The amendment, filed April 8, 2026, is entered, wherein claims 1 – 2, 11, 19, 23, 27, and 38 are amended, claims 8, 33 – 35, and 37 are withdrawn, and claims 3, 6 – 7, 9 – 10, 12 – 15, 17 – 18, 20 – 21, 25 – 26, 31 – 32, and 36 are canceled.
Claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 are examined on the merits herein.
Priority
3. This application is a national stage application of PCT/US2020/015898, filed January 30, 2020, which claims benefit of domestic application 62/800,369, filed February 1, 2019.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/800,369, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The domestic application 62/800,369 does not provide support for the limitations of “alkyl-OH, alkyl-O-alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-aryl or alkyl-heteroaryl” recited in claims 1, 22, and 38 and “-NH(CO)-alkyl, -NH(CO)NH-alkyl, -NH(CO)-aryl, or -NH(CO)NH-aryl” recited in claims 1, 22, and 38. Thus, the priority date of claims 1, 22, and 38 and their dependent claims 4 – 5, 11, 16, 19, 23 – 24, and 27 – 30 is January 30, 2020.
Withdrawn Rejections
4. The rejection of claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30 in the previous Office Action, mailed January 8, 2026, under 35 U.S.C. 103 as being unpatentable over Gassaway et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 in the previous Office Action, mailed January 8, 2026, on the ground of nonstatutory double patenting as being unpatentable over claim 58 of copending Application No. 17/938,003 in view of Gassaway et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 in the previous Office Action, mailed January 8, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4, 33, 127, and 139 of copending Application No. 17/304,713 in view of Gassaway et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 in the previous Office Action, mailed January 8, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 7, and 9 of U.S. Patent No. 11912707B2 in view of Gassaway et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 in the previous Office Action, mailed January 8, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4, 6 – 11, and 16 – 22 of copending Application No. 18/437,646 in view of Gassaway et al. has been considered and is withdrawn in view of the amended claim 1.
The following are modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed April 8, 2026, wherein claims 1 – 2, 11, 19, 23, 27, and 38 are amended, claims 8, 33 – 35, and 37 are withdrawn, and claims 3, 6 – 7, 9 – 10, 12 – 15, 17 – 18, 20 – 21, 25 – 26, 31 – 32, and 36 are canceled. Previously and newly cited references have been used to establish the modified / new grounds of rejection.
New Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, line 22, “or” immediately after “-NH(CO)-aryl,” should be removed.
Appropriate correction is required.
Modified / New 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Gassaway et al. (WO2017165738A1) in view of Takayama et al. (Tetrahedron Letters, 1995, Vol. 36, Issue 51, page 9337 – 9340, Reference included with PTO-892), Gribble et al. (Heterocycles, 1981, Vol. 16, Issue 12, Reference included with PTO-892), and Timmins (Expert Opinion on Therapeutic Patents, 2014, Vol. 24, Issue 10, Reference included with PTO-892).
a. Gassaway et al. teach a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
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wherein the pharmaceutical composition is enriched in the compound that contains deuterium in place of -H (page 3, lines 20 – 25; page 4, lines 1 – 16). A compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% over its non-enriched counterpart (page 45, line 37; page 46, lines 1 – 2). In some embodiments, the compound is (page 6, line 11):
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Gassaway et al. also disclose that any notation of a hydrogen in structure throughout, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H (D), or 3H (T) (page 45, lines 22 – 25). Moreover, Gassaway et al. teach a pharmaceutical composition in unit dosage form, which comprises (i) an amount of any compound recited and (ii) an amount of an NMDA receptor antagonist (page 43; lines 4 – 9), wherein the NMDA receptor antagonist is ibogaine or noribogaine (page 37, lines 26 – 27).
However, Gassaway et al. do not explicitly teach the compound having deuterium-enriched -H site at the R6 position.
Takayama et al. teach the first total synthesis of mitragynine (Title), wherein the synthetic route of mitragynine is (page 9339, Schemes 2 and 3):
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which illustrates that NaBH4 is used in the process for the reduction of double bond. The resulting intermediate contains the H at the claimed R6 position. Thus, Takayama et al. teach that NaBH4 is a conventional reagent used in the synthesis of mitragynine for the reduction of the indole double bond.
Gribble et al. teach the reduction of indole double bond using NaBH4 in the presence of CF3CO2H (page 2110):
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Gribble et al. also teach stereoselective reduction of an indolo[2,3-a]quinolizine compound using sodium borohydride in trifluoroacetic acid (Title).Gribble further teach preparing deuterated derivatives using NaBD4 in the presence of CF3CO2H (page 2110):
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In particular, Gribble et al. teach that treating the indolo[2,3-a]quinolizine compound with NaBD4/CF3CO2H produces deuterated compound 4 in 66% yield (page 2110, para. 2), wherein deuterium is incorporated at a specific ring position. Thus, Gribble et al. teach that selective, single-position deuterium incorporation in a related indoloquinolizine scaffold is known and successfully achieved using NaBD4/CF3CO2H.
Finally, Timmins teaches that replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in metabolism and thereby cause beneficial changes in the biological effects of drug, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing. Such replacement may also have the effect of lowering toxicity by reducing the formation of a toxic metabolite (page 2, para. 1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the deuterium-enriched mitragynine-type compound as taught by Gassaway et al. by substituting NaBH4 with NaBD4 in view of Takayama et al., Gribble et al., and Timmins because Gassaway et al. teach deuterated mitragynine-type compounds and explicitly contemplate replacement of hydrogen atoms with deuterium isotopes and Timmins teaches that replacement of hydrogen with deuterium in drug molecules is known to alter metabolism, improve pharmacokinetic properties and reduce formation of toxic metabolites. Takayama et al. teach the total synthesis of mitragynine and disclose a reduction step utilizing NaBH4 that introduces the hydrogen atom to the claimed R6 position. Gribble et al. teach that NaBD4 may be substituted for NaBH4 in a related indolo[2,3-a]quinolizine scaffold to produce the corresponding deuterated analog by incorporation of deuterium at the hydride-addition position. Therefore, one of ordinary skill in the art would have recognized that substitution of NaBD4 for NaBH4 in the Takayama synthesis would predictably introduce deuterium at the position corresponding to the claimed R6 position while producing the corresponding deuterium-enriched mitragynine analog as taught by Gassaway et al. One of ordinary skill in the art would have been motivated to substitute NaBD4 for NaBH4 in the Takayama synthesis in order to prepare a deuterium-enriched mitragynine analog and obtain the known benefits associated with deuterium substitution taught by Timmins, including altered metabolism and reduced formation of undesirable metabolites. One of ordinary skill in the art would have had a reasonable expectation of success to prepare the deuterium-enriched mitragynine-type compound as taught by Gassaway et al. by substituting NaBH4 with NaBD4 in view of Takayama et al., Gribble et al., and Timmins because Gribble et al. demonstrate successful incorporation of deuterium through the analogous reagent substitution in a closely related indoloquinolizine system, and the substitution of NaBD4 for NaBH4 is a known and predictable technique for obtaining the corresponding deuterated product.
Moreover, the claimed deuterium-enriched limitation is also satisfied because intentional incorporation of deuterium using NaBD4/ acid would produce deuterium at the target hydrogen-bearing site at a level above natural abundance, which is above 0.0156%.
Regarding claim 11, Gassaway et al. further teach that any notation of hydrogen in the disclosed structures is intended to represent all isotopes of hydrogen, including deuterium, and teach compounds enriched in deuterium at hydrogen sites. Once the R6-deuterium-enriched compound is rendered obvious as discussed above, therefore, it would have been obvious to further enrich one or more additional hydrogen-bearing positions with deuterium, including H1 – H11, R7, R8, and/or R9 because Gassaway et al. teach deuterium substitution at hydrogen-bearing positions of the mitragynine-type scaffold.
Regarding claim 19, Gribble et al. teach preparation of a deuterated analog using NaBD4/CF3CO2H and reports that the deuterated compound 4 is obtained in 66% yield. The reported 66% yield shows that Gribble et al. successfully prepared and isolated the deuterated product in substantial amount. Although yield is not the same as percent deuterium incorporation, the use of NaBD4 as a deuterium source and identification of the product as a deuterated compound would have taught one of ordinary skill in the art that deuterium is intentionally incorporated at the target position above natural abundance. Because claim 19 recites a broad deuterium level of 0.02% to 100%, the claimed range encompasses such intentionally deuterium-enriched products.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed April 8, 2026, have been fully considered and are found to be not persuasive.
Applicant argues that Gassaway et al. do not specifically disclose or suggest compounds wherein R6 is deuterium enriched. Applicant argues that Gassaway et al. merely provide a general disclosure that hydrogen may include isotopes such as deuterium and that the specifically exemplified compounds contain deuterium enrichment at positions other than R6. Applicant further argues that selection of R6 requires impermissible hindsight reconstruction. However, the arguments are not persuasive because the present rejection does not rely on Gassaway et al. alone for the R6 deuterium-enriched limitation. Gassaway et al. is not limited to the specifically exemplified deuterated positions. Instead, Gassaway et al. teach deuterated mitragynine-type compounds and pharmaceutical compositions thereof, and further teach that hydrogen notation in the disclosed structures may be isotopes of hydrogen, which include deuterium. Therefore, Gassaway et al. provide the mitragynine-type compound in which hydrogen positions are eligible for isotopic substitution, including at the claimed R6 position. Takayama et al. is relied upon to teach the use of NaBH4 to reduce the indole double bond in the synthesis of mitragynine, wherein the introduction of hydrogen atom is at the claimed R6 position. Gribble et al. is relied upon to teach selective incorporation of deuterium at a corresponding single hydrogen-bearing position in a related indoloquinolizine scaffold. Timmins is relied upon for the teaching that replacement of hydrogen with deuterium in drug molecules will lower the toxicity because of the reduction in the formation of toxic metabolites. Accordingly, the combination teaches or suggests preparing the mitragynine-type compound of Gassaway et al. with deuterium enrichment at the claimed R6 position.
Applicant argues that 3-deuteromitragynine unexpectedly attenuates formation of 3-dehydromitragynine (DHM). Applicant asserts that DHM is associated with toxicity and that deuteration at the R6 position reduces DHM formation while maintaining formation of 7-hydroxymitragynine and maintaining analgesic activity. Applicant further argues that 3-deutero-7-hydroxymitragynine exhibits improved stability and reduced DHM formation relative to non-deuterated 7-hydroxymitragynine. These arguments have been considered but are not persuasive. Timmins teaches that replacement of hydrogen with deuterium in drug molecules can alter metabolism and may reduce toxicity by reducing formation of toxic metabolites. Thus, Applicant’s results that deuterium reduces formation of DHM, which Applicant characterizes as a toxic metabolite, is consistent with the expected effect taught by Timmins. Accordingly, even if Applicant’s data show reduced DHM formation relative to the corresponding non-deuterated compounds, such results do not establish unexpected results because reduction in toxic metabolite formation is the type of result Timmins teaches that is obtained by deuterium substitution. The present rejection is based on the combined teachings of Gassaway et al., Takayama et al., Gribble et al., and Timmins. Gassaway et al. teach mitragynine-type compounds, deuterated analogs thereof, and pharmaceutical compositions comprising such compounds. Gassaway et al. further teach that hydrogen notation in the disclosed structures may be isotopes of hydrogen, which include deuterium. Takayama et al. teach that first total synthesis of mitragynine, which involves the use of NaBH4 to reduce the indole double bond. Gribble et al. teach selective, single-position deuterium incorporation at a corresponding hydrogen bearing position in a related indoloquinolizine scaffold using NaBD4/acid conditions. Timmins teaches that deuterium addition to the drug molecules may lower toxicity. Thus, the rejection is not based merely on the non-deuterated compounds used as the control, but on the combined teachings of Gassaway et al., Takayama et al, Gribble et al., and Timmins, which teach deuterated mitragynine-type compounds and site-specific deuterium incorporation. Applicant’s evidence shows results for specific tested compounds, including 3-deuteromitragynine and 3-deutero-7-hydroxymitragynine. However, the pending claims are broader than these specific tested species. The claims encompass additional substituent variations and additional deuteration at other positions. Applicant has not established that the asserted reduction in DHM formation, improved stability, maintained 7-hydroxymitragynine formation, or maintained analgesic activity would be obtained across the full scope of the claims. Moreover, Timmins explicitly teaches the benefits of replacing hydrogen with deuterium, which includes the reduction in the formation of toxic metabolites. Thus, a reduction in formation of a metabolite, including a toxic metabolite, would have been an expected result of deuterium substitution rather than evidence of unexpected properties. Applicant’s data, therefore, demonstrate the known consequence of deuterium incorporation taught by Timmins rather than a property that would have been unexpected to one of ordinary skill in the art.
Applicant argues that the unexpected results are commensurate in scope because independent claims 1 and 22 require deuterium enrichment at R6, and that additional deuteration at other positions is a reasonable extrapolation. However, the argument is not persuasive. A statement that broader embodiments are a reasonable extrapolation is insufficient without supporting evidence. Applicant has not provide evidence showing that compounds having additional deuterium enrichment at other positions or other structural variations would exhibit the same asserted properties as the specific tested compounds. Accordingly, Applicant’s evidence does not establish unexpected results commensurate in scope with the pending claims.
Modified / New 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, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 58 of copending Application No. 17/938,003 in view of Gassaway et al. (WO2017165738A1), Takayama et al. (Tetrahedron Letters, 1995, Vol. 36, Issue 51, page 9337 – 9340, Reference included with PTO-892), Gribble et al. (Heterocycles, 1981, Vol. 16, Issue 12, Reference included with PTO-892), and Timmins (Expert Opinion on Therapeutic Patents, 2014, Vol. 24, Issue 10, Reference included with PTO-892).
a. ‘003 teaches a pharmaceutical composition comprising (A) a compound of the formula:
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(B) an excipient (claim 58).
However, ‘003 does not teach the compound with deuterium at the R6 position of the claimed compound. ‘003 does not teach the pharmaceutical composition comprising a pharmaceutically acceptable carrier and further comprising NMDA receptor antagonist, such as ibogaine or noribogaine. ‘003 also does not teach the level of deuterium at the deuterium-enriched -H site.
Gassaway et al. teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
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wherein the pharmaceutical composition is enriched in the compound that contains deuterium in place of -H (page 3, lines 20 – 25; page 4, lines 1 – 16). A compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% over its non-enriched counterpart (page 45, line 37; page 46, lines 1 – 2). In some embodiments, the compound is (page 6, line 11):
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Gassaway et al. also discloses that any notation of a hydrogen in structure throughout, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H (D), or 3H (T) (page 45, lines 22 – 25). Moreover, Gassaway et al. teaches a pharmaceutical composition in unit dosage form, which comprises (i) an amount of any compound recited and (ii) an amount of an NMDA receptor antagonist (page 43; lines 4 – 9), wherein the NMDA receptor antagonist is ibogaine or noribogaine (page 37, lines 26 – 27).
Takayama et al. teach the first total synthesis of mitragynine (Title), wherein the synthetic route of mitragynine is (page 9339, Schemes 2 and 3):
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which illustrates that NaBH4 is used in the process for the reduction of double bond. The resulting intermediate contains the H at the claimed R6 position. Thus, Takayama et al. teach that NaBH4 is a conventional reagent used in the synthesis of mitragynine for the reduction of the indole double bond.
Gribble et al. teach stereoselective reduction of an indolo[2,3-a]quinolizine compound using sodium borohydride in trifluoroacetic acid (Title).Gribble further teach preparing deuterated derivatives using NaBD4 om CF3CO2H (page 2110):
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In particular, Gribble et al. teach that treating the indolo[2,3-a]quinolizine compound with NaBD4/CF3CO2H produces deuterated compound 4 in 66% yield (page 2110, para. 2), wherein deuterium is incorporated at a specific ring position. Thus, Gribble et al. teach that selective, single-position deuterium incorporation in a related indoloquinolizine scaffold is known and successfully achieved using NaBD4/CF3CO2H.
Finally, Timmins teaches that replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in metabolism and thereby cause beneficial changes in the biological effects of drug, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing. Such replacement may also have the effect of lowering toxicity by reducing the formation of a toxic metabolite (page 2, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compound of ‘003 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., and Gribble et a. because ‘003 teaches the corresponding mitragynine-type composition comprising the non-deuterated compound and an excipient, Gassaway et al. teach that mitragynine may be deuterated and teach that hydrogen notation in the disclosed structures may be isotopes of hydrogen, which includes deuterium, Takayama et al. teach the first total synthesis of mitragynine using NaBH4, and Gribble et al. teach selective, single-position incorporation of deuterium at a corresponding position in a related indolo[2,3-a]quinolizine scaffold using NaBD4/CF3CO2H, and report production of deuterated compound 4 in 66% yield. Takayama et al. teach the total synthesis of mitragynine and disclose a reduction step utilizing NaBH4 that introduces the hydrogen atom to the claimed R6 position. Gribble et al. teach that NaBD4 may be substituted for NaBH4 in a related indolo[2,3-a]quinolizine scaffold to produce the corresponding deuterated analog by incorporation of deuterium at the hydride-addition position. Therefore, one of ordinary skill in the art would have recognized that substitution of NaBD4 for NaBH4 in the Takayama synthesis would predictably introduce deuterium at the position corresponding to the claimed R6 position while producing the corresponding deuterium-enriched mitragynine analog as taught by Gassaway et al. One of ordinary skill in the art would have been motivated to substitute NaBD4 for NaBH4 in the Takayama synthesis in order to prepare a deuterium-enriched mitragynine analog and obtain the known benefits associated with deuterium substitution taught by Timmins, including altered metabolism and reduced formation of undesirable metabolites. One of ordinary skill in the art would have had a reasonable expectation of success to modify the compound of ‘003 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., Gribble et al., and Timmins because Gribble et al. demonstrate successful incorporation of deuterium through the analogous reagent substitution in a closely related indoloquinolizine system, and the substitution of NaBD4 for NaBH4 is a known and predictable technique for obtaining the corresponding deuterated product.
Moreover, the claimed deuterium-enriched limitation is also satisfied because intentional incorporation of deuterium using NaBD4/ acid would produce deuterium at the target hydrogen-bearing site at a level above natural abundance, which is above 0.0156%.
Regarding claim 11, Gassaway et al. further teach that any notation of hydrogen in the disclosed structures is intended to represent all isotopes of hydrogen, including deuterium, and teach compounds enriched in deuterium at hydrogen sites. Once the R6-deuterium-enriched compound is rendered obvious as discussed above, therefore, it would have been obvious to further enrich one or more additional hydrogen-bearing positions with deuterium, including H1 – H11, R7, R8, and/or R9 because Gassaway et al. teach deuterium substitution at hydrogen-bearing positions of the mitragynine-type scaffold.
Regarding claim 19, Gribble et al. teach preparation of a deuterated analog using NaBD4/CF3CO2H and reports that the deuterated compound 4 is obtained in 66% yield. The reported 66% yield shows that Gribble et al. successfully prepared and isolated the deuterated product in substantial amount. Although yield is not the same as percent deuterium incorporation, the use of NaBD4 as a deuterium source and identification of the product as a deuterated compound would have taught one of ordinary skill in the art that deuterium is intentionally incorporated at the target position above natural abundance. Because claim 19 recites a broad deuterium level of 0.02% to 100%, the claimed range encompasses such intentionally deuterium-enriched products.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4, 33, 127, and 139 of copending Application No. 17/304,713 in view of Gassaway et al. (WO2017165738A1), Takayama et al. (Tetrahedron Letters, 1995, Vol. 36, Issue 51, page 9337 – 9340, Reference included with PTO-892), Gribble et al. (Heterocycles, 1981, Vol. 16, Issue 12, Reference included with PTO-892), and Timmins (Expert Opinion on Therapeutic Patents, 2014, Vol. 24, Issue 10, Reference included with PTO-892).
b. ‘713 teaches a compound of Formula (I’):
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and further teaches a compound as shown below:
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(claims 1 – 2, 4, 33, and 127).
‘713 also teaches a pharmaceutical composition comprising the compound and optionally a pharmaceutically acceptable carrier (claim 139).
However, ‘713 does not teach the compound with deuterium at the R6 position of the claimed compound. ‘713 does not teach the pharmaceutical composition comprising NMDA receptor antagonist, such as ibogaine or noribogaine. ‘713 also does not teach the level of deuterium at the deuterium-enriched -H site.
Gassaway et al. teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
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wherein the pharmaceutical composition is enriched in the compound that contains deuterium in place of -H (page 3, lines 20 – 25; page 4, lines 1 – 16). A compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% over its non-enriched counterpart (page 45, line 37; page 46, lines 1 – 2). In some embodiments, the compound is (page 6, line 11):
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Gassaway et al. also discloses that any notation of a hydrogen in structure throughout, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H (D), or 3H (T) (page 45, lines 22 – 25). Moreover, Gassaway et al. teaches a pharmaceutical composition in unit dosage form, which comprises (i) an amount of any compound recited and (ii) an amount of an NMDA receptor antagonist (page 43; lines 4 – 9), wherein the NMDA receptor antagonist is ibogaine or noribogaine (page 37, lines 26 – 27).
Takayama et al. teach the first total synthesis of mitragynine (Title), wherein the synthetic route of mitragynine is (page 9339, Schemes 2 and 3):
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which illustrates that NaBH4 is used in the process for the reduction of double bond. The resulting intermediate contains the H at the claimed R6 position. Thus, Takayama et al. teach that NaBH4 is a conventional reagent used in the synthesis of mitragynine for the reduction of the indole double bond.
Gribble et al. teach stereoselective reduction of an indolo[2,3-a]quinolizine compound using sodium borohydride in trifluoroacetic acid (Title).Gribble further teach preparing deuterated derivatives using NaBD4 om CF3CO2H (page 2110):
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In particular, Gribble et al. teach that treating the indolo[2,3-a]quinolizine compound with NaBD4/CF3CO2H produces deuterated compound 4 in 66% yield (page 2110, para. 2), wherein deuterium is incorporated at a specific ring position. Thus, Gribble et al. teach that selective, single-position deuterium incorporation in a related indoloquinolizine scaffold is known and successfully achieved using NaBD4/CF3CO2H.
Finally, Timmins teaches that replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in metabolism and thereby cause beneficial changes in the biological effects of drug, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing. Such replacement may also have the effect of lowering toxicity by reducing the formation of a toxic metabolite (page 2, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compound of ‘713 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., and Gribble et a. because ‘713 teaches the corresponding mitragynine-type composition comprising the non-deuterated compound and an excipient, Gassaway et al. teach that mitragynine may be deuterated and teach that hydrogen notation in the disclosed structures may be isotopes of hydrogen, which includes deuterium, Takayama et al. teach the first total synthesis of mitragynine using NaBH4, and Gribble et al. teach selective, single-position incorporation of deuterium at a corresponding position in a related indolo[2,3-a]quinolizine scaffold using NaBD4/CF3CO2H, and report production of deuterated compound 4 in 66% yield. Takayama et al. teach the total synthesis of mitragynine and disclose a reduction step utilizing NaBH4 that introduces the hydrogen atom to the claimed R6 position. Gribble et al. teach that NaBD4 may be substituted for NaBH4 in a related indolo[2,3-a]quinolizine scaffold to produce the corresponding deuterated analog by incorporation of deuterium at the hydride-addition position. Therefore, one of ordinary skill in the art would have recognized that substitution of NaBD4 for NaBH4 in the Takayama synthesis would predictably introduce deuterium at the position corresponding to the claimed R6 position while producing the corresponding deuterium-enriched mitragynine analog as taught by Gassaway et al. One of ordinary skill in the art would have been motivated to substitute NaBD4 for NaBH4 in the Takayama synthesis in order to prepare a deuterium-enriched mitragynine analog and obtain the known benefits associated with deuterium substitution taught by Timmins, including altered metabolism and reduced formation of undesirable metabolites. One of ordinary skill in the art would have had a reasonable expectation of success to modify the compound of ‘713 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., Gribble et al., and Timmins because Gribble et al. demonstrate successful incorporation of deuterium through the analogous reagent substitution in a closely related indoloquinolizine system, and the substitution of NaBD4 for NaBH4 is a known and predictable technique for obtaining the corresponding deuterated product.
Moreover, the claimed deuterium-enriched limitation is also satisfied because intentional incorporation of deuterium using NaBD4/ acid would produce deuterium at the target hydrogen-bearing site at a level above natural abundance, which is above 0.0156%.
Regarding claim 11, Gassaway et al. further teach that any notation of hydrogen in the disclosed structures is intended to represent all isotopes of hydrogen, including deuterium, and teach compounds enriched in deuterium at hydrogen sites. Once the R6-deuterium-enriched compound is rendered obvious as discussed above, therefore, it would have been obvious to further enrich one or more additional hydrogen-bearing positions with deuterium, including H1 – H11, R7, R8, and/or R9 because Gassaway et al. teach deuterium substitution at hydrogen-bearing positions of the mitragynine-type scaffold.
Regarding claim 19, Gribble et al. teach preparation of a deuterated analog using NaBD4/CF3CO2H and reports that the deuterated compound 4 is obtained in 66% yield. The reported 66% yield shows that Gribble et al. successfully prepared and isolated the deuterated product in substantial amount. Although yield is not the same as percent deuterium incorporation, the use of NaBD4 as a deuterium source and identification of the product as a deuterated compound would have taught one of ordinary skill in the art that deuterium is intentionally incorporated at the target position above natural abundance. Because claim 19 recites a broad deuterium level of 0.02% to 100%, the claimed range encompasses such intentionally deuterium-enriched products.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 7, and 9 of U.S. Patent No. 11912707B2 in view of Gassaway et al. (WO2017165738A1), Takayama et al. (Tetrahedron Letters, 1995, Vol. 36, Issue 51, page 9337 – 9340, Reference included with PTO-892), Gribble et al. (Heterocycles, 1981, Vol. 16, Issue 12, Reference included with PTO-892), and Timmins (Expert Opinion on Therapeutic Patents, 2014, Vol. 24, Issue 10, Reference included with PTO-892).
c. ‘707B2 teaches a compound having the structure (claim 1):
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‘707B2 further teaches a compound having the structure (claims 2 – 4):
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The compound is deuterium enriched (claim 5). ‘707B2 also discloses a pharmaceutically composition comprising the compound and a pharmaceutically acceptable carrier (claim 7).
However, ‘707B2 does not teach the compound with deuterium at the R6 position of the claimed compound. ‘707B2 does not teach the pharmaceutical composition comprising NMDA receptor antagonist, such as ibogaine or noribogaine.
Gassaway et al. teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
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wherein the pharmaceutical composition is enriched in the compound that contains deuterium in place of -H (page 3, lines 20 – 25; page 4, lines 1 – 16). A compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% over its non-enriched counterpart (page 45, line 37; page 46, lines 1 – 2). In some embodiments, the compound is (page 6, line 11):
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Gassaway et al. also discloses that any notation of a hydrogen in structure throughout, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H (D), or 3H (T) (page 45, lines 22 – 25). Moreover, Gassaway et al. teaches a pharmaceutical composition in unit dosage form, which comprises (i) an amount of any compound recited and (ii) an amount of an NMDA receptor antagonist (page 43; lines 4 – 9), wherein the NMDA receptor antagonist is ibogaine or noribogaine (page 37, lines 26 – 27).
Takayama et al. teach the first total synthesis of mitragynine (Title), wherein the synthetic route of mitragynine is (page 9339, Schemes 2 and 3):
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which illustrates that NaBH4 is used in the process for the reduction of double bond. The resulting intermediate contains the H at the claimed R6 position. Thus, Takayama et al. teach that NaBH4 is a conventional reagent used in the synthesis of mitragynine for the reduction of the indole double bond.
Gribble et al. teach stereoselective reduction of an indolo[2,3-a]quinolizine compound using sodium borohydride in trifluoroacetic acid (Title).Gribble further teach preparing deuterated derivatives using NaBD4 om CF3CO2H (page 2110):
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In particular, Gribble et al. teach that treating the indolo[2,3-a]quinolizine compound with NaBD4/CF3CO2H produces deuterated compound 4 in 66% yield (page 2110, para. 2), wherein deuterium is incorporated at a specific ring position. Thus, Gribble et al. teach that selective, single-position deuterium incorporation in a related indoloquinolizine scaffold is known and successfully achieved using NaBD4/CF3CO2H.
Finally, Timmins teaches that replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in metabolism and thereby cause beneficial changes in the biological effects of drug, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing. Such replacement may also have the effect of lowering toxicity by reducing the formation of a toxic metabolite (page 2, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compound of ‘707B2 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., and Gribble et a. because ‘707B2 teaches the corresponding mitragynine-type composition comprising the non-deuterated compound and an excipient, Gassaway et al. teach that mitragynine may be deuterated and teach that hydrogen notation in the disclosed structures may be isotopes of hydrogen, which includes deuterium, Takayama et al. teach the first total synthesis of mitragynine using NaBH4, and Gribble et al. teach selective, single-position incorporation of deuterium at a corresponding position in a related indolo[2,3-a]quinolizine scaffold using NaBD4/CF3CO2H, and report production of deuterated compound 4 in 66% yield. Takayama et al. teach the total synthesis of mitragynine and disclose a reduction step utilizing NaBH4 that introduces the hydrogen atom to the claimed R6 position. Gribble et al. teach that NaBD4 may be substituted for NaBH4 in a related indolo[2,3-a]quinolizine scaffold to produce the corresponding deuterated analog by incorporation of deuterium at the hydride-addition position. Therefore, one of ordinary skill in the art would have recognized that substitution of NaBD4 for NaBH4 in the Takayama synthesis would predictably introduce deuterium at the position corresponding to the claimed R6 position while producing the corresponding deuterium-enriched mitragynine analog as taught by Gassaway et al. One of ordinary skill in the art would have been motivated to substitute NaBD4 for NaBH4 in the Takayama synthesis in order to prepare a deuterium-enriched mitragynine analog and obtain the known benefits associated with deuterium substitution taught by Timmins, including altered metabolism and reduced formation of undesirable metabolites. One of ordinary skill in the art would have had a reasonable expectation of success to modify the compound of ‘707B2 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., Gribble et al., and Timmins because Gribble et al. demonstrate successful incorporation of deuterium through the analogous reagent substitution in a closely related indoloquinolizine system, and the substitution of NaBD4 for NaBH4 is a known and predictable technique for obtaining the corresponding deuterated product.
Moreover, the claimed deuterium-enriched limitation is also satisfied because intentional incorporation of deuterium using NaBD4/ acid would produce deuterium at the target hydrogen-bearing site at a level above natural abundance, which is above 0.0156%.
Regarding claim 11, Gassaway et al. further teach that any notation of hydrogen in the disclosed structures is intended to represent all isotopes of hydrogen, including deuterium, and teach compounds enriched in deuterium at hydrogen sites. Once the R6-deuterium-enriched compound is rendered obvious as discussed above, therefore, it would have been obvious to further enrich one or more additional hydrogen-bearing positions with deuterium, including H1 – H11, R7, R8, and/or R9 because Gassaway et al. teach deuterium substitution at hydrogen-bearing positions of the mitragynine-type scaffold.
Regarding claim 19, Gribble et al. teach preparation of a deuterated analog using NaBD4/CF3CO2H and reports that the deuterated compound 4 is obtained in 66% yield. The reported 66% yield shows that Gribble et al. successfully prepared and isolated the deuterated product in substantial amount. Although yield is not the same as percent deuterium incorporation, the use of NaBD4 as a deuterium source and identification of the product as a deuterated compound would have taught one of ordinary skill in the art that deuterium is intentionally incorporated at the target position above natural abundance. Because claim 19 recites a broad deuterium level of 0.02% to 100%, the claimed range encompasses such intentionally deuterium-enriched products.
Claims 1 – 2, 4 – 5, 11, 16, 19, 22 – 24, 27 – 30, and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4, 6 – 11, and 16 – 22 of copending Application No. 18/437,646 in view of Gassaway et al. (WO2017165738A1), Takayama et al. (Tetrahedron Letters, 1995, Vol. 36, Issue 51, page 9337 – 9340, Reference included with PTO-892), Gribble et al. (Heterocycles, 1981, Vol. 16, Issue 12, Reference included with PTO-892), and Timmins (Expert Opinion on Therapeutic Patents, 2014, Vol. 24, Issue 10, Reference included with PTO-892).
d. ‘646 teaches a compound having the structure (claims 1 and 16):
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‘646 further teaches the compound having the structure (claims 2 – 4 and 16 – 18):
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The compound taught is deuterium enriched at the positions of R2, R3, and R4 (claims 6 – 7 and 19 - 20). ‘646 further teaches a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier (claim 8). The pharmaceutical composition is enriched in the compound that contains deuterium in place of -H (claims 9 and 16), wherein the isotopic purity at each position of the R2, R3, and R4 methyl group is 95% or greater in deuterium (claim 10 – 11 and 21 – 22).
However, ‘646 does not teach the compound with deuterium at the R6 position of the claimed compound. ‘646 does not teach the pharmaceutical composition comprising NMDA receptor antagonist, such as ibogaine or noribogaine.
Gassaway et al. teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
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wherein the pharmaceutical composition is enriched in the compound that contains deuterium in place of -H (page 3, lines 20 – 25; page 4, lines 1 – 16). A compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% over its non-enriched counterpart (page 45, line 37; page 46, lines 1 – 2). In some embodiments, the compound is (page 6, line 11):
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Gassaway et al. also discloses that any notation of a hydrogen in structure throughout, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H (D), or 3H (T) (page 45, lines 22 – 25). Moreover, Gassaway et al. teaches a pharmaceutical composition in unit dosage form, which comprises (i) an amount of any compound recited and (ii) an amount of an NMDA receptor antagonist (page 43; lines 4 – 9), wherein the NMDA receptor antagonist is ibogaine or noribogaine (page 37, lines 26 – 27).
Takayama et al. teach the first total synthesis of mitragynine (Title), wherein the synthetic route of mitragynine is (page 9339, Schemes 2 and 3):
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which illustrates that NaBH4 is used in the process for the reduction of double bond. The resulting intermediate contains the H at the claimed R6 position. Thus, Takayama et al. teach that NaBH4 is a conventional reagent used in the synthesis of mitragynine for the reduction of the indole double bond.
Gribble et al. teach stereoselective reduction of an indolo[2,3-a]quinolizine compound using sodium borohydride in trifluoroacetic acid (Title).Gribble further teach preparing deuterated derivatives using NaBD4 om CF3CO2H (page 2110):
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In particular, Gribble et al. teach that treating the indolo[2,3-a]quinolizine compound with NaBD4/CF3CO2H produces deuterated compound 4 in 66% yield (page 2110, para. 2), wherein deuterium is incorporated at a specific ring position. Thus, Gribble et al. teach that selective, single-position deuterium incorporation in a related indoloquinolizine scaffold is known and successfully achieved using NaBD4/CF3CO2H.
Finally, Timmins teaches that replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in metabolism and thereby cause beneficial changes in the biological effects of drug, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing. Such replacement may also have the effect of lowering toxicity by reducing the formation of a toxic metabolite (page 2, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compound of ‘646 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., and Gribble et a. because ‘646 teaches the corresponding mitragynine-type composition comprising the non-deuterated compound and an excipient, Gassaway et al. teach that mitragynine may be deuterated and teach that hydrogen notation in the disclosed structures may be isotopes of hydrogen, which includes deuterium, Takayama et al. teach the first total synthesis of mitragynine using NaBH4, and Gribble et al. teach selective, single-position incorporation of deuterium at a corresponding position in a related indolo[2,3-a]quinolizine scaffold using NaBD4/CF3CO2H, and report production of deuterated compound 4 in 66% yield. Takayama et al. teach the total synthesis of mitragynine and disclose a reduction step utilizing NaBH4 that introduces the hydrogen atom to the claimed R6 position. Gribble et al. teach that NaBD4 may be substituted for NaBH4 in a related indolo[2,3-a]quinolizine scaffold to produce the corresponding deuterated analog by incorporation of deuterium at the hydride-addition position. Therefore, one of ordinary skill in the art would have recognized that substitution of NaBD4 for NaBH4 in the Takayama synthesis would predictably introduce deuterium at the position corresponding to the claimed R6 position while producing the corresponding deuterium-enriched mitragynine analog as taught by Gassaway et al. One of ordinary skill in the art would have been motivated to substitute NaBD4 for NaBH4 in the Takayama synthesis in order to prepare a deuterium-enriched mitragynine analog and obtain the known benefits associated with deuterium substitution taught by Timmins, including altered metabolism and reduced formation of undesirable metabolites. One of ordinary skill in the art would have had a reasonable expectation of success to modify the compound of ‘646 by replacing the hydrogen at the claimed R6 position with deuterium in view of Gassaway et al., Takayama et al., Gribble et al., and Timmins because Gribble et al. demonstrate successful incorporation of deuterium through the analogous reagent substitution in a closely related indoloquinolizine system, and the substitution of NaBD4 for NaBH4 is a known and predictable technique for obtaining the corresponding deuterated product.
Moreover, the claimed deuterium-enriched limitation is also satisfied because intentional incorporation of deuterium using NaBD4/ acid would produce deuterium at the target hydrogen-bearing site at a level above natural abundance, which is above 0.0156%.
Regarding claim 11, Gassaway et al. further teach that any notation of hydrogen in the disclosed structures is intended to represent all isotopes of hydrogen, including deuterium, and teach compounds enriched in deuterium at hydrogen sites. Once the R6-deuterium-enriched compound is rendered obvious as discussed above, therefore, it would have been obvious to further enrich one or more additional hydrogen-bearing positions with deuterium, including H1 – H11, R7, R8, and/or R9 because Gassaway et al. teach deuterium substitution at hydrogen-bearing positions of the mitragynine-type scaffold.
Regarding claim 19, Gribble et al. teach preparation of a deuterated analog using NaBD4/CF3CO2H and reports that the deuterated compound 4 is obtained in 66% yield. The reported 66% yield shows that Gribble et al. successfully prepared and isolated the deuterated product in substantial amount. Although yield is not the same as percent deuterium incorporation, the use of NaBD4 as a deuterium source and identification of the product as a deuterated compound would have taught one of ordinary skill in the art that deuterium is intentionally incorporated at the target position above natural abundance. Because claim 19 recites a broad deuterium level of 0.02% to 100%, the claimed range encompasses such intentionally deuterium-enriched products.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2, 4 – 5, 16, 19, 22, 24, 27, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 7, and 9 of U.S. Patent No. 10961244B2 in view of Timmins (Expert Opinion on Therapeutic Patents, 2014, Vol. 24, Issue 10, Reference included with PTO-892), Takayama et al. (Tetrahedron Letters, 1995, Vol. 36, Issue 51, page 9337 – 9340, Reference included with PTO-892), and Gribble et al. (Heterocycles, 1981, Vol. 16, Issue 12, Reference included with PTO-892).
e. ‘244B2 teaches a process for producing a compound having the structure (claim 1):
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In one embodiment, the compound produced has the structure (claim 7):
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However, ‘244B2 does not teach the compound with deuterium at the R6 position of the claimed compound.
Timmins teaches that replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in metabolism and thereby cause beneficial changes in the biological effects of drug, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing. Such replacement may also have the effect of lowering toxicity by reducing the formation of a toxic metabolite (page 2, para. 1).
Takayama et al. teach the first total synthesis of mitragynine (Title), wherein the synthetic route of mitragynine is (page 9339, Schemes 2 and 3):
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which illustrates that NaBH4 is used in the process for the reduction of double bond. The resulting intermediate contains the H at the claimed R6 position. Thus, Takayama et al. teach that NaBH4 is a conventional reagent used in the synthesis of mitragynine for the reduction of the indole double bond.
Gribble et al. teach stereoselective reduction of an indolo[2,3-a]quinolizine compound using sodium borohydride in trifluoroacetic acid (Title).Gribble further teach preparing deuterated derivatives using NaBD4 om CF3CO2H (page 2110):
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In particular, Gribble et al. teach that treating the indolo[2,3-a]quinolizine compound with NaBD4/CF3CO2H produces deuterated compound 4 in 66% yield (page 2110, para. 2), wherein deuterium is incorporated at a specific ring position. Thus, Gribble et al. teach that selective, single-position deuterium incorporation in a related indoloquinolizine scaffold is known and successfully achieved using NaBD4/CF3CO2H.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compound produced by the process of ‘244B2 by replacing the hydrogen at the claimed R6 position with deuterium in view of Timmins, Takayama et al., and Gribble et a. because ‘244B2 teaches producing the corresponding non-deuterated mitragynine-type compound and Timmins teaches that replacement of hydrogen with deuterium in drug molecules may alter metabolism and may lower toxicity by reducing formation of toxic metabolites. Thus, Timmins provides motivation to prepare a deuterated analog of the mitragynine-type compound produced by ‘244B2. Takayama et al. teach the total synthesis of mitragynine and disclose a NaBH4 reduction step that introduces hydrogen at the position corresponding to the claimed R6 position. Gribble et al. teach that NaBD4 may be used in place of NaBH4 in a related indolo[2,3-a]quinolizine scaffold to prepare a deuterated analog, and further teach production of deuterated compound 4 in 66% yield. Therefore, one of ordinary skill in the art would have been motivated to substitute NaBD4 for NaBH4 in the known mitragynine synthetic route to obtain the corresponding R6-deuterium-enriched compound. One of ordinary skill in the art would have had a reasonable expectation of success to modify the compound produced by the process of ‘244B2 by replacing the hydrogen at the claimed R6 position with deuterium in view of Timmins, Takayama et al., and Gribble et a. because Takayama et al. show that NaBH4 reduction is operative in mitragynine synthesis and Gribble et al. show that the corresponding NaBD4 reduction successfully incorporates deuterium at the hydride-addition position in a related scaffold. The claimed deuterium-enrichment level is also met or rendered obvious because the intentional incorporation of deuterium using NaBD4/ acid would produce deuterium at the target hydrogen-bearing site at a level above natural abundance, which is above 0.0156%.
Regarding claim 19, Gribble et al. teach preparation of a deuterated analog using NaBD4/CF3CO2H and reports that the deuterated compound 4 is obtained in 66% yield. The reported 66% yield shows that Gribble et al. successfully prepared and isolated the deuterated product in substantial amount. Although yield is not the same as percent deuterium incorporation, the use of NaBD4 as a deuterium source and identification of the product as a deuterated compound would have taught one of ordinary skill in the art that deuterium is intentionally incorporated at the target position above natural abundance. Because claim 19 recites a broad deuterium level of 0.02% to 100%, the claimed range encompasses such intentionally deuterium-enriched products.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed April 8, 2026, have been fully considered and are not found to be persuasive.
Regarding the rejection, Applicant requests that the rejections be held in abeyance until otherwise allowable subject matter has been identified. As no allowable subject matter has been identified, the double patenting rejections are maintained.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the modified / 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 HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached Monday - Thursday 7:30 - 17:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SCARLETT GOON can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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