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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/6/2025 has been entered.
Status of 17/626,349
Claims 1-29 and 31-51 are currently pending.
Priority
Instant application 17/626,349, filed 1/11/2022, claims priority as follows:
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Receipt of the certified copy of the foreign priority application is acknowledged.
Information Disclosure Statement
All references from the IDS’s filed on 4/11/2022, 7/12/2023, 7/25/2024, and 9/5/2024 have been considered unless marked with a strikethrough.
Response to Arguments/Amendments
The amendment filed 10/6/2025 has been entered. Applicant has amended claims 25-27, and cancelled claim 30.
In the Final dated 7/9/2025, claims 25-28, 30-39, and 41-42 were rejected under 35 U.S.C. 103. In response, Applicant has cancelled claim 30, and amended claims 25-27 to further narrow the scope of the compounds of the claims. Applicant argues that the claimed recitations are neither fully taught nor reasonably suggested by the cited art, alone or in combination as asserted. Specifically, Applicant argues the references Watanabe and Shindo address different problems with different substrates, neither documents suggest combining the approaches for dual functionality, and Shindo teaches away from the art by the presence of the over-reduced byproduct. Applicants arguments have been considered, but are not persuasive because though Watanabe and Shindo are different substrates, one of ordinary skill would be further motivated to improve the yield of the substrates of Watanabe, and would be motivated to continue to explore reaction conditions to lower the step count of the synthesis to arrive at dual functionality. Optimizing reactions and telescoping syntheses are common practice in organic chemistry. Additionally, the Examiner argues Shindo does not in fact teach away from the instant disclosure because Shindo does teach that the production of the over-reduced byproduct, compound 3, can be harnessed by manipulating the reaction conditions (i.e. changing the lithium equivalency and lowering the reaction temperature). Quantitative yield is not expected to one of ordinary skill in the art, and the instant specification supports this argument, as the yield of Example 3 of the instant disclosure is 47%.
The Examiner notes an alternative interpretation of the R0 limitation than that of the Non-Final and Final rejections dated 2/7/2025 and 7/9/2025, respectively, and recognizes that the N-Bn of the compounds of Watanabe corresponds to N-R0 of the compound of instant Formula (IV). In order to arrive at the compound of instant Formula (V) in the method of the instant claims, the benzyl group of Watanabe needs to be converted to a hydrogen. The benzyl deprotection of a heterocycle containing a single nitrogen with lithium and ethylenediamine is known in the art, and thus one of ordinary skill would be motivated to apply the knowledge to because the reactions are mechanistically identical regardless of the skeleton. The rejection has been updated to reflect this change. See the 103 rejection below.
In the Non-Final dated 2/7/2025 and the Final dated 7/9/2025, claims 25-28, 30-39, and 41-42 were rejected on the grounds of nonstatutory double patenting. In response, Applicant argues that the structure of the target compound is different than that of the instant claims, and the arguments are considered persuasive. The product (compound of Formula (II)) of the ‘830 Patent does differ from the product (compound of instant Formula (V)) of the instant claims by substituent at the 3-position of the aromatic ring. In the compound of the ‘830 Patent, it remains a methoxy group, but is converted to a free alcohol in the compound of the instant claims. This argument overcomes the rejection, and the rejection is withdrawn.
Election/Restriction
Applicants’ election of Group III (claims 25-44), drawn to a method of producing compounds of formula (V) from compounds of formula (VI) with lithium metal and an amine, in the reply filed 1/13/2025 is acknowledged. Furthermore, Applicant’s election of Species XXXXI through Species XXXXXX, a method for producing compounds represented by General Formula (V), where R1 is a cyclopropylmethyl group, D1 is CH2, B1 is a methylene group, A1 is CH, X0 is a carbon atom, and k is 1:
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is also acknowledged. R0 is not defined in the Applicant response filed 1/13/2025; however, instant claim 25 allows R0 to be defined as a hydrogen atom, an aralkyl group, an alkenyl group, or a silyl protecting group.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched and applicable prior art was identified in the Non-Final dated 2/7/2025. The rejection has been maintained in the Final dated 7/9/2025, and is maintained in the present Office Action. Claims 25-28, 31-39, and 41-42 read on the elected species. Claims 1-24, 29, 40, and 43-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species/groups, there being no allowable generic or linking claim. Because this Office Action contains solely maintained rejections, newly added claim 51 is not added to the rejections and is therefore withdrawn.
Claim Objections
Claim 25 is objected to for a minor informality. Claim 25 recites, “wherein R1 have a meaning”, but should recite, “wherein R1 has a meaning”. 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.
Claims 25-28, 31-39, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Watanabe (Watanabe, Y. et. al. Bioorg. Med. Chem. Lett. 2017, 27, 3495-3498., cited in the IDS of 4/11/2022) in view of Shindo (Shindo, T. et. al. Synthesis. 2004, 5, 692-700., cited in the IDS of 7/25/2024), Angle (Angle, S. R. and Henry, R. M. J. Org. Chem. 1998, 63, 7490-7497), and Rabideau (Rabideau, P.W. and Marcinow, Z. (2004) The Birch Reduction of Aromatic Compounds. In Organic Reactions, (Ed.)).
The instant claims are drawn to a method of producing a morphinan derivative:
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From a compound represented by General Formula (IV):
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where R1 is a cyclopropylmethyl group, D1 is CH2, B1 is a methylene group, A1 is CH, X0 is a carbon atom, k is 1, R17 is a C1-10 alkyl group, R16 is a C6-C10 aryl group, and R0 is a hydrogen atom, an aralkyl group, an alkenyl group, or a silyl protecting group. The reaction conditions recited in the instant claims to perform this transformation in one step include lithium metal, an amine, and an organic solvent.
Determining the scope and contents of the prior art
The reference Watanabe teaches the design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton (abstract). Specifically, Watanabe teaches the dehydroxylation of a phenyl ether at the 4-position of Compound 6 with sodium silica gel stage I, ethylenediamine, and tetrahydrofuran (THF) at room temperature (page 3946, Scheme 1):
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Compound 6, the starting material for the reaction of Watanabe, reads on instant General Formula (IV),
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where R1 is a cyclopropylmethyl group, D1 is CH2, B1 is a methylene group, A1 is CH, X0 is a carbon atom, k is 1, R17 is a methyl group, R16 is a phenyl group, and R0 is a benzyl group.
Furthermore, ethylenediamine is a compound of instant General Formula (III), of claim 36:
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Where Rh, Rg, and Ri are all H and m is 1.
The reference Shindo teaches the scope and limitations of lithium-ethylenediamine-THF-mediated reductive bond cleavage at the α-position of aromatic rings (abstract). Shindo teaches the deprotection of methyl ethers with lithium and ethylenediamine in THF at room temperature (page 692, Scheme 2):
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Further, Shindo teaches the dehydroxylation of aryl rings with the lithium metal, ethylenediamine, and THF reaction conditions as Compound 3. Compound 3 was produced in the presence of excess lithium and excess ethylenediamine as an over-reduced byproduct (page 692, col 2).
With respect to claims 25, 32, and 37, Shindo teaches lithium equivalences ranging from 2.3 to 11 (page 692, Table 1).
With respect to claims 41 and 42, Shindo teaches the reaction screening entries at room temperature and -10°C (page 692, Table 1 and page 696, col 2, second paragraph).
The reference Angle teaches the synthesis of (—)-methyl palustramate, and specifically teaches the benzyl deprotection of the nitrogen in the ring of compound 21 with lithium, ethylenediamine, and triethylamine in THF (page 7492, Scheme 5):
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.
The reference Rabideau is a review of the Birch reduction reaction, and teaches that the metals most frequently employed for Birch reductions include sodium and lithium (page 39, paragraph 3). Rabideau further discloses lithium is most reactive and therefore is often the metal of choice for Birch reductions.
Ascertaining the differences between the prior art and the claims at issue
The reference Watanabe fails to teach the presence of lithium metal in the reaction, the deprotection of the methyl ether at the 3-position of the aromatic ring, and the benzyl deprotection of the compound of General Formula (IV).
Shindo fails to teach the deprotection of the methyl ether on the fully elaborated elected species of the instant claims, the adjacent dehydroxylation at the 4-position of the aryl ether in the same step.
Angle fails to teach the benzyl deprotection on the fully elaborated elected species of the instant claims, the deprotection of the methyl ether at the 3-position, and the adjacent dehydroxylation at the of the compounds of General Formula (IV).
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the progress of reaction development on compounds in the morphinan family. Said artisan has also reviewed the problems in the art as regards to progress of reaction development on compounds in the morphinan family and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (B), it would have been prima facie obvious to substitute the sodium silica gel stage I of Watanabe for the lithium metal of Shindo and Angle to arrive at the instant claims because sodium and lithium are Group I metals and are expected to have similar properties in the reduction reaction, as taught by Rabideau. In light of the teachings of Shindo, Angle, and Rabideau, a skilled artisan would be motivated before the effective filing date to substitute the sodium silica gel stage I taught by Watanabe with the lithium metal to perform the deprotection of the methyl ether at the 3-position, the dehydroxylation of the aryl ether at the 4-position of the aromatic ring, and the benzyl deprotection of the pyrrolidine. Further, a skilled artisan would have reasonably predicted that such a substitution would result in successful dehydroxylation of the aryl ether at the 4-position, deprotection of the methyl ether at the 3-position, and benzyl deprotection of the pyrrolidine in the same step in light of the teachings of Watanabe, Shindo, Angle, and Rabideau.
With respect to claims 37 and 41-42, drawn to equivalents of lithium metal in the reaction and the temperature of the reaction, it would have been prima facie obvious to one having ordinary skill in the art to arrive at the instant claims because according to MPEP § 2144.05, differences in reagent equivalencies and reaction temperature do not support novelty showing an absence of criticality. It would be well within the skill of a chemist to perform routine optimization to arrive at a claimed reagent equivalency and reaction temperature. The artisan would have been expected before the effective filing date of the claimed invention to use the teachings of Watanabe, Shindo, Angle, and Rabideau to change the reagent equivalency and reaction temperature in the reaction to yield a predictable result.
Conclusion
Claims 25-28, 31-39, and 41-42 are rejected. Claims 1-24, 29, 40, and 43-51 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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