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
This office action is in reply to the application 18/844,216 filed on 05 September 2024, 371 of PCT/US2023/014595 filed on 06 March 2023, with PRO 63/316,972 filed 05 March 2022. Claims 1, 3-10, 12-14, 16-18 and 20 are amended. Currently, claims 1-21 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 05 September 2024 and 05 March 2025 were filed on and after the mailing date of the application on 05 September 2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figures 1-4 are not well resolved (i.e. too blurry). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 20 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Misakyan et al. (Structure-activity relationships of withanolides as antiproliferative agents for multiple myeloma: comparison of activity in 2D models and a 3D coculture model, J. Nat. Prod. 2021, 84, 2321-2335).
Misakyan discloses structure 43 (pg. 2323, table 2), illustrated below, synthesized from Withanolide D using catalytic hydrogenation (hydrogen, palladium over activated carbon in ethanol) (pg. 2324, col. 2):
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As such, Misakyan anticipates claim 20.
Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ambrus et al. (Microbial transformation of β-sitosterol and stigmasterol into 26-oxygenated derivatives, Steroids 1995, 60, 621-625), .
Ambrus discloses 6β-hydroxy-4,22-stigmastadien-3-one (compound VII), pg. 624 – Fig. 2, which reads on WC-1-297-1, illustrated below:
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.
Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Foley et al. (Synthesis and characterization of stigmasterol oxidation products, J. Agric. Food Chem. 2010, 58, 1165-1173).
Foley discloses structure 6, pg. 1170 – Fig. 3, which reads on WC-1-289-1, illustrated below:
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.
Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Komura et al. (FeCl3•6H2O as a versatile catalyst for the esterification of steroid alcohols with fatty acids, Synthesis 2008, 21, 3407-3410).
Komura discloses stigmasterol, pg. 3407 – Fig. 1, which reads on WC-1-195-SM, illustrated below:
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Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cui et al. (Synthesis and evaluation of some steroidal oximes as cytotoxic agents: structure/activity studies (I), Steroids 2009, 74, 62-72).
Cui discloses structure 5b, pg. 64 – scheme 2, which reads on WC-1-181-1, illustrated below:
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As such, claim 21 is anticipated.
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 non-obviousness.
Claims 1, 3, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Kovganko et al. (Advances in the chemical synthesis of withanolides, Chemistry of Natural Compounds 1997, 33, 2, 133-145; entered into the IDS on 05 September 2024) and Liffert et al. (Withanolide A: synthesis and structural requirements for neurite outgrowth, Chem. Sci. 2013, 4, 2851) in view of Perez et al. (Synthesis and structure of titanium alkoxide complexes with bulky ligands derived from natural products asymmetric epoxidation of cinnamyl alcohol, J. Organometallic Chem. 2003, 679, 220-228).
Kovganoko discloses a synthetic route to Withanolide D, describing the epoxidation of the unprotected alkene intermediate 116 to Withanolide utilizing mCPBA, illustrated below (pg. 142):
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Similarly, Liffert discloses a synthetic route to Withanolide A, including an intermediate step which describes the epoxidation of siloxy-protected alcohol alkene 13 to give epoxy 14 using mCPBA, illustrated below (pg. 2853, scheme 2):
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They do not, however, teach epoxidation through a titanium alkoxide catalyst and tert-butyl hydrogen peroxide.
Perez rectifies this deficiency by teaching epoxidation via titanium isopropoxide and tert-butyl hydrogen peroxide to form epoxides from allylic alcohols in the Sharpless epoxidation manner (pg. 224, table 1):
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While the synthetic routes and reagents to Withanolide A and D do not read upon the synthetic steps claimed, electron-rich olefin epoxidations are a well-known class of chemical transformations within the organic synthetic field. The prior art demonstrates this by utilizing mCPBA, a commonly used reagent, for the epoxidation of the electron-rich olefin over the more electron-deficient α-β unsaturated enone. Sharpless epoxidation is also well-known and widely utilized, as demonstrated by Perez back in 2003. As such, while the application of Sharpless epoxidation to the precursors of Withanolide A and D may be novel, it seems to the Examiner that the person of ordinary skill in the art could have expected to obtain the same result merely by screening known routes of epoxidation with a reasonable chance of success without significant experimental burden. A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art.
As such, it would have been prima facie obvious, to the person of ordinary skill in the art, before the effective filing date, to screen epoxidation conditions, including the well-known Sharpless epoxidation, to arrive at Withanolide A and D as the prior art demonstrates that the target olefin can readily be converted into the epoxide by mCPBA.
Regarding the limitations of claim 3, synthesizing Withanolide A from Withacoagin utilizing titanium alkoxide and tert-butyl hydroperoxide, are met by Liffert and Perez.
With respect to the limitation of claim 17, Withanolide D prepared by a process of claim 1, are met as stated in paragraphs 13-17 above.
Concerning the limitation of claim 18, Withanolide A prepared by a process of claim 3, are met as stated in paragraph 19 above.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Atta-ur-Rahman et al. (Withanolides from Withania coagulans, Phytochemistry 2003, 63, 387-390) in view of Stephenson et al. (Mechanism of allylic hydroxylation by selenium dioxide, J. Org. Chem. 1979, 44, 25, 4683-4689).
Atta-ur-Rahman discloses 20β-hydroxy-1-oxo-(22R)-with a-2,5,24-trienolide, isolated from Withania, a shrub existing in an area ranging from the east Mediterranean to south Asia (pg. 388, structure 1).
They do not, however, teach hydroxylating the enolide to give the compound of formula I.
Stephenson overcomes this obstacle by teaching a well-known method of hydroxylating an allylic position via selenium oxide. As the methylene of the enone ring is engaged allylic to the adjacent olefins, allylic oxidation by selenium dioxide described by Stephenson as a well-known means to introduce oxygen to a hydrocarbon molecule, while novel in its instant application, appears to an obvious result to a person of ordinary skill in the art.
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to perform hydroxylation of the structure of formula II via Sharpless hydroxylation to obtain the structure of formula I with a reasonable chance of success utilizing well-known techniques in the organic synthetic field.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Atta-ur-Rahman et al. in view of Liffert et al.
Atta-ur-Rahman discloses 20β-hydroxy-1-oxo-(22R)-with a-2,5,24-trienolide (pg. 388, structure 1).
They do not, however, teach a protecting group and removal of that protecting group on the chiral alcohol.
Liffert fixes this paucity by demonstrating in the synthesis of Withanolide A the use of a hydroxy protecting group, methoxymethyl ether, and its subsequent removal after epoxidation under acidic conditions (pg. 2853, scheme 2):
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As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of a well-known hydroxy protecting group such as methoxymethyl ether, and standard reaction conditions to remove the protecting group, such as under acidic conditions, as demonstrated by Liffert using structurally similar compounds.
With regards to the limitations of claim 6, preparing the compound of formula III by a process comprising treating a compound of formula IV with an oxidant to provide the compound of formula III, are met as Liffert teaches oxidizing allylic alcohol 9 to enone 10 through the treatment of tetrapropylammonium perruthenate as illustrated below (pg. 2852, scheme 1):
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Claims 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Atta-ur-Rahman and Liffert as applied to claims 5-6 above, and further in view of Khripach et al. (Synthesis and radical oxidation of steroidal 1-oxo-5α-alcohols, ARKIVOC 2008 ix, 20-28).
Atta-ur-Rahman and Liffert establish the basis of obviousness for the preparation of a compound of formula IV.
They do not, however, describe arriving at that compound via the route of a 2-nitrophenyl selenide intermediate.
Khripach overcomes this deficiency by teaching the use of hydrogen peroxide to treat structurally similar steroid 8 to yield alcohol 9 (pg. 22, scheme 2):
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As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of an oxidant such as hydrogen peroxide to obtain alcohol 9 from the 2-nitrophenyl selenide adduct.
With concern to the limitations of claim 8, preparing the compound of formula V by a process of treating a compound of formula VI with 2-nitrophenyl selenocyanate in the presence of a phosphine, are met as Khripach teaches treating alcohol 7 with 2-nitrophenyl selenocyanate and tributylphosphine to yield adduct 8 (pg. 22, scheme 2):
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Regarding the limitations of claim 9, preparing the compound of formula VI by a process comprising treating a compound of formula VII with a compound of formula VIII, are met as Liffert teaches forming structurally relevant 12 from aldehyde 4 using the same intermediate after treatment with LiHMDS (pg. 2853, scheme 2):
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With respect to the limitations of claim 10, preparing the compound of formula VII by a process comprising treating a compound of formula IX under reaction conditions suitable for conversion of the 1,3-dithiolane moiety in formula IX into an aldehyde moiety, are met as Liffert teaches transforming structurally relevant 3 to aldehyde 4 through treatment with N-chlorosuccinimide (pg. 2852, scheme1):
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Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Atta-ur-Rahman, Liffert, and Khripach as applied to claims 7-10 above, and further in view of Takahashi et al. (Practical and facile route to a functional intermediate from stigmasterol for the synthesis of 1α-hydroxyvitamin D5 and related compounds, Heterocycles 2016, 93, 1, 101-114).
Atta-ur-Rahman, Liffert and Khripach, through the synthetic strategies outlined in paragraphs 30 to 37, could reasonably reach a compound of formula IX.
They do not, however, teach realizing a compound of formula IX from a Luche reduction of a compound of formula X.
Takahashi rectifies this by teaching this reduction with a structurally similar and relevant 19 which contains the same functional moieties using cerium trichloride and sodium borohydride to yield compound 20 (pg. 104, scheme 2):
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As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider realizing the alcohol of formula IX from the enone of compound X, using the reduction taught by Takahashi who applies this selective reduction to a structurally similar steroid.
Regarding the limitations of claim 12, preparing the compound of formula X by a process comprising treating a compound of formula XI with an alkoxide base, are met as Takahashi teaches conversion of quinone 18 to enone 19 using tert-butyl alkoxide (pg. 104, scheme 2):
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Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Atta-ur-Rahman, Liffert, Khripach, and Takahashi as applied to claims 11-12 above, and further in view of N-tert-butylbenzenesulfinimdoyl chloride (N-tert-butylbenzenesulfinimdoyl chloride, en.wikipedia.org/wiki/N-tert-Butylbenzenesulfinimidoyl_chloride).
Takahashi teaches the transformation from enone 17 to quinone 18 (pg. 104, scheme 2):
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They do not, however, use N-tert-butylbenzenesulfinimdoyl chloride, instead opting for using oxidizing reagent DDQ.
This is addressed by Wikipedia’s page on N-tert-butylbenzenesulfinimdoyl chloride, who teaches that this is an electrophilic oxidant used in organic synthesis. While its application in the instant claim is novel, it appears obvious to try to the person of ordinary skill in the art, with a small, finite number of oxidizing agents applicable to this known transformation.
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to screen oxidizing reagents to realize this transformation with a reasonable chance of success.
With regards to the limitations of claim 14, preparing the compound of formula XII by a process of treating a compound of formula XIII under suitable reaction conditions for introduction of a protection group PG, are met as Liffert teaches introducing the methoxymethyl ether protecting group on structurally relevant 3 to give aldehyde 4 (pg. 2852, scheme 1):
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With regards to the limitations of claim 15, preparing the compound of formula XIII by a process comprising treating a compound of formula XIV with aluminum isopropoxide, are met as Takahashi teaches the use of aluminium triisopropoxide to transform relevant structure 16 to structure 17 (pg. 104, scheme 2):
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Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Atta-ur-Rahman, Liffert, Khripach, Takahashi and N-tert-butylbenzenesulfinimdoyl chloride as applied to claims 13-15 above, and further in view of Shingate et al. (Stereoselective syntheses of 20-epi cholinic acid derivatives from 16-dehydropregnenolone acetate, Tetrahedron 2007, 5622-5635).
The combined prior art teaches the synthesis of a compound of formula XIV.
They do not, however, teach the addition of the dithiane to the aldehyde.
Shingate addresses this by teaching the addition of dithiane to acetyl 15 after treatment with butyl lithium to yield relevant structure 16 (pg. 5623, scheme 1):
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While Shingate utilizes the silyl-protected analog of the compound of Pregnenlone, the transformation and outcome are for all purposes identical.
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the introduction of the dithiane moiety to Pregnenlone as had been demonstrated by Shingate.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Nittala et al. (Chlorinated withanolides from withania somnifera and acnistus breviflorus, Phytochemistry 1981, 20, 11, 2547-2552) in view of Sabitha et al. (Highly regioselective ring opening of epoxides and aziridines using cerium (III) chloride, Tetrahedron Letters 2001, 42, 3955-3958).
Nittala discloses both Withanolide D (structure 7, pg. 2548) and the epichloro analog 1a (structure 1a, pg. 2548), including its transformation through treatment with 32% aq. HCl solution (pg. 2550, col. 2).
They do not, however, teach forming the epichloro analog using cerium trichloride.
Sabitha addresses this obstacle by teaching the use of cerium trichloride heptahydrate for the regioselective ring opening of epoxides, where the chloride inserts at the more sterically available carbon of the epoxide (pg. 3955, scheme 1).
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the formation of the epichloro analog of Withanolide D as a known structure, via a known route of ring opening as taught by Sabitha with a reasonable expectation of success.
Allowable Subject Matter
Claims 4 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Structures WC-1-297-1, WC-1-289-1, and the last unlabeled structure of claim 21 are allowable subject matter.
Reasons For Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: the hydroxylation rearrangement as described in claim 4 by a photocatalyst followed by reduction, while not completely unknown, does not appear to be an obvious transformation, particularly for this substrate. The structures WC-1-297-1, WC-1-289-1 and the unlabeled structure are not described in the prior art in a 100% embodiment.
Summary
Claims 1-3 and 5-19 are rejected under 35 U.S.C. 103. Claims 20-21 are rejected under 35 U.S.C. 102(a)(1). Claim 4 is objected to as being dependent on a rejected base claim.
Conclusion
Claims 1-3 and 5-21 are rejected. Claim 4 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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