DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-14 are pending.
Priority
Instant application 18/574,513, filed 12/27/2023 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 12/27/2023 and 05/13/2026 have been considered unless marked with a strikethrough.
Response to Amendment
The amendment filed 05/13/2026 has been entered. Claims 1, 3-6, 8-11, 13, and 14 are amended. Claims 15 and 16 have been cancelled.
Claim 8 was previously objected to over a typographical error. In response, Applicant’s amendments to claim 8 have overcome the objection. Therefore, the previous objection is withdrawn.
Claims 1, 3-9, and 11 were rejected under 35 U.S.C. 112(b) as indefinite. In response, Applicant’s amendments to the claims have overcome the objection. Therefore, the previous rejection under section 112(b) is withdrawn.
Claims 15 and 16 were rejected under 35 U.S.C. 112(d). Claims 15 and 16 have been canceled, rendering the rejection moot. Therefore, the previous rejection under section 112(d) is withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
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 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over JAIN (WO 2011106570 A1; 2011; IDS) in view of SHANGHAI (CN108069869A; 2018; IDS)
The disclosure is generally directed to a new process for preparing the nonsteroidal antiandrogen Enzalutamide. The claims are drawn to a process for preparing a compound of formula (I) by coupling formula (II) and formula (III) as represented below:
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Additional claims are drawn to the intermediate compound used in the aforementioned process (claims 10-12); and a process for preparing the intermediate compound (claims 13-14).
Close prior art is JAIN. JAIN discloses (Example 5, para. [0116] on page 46) the coupling of ester fragment A with fragment B (the aryl isothiocyanate of formula (IIIa) in recited by the instant claims) to furnish the thiohydantoin ring of enzalutamide:
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The only difference between JAIN and the claims is that the claims require an “activated” ester, wherein R’’’ in formula (II) is a phenyl ring substituted with NO2 or halide; whereas in JAIN the equivalent R’’’ group is a methyl ester.
However, SHANGHAI teaches (page 15, para. [0135]) a process for preparing apalutamide, which is a thiohydantoin drug structurally analogous to enzalutamide, by coupling a compound of formula II-7 with compound TFP-6:
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Note that compound II-7 comprises a p-nitrophenyl ester group. The intermediate compound II-7 is prepared by condensation of the corresponding carboxylic acid with p-nitrophenol (page 13, para. [0113]):
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Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (G), it would have been prima facie obvious to modify the methyl ester in fragment A of JAIN to a p-nitrophenyl ester as taught by SHANGHAI. Both enzalutamide and apalutamide are thiohydantoin-based antiandrogen drugs. Both are synthesized by coupling an N-substituted amino acid ester intermediate with an aryl isothiocyanate to form the thiohydantoin ring. Activated esters are a well-established concept in organic synthesis. The structural similarity between the two drug targets and the shared mechanism of the key ring-forming step would motivate a person of ordinary skill to apply the activated ester approach of SHANGHAI to the enzalutamide synthesis of JAIN with a reasonable expectation of success. Moreover, applicant admits in the background of the application that there were known problems with the JAIN synthesis (specification, page 2, lines 7-10):
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The aforementioned problems would have motivated the person of ordinary skill to identify and attempt an alternative synthesis strategy, such as the one disclosed by SHANGHAI.
The intermediate compounds recited by claims 10-12, and the process for preparing the intermediate compound recited by claims 9, 13-13 are obvious in view of SHANGHAI’s teachings regarding the preparation of the p-nitrophenyl ester analogue intermediate II-7.
Accordingly, claims 1-14 are obvious over JAIN in view of SHANGHAI.
Response to Arguments
Applicant’s arguments (Remarks 05/13/2026) traversing the rejection of claims 1-14 over JAIN in view of SHANGHAI have been fully considered but are not found persuasive.
Applicant relies on comparative Examples 6 and 7 to argue (a) that a comparable titrated yield of 90.6% is achieved using only 1.2 equivalents of compound (IIIa), representing a 40% reduction in consumption of that reagent (Remarks, page 10); and (b) that total degradation impurities fall from 23.7% under the prior art conditions to 8.3% under the claimed conditions, representing a nearly three-fold reduction in the formation of process impurities (Remarks, page 11).
The examiner acknowledges that the data referred to in the Remarks are accurate. Table 1 reports 91.0% titrated yield and 23.7% total degradation impurities for the methyl ester (“Frag. B”) at 2.0 equivalents at the 24-hour sampling point; and Table 2 reports 90.6% yield and 8.3% impurities for compound (IIb) (“Frag B”) at 1.2 equivalents at the 24-hour sampling point.
However, the arguments characterizing these data as evidence of unexpected results are not persuasive. Arguments presented by the applicant cannot take the place of evidence in the record. See MPEP 716.01(c).
The rejection of record is not over JAIN alone. The rejection cites JAIN as modified by SHANGHAI, the modification being replacement of the methyl ester with an activated aryl ester, particularly the p-nitrophenyl ester. Applicant’s comparison is between the claimed process and the methyl ester process of JAIN. Applicant has not compared the claimed process against any aryl ester, nor against compound II-7 of SHANGHAI. A showing that the modified process outperforms the unmodified primary reference demonstrates only that the modification does what the rejection proposed it would do.
Applicant bears the burden of explaining the proffered data and establishing that the asserted advantage is attributable to the claimed distinguishing feature. See MPEP 716.02(b). Comparative Examples 6 and 7 differ in at least two variables: (i) the identity of the ester moiety and (ii) the equivalents of compound (IIIa). Every impurity reported in the “Σ degradation impurities Frag. B” column of both tables (methyl thiocarbamate, thiourea, urea, trimer guanidine) is derived from compound (IIIa), as established by applicant’s table and page 7, line 13 to page 8, line 6 in the specification. Example 6 charges 1.0 equivalents of compound (IIIa) in excess of stoichiometry, whereas Example 7 charges 0.2 equivalents in excess. Thus, Example 7 has a five-fold difference in the quantity of the substance that degrades, yet the observed impurity difference is only approximately 2.9-fold (“nearly three-fold”). In view of the quantity of impurities present despite a five-fold reduction in the impurity-forming compound, the argument that the claimed process unexpectedly suppresses formation of key process impurities is not found persuasive.
Please also note that the two Examples are not matched in molar concentration. Both Examples charge 2 grams of the respective fragment A ester (corresponding to 7.45 mmol in Example 6 and approximately 5.33 mmol in Example 7) with solvent measured in volumes relative to mass (“2 vol”, “1 vol”). The Example corresponding to the claimed process is therefore run at a lower concentration than the compared prior art process, which is a third variable difference between the two compared processes.
The record contains no experiments running the methyl ester at 1.2 equivalents or compound (IIb) at 2.0 equivalents. Without this control, the reduction from 23.7% to 8.3% cannot be attributed to the activated-ester limitation recited in the claims rather than to the reduced amount of compound (IIIa) in the reaction (a feature which is not recited in the claims).
Please also note that the comparison as presented omits an impurity unique to the claimed process. Example 7 generates 6.5% p-nitrophenol, which has no counterpart in Example 6. Summing all non-product peaks, the total impurities are 33.7% in Example 6 and 27.9% in Example 7. The improvement in overall reaction cleanliness is thus approximately 5.8 percentage points, which is much lower than the 15.4-point difference implied by the argument.
Applicant’s own specification supplies the mechanistic rationale for the result asserted as unexpected. Page 7, lines 13-27 states that the requirement for excess fragment B in the prior art process “is likely due to the tendency of the methanol, produced during the course of the reaction, to react with fragment B itself,” forming methyl thiocarbamate and thereby “subtract[ing] fragment B from the reaction mixture” (page 7, lines 17-21). A person of ordinary skill in the art, having that understanding, would expect that substituting an activated aryl ester (which liberates a poorly nucleophilic phenol in place of a nucleophilic alcohol) would reduce consumption of the isothiocyanate and reduce the associated degradation products. Expected beneficial results are evidence of obviousness, not of nonobviousness. See MPEP 716.02(c)(II). That applicant predicted the result, disclosed the prediction as the basis for the invention, and then confirmed it experimentally weighs against a finding of unexpectedness.
Moreover, the showing of results is a difference in degree rather than in kind. Applicant expressly concedes that the yield is “comparable” (90.6% versus 91.0%). The only meaningful difference in results is a reduction in a byproduct that both processes make, of a type and in a direction that the art would predict. Absent evidence that the magnitude of the difference would itself have been surprising to the skilled artisan, a difference in degree does not establish unexpected results. See MPEP 716.02(a).
Evidence of unexpected results must be commensurate in scope with the claims. See MPEP 716.02(d). The present results are not commensurate for multiple reasons.
First, the stoichiometry on which the argument relies is not claimed. No claims recite a ratio or equivalency of compound (III) relative to compound (II). Claims 1-9 encompass a process employing 2.0 equivalents or any greater quantity of compound (III), which are conditions under which the asserted advantage is absent; and Table 2 suggests that the benefit degrades within the tested window: total degradation impurities rise from 8.4 % to 10.6% on increasing the amount from 1.2 to 1.4 equivalents at 30 hours. Evidence confined to conditions not recited in the claims cannot rebut a rejection of claims encompassing conditions under which the advantage is not obtained. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Second, a single species is presented against a genus of substantial breadth. Claim 1 encompasses essentially any N-aryl α,α-disubstituted amino acid aryl ester coupled with any aryl isothiocyanate, with R1 and R2 each independently H, halide, C1-C8, alkyl, or C6-C10 aryl; and with ten independently variable ring substituents. The comparative data address one ester (IIb) coupled with one isothiocyanate (IIIa).
Third, claims 10-14 are not addressed by the showing of evidence. SHANGHAI discloses compound II-7, which differs from claimed compound (IIb) only in bearing a spiro-fused cyclobutane in place of the gem-dimethyl group at the quaternary carbon, and JAIN supplies the gem-dimethyl fragment. Rebuttal of a prima facie case grounded on close structural similarity requires comparison against the closest disclosed analog. Claim 13 recites esterification of the acid of Formula (IV) with a phenol derivative R’’’OH without reciting any coupling reagent or condition. Example 9 of SHANGHAI discloses the same esterification process, using DCC and DMAP, on a structurally analogous acid.
Reconsidering the entire record, and weighing Applicant’s evidence together with the evidence supporting the prima facie case, the examiner finds that the rebuttal evidence does not outweigh the evidence of obviousness.
Therefore, in view of the foregoing, the rejection of claims 1-14 is maintained.
Please note that in the interest of compact prosecution, the following would be expected to advance prosecution:
(i) A declaration under 37 CFR 1.132 reporting the coupling of the methyl ester of the JAIN publication at 1.2 equivalents of compound (IIIa), and/or the coupling of compound (IIb) at 2.0 equivalents, under conditions otherwise identical to Examples 6 and 7. This would isolate the ester variable and would substantiate the assertion at page 11, lines 18-19 of the specification that the reaction employing the methyl ester “does not proceed to complete conversion” at amounts below 2.0 equivalents;
(ii) Comparative data for additional R’’’ species distributed across the claimed genus, sufficient to establish that the asserted advantage is a property of the genus as claimed rather than of a single species; and
(iii) Amendment of the independent claims to recite the equivalents of compound (III) supported at page 12, lines 3-8 of the specification, together with narrowing of R’’’ toward the species having supporting data, so that the claims are aligned with the conditions under which the evidence was generated.
Conclusion
Claims 1-14 are rejected.
THIS ACTION IS MADE FINAL. 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 Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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