DETAILED ACTION
Notice of 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 the Claims
The amendments filed 12/08/2025 have been entered.
Response to Arguments
Applicant’s arguments, filed 12/08/2025, have been fully considered.
Applicant traverses the rejection of claims under 35 U.S.C. 103(a) as being unpatentable over Kim et al in view of Yoon, which Applicant summarizes as follows (Applicant Arguments, Pages 7-8):
“According to the Examiner, primary reference Kim teaches the immunosuppressive FK506 derivative 31-O-demethyl-36,37-dihydro FK506 (as evidenced by CAS) which differs from 9-deoxo-31-O-demethyl-36,37-dihydro-prolyl FK506 covered by claim 1 by including a piperidine ring instead of a pyrrolidine ring; and includes a 9-oxo group instead of a 9-deoxo group. See the Office Action, page 4, items 12 and 13.
Yoon, the secondary reference, was relied on by the Examiner for teaching the compound 9-deoxo-prolyl-FK506 that allegedly lacks immunosuppressive activity. This compound, as compared to FK506, includes a pyrrolidine ring and a 9-deoxo group. See the Office Action, pages 4 and 5, item 14.
The Examiner proceeded to conclude that it would have been obvious to modify the Kim immunosuppressive compound 31-O-demethyl-36,37-dihydro FK506 to produce a compound with lower immunosuppressive activity by replacing the piperidine ring with a pyrrolidine ring and replacing the 9-oxo group with a 9-deoxo group to arrive at a compound covered by claim 1. See the Office Action, pages 5 and 6. items 15 and 16.”
Applicant’s summary, however, ignores a critical basis of the rejection. Namely, that Yoon does not merely teach “the compound 9-deoxo-prolyl-FK506 that allegedly lacks immunosuppressive activity”, as indicated by Applicant but, in fact, teaches modifying the parent compound FK506 by (1) replacing the piperdine ring in FK 506 with a pyrrolidine ring and (2) replacing the 9-oxo group in FK 506 with a 9-deoxo group to arrive at the functionally related compound 9-deoxo-prolyl-FK506 lacking immunosuppressive activity. Based on this teaching, it would have been obvious to similarly modify the immunosuppressant compound 31-O-demethyl-36,37-dihydro FK506 taught by Kim et al by (i.e., by (1) replacing the piperdine ring with a pyrrolidine ring and (2) replacing the 9-oxo group with a 9-deoxo group) in an effort to formulate a derivative of 31-O-demethyl-36,37-dihydro FK506 (taught by Kim et al) having no immunosuppressant activity and, thus, reduced side effects for use in treating nervous system disorders, with a reasonable expectation of success.
Regarding the above modifications which form the basis of the rejection, Applicant next argues that “[i]n view of the highly complex structure and substantial molecular size of the compound of the present invention, such modifications would not be feasible through ordinary chemical synthesis” (Applicant Arguments, Page 8) and “as disclosed in the instant Specification, the inventors have successfully produced the claimed compound of Formula 2 through a biosynthetic process involving genetically modified microorganisms” (Applicant Arguments, Page 9). As argued by Applicant, “to produce the claimed compounds, different types of genes were inactivated as compared to Yoon. Therefore, even with reference to Yoon, it would not have been obvious to obtain the claimed compound starting from the Kim compounds” (Applicant Arguments, Page 9).
The argument is not found persuasive. At the time the invention was made, a variety of prior art in addition to the prior art of record taught the biosynthesis of numerous related FK506 analogs (e.g., Mo et al (J Am Chem Soc 133:976-985, 2011); Chen et al (J Bacteriol 195:1931-1939, 2013); Shinde et al (RSC Adv 5:6823-6828, 2015); Beom et al (J Nat Prod 82:2078-2086, 2019); etc.). Based on what was known at the time the invention was made, it is maintained that a person of ordinary skill in the art could have synthesized 9-deoxo-31-O-demethyl-36,37-dihydro-prolyl FK506 with a reasonable expectation of success.
Applicant next argues that “9-deoxo-prolyl-FK506 of Yoon... may be regarded as the closest structural compound to the compounds of Formula 1 to 4 of the present invention. Nevertheless, despite such structure similarity, all of the claimed compounds exhibit significantly higher neurite growth-promoting effects as compared to 9-deoxo-prolyl-FK506, as shown in the graph below” (Applicant Arguments, Pages 9-10):
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The argument is not persuasive. At the outset, the graph is blurry and difficult to read, and it is unclear whether it truly demonstrates any statistically significant increase in neurite growth-promoting effects of the instantly claimed compounds relative to 9-deoxo-prolyl-FK506. Additionally, evidence of unexpected results must be supported by an appropriate affidavit or declaration. And, finally, unexpected results must be established by factual evidence by comparing the claimed invention with that of the closest prior art. In re Burckel, 592 F.2d 1175 (CCPA 1979). In the instant case, the closest prior art is considered to be 31-O-demethyl-36,37-dihydro FK506 as taught by Kim et al, not 9-deoxo-prolyl-FK506.
Applicant next argues that “[i]n addition to improved neurite growth-promoting activity, the claimed compounds exhibit (further reduced) immunosuppressive activity as compared to 31-O-demethyl-36,37-dihydro FK506 of Kim and 9-deoxo-prolyl-FK506 of Yoon” (Applicant Arguments, Page 10). In particular, Applicant argues that “FK506... exhibits high immunosuppressive activity with an IC50 value of 0.027 ng/mL” (Applicant Arguments, Page 10), “31-O-demethyl-36,37-dihydro FK506 of Kim exhibits an IC50 value of 1.723 ng/mL” and “9-deoxo-prolyl-FK506 of Yoon exhibits an IC50 value of 268.300027 ng/mL, approximately 9,940 times lower than that of the parent compound FK506”, whereas “the claimed compounds exhibit immunosuppressive activity that is unexpectedly further reduced” to IC50 values ranging between 3088.100 – 7091.0000 (Applicant Arguments, Pages 10-11).
The argument is not found persuasive. As discussed in the basis of the rejection, Yoon teaches that modifying the parent compound FK506 (i.e., by (1) replacing the piperdine ring in FK 506 with a pyrrolidine ring and (2) replacing the 9-oxo group in FK 506 with a 9-deoxo group) results in the structurally related compound 9-deoxo-prolyl-FK506 lacking immunosuppressive activity. And based on this showing, it would have been prima facie obvious to modify the immunosuppressant compound 31-O-demethyl-36,37-dihydro FK506 taught by Kim et al (i.e., by similarly (1) replacing the piperdine ring with a pyrrolidine ring and (2) replacing the 9-oxo group with a 9-deoxo group) in an effort to formulate a derivative of 31-O-demethyl-36,37-dihydro FK506 having further reduced or no immunosuppressant activity. Considering that Yoon teach that these modifications lowered the immunosuppressant activity of FK506 by approximately 9,940 times (as argued by Applicant), it is not unexpected that carrying out the same modifications to 31-O-demethyl-36,37-dihydro FK506 (taught by Kim et al) lowered the compound’s immunosuppressant activity by approximately 3,225 times.
Lastly, Applicant traverses the rejections of claims on the grounds of non-statutory double patenting over U.S. Patent No. 12,011,497 and copending Application No. 17/772,193 (Applicant Arguments, Page 13).
The rejections have been WITHDRAWN in view of Applicant’s arguments, which are found persuasive.
Claim Rejections - 35 USC § 103
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.
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 and 19 are rejected under 35 U.S.C. 103(a) as being unpatentable over Kim et al (WO 2011/068341 – based on the attached machine translation and further based on CAS ACCESSION NUMBER 2011:717930; of record) in view of Yoon (KR 2016-0067079 – provided in Applicant’s IDS dated 4/28/2022 and based on the attached machine translation; of record).
Claim 1 is drawn to the compound 9-deoxo-31-O-demethyl-36,37-dihydro-prolyl FK506 having the following structure:
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Kim et al teach methods of producing tricyclocompounds including tacrolimus (FK 506), ascomycin (FK 520), and various analogs thereof (Abstract) for use “as an immunosuppressive agent” (Paragraph 1; see also CAS ACCESSION NUMBER 2011:717930: “[t]he compounds provided in this invention can be used as immunosuppressants” (Abstract)), in particular wherein the analog is “31-O-desmethyl-36,37-dihydro tacrolimus” (Paragraphs 179 and 180), which is understood as 31-O-demethyl-36,37-dihydro FK506 having the following structure (see also CAS RN 1310683-75-0 in CAS ACCESSION NUMBER 2011:717930):
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As indicated by arrows, the compound of Kim et al differs from the instantly claimed compound in:
(a) comprising a piperidine ring where the instant compound comprises a pyrrolidine ring; and
(b) comprising a 9-oxo group where the instant compound comprises a 9-deoxo group.
Yoon teaches “FK506 derivatives without immunosuppressive activities” which “can promote neuroregeneration” while, due to having “no immunosuppressive activities… reducing side effects in treating nervous system disorders” (Abstract). In particular, Yoon teaches 9-deoxo-prolyl-FK506 (Page 4, Formula 2):
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which entails an FK 506 derivative obtained by:
(a) replacing the piperdine ring in FK 506 with a pyrrolidine ring; and
(b) replacing the 9-oxo group in FK 506 with a 9-deoxo group:
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FK 506 Yoon Formula 2
Accordingly, based further on Yoon, it would have been obvious to modify the immunosuppressant compound 31-O-demethyl-36,37-dihydro FK506 taught by Kim et al by:
(a) replacing the piperdine ring with a pyrrolidine ring; and
(b) replacing the 9-oxo group with a 9-deoxo group.
It would have been obvious to do so in an effort to formulate a derivative of 31-O-demethyl-36,37-dihydro FK506 taught by Kim et al having no immunosuppressant activity and, thus, reduced side effects for use in treating nervous system disorders, with a reasonable expectation of success.
As such, claim 1 is rejected as prima facie obvious.
Claim 19 is drawn to a composition comprising the compound of claim 1 and an excipient.
Yoon further teaches a “pharmaceutical composition of the invention… formulated using the pharmaceutically acceptable carrier or the diluting agent” wherein “the carrier may be… sterilized water” (Page 6).
As such, claim 19 is also rejected as prima facie obvious.
Conclusion
No new ground(s) of rejection are 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 extension fee 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 date of this final action.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611