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 .
Priority
The instant application, filed 09/23/2023, is a 371 filing of PCT/US2022/021609, filed 03/23/2022, which claims domestic priority to provisional U.S. application number 63/164,704, filed 03/23/2021.
Preliminary Amendments and Claim Status
The amendment filed on 09/25/2025 is acknowledged and entered.
Claims 6-8 are amended;
Claims 1-3, 31-52, 57 and 58 are cancelled;
Claims 8, 13, 16-19, 22-26, 53-56, 59, 60, and 62-68 remain withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species.
Claims 4-7, 9-12, 14, 15, 20, 21, 27-30, 53-56, 61, and 69 read on an elected species and invention
Claims 4-30, 53-56 and 59-69 are pending and are under prosecution
Response to arguments
Applicant’s arguments filed September 25, 2025 with respect to the traversal of claim withdrawal, claim objection, and rejections under 35 U.S.C. § 103 and nonstatutory double patenting have been fully considered.
With respect to the traversal of the withdrawal of claims 8, 13, 16-19, 22-26, 53-56, 59, 60, and 62-68, the initial response to the requirement for restriction and election of species did not include a traversal made by applicant. As such, explanation for the withdrawal of the claims was provided, other than that only claims 4-7, 9-12, 14, 15, 20, 21, 27-30, 53-56, 61, and 69 read on the elected species and elected invention. The withdrawal of the claims is not a relinquishment of the subject matter, but is merely made to facilitate examination based on the examination of the elected species within the Markush-type claims. As such, the withdrawal of claims 8, 13, 16-19, 22-26, 53-56, 59, 60, and 62-68 is maintained.
With respect to the objection to claim 29, in light of applicant’s arguments filed 09/25/2025, the objection is hereby withdrawn.
With respect to the rejection 35 U.S.C. § 103 as being unpatentable over Wender et al. (US 20110014699 A1, published January 20, 2011, included in applicant IDS filed 03/24/2022), hereinafter Wender, in view of Patani et al. (Chem Rev (1996) 96, pg. 3147-3176, published December 19, 1996), hereinafter Patani, the arguments made by applicant are herein addressed.
Applicant argues that the reasoning in the office action, filed 06/25/2025, fails to establish a motivation to modify Wenders compound 26 to introduce an amino group at the C-13 position and that such a modification would have not been obvious to a person of ordinary skill in the art.
Applicant’s argument is unconvincing because Wender expressly discloses compound 26 and diterpenoid analogs that act on PKC, and teaches routine substitution to modulate activity throughout the disclosure. Patani teaches hydrogen to amino exchanges as a classical rational bioisosteric modification. According to MPEP § 2143, a person of ordinary skill in the art faced with a finite set of predictable options would have been motivated to make this well-known necessary change with a reasonable expectation of success in optimizing PKC binding.
Applicant further argues that Patani, “admits unpredictability” and therefore discourages the amino for hydrogen substitution.
Applicant’s argument is unconvincing because Patani’s acknowledgment of empirical variability does not constitute a teaching away. As explained in MPEP § 2144.05, a reference does not teach way merely because results vary; it must clearly criticize or discourage the approach. Patani’s table 9 specifically list amino substitution as among the most common bioisosteric replacements used to alter and improve pharmacological potency. As such, a person of ordinary skill in the art would recognize that such substitutions are routine design optimization, and not departures from accepted practice.
Applicant argues that structural differences—specifically the shorter linker and absence of the substitution at C-13—render Wenders compound 26 too dissimilar from the claimed species to support an obviousness rejection.
Applicant’s argument is unconvincing because the courts have consistently held a compounds differing only by homologous -CH2- extensions are considered close structural analogs with predictable properties. Wender teaches homologous diterpenoid species varying in sidechain length to modulate activity, thereby suggesting modification of precisely such positions. The examiner’s rationale to extend or alter the chain at C-13 is therefore directly supported by both Wenders disclosure, and long-standing medicinal chemistry practices, as well precedential as federal court decisions (In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Applicant further argues that Wender “teaches away” because introduction of polar substituents allegedly reduce potency in some analogs presented in the disclosure.
Applicant’s argument is unconvincing because teaching away requires an explicit discouragement, not the mere report of lower activity for a subset of analogs. According to MPEP § 2141.02 (VI),
"(T)he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
As such, the disclosure of lower activity or certain analogs is not considered a teaching away, but in fact, a mere demonstration of the differences in potency which can be achieved by a myriad of substitutions, demonstrating that this particular scaffold presents fertile ground for a person of ordinary skill in the art to modify. Wender’s structure-activity data encourage continue exploration of C-13 modifications to fine-tune PKC selectivity, and do not state or imply that the amino substitution would be undesirable. A person of ordinary skill in the art would reasonably interpret the data presented by Wender as part of a routine SAR optimization, rather than a directive against modification.
Applicant argues that the instant case is analogous to Takeda v. Alphapharm, Otuska v. Sandoz and Daiichi Sankyo v. Mylan, for the Federal Circuit found no motivation to modify structurally similar lead compounds.
Applicant’s argument is unconvincing because the particular case is referenced addressed broader prior art genera containing hundreds of possible leads whereas Wender identifies a specific, well-characterized lead compound (compound 26) for PKC modulation. The instantly claimed derivative presents a single, predictable variation of that same scaffold. Further, Takeda and Otuska concerned unpredictable stereochemical and metabolic behavior, which are not at issue here. The factual context aligns instead with In re Merck, 800 F.2d 1091 (Fed. Cir. 1986), and KSR, which support obviousness for structurally analogous compounds modified by well-known bioisosteric replacement techniques.
Applicant argues that potency decreases in certain substituted analogs and statements in Patani regarding, “empirical approaches” demonstrate unpredictability and is sufficient to preclude a reasonable expectation of success.
Applicant’s argument is unconvincing because variability in potency is inherent to routine optimization, and does not negate the predictability of the structural modification itself. As held in In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), where general conditions are known to produce the desired results, discovering the optimum values by routine experimentation it obvious. The art collectively supports a reasonable expectation that amino substitution at positions C-13 would yield a compound of comparable activity suitable for evaluation as a PKC modulator.
Applicant argues that Wender provides no express direction to modify at C-13, and the examiner’s rationale is based solely on hindsight.
Applicant’s argument is unconvincing because both Wender and Patani teach substitution on peripheral carbons to alter lipophilicity and pharmacologic profiles. Wenders disclosure of variable sidechains, and Patani’s general rule of isosteric replacement together supply and articulate reasoning under MPEP § 2141.02 (VI). The combination does not rely on hindsight, but on the direct and explicit suggestion in the prior art to employ such modifications as part of routine lead optimization.
Applicant argues that examiner’s position conflicts with the Federal Circuit decisions such as in Takeda, Daiichi, and Otsuka, which found no reasonable expectation of success.
Applicant’s argument is unconvincing because the facts here differ substantially: the prior art compound, compound 26, is not one of millions within an untested genus, but a specific bioactive lead with known PKC activity. The modification is minor, the art teaches the technique, and there is no evidence of unexpected results presented within the instant specification or by applicant’s arguments. Therefore, the examiner’s determination of obviousness is fully consistent with controlling precedent and the guidance of MPEP §§ 2141-2144.09.
Accordingly, all arguments presented by Applicants have been addressed and are found unpersuasive for the reasons presented herein and in the previous non-final rejection. Applicants are reminded that “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). The original rejection under 35 U.S.C. § 102 is hereby maintained.
With respect to the nonstatutory double patenting rejection, Applicant’s arguments are herein addressed.
Applicant argues that the provisional nonstatutory double patenting rejection over claims 36-45, 47, 48, 50, 52, 53, 59, 64, and 66-69 of copending Application No. 18/283,787, (US 20240197666 A1) should be withdrawn because the instant application, and the reference application allegedly share the same effective US filing date, and therefore no difference in patent term exists.
Applicant’s argument is unconvincing because the provisional double patenting rejection was properly made in accordance with MPEP §§ 804 and 804.02, which direct the provisional double patenting rejection must be entered whenever the application and the reference case claim non-patently distinct subject matter, regardless of whether the effective filing dates appear identical at the time of prosecution. According to MPEP § 804.02 (III),
Applicants are cautioned that reliance upon a common issue date cannot effectively substitute for the filing of one or more terminal disclaimers in order to overcome a proper nonstatutory double patenting rejection, particularly since a common issue date alone does not avoid the potential problems of dual ownership by a common assignee, or by parties to a joint research agreement, of patents to patentably indistinct inventions. In any event, the Office cannot ensure that two or more applications will have a common issue date.
Applicant is reminded that the purpose of a provisional double patenting rejection is to preserve the issue pending final resolution of codependency, common ownership, and potential terminal disclaimer requirements before allowance.
Applicant’s argument is determined to be unconvincing because the record does not establish that both applications will remain an identical patent term position at the time of issuance. Differences in filing date, priority treatment, or patent term adjustment may alter exploration. Thus, consistent with MPEP § 804.02 (II), the provisional double patenting rejection is maintained until the office conference common ownership, determines whether a terminal disclaimer is necessary to obviate the rejection prior to allowance.
Accordingly, the provisional nonstatutory double patenting rejection is maintained pending final determination of the patent term relationship between the instant application and the co-pending application. Applicant may file an appropriate terminal disclaimer or provide documentary evidence demonstrate an identical term and ownership should they wish to overcome the rejection.
Claim Rejections – 35 U.S.C. § 103
The text of those sections of title 35, U.S. Code not included in this action can be found in the prior Office action.
Claims 4-7, 9-12, 14, 15, 20, 21, 27-30, 53-56, 61, and 69 are rejected under 35 U.S.C. § 103 as being unpatentable over Wender et al. (US 20110014699 A1, published January 20, 2011, included in applicant IDS filed 03/24/2022), hereinafter Wender, in view of Patani et al, (Chem Rev (1996) 96, pg. 3147-3176, published December 19, 1996), hereinafter Patani.
The instant claims are drawn to a compound of Formula (II), which are diterpenoid compounds that act on protein kinase C (PKC). Formula (II) is reflected in Figure 1, below.
Wender teaches compounds of the general formula
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252
313
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(claim 1) as well as methods aimed at the targeting of PKC using the claimed composition (claims 9, 19). More specifically, in Figure 1C, Wender teaches compound 26, also known as CAS Registry Number: RN 1262390-01-1 [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1262390-01-1, Entered STN: 09 Feb 2011].
Figure 1. Structural comparison of prior art compound and instantly claimed Formula (II)
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429
611
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Fig 1. a) Wender CAS Registry Number: RN 1262390-01-1; b) instantly claimed Formula (I)
R2, R11, R17, and R18 are CH3
R3 is O double bonded to the ring carbon
R4, R6, and R9 are OH
R5 , R5’, R7, R12, and R14 are H
R6’ and R7’ form a bond
R21 is C6 aryl (phenyl)
n is 0
L is -CH2-
Although the linker L of compound 26 is taught by Wender is shorter than that of the elected species, there are no teachings to exclude long carbon chains at this position (claim 17). Finally, Wender discloses the combination of the claimed compositions with a pharmaceutically acceptable carrier to form a pharmaceutical composition (paragraph [0176]).
Wender fails to teach the amino group adjacent to the OC(O)CH2- found in Formula (II).
The deficiencies of Wender in teaching the amino substituent on Formula (II) are remedied by Patani, who teaches rational approaches in drug design, which encompass substitutions used by those skilled in the art to develop novel and more-potent therapeutics.
Wherein NH2 in the elected species is H in the prior art compound: this substitution is considered to be a classical bioisostere, well-known to the ordinary artisan in skilled in rational drug design to be used in the process of the development of novel therapeutics. With respect to classical bioisosteres, Patani teaches that the substitution of hydrogen by amino is one of the more commonly employed isosteric replacements (page 3152, section II, segment A, item 4 of Patani). This teaching is based on Grimm’s Hydride displacement law which describes how chemical groups can mimic each other, and is one of the most crucial lead modification tools in rational drug design. Therefore, it would have been prima facie obvious for a person having ordinary skill in the art prior to the effective filing date to modify the compounds described by Wender to include amino in the place of Hydrogen, as taught by Patani on the substituent, in order to chemically modify the original compounds with a reasonable expectation of success.
Regarding the difference in chain linker, connecting the phenyl group to the rest of the chemical moiety, the prior art compound and the instantly claimed compound are is considered homologous structures, differing by successive CH2 groups. The courts have determined that this level of structural difference is considered obvious,
In re Grose, 201 USPQ 57, 63, “The known structural relationship between adjacent homologues, for example, supplies a chemical theory upon which a prima facie case of obviousness of a compound may rest.” See specifically In re Shetty, 195 USPQ 753; In re Wilder, 195 USPQ 426 and Ex Parte Greshem, 121 USPQ 422, all of which feature a compound with a C2 link rejected over a compound with a C1 link. Similarly, In re Chupp, 2 USPQ2d 1437 and In re Coes, 81 USPQ 369 have a compound with a C1 link unpatentable over prior art showing C2 link. Note Ex parte Agouridas, 65 USPQ2d 1142, where a C4 chain was held obvious over a C3 chain. Note also In re Schaub, 190 USPQ 324, 326, where compounds with C5 and C6 chains were called “adjacent homologs in the classic sense”. Ex parte Ruddy, 121 USPQ 427 has a C3 link unpatentable over a C1 link. Ex parte Nathan, 121 USPQ 349 found the insertion of a C2H4 link obvious. In all of these cases, the variation was found to be obvious on the basis of close structural similarity; no secondary teaching was employed. As was stated directly in THE GENERAL TIRE & RUBBER COMPANY v. JEFFERSON CHEMICAL COMPANY, INC., 182 USPQ 70 (1974): “If any structural change is obvious to one skilled in the art, a substitution of the next higher homolog would seem to be.” Note also In re Jones, 21 USPQ2d 1942, which states at 1943 “Particular types or categories of structural similarity without more, have, in past cases, given rise to prima facie obviousness”; one of those listed is “adjacent homologues and structural isomers”. Similar is In re Schechter and LaForge, 98 USPQ 144, 150, which states “a novel useful chemical compound which is homologous or isomeric with compounds of the prior art is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compounds.” Note also In re Deuel 34 USPQ2d 1210, 1214 which states, “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.”
Therefore, it would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant claims to modify and lengthen the CH2CH2 linker based on close structural similarity, in order obtain compounds with improved properties.
In the interest of brevity, the aforementioned teachings are herein applied to each claim individually, and the claims stand rejected.
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 4-7, 9-12, 14, 15, 20, 21, 27-30, 53-56, 61, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36-45, 47, 48, 50, 52, 53, 59, 64, and 66-69 of copending Application No. 18/283,787, (reference application published as U.S. 2024/0197666 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending application is drawn to methods comprising the use of the instantly claimed compounds.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. If a notice of allowance is issued in the co-pending application 18/283,787, upon issue of the patent, the provisionary NSDP rejection over the co-pending application will convert to a NSDP rejection over the published patent.
Conclusion
No claims are allowed.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623