Detailed Action
The present office action is in response to the remarks filed on 09 Apr 2026.
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
Claims 1-2, 4-6, 8, and 15-17 of the pending application have been examined on the merits. Claims 3 and 10-14 remain withdrawn. Claim 15 is newly withdrawn as being drawn to a non-elected species (see “Response to Applicant Reply” below). Acknowledgement is made of the amendments filed 09 Apr 2026. Acknowledgement is made of the cancellation of claims 7 and 9. Acknowledgement is made of the newly added claims 15-17.
Priority
The instant application retains the effective filing date of 12 Mar 2020.
Response to Applicant Reply
Acknowledgement is made of the amendments filed 09 Apr 2026.
Newly submitted claim 15 is directed to an invention that lacks unity with the invention originally claimed for the following reasons: claim 15 is drawn to a non-elected species.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 15 is withdrawn from consideration as being directed to a nonelected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
The objection and rejections of claims 7 and 9 are rendered moot following the cancellation of the claims.
The objection to claims 1-2, 4-6, and 8 are rendered moot following applicant amendments.
The rejections of claims 1-2, 4-6, and 8 over 35 U.S.C. § 112(b) are rendered moot following applicant amendments.
The rejection of claims 1-2 and 4-5 under 35 U.S.C. § 102(a)(1) over US 2019/0210996 (provided in IDS 07/21/15) is rendered moot following applicant amendments.
The rejection of claims 1-2 and 4-5 under 35 U.S.C. § 102(a)(1) over Powell et al. (J Med Chem, 2018, 61:4249-4255; provided in the office action mailed 20 May 2025) is rendered moot following applicant amendments.
Regarding the rejection of claims 1-2, 4-6, and 8 under 35 U.S.C. § 103 over WO 2018/098280 (provided in IDS 07/21/25), hereinafter ‘280, further in view of Bavetsias et al. (Front Oncol, 2015, 5:278; provided in the office action mailed 09 Dec 2025), hereinafter Bavetsias, Durlacher et al. (Clin Exp Pharmacol Physiol, 2016, 43:585-601; provided in the office action mailed 09 Dec 2025), hereinafter Durlacher, and Lohbeck et al. (Bioorg Med Chem Lett, 2016, 21:5260-5262; provided in the office action mailed 09 Dec 2025), hereinafter Lohbeck., applicant's arguments filed 09 Apr 2026 have been fully considered but they are not persuasive. In the reply filed 09 Apr 2026, applicant argues that the linker of Compound I-23 of ‘280 is not a linker according to claim 1 because 2 hydrogen atoms of the terminal-CH2-groups have to be counted and are so the linker of compound I-23 has 15 atoms instead of the max of 13 as found in claim 1 (pg. 12). Applicant further argues that ‘280 does not disclose the specific combination of features that would result in a functional PROTAC (pg. 12).
This is not persuasive. As stated in MPEP § 2145(IV), “[o]ne cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).” Examiner notes that in the office action mailed 09 Dec 2025, it is found that compound I-23 as found in ‘280 does not have the same PEG linker length as the instantly elected compound. Lohbeck is relied on to teach the modification of linker length and composition of reference Compound I-23 to arrive at the instantly elected species.
Applicant argues that the specificity of alisertib as selective inhibitor of Aurora A as found in Bavetsias and Durlacher does not mean that alisertib would work in biological systems in a PROTAC (pg. 13).
This is not persuasive. As stated in MPEP § 2145(IV), “[o]ne cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).”
Applicant argues that Lohbeck discloses the possibility to synthesize a number of possible PROTACs by using a PROTAC toolbox, but that the instant application shows that the VHL ligands would not result in viable PROTAC molecules (pg. 13). Applicant argues that the linkers in the toolbox are not restricted to a chain of 5 to 13 subsequently arranged atoms nor to linkers containing ether groups or thioether groups (pg. 13). Applicant argues that the references do not point to the advantageous feature of linkers having a chain of only 5 to 13 arranged atoms (pg. 13).
This is not persuasive. As stated above, the teachings of the references taken together show the obviousness of the instantly elected compound by showing the compound taught by ‘280 has the same E3 ubiquitin ligase binder and Aurora A binding moiety, but differs in the PEG length of the linker. Lohbeck teaches a toolbox that the artisan would find it obvious to use and iterate to find PROTAC binders for Aurora A, and so create the instantly elected compound by varying linker length. Further, it is unclear where in the disclosure shows that the linker length of 5-13 atoms is so advantageous as to be surprising in results. There are no experiments in the disclosure that compare the linker lengths of less than 5 atoms and greater than 13 atoms to show the advantageous results argued for in applicant remarks.
In light of the discussion above, the rejection of claims 1-2, 4-6, and 8 under 35 U.S.C. § 103, as obvious over ‘280, Bavetsias, Durlacher, and Lohbeck is maintained for the reasons of record and . restated below. The rejection further applies to newly added claims 16-17, necessitated by applicant amendments.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
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.
Claim(s) 1-2, 4-6, 8, and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over ‘280, further in view of Bavetsias, Durlacher, and Lohbeck.
Applicants have elected group I, claims 1-6, 8, and 16-17, and the species JB170 which has the following chemical structure:
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‘280 teaches that bifunctional compounds composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety have been shown to induce proteasome-mediated degradation of selected proteins and these molecules offer the possibility of temporal control over protein expression, and these molecules could be useful as biochemical reagents for the treatment of diseases (pg. 1, lines 18-21). ‘280 further teaches a bifunction compound of Formula (X):
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Where the targeting ligand is capable of binding at least one targeted protein, the linker covalently binds the targeting ligand to the degron, and the degron binds a ubiquitin ligase, such as E3 ubiquitin ligase (pg. 2, lines 20-27). One of the species of Formula (X) that relates to the instant claims is Compound I-23 (pg. 92):
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Where the targeting ligand is the same as the instant claims, the degron is thalidomide, and the linker has the structure of Formula (L1e) (pg. 82):
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where p1 is 3; p2 is 1; and p3 is 3 (pg. 68). '280 continues and teaches that the linker can be designed and optimized based on structure-activity relationship an X-ray crystallography of the targeting ligand with regard to the location of attachment for the linker and that optimal linker length and composition vary by the targeting ligand and can be estimated based upon X-ray structure of the targeting ligand bound to its target. Further, that linker length and composition can be modified to modulate metabolic stability and pharmacokinetic and pharmacodynamics parameters (pg. 88, lines 6-12). However, reference Compound I-23 differs from the instantly elected JB170 in the PEG linker length.
Bavetsias teaches that Aurora-A kinase has been found to be overexpressed in a broad range of human tumors, including primary colorectal carcinoma, gliomas, breast, ovarian, and pancreatic cancers and that the overexpression of Aurora kinases in tumors suggests that a wide range of cancers could respond therapeutically to inhibitors of the Aurora kinases (pg. 1 to pg. 2, column 1). Bavetsias further teaches that alisertib is a selective inhibitor of Aurora-A kinase with an IC50 of 1.2 nM, has been extensively characterized using in vitro and in vivo preclinical models, and displays antiproliferative activity in a wide range of human tumor cells lines, further teaching that alisertib has the following structure (pg. 3, Table 1; and pg. 3, column 2):
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Alisertib has the same structure as the targeting ligand of reference Compound I-23 and the instant compound JB170.
Durlacher teaches that Aurora Kinase A inhibitors have advantages over pan-selective Aurora inhibitors by avoiding Aurora Kinase B-mediated neutropenia (pg. 591, column 1).
Lohbeck teaches that, ideally, a research would synthesize a library of PROTAC compounds with different linker lengths coupled to multiple E3 ligase ligands to test for efficacy (pg. 5260, column 2). Lohbeck further teaches the creation of a PROTAC toolbox for the practical synthesis of a thalidomide derivative which can easily be converted into multiple PROTAC precursors and teaches the structures of four precursors (pg. 5262, column 1):
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The PROTAC precursors taught by Lohbeck include Compound 12, which has the same E3-ubiquitin ligase binding moiety as reference Compound I-23 and instant Compound JB170. Lohbeck teaches compounds 10-13 have linkers comprised of 6, 7, 11, and 16 linear atoms respectively, giving a good variety of lengths with which to probe PROTAC efficiency.
Based on the teachings of ‘280, Bavetsias, Durlacher, and Lohbeck, a person of ordinary skill in the art would take the bifunctional Compound I-23, taught by ‘280, and create a PROTAC library of thalidomide-derived ligands, as taught by ‘Lohbeck, to target Aurora-A kinase for the temporal control over protein expression and use as a biochemical reagent for the treatment of diseases, such as primary colorectal carcinoma, gliomas, breast, ovarian, and pancreatic cancers, which overexpress Aurora-A kinase, as taught by Bavetsias. The artisan would further be motivated to choose alisertib as the targeting ligand because of its selective inhibition of Aurora-A kinase over other pan-Aurora kinase inhibitors to avoid Aurora Kinase B-mediated neutropenia, as taught by Durlacher. The artisan would also be motivated to change the linker of Compound I-23 because linker length and composition can be modified to modulate metabolic stability and pharmacokinetic and pharmacodynamics parameters, as taught by ‘280. By starting at Compound I-23, found in ‘280, and modifying the linker length and composition using the methods taught by Lohbeck, a person having ordinary skill in the art would design the instant compound JB170 to test specific degradation of Aurora-A kinase in a wide variety of cancer cell lines.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed. Applicant's amendment necessitated the new ground(s) of rejection 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 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 Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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