Detailed Action
The present office action is in response to the application filed on 12 Sep 2022.
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, and 3-9 of the pending application have been examined on the merits. Claims 3 and 10-14 stand withdrawn (see “Response to Applicant Election” below).
Priority
Applicants identify the instant application, Serial #: 17/906,184, filed 12 Sep 2022, as a National Stage Entry of International Patent Application #: PCT/EP2021/056048, filed 10 Mar 2021, which claims foreign priority from Foreign Application #: EP20162690.0, filed 12 Mar 2020.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 21 Jul 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Reply to Applicant Election
Applicant’s election of Group I, with compound JB170 as the species election, in the reply filed on 21 Jul 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). A search for the elected species returned prior art and so the claims which do not read on the elected group or species stand withdrawn.
Claim 3 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 10-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group. Election was made without traverse in the reply filed on 21 Jul 2025.
Examiner notes that the relevant anticipation rejections below are based upon art which was found incidental to the search for the elected species. This is not indicative that the entire scope of the claim has been examined; however, the following art is being applied in an effort to promote compact prosecution of the case.
Claim Objections
Claims 1-2 and 4-9 are objected to because of the following informalities: claim 1 starts with “Proteolysis” instead of the grammatically correct “A Proteolysis…” Claims 2 and 4-9 start with “PROTAC” instead of the grammatically correct “A PROTAC…” Appropriate correction is required. Applicant may overcome this objection by amending the claims to include “A” in front of the current starting word or acronym for each claim.
Claim 1 is objected to because of the following informalities: claim 1 states in lines 19-20, “wherein functional groups are selected from…” instead of “wherein said functional groups are selected from…” Appropriate correction is required. Applicant may overcome this objection by amending claim 1 to add “said” in front of “functional groups” in line 19.
Claim 9 is objected to because of the following informality: claim 9 includes pictures of chemical structures which are of low resolution and hard to distinguish. Examiner asks applicant to reupload the pictures with a high resolution in black and white. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
Claims 1-2 and 7-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 states in lines 6 and 11, “wherein L comprises or consists of…” prior to a Markush grouping defining the variable L. MPEP § 2173.05(h)(I) states:
A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022)
Claim 1 is rejected for being indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. Applicant may overcome this rejection by amending to make it clear which alternatives are encompassed by the claim.
Claim 1 includes the following limitation in lines 6-8, “wherein L comprises or consists of an alkyl ether residue or a polyalkyl ether residue or an alkyl ether residue or a polyalkyl ether residue in which at least one C-C bond is replaced by a C=C double bond…” and a limitation on lines 11-13 which states, “wherein L comprises or consists of an alkyl thioether residue or a polyalkyl thioether residue or an alkyl thioether residue or a polyalkyl thioether residue in which at least one C-C bond is replaced by a C=C double bond…” A person having ordinary skill in the art would be confused about the interpretation of the two lists above. For instance, the artisan would wonder whether “alkyl ether residue” is included twice in line 7 as a typo or whether applicant means that L can be an alkyl ether residue or polyalkyl ether residue, where the alkyl ether residue and polyalkyl ether residue optionally have at least one C-C bond replaced by a C=C double bond. Thus claim 1 is indefinite. Applicant may overcome this rejection by clarifying what is meant in both of these limitations.
In the interest of furthering compact prosecution, examiner is interpreting claim 1 to mean L comprises an alkyl ether residue, polyalkyl ether residue, alkyl thioether residue, or polyalkyl thioether residue, where the alkyl ether residue, polyalkyl ether residue, alkyl thioether residue, and polyalkyl thioether residue optionally have at least one C-C bond replaced by a C=C double bond.
Regarding claims 2-3 and 5, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Applicant may overcome this rejection by amending to remove the phrase “in particular” from claim 2.
Claim 2 recites the limitations "amide bond A…peptide bond A…amide bond B…peptide bond B" in . There is insufficient antecedent basis for this limitation in the claim. There is no mention of an amide bond A/B or peptide bond A/B in claim 1, which claim 2 depends from. Applicant may overcome this rejection by amending to show proper antecedent basis for the limitations in claim 2.
Claim 7 states in line 2, “wherein AAB comprises…” prior to a Markush grouping defining the variable AAB. MPEP § 2173.05(h)(I) states:
A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022)
Claim 7 is rejected for being indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. Applicant may overcome this rejection by amending to make it clear which alternatives are encompassed by the claim.
Claim 8 states in line 2, “wherein AAB comprises…” prior to a Markush grouping defining the variable AAB. MPEP § 2173.05(h)(I) states:
A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022)
Claim 8 is rejected for being indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. Applicant may overcome this rejection by amending to make it clear which alternatives are encompassed by the claim.
Claim 9 contains a Markush grouping which does not have the correct coordinating conjunctions to properly limit the alternatives defined in the list. See MPEP § 2117(I). Applicant may overcome this rejection by adding the proper coordinating conjunction to each Markush group in need of one.
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.
Claim(s) 1-2 and 4-5 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2019/0210996 (provided in IDS 07/21/25), hereinafter ‘996, in light of Zhang et al. (J Proteome Res, 2013, 12:3104-3116; cited for evidentiary purposes), hereinafter Zhang. This rejection is not indicative that the entire scope of the claim has been examined; however, the following art is being applied in an effort to promote compact prosecution of the case.
‘996 teaches compounds which are useful for the selective degradation of a variety of kinases, including Aurora-A Kinase, which have Formula (I) (paragraph [0001]; [0004]; [0009]; and [0013]):
PNG
media_image1.png
21
274
media_image1.png
Greyscale
‘996 further teaches a species of Formula (I) with the structure (paragraph [0141]):
PNG
media_image2.png
215
602
media_image2.png
Greyscale
where the cereblon binder is pomalidomide; the linker is
PNG
media_image3.png
53
225
media_image3.png
Greyscale
; and the targeting ligand is a promiscuous kinase binder with the following structure (paragraphs [0038]; and [0137]):
PNG
media_image4.png
158
292
media_image4.png
Greyscale
‘998 teaches that the reference compound has the capacity to bind and regulate Aurora-A kinase (paragraph [0156]). The compound thus has a PROTAC with the cereblon binder pomalidomide, a linker of straight chain linker composed of polyalkyl ether units totaling 13 atoms not counting the amide bond connected to the cereblon binding moiety, and a promiscuous kinase with the capacity to bind to Aurora-A kinase. Zhang, cited for evidence, teaches the targeting ligand is CTx-0294885 which inhibits Aurora-A kinase at low nanomolar concentrations (pg. 3107, Fig. 1B; pg. 3108, column 1; and Supplementary Table 2). Thus claims 1-2 and 4-5 are anticipated by ‘996.
Claim(s) 1-2, 4-5 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Powell et al. (J Med Chem, 2018, 61:4249-4255; provided in the office action mailed 20 May 2025), hereinafter Powell. This rejection is not indicative that the entire scope of the claim has been examined; however, the following art is being applied in an effort to promote compact prosecution of the case.
Powell teaches a PROTAC molecule comprising pomalidomide, a polyalkyl ether linker made up of 9 units not counting the amide bond between pomalidomide and the linker, and either TAE684 or LDK378 (pg. 4250, column 1; and pg. 4250, Fig. 1). Powell also teaches TAE684 and LDK378 have off-target effects of binding to Aurora-A kinase (pg. 4250, column 1). Therefore, claims 1-2 and 4-5 are anticipated by Powell.
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 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 and 4-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/098280 (provided in IDS 07/21/25), hereinafter ‘280, further in view of Bavetsias et al. (Front Oncol, 2015, 5:278), hereinafter Bavetsias, Durlacher et al. (Clin Exp Pharmacol Physiol, 2016, 43:585-601), hereinafter Durlacher, and Lohbeck et al. (Bioorg Med Chem Lett, 2016, 21:5260-5262), hereinafter Lohbeck.
Applicants have elected group I, claims 1-9, and the species JB170 which has the following chemical structure:
PNG
media_image5.png
219
150
media_image5.png
Greyscale
‘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):
PNG
media_image6.png
35
321
media_image6.png
Greyscale
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):
PNG
media_image7.png
153
590
media_image7.png
Greyscale
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):
PNG
media_image8.png
90
407
media_image8.png
Greyscale
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):
PNG
media_image9.png
227
446
media_image9.png
Greyscale
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):
PNG
media_image10.png
300
333
media_image10.png
Greyscale
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.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625