DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 9-16, and 18-20 are pending in this application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 24 Sep. 2025 has been entered.
Status of Claims
Claims 1-8, and 17 are cancelled. Claim 18 is amended.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 Sep. 2025 has been considered by the examiner.
Response to Amendment
The amendments filed on 24 Sep. 2025 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 18-20 under 35 USC 103 as being unpatentable over Illig et al. (Bioorg. Med. Chem. Lett.; published 2008; “Illig et al. III”), in view of Bernard-Gauthier et al. (Bioorg. Med. Chem. Lett.; published 2014) and Illig et al. (WO 2006/047504 A1; published 2006) is withdrawn.
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) 9-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Illig et al. (Bioorg. Med. Chem. Lett; published 2008), in view of Bernard-Gauthier et al. (Bioorg. Med. Chem. Lett.; published 2014) for the reasons cited in the Office action filed on 31 Mar. 2025.
Claim(s) 9-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Illig et al. (Bioorg. Med. Chem. Lett; published 2008), in view of Bernard-Gauthier et al. (Bioorg. Med. Chem. Lett.; published 2014), in further view of Illig et al. (WO 2006/047504 A1; published 4 May 2003; “Illig et al. III”) for the reasons cited in the Office action filed on 31 Mar. 2025.
Applicants Arguments
Applicants assert that a POSA must have had a reasonable expectation of success in achieving the claimed invention in view of the prior art. In this case, a POSA would not have had a reasonable expectation of success. Even if a compound is a potent CSF1R inhibitor with good bioavailability, it does not necessarily follow that a radiolabeled variant of the compound will exhibit good performance as a PET imaging agent. A recent study by Foss demonstrated that a radiolabeled [11C] variant of Illig’s compound 8 exhibited poor imaging properties in baboon. Foss explains that [11C]1 exhibited poor in vivo brain uptake, making it unsuitable for CNS PET studies. In Attili, the 11C-labeled compound, [11C]26, did not show any specific CSF1R binding in the brain. Despite Illig’s compounds 8 and 26 exhibiting good performance as CSF1R inhibitors, these compounds did not perform well as PET tracers. Illig’s compound 24 exhibited similar performance to Illig’s compounds 8 and 26 as a CSF1R inhibitor. A radiolabeled variant of compound 24 exhibits excellent PET imaging properties, whereas Illig’s compounds 8 and 26 did not. A person of ordinary skill in the art would not have had a reasonable expectation of success at achieving the claimed invention, particularly in view of the numerous failures of derivatives of Illig’s compounds at performing as PET imaging agents. A person of ordinary skill in the art would not have been motivated and would not have had a reasonable expectation of success in modifying Illig’s compound 24 based on its performance as a CSF1R inhibitor.
Applicant's arguments filed 24 Sep. 2025 have been fully considered but they are not persuasive. Illig provides for the CSF-1R inhibitor compound 24
PNG
media_image1.png
92
140
media_image1.png
Greyscale
where B=
PNG
media_image2.png
44
58
media_image2.png
Greyscale
and C=
PNG
media_image3.png
47
77
media_image3.png
Greyscale
having a CSF-1R IC50 of 0.8 nM determined using in vitro CSF-1R inhibition experiments. According to Illig, CSF-1R is associated with diseases such as rheumatoid arthritis and metastatic cancer. At pg. 1646 and table 4, Illig teaches that compound 24 showed good oral bioavailability, an adequate half-life and moderate plasma clearance. In this case, Illig provides an adequate reasonable expectation of success that compound 24 would be a suitable imaging agent for in vitro and/or in vivo detection of CSF-1R associated diseases including metastatic cancer. Under AIA , predictability is determined before the effective filing date. Conclusive proof of efficacy is not required to show a reasonable expectation of success; nor is there a requirement for absolute predictability. See OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019). There would have been a reasonable expectation of success since Illig teaches that compound 24 binds to CSF-1R with high affinity and that compound 24 shows good bioavailability and moderate clearance suggesting an advantage for quantitative PET imaging. Foss and Attili only support the Examiner’s position that a person of ordinary skill in the art would have been motivated by the teachings of Illig before the effective filing date with a reasonable expectation of success to select and then modify one of the most promising compounds therein by substituting an Me- with [11C]Me for imaging and detection of CSF-1R in vitro and in vivo. Foss selected and then modified compound 8 in Illig by 11C substitution. Attili selected and then modified compound 26 in Illig by 11C substitution.
Foss was published after the effective filing date of the claimed invention. Foss could not have informed one of ordinary skill in the art before the effective filing date about the predictability of compound 24 in Illig for PET imaging CSF-1R in vitro or in vivo. None of claims 9-14 require in vivo imaging of CSF-1R.
Attili does not inform one of ordinary skill in the art about the predictability of compound 24 in Illig for PET imaging CSF-1R in vitro or in vivo. Attili teaches a different compound having a different metabolism and different physiochemical properties and lower binding affinity than compound 24 in Illig. In order for Attilli to have dissuaded Applicants from selecting and modifying compound 24 in Illig, Applicant would have had to of been aware of Attili before the effective filing date. Both Illig and Attili teach that CSF-1R is overexpressed in a number of disease states but Attili teaches biodistribution and blocking experiments in healthy adult mice and Attili implies autoradiography experiments one healthy rat brain slice. Attili does not inform one of ordinary skill in the art about PET detecting elevated CSF-1R expression in various disease states.
At abstract, Bernard-Gauthier teaches that the results from the biological evaluation of compound 10 and the radiosynthesis of [18F]10 support the further investigation of the tracer as a potential PET imaging for CSF-1R. At table 1, compound 1 is reported as having a lower binding affinity for CSF-1R than compound 24 in Illig. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify compound 24 in Illig by substituting the N-Me with N-[11C]Me with a reasonable expectation of success as taught by Illig and Bernard-Gauthier because the substituting would have been expected to enable further PET investigation of the obvious [11C]24 expected to be suitable for PET imaging of CSF-1R in a number of disease states associated with elevated CSF-1R expression.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Illig et al. (Bioorg. Med. Chem. Lett; published 2008), in view of Bernard-Gauthier et al. (Bioorg. Med. Chem. Lett.; published 2014) and Kniess et al. (MedChemComm; published 2015; see attached 892), in further view of Illig et al. (WO 2006/047504 A1; published 4 May 2006; see IDS filed 25 Mar. 2022; “IIIig et al. II”).
Illig et al. teach as discussed above. Illig et al. teach the discovery of novel FMS kinase inhibitors as anti-inflammatory agents (see pg. 1642). Illig et al. teach that colony stimulating factor is also known as FMS (see pg. 1642). Illig et al. teach the inhibition of FMS appears to be of therapeutic value in treating diseases such as rheumatoid arthritis and metastatic cancer to the bone where osteoclasts and macrophages are pathogenic (see pg. 1642). Illig et al. teach that compound 24 of formula
PNG
media_image4.png
173
255
media_image4.png
Greyscale
wherein B is
PNG
media_image5.png
76
112
media_image5.png
Greyscale
and C is
PNG
media_image6.png
88
140
media_image6.png
Greyscale
has an FMS IC50 of 0.0008 µM (see pg. 1645). Illig et al. teach that the involvement of macrophages and cells of the macrophage lineage in inflammation, metastatic bone disease, and arthritis, these agents may have good utility for the treatment of these diseases (see pg. 1647). Illig et al. teach fluorinated compounds 23 and 27 (tables 1 and 2). Illig et al. teach that having achieved good in vitro potency, the pharmacokinetic profiles of several of the more potent compounds (e.g. 24) were evaluated. The pharmacokinetic parameters for these compounds are shown in table 4 (pg. 1646; table 4).
Illig et al. do not teach a compound of instant formula (1k)
PNG
media_image7.png
147
285
media_image7.png
Greyscale
or a method for imaging CSF1R in a subject afflicted with a neuroinflammatory disorder such as AD.
Bernard-Gauthier et al. teach 5-(4-((4-[18F]fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine-2,4-diamine: a selective dual inhibitor for potential PET imaging of Tfrk/CSF-1R (see title). Bernard-Gauthier et al. teach that the high selectivity of 9 could constitute a promising basis for the development of PET-TKI probes with potential imaging applications for CFF-1R, since CSF-1R also represents a useful PTE imaging target. CSF-1R regulates mononuclear phagocyte differentiation and proliferation and as such plays a central role in multiple macrophage-mediated pathological conditions. In particular, infiltration of TAMs within tumor microenvironments relying on CSF-1R for survival and differentiation is associated with poor prognosis in numerous cancers. The structure of GW2580 possesses two aromatic methoxy moieties potentially amenable for carbon-11 (t1/2= 20 min) labeling (see pg. 4785). Fluorine-18 displays better nuclear properties which allow for a more flexible radiosynthesis and lead to high quality PET images. The derivatives were selected in order to be accessible as 18F-isotopolugues (pg. 4785).
Kniess et al. teach 2-[18F]fluoroethyl tosylate as a versatile tool for building 18F-based radiotracers for PET (see title). In general, the fluoroethyl group holds similar steric properties like methyl and ethyl groups and is expected to maintain the pharmacological properties of the lead compound. The increased lipophilicity originating from the fluoroethyl group may be beneficial for addressing specific targets or organs, e.g. brain. From a radiochemists point of view,the [18F]fluoroethyl group may act as a surrogate for a [11C]methyl radiolabel because it can be coupled to the same functional groups. Precursors already available for methylation with [11C]methyl iodide can be used without modification for [18F]fluoroethylation (pg. 1715). Kniess et al. teach N-[18F]fluoroethylamines (pgs. 1733-1738).
Illig et al. II teach aromatic amides as inhibitors of C-FMS kinase (see title). Illig et al. teach that examples of diseases that can be effective treated include Alzheimer’s disease and multiple sclerosis (see pg. 30). Illig et al. II teach 4-cyano-1H-pyrrole-2-carboxylic acid (see pgs. 36 and 106).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Illig et al. (compound 24) by substituting its N-Me with N-Et18F as taught by Bernard-Gauthier et al. and Kniess et al. because the substituting would have been expected to advantageously enable a PET imaging probe for disease associated CSF-1R and enable a surrogate for a [11C]methyl group while advantageously providing a longer half-life and benefiting targeting organs including the brain. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Illig et al. by administering the obvious [18F]FEt-24 to a subject suspected of having AD or MS and PET image the subject as taught by Illig et al. II, Bernard-Gauthier et al. and Kniess et al. because it would have been expected to enable non-invasive in vivo PET diagnosis of CSF-1R associated AD or MS in the subject.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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, Michael Hartley can be reached on (571)272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618