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 .
Summary
Claims 1-3, 25-31, 44-47, 97, 104-108, and 112 are pending in this office action. Claims 4-24, 32-43, 48-96, 98-103, 109-111, and 113-130 are cancelled. All pending claims are under examination in this application.
Priority
The current application filed on February 14, 2024 is a 371 of PCT/US2022/040778 filed August 18, 2022, which in turn claims domestic priority to provisional patent application 63/234,435 filed on August 18, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statements filed on February 14, 2026 and August 28, 2024 are acknowledged. A signed copy of both documents are attached to this office action.
Claim Objections
Claims 3, 26-31, 44-45, 47, and 105 are objected to because of the following informalities:
Claim 3: The structure needs alignment.
Claims 26 and 27: n2 needs to be deleted and n2 needs to be amended in its place.
Claim 27, 28, 30, 31, 45, and 105: Please close and center the (z)z1, there is to much space near “z.” [Claims 46 and 106 looks perfect].
Claims 26, 29, 44, and 47: The structures have only “z” with no parenthesis and potential di- or tri-substitution on the ring of choice, within the structure. Is this intentional or an error?
Appropriate correction is required.
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 non-obviousness.
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 1-3, 25-31, 44-47, 97, 104-108, and 112 are rejected under 35 U.S.C. 103 as being unpatentable over Poplawski et al. (J. Med. Chem., 2013) in view of Yang et al. (US2020/0330624A1), Alfaro et al. (US2019/0185451A1), and Ferrer-Gonzalez et al. (Scientific Reports, 2019).
[The Examiner is going to introduce each reference and then combine them in the rejection of the instant claims.]
1. Poplawski et al.
Poplawski et al. is considered the closest prior art to the present invention as it teaches identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase (see title). Also, Poplawski et al. disclose that fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-o-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid-based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets (see abstract).
2. Yang et al.
Yang et al. teach imaging and radiotherapeutics agents targeting fibroblast-activation protein-alpha (FAP-alpha) (see title). Additionally, Yang et al. disclose imaging and radiotherapeutics agents targeting fibroblast-activation protein-a (FAP-a) and their use in imaging and treating FAP-a. related diseases and disorders are disclosed (see abstract).
3. Alfaro et al.
Alfaro et al. teach inhibitors of fibroblast activation protein (see title). In addition, Alfaro et al. disclose compounds and compositions for modulating fibroblast
activation protein (FAP) are described. The compounds and compositions may find use as therapeutic agents for the treatment of diseases, including hyperproliferative diseases (see abstract).
4. Ferrer-Gonzalez et al.
Ferrer-Gonzalez et al. teach structure-guided design of a fluorescent probe for the visualization of FtsZ in clinically important gram-positive and gramnegative bacterial pathogens (see title). Also, Ferrer-Gonazalez et al. disclose that addressing the growing problem of antibiotic resistance requires the development of new drugs with novel antibacterial targets. FtsZ has been identified as an appealing new target for antibacterial agents. Here, we describe the structure-guided design of a new fluorescent probe (BOFP) in which a BODIPY fluorophore has been conjugated to an oxazole-benzamide FtsZ inhibitor. Crystallographic studies have enabled us to identify the optimal position for tethering the fluorophore that facilitates the high-affinity FtsZ binding of BOFP. Fluorescence anisotropy studies demonstrate that BOFP binds the FtsZ proteins from the Gram-positive pathogens Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae with Kd values of 0.6-4.6 µM. Significantly, BOFP binds the FtsZ proteins from the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii with an even higher affinity (Kd = 0.2-0.8 µM). Fluorescence microscopy studies reveal that BOFP can effectively label FtsZ in all the above Gram-positive and Gram-negative pathogens. In addition, BOFP is effective at monitoring the impact of non-fluorescent inhibitors on FtsZ localization in these target pathogens. Viewed as a whole, our results highlight the utility of BOFP as a powerful tool for identifying new broad-spectrum FtsZ inhibitors and understanding their mechanisms of action (see abstract).
Combination of Poplawski et al. and Yang et al.
Regarding instant claims 1, 25-26, 29, 44, 97, and 104, Poplawski et al. and Yang et al. teach a compound that targets fibroblast activation protein (FAP). The necessary citations within Poplawski et al. and Yang et al. that correspond to instant claims 1, 25-26, 29, 44, 97, and 104 are compiled within Table I. For the purposes of rejection, instant claim 1 is shown below and mapped with the prior art. All other instant claims meet the mapped limitations.
Table I
Instant Claims 1, 25-26, 29, 44, 97, and 104
Poplawski et al. and Yang et al. Citations
A compound having a structure represented by formula I or a pharmaceutically acceptable salt thereof:
Poplawski et al. teach a FAP inhibitor (see abstract; and pg 24, Table 2, Compound 11, FAP IC50(nM)=16 plus or minus 2.9 within Poplawski et al.) compound having a structure represented by formula I or a pharmaceutically acceptable salt thereof, wherein FAPx is FAPi.
PNG
media_image1.png
200
400
media_image1.png
Greyscale
FAPi is a compound which covalently binds to FAP (see pg 3, para 3- para 4, boronic acid-based inhibitors within Poplawski et al.); A is aryl; Z is a halogen and n1 is 1 (see pg 24, Table 2, Compound 11 within Poplawski et al.).
PNG
media_image2.png
200
73
media_image2.png
Greyscale
where R =
PNG
media_image3.png
200
400
media_image3.png
Greyscale
(see compound11 of Table 2, respectively, within Poplawski et al.).
Poplawski does not teach a compound wherein Z is a radioactive halogen isotope or trialkylammonium. However, Yang et al. teach an imaging and radiotherapeutic agent targeting fibroblast-activation protein-alpha (see abstract; and para
[0033] within Yang et al.).
Yang et al. disclose derivatives analogous in structure to formula I, wherein FAPx is FAPi; A is a bivalent linker; Z is a radioactive halogen isotope and n1 is 1
(see para [0005], Formula (I); para [0009], A; para [0076], L; para [0079]-[0080], Z; within Yang et al.).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Poplawski et al. and Yang et al. prior to the effective filing date of the claimed invention, as both are directed to Fibroblast Activation Protein (FAP) targeted therapeutic agents. Substitution of a radioactive halogen isotope as disclosed in Yang et al. in place of the fluorine atom of the FAP inhibitor disclosed in Poplawski et al. would be routine for a skilled artisan. The motivation to combine the two references would be to design a FAP-targeted imaging agent having a structure represented by formula I, for diagnosis and/or monitoring of cancer in a subject (see para [0011] and [0014] within Yang et al.).
Combination of Poplawski et al., Yang et al., and Alfaro et al.
Regarding instant claims 2, 27, 30, 45, 47, 107-108, and 112, Poplawski et al., Yang et al., and Alfaro et al. disclose a compound having a structure represented by formula XI (and other related formulas) or a pharmaceutically acceptable salt thereof.
The resulting structure is a hybrid of the Poplawski et al., Yang et al., and Alfaro et al. references. Poplawski et al. disclose the following analogues:
PNG
media_image4.png
200
96
media_image4.png
Greyscale
where R =
PNG
media_image5.png
194
264
media_image5.png
Greyscale
and
PNG
media_image2.png
200
73
media_image2.png
Greyscale
where R =
PNG
media_image3.png
200
400
media_image3.png
Greyscale
(see compounds 5 and 11 of Tables 1 and 2, respectively, within Poplawski et al.).
Alfaro et al. disclose the following analogues:
PNG
media_image6.png
200
336
media_image6.png
Greyscale
and
PNG
media_image7.png
200
400
media_image7.png
Greyscale
(see compounds 52 and 53 of Table 1, within Alfaro et al.). Furthermore, Yang et al. disclose the use of radioactive halogen isotopes (see Table I within instant claim 1). A skilled artisan (POSITA; person having ordinary skill in the art) could synthetically combine the western and eastern portions of the above analogues disclosed in different references to ascertain the desired derivatives that meet the instant claim limitations under routine experimental conditions.
Additionally, Alfaro et al. disclose the use of a pharmaceutically acceptable carriers or excipients (see paragraph [0356] within Alfaro et al.). Also, Alfaro et al. disclose methods of measuring tumor growth [upon administration of the analogue], tumor proliferation, and tumorigenicity are known in the art, for example by repeated imaging of the individual (see paragraph [0370] within Alfaro et al.). In this manner, a skilled artisan (POSITA) could “detect” a tumor cell within a subject. Finally, Alfaro et al. disclose kits for the treatment any disease or described herein, for example for the treatment of cancer (see paragraph [0401] within Alfaro et al.).
Regarding instant claims 3, 28, 31, and 46, Poplawski et al., Yang et al., and Alfaro et al. disclose a compound having a structure represented by formula XXI (and other related formulas) or a pharmaceutically acceptable salt thereof.
Please see the citations and discussion within instant claims 1, 25-26, 29, 44, 97, 104, 2, 27, 30, 45, and 47 for the necessary rejection text. In addition, Alfaro et al. allows for structures where A1 is substituted with a halogen derivative (see paragraphs [0008-0041]; specifically paragraphs [0036-0041] within Alfaro et al.). This is as an alternative to the terminal ring containing the halide.
Combination of Poplawski et al., Yang et al., Alfaro et al., and Ferrer-Gonzalez et al.
Regarding instant claims 105 and 106, Poplawski et al., Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. disclose the compound of instant claim 27, wherein the compound has a structure represented by formula (IV-B-1 and IV-C-1) or a pharmaceutically acceptable salt thereof.
Please see the citations and discussion within instant claims 1, 25-26, 29, 44, 97, 104, 2, 27, 30, 45, 47, 3, 28, 31, and 46 for the necessary rejection text. Furthermore, Ferrer-Gonzalez et al. disclose the use of a next-generation fluorescent FtsZ probe (BOFP) (see page 2, paragraph 4 within Ferrer-Gonzalez et al.) that could be synthetically incorporated by a skilled artisan (POSITA) within position A2.
[AltContent: arrow]
(see page 4, Figure 2 within Ferrer-Gonzalez et al.). The group for attachment (indicated with the blue arrow) could be adjusted accordingly for successful incorporation into the target molecule by a skilled artisan.
Analogous Art
The Poplawski et al., Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. references are directed to the same field of endeavor as the instant claims, that is, a compound that targets fibroblast activation protein (FAP), as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the analogue targeting FAP disclosed by Poplawski et al., using the teachings of Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. in order to arrive at the subject matter of the instant claims.
The Poplawski et al., Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. references all have considerable overlap in the FAP derivative arts. In this instance, Poplawski et al. supplies the template for the FAP analogues, Yang et al. supplies the synthetic design using radioactive elements, Alfaro et al. supplies a disclosure for the modification of the FAP derivatives, while Ferrer-Gonzalez et al. supplies the support for use of the fluorescent probe, BOFP. [Despite Ferrer-Gonzalez et al. not being directly within the FAP arts, the reference illustrates an example of the fluorescent probe, BOFP, which has a direct impact toward the present application.] All references are directed to the FAP derivatives and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop a modified FAP analogue.
Given these teachings, a POSITA would have been motivated to combine the template for the FAP derived targets as disclosed by Poplawski et al., the required synthetic use of radiolabeled aromatic rings supplied by Yang et al., the support for the modification of FAP analogues disclosed by Alfaro et al., and the support for the use of the fluorescent probe, BOFP, disclosed by Ferrer-Gonzalez et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the FAP targeting derivatives taught by Poplawski et al. along with the use of the necessary claim limitations taught by Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. would have been viewed by a POSITA as routine design optimizations or known modifications for FAP targeted analogues. The motivation to combine the two references would be to design a FAP-targeted imaging agent having a structure represented by a variety of formulas within the instant application, for diagnosis and/or monitoring of cancer in a subject (see para [0011] and [0014] within Yang et al.). Implementing these features in Poplawski et al.’s FAP targeted analogues would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Poplawski et al., Yang et al., Alfaro et al., and Ferrer-Gonzalez et al. provides all the elements of the claimed invention. The resulting FAP targeted derivatives, constitute no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN W LIPPERT III whose telephone number is (571)270-0862. The examiner can normally be reached Monday - Thursday 9:00 AM - 5:00 PM.
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, Robert A Wax can be reached on 571-272-0623. 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.
/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/ Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights