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 .
Election/Restrictions
Applicant’s election of group I and the compound 18F28 (R1 = 18F; R2 = R3 = R4 = H) in the reply filed on August 4, 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)). Merely stating that Applicants disagree with the implication or inference of the claims not being patentable over the prior art used to break unity in the Requirement for Restriction/Election mailed June 3, 2025 does not distinctly and specifically point out the supposed errors in the restriction requirement.
The requirement is still deemed proper and is therefore made FINAL.
Drawings
The drawings are objected to because the chemical structures in figures 1 – 4 are not sufficiently clear. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
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, 7 – 10 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Goodman et al. (US 5,817,776; cited on IDS filed February 1, 2023) in view of Park et al. (Annu Rev Pharmacol Toxicol, 2001; cited on IDS filed February 1, 2023) and Biffinger et al. (ChemBioChem, 2004).
Goodman et al. discloses compounds including
PNG
media_image1.png
114
147
media_image1.png
Greyscale
(Example 3, col 14, ln 1 onward). The compounds that are useful as tumor binding agents and as NMDA receptor binding ligands with the radioisotopic forms being especially useful for tumor imaging techniques (col 4, ln 45 – 48) and that can detect and evaluate brain and body tumors with advantageous properties including rapid uptake and prolonged retention in tumors and isotopes for visualization (col 3, ln 34). 18F is useful for positron emission tomography and the half-life of 110 minutes allows sufficient time for incorporation into a radio-labeled tracers, purification and administration to an animal or human subject (col 1, ln 41 – 48). Pharmaceutical compositions of the compounds are also disclosed (col 3, ln 42 – 44), which would comprise the compound and at least one pharmaceutically acceptable excipient.
The presence of compounds having a second fluorine atom adjacent to the 18F is not disclosed.
Park et al. discloses that the replacement of a hydrogen atom or hydroxyl group with a fluorine atom is widely used in drug development to alter biological function (p 444, ¶ 1). The inclusion of a fluorine atom in a drug molecule can influence both the disposition of the drug and interactions between the drug and pharmacological target (p 443, ¶ 2 and Figure 1). The replacement of a single aromatic hydrogen atom usually results in only a modest increase in lipophilicity whereas a CF3 group is among the most lipophilic of all substituents (p 446, ¶ 3). Certain fluorine containing functional groups enhance lipophilicity and therefore passive diffusion across membranes and allows for noninvasive techniques to be used to assess penetration of the drug to the site action such as the brain, a tumor or a site of infection (p 447, ¶ 4).
Biffinger et al. discloses that the hydrophobic nature of fluorinated compounds is cited for improved transport across the blood brain barrier (p 622, col 1, ¶ 1). The polar hydrophobic nature of fluorine can lead to increased affinity for natural receptors (p 626, col 2, ¶ 2). Fluoroalkylated compounds exhibit greater affinity when binding and is attributed solely to the larger hydrophobic surface area desolvated upon binding (¶ bridging cols 1 and 2 on p 622).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a second fluorine atom into the compounds such as that of Example 3 of Goodman et al., arriving at the elected species. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because fluorine atoms are polar hydrophobic moieties and replacement of hydrogen atoms with fluorine is widely used in drug development. Park et al. discloses that more fluorine atoms lead to greater increases in lipophilicity (a single H versus CF3) and that the overall hydrophobicity of a compound can alter diffusion across membranes such as the blood barrier as taught by Biffinger et al. while also altering affinity for targets. Goodman et al. uses the disclosed compounds with a single fluorine atom for imaging of brain and body tumors and also as ligand for the NMDA receptor. The addition of a second fluorine atom to the compound of example 3 would reasonably be expected to further increase the ability of the compound to cross the blood brain barrier to provide for better imaging of brain tumors and/or modulate affinity for the NMDA receptor compared to the single fluorine containing version and one of ordinary skill in the art would optimize the overall hydrophobicity of the compound to modulate characteristics such as binding affinity to the target and ability to cross membranes such as the blood brain barrier.
Various stereocenters are present in the resulting molecule that give rise to various enantiomers of the claimed compound and various mixtures of such compounds are recited in claims 8 – 10. When no stereochemistry is specifically specified as in Goodman et al., the various enantiomers of the compounds are present in the resulting product. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties (MPEP 2144.09). The isolation and separation of stereoisomers of a known racemate is prima facie obvious unless there are unexpected results.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Goodman et al., Park et al. and Biffinger et al. as applied to claims 1, 2, 7 – 10 and 16 above, further in view of Klunk et al. (US 2008/0219931)
Goodman et al., Park et al. and Biffinger et al. are discussed above.
Specifics of the pharmaceutical composition such as the presence of a phosphate buffer is not disclosed.
Klunk et al. discloses compounds that are administered to a patient for imaging (whole document, e.g., abstract), advantageously in the form of injectable composition (¶ [0093]). A disclosed pharmaceutically acceptable carrier is phosphate buffer containing NaCl (¶ [0093]). The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to routine skills in the art (¶ [0096]).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a carrier such as the phosphate buffer containing NaCl carrier for injectable imaging agents disclosed by Klunk et al. for the compounds rendered obvious by Goodman et al., Park et al. and Biffinger et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because one of ordinary skill in the art knows that pharmaceutically acceptable excipients are used in the preparation of pharmaceutical compositions and material such as phosphate buffer with NaCl is one such carrier. The pH of such compositions is among the parameters that one of ordinary skill in the art would select based on factors such as the pKa of the buffers selected and appropriate pH values for the composition. There is no evidence of record as to the criticality of the claimed pH range.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 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, Michael Hartley can be reached at 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 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.
/Nissa M Westerberg/Primary Examiner, Art Unit 1618