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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 19, 2026 has been entered.
Applicants' arguments, filed May 19, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Response to Amendment
The declaration under 37 CFR 1.132 filed May 19, 2026 is insufficient to overcome the rejection of the pending claims based upon Goodman et al., Park et al. and Biffinger et al. as set forth in the last Office action because: the reasoning underpinning the legal conclusions have not been provided and the data does not provide sufficient evidence in support of the alleged unexpected results.
The declaration states that the declarant Mark M. Goodman, who is also an inventor of the instant application, disagrees with the assertions by the Examiner that fluorine is a bioisostere for hydrogen and that the Park 2001 and Biffinger provide synthetic methods for preparing disubstituted amino acid derivatives as claimed as if binding is perturbed is unpredictable.
These statements are unpersuasive. While an opinion as to a legal conclusion is not entitled to any weight, the underlying basis for the opinion may be persuasive. In re Chilowsky, 306 F.2d 908, 134 USPQ 515 (CCPA 1962) (MPEP 716.01(c)). No underlying basis for the conclusion of fluorine not being a bioisostere for hydrogen have been provided for the Examiner to evaluate which is based upon the disclosures of the Park reference. Park 2001 and Biffinger are relied upon for rendering obvious the presence of a second fluorine atom in the compounds of Goodman et al. and as the claims are drawn to a product and not a method of synthesizing such compounds, the applied prior art need not explicitly disclose synthesis methods for such compounds. Without explanation as to the conclusion that contradicts Park et al. that discusses fluorine substitution in drug design, that there is no reasonable expectation of success has not been established. The evidence of record has not established that one of ordinary skill before the effective filing date of the instant invention would not have been enabled to make the claimed compounds.
Few details on the experiments performed are provided in declaration but the data presented in the appendix is summarized in the following table:
Structure
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122
147
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119
119
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Greyscale
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110
114
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141
148
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Name
4b
9
28
15
9L control
6.33/-
23.4/-
7.82/-
23.5/-
9L BCH
1.84/71%
4.71/80%
2.11/73%
3.91/83%
9L MeAIB
3.94/38%
23.7/NI
9.96/NI
24.8/NI
9L ASC
2.25/65%
9.11/61%
ND
11.1/53%
DU145 control
8.0/-
ND
ND
34.0/-
DU 145 BCH
1.0/88%
ND
ND
2.03/94%
DU 145 MeAIB
7/12.5%
ND
ND
31.9/7%
All numbers are cellular uptake/percent inhibition; NI = no inhibition; ND = data not reported in declaration
The cited compound of Goodman et al. of
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95
103
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has the single fluorine atom on second ring carbon atom away from the ring carbon with the nitrogen and C(=O) substituents was not compared. Instead, comparative compound 4b has the single fluorine atom on the ring carbon atom next to the ring carbon with the nitrogen and C(=O) substituents. Therefore the data above does not represent a comparison with the closest prior art. Some level of different properties would reasonably be expected as the compounds have different structures and without establishing what the expected results would be, if the obtained results are in fact unexpected cannot be determined. Compounds 9 and 28, both of which fall within the scope of the claims, have fully opposite stereochemistry and dramatically different activity that for several parameters is on par with comparative compound 4b. This suggests that even at the identical position on the ring, the exact structure of the compound can have large effects on cellular uptake and that moving a single F atom from the ring carbon next to the carbon with the nitrogen and C(=O) substituents one ring carbon atom further away could lead to potentially large differences in the properties/behavior for the comparative compound. The data also lacks any indication of the error or standard deviation of the measurements. This makes it difficult to determine if the values such as 6.33 and 7.82 for the cellular uptake compound 4b and 28 respectively in 9L cells are actually different or fall within the experimental error. Lastly, any evidence of unexpected results must be reasonably commensurate in scope with the claims and compounds 9, 28 and 15 are insufficient to establish unexpected results that are reasonably commensurate in scope with the claims. These compounds have all of R2, R3 and R4 being hydrogen. Each of the variables is defined in the claims more broadly, and R3 and R4 can even come together to form a heterocyclic ring. Therefore, even if a comparison with the closest prior art was carried out and the obtained results were in fact different from the expected results, the evidence of record would not be reasonably commensurate in scope with the claims. The evidence of record in support of unexpected results would not be sufficient to outweigh the prima facie case of obviousness.
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, 7 – 10 and 16 were 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). This rejection is MAINTAINED for the reasons of record set forth herein.
Goodman et al. discloses compounds including
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(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 ring carbon bearing 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.
Applicants argue that the difluoro substituted cyclopentyl amino acids compounds were developed to address shortcomings of FACPC, compound 37 of the applied Goodman et al. reference that does not have desired properties for clinical development. The Examiner has asserted that peer review journal articles are not sufficient evidence of non-obvious and Applicants disagrees. All of the evidence of record must be considered and a peer review article and acclaimed by the skilled artisan is highly relevant and more should be considered quintessential to the inventive evaluation.
These arguments are unpersuasive. The peer reviewed journals were not rejected because of the type of material being relied up but the evidence that is added to the record by the content of those publications. Applicants arguments, discussed on p 4 onward of the Office Action mailed December 22, 2025 onward was that publication of a peer-reviewed article means the subject matter in that publication would not be considered obvious to the skilled artisan. Patentability determinations are legal conclusions based on the relevant underlying patent laws of each patent authority and these arguments have not established that the publication of a paper describing compounds falling with the claims in a peer reviewed journal fully satisfies all the legal requirements to patentably distinguish the instant claims over the prior art.
Applicants also argue that none of the applied references describe or provide a synthetic method for preparing di-substituted cyclopentane amino acid derivatives as claimed. The Examiner argues that Park and Biffinger provide a synthetic method for the claimed compounds and Applicants respectfully disagree. The two fluorine atoms are on different carbon atoms in the claimed compounds while they are on the same carbon atom in Park.
These arguments are unpersuasive. It appears Applicants might be referring to page 5, ¶ 2 of the Final Rejection mailed December 22, 2025, wherein the Examiner states “failure of the applied prior art to explicitly disclose synthetic methodology for di-substituted amino acid derivatives as claimed does not render the instant claims patentable”. This is not indicating that Park and/or Biffinger discloses synthetic methods for the instant claims but that they do not. The instant claims are drawn to a product and not a process for synthesizing the claimed compounds and therefore the prior art need not provide disclosure as to the synthetic route for such compounds. The arguments and evidence of record have not established that one of ordinary skill in the art before the effective filing date would have been able to synthesize such compounds with undue experimentation that would require analysis of the Wands factors, for example.
Applicants also argue that the Examiner has argued that fluorine is a bioisostere for hydrogen but this is an inaccurate statement. Whether fluorine will cause steric perturbations with respect to the mode of binding in the context of a fluorinated compound in circulation is unpredictable, with reference made to the declaration by Dr. Mark Goodman. Fluorine has a higher electronegativity and might induce altered biological responses.
These arguments are unpersuasive. The arguments and evidence of record do not overcome the cited teachings of Park et al. which states “[t]he replacement of a hydrogen atom or hydroxyl group by a fluorine atom is a strategy widely used in drug development to alter biological function” (p 444, ¶ 1).” The rest of that paragraph even mentions the higher electronegativity so such a consideration is known when making this substitution. The declaration was discussed in detail above and will not be reiterated here. Only a reasonable and not an absolute expectation of success is required for a prima facie case of obviousness. The fluorine substituted compounds are not expected to behave identically to the unsubstituted compound but one of ordinary skill in the art would have the required reasonable expectation of success to add an additional fluorine atom to the compounds of Goodman et al. to further tune the properties of the compound as discussed by Park et al. and Biffinger et al.
The remarks reference the concurrently filed declaration for the unexpected, improved properties of the claimed compounds. Lower radioactivity in the bladder, which can mask prostate cancer tumor detection and metastasis to proximal lymph nodes were unpredictable prior to testing. It is perfectly acceptable to claim a new composition that has unexpectedly advantageous properties as a composition inherently has the properties.
The declaration was discussed above and the evidence in support of the alleged unexpected results was not found persuasive for the reasons discussed in detail above. Applicants bear the burden of explaining the evidence offered in support of unexpected results (see MPEP 716.02 et seq. for a complete discussion of unexpected results) and there is no discussion of the data related to these properties in the record, what the expected results would have been and how that data, if different from the expected results, is reasonably commensurate in scope with the claims. The evidence of record in support of the allegations of unexpected results is insufficient to outweigh the prima facie case of obviousness and therefore the claims are not patentably distinguished over the prior art and the rejection is maintained.
Claim(s) 17 and 18 were 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, 7 – 10 and 16 above, and further in view of Klunk et al. (US 2008/0219931). This rejection is MAINTAINED for the reasons of record set forth herein.
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.
Applicants argue that Klunk does not describe the specific di-fluoro substituted cyclopentane amino acid derivatives claimed or suggest the desirable pharmacokinetic and tumor infiltrating properties for imaging.
These arguments are unpersuasive. Goodman et al., Park et al. and Biffinger et al. are relied upon to teach the structure of the claimed compounds and the arguments regarding these references are addressed in detail above. Klunk is relied upon to teach pharmaceutically acceptable carriers such as phosphate buffer and is not required to teach the structure of the claimed compounds.
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.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
