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, 6-7, 10, 12, 14-15, 18-19, 22, 24-25, 27-29, and 36-38 are pending in this office action. Claims 4-5, 8-9, 11, 13, 16-17, 20-21, 23, 26, and 30-35 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on September 6, 2024 is a 371 of PCT/AU2023/050157 filed on March 8, 2023. The current application claims foreign priority to AU2022900560 filed on March 8, 2022.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on September 6, 2024 is acknowledged. A signed copy of this document is attached to the office action.
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, 6-7, 10, 12, 14-15, 18-19, 22, 24-25, 27-29, and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Journal of the American Chemical Society, 2020) in view of Luthra et al. (US2015/0126708A1) and Dong et al. (Journal of Materials Chemistry C, 2020).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Lee et al.
Lee et al. is the closest prior art to the present invention as it teaches activity-based sensing with a metal-directed acyl imidazole strategy reveals cell type-dependent pools of labile brain copper (see title). Additionally, Lee et al. disclose that the copper is a required nutrient for life and particularly important to the brain and central nervous
system. Indeed, copper redox activity is essential to maintaining normal physiological responses spanning neural signaling to metabolism, but at the same time copper misregulation is associated with inflammation and neurodegeneration. As such, chemical probes that can track dynamic changes in copper with spatial resolution, especially in loosely bound, labile forms, are valuable tools to identify and characterize its contributions to healthy and disease states. In this report, we present an activity-based sensing (ABS) strategy for copper detection in live cells that preserves spatial information by a copper-dependent bioconjugation reaction. Specifically, we designed
copper-directed acyl imidazole dyes that operate through copper-mediated activation of acyl imidazole electrophiles for subsequent labeling of proximal proteins at sites of elevated labile copper to provide a permanent stain that resists washing and fixation. To showcase the utility of this new ABS platform, we sought to characterize labile copper pools in the three main cell types in the brain: neurons, astrocytes, and microglia. Exposure of each of these cell types to physiologically relevant stimuli shows distinct changes in labile copper pools. Neurons display translocation of labile copper from somatic cell bodies to peripheral processes upon activation, whereas astrocytes and microglia exhibit global decreases and increases in intracellular labile copper pools, respectively, after exposure to inflammatory stimuli. This work provides foundational information on cell type-dependent homeostasis of copper, an essential metal in the
brain, as well as a starting point for the design of new activity-based probes for metals and other dynamic signaling and stress analytes in biology (see abstract).
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2. Luthra et al.
Luthra et al. teach a radiofluorination method (see title). In addition, Luthra et al. disclose that the present invention provides a method of radio fluorination of biological targeting molecules (BTMs) with the radioisotope 18F. Also provided are novel conjugates useful in the 18F-radio fluorination method, and the use of such conjugates and automated synthesizer apparatus including cassettes for carrying out the method (see abstract).
3. Dong et al.
Dong et al. teach 1,8-naphthalimide-based fluorescent chemosensors: recent advances and perspectives (see title). Furthermore, Dong et al. disclose 1,8-naphthalimide, as one of the classical dyes and fluorophores, has been widely used in analytical chemistry, materials chemistry, and biochemistry fields because of its excellent characteristic photostability, good structural flexibility, high fluorescence quantum yield, and large Stokes shift. This review mainly focuses on 1,8-naphthalimide and its derivatives in ion detection, molecular recognition, material applications, and bioimaging in the past five years. Simultaneously, we hope to develop more powerful fluorescent chemosensors for broad and exciting applications in the future (see abstract).
Combination of Lee et al. and Luthra et al.
Regarding instant claim 1, Lee et al. and Luthra et al. teach a probe for detecting a transition metal. The necessary citations within Lee et al. and Luthra et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Lee et al. and Luthra et al. Citations
A probe for detecting a transition metal, the probe comprising:
Lee et al. disclose activity-based sensing with a metal-directed acyl imidazole strategy reveals cell type-dependent pools of labile brain copper (see title and abstract within Lee et al.).
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Additionally, Lee et al. disclose both analogues CD649 and CD433 which both meet the instant claim 1 limitations (see Scheme 1 within Lee et al.). Figure I depict one of these compounds, CD649.
Figure I
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The black box is indicative of the chelating portion of the analogue. The green box is indicative of the linker portion of the molecule. The remainder of the derivative is indicative of a fluorescent dye (detectable by imaging);
Wherein the linker is configured to react with a nucleophile when the metal chelating portion coordinates with the transition metal (For labeling proximal proteins in live cells in a copper-dependent manner, the CD probes
should bind and react through accessible nucleophilic amino acids; see page 4, 4th paragraph; also see graphical abstract; both within Lee et al.).
Lee et al. fails to incorporate a radiolabeled moiety within the fluorescent dye. However, Luthra et al. is in the art of radiolabeling with 18F (see title and abstract within Luthra et al.) and meets this limitation.
Luthra et al. disclose the use of biological targeting molecules (BTMs) that are chelators (see paragraph [0053] within Luthra et al,), and subjection to 18F labeling. [Luthra et al. incorporates a triazole moiety through “click chemistry” and the resulting tosylate group is directly converted to a 18F labeled analogue (see paragraph [0134] and Example 3; both within Luthra et al.)].
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Lee et al. with the teachings of Luthra et al. to insert a radiolabeled 18F. The motivation for doing so would be to create an analogue which binds a transition metal, such as copper, with a radiolabeled 18F for the purposes of enhanced imaging.
Regarding instant claim 2, Lee et al. and Luthra et al. teach wherein the transition metal is selected from Cu(I), Cu(II), Zn(II), Fe(II), Fe(III), Co(II), Mn(II), Ni(II) or Cd(II).
Lee et al. disclose that the CD probes have affinity for both Cu(I) and Cu(II) (see page 5, paragraph 2 within Lee et al.).
Regarding instant claim 3, Lee et al. and Luthra et al. teach wherein the metal chelating portion further comprises at least one sulfur and/or oxygen heteroatom which coordinates to the transition metal.
Lee et al. disclose the probe, CD649, has two sulfur atoms available for coordination to the transition metal (see Table I of instant claim 1).
Regarding instant claim 6, Lee et al. and Luthra et al. teach wherein Ar is selected from the group consisting of pyrrolinyl, pyrrolyl, pyrazolinyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and thiazinyl.
Lee et al. disclose the use of an acyl imidazole moiety within their probes (see title and abstract within Lee et al.).
Regarding instant claim 7, Lee et al. and Luthra et al. teach wherein the metal chelating portion is
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Lee et al. disclose the identical metal chelating functionality as shown within instant claim 7 (see the discussion and citations within instant claim 1).
Combination of Lee et al., Luthra et al., and Dong et al.
Regarding instant claims 10, 12, 14, and 18-19, Lee et al., Luthra et al., and Dong et al. teach wherein the label portion comprises a naphthalimide fluorophore.
Despite the analogues of Lee et al. not having a naphthalimide fluorophore present, a skilled artisan (POSITA; person having ordinary skill in the art) would be able to substitute in the naphthalimide fluorophore for the existing fluorophore within Lee et al. under routine experimental conditions.
Dong et al. disclose a review on 1,8-naphthalimide-based fluorescent chemosensors: recent advances and perspectives (see title and abstract within Dong et al.).
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Dong et al. disclose 1,8-naphthalimide, as one of the classical dyes and fluorophores, has been widely used in analytical chemistry, materials chemistry, and biochemistry fields because of its excellent characteristic photostability, good structural flexibility, high fluorescence quantum yield, and large Stokes shift (see abstract within Dong et al.). In addition, Dong et al. disclose that the naphthalene ring acts as a p bridge, R1 is an electron-donating group (such as -NH2 and -OH) (see page 13501, right column, 1st paragraph within Dong et al.). The amino moiety in this position is needed for covalent bonding to the linker portion of the analogue.
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Furthermore, Dong et al. disclose the derivative where R2 is -CH2CH2OH (see page 13503, Figure 7 within Dong et al.). The hydroxyl group can be converted to the tosylate and then readily transformed into the 18F analogue (see paragraph [0134] and Example 3; both within Luthra et al.). A skilled artisan (POSITA) would then have all the synthetic pieces to construct the following derivative:
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based on the Lee et al., Luthra et al., and Dong et al. disclosures.
Combination of Lee et al. and Luthra et al.
Regarding instant claim 15, Lee et al. and Luthra et al. teach wherein the linker is C1-C6 alkyl, optionally comprising 1, 2 or 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom or any combination thereof and is covalently bound to both the metal chelating portion and the label portion.
Lee et al. disclose the linker -(CH2-)2O(CH2-)2NH- (see the discussion and citations within instant claim 1).
Regarding instant claim 22, Lee et al. and Luthra et al. teach a method for measuring a transition metal in vivo, comprising administering to a subject an effective amount of the probe of instant claim 1 and detecting the label portion after a period of time between administering the probe to the subject and detecting the label portion, wherein the period of time is between about 3 minutes and about 1 hour, wherein the measuring comprises detecting the label portion, and/or locating regions of high or low intensity of the label portion, and wherein the administering is selected from oral administration, subcutaneous injection or infusion, and intravenous injection or infusion.
Lee et al. disclose the administration and detection of the CD analogues or fragments thereof at different time periods (see page 5, 2nd and 3rd paragraph; see also page 6, 2nd paragraph; and page 7, 2nd and 3rd paragraph; all within Lee et al.). A skilled artisan (POSITA) would analyze these results and adjust the time periods based on the condition being monitored. Regions of high and low intensity from the label portion would be graphed/visualized and correlated to various health conditions.
Lee et al. also administers by syringe mL amounts of the CD probes (see see page 5, 2nd and 3rd paragraph within Lee et al.) to under both in vitro and in vivo conditions (see page 5, 2nd and 3rd paragraph; see also page 6, 2nd paragraph; and page 7, 2nd and 3rd paragraph; all within Lee et al.).
Regarding instant claim 24, Lee et al. and Luthra et al. teach wherein measuring the transition metal in vivo is used for identifying a region of transition metal dyshomeostasis in the subject, the method further comprising comparing regions of high or low intensity of the label portion to a control subject without transition metal dyshomeostasis.
Lee et al. disclose CD probes respond in a copper-dependent manner by increased covalent labeling of the dye with proximal proteins in cells at sites with elevated labile copper pools, which minimizes dye diffusion away from copper hotspots and preserves spatial information (see page 8, Conclusions within Lee et al.). In this manner, a skilled artisan (POSITA) would be able to monitor the label portion and analyze regions of both high and low intensity. Also see the discussion and citations within instant claim 22.
Regarding instant claims 25, 27-28, and 29, Lee et al. and Luthra et al. teach wherein the at least one biological system comprises a central nervous system, and wherein the at least one biological system of the subject comprises the central nervous system, the hepatic system, the endocrine system, or any combination thereof, and the condition is selected from Parkinson's disease, Alzheimer's disease, stroke, amyotrophic lateral sclerosis (ALS), Wilson's disease, multiple sclerosis (MS), Menkes disease, copper storage hepatopathy, diabetes mellitus, and neuroblastoma.
Please see the discussion and citations within instant claims 22 and 24 regarding monitoring the high and low intensity of label portion (creating a subject map). Lee et al. disclose the role of copper in both the brain and central nervous system (CNS) (see abstract and introduction within Lee et al.). Furthermore, Lee et al. sought to characterize labile copper pools in three main cell types within the brain (see abstract; also see CD649 Enables Activity-Based Sensing of Copper in Major Brain Cell Types on page 7 within Lee et al.):
Neurons
Microglia
Astrocytes
Despite Lee et al. not disclosing a specific focus disease, the fact remains that Lee et al. does disclose the broad biological CNS system to focus on. Lee et al. disclose that in cultured primary hippocampal neurons, CD649 can track redistributions of labile copper pools from somatic cell bodies to peripheral processes upon depolarization. This probe also reveals distinct cell-specific responses in labile copper dynamics with inflammatory stimuli, where inflammation triggers relocation of labile copper in astrocytes and a labile copper increase in microglia. We speculate that the opposing dynamics of labile copper in these two cell types may contribute to neuroinflammatoiy reactions, where labile copper contraction in astrocytes is compensated by labile copper expansion in microglia as signal to communicate between cell types. Such crosstalk could serve as a neuroprotective mechanism in neurodegenerative disease. Current efforts are geared toward expanding the palette of ABS probes that operate by dual sensing/ bioconjugation mechanisms for dual imaging/proteomics purposes, as well as applying CD649 and related chemical tools to decipher the biology of metals in the brain and beyond.
Using the above analysis for the CNS as a guide, a skilled artisan (POSITA) would be drawn to investigate from the list including Parkinson's disease, Alzheimer's disease, stroke, amyotrophic lateral sclerosis (ALS), Wilson's disease, multiple sclerosis (MS), Menkes disease, copper storage hepatopathy, diabetes mellitus, and neuroblastoma.
Regarding instant claim 36, Lee et al. and Luthra et al. teach a method of labelling a site of a transition metal in a biological tissue, comprising: (a) contacting the probe of instant claim 1 with the biological tissue, wherein the metal chelating portion of the probe binds to the transition metal, whereby binding of the transition metal to the metal chelating portion cleaves the metal chelating portion from the linker to form a reactive acyl group; (b) contacting the reactive acyl group with a nucleophile, resulting in binding of the label portion and the linker to the nucleophile; and (c) measuring the location of the label portion after a period of time between about 3 minutes and about 1 hour after contacting the probe with the biological tissue.
Instant claim 36 follows the protocol of Lee et al. regarding the steps a-c. Regarding (a) after introduction into a biological tissue/system, the metal chelating portion of the analogue would bind to copper. Regarding (b) the nucleophilic amino acid would react and covalently bond the label portion and the linker to the nucleophile. Additionally, please see instant claim 24 for the necessary rejection text. Finally, regarding (c) measuring the location of the label portion after a period of time between about 3 minutes and about 1 hour after contacting the probe with the biological tissue. A skilled artisan (POSITA) would modify the measurement time period as appropriate for the particular criteria. Please see the discussion and citations within instant claims 1, 22, 24-25, and 27-29 for the necessary rejection text.
Regarding instant claim 37, Lee et al. and Luthra et al. teach wherein the nucleophile is an amino acid.
Lee et al. disclose where the nucleophile is an amino acid (see the discussion and citations within instant claim 1).
Combination of Lee et al., Luthra et al., and Dong et al.
Regarding instant claim 38, Lee et al., Luthra et al., and Dong et al. teach wherein the label is detectable by both fluorescence and PET imaging.
Please see the discussion and citations within instant claims 10, 12, 14, and 18-19. Using the discussed analogue shown below:
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A fluorescence is present from the naphthalimide fluorophore, and the terminal F, which could be an 18F moiety, would be available for PET imaging.
Analogous Art
The Lee et al., Luthra et al., and Dong et al. references are directed to the same field of endeavor as the instant claims, that is, a probe for detecting a transition metal, 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 copper chelating acyl imidazole composition disclosed by Lee et al., using the teachings of Luthra et al. and Dong et al. in order to arrive at the subject matter of the instant claims.
The Lee et al., Luthra et al., and Dong et al. references all have considerable overlap in the application of chelation-imaging arts. In this instance, Lee et al. supplies the template for copper chelating acyl imidazole composition, Luthra et al. supplies the motivation to incorporate radiolabeled 18F with an established chelator, while Dong et al. supplies the support for the naphthalimide fluorophore. All references are directed to solubilizing agents and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to develop a radiolabeled chelating agent imaging composition.
Given these teachings, a POSITA would have been motivated to combine the template for copper chelating acyl imidazole composition as disclosed by Lee et al., the motivation to incorporate radiolabeled 18F with an established chelator disclosed by Luthra et al, and the support for the naphthalimide fluorophore taught by Dong 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 copper chelating acyl imidazole composition taught by Lee et al. along with the use of the necessary claim limitations taught by Luthra et al. and Dong 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 both Luthra et al. and Dong et al. would have been viewed by a POSITA as routine design optimizations or known modifications for solubilizing drug candidates. The motivation for doing so would be to create an analogue which binds a transition metal, such as copper, with a radiolabeled 18F for the purposes of enhanced imaging. Implementing these features in Lee et al.’s the copper chelating acyl imidazole composition would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Lee et al., Luthra et al., and Dong et al. provides all the elements of the claimed invention. The resulting radiolabeled copper chelating acyl imidazole composition constitutes 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.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
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