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 .
Claims 1-18, filed 3/16/2023, are acknowledged. Claims 1-18 are pending and considered on the merits below.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statements filed on 3/17/2023, 03/17/2023, 3/20/2023, 12/26/2023 are in compliance with the provisions of 37 CFR 1.97 and have been considered. An initialed copy of the Form 1449 is enclosed herewith.
Claim Objections
Claim 8 is objected to because of the following informalities: there should only be one comma after Cu ions.
Claim 10 is objected to because of the following informalities: remove “the” between “to” and “claim 1”.
Claim 13 is objected to because of the following informalities: remove “the” between “to” and “claim 1”.
Claim 13 is objected to because of the following informalities: line 1: change “and” to “wherein”.
Claim 14 is objected to because of the following informalities: put a period at the end of the claim.
Claim 18 is objected to because of the following informalities: remove “the” between “to” and “claim 12”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2 and 11, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5, 7, 9-15, and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zorlu et al. (Chem. Eur. J. 2020, 26, 11129– 11134, provided on the IDS on 3/17/2023).
Regarding claim 1, Zorlu describes a method for detecting free metal ions in a sample (abstract) comprising:
providing a liquid sample potentially comprising free metal ions (page 11131 “mouse ribs as an example for naturally occurring HAP (calcium ions). The sections were incubated… in HEPES buffer for varying times at room temperature,”),
adding to said sample a fluorescent probe comprising
i. an organic fluorescent core and ii. at least one metal binding functional group selected from a group comprising a phosphonic acid group and an arsonic acid group and being covalently linked to a sp or a sp2-carbon atom or a nitrogen atom of the fluorescent core via a P or As atom (scheme 1 and page 11131 “The sections were incubated with p-H8TPPA, m-H8TPPA and p-H8TPPA -iPr8”); and
measuring fluorescence of said sample ( “Figure 2. The absorbance (A) and fluorescence (B) spectra”).
Regarding claim 2, Zorlu describes the method according to claim 1, wherein the organic fluorescent core is selected from group comprising tetrapyrrole derivatives, such as porphyrin or phthalocyanine, acridine, BODIPY, cyanine or cyanine derivatives, carbazole, coumarin or coumarin derivatives, xanthene or xanthene derivatives such as fluorescein or rhodamine (scheme 1).
Regarding claim 3, Zorlu describes the method according claim 1, to wherein the fluorescent probe comprises two or more metal binding functional groups (page 11130 “the phosphonic acid metal binding unit”).
Regarding claim 4, Zorlu describes the method according to claim 1, wherein the fluorescent probe is selected from a group comprising 5,10,15,20-tetrakis[p-phenylphosphonic acid porphyrin (p-H8TPPA), and 5,10,15,20-tetrakis[m-phenylphosphonic acid] porphyrin (m-H8TPPA) (scheme 1 and page 11131 “The sections were incubated with p-H8TPPA, m-H8TPPA”).
Regarding claim 5, Zorlu describes the method according to claim 1, wherein the measuring fluorescence includes exciting the sample with a light of an excitation wavelength and detecting emitted light at an emission wavelength (figure 2b).
Regarding claim 7, Zorlu describes the method according to the claim 1, wherein presence of the metal ions leads to a concentration-dependent decrease, increase or shift of fluorescence compared to a reference sample, wherein the method includes determining a concentration of metal ions in said sample (page 11131 “the dye binding to HAP is concentration dependent. When the mouse ribs were incubated with 1 mgmL-1 p-H8TPPA in HEPES for differing times from 120 to 10 mins (Figure S18 A–E), there was a clear decrease in fluorescence intensity but even the 10 min short incubation yielded an appreciable fluorescence compared to the negative control (Figure S18E compared to Figure S18 F).”).
Regarding claim 9, Zorlu describes the method according to claim 1, wherein the metal ions are ions of a group of metals comprising Fe, Mg and Ca, wherein the ions are one of divalent and non-divalent (page 11131 “HAP (divalent calcium ions)”).
Regarding claim 10, Zorlu describes the method according to the claim 1, wherein presence of the metal ions leads to a concentration dependent increase of fluorescence compared to a reference sample, and the method further includes determining a concentration of metal ions in said sample (page 11131 “the dye binding to HAP is concentration dependent. When the mouse ribs were incubated with 1 mgmL-1 p-H8TPPA in HEPES for differing times from 120 to 10 mins (Figure S18 A–E), there was a clear decrease in fluorescence intensity but even the 10 min short incubation yielded an appreciable fluorescence compared to the negative control (Figure S18E compared to Figure S18 F).”).
Regarding claim 11, Zorlu describes the method according to claim 1, wherein the step of providing a liquid sample includes providing a biological sample, such as a bodily fluid, a tissue sample or a sample comprising cells (page 11131 “mouse ribs”).
Regarding claim 12, Zorlu describes the method according to claim 1,wherein the step of providing a liquid sample includes providing a sample comprising cells and the fluorescent probe in the adding step is cell permeable (page 11132 “p-H8TPPA provides two more positives -cell permeability and cellular retention- desirable for imaging Applications”).
Regarding claim 13, Zorlu describes the method according to the claim 12, and the measuring step includes measuring the fluorescence in association with a step microscopically analyzing the cells (figure 1 and page 11131 “fluorescence microscopy”).
Regarding claim 14, Zorlu describes the method according to claim 1, further including calculating a concentration of free metals based on the mass action law involving calibration based on addition of a chelator and/or metal ions (page 11131 “This indicates that the dye binding to HAP is concentration dependent. When the mouse ribs were incubated with 1 mgmL-1 p-H8TPPA in HEPES for differing times from 120 to 10 mins (Figure S18 A–E), there was a clear decrease in fluorescence intensity but even the 10 min short incubation yielded an appreciable fluorescence compared to the negative control (Figure S18E compared to Figure S18 F).” Examiner’s note: the applicant defines “mass action law” in [0161] as “The mass action law (or law of mass action) is the proposition that the rate of a chemical reaction is directly proportional to the product of the activities or concentrations of the reactants. It explains and predicts behaviors of solutions in dynamic equilibrium. Specifically, it implies that for a chemical reaction mixture that is in equilibrium, the ratio between the concentration of reactants and products is constant. Thus as indication by page 11131 the concentration of the metal in HAP is proportional to the dye binding).
Regarding claim 15, Zorlu describes the method according to claim 1, including using the method in clinical diagnostics for determining available levels of free metal ions in a patient sample (abstract “Due to the lower reported toxicity of (p-H8TPPA), these probes could find applications in monitoring bone resorption or adsorption, or imaging vascular or soft tissue calcifications for breast cancer diagnosis etc.”).
Regarding claim 17, Zorlu describes the method according to claim 9, wherein the metal ions are one of divalent and non-divalent (page 11131 “HAP (divalent calcium ions)”).
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) 6, 8, 16, 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zorlu et al. (Chem. Eur. J. 2020, 26, 11129– 11134, provided on the IDS on 3/17/2023) in view of Carter et al. (Chem. Rev. 2014, 114, 4564−4601, provided on the IDS on 3/17/2023).
Regarding claim 6, Zorlu describes the method according to claim 1, however is silent to wherein the metal ions are ions of a group of metals comprising Cu, Zn, Pb, Hg, Cd, Co and Mn, wherein the ions are preferably divalent.
Carter describes copper (Cu) metal ion detection (page 4585 “to detect Cu+”). Carter further suggests that there is a link between calcium and copper when performing metal detection (page 4585 “This study established a link between copper mobilization and calcium release”). Additionally, Carter provides motivation to also incorporate copper detection because it is an essential metal for many life forms that can be challenging to detect (pages 4564 and 4584).
Therefore it would have been obvious to one skilled in the art at the time the invention was filed to incorporate the detection of Cu into the method of Zorlu as suggested by Carter because this would allow for detection of an essential bio-metal.
Regarding claims 8 and 16, Zorlu describes the method according to claim 1, wherein the fluorescent probe is one of p-H8TPPA and m-H8TPPA (abstract).
However Zorlu is silent to wherein the metal ions are Cu ions.
Carter describes copper (Cu) metal ion detection (page 4585 “to detect Cu+”). Carter further suggests that there is a link between calcium and copper when performing metal detection (page 4585 “This study established a link between copper mobilization and calcium release”). Additionally, Carter provides motivation to also incorporate copper detection because it is an essential metal for many life forms that can be challenging to detect (pages 4564 and 4584).
Therefore it would have been obvious to one skilled in the art at the time the invention was filed to incorporate the detection of Cu into the method of Zorlu as suggested by Carter because this would allow for detection of an essential bio-metal.
Regarding claim 18, Zorlu describes the method according to the claim 12, however is silent to wherein the step of microscopically analyzing the cells includes confocal fluorescent microscopy.
Carter describes using “a novel ex situ confocal microscopy technique, Petrat et al. measured the concentration of labile iron in hepatocytes to be approximately 2.5−9.8 μM” (page 4588). This suggest motivation to incorporate it into detection methods as it has a novel detection range.
Therefore it would have been obvious to one skilled in the art at the time the invention was filed to incorporate a confocal fluorescent microscopy into the method of Zorlu as suggested by Carter because this would allow for a novel detection range for the metal ions.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY R BERKELEY whose telephone number is (571)272-9831. The examiner can normally be reached M-Th 9-6.
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/EMILY R. BERKELEY/
Examiner
Art Unit 1796
/ELIZABETH A ROBINSON/Supervisory Patent Examiner, Art Unit 1796
Prosecution Insights