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 .
Priority
This application claims benefit of priority to Provisional Application 63/187,965 filed on 05/13/2021. Support for the instant claims can be found in the Provisional Application, therefore, for examination purposes, the effective filing date of the claimed invention is 05/13/2021.
Information Disclosure Statement
The Information Disclosure Statements filed on 09/21/2022 have been acknowledged and considered.
Drawings
The drawings are objected to because the drawings contain figures that are not in black and white, including Figures 1B, 2A-D, 3, 4A-B, 5A-B, 6A-C and 7. 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.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Election/Restrictions
Applicant’s election without traverse of Group II, claims 13-20, in the reply filed on 08/20/2025 is acknowledged.
Regarding the election of species, Applicant elected: a cell line as the specific type of cell, a lipid/calcium/phosphate (LCP) nanoparticle as the specific type of nanoparticle, N6-benzyl-ATP as the specific ATP analog, serine/threonine kinase as the specific type of kinase, detection of thiophosphorylation as the specific detectable label and AKT as the specific mutated kinase.
Applicant's election with traverse of the elected species listed immediately prior in the reply filed on 08/20/2025 is acknowledged. The traversal is on the grounds that each of the categories would be searchable without undue burden on the office. This is not found persuasive because, as stated in the Requirement for Restriction/Election of 06/20/2025, the species are independent or distinct because the types of cells, types of nanoparticles, types of ATP analogs, types of kinases, types of detectable labels and types of mutated kinases are not regarded as being of similar in nature because all of the alternatives do not share a common property or activity, and, absent evidence to the contrary, would be expected to have different functions and effects. Due to these differences, the species require a different field of search, resulting in undue burden of search on the Examiner. The species will be rejoined if a generic claim is found allowable.
The requirement is still deemed proper and is therefore made FINAL.
Amendment and Claim Status
In the reply filed on 08/20/2025, Applicant indicated claims 1-12 were withdrawn in response to the restriction requirement.
Claims 1-20 are currently pending.
Claims 1-12 are withdrawn by the Examiner as they are not encompassed by the election.
Claims 13-20 are under examination.
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 13-20 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.
Claim 13 recites “wherein the ATP analog comprises a detectable label, and after a predetermined period of time, detecting a detectable label on a substrate from the ATP analog-nanoparticle conjugate contacts the one or more mutated kinases in cellulo, and …” in lines 6-8 of the claim. It is unclear exactly what is being claimed in the last portion of the recited lines. It appears, when the claim is taken as a whole, Applicant is intending to claim the ATP-analog-nanoparticle conjugate comes into contact with the mutated kinase. However, the Examiner, or one of one of ordinary skill in the art, cannot ascertain the full scope or metes and bounds of the claim as it is unclear what “wherein the ATP analog comprises a detectable label, and after a predetermined period of time, detecting a detectable label on a substrate from the ATP analog-nanoparticle conjugate contacts the one or more mutated kinases in cellulo, and …” means. Therefore, claim 13, and all claims dependent upon claim 13, are indefinite. If Applicant means, as stated above, that the ATP-analog-nanoparticle conjugate comes into contact with the mutated kinase, it is suggested to amend the claim to recite “ … and after a predetermined period of time, detecting a detectable label on a substrate from the ATP analog-nanoparticle conjugate when it contacts the one or more mutated kinases in cellulo …” or “ … and after a predetermined period of time, detecting a detectable label on a substrate from the ATP analog-nanoparticle conjugate once it contacts the one or more mutated kinases in cellulo …”, or something similar.
Claim 13 is drawn to a system for detecting kinase activity. The system, as-claimed, is interpreted by the Examiner to be directed to a product, as made clear in the Requirement for Restriction/Election mailed on 06/20/2025 by separating the method claims from the system (kit) claims, which Applicant did not dispute. A ‘system’ claim is not always indefinite. A ‘system’ claim wherein one of ordinary skill in the art would be able to readily determine whether the claim is directed to a product or a method would not necessarily be indefinite. See MPEP 2173.05(p)(II). Claim 13 recites “wherein the cell is contacted with an ATP analog-nanoparticle … of the ATP analog-nanoparticle” in lines 4-5 of the claim, “…. and after a predetermined period of time, detecting a label on a substrate … in cellulo” in lines 6-8 of the claim and “wherein the detectable label was transferred from the ATP … one or more mutated kinases” in lines 9-10 of the claim. These are all method steps. It is unclear how the aforementioned method steps are intended to limit the system. A system, which is a product, is a tangible, physical thing, not a method.
Thus, it is unclear how the method steps are intended to limit the system. These method steps are interpreted as laudatory because the Examiner cannot determine from the claims as-written, in light of the Specification, how Applicant is trying to limit the product, the system, by reciting method steps. Therefore, claim 13, and all claims dependent upon claim 13, are rendered indefinite.
The limitations within claim 13 that are clear include: “a well that comprises cells that comprise one or more mutated kinases, wherein the one or more mutated kinases comprise a mutation that enlarges an ATP binding pocket of the kinase” from lines 2-3 and “wherein the ATP analog comprises a detectable label” from line 6 of the claim. However, the ”ATP analog” lacks antecedent basis because the limitation regarding the ATP analog is part of the method step, which is being examined as being laudatory. Even so, for the purposes of compact prosecution and applying prior art, Claim 13 is being interpreted as a system comprising: a well that comprises cells that comprise one or more mutated kinases, wherein the one or more mutated kinases comprise a mutation that enlarges an ATP binding pocket of the kinase, wherein the system comprises an ATP analog and wherein the ATP analog comprises a detectable label.
Claim 15 recites “wherein the system determines the presence of the substrate in a sample, wherein the substrate is a known substrate for the one or more kinases, or detecting the presence of a previously unknown substrate for the one or more kinases” in lines 1-3 of the claim. It is unclear what this claim is intended to limit as this determination is made from the method steps recited in claim 13 and the Examiner cannot make a reasonable interpretation of the claim as the claim is a result of a method step, yet the claim is directed to a product. Additionally, this claim has antecedence to the method steps in claim 13, furthering the indefiniteness of the claim. For the purposes of examination and applying prior art, this claim is being interpreted as laudatory.
Claim 16 recites “AGC kinases (PKA, PKG, PKC, PKN, PDK1, AKT, SGK, RSK, RSKR, RSKL, GRK, NDR, MAST, DMPK, YANK, AND PTF subfamilies) …, CMGC kinases (CDK, MAPK, GSK3 and CLK subfamilies …” in lines 2-4 of the claim. The use of parentheses in this manner renders the claim indefinite as it is exemplary language because it is unclear, and one of ordinary skill in the art would not be able to determine, if the species within the parentheses are simply suggestions or if the species within the parentheses are actual limitations of the claim. It is noted that Applicant has elected a specific species, an AKT kinase, and the entire scope of the claim is not being examined at this time. However, the use of parentheses still renders the claim indefinite.
Claims 17-18 further recite method steps. For the reasons listed above, claims 17-18 are rendered indefinite and are being examined as laudatory.
Claim 20 is indefinite for the same reasons stated above regarding claim 13. Claim 20 is directed to a kit, which is a product, yet the claim contains method steps. It is unclear how the method steps are intended to limit the product.
For the purposes of compact prosecution and applying prior art, claim 20 is being interpreted as: a kit, comprising: a well that comprises cells that comprise one or more mutated kinases, wherein the one or more mutated kinases comprise a mutation that enlarges an ATP binding pocket of the kinase and an ATP analog-nanoparticle conjugate capable of intracellular delivery of the ATP analog-nanoparticle conjugate. It is noted the kit being for ‘detecting kinase activity in vivo’ is an intended use and is not being examined as a limitation.
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.
Claims 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sicinski et al. (WO 2018035296 A1, 02/22/2018).
Regarding claim 13, see 112b above. As stated above, claim 13 is being interpreted as a system comprising: a well that comprises cells that comprise one or more mutated kinases, wherein the one or more mutated kinases comprise a mutation that enlarges an ATP binding pocket of the kinase, wherein the system comprises an ATP analog and wherein the ATP analog comprises a detectable label.
Sicinski et al. disclose:
methods for in situ detection of protein substrates of an analog-sensitive kinase. The methods are particularly useful for identification of kinase activity in cells in culture and within tissues at subcellular levels at various physiological and pathological conditions, or for quantification of overall kinase activity at cellular or subcellular levels. Kits comprising agents for using the methods are also provided.
An aspect of the invention provides a method for in situ visualization of kinase activity in a sample comprising a kinase, the method comprising: (a) incubating the sample with a fixative; (b) incubating the sample with an ATP analog, such that the kinase accepts the ATP analog as a phosphate donor substrate, such that the γ-phosphate of the ATP analog- comprises a transferrable label; and (c) detecting the transferrable label (Page 2, Lines 8-17).
Sicinski et al. go on to disclose a specific example, Example 2, where a murine kinase, CDK1, was engineered with two substitution, M32V and F80G (Page 22, Lines 3-4), reading on a mutated kinase with a mutation that enlarges the ATP binding pocket of the kinase. Cells comprising the mutated kinases were cultured on glass coverslips (Page 22, Lines 7-8) and incubated with furfuryladenosine-5’-O-(3-thiotriphosphate) (Page 22, Lines 10-11), furfuryladenosine-5’-O-(3-thiotriphosphate) reads on an ATP analog, allowing thiophosphorylation of substrates of the mutated kinase (Page 22, Lines 13-14). The thiophosphorylated residues of the substrates were alkylated with PBBM (Page 22, Lines 15-16) and subsequently visualized with an antithiophosphoester antibody and a secondary antibody coupled with AlexaFluor 594 (Page 22, Lines 18-19). Thus, the glass coverslip, reading on a system, comprising the mutated kinase and the furfuryladenosine-5’-O-(3-thiotriphosphate) that contained the label that was passed to the substrate, reads on a system comprising one or more mutated kinases with a mutation that enlarges the ATP binding pocket and an ATP conjugate with a detectable label.
Sicinski et al. further disclose in some embodiments the sample is a monolayer of cells mounted on a support material, such as a coverslip, a tissue section, or a population of cells in suspension (Page 15, Lines 23-25).
Sicinski et al. do not disclose the system comprises a well.
However, as Sicinski et al. disclose the cells can be in suspension, and cells in suspension are very commonly in wells, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized cells in suspension in wells as the system in Sicinski et al. because utilizing wells for culturing cells is well-known in the art. It is well-known in the art that culturing cells can be carried out in wells, for example, in a multi-well plate.
Regarding claim 14, as disclosed above regarding claim 13, Sicinski et al. disclose mutating CDK1. CDK1 is a serine/threonine kinase, which is the specific kinase elected by Applicant.
Regarding claim 15, see 112b above. This claim is interpreted as laudatory.
Regarding claim 16, see 112b above. It is noted Applicant elected AKT. Sicinski et al. disclose the kinase can be any kinase selected from a Markush group which includes AKT (Claim 34 of Sicinski et al.).
Regarding claims 17-18, see 112b above. This claim is interpreted as laudatory.
Regarding claim 19, as discussed above regarding claim 13, Sicinski et al. disclose incubating mutant murine stem cells comprising a CDK1 with an M32V substitution and an F80G mutation on a glass coverslip. Sicinski et al. further disclose murine CDK5 was engineered with an F80G substitution and substituted from the wild type CDK5 in mice (Page 23, Line 16-17). Brain sections from the mice were mounted on glass coverslips (Page 23, Lines 20-21). It is noted ‘each well is used to detect an activity of a different mutated kinase on the one or more substrates’ is an intended use and the use of a well does not materially change or alter any characteristic of the instantly-claimed components . Thus, Sicinski et al. disclose two glass coverslips wherein each comprises a different mutated kinase.
Sicinski et al. do not explicitly disclose wells.
However, as discussed above regarding claim 13, Sicinski et al. do disclose the cells can be in suspension, and cells in suspension are well-known in the art to be in wells. Wells provide the ability to simultaneously examine multiple samples, while keeping the samples separated. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized cells in suspension in wells as the system in Sicinski et al. because of the ability to examine multiple samples at once and utilizing wells for culturing cells is well-known in the art.
Claims 13-20 are rejected under 35 U.S.C. 103 as being unpatentable over Sicinski et al. (WO 2018035296 A1, 02/22/2018) in view of Huang et al. (US 20120201872 A1, 08/09/2012).
Regarding claim 20, see 112b above. To reiterate, claim 20 is being interpreted as: a kit, comprising: a well that comprises cells that comprise one or more mutated kinases, wherein the one or more mutated kinases comprise a mutation that enlarges an ATP binding pocket of the kinase and an ATP analog-nanoparticle conjugate capable of intracellular delivery of the ATP analog-nanoparticle conjugate.
Sicinski et al. disclose, as discussed above regarding claim 13, kits comprising agents for using the methods are also provided. Sicinski et al. further disclose the kit comprises a fixative; an ATP analog, wherein the γ-phosphate of the ATP analog comprises a transferrable label; and one or more agents for detecting the transferrable label (Page 17, Lines 2-4). Sicinski et al. go on to disclose the Shokat method, introducing a mutation of a bulky gatekeeper residue in the ATP-binding pocket of a kinase which allows the kinase to utilize a bulky ATP analog that is not usable by wild-type kinases (Page 1, 17-18), requires a membrane permeabilization step due to the impermeability of the bulky ATP analogs which disrupts cellular and intracellular architecture, leading to the model not be representative of the cell in its native state (Page 1, Lines 26-28). Therefore, there is a need for methods that can be used in situ for detecting kinase activity while maintaining the natural state of the cell (Page 2, Lines 4-5).
Sicinski et al. do not disclose the kit comprising a well, a mutated kinase or an ATP analog-nanoparticle conjugate.
However, Sicinski et al. do disclose the cells can be in suspension, and cells in suspension are very commonly in wells. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized a well to contain the components of the kit of Sicinski et al.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have included one or more of the mutated kinases disclosed by Sicinski et al. in the kit because Sicinski et al. disclose the kit comprising agents for using the methods. To fully utilize the method, one would need the mutated kinase used in the method. Thus, it would have been obvious to include one or more of the mutated kinases in the kit of Sicinski et al. so that the kit would provide the ability to fully utilize the method disclosed by Sicinski et al.
Moreover, Huang et al. disclose methods and compositions for delivering bioactive compounds to a cell, tissue or physiological site (See entire document, More specifically, the Abstract). Compositions include delivery system complexes comprising a biodegradable ionic precipitate comprising a bioactive compound, wherein the precipitate is encapsulated by a liposome, wherein the bioactive compound can comprise any type of bioactive compound and wherein the delivery system complexes can be formulated into liposome/calcium phosphate (LCP) nanoparticles (Paragraph [0005]).
As such, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized a liposome/calcium phosphate nanoparticle (LCP), reading on a lipid/calcium/phosphate (LCP) nanoparticle which is the elected species of nanoparticle, to form an ATP analog-nanoparticle conjugate in the kit of Sicinski et al. because Sicinski et al. disclose there is a need for in situ detection of kinase activity where the natural state of the cell is maintained and utilizing an LCP nanoparticle was a known and effective means of delivering a bioactive compound, of which ATP analogs are, to a cell as taught by Huang et al.
The Supreme court acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
The Examiner is therefore of the opinion that from the combined teachings of the references cited above, that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art especially in the absence of unexpected results.
Conclusion
Claims 13-20 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY T WHITE whose telephone number is (571)272-0683. The examiner can normally be reached Monday - Friday 8:30 - 5:00 EST.
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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653