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 .
Claim Status
No amendments have been provided in the instant response. Original claims 1-20 filed 3/11/2022 are pending.
Election/Restriction
Applicant’s election without traverse of Group III and the species of monocyte as cell type, coilin and nuclear protein and nusinersen as treatment in the reply filed on 9/9/2025 is acknowledged.
In review of the claims of the elected invention, it appears the method of group I for assessing the distance between two fluorescently labelled proteins is required of elected group III and for Group II where treatment must be assessed as part of the analysis using the method of group I. Upon initial search and review, it does not appear to be an undue burden to examine all the groups in view of the election. Accordingly, the restriction requirement between groups I-III is withdrawn.
Additionally, in review of the art it appears that nuclear proteins associated with spinal atrophy were assessed in multiple types of cells and tissue types, and various possible treatments recited in the claims were known and used for spinal atrophy. Accordingly, upon initial search it does not appear to be an undue burden to examine all the recited species, and the restriction requirement between the species is withdrawn.
Claims 1-20, drawn to a method of assessing the location of proteins associated with spinal atrophy for possible treatment for spinal muscular atrophy are currently under examination.
Priority
This application filed 3/11/2022 claims benefit to foreign application JP2021-040682 filed 3/12/2021 in Japan.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. See paper entered 4/18/2022 (copy electronically retrieved from WIPO).
Information Disclosure Statement
The four information disclosure statements (IDS) submitted on 3/11/2022-10/18/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
It is noted that several of the cited references are Office actions are from foreign offices, some translated and some providing a summary. It is noted that for review of these, the pending claims that were reviewed in these actions were not provided, but for completeness and clarity of the record the cited references when provided in this prosecution were not considered in light of the instant claims. The foreign statutes and comments of the reviewers were not clearly in context of the pending claims and were not considered for their logic nor factual accuracy of comments in actions from other foreign offices.
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 1-20 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.
Claims 1, 4 and 7 are indefinite in reciting, “SMN”. Acronyms or abbreviations should be fully defined and recited at least one time in a given set of claims.
Claims 1, 4 and 7 are vague and unclear in reciting, “acquiring an intracellular distance” between “bright” spots because it is unclear what is meant by bright versus possible background and is lacking a comparative basis for defining its metes and bounds. Also, it is unclear if there is more than one bright spot for one or both labels, what steps or what comparison is to be performed and what value of a distance is supposed to be obtained. Further, the metes and bounds of a ‘threshold value’ is not recited nor is it defined in the specification, and it appears to be a relative term or undefined term required to practice the method of analysis.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim analysis
Claim 1 is the broadest claim and is directed to analyzing fluorescence images which represent location of SMN proteins which were identified using two fluorescent dyes and measure the distance between the two detected labels. More specifically, in the analysis differences in the distances if they exist can be interpreted to be correlated to be an indicator of spinal muscular atrophy affection. Claim 4 provides for similar steps and correlations. Claim 7 provides for an additional step where treatment is assessed by observing changes in distances/location of the dyes in response to and in the absence of treatment.
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of a process.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of accessing image data. The step of assessing an image and measuring distance between to observable labels in an image are instructional steps. Further, once a distance is measured the measurement is used to correlate to a specific condition of spinal muscular atrophy, when the appropriate SMN proteins are detected and the correlation between the SMN is informative of spinal muscular atrophy. In view of the guidance of the specification, the claim requires assessing images and computing a distance of any observed label that can be observed. The judicial exception is a set of instructions for analysis of image data, and appear to be directed to Mathematical Concepts to the extent that distances are assessed and correlated to spinal muscular atrophy and also directed to Mental Processes, which are concepts performed in the human mind (including an observation, evaluation, judgment, opinion) for making the observation of an image. The breadth of “acquiring” encompasses non-transformative visual assessment of an individual image coupled with prior or known knowledge of the correlation of said distance with spinal muscular atrophy. This breadth does not impose a meaningful limit on the claim scope, such that all others are not precluded from using the natural principle of observing a biological process that represents the state of the cell and represents the presence of spinal muscular atrophy. Although the claims recite “fluorescence image’ this image can be physical and observable, but to the extent that it can be digital the courts have also identified limitations that did not integrate a judicial exception into a practical application; for example, merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). Computing, constructing datasets and using statistical models was well understood, conventional, and routinely performed in the art at the time the application was filed. Furthermore, the limitation of the wherein clause that a distance is associated with a condition is simply informative and descriptive of what the image may represent. See MPEP § 2106.05(g) for a discussion on adding insignificant extra-solution (both pre-solution and post-solution) activity to the judicial exception. See also MPEP § 2106.05(h) for a discussion on generally linking the use of a judicial exception to a particular technological environment or field of use.
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In the instant case, the claims do not have an additional element beyond making observation and measuring ‘labels’ that can be measured. This judicial exception requires steps recited at high level of generality and are only stored on a non-transitory, and is not found to be a practical application of the judicial exception as broadly set forth.
For step 2B of the 101 analysis, each of the independent claims recites additional elements and are found to be the steps of obtaining image data. As such, the claims do not provide for any additional element to consider under step 2B. It is noted that in explaining the Alice framework, the Court wrote that "[i]n cases involving software innovations, [the step one] inquiry often turns on whether the claims focus on the specific asserted improvement in computer capabilities or, instead, on a process that qualifies as an abstract idea for which computers are invoked merely as a tool." The Court further noted that "[s]ince Alice, we have found software inventions to be patent-eligible where they have made non-abstract improvements to existing technological processes and computer technology." Moreover, these improvements must be specific -- "[a]n improved result, without more stated in the claim, is not enough to confer eligibility to an otherwise abstract idea . . . [t]o be patent-eligible, the claims must recite a specific means or method that solves a problem in an existing technological process.” As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of image data. While the instruction can be stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the previous claims to a computer medium and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer. Based upon an analysis with respect to the claim as a whole, claims 1-20 do not recite something significantly different than a judicial exception. Dependent claims set forth additional steps which are more specifically define the considerations and steps of calculating, and comparing, and do not add additional elements which result in significantly more to the claimed method for the analysis. In the instant case, the claims comprise steps of comparing image data and is considered the judicial exception. It is noted that while the claims set forth or imply information about the image being analyzed (that they are correlated to spinal muscular atrophy), this is only description of the data being analyzed and context and user defined. As such, the instant claims set forth an inventive concept that are drawn only to an abstract process that only manipulates data and, therefore, are not directed to statutory subject matter. No additional steps are recited in the instantly claimed invention that would amount to significantly more than the judicial exception. Without additional limitations, a process that employs mathematical algorithms (measuring distances) to generate additional information is not patent eligible. Furthermore, if a claim is directed essentially to a method of calculating, using a mathematical formula, even if the solution is for a specific purpose, the claimed method is non-statutory. In other words, patenting abstract idea (designing probes to a target sequence) cannot be circumvented by attempting to limit the use to a particular technological environment or purpose and desired result.
One way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
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.
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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Saito et al. (US 2017/0115297 (27 April 2017), Sapaly et al. (Small-molecule flunarizine increases SMN protein in nuclear Cajal bodies and motor function in a mouse model of spinal muscular atrophy. Scientific Reports. 8:2075 1-16 (01 February 2018)), Tucker et al. (Residual Cajal bodies in coilin knockout mice fail to recruit Sm snRNPs and SMN, the spinal muscular atrophy gene product The Journal of Cell Biology, Volume 154, Number 2, July 23, 2001) and AMNIS (Image Stream MkII imaging flow cytometers (2014)).
Saito et al. disclose a method of analyzing survival motor neuron (SMN) protein in whole blood sample of a subject (Abstract; [0016, 0047]). The method comprises: obtaining a sample (whole blood sample) comprising blood-derived nucleated cells (PBMC: peripheral blood mononuclear cells) from a subject [0035, 0047, 0048]; subjecting the blood sample to erythrocyte hemolysis treatment to obtain blood-derived nucleated cells or PBMC [0026, 0039, 0048, 0050]; and labeling one or more surface antigen markers including CD14, CD45, CD3, and CD33 of the PBMCs with surface antigen-specific fluorophore-labelled antibodies: anti-CD14, anti-CD45, anti-CD3 and anti-CD33 that bind to CD14, CD45, CD3, and CD33 of the blood-derived nucleated cells [0039, 0069, 0075]. The method further teach labeling SMN protein in the surface antigen-labeled blood-derived nucleated cells with a first fluorescent dye (fluorescein-conjugated anti-SMN antibody: Cy3, Cy7, APC, PE, Alexa Fluor) [0018, 0022, 0023, 0029, 0049, 0060, 0061]; labeling nuclei of the surface antigen-labeled blood-derived nucleated cells having first fluorescent dye-labeled SMN protein with a second fluorescent dye (nuclear stain: HOESCH, DAPI, Propidium Iodide, fluorescent labeled anti-lamin or anti-histone) [0019, 0023, 0030, 0063]; and selecting one cell population (i.e. lymphoblast) from a plurality of surface antigen-labeled blood-derived nucleated cells or PBMCs having the first fluorescent-labeled SMN and the second fluorescent labeled nuclei [0020, 0024] based on fluorescence intensity (FI) and side scattering (SSC) using imaging flow cytometry ([0016-0021, 0024, 0031, 0035, 0039l 0043]; Figure 2; Figure 10). Saito et al. specifically teach that the one cell population selected comprises monocytes which express CD14 surface antigen marker [0069, 0075]. The method further comprises analyzing the expression of an SMN protein in the fluorophore-labeled monocytes based on the fluorescence emitted by the first fluorescent dye [0022] that indicates the presence of nuclear SMN protein [0016-0022, 0029-0031] using imaging flow cytometry ([0035, 0036, 0039, 0085]; Figure 1, Figure 2).
Saito et al. teach that a measured or quantitated decrease in SMN protein in the monocytes of the subject compared against measured or quantitated normal level of SMN protein of a healthy normal subject indicates the subject to have spinal muscular atrophy (SMA) [0032, 0047, 0083, 0087]. A measured or quantitated decreased level of SMN protein in the monocytes of the subject compared against a measured or quantitated normal level of SMN protein in a healthy normal subject indicates the subject NOT to have SMA [0035, 0036, 0047, 0088]. A measured or quantitated increase in level of SMN protein in the monocytes of the subject after administration of SMA Drug compared against a measured or quantitated level of SMN protein in the subject before administration of the SMA Drug indicates that the SMA Drug is effective for increasing or normalizing the level of the SMN protein in the monocytes and treating SMA in the subject [0033, 0047, 0050, 0089]. Saito et al. does not specifically teach to measure the expression of an SMN nuclear body in the nucleus by measuring a fluorescence intensity of a nuclear portion in the shape of a spot in the fluorescence emitted.
However, Sapaly et al. teach that SMA caused by mutations of the SMN gene leading to decrease in SMN protein levels and that SMN deficiency alters nuclear body or Cajal body (CB) formation (Abstract). SMN protein has a specific localization in the nucleus, and is found specifically concentrated in the nuclear bodies and that altered nuclear body (CB) localization of SMN protein is the hallmark of childhood SMA disease (p. 1, 2nd full ¶). Sapaly et al. teach analyzing and imaging the expression (localization) of an SMN nuclear body in the nucleus by measuring fluorescence intensity of the nuclear portion in the shape of a spot in the fluorescence as shown in Figure 3 (p. 4, last ¶ to p. 5. Although Sapaly et al. does not teach using an imaging flow cytometer with an objective lens magnification of 40 times or more, AMNIS teaches ImageStream MkII imaging flow cytometers capable of high-resolution, high-sensitivity imaging flow cytometry and having a magnification of 40 times to 60 times (40 times or more). Applicant, by way of disclosure, taught using conventional commercially known imaging flow cytometers and specifically taught using ImageStream MkII imaging flow cytometer by AMNIS [0082, 0096]. Similarly, Tucker et al. (provide for the visulazation of esidual Cajal bodies in coilin knockout mice fail to recruit and the location within a cell Sm snRNPs and SMN.
It would have been obvious to one of ordinary skill in the art before the invention was filed to incorporate the teaching of Sapaly in analyzing the expressions of SMN protein nuclear body using the imaging flow cytometer of AMNIS which is capable of high-resolution, high-sensitivity imaging flow cytometry with 40 times magnification into the method of analyzing SMN protein expression of Saito that determines if a subject has SMA because Saito taught that SMA patients are shown to have decreased levels of SMN protein, and Sapaly further found that SMN deficiency manifested as decrease in SMN protein levels resulting from SMA alters nuclear body formation and localization as detected by high resolution AMNIS imaging flow cytometry and that altered nuclear body (CB) localization of SMN protein is the hallmark of childhood SMA disease.
Conclusion
No claim is allowed.
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/Joseph Woitach/ Primary Examiner, Art Unit 1687