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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Acknowledgment is made of applicants' claim for foreign priority to Japanese applications JP 2022-005252 filed on 01/17/2022. Certified copies of the foreign priority document(s) are present in the application file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/10/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
Claims 1-17 are pending and under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claim states that:
“A method for evaluating cardiomyocytes using Raman scattering, the method comprising:
acquiring a Raman spectrum of cardiomyocytes artificially induced to differentiate from pluripotent stem cells;
acquiring an intensity of Raman-scattered light for a protein containing at least one of heme b and heme c as a prosthetic group from the Raman spectrum; and
evaluating a state of progress of maturation of the cardiomyocytes on the basis of the intensity of the Raman-scattered light.”
The Applicants have claimed a method of monitoring differentiation of cardiomyocytes using Raman scattering by using the heme b or heme c of any protein containing these prosthetic groups. However, the experimental data in the application did not teach the use of any heme b or heme c protein for monitoring maturation of cardiomyocytes. Applicant’s data is limited to monitoring the Raman peaks attributed to specific molecules such as oxymyoglobin and cytochrome c, as well as measuring their intensity. The specification further taught that the calculated Raman intensity of reduced cytochrome c correlates with cardiomyocyte differentiation or maturation. However, the specification does not similarly describe that the Raman intensity of the broader genus of proteins containing heme b and/or heme c, nor does it demonstrate that the Raman intensity of such proteins generally correlates with cardiomyocyte maturation. It is generally known that mature cardiomyocytes contain numerous heme b or heme c proteins such as but not limited to catalase, or cytochrome b, (See Sawicki et al), which neither the specification nor the prior art characterizes as being associated with the maturation process of cardiomyocytes. Accordingly, the specification does not reasonably convey to a person of ordinary skill in the art that the inventors were in possession of the full scope of the claimed invention at the time of filing.
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.
Regarding claims 1 and 17: The claims are directed to method for evaluating cardiomyocytes using Raman scattering. The claim is directed to a method or a process, which is a statutory category of invention
(Step 1: YES).
The claim is then analyzed to determine whether it is directed to any judicial exception. The claim is directed to the following steps:
acquiring a Raman spectrum of cardiomyocytes artificially induced to differentiate from pluripotent stem cells;
acquiring an intensity of Raman-scattered light for a protein containing at least one of heme b and heme c as a prosthetic group from the Raman spectrum; and
evaluating a state of progress of maturation of the cardiomyocytes on the basis of the intensity of the Raman-scattered light.
As such the claim requires steps of acquiring and evaluating data, which are mental steps similar to other concepts found to be abstract by the courts. The claim is directed to an abstract idea (Step 2A prong 1: YES).
The claim is then analyzed to determine if additional elements integrates the
judicial exception into a practical application. The claim recites no additional elements and is limited to mental steps of evaluating Raman-scattered light. (Step 2A prong 2: NO). Therefore, the claim is directed to a law of nature judicial exception.
Next, the claim as a whole is evaluated to determine if there are additional limitations that amount to significantly more than the abstract idea. The claim recites no additional elements and is limited to mental steps of evaluating Raman-scattered light. (Step 2B: NO)
The claim is patent ineligible.
Regarding claims 2-16: These claims do not further limit the method of claim 1 or add significantly more than the abstract idea; the analysis for these claims is the same as for claim 1.
The claims are patent ineligible.
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.
Claims 1-6, 11-15, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chaichi et al (Biosensors (Basel). 2018 Nov 12; hereinafter "Chaichi;" See PTO-892 and Downes et al (Sensors 2010; hereinafter "Downes;" See PTO-892) in view of Li et al (Commun Biol. 2020 Mar 13; hereinafter "Li;" See PTO-892).
Regarding claim 1-2, 5, 6, 11-14, 17: Downes was directed to use of “label-free optical spectroscopy techniques which are able to non-invasively measure the (bio)chemistry in biological systems.” (See Downes Abstract). Downes further indicated that “The greatest challenges in regenerative medicine are to ensure high purity of isolated stem cells, and to control the differentiation of stem cells. Both of these issues are addressed by applying non-invasive real-time Raman characterization to stem cells and their derivatives.” (See Downes p. 1878, para 2)
It is noted that Downes did not teach acquiring Raman-scattered light intensity of a protein containing heme b or heme c as a prosthetic group for evaluating maturation of cardiomyocytes. Chaichi taught application of Raman spectroscopy in cardiovascular biology. For example, Chaichi taught “Raman microspectroscopy (RMS) has been used to understand the live-cell behavior of hESCs differentiated into cardiomyocytes in vitro. Time-resolved Raman spectra were recorded (from several hours) to detect changes at the molecular level. Immunofluorescence staining of cardiomyocyte differentiated embryoid bodies (EBs) displayed α-actinin and cTnI, which are crucial for contractile functions” (See Chaichi p. 11, para 2). Chaichi further taught that “The four signature peaks of cardiomyocytes at 755, 1133, 1318, and 1590 cm−1 corresponding to heme proteins were exhibited both by MI and non-MI.” “The 755 cm−1 band corresponded to cytochrome c, cytochrome b5, myoglobin, and hemoglobin, and hence was found in both MI and non-MI.” (See Chaichi p. 11, para 3). As such Chaichi taught the presence of a heme b or heme c Raman peak in cardiomyocytes. Chaichi also specifically taught that “in resonance Raman (Figure 8c) the excitation wavelength overlaps the excited electronic state, resulting in an increase of scattering intensities by factors of 102 to 106, capable of reaching detection limits up to the 10−9 to 10−12 M range.” As such, Chaichi taught that Raman peak intensities corresponding to the heme associated bands are quantitatively analyzed and correlated with biological state. As an example, Chaishi taught comparison of non-infracted myocardium (non-MI) and MI peak intensities to as being indicate of pathological changes within cardiac tissues.
Li taught that myoglobin (MB) is upregulated during maturation of human induced pluripotent stem cell-derived cardiomyocytes. For example, Li taught that “analysis of messenger RNA (mRNA) expression revealed a number of upregulated genes, including MYH7 (encoding β-MHC) and genes involved in sarcomere structures (ACTN2 and DES), ventricular structures (MYL2 and MYL3), ER-Ca2+ function (PLN), myoglobin (MB), and β1-adrenoceptor (ADRB1).” (See Li p.2, col. 2, 2nd para). As such it was known prior to the filing of instant application that myoglobin was a marker associated with cardiomyocyte maturation.
It would have been obvious to one of ordinary skill in the art in view of teachings of the prior art prior to the filing of the instant application to monitoring differentiation method of Downes by monitoring the Raman intensity of a heme-containing protein such as myoglobin as taught by Chaichi and Li. Downes taught the use of Raman spectroscopy as a non-invasive indicator of cardiomyocyte maturation with a reasonable expectation that changes in Raman intensity of myoglobin as a non-invasive indicator of cardiomyocyte maturation with a reasonable expectation that changes in Raman intensity would reflect the increased expression of myoglobin accompanying maturation.
Regarding claim 4, 15: Chaichi taught excitation at 532 nm. (See Chaichi Figure 6).
Regarding claim 3: Chaishi taught acquisition of Raman spectra from cardiac tissues and cardiomyocytes and explained that Raman peaks associated with oxymyoglobinreflect biochemical state of cardiac cells. A person of ordinary skill in the art would have been motivated to combine these teachings by using Raman spectroscopy to monitor oxymyoglobin-associated Raman signals as an indicator of cardiomyocyte maturation. Because oxymyoglobin is an oxygen-bound form of myoglobin and mature cardiomyocytes are known to exhibit increased myoglobin mRNA, one of ordinary skill in the art would have expected to Raman signal corresponding to oxymyoglobin to change during the maturation.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Chaichi et al (Biosensors (Basel). 2018 Nov 12; hereinafter "Chaichi;" See PTO-892 and Downes et al (Sensors 2010; hereinafter "Downes;" See PTO-892) in view of Li et al (Commun Biol. 2020 Mar 13; hereinafter "Li;" See PTO-892) further in view of Helms et al (The FASEB Journal, 2019; hereinafter "Helms;" See PTO-892).
The teachings of Downes and Chichi in view of Li are set forth above. The cited prior art did not teach or suggest cardiac organoids as required by the claim. For example, Helms taught a “cardiac organoids consisting of all four predominant cardiac cell types (CM, epiC, endothelial, and CF) differentiated from a single hiPSC source using two differentiation methods for cardiac fibroblasts and two 3D culture techniques.” (See Helms Abstract). Also noted that their protocols could also generate spheroids. (See Helms Abstract). As such it would have been obvious for a person of ordinary skill in the art to perform the Raman evaluation of claim 6 using cardiomyocytes organoids as a spheroid or organoids. It is also noted that Helms taught that “[t]he spheroids were then cultured for seven days in standard gravity (suspension) or simulated microgravity (rotating bioreactor) environment, with media change every two days. After seven days the organoids were analyzed for organization through immunofluorescence, maximum pacing frequency, calcium transients, and motion contraction velocities..” (See Helms Abstract). As such these organoids read on cell mass as required by claim 8-10.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Chaichi et al (Biosensors (Basel). 2018 Nov 12; hereinafter "Chaichi;" See PTO-892 and Downes et al (Sensors 2010; hereinafter "Downes;" See PTO-892) in view of Li et al (Commun Biol. 2020 Mar 13; hereinafter "Li;" See PTO-892) further in view of Masumoto et al (Curr Treat Options Cardiovasc Med. 2016 Nov; hereinafter "Masumoto;" See PTO-892).
The teachings of Downes and Chaichi in view of Li are set forth above. The cited prior art did not teach or suggest a sheet-shaped aggregate of cardiomyocytes. However, production of sheet-shaped embryonic stem cell-derived and human induced pluripotent stem cell-derived cardiac tissue sheets was known in the art. For example, Masumoto taught “cardiovascular cell differentiation from human induced pluripotent stem (iPS) cells and bioengineered 3D cardiac tissues based on cell sheets, to effectively engraft transplants for stem cell-based cardiac regenerative therapy.” (See Masumoto, p. 65, col.2, 2nd para). As such it would have been obvious for a person of ordinary skill in the art to perform the Raman evaluation of claim 6 using cardiomyocytes aggregates as cell sheets.
Claims 16 is rejected under 35 U.S.C. 103 as being unpatentable over Chaichi et al (Biosensors (Basel). 2018 Nov 12; hereinafter "Chaichi;" See PTO-892 and Downes et al (Sensors 2010; hereinafter "Downes;" See PTO-892) in view of Li et al (Commun Biol. 2020 Mar 13; hereinafter "Li;" See PTO-892) further in view of Votteler et al (J Vis Exp. 2012 May 29; hereinafter "Votteler;" See PTO-892).
The teachings of Downes and Chichi in view of Li are set forth above. The cited prior art did not teach or suggest lowering of temperature of cardiomyocytes to 4 deg C as required by the claim. However, Votteler taught that “[n]ative tissues are dissected and stored in phosphate buffered saline (PBS) at 4 °C prior measurements.” (See Votteler Abstract). Thus, Votteler demonstrated that conducting Raman measurements under low temperature was routine in the art.
It would have been obvious to a person of ordinary skill in the art to perform the Raman spectroscopic method of Downes and Chaichi while maintaining the cardiomyocytes at ~4 deg C or lower, as taught by Votteler, because doing so was known in the art. The claimed feature was therefore no more than application of a known experimental condition to a known Raman spectroscopic method.
Conclusion
No claim is allowed.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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