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 .
Remarks
In response to communications sent September 9, 2025, claim(s) 3-10 and 12-18 is/are pending in this application; of these claim(s) 3 is/are in independent form. Claim(s) 1, 2, and 11 is/are cancelled.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 9, 2025 has been entered.
Response to Arguments
Applicant’s arguments, see page 5 lines 5-7, filed September 9, 2025, with respect to claims 10 and 12-13 have been fully considered and are persuasive. The rejection of May 15, 2025 has been withdrawn.
Applicant’s arguments, see page 5 lines 8-14, filed September 9, 2025, with respect to claim 16 have been fully considered and are persuasive. The rejection of May 15, 2025 has been withdrawn.
Applicant's arguments filed September 9, 2025 have been fully considered but they are not persuasive. Applicant argues that Tung in view of Blazeski teaches a maximum capture rate and that at which there is a loss of 1:1 pace capture, and that Khine does not cure this purported deficiency because it does not involve pacing frequencies. The Examiner is dropping the Khine reference from the rejection, because Blazeski teaches the element of reporting pace-capture at various rates on a binary scale. In particular Figure 8D shows a quantity called the relative maximum capture rate. It is at once envisaged from the graph that any capture rate above the indicated maximum will be group of cells having “lost beats compared to paced beats” and any capture rate below the indicated maximum would have some “extra beats compared to paced beats”. The indicated maximum pace capture rate is a threshold hold demarcating, in a binary way, which pacing frequencies, for a given drug concentration, are at either binary extreme—lost beats vs. extra beats. Therefore, the rejection is not withdrawn, and the Khine reference is unnecessary to show the binary classification scale of pacing behavior.
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.
Claim(s) 3-10 and 12-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tung et al. (PGPub 20170173215, PTO-892 filed 08/29/2024) in view of Blazeski et al. (Engineered heart slices for electrophysiological and contractile studies, Biomaterials. 2015 Jul; 55: 119– 128, PTO-892 filed 08/29/2024).
As to claims 3, 5 and 14, Tung provides a method of investigation pharmacological interventions of a variety of cardiac diseases (see Abstract, and par.82):
contacting at least one sample comprising one or more cardiac cells with the compound (see par.6-7: Tung teaches that a sample comprises one or more cardiac cells, i.e., engineered heart slices_EHS, see Abstract, par.10 and par.69: Tung further teaches that the method can include one or more biologically active agents which refers to a chemical or biological compound that induces a desired pharmacological and/or physiological effect, wherein the effect may be prophylactic or therapeutic, this teaching anticipates contacting the sample with the compound);
pacing the one or more cardiac cells at a fixed rate (see par.28, teaching 1 Hz pacing in 10 ms apart).
Moreover, the incidence rate for pacing stimuli to initiate reentrant arrhythmias in EHS is quantified by increasing the basal pacing rate in discrete steps from 0.5 to 3 Hz (see par.97).
However, Tung fails to explicitly disclose pacing at two or more fixed rates, measuring a pace-capture at each of the two or more fixed rates, and reporting the pace-capture at each of the two or more fixed rates on a binary classification scale indicating a fraction of the one or more cardiac cells with extra beats compared to paced beats and a fraction of the one or more cardiac cells with lost beats compared to paced beats.
Blazeski, a non-patent literature of Tung’s method, discloses a representation method of physiological behavior of engineering cardiac tissues, including pacing the heart slices (e.g., two or more cardiac cells) at two or more fixed rates (see section 3.4, teaching that engineered heart slices (EHS) made from rat ECM were field stimulated at different pacing rates, pacing rates increase from 1 to 5 Hz).
Furthermore, Blazeski discloses contacting the EHS with a compound, e.g., lidocaine to study the electrophysiological response of the sample to drug level. See section 2.5: Blazeski discloses that EHS were challenged with stepwise increasing doses of lidocaine ranging from 90 μM to 360 μM and paced at increasing rates at each drug level. The teaching demonstrates the applicability of the method to study drug effects on cardiac tissue (see section 4.4).
Moreover, Blazeski discloses recording the spontaneous beating condition of EHS made with pig ECM during culture, i.e., prior to pacing the cells with fixed rates (see section 2.4). This teaching anticipates the limitation in claim 5.
Blazeski further teaches measuring pace-capture of the one or more cardiac cells in response to the compound at each of the two or more fixed rate (see section 2.5 par.2: Blazeski teaches the method can be able to measure the electrophysiological function until loss of capture, some EHS were challenged with stepwise increasing doses of lidocaine ranging from 90 μM to 360 μM and paced at increasing rates at each drug level; see section 3.4 par.1 and section 4.4: teaching that maximum capture rate of EHS, decreases with the increasing doses of lidocaine; see Fig.8D: showing the change of maximum capture rate with lidocaine dose).
The teaching above encompasses the measuring and reporting the pace-capture, e.g., maximum capture rate at each of the fixed rates indicating the increase or decrease beating rates of the EHS sample compare to paced beats, e.g., control.
It is noted that Tung and Blazeski are analogous because they are directed to the method of testing an effect of a compound on a cardiac cells or tissue in vitro. Their methods are able to measure and report the beating rates under the influence of a compound at a fixed rate.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Tung, pacing the two or more cardiac cells at two or more fixed rates and measuring pace-capture of the sample in response to the compound at each of the two or more fixed rates as taught by Blazeski, and reporting the pace-capture on binary classification scale as also taught by Blazeski using the maximum pacing rate to demarcate two extremes of the binary classification of the pace capture.
It is because Blazeski, which is a non-patent literature of Tung, further clarify the method of Tung that pacing the two or more cardiac cells at two or more fixed rates for the purpose of creating an attractive model for physiological and pathophysiological studies because of their contractile and electrophysiological function at a tissue level (see section 4.5 of Blazeski). Moreover, the Blazeski shows that the method can be used for measuring and reporting the capture rate as discussed above. In addition, Blazeski teaches that the results can be reported on binary scale by indicating which capture rates are above or below a threshold.
One having ordinary skill in the art would have had a reasonable expectation of success in combining Tung and Blazeski because they are both directed to electrophysiological and contractile studies on cardiac cells.
As to claim 4, Tung in view of Blazeski teach the invention as discussed above. Also, Tung teaches the method can be done on a plurality of samples, wherein each sample comprises at least one cardiac cell (see par.47-48, the present invention provides at least two or more 3D biocompatible decellularized mammalian cardiac tissue slice matrix).
As to claims 6-9, Tung in view of Blazeski teach the invention as discussed above. Tung discloses that the standard fixed rate is 1 Hz. Then, the incidence rate for pacing stimuli to initiate reentrant arrhythmias in EHS is quantified by increasing the basal pacing rate in discrete steps from 0.5 to 3 Hz. See paragraph 97.
In addition, Blazeski teaches that EHS were paced at 2 Hz, then in increments of 1 Hz up to 5 Hz, and then in smaller increments until loss of capture. See section 2.5. See Fig.6-7: showing pacing the cardiac cells at 4-5 fixed rates.
While Tung and Blazeski do not specifically teach the same range of fixed rates, they do suggest pacing the cells to a variety of fixed rates around the standard fixed rate. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable.
It would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the art because the contractile and electrophysiological function at a tissue level to different pacing rates is an attractive model for physiological and pathophysiological studies (see Blazeski section 4.5). Therefore, the modification would result in a predictable outcome.
As to claim 10, Tung in view of Blazeski teach the invention as discussed above. Tung discloses that the measurement for the fixed rate response of the one or more cells
comprises repolarization time, contraction strength, and conduction velocity (see Tung at least par.14, 24, 27-28, 94).
As to claims 12-13, Tung in view of Blazeski teach the invention as discussed above.
Tung and Blazeski show that the reported fixed response of each cardiac cell is compiled into a
single visual representation and is color coded (see Tung par.29 and Blazeski Fig.6).
As to claims 15-16, Tung in view of Blazeski teach the invention as discussed above. Tung discloses that the spontaneous response of the one or more cardiac cells are also measured (see Tung par.35, 94; Blazeski Abstract, section 2.4, 2.5 4.3).
As to claims 17-18, Tung in view of Blazeski teach the invention as discussed above. Tung shows an optical voltage mapping of EHS during spontaneous activity in Fig. 13. Blazeski shows the optical mapping during spontaneous activity or electrical pacing, wherein action potentials propagate through the entire surface of the EHS in Fig.7.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jesse P Frumkin whose telephone number is (571)270-1849. The examiner can normally be reached Monday - Saturday, 10-5 ET.
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/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 November 20, 2025