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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04-21-2026 has been entered.
Applicant's arguments filed on 04-21-2026 and amendments to the claims filed on 07-15-2025 have been received and entered. Claims 1, 4-5, 7, have been amended. Claims 2-3, 6, 13-14 have been canceled. Claims 24-29 have been added. Claims 1, 4-5, 7-12, 15-29 are pending in the instant application.
Election/Restrictions
Applicant’s election of Group I (claims 1-5) in the reply filed on 10-17-2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 7-12, 15-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10-17-2024.
Claims 1, 4-5, 24-29 are under consideration.
Priority
This application is a 371 of PCT/EP2020/065703 filed on 06/05/2020 that claims priority from foreign application EP 19178657.3 filed on 06/06/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04-21-2026 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Maintained in modified form-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.
Claims 1, 4-5, 24-29 are rejected under 35 U.S.C. 103 as being unpatentable over Shim et al (Pub. No.: US 2014/0363841 A1, Pub. Date: Dec. 11, 2014) in view of Matheny et al (Pub. No.: US 2012/0251507 A1, Pub. Date: Oct. 4, 2012)
Claim interpretation:
The base claim 1 recite only one active step: “…the step of culturing stem cell derived cardiomyocytes in a medium comprising a combination of anti-arrythymic agents selected from class I, class II, and class III antiarrhythmic agents, or a combination thereof, wherein the class I antiarrhythmic agent is lidocaine or mexiletine, the class II antiarrhythmic agent is metoprolol or propanolol, and/or the class III antiarrhythmic agent is amiodarone or sotalol …”. Thus, under broadest reasonable interpretation, the claims encompass a combination of agents: two or more of class I or two or more of class II or two or more of class III antiarrhythmic agents, or two or more of combination of class I and/or class II and/or class III.
According to the base claim 1, practicing the only one active step can result in the intended effect of “obtaining an antiarrythymic cardiomyocyte cell population”.
Regarding to claim 1, Shim et al teach invention relates to iPSC-derived cardiomyocyte-like cells for predicting risk and/or predisposition to cardiac arrhythmia in a subject ([0001], page 1). Shim et al teaches anti-arrhythmogenic drug induced electrical alterations in hiPSC-CMs ([0091], page 5).
Shim et al teach culturing hiPSC-CMs (human induced pluripotent stem cell-derived cardiomyocyte-like cells) in a medium comprising beta-blockers such as propranolol or nadolol can reverse increasing in beating frequencies caused by beta-adrenergic agonist, isoprenaline (FIG. 2B-C, E-F) ([0097], page 5).
Shim et al teach various electrophysiological properties of hiPSC-CMs when exposed to the different agents were studied ([0067], page 4). The following anti-arrhythmic drugs were studied: Quinidine (Class Ia), Lidocaine (Class Ib), Flecainide (Class Ic), Sotalol (Class II and III), Amiodarone (Class III with I, II and IV activities), Verapamil (Class IV), Nadolol (Class II), Atenolol (Class II), Propranolol (Class II) (see [0069]-[0078], page 4).
Shim et al teach the agent may be useful for ameliorating, controlling, eliminating, preventing, reducing and/or treating a cardiac condition and may be further tested ([0044], page 2). However, Shim et al do not specifically teach a combination of anti-arrythymic agents selected from class I, class II, and class III antiarrhythmic agents, or a combination thereof. Matheny et al cure the deficiency.
Matheny et al teach compositions and methods for treating or preventing a cardiac arrhythmia in a subject (Abstract). The composition comprises one or more cells such as cardiomyocyte ([0140], page 13). The composition can further comprise one or more of Quinidine, Procainamide, Disopyramide, Lidocaine, Phenyloin, Mexiletine, Flecamide, Propafenone, Moricizine, Propranolol, Esmolol, Timolol, Metoprolol, Atenolol, Amiodarone, Sotalol, Ibutilide, Dofetilide, Verapamil, Diltiazem, Adenosine and Digoxin ([0145], page 13).
Regarding to claim 1, the claimed: the antiarrhythmic cardiomyocyte cell population has reduction in beat-to-beat variability when compared to stem cell derived cardiomyocytes, the above combined references teach the combination of anti-arrythymic agents as same as the claimed inventions; thus, it is expected for the same anti-arrythymic agents to have the same functions/characteristics. According to MPEP 2112 (II), inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
It is noted that Shim et al teach the agent may be useful for ameliorating, controlling, eliminating, preventing, reducing and/or treating a cardiac condition and may be further tested ([0044], page 2), and Shim et al also teach anti-arrhythmogenic drug induced electrical alterations in hiPSC-CMs ([0091], page 5): a) Effects of sodium (Na+) channel blockers on hiPSC-CMS by using Quinidine (Class Ia) ([0092]-[0093], page 5); b) Effects of beta-blockers on hiPSC-CMs by using nadolol and propranolol ([0096]-[0097], page 5); c) Effects of potassium (K) channel blockers on hiPSC-CMS by using Sotalol (Class II and III) and amiodarone (Class III with I, II and IV activities) ([0098]-[0099], page 5); d) Effects on calcium (Ca2+) channel blockers on hiPSC-CMS by using Verapamil (Class IV) ([0100]-[0101], page 5). Additionally, Matheny et al stated that there are many classes of anti-arrhythmic medications with different mechanisms of action and many different individual drugs within these classes. Thus, the method can further comprise administering to the subject one or more anti-arrhythmic medications ([0082], page 7).Thus, it would have been obvious for a person of ordinary skill in the art to use antiarrhythmic agent such as amiodarone or sotalol in combination with antiarrhythmic agents such as mexiletine and lidocaine etc.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Shim et al by using a combination of anti-arrythymic agents as taught by Matheny et al, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Shim et al teach the method is for screening for a cardiovascular agent for ameliorating, controlling, eliminating, preventing, reducing and/or treating a cardiac condition (see claim 12, page 8) and predicting risk of and/or predisposition to cardiac arrhythmia in a subject (Abstract), and, additionally, Matheny et al provided compositions and methods for treating or preventing a cardiac arrhythmia in a subject (abstract). Matheny et al also teach positive remodeling which refers to beneficial regeneration and/or restructuring of damaged heart tissue; such positive remodeling promotes growth of new cells while preserving the functionality of the heart and preventing formation of scar tissue ([0183], page 18). Matheny et al also stated that there are many classes of anti-arrhythmic medications with different mechanisms of action and many different individual drugs within these classes. Thus, the method can further comprise administering to the subject one or more anti-arrhythmic medications ([0082], page 7). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Matheny et al was successful in modulation of cardiac remodeling with acellular matrix emulsion which is associated with myofibroblast proliferation and angiogenesis via recruiting c-kit positive cells after myocardial infarction (Example 2, [0229]-[0231], page 23).
Regarding to claims 4-5, Matheny et al teach compositions and methods for treating or preventing a cardiac arrhythmia in a subject (Abstract). The composition comprises one or more cells such as cardiomyocyte ([0140], page 13). The composition can further comprise one or more of Lidocaine, , Mexiletine, Propranolol, , Metoprolol, Amiodarone, Sotalol, etc. ([0145], page 13).
Regarding to claims 24-29, Shim et al teach sotalol at 50 µM concentration demonstrated a 65% prolongation of cFPDs (field potential duration) (FIG. 3A-B), amiodarone (1 µM) showed a 37% prolongation of cFPDs (FIG. 3C-D) (See [0099], page 5). Moreover, FIG. 5 shows the non-linear regression analysis of dose dependent response of various drugs on cFPDs ([0016], page 1) (concentration of antiarrhythmic agents can be ranging between 0.01-10 µM see Fig 5 below ). Thus, it is indicating that the concentration of antiarrhythmic agents was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to optimize the concentration of antiarrhythmic agents to be in the range of 1nM-100nM or 0.1µM - 100µM as the claimed invention out of the course of routine optimization. Performing optimization of the concentration of antiarrhythmic agents would allow for selecting best concentration for the cell culture
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Response to Arguments
Applicant's arguments filed 04-21-2026 have been fully considered but they are not persuasive.
Applicant argues that “….Shim teaches a method for screening an agent as a drug candidate using induced pluripotent stem cell-derived cardiomyocyte-like cells and the agent at different dosages and further predicting risk of and/or predisposition to cardiac arrhythmia … However, Shim neither teaches generating an antiarrhythmic cardiomyocyte cell population using a combination of antiarrhythmic agents nor does it teach the specific combinations of antiarrhythmic agents used in the present invention. This deficiency is not cured by Matheny, which merely cites to a list of pharmaceuticals on page 13, [0145] without providing any additional, specific methods to make compositions necessary for performing the present invention or any data to motivate a POSITA to any specific combination of the present invention. Unfortunately, the Examiner is engaging in the benefit of impermissible hindsight …. even when considered together, Shim and Matheny do not provide any direction toward achieving the present invention.”
“Applicant has identified the fundamental legal deficiencies showing 1) the lack of motivation to combine Shim and Matheny, 2) the absence of direction or guidance from said cases to arrive at the present invention, 3) the failure to establish a reasonable expectation of success, and 4) the use of impermissible hindsight”
Remarks (Page 4-5)
Response to Arguments:
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the Shim and Matheny references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, One of ordinary skill in the art would have been motivated to combine the references because Shim et al teach the method is for screening for a cardiovascular agent for ameliorating, controlling, eliminating, preventing, reducing and/or treating a cardiac condition (see claim 12, page 8) by exposing hiPSC-CMs to different agents ([0067], page 4) such as Quinidine (Class Ia), Lidocaine (Class Ib), Flecainide (Class Ic), Sotalol (Class II and III), Amiodarone (Class III with I, II and IV activities), Verapamil (Class IV), Nadolol (Class II), Atenolol (Class II), Propranolol (Class II) (see [0069]-[0078], page 4). Additionally, Matheny et al provided compositions and methods for treating or preventing a cardiac arrhythmia in a subject (abstract). Matheny et al also teach positive remodeling which refers to beneficial regeneration and/or restructuring of damaged heart tissue; such positive remodeling promotes growth of new cells while preserving the functionality of the heart and preventing formation of scar tissue ([0183], page 18). Matheny et al also stated that there are many classes of anti-arrhythmic medications with different mechanisms of action and many different individual drugs within these classes. Thus, the method can further comprise administering to the subject one or more anti-arrhythmic medications ([0082], page 7). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Matheny et al was successful in modulation of cardiac remodeling with acellular matrix emulsion which is associated with myofibroblast proliferation and angiogenesis via recruiting c-kit positive cells after myocardial infarction (Example 2, [0229]-[0231], page 23).
In response to applicant’s argument that there is absence of direction or guidance from said cases to arrive at the present invention, it is noted that Shim et al teach culturing hiPSC-CMs (human induced pluripotent stem cell-derived cardiomyocyte-like cells) in a medium comprising beta-blockers such as propranolol or nadolol can reverse increasing in beating frequencies caused by beta-adrenergic agonist, isoprenaline (FIG. 2B-C, E-F) ([0097], page 5).
In response to applicant’s argument that the examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Shim et al teaches anti-arrhythmogenic drug induced electrical alterations in hiPSC-CMs ([0091], page 5). Shim et al teach various electrophysiological properties of hiPSC-CMs when exposed to the different agents were studied ([0067], page 4). Shim et al teach the agent may be useful for ameliorating, controlling, eliminating, preventing, reducing and/or treating a cardiac condition and may be further tested ([0044], page 2). However, Shim et al do not specifically teach a combination of anti-arrythymic agents selected from class I, class II, and class III antiarrhythmic agents, or a combination thereof. Matheny et al cure the deficiency. Matheny et al teach compositions and methods for treating or preventing a cardiac arrhythmia in a subject (Abstract). The composition comprises one or more cells such as cardiomyocyte ([0140], page 13). The composition can further comprise one or more of Quinidine, Procainamide, Disopyramide, Lidocaine, Phenyloin, Mexiletine, Flecamide, Propafenone, Moricizine, Propranolol, Esmolol, Timolol, Metoprolol, Atenolol, Amiodarone, Sotalol, Ibutilide, Dofetilide, Verapamil, Diltiazem, Adenosine and Digoxin ([0145], page 13). One of ordinary skill in the art would have been motivated to modify the method of Shim by using combination of different anti-arrhythmic agents as taught by Matheny et al because Matheny et al also stated that “there are many classes of anti-arrhythmic medications with different mechanisms of action and many different individual drugs within these classes. Thus, the method can further comprise administering to the subject one or more anti-arrhythmic medications” ([0082], page 7).
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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