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 .
Applicant's amendments to the claims and arguments 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Claims 7-12, 15-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.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.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1-3 were rejected under 35 U.S.C. 102 (a)(1) / 102(a)(2) as being anticipated by Shim et al (Pub. No.: US 2014/0363841 A1, Pub. Date: Dec. 11, 2014). In view of Applicants' amendment of base claim 1 and cancelation of claims 2-3, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1-3 were rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Matsa et al (European Heart Journal (2011) 32, 952–962, doi:10.1093/eurheartj/ehr073). In view of Applicants' amendment of base claim 1 and cancelation of claims 2-3, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1, 4-5 were 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). In view of Applicants' amendment of base claim 1 and dependent claims 4-5, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1, 4-5 were rejected under 35 U.S.C. 103 as being unpatentable over Matsa et al (European Heart Journal (2011) 32, 952–962, doi:10.1093/eurheartj/ehr073) in view of Toivonen et al (Circulation . 1991 Jul;84(1):101-8. doi: 10.1161/01.cir.84.1.101.). In view of Applicants' amendment of base claim 1 and dependent claims 4-5, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
New-Claim Rejections - 35 USC § 103 - necessitated by amendments
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)
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 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 07-15-2025 have been fully considered but they are not persuasive.
Applicant argues that
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 (remarks, page 8).
First, the Examiner points to page 13, [0140] to show cardiomyocytes as cells comprising the mammalian ECM in Matheny compositions. In actuality, paragraph [0140] lists no fewer than 46 types of cells that can be used to comprise the mammalian ECM of Matheny' s invention with no additional information as to when or why to choose one cell type over the other. Next, the Examiner points to page 13, [0145] for pharmaceuticals - one or more of Quinidine, Procainamide, Disopyramide, Lidocaine, Phenyloin, Mexiletine, Flecamide, Propafenone, Moricizine, Propranolol, Esmolol, Timolol, Metoprolol, Atenolol, Amiodarone, Sotalol, lbutilide, Dofetilide, Verapamil, Diltiazem, Adenosine and Digoxin - comprised with the compositions of the mammalian ECM with no further teaching, suggestion, or motivation for why a POSITA would choose any of the pharmaceuticals. Quite importantly, Matheny itself does not disclose any specific methods for making compositions necessary for performing the invention. On page 15, [0164], Matheny points to several US patents using small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), and liver basement membrane (LBM). Merely piecing together a list of reagents and conditions from such a body of art is not sufficient to pass for a teaching, suggestion, or motivation that is required by KSR. ("[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art." KSR, 127 S. Ct. at 1741.) Furthermore, Matheny does not provide any teaching, suggestion, or motivation on how to produce an antiarrhythmic cardiomyocyte cell population having a reduction of beat-to-beat variability when compared to stem cell derived cardiomyocytes. (remarks, page 10).
Response to Arguments:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). 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).
Applicant argues that Matheny' s invention provide no additional information as to when or why to choose one cell type over the other in paragraph [0140], page 13. However, Matheny et al concern about compositions and methods for treating or preventing a cardiac arrhythmia in a subject (Abstract). Thus, a person of ordinary skill in the art would know select appropriate cells according to the teaching of Matheny et al.
Applicant argues that [0145] provide no further teaching, suggestion, or motivation for why a POSITA would choose any of the pharmaceuticals. It is noted that 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.
Matheny et al do disclose any specific methods for making compositions necessary for performing the invention: 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). Matheny et al 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).
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).
As per MPEP 716.01(c) (II), Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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