Going 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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. DE102016223423.4, filed on November 25, 2016.
Claim Status
In the response filed on Sept. 15, 2025, Applicant has amended claims 1, 3, 5, 8, 11, and 22-23, and canceled claims2, 4, and 6-7, and added new claim 24. Currently, claims 12-20 are withdrawn due to Applicant election of a method for measuring conduction elected on Dec. 21, 2021.
Currently, claims 1, 3, 5, 8-11, and 21-24 are under examination.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action mailed June 13, 2025, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The rejection of claims 8 and 11 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to Applicant’s amendments.
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.
Claim 1 is 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.
Regarding claim 1, the claim recites “(vii) comparing the values measured according to (vi) and the values measured according to (iii) or the values measured according to (b).” The term “or” before the phrase “the values measured according to (b);” makes it unclear if the values measured according to (b) are being compared to the values measured according to (vi) or the values measured according to (iii) or if the values measured according to (b) are being compared to the total values of the values measured according to (vi) and the values measured according to (iii). Further, the comparison of (b) cannot be compared to itself. Therefore, it is not apparent as two what values are being compared to each other in the claim and has been rendered indefinite because what is being compared to each other is unclear. For compact prosecution the claim step (vii) will be interpreted as comparing any of the values in steps (iii), (vi), or (b).
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.
Claim 1, 3, 8-11 and 23-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
This is a new rejection necessitated by amendment to the claims.
Claim 1 recites “a method for determining cardiac conduction, comprising: (i) providing induced sinoatrial bodies (iSABs) comprising cardiac pacemaker cells; (ii) providing working-myocardium cardiomyocytes; (iii) measuring the cardiac conduction; (iv) comparing the measured cardiac conduction according to (iii) with a reference value, the comparing comprising a. administering a reference substance, b. measuring the cardiac conduction in the presence of the reference substance administered according to (a); and (c) comparing the values measured according to (iii) and the values measured according to (b); (v) washing out the reference substance administered according to (iv); (vi) measuring the cardiac conduction: and (vii) comparing the values measured according to (vi) and the values measured according to (iii) or the values measured according to (b); or comparing the values measured according to (vi), the values measured according to (iii), and the values measured according to (b); wherein the induced sinoatrial bodies according to (i) and the working-myocardium cardiomyocytes according to (ii) are arranged so that there is a spatially limited, direct contact between at least part of the iSABs according to (i) and at least part of the working-myocardium cardiomyocytes according to (ii)”.
Per the 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG) published on January 7, 2019 (84 Fed. Reg. 50), if a claim recites a limitation that can practically be performed in the human mind, the limitation falls within the mental processes grouping, and the claim recites an abstract idea. Claims recite a mental process when they contain limitations that can practically be performed in the human mind, including for example, observations, evaluations, judgments, and opinions.
The courts consider a mental process (thinking i.e. comparing) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work' that are open to all.' " 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work' " (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same).
Regarding claim 1, the “comparing” step is considered to embrace a mental process. See also MPEP 2106.04(a-b).
Step 1-Statutory Category: According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e. process, machine, manufacture, or composition of matter). Claim 1 is drawn to a method for comparing the cardiac conduction. Thus, the process meets the requirements for step 1 of the analysis as it is drawn to a method.
Next the claim is assessed to determine if it is directed to a judicial exception under step 2A. Under 2019 PEG, “directed to" is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application", requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful limitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 210 6.05 for examples of integration of practical application).
Step 2A Judicial Exception-Prong 1 (claim is directed to a judicial exception): Prong 2A asks whether the claim recites an abstract idea, law of nature, or natural phenomenon (product of nature).
Regarding independent Claim 1 recited a judicial exception in step (vii) which is directed to “comparing the values measured according to (vi) and the values measured according to (iii) or the values measured according to (b); or comparing the values measured according to (vi), the values measured according to (iii), and the values measured according to (b); wherein the induced sinoatrial bodies according to (i) and the working-myocardium cardiomyocytes according to (ii) are arranged so that there is a spatially limited, direct contact between at least part of the iSABs according to (i) and at least part of the working-myocardium cardiomyocytes according to (ii)”, which requires a mental step. The claim 1, “comparing” step of comparing the cardiac conduction measured is an abstract idea involving mental processes because a simple comparison of the cardiac conduction obtained can be performed mentally. Furthermore, the wherein clause after the comparing step just further describes the arrangement. Therefore, the claims recite a mental process even if they are described in the specification and/or claimed as being performed on a device. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 3, dependent on claim 1, recites the step “wherein the reference substance is selected from the group of heart rate-lowering substances or from the group of heart rate-raising substances, preferably from the group consisting of isoprenaline, ZD-7288, zatebradine and ivabradine”. Claim 3 just describes the reference substance. Therefore, claim 3 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 8, dependent on claim 1, recites the step “wherein the working-myocardium cardiomyocytes according to (ii) comprise atrial cells or ventricular cells or atrial and ventricular cells”. Claim 8 just describes the working-myocardium cardiomyocytes. Therefore, claim 8 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 9, dependent on claim 1, recites “which is carried out in vitro”. Claim 9 just describes the type of method. Therefore, claim 9 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 10, dependent on claim 1, recites “wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from multipotent or pluripotent stem cells, preferably from pluripotent stem cells”. Claim 10 just describes the iSABs. Therefore, claim 10 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 11, dependent on claim 1, recites “wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from nonhuman embryonic stem cells, nonhuman induced pluripotent stem cells, human induced pluripotent stem cells, parthenogenetic stem cells, or spermatogonial stem cells”. Claim 11 just further describes the iSABs. Therefore, claim 11 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 23, dependent on claim 1, recites “wherein the cardiac conduction is measured by means of electrocardiogram (ECG) or microelectrode array (MEA)”. Claim 23 just further describes the type of measurement that is being compared. Therefore, claim 23 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding dependent claim 24, dependent on claim 1, recites “wherein the iSABs and the working-myocardium cardiomyocytes are spatially separated and provided on a planar substrate, and wherein the measured cardiac conduction measures a signal passing from the iSABs to the working myocardium cardiomyocytes and the resulting contraction of the working-myocardium cardiomyocytes”. Claim 24 describes the arrangement of the iSABs and the working-myocardium cardiomyocytes. Therefore, claim 24 does not remedy the deficiency of claim 1. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Furthermore, there is nothing about claims 1, 3, 8-11 and 23-24 that include additional elements that are sufficient to amount to significantly more than the judicial exception since the invention as claimed does not introduce or recite any step of compositions that is beyond that which is well understood, routine and conventional.
Step 2A Judicial Exception-Prong 2 (Judicial exception is integrated into a practical application): The phrase, "integration of a practical application", requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful Iimitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 2106.05 for examples of integration of practical application). Prong 2 asks whether a claim recites additional elements that integrate the judicial exception into a practical application.
Regarding Independent claim 1, after step “(vii) comparing the values measured according to (vi) and the values measured according to (iii) or the values measured according to (b); or comparing the values measured according to (vi), the values measured according to (iii), and the values measured according to (b)” the claim recites “wherein the induced sinoatrial bodies according to (i) and the working-myocardium cardiomyocytes according to (ii) are arranged so that there is a spatially limited, direct contact between at least part of the iSABs according to (i) and at least part of the working-myocardium cardiomyocytes according to (ii)”. Thus, there is no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 3, dependent on claim 1, recites the step “wherein the reference substance is selected from the group of heart rate-lowering substances or from the group of heart rate-raising substances, preferably from the group consisting of isoprenaline, ZD-7288, zatebradine and ivabradine”. Claim 3 just describes the reference substance. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 8, dependent on claim 1, recites the step “wherein the working-myocardium cardiomyocytes according to (ii) comprise atrial cells or ventricular cells or atrial and ventricular cells”. Claim 8 just describes the working-myocardium cardiomyocytes. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 9, dependent on claim 1, recites “which is carried out in vitro”. Claim 9 just describes the type of method. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 10, dependent on claim 1, recites “wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from multipotent or pluripotent stem cells, preferably from pluripotent stem cells”. Claim 10 just describes the iSABs. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 11, dependent on claim 1, recites “wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from nonhuman embryonic stem cells, nonhuman induced pluripotent stem cells, human induced pluripotent stem cells, parthenogenetic stem cells, or spermatogonial stem cells”. Claim 11 just further describes the iSABs. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 23, dependent on claim 1, recites “wherein the cardiac conduction is measured by means of electrocardiogram (ECG) or microelectrode array (MEA)”. Claim 23 just further describes the type of measurement that is being compared. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding dependent claim 24, dependent on claim 1, recites “wherein the iSABs and the working-myocardium cardiomyocytes are spatially separated and provided on a planar substrate, and wherein the measured cardiac conduction measures a signal passing from the iSABs to the working myocardium cardiomyocytes and the resulting contraction of the working-myocardium cardiomyocytes”. Claim 24 describes the arrangement of the iSABs and the working-myocardium cardiomyocytes. Thus, there are no additional steps requiring a practical application (e.g. applying a treatment, action, or substance). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Thus, claims 1, 3, 8-11, and 23-24 meet the requirements of step 2A as being directed to a judicial exception.
Step 2B Significantly More: The "significantly more" analysis determines that a claim is patent eligible if the claims recite structures or functions that transform the natural product in a manner that make the product markedly different from the judicial exception. The nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state.
Claim 1 does not add significantly more than the judicial exception. The claim recites “(vii) comparing the values measured according to (vi) and the values measured according to (iii) or the values measured according to (b); or comparing the values measured according to (vi), the values measured according to (iii), and the values measured according to (b); wherein the induced sinoatrial bodies according to (i) and the working-myocardium cardiomyocytes according to (ii) are arranged so that there is a spatially limited, direct contact between at least part of the iSABs according to (i) and at least part of the working-myocardium cardiomyocytes according to (ii)”. Therefore, step (vii) and the wherein clause does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 1 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 3 does not add significantly more than the judicial exception. Claim 3 recites the step “wherein the reference substance is selected from the group of heart rate-lowering substances or from the group of heart rate-raising substances, preferably from the group consisting of isoprenaline, ZD-7288, zatebradine and ivabradine”. Claim 3 just describes the reference substance. Therefore, claim 3 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 3 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 8 does not add significantly more than the judicial exception. Claim 8 recites the step “wherein the working-myocardium cardiomyocytes according to (ii) comprise atrial cells or ventricular cells or atrial and ventricular cells”. Claim 8 just describes the working-myocardium cardiomyocytes. Therefore, claim 8 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 8 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 9 does not add significantly more than the judicial exception. Claim 9 recites “which is carried out in vitro”. Claim 9 just describes the type of method. Therefore, claim 9 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 9 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 10 does not add significantly more than the judicial exception. Claim 10 recites “wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from multipotent or pluripotent stem cells, preferably from pluripotent stem cells”. Claim 10 just describes the iSABs. Therefore, claim 10 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 10 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 11 does not add significantly more than the judicial exception. Claim 11 recites “wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from nonhuman embryonic stem cells, nonhuman induced pluripotent stem cells, human induced pluripotent stem cells, parthenogenetic stem cells, or spermatogonial stem cells”. Claim 11 just further describes the iSABs. Therefore, claim 11 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 11 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 23 does not add significantly more than the judicial exception. Claim 23 recites “wherein the cardiac conduction is measured by means of electrocardiogram (ECG) or microelectrode array (MEA)”. Claim 23 just further describes the type of measurement that is being compared. Therefore, claim 23 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 23 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Claim 24 does not add significantly more than the judicial exception. Claim 24 recites “wherein the iSABs and the working-myocardium cardiomyocytes are spatially separated and provided on a planar substrate, and wherein the measured cardiac conduction measures a signal passing from the iSABs to the working myocardium cardiomyocytes and the resulting contraction of the working-myocardium cardiomyocytes”. Claim 24 describes the arrangement of the iSABs and the working-myocardium cardiomyocytes. Therefore, claim 24 does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 24 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
It is well established that data gathering steps required to use the correlation do not add a meaningful limitation to the method as they are insignificant activity (see also MPEP 2106.05(g)).
Accordingly, the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions. (see MPEP 2106.04(a)(2)(III).)
In conclusion, claims 1, 3, 8-11, and 23-24 recites abstract ideas which are not considered to disclose eligible subject matter under 35 U.S.C. 101, and therefore are deemed not patent eligible.
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.
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, 3, 5, 8-11, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over David et al. (DE102013114671, published Oct. 29, 2015; prior art of record, see attached WIPO Patentscope PDF translation), in view of Marban et al., (US2015/0359845 A1, published 2015, prior art of record), and Jung et al (Stem Cell Reports, 2: 592–605, published 2014; see IDS 7/22/2019, prior art of record).
This is a new rejection necessitated by amendment to the claims. However, since it is substantially similar to a rejection set forth in the final Official action mailed June 13, 2025, any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claim Interpretation: The invention as claimed embraces a method for measuring cardiac conduction. The specification discloses cardiac conduction (i.e. conductive communication) meaning the passing-on of electrical impulses (see e.g. para. 94). David discloses electrophysiological and calcium signaling properties, where “functional coupling is evident from synchronized Ca2+ transients between iSABs and the myocardial cells of the slice” (see e.g. para. 34), which reads on the passing-on of electrical impulses corresponding to the claim limitation of the cardiac conduction absent evidence to the contrary.
Regarding claim 1, 5, 9, and 24, David discloses a method for determining cardiac conduction in vitro (see e.g. para. 4, 10, 15-16, 34-38, 42, 44, 49-50, 57, fig. 4). Further, David discloses using the single-cell patch clamp technique, which measures action potential (AP) and currents (see e.g. para. 60-67, fig. 6-9, and table 1-2), and the density of HCN channels (i.e. “Funny channel”, calcium transients) for analyzing the electrophysiological parameters and calcium transients (see e.g. para. 25), corresponding to the claim limitation of cardiac conduction (see e.g. para. 25-35, and 44-46, fig. 4) absent evidence to the contrary.
Regarding claim 1 and 5 step (i), and 24, David discloses generating somatic cell nuclei (i.e. sinus node cells or cardiac pacemaker cells) from stem cells that express a TBX transcription factor, or a TBX protein (e.g. TBC3 or TBX18) that is introduced into the stem cells, corresponding to the claim limitation of providing induced sinoatrial bodies (iSABs) comprising cardiac pacemaker cells (see e.g. para. abstract, 4, 11, 16-17, 24-28, 30, 34 and 45; claims 1-8, figs. 1, and 3-4).
Regarding claim 1 step (ii) and 5 step (i), and 24, David discloses murine cardiac muscle cultures (e.g. ventricular slices) with myocardial cells which corresponds to the claim limitation of working-myocardium cardiomyocytes (see e.g. paras. 15, 26, 30- 45; figure 2-4) absent evidence to the contrary. Additionally, David discloses a direct contact area (i.e. third region) between the first and second region absent evidence to the contrary. Further, David discloses time-locked coupling of the calcium signal in part of the iSAB with calcium response in part of the myocyte (see e.g. fig. 4). Furthermore, the third region (i.e. direct contact area) is spatially limited because of the single highly synchronized calcium transient signal as indicated by the vertical lines (See adapted fig. 4).
Regarding claim 1 step (iii) and 5 step (ii-iv) and 24 , David discloses measuring the cardiac conduction by the patch clamp technique and the density of HCN (e.g. calcium funny) channels (see e.g. para. 25-35, 44-46, fig. 4). Further David discloses the induced sinoatrial bodies according to (i)(see e.g. fig. 4 labeled a) and the working-myocardium cardiomyocytes according to (ii) (see e.g. fig. 4 labeled b) being arranged so that there is a spatially limited (i.e. synchronized calcium transients), direct contact between at least part of the iSABs according to (i) and at least part of the working-myocardium cardiomyocytes according to (ii)(see e.g. adapted Fig. 4G below). David discloses cultivation of the iSABs for three weeks on gelatin-coated cell culture dishes resulted in adherent, highly synchronized cell layers beating (see e.g. para 29). Further, David discloses that the iSABs seeded on the slices were able to adhere to and persist on the slices (see e.g. para. 34, fig. 4), which were on the gelatin-coated dishes, corresponding to the claim limitation of provided on planar substrates. Furthermore, David discloses that the third region is spatially limited as shown by the functional coupling (i.e. electrical impulses) of the single highly synchronized calcium transient signal, as indicated by the vertical lines (see adapted fig. 4), corresponding to the direct contact (i.e. third region) between the iSABs and the working-myocardium cardiomyocytes as claimed.
Regarding claims 1 (iv-vii) and 5 (iii-vi) and 24, David discloses an extracellular (i.e. bath) block solution (see e.g. para. 44). Further, David discloses measuring the cardiac conduction via patch clamp technique and the density of HCN channels (i.e. calcium funny, calcium transients)(see e.g. para. 25-35, and 44-46, fig. 4). David discloses the comparison of the cardiac conduction measured in (iii) with a reference value (i.e. control)(see e.g. fig. 3e), the comparison preferably comprising (iv) administering a reference substance (i.e. ZD-7288);(v) measuring the cardiac conduction (i.e. HCN channels) in the presence of the reference substance according to (iv)(vi) comparing the values measured according to (iii) and the values measured according to (v)(See e.g. para. 44-46, fig. 3E).
David is silent regarding washing out the substance to be investigated and additional measuring the cardiac conduction steps.
However, the prior art of Marban discloses whole-cell electrophysiology recording and intracellular calcium recording which includes a wash out step and then measuring cardiac conduction (see e.g. para. 117, 123, and 130). Further, Marban discloses Tbx18-transduced induced sinoatrial node (SAN)(i.e. iSAN) pacemaker cells (see e.g. para. 60-62 and 166, figs. 7-8).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods as taught by David with the washing out and measuring as well as a comparing step (as taught by Marban) because Marban discloses that calcium transients are presented as background and need to be subtracted in order to normalized fluorescence (see e.g. para. 123). Further, Marban discloses that this is important in order for Ca2+ imaging of calcium transients to be obtained by averaging the signal through the entire cell (see e.g. para. 123). Thus, Marban teaches known prior art methods regarding measuring cardiac conduction (see e.g. para. 123), which would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods to yield predictable results. Therefore, it would have been obvious for a person of ordinary skill in the art to have a washing out of the substance step and have an addition measuring of cardiac conduction. Moreover, both David and Marban teach measuring cardiac conduction via pacemaker-like cells using patch-clamp techniques and calcium imaging (see e.g. para. 44-45 and 117-123, respectively). Therefore, incorporating a wash out step, additional measuring step, and comparing the values measured would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. biological pacemakers) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 3, David discloses a reference substance is selected from the group of heart rate-lowering substances or from the group of heart rate-raising substances, preferably from the group consisting of isoprenaline (i.e. isoproterenol, β-adrenergic)(see e.g. para. 26, 44, 67), ZD-7288 (see e.g. para. 31 and 46).
Regarding claim 8, as discussed above, David discloses working-myocardium cardiomyocytes being arranged in a spatially separated manner, but in conductive communication with one another (see e.g. fig. 4). Further, David discloses working-myocardium cardiomyocytes comprising atrial cells or ventricular cells (see e.g. fig. 2c, para. 26, 55).
Regarding claim 10, David discloses wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from multipotent or pluripotent stem cells (see e.g. claim 3, para. 36 and 42).
Regarding claim 11, David discloses wherein the induced sinoatrial bodies (iSABs) comprising pacemaker cells are generated from nonhuman embryonic stem cells or nonhuman induced pluripotent stem cells or human induced pluripotent stem cells or parthenogenetic stem cells or spermatogonial stem cells, (see e.g. claim 4, para. 42).
Regarding claim 21, David discloses that the cells within the iSABs were positive for connexins Cx45 and Cx30.2 (see e.g. para. 28, Fig. 3B).
Regarding claims 22-23, as stated supra, David discloses electrophysiological parameters (see e.g. para. 44-45, fig. 4).
David is silent regarding the measuring steps by means of electrocardiogram (ECG)(i.e. EKG).
However, the prior art of Marban discloses expressing Tbx18 in adult guinea pig ventricles, as well as electrophysiological and morphological features of Tbx18-ventricular myocytes (VMs) generally resembled those of native sinoatrial node (SAN) cells (see e.g. para. 156, figs. 7-9).
Regarding claims 22-23, Marban et al., discloses measuring ECG (i.e. EKG) traces from TBX18 animals, (see e.g. para. 60-62 and 166, figs. 7-8).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of measuring cardiac conduction as taught by David with incorporating an ECG measuring step as taught by Marban because Marban discloses that ECG measurements are an efficient tool for measuring (see. E.g. para. 60-62). Further,, Marban discloses that ECG measurements show efficient that somatic gene transfer of Tbx18 in the ventricle that yielded induced SAB (iSAB) cells which faithfully recapitulate the key phenotypic properties of genuine SAN cells (see e.g. paras. 60-62). Additionally, the prior art of Jung discloses that measuring spontaneous beating activity via electrodes is an ideal system for testing the functionality of iSABs (See e.g. page 597). Furthermore, incorporating the ECG measurements as taught by Marban would have led to predictable results with a reasonable expectation of success because both David and Marban teach generating somatic cell nuclei (i.e. sinus node cells) that express a TBX transcription factor (i.e. TBX18). Therefore, a person of ordinary skill in the art would have combined similar techniques for measuring cardiac conduction, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. biological pacemakers) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal
Applicants asserts that David and Jung are the inventor’s own work and describe the methods to produce and characterize the engineered pacemaker cells (i.e. the iSAB cells)(Remarks, page 13). Applicant argues that “David and Jung teach the impact of substances on the iSAB cells themselves and fail to teach the impact of a substance on a working-myocardium cardiomyocyte that is "powered" or stimulated by the iSAB cells” (remarks, page 10). Applicant asserts that the “aim of the method is to have a measurement step that is more than just reading an electrical signal emitted by the iSAB” (remarks, page 10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
It is noted that Applicant recognizes that David and Jung are the inventor’s own work and describe the methods to produce and characterize the engineered pacemaker cells (i.e. the iSAB cells)(Remarks, page 13).
In response to Applicants argument regarding the “impact”, it is unclear what Applicant’s argument is referring to since the claim is broadly directed to a method of determining cardiac conduction as a whole. Further, it is unclear how the impact of the substance is different on the iSAB cells versus the working-myocardium cardiomyocyte because Applicant has a claim limitation so that at least part of the iSAB cell is in direct contact with the working-myocardium cardiomyocyte (see wherein clause of claim 1). As discussed above, David discloses generating somatic cell nuclei (i.e. sinus node cells or cardiac pacemaker cells) from stem cells (i.e. induced sinoatrial bodies (iSABs)) comprising cardiac pacemaker cells (see e.g. para. abstract, 4, 11, 16-17, 24-28, 30, 34 and 45; claims 1-8, figs. 1, and 3-4) and murine cardiac muscle cultures (e.g. ventricular slices) with myocardial cells (i.e. working-myocardium cardiomyocytes)(see e.g. paras. 15, 26, 30- 45; figure 2-4) absent evidence to the contrary.
It is noted that the Applicant is aiming to have a method with a measuring step that is more than just reading an electrical signal emitted by the iSAB. However, the Examiner is not able to answer this assertion because the Applicant’s response has not shown or directed their response to a claim limitation that is not obvious over the prior art.
Applicant asserts that “the method in the present application incorporates the engineered cells taught by David and Jung into an in vitro system for testing the impact of a substance on the ability of the working-myocardium cardiomyocytes to receive and respond to (i.e., contraction) the signals sent by the iSABs”(Remarks, page 10). Applicant asserts that “it should be appreciated that one purpose of the present application is to measure the response of the heart cells to a substance. The inventors have elegantly designed a system where the iSABs act as an engine to stimulate contraction of the working-myocardium cardiomyocytes so that investigators may understand the impact of various substances on the heart's ability to pump blood. This in vitro system, and methods of use, have the advantage of incorporating a patient's own cells for a personalized treatment plan and evaluation” (Remarks page 11).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument that “it should be appreciated that one purpose of the present application is to measure the response of the heart cells to a substance,” a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. In the instant case, as stated supra, David et al discloses cardiac conduction (i.e. the passing on of electrical impulses) which occurs from the iSABs to the working-myocardium cardiomyocytes and calcium transients, which are dependent on voltage-gated ion channels (see e.g. para 44-50; adapted Fig. 4G above). If the prior art structure is capable of performing the intended use, then it meets the claim.
It is acknowledged that the Applicants invention incorporates the engineered cells taught by David and Jung into an in vitro system for testing the impact of a substance on the ability of the working-myocardium cardiomyocytes to receive and respond to (i.e., contraction) the signals sent by the iSABs. However, the claim limitations are broad in scope, and it is not clear how the claim limitations differ from David, Jung and Marban. Therefore, Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Applicant argues that all references fail to teach an in vitro system comprising “a third region separating the first and the second region, wherein the third region is a spatially limited, direct contact area between the first and the second region” (Remarks, page 11).
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicants argument, it is noted that a third region may be “between” and “separating” a first and second region, because both of the words “between” and “separating” refer to the act of dividing two parts (i.e. the first and second region) and are not opposite meaning to one another. As discussed above, David discloses a third region (i.e. contact area of calcium transient channels) having direct contact between at least part of the iSABs and myocardium cardiomyocytes and the presence of the cardiac pacemaker marker (e.g. HCN4) (see e.g. para. 26, 36, 55-56, and 66). Further, David teaches iSABs containing at least one contracting region over time (Figure 4c) that is spatially limited direct contact (i.e. third region) between at least part of the iSABs and working-myocardium cardiomyocytes as discussed above.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 9AM - 5:00PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631