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 .
Amendments
In the reply filed 06/24/2025, Applicant has amended claims 25 and 101.
Claim Status
Claims 25, 30-31 and 87-93, 95-96 and 101-108 are pending.
Claims 90, 95-96, 101 and 105-106 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/21/2023 and during a telephonic interview on 10/20/2023.
Claims 25, 30-31, 87-89, 91-93, 102-104 and 107-108 are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 112(a)
The prior rejection of claims 25, 30-31, 87-89, 91-93, 102-104 and 107-108 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not provide enablement for the scope of the claimed invention has been withdrawn in light of Applicant’s amendment to claim 25 to recite “activated cardiac fibroblasts”.
Withdrawn Claim Rejections - 35 USC § 101
The prior rejection of claims 25, 30-31, 87-89, 91-93, 102-104 and 107-108 under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter has been withdrawn in light of Applicant’s amendment to claim 25 to remove the steps of “evaluating” and “comparing”.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 25, 30-31, 87-89, 91-93, 102-104 and 107-108 under 35 U.S.C. 103 set forth in the prior Office action mailed on 03/24/2025 has been withdrawn in light of Applicant’s amendment to claim 25 to remove the step of “comparing the genetic signature of the activated fibroblasts population”. In other words, the amended claim does not require isolating a population of activated cardiac fibroblasts from the subject for evaluating and comparing the genetic signature of that specific population.
New 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 25, 30-31, 87-88, 91-93, 102-104 and 107-108 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (Circulation. 2001;103:736-742. Prior art of record) in view of Daseke et al (Matrix Biology. 2020; 91-92: 109-116. Prior art of record).
With respect to claim 25, Jin teaches a method of identifying cardiac gene expression in a myocardial infarction (MI) model and a step of administering a cardiomyopathy therapy (title, abstract).
Regarding administering to a subject a cardiomyopathy therapy, Jin teaches a subject with cardiomyopathy (a rat MI model) is given a pharmacological intervention of a small molecule ACE inhibitor captopril (p. 736, last para).
Regarding the administering being based on the presence of a population of activated cardiac fibroblasts comprising a genetic signature in a sample provided from the subject, Jin teaches evaluating and comparing gene expression profiles in a cardiac tissue from the MI model (i.e., a sample provided from the subject), with controls by DNA microarray and RT-PCR and teaches the cardiac tissue from the MI group comprises increased expression of thrombospondin-4 and collagen I (Col1a1) compared to control (abstract, p. 737, left col, last three sections and right col, last section “Effects of MI on Myocardial Gene Expression”, also see Table 2 and Fig 4). Jin summarizes that “ACE inhibition can inhibit some of the changes in gene expression that are induced by MI” and speculates that changes in “expression of these genes may be causally related to an element of the pathophysiology that is improved by ACE inhibition” (p. 741 4th & 6th para. respectively). Thus, it would have been obvious to base ACE inhibitor treatment on the same MI-induced gene expression changes that the ACE inhibitor treatment was successfully shown to reverse.
However, although Jin teaches increased expression of thrombospondin-4 and collagen I (Col1a1) in the cardiac samples provided from the MI group relative to the samples from the control (see above), Jin is silent on the presence of a population of activated cardiac fibroblasts in the sample.
Daseke teaches cardiac fibroblast activation occurs after myocardial infarction (MI) (see abstract and Fig 1) and teaches activated cardiac fibroblasts are the major players in scar formation following MI (p. 113, “Conclusions” para 1). Daseke teaches collagen I alpha 1 (Col1a1) is increased in activated cardiac fibroblasts from day 1 after MI (and sustains to at least 28 days, see Fig 1, also see teaching of secretome analysis at day 7 in infarct cardiac fibroblast culture in p. 113, left col, para 1), thus teaches Col1a1 is a genetic signature for activated cardiac fibroblasts.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have appreciated that there would have been a population of activated cardiac fibroblasts, comprising a genetic signature comprising increased expression of thrombospondin-4 and collagen I (Col1a1), present in the cardiac samples provided from the MI group relative to the samples from the control in Jin’s method as suggested by Daseke, because Jin teaches increased expression of thrombospondin-4 and collagen I (Col1a1) in the cardiac samples provided from the MI group relative to the control (p. 737, last section) and because Daseke teaches cardiac fibroblasts are activated after MI (see abstract and Fig 1) and collagen I alpha 1 (Col1a1) is a genetic signature for activated cardiac fibroblasts after MI (with increased expression from day 1 to at least day 28, see e.g., Fig 1). Since Jin summarizes that “ACE inhibition can inhibit some of the changes in gene expression that are induced by MI” and the changes in “expression of these genes may be causally related to an element of the pathophysiology that is improved by ACE inhibition” (p. 741 4th & 6th para. respectively), one of ordinary skill in the art would have had a reason to base ACE inhibitor treatment on the presence of activated cardiac fibroblasts comprising a genetic signature of MI-induced gene expression changes that the ACE inhibition was successfully shown to reverse.
Furthermore, regarding the genetic signature comprising increased expression of FAM155A, TSHZ2, COL22A1, POSTN and thrombospondin-4, it is noted that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. See MPEP 2112 II. Notably, the prior art Jin, in view of Daseke, makes it clear that Jin’s cardiomyopathy subjects have a population of activated cardiac fibroblasts comprising the genetic signature of increased expression of Col1a1, thrombospondin-4 (THBS4), and periostin (POSTN) (Jin, p. 737, last full para, see Table 2 and Fig 4 for increased Col1a1 and THBS4. Also see Daseke’s teaching of increased Col1a1 (Fig 1 and p. 113, left col, para 1) and periostin (POSTN) in activated cardiac fibroblasts (i.e., contractile fibroblasts, p. 112, right col, para 2)), thus the missing descriptive matter of increased expression of FAM155A, TSHZ2 and COL22A1 is necessarily present in the population of activated cardiac fibroblasts of Jin in view of Daseke, and that it would have been so recognized by persons of ordinary skill. Since the Patent Office does not have the facilities for examining and comparing applicant’s activated cardiac fibroblasts with the activated cardiac fibroblasts of the prior art reference, the burden is upon applicants to show a distinction between the material structural and functional characteristics of the claimed activated fibroblasts and the activated cardiac fibroblasts of the prior art. See MPEP 2112 V.
With respect to claim 30 directed to the cardiomyopathy therapy comprising pharmacological intervention and claim 31 directed to the therapy comprising use of an ACE inhibitor, as stated supra, Jin teaches a pharmacological intervention is given by administering a small molecule ACE inhibitor captopril (p. 736, last para).
With respect to claim 87 directed to the subject being at risk of having cardiomyopathy and claim 88 directed to the subject having cardiac disease predisposing the subject to cardiomyopathy, as stated supra, Jin teaches a MI rat model produced by left coronary arterial ligation (p. 737, last para) and teaches the rat model has moderate-sized infarcts (p. 737, Results subsection 1), thus teaches the subject is at risk of having cardiomyopathy (i.e., after MI) and has cardiac disease (i.e., MI) predisposing the subject to cardiomyopathy.
With respect to claim 91 directed to the genetic signature further comprising increased expression of additional gene product, claims 92-93 directed to additional gene product being COL1A1, and claim 104 directed to the genetic signature further comprising increased expression of COL1A1, as stated supra, Jin teaches expression of Collagen I (Accession number Z78279, which is rat Col1a1) is increased (see Table 2 and Fig 4). Regarding the increased Col1a1 being a genetic signature for activated cardiac fibroblasts, as stated supra, Daseke teaches collagen I alpha 1 (Col1a1) is increased in activated cardiac fibroblasts from day 1 after MI (and sustains to at least 28 days, see Fig 1, also see teaching of secretome analysis at day 7 in infarct cardiac fibroblast culture in p. 113, left col, para 1), thus teaches Col1a1 is a genetic signature for activated cardiac fibroblasts.
With respect to claim 102 directed to the therapy comprising a therapeutically effective amount of an agent capable of modulating the genetic signature and claim 103 directed to the modulating the genetic signature comprising decreasing the expression of a gene product of the genetic signature, as stated supra, Jin teaches the treatment comprises an ACE inhibitor captopril and teaches treatment decreases the expression of thrombospondin-4 (p. 741, right col, 1st full para, see Table 2), thus teaches the treatment comprises a therapeutically effective amount of an agent (i.e., captopril) that is capable of decreasing the expression of thrombospondin-4.
With respect to claim 107 directed to the agent being a small molecule and claim 108 directed to the agent being a small molecule ACE inhibitor, as stated supra, Jin teaches the therapeutic agent is a small molecule ACE inhibitor captopril (p. 736, last para).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 89 is rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (Circulation. 2001;103:736-742. Prior art of record) in view of Daseke et al (Matrix Biology. 2020; 91-92: 109-116. Prior art of record), as applied to claim 25 above, and further in view of Pfeffer et al., (Am J Physiol. 1991; 260(5 Pt 2):H1406-14. Prior art of record).
Claim 89 is directed to the cardiomyopathy being dilated cardiomyopathy.
As stated supra, Jin, in view of Daseke, suggests a method comprising administering a cardiomyopathy therapy based on the presence of a population of activated cardiac fibroblasts comprising a genetic signature. Regarding the type of cardiomyopathy, Jin teaches a MI model produced by left coronary arterial ligation as described previously [6] (p. 737, last para. It is noted that Reference [6] is Pfeffer (1991) cited here) and teaches heart failure after MI (it is noted that the heart failure is usually due to dilated cardiomyopathy, p. 736, 1st para, and p. 741, second to the last para).
However, Jin does not specifically teach the cardiomyopathy model is a dilated cardiomyopathy model.
Pfeffer (1991), cited as Reference #6 by Jin for teaching producing the MI cardiomyopathy model, teaches that the MI model produced by left coronary arterial ligation has significant ventricular dilation (see Figs 1-2, especially Fig 1B and 2B “moderate” since this is the infarct size used by Jin) from day 7 and later (note that Jin uses a time point of 8 weeks (i.e., day 56)). Thus, Pfeffer teaches the cardiomyopathy model produced in Jin has dilated cardiomyopathy.
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have appreciated that the cardiomyopathy model of Jin would have been a dilated cardiomyopathy model as taught by Pfeffer. One of ordinary skill in the art would have had a reason to choose this dilated cardiomyopathy model because Jin teaches mortality and morbidity from heart failure after MI (usually due to dilated cardiomyopathy) remain high and suggests searching for new treatment strategies (p. 741, second to the last para).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 06/24/2025 are acknowledged.
Applicant first argues that amendment to claim 25 to recite “activated cardiac fibroblasts” overcomes the prior 112a lacking enablement rejection, and amendment to claim 25 to remove the steps of “evaluating” and “comparing the genetic signature of the activated fibroblasts population” overcomes the prior 101 rejection (Remarks, p. 6-7).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejections of 112a and 101 have been withdrawn. Furthermore, the prior rejection of 103 has been withdrawn since Applicant amended claim 25 to remove the step of “comparing the genetic signature of the activated fibroblasts population”. In other words, the amended claim does not require isolating a population of activated cardiac fibroblasts from the subject for evaluating and comparing the genetic signature of that specific population. However, as necessitated by amendment, the prior art Jin, Daseke and Pfeffer have been re-applied to make obvious the claimed method.
Applicant further argues that Examiner has not provided any rationale or evidence to support that the activated cardiac fibroblast populations disclosed in Jin and Daseke necessarily have the genetic signature recited in claim 25. Daseke shows 13 different genes that may or may not be upregulated in different populations of activated cardiac fibroblasts depending on the timing point at which gene expression was assessed. In the present Application, a cluster of activated cardiac fibroblasts (having the genetic signature recited in claim 25) has been found in 2989 cell nuclei from 12 patients with dilated cardiomyopathy (largely derived from a single DCM patient #P1304, see Fig 4A). This population of activated cardiac fibroblasts is highly specific for identifying individuals with cardiomyopathy, and in particular, the upregulation of FAM155A and TSHZ2 is not known to be associated with cardiomyopathy prior to the filing of the present Application (see specification [0093]) (Remarks, p. 7-8).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to the argument that Examiner has not provided any rationale or evidence to support that the activated cardiac fibroblast populations disclosed in Jin and Daseke necessarily have the genetic signature recited in claim 25, as a first matter, as stated supra as well as in the prior rejection, Jin teaches increased expression of thrombospondin-4 and collagen I (Col1a1) in the cardiac samples provided from the MI group (8 weeks after MI) relative to the control (p. 737, last section, see Table 2 and Fig 4). Daseke teaches cardiac fibroblasts are activated after MI (see abstract and Fig 1) and collagen I alpha 1 (Col1a1) is a genetic signature for activated cardiac fibroblasts after MI (with sustained increased expression from day 1 to at least day 28, see e.g., Fig 1) and periostin (POSTN) expression is increased in activated cardiac fibroblasts (i.e., contractile fibroblasts in the infarct region of MI to maintain structural integrity during the process of scar formation, p. 112, right col, para 2). Accordingly, one of ordinary skill in the art would have appreciated that Jin’s cardiac samples from MI group would have comprised a population of activated cardiac fibroblasts, and the increased expression of thrombospondin-4 and Col1a1 in the MI samples would have been due to the sustained increased expression of the genes from the activated cardiac fibroblasts present in the samples as suggested by Daseke. Applicant’s argument that Daseke shows 13 different genes that may not be upregulated depending on the timing points (it is noted that neither of these genes is recited by Jin or instant claim 25 except Col1a1), does not negate the teaching of Daseke that Col1a1 is a genetic signature for a population of activated cardiac fibroblasts after MI that has sustained increased expression of Col1a1 from day 1 to at least day 28 (see e.g., Fig 1).
Regarding the rationale that Jin’s activated cardiac fibroblasts, having a genetic signature of increased expression of Col1a1, thrombospondin-4 and periostin as suggested by Jin and Daseke and as recited in claim 25, would necessarily have increased expression of other gene products FAM155A, TSHZ2 and COL22A1 as recited in claim 25, as stated supra, Jin in view of Daseke teaches a population of activated cardiac fibroblasts present in cardiac samples collected 8 weeks after MI (Jin, p. 737, right col, last section “Effects of MI on Myocardial Gene Expression”), and teaches the MI model is produced as described in Jin’s Reference #6 which is Pfeffer (1991) as stated supra and in the prior rejection. Pfeffer (1991) teaches the MI model has significant ventricular dilation (see Pfeffer Figs 1-2, especially Fig 1B and 2B “moderate” since this is the infarct size used by Jin) from day 7 and later (note that Jin uses a time point of 8 weeks, i.e., day 56). Thus, Pfeffer teaches the cardiomyopathy model produced in Jin has dilated cardiomyopathy.
As Applicant has argued that the present Application identifies a population of activated cardiac fibroblast having a genetic signature of upregulation of known markers periostin, COL1A1, thrombospondin-4 and COL22A1, as well as previously unreported genes such as FAM155A and TSHZ2 (specification [0093] and Remarks, p. 8, last para), it is noted that Applicant has identified this population of activated cardiac fibroblasts from 2989 fibroblast nuclei from 12 patients with dilated cardiomyopathy (largely derived from a single DCM patient #P1304, see Fig 4A, [0093] and Remarks, p. 8, last para). Accordingly, both Jin and the present Application teach identification of a population of activated cardiac fibroblasts from subjects having dilated cardiomyopathy and both teach this population of activated cardiac fibroblasts comprises a genetic signature of increased expression of known markers of periostin, COL1A1 and thrombospondin-4. Thus, both Jin and the present Application identify the same type of population of activated cardiac fibroblasts from the same type of subjects (i.e., having the same dilated cardiomyopathy). Therefore, the missing descriptive matter of increased expression of other gene products FAM155A, TSHZ2 and COL22A1 is necessarily present in the population of activated cardiac fibroblasts of Jin in view of Daseke, and that it would have been so recognized by persons of ordinary skill.
Finally, regarding the argument that the upregulation of FAM155A and TSHZ2 is not known to be associated with cardiomyopathy prior to the filing of the present Application (see specification [0093]) (Remarks, p. 7-8), it is noted that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the filing time of invention, but only that the subject matter is in fact inherent in the prior art reference. See MPEP 2112 II. In the instant case, as discussed above, Jin, in view of Daseke, identify the same type of population of activated cardiac fibroblasts from the same type of subjects (i.e., having dilated cardiomyopathy) as the present Application. Therefore, the missing descriptive subject matter of increased expression of previously unknown gene products FAM155A and TSHZ2 as well as COL22A1 is in fact necessarily present in the population of activated cardiac fibroblasts of Jin in view of Daseke.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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