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 .
DETAILED ACTION
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 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.
Response to Amendments
Applicant’s amendments, corrected drawings and specification, and response filed Dec. 10, 2025 have been received and entered into the case.
Status of the Claims
Claims 1-20 are currently pending.
Claim 12 is amended.
Claims 1-11, 13-16, 19 and 20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 12, 17 and 18 have been considered on the merits.
Drawing Objections
The drawing objections are withdrawn due to amendment.
Specification Objections
The specification objections are withdrawn due to amendment.
Claim Objections
The claim objections are withdrawn due to amendment.
Claim Suggestion
New claim suggestions have been added due to amendment.
In claim 12, it is suggest that the phrase:
“the hUC-MSC-ES overexpressing an ischemic myocardium-targeting peptide (IMTP) prepared by a method for preparing the hUC-MSC-ES overexpressing the IMPT wherein the method comprises the following steps”,
in the interest of improving claim form, be amended to recite:
“the hUC-MSC-ES overexpressing an ischemic myocardium-targeting peptide (IMTP)[[,]] for preparing the hUC-MSC-ES overexpressing the IMPT comprises the following steps”.
Appropriate correction is appreciated.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn due to amendment.
New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment.
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 17 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.
In claim 17, line 1, the phrase "the related disease" lacks sufficient antecedent basis and renders the claim and its dependents indefinite. This term has been deleted from claim 12 from which the claim depends from.
Appropriate correction is required.
New claim rejections under 35 USC § 112, (d) or fourth paragraph (pre-AIA ), are withdrawn due to amendment.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 12 requires the subject to have myocardial ischemia/reperfusion injury (MIRI), inflammation, arrhythmia, ventricular remodeling, myocardial fibrosis, and post-MI heart failure caused by MIRI. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The claim rejections under 35 USC § 102 are revised due to amendment.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 12 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (Journal of the American Heart Association, 2018) (ref. of record).
With respect to claim 12, Wang teaches a method of treating and alleviating ischemic myocardium and acute myocardial infarction (a myocardial ischemia/reperfusion injury) by administering to a subject mesenchymal stem cell exosomes (MSC-ES) overexpressing ischemic myocardium-targeting peptide (IMTP) (abstract).
Wang does not teach the method where the MSC-ES are derived from human umbilical cord MSCs as recited in claim 12. Similarly, Wang does not teach the exact method of preparing the MSC-ES overexpressing IMTP as recited in claim 12.
Although, Wang does not teach the exact method by which MSC-ES are produced as in claim 12, these limitations are interpreted as product by process type limitations. If the claimed product is the same or obvious from a product in the prior art (i.e. the product disclosed in the cited reference), the claim is unpatentable even though the reference product was made by a different process. Furthermore, it is noted that the method for producing the MSC-ES for the administration of the MSC-ES to a subject is immaterial or inconsequential to the operation of the method. In other words, the MSC-ES of Wang is the same enzyme as the claimed invention regardless of method of production absent a showing of secondary considerations.
Additionally, Wang teaches many of the same product by process steps for producing the MSC-ES. With respect to the first recited step, Wang teaches preparing the MSC-ES by inserting a double-stranded fragment of Lamp2b+IMPT into the lentivirus-based vector pCDH-CMV-MSC-EF1-copGFP to obtain a recombinant vector (pg. 2 last para. and Fig. 1). With respect to the second recited step, Wang teaches co-transfecting host cells with the recombinant vector and a packaging system to obtain lentiviral particles (pg. 3 Col. 1 first para. and pg. 5 Col. 1 para. 3). With respect to the third recited step, Wang teaches infecting BMSCs with the lentiviral particles to obtain BMSCs overexpressing IMTP (pg. 3 Col. 1 first para. and pg. 5 Col. 1 para. 5 to pg. 6 para. 2). With respect to the fourth recited step, Wang teaches preparing conditioned medium of the BMSCs overexpressing IMTP (pg. 3 Col. 1 para. 2 and pg. 5 Col. 1 para. 3 to pg. 6 para. 2). With respect to the fifth recited step, Wang teaches collecting MSC-ES overexpressing IMTP (pg. 3 Col. 1 para. 2 and pg. 5 Col. 1 para. 3 to pg. 6 para. 2).
With respect to claims 12 and 17, Wang teaches that a mouse model of myocardial infarction administered the MSC-ES-IMTP (IMPT-exosomes) exhibited less inflammation then mice administered blank-exosomes and less fibrosis (pg. 3 last para., pg. 8 para. 2, pg. 10 para. 2). Furthermore, the treating or alleviating of inflammation, arrhythmia, ventricular remodeling, myocardial fibrosis, and post-MI heart failure caused by MIRI is inherent to MSC-ES. In addition, to showing that MSC-ES treat and alleviate inflammation and reduce myocardial fibrosis, Wang reports that MSC-ES have been shown to have many effects on cardiac diseases including anticardiac remodeling effects (treat or alleviate ventricular remodeling) and recovery of cardiac function (treat or alleviate ventricular remodeling).
Therefore, the reference anticipates the claimed subject matter.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to amendment.
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 12, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Journal of the American Heart Association, 2018) (ref. of record).
With respect to claim 12, Wang teaches a method of treating and alleviating ischemic myocardium and acute myocardial infarction (a myocardial ischemia/reperfusion injury) by administering to a subject mesenchymal stem cell exosomes (MSC-ES) overexpressing ischemic myocardium-targeting peptide (IMTP) (abstract).
Wang does not teach the method where the MSC-ES are derived from human umbilical cord MSCs as recited in claim 12. Similarly, Wang does not teach the exact method of preparing the MSC-ES overexpressing IMTP as recited in claim 12.
Although, Wang does not teach the exact method by which MSC-ES are produced as in claim 12, these limitations are interpreted as product by process type limitations. If the claimed product is the same or obvious from a product in the prior art (i.e. the product disclosed in the cited reference), the claim is unpatentable even though the reference product was made by a different process. Furthermore, it is noted that the method for producing the MSC-ES for the administration of the MSC-ES to a subject is immaterial or inconsequential to the operation of the method. In other words, the MSC-ES of Wang is the same enzyme as the claimed invention regardless of method of production absent a showing of secondary considerations.
Additionally, Wang teaches many of the same product by process steps for producing the MSC-ES. With respect to the first recited step, Wang teaches preparing the MSC-ES by inserting a double-stranded fragment of Lamp2b+IMPT into the lentivirus-based vector pCDH-CMV-MSC-EF1-copGFP to obtain a recombinant vector (pg. 2 last para. and Fig. 1). With respect to the second recited step, Wang teaches co-transfecting host cells with the recombinant vector and a packaging system to obtain lentiviral particles (pg. 3 Col. 1 first para. and pg. 5 Col. 1 para. 3). With respect to the third recited step, Wang teaches infecting BMSCs with the lentiviral particles to obtain BMSCs overexpressing IMTP (pg. 3 Col. 1 first para. and pg. 5 Col. 1 para. 5 to pg. 6 para. 2). With respect to the fourth recited step, Wang teaches preparing conditioned medium of the BMSCs overexpressing IMTP (pg. 3 Col. 1 para. 2 and pg. 5 Col. 1 para. 3 to pg. 6 para. 2). With respect to the fifth recited step, Wang teaches collecting MSC-ES overexpressing IMTP (pg. 3 Col. 1 para. 2 and pg. 5 Col. 1 para. 3 to pg. 6 para. 2).
With respect to claims 12 and 17, Wang teaches that a mouse model of myocardial infarction administered the MSC-ES-IMTP (IMPT-exosomes) exhibited less inflammation then mice administered blank-exosomes and less fibrosis (pg. 3 last para., pg. 8 para. 2, pg. 10 para. 2). Furthermore, the treating or alleviating of inflammation, arrhythmia, ventricular remodeling, myocardial fibrosis, and post-MI heart failure caused by MIRI is inherent to MSC-ES. In addition, to showing that MSC-ES treat and alleviate inflammation and reduce myocardial fibrosis, Wang reports that MSC-ES have been shown to have many effects on cardiac diseases including anticardiac remodeling effects (treat or alleviate ventricular remodeling) and recovery of cardiac function (treat or alleviate ventricular remodeling).
With respect to claim 18, Wang teaches administering 4x109 particles/50 µg/100 µL PBS/mouse. Although Wang does not teach the range recited in claim 18, one of ordinary skill in the art would recognize that the dose of MSC-ES administered is a result effective variable and that the dose of MSC-ES administered would be matter of routine optimization depending on such factors as the condition of the subject and the number of doses. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) -MPEP § 2144.05.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Dec. 10, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 102, Applicant argues that bone-marrow-derived mesenchymal stem cell-derived exosomes (MSC-ESs) and umbilical cord MSC-ESs are markedly different and differ in size, originate from entirely separate tissues and belong to distinct functional categories. Applicant argues that the biological activity of exosomes depends on the parent cell source, engineering modification and specific disease context making the relationships complex and unpredictable (Remarks pg. 13 para. 5). However, this argument was not found to be persuasive, since Wang teaches a method of treating and alleviating ischemic myocardium and acute myocardial infarction (a myocardial ischemia/reperfusion injury) by administering to a subject mesenchymal stem cell exosomes (MSC-ES) overexpressing ischemic myocardium-targeting peptide (IMTP) (abstract). Although, the source of tissue of the exosomes is different in Wang, the exosomes are having the same effect of treating MIRI in a subject suggesting the source of the exosome is not critical to the treating of MIRI in a subject.
Applicant argues that the exosomes in Wang (ranging from 30-150 nm) are larger than the ones disclosed in the instant specification (75.88±14.21 nm) (Remarks pg. 13 last para.). However, this argument was not found to be persuasive, since the size of the exosomes does not appear to be critical to the treating of MIRI in a subject because the exosome of Wang are successful in the treatment of MIRI.
Applicant argues that the hUC-MSC-EXO has an unique RNA signature that is distinct from BM-MSC-EXO and is enriched in cardio-protective miRNAs (Remarks pg. 13 last para.). However, this argument was not found to be persuasive, since no evidence has been provided clearly demonstrating this. As stated in the MPEP 716.01(c) I, “Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of 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 applicant.” Attorney statements or arguments cannot take the place of evidence which must be supported by an appropriate affidavit or declaration. MPEP 716.01(c) II
Applicant argues that the claimed hUC-MSC-ESs reduced fibrosis by 83.1 and 81.9% compared to control groups whereas the MSC-ESs of Wang reduced fibrosis by 55.9% compared to a control group. Applicant further argues that this two-fold difference in fibrosis reduction of the ESs is due to the source of tissues (Remarks pg. 13 last para.). However, this argument was not found to be persuasive, since Wang is measuring fibrosis length and not the number of CM (cardiomyocytes) and collagen fibers as measured in the instant specification (0207 and Fig. 14). These measurements of myocardial fibrosis appear to be different. In addition, the subject animal is different in both. Wang treats mice whereas in the specification rats are treated. Specifically, Wang states that fibrosis length is reduced in the IMPT-exosome treated mice (31.8±1.9%) compared to blank-exosome treated mice (47.9±1.1%) and PBS treated mice (55.9±2.0%), and that both IMPT-exosome treated mice and blank-exosome treated mice had reduced fibrosis length compared to the PBS treated mice (pg. 4 Col. 1 para. 1 and Fig. 12A and 12B). The results in the specification show the amount of myocardial fibrosis based on measuring CMs and collagen fibers is reduced for both control-ES treated rats (51.9%) and Blank-ES treated rats (55.3%) compared to PBS treated rats and the IMPT-ES treated rats was reduced by 83.1% and 81.9% compared to the control-ES treated rats and Blank-ES treated rats (0207 and Fig. 14). Furthermore, it is noted that the claim includes both hUC-MSC-ES which do not over-express IMTP.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that one skilled in the art would not have the motivation to replace the source of ESs or have a reasonable expectation of success in doing so, since Wang does not teach that there are differences between ES from bone marrow MSCs and ES from umbilical cord MSC, which perform better (Remarks pg. 14 para. 8). However, this argument was not found to be persuasive, since no convincing evidence has been presenting demonstrating that the bone-marrow derived MSC exosomes do not perform as well as umbilical cord MSC exosomes as explained in the response to the arguments to the rejections under 35 U.S.C. § 102.
Applicant argues that the claimed process produces new and unexpected results including a superior effect of myocardium fibrosis reduction over Wang, and excellent calcium overload reduction which is not taught in Wang (Remarks pg. 14 para. 10-11). However, these arguments were not found to be persuasive, since it is unclear that the claimed process produces new and unexpected results including a superior effect of myocardium fibrosis reduction over Wang, since the experiments measure fibrosis differently using different animal models. In response to applicant's argument that Wang fails to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., calcium overload reduction) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that they have compared ES from UC-MSCs and BM-MSCs and found that hUC-MSC-ESs are superior to BM-MSC-ESs in several aspects of mechanism which gives its excellent therapeutical efficacy as shown in Fig. 1 of the Remarks. Applicant argues that Fig. 1 shows that when human embryonic stem cell-derived cardiomyocytes (hESCs-CMs) are treated with hUC-MSC-ESs there is a slight reduction in apoptosis, lower intracellular free calcium levels and a decrease in autophagy-related proteins compared to cells treated with BM-MSC-ESs (Remarks pg. 15 to pg. 16 para. 1). Applicant argues that Fig. 2 demonstrates that there is an improvement in ferroptosis and pyroptosis in hESCs-CMs when the cells are treated with hUC-MSC-ESs compared to when the cells are treated with BM-MSC-ESs (Remarks pg. 16 last para. to pg. 17). Applicant argues that Fig. 3 demonstrates that there is a slight improvement in the reduction in mitochondrial quantity and dysfunction in hESCs-CMs when the cells are treated with hUC-MSC-ESs compared to when the cells are treated with BM-MSC-ESs and that engineered IMTP-hUC-MSC-ES enhances these effects (Remarks pg. 18 para. 1). However, these arguments were not found to be persuasive, since no evidence has been provided clearly demonstrating this. As stated in the MPEP 716.01(c) I, “Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of 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 applicant.” Attorney statements or arguments cannot take the place of evidence which must be supported by an appropriate affidavit or declaration. MPEP 716.01(c) II
Conclusion
No claims are 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632