DETAILED ACTION
Applicant’s response filed August 7, 2026 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 1-2, 4, 10, 17-18, 21, 27-29, 32-33, 39-43, and 49-62 from the claim set filed August 7, 2026 are pending. Claims 1, 4, and 58 are amended and new claims 59-62 are added. Claims 3, 5-9, 11-16, 19-20, 22-26, 30-31, 34-38, and 44-48 are cancelled. Claims 17-18, 21, 27-29, 32-33, 39-43, and 49-57 are withdrawn. Thus claims 1-2, 4, 10, and 58-62 are being examined on the merits herein.
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 .
Objection(s)/Rejection(s) Maintained
&
Response to Applicant Remarks
Drawings
RE: The drawings are objected to because FIG 1C refers to color (i.e., blue, red and green fluorescence) but said figure is in black and white. Thus, the data illustrated in FIG. 1C cannot be ascertained. If the structural detail in FIG. 1C is essential for a proper understanding of the disclosed invention, Applicant may consider submitting color photographs by submitting a petition filed under 37 CFR 1.84(a)(2).
Appropriate correction is required.
It is noted that color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Examiner notes Applicant filed a petition under 37 CFR 1.84(a)(2) dated 8/7/2026. As said petition has not been granted as of yet by the Office, the previously filed objection is maintained.
Specification
RE: The disclosure is objected to because of the following informalities: p10, lines 6-14 describe FIG 1C and refers to colors (i.e., red and green) but said figure is in black and white.
The disclosure is objected to because of the following informalities: p11, lines 2-9 describe FIG 2C and refers to colors (i.e., red and green) but said figure is in black and white.
The disclosure is objected to because of the following informalities: p14, lines 6-8 describe FIG 5E and refers to colors (i.e., blue and green) but said figure is in black and white.
As set forth above, if the structural detail in said Figures is essential for a proper understanding of the disclosed invention, Applicant may consider submitting color photographs by submitting a petition filed under 37 CFR 1.84(a)(2).
Appropriate correction is required.
Examiner notes Applicant filed a petition under 37 CFR 1.84(a)(2) dated 8/7/2026. As said petition has not been granted as of yet by the Office, the previously filed objection is maintained.
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.
RE: Claims 1-2, 4, 10, and 58 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
Applicant amended claim 1 to now require “wherein the endothelial exosome is isolated from an endothelial cell, and wherein the at least one exogenous miR is selected from the group consisting of miR1, miR133, miR138, miR148a-3p, miR206, miR208, miR499-5p, and any combination thereof.”
Applicant remarks regarding the previously filed rejection have been considered but have not been found persuasive.
Applicant remarks state that where a nature-based product is claimed as a combination of multiple components, the analysis to be applied must be applied to the resultant combination, rather than to the components in isolation. Applicant remarks state amended claim 1 does not claim an endothelial exosome and a miR as two unassociated natural products. It claims a loaded endothelial exosome in which an exogenous miR from a defined Markush group is located within the exosome. Applicant remarks further state the specification teaches loading C166 endothelial exosomes by transfection and thus the relevant comparison is the claimed resultant loaded-exosome composition to a naturally occurring endothelial exosome in its natural state, not an endothelial exosome and a free miRNA separately.
Examiner has considered Applicant remarks but have not found said remarks to be persuasive. As stated in the previously filed rejection, Examiner respectfully notes claim 1 encompasses two naturally occurring products, i.e., (1) an endothelial exosome and (2) at least one exogenous miR selected from the group consisting of miR1, miR133, miR138, miR148a-3p, miR206, miR208, miR499-5p, and any combination thereof. Thus, claim 1 is solely directed to naturally occurring products. Examiner respectfully notes that claim 1 solely requires “at least one” miR. As an example, Hehl (Hehl et al., Atherosclerosis 395 (2024)) teaches of the expression levels of miR-148a-3p in human coronary artery endothelial cells (p1, bottom of 1st column-top of second column). Thus, it is highly likely the exosome derived from said cells would comprise miR-148a-3p. Further, Examiner respectfully notes Venkat (Venkat et al., Stroke (2019) 50(10); PTO 892) teaches miR-126 is expressed in high levels in both endothelial cells and endothelial cell exosomes (Results, p1). Venkat additionally teaches exosomes facilitate intercellular communication and cell-specific transfer of microRNAs (Introduction, p2). The teachings of Venkat support Examiner’s stance that it is highly likely a cell expressing a particular miRNA would, at various timepoints, produce exosomes expressing said particular miRNA for cell-specific transfer.
Thus, the claim as a whole, considering all claim elements both individually and in combination, does not amount to significantly more than a natural composition. There is no indication in the specification that by combining said natural products that any characteristics (structural, functional, or otherwise) are developed that are markedly different from what occurs in nature. The combination of natural products required by claim 1 does not improve or change in any way each component’s natural functioning.
Thus, the relevant comparison as noted by Applicant, i.e., “the claimed resultant loaded-exosome composition” is a naturally occurring endothelial exosome comprising at least on miR. The transfection of an endothelial exosome with, for example, miR-148a-3p, does not markedly change the exosome in a manner to distinguish said exosome from its naturally occurring counterpart.
Therefore, Examiner respectfully notes, Applicant remarks are not found persuasive in said regards.
Applicant remarks state the specification contains concrete evidence of changed functionality in loaded-exosome embodiments. Applicant remarks have been carefully considered but have not been found persuasive.
As stated in Applicant remarks: “C166-derived exosomes loaded with miR combo induced fibroblast to cardiomyocyte reprogramming, and the specification reports that the number of reprogramming events was approximately 50% higher with C166-derived exosome delivery than with lipid delivery despite equivalent intracellular miRNA levels.” Applicant refers Examiner to [0067]-[0068], [0098], and [0200].
Examiner respectfully notes paragraph [0200] states, in concordance with the above quoted Applicant remarks “the number of reprogramming events were 50% higher with the C166-derived exosome delivery route despite equivalent levels of miRNAs being delivered into the cells.” The claims as currently written however, are not specific to C166-derived exosomes but are general to endothelial exosomes. Additionally, Examiner respectfully notes that throughout the specification, and as noted in the above quoted Applicant remarks, the phrase “miR combo” is referred to [0067]-[0068], [0098], [0200]. Per paragraph [0093], fibroblasts within cardiac scar tissue are reprogrammed into cardiomyocytes via a set of four miRNAs, referred to as “miR combo”. It appears, based on paragraph [0094], said miR combo is the combination of miR1, miR133a-5p, miR208a-5p, and miR-499A-5p. However, claim 1 as currently written does not require four miRNAs but rather requires at least one miRNA.
Therefore, Examiner respectfully notes, Applicant remarks are not found persuasive in said regards.
In regards to Applicant remarks concerning Funk Bros and specifically to “The claimed loaded arrangement, together with the specification’s evidence concerning loaded exosome behavior, is materially different from the unchanged natural functions”, Examiner respectfully reiterates, the claims as currently written are not requiring the specific miR combination nor are they requiring the specific C166 endothelial exosomes.
Therefore, Examiner respectfully notes, Applicant remarks are not found persuasive in said regards.
In regards to Applicant remarks concerning the teachings of Hehl, Applicant remarks have been carefully considered but have not been found persuasive. Hehl teaches cardiac endothelial cells express miR-148a-3p. Thus, it is highly likely that miR-148a-3P would appear in the cell’s exosomes. In addition, Examiner respectfully notes Venkat (Venkat et al., Stroke (2019) 50(10); PTO 892) teaches miR-126 is expressed in high levels in both endothelial cells and endothelial cell exosomes (Results, p1). Venkat additionally teaches exosomes facilitate intercellular communication and cell-specific transfer of microRNAs (Introduction, p2). The teachings of Venkat support Examiner’s stance that it is highly likely a cell expressing a particular miRNA would, at various timepoints, produce exosomes expressing said particular miRNA for cell-specific transfer.
Thus, claim 1 is drawn to a naturally occurring product.
Therefore, the previously filed rejections are maintained and updated below for Applicant amendment.
Claims 1-2, 4, 10, and 58-62 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
The rationale set forth below conforms to current Office practice for examination of claims under § 101.
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. All the claims are directed to a statutory category, e.g., a composition (Step 1: YES).
The next part of the analysis involves whether the claimed invention recites or is directed to one or more judicial exceptions (Step 2A, prong one).
Claim 1: Claim 1 is directed to a biological composition comprising a loaded endothelial exosome and at least one exogenous miR within said endothelial exosome.
Examiner respectfully notes claim 1 encompasses two naturally occurring products, i.e., (1) an endothelial exosome and (2) at least one exogenous miR. Thus, claim 1 is solely directed to naturally occurring products. While Examiner acknowledges that Applicant states the miR is exogenous to the endothelial exosomes, Examiner respectfully notes that claim 1 recites miR-148a-3p among the listing of miR that may be included in said exosomes. Examiner respectfully notes Hehl (Hehl et al., Atherosclerosis 395 (2024)) teaches of the expression levels of miR-148a-3p in human coronary artery endothelial cells (p1, bottom of 1st column-top of second column). Thus, it is highly likely the exosome derived from said cells would comprise miR-148a-3p.
Thus, the claim as a whole, considering all claim elements both individually and in combination, does not amount to significantly more than a natural composition. There is no indication in the specification that by combining said natural products that any characteristics (structural, functional, or otherwise) are developed that are markedly different from what occurs in nature. The combination of natural products required by claim 1 does not improve or change in any way each components natural functioning.
“To show a marked difference, a characteristic must be changed as compared to nature and cannot be an inherent or innate characteristic of the naturally occurring counterpart. Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948).
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101.
Claims 2, 4, 10, and 58-62: Said claims are directed to further defining the type of exosome and miRNA of claim 1. Said claims recite naturally occurring exosomes and miRNAs. Thus, said claims are reciting products of nature. Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101.
Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101.
The next part of the analysis involves whether the claimed invention recites additional elements that integrate the judicial exception into a practical application (Step 2A, prong two).
Given the claims are directed to a composition, the claims do not recite additional steps that integrate the judicial exception into a practical application (Step 2A, prong two: No).
The final part of the analysis involves whether the claimed invention, as a whole, recite something “significantly more” than the judicial exceptions (Step 2B).
In view of the above and considered as a whole, the claimed composition does not have markedly different characteristics from what occurs in nature and such elements discussed above are not significantly more than the indicated judicial exceptions. Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101 (Step 2B: NO).
Thus, the claims are properly rejected.
Objection(s)/Rejection(s) Withdrawn
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
RE: Claims 1, 2, and 58 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Zhang (US 2022/0000932 A1, published 1/6/2022, EFD 9/27/2019; PTO 892).
Applicant amended claim 1 to now require “wherein the endothelial exosome is isolated from an endothelial cell, and wherein the at least one exogenous miR is selected from the group consisting of miR1, miR133, miR138, miR148a-3p, miR206, miR208, miR499-5p, and any combination thereof.”
Examiner respectfully notes that the limitation specifying “wherein the at least one exogenous miR is selected from the group consisting of miR1, miR133, miR138, miR148a-3p, miR206, miR208, miR499-5p, and any combination thereof” represents the incorporation of dependent claim 4 into independent claim 1. Said limitation was previously addressed by applying the teachings of Raso to the teachings of Zhang. As such, the previously filed 102 rejection is withdrawn.
However, Applicant amendment has necessitated new grounds of rejection as set forth below.
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.
RE: Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Raso (Raso, et al., Mol Ther (2018) 27(3): 584-599; PTO 892).
RE: Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Heineke (US 20200140860 A1, published 5/7/2020, EFD 5/30/2018; PTO 892).
For the reasons discussed above, the anticipation rejection over Zhang is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection as set forth below.
New Ground(s) of Rejection, Necessitated by Amendment
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.
Claims 1-2, 58-59, and 61-62 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Raso. Claim 62 is rejected as being unpatentable over Zhang in view of Raso, as evidenced by Cytion (retrieved from the internet 9/29/2026; https://www.cytion.com/us/About-Cytion/Articles-guides/Cell-Line-Encyclopedia/bEnd.3-The-Mouse-Brain-Microvascular-Endothelial-Cell-Line-for-Blood-Brain-Barrier-Research; PTO 892).
In regards to claims 1-2 and 59, Zhang teaches of the treatment and prevention of cerebrovascular injury caused by stroke via administering a therapeutically effective amount of mammalian exosomes loaded with one or more microRNAs selected from miR-19a, miR-21, and miR-146a (Abstract). Zhang teaches the major causes of death in stroke-related mortalities are a consequence of neurological damage and/or cardiovascular complications [0004]. Zhang teaches a therapeutically effective amount is broadly used herein to mean an amount of mammalian exosomes that when administered to a patient, ameliorates, diminishes, improves or prevents a symptom of cardiovascular disorder or disease in a patient who has suffered a stroke [0125].
As noted supra, Zhang teaches of mammalian exosomes containing one or more microRNAs selected from miR-19a, miR-21, and miR-146a (Abstract) and teaches said exosomes can be transfected/loaded [0174] with said microRNAs. Further, Zhang teaches of endothelial exosomes ([0087], Fig 1C) and specifically teaches mammalian exosomes can be derived or isolated from …, endothelial cells, cerebral endothelial cells, … [0038] (claim 2). Additionally, Zhang teaches a mammalian exosome can be a mammalian cell-derived exosome that initially contained no miR-19a, miR-21, miR-146a, or any combination thereof, but which was transformed with miR-19a coding nucleic acids, miR-21 coding nucleic acids, miR-146a coding nucleic acids or any combination thereof [0302]. This reads on said miRNAs being exogenous miRNAs. Further, Examiner respectfully notes “exogenous” miR is product by process language which appears to define the miR. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
Thus, Zhang teaches a loaded exosome comprising an endothelial exosome, and at least one exogenous miR within said endothelial exosome.
Zhang does not teach wherein at least one of the exogenous miR is selected from the group consisting of miR1, miR126, miR133, mir138, miR148a-3p, miR206, mir208, miR499-5p and any combination thereof.
Raso teaches of the therapeutic delivery of miR-148a (i.e., miR-148a-3p (p586, 1st column, last paragraph)) (claim 59) and teaches said delivery suppresses ventricular dilation in heart failure (Title). Raso teaches adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation (Abstract). Thus, Raso teaches the therapeutic effectiveness of delivering miR-148a-3p for the treatment of cardiovascular disease or disorders.
As discussed supra, Zhang teaches cardiovascular complications involved in stroke-related mortalities and teaches of the therapeutic delivery of microRNAs via administering a therapeutically effective amount of mammalian exosomes loaded with miRNAs. Zhang teaches said delivery of microRNAs improves or prevents symptoms of cardiovascular disease in a patient who has suffered a stroke. As Raso teaches the delivery of microRNA-148a-3p for the suppression of ventricular dilation in heart failure and thus teaches improving or preventing symptoms of cardiovascular disease, it therefore would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the microRNA of Zhang for the microRNA of Raso. The skilled artisan would have had a reasonable expectation of successfully substituting said microRNAs. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claims are obvious and are properly rejected.
In regards to claim 58, Zhang and Raso teach the loaded exosome of claim 1. Further, Zhang teaches mammalian exosomes enriched with microRNAs can comprise human endothelial cells [0056] and moreover teaches mammalian exosomes can be human exosomes derived from a human cell culture. Human exosomes can be derived from human endothelial cells [0059].
Thus, the claim is obvious and is properly rejected.
In regards to claim 61, Zhang and Raso teach the loaded exosome of claim 2. Further, Zhang teaches mammalian exosomes enriched with miR can comprise human endothelial cells and further teaches human endothelial cells can comprise primary human endothelial cells [0056].
Thus, the claim is obvious and is properly rejected.
In regards to claim 62, Zhang and Raso teach the loaded exosome of claim 61. As noted below in the 112d rejection of claim 62, said claim is not further limiting of claim 61. Claim 62 appears to broaden the scope of claim 61 in that the endothelial cell from which the exosome may be isolated from may be human or mouse (i.e., bEnd.3 or C166).
However, Examiner notes Zhang teaches primary cerebral endothelial cells from which the exosomes may be isolated [0334]. As a POSITA will appreciate, and as evidenced by Cytion, bEnd.3 cells are mouse brain (i.e., cerebral) endothelial cells (Introduction). As claim 62 is not further limiting of claim 61 as currently written, and claim 61 requires human endothelial cells, Examiner is thus interpreting the mouse cells of claim 62 to read on their human counterparts. Therefore, Examiner is applying the teachings of Zhang, i.e., cerebral endothelial cells.
It is also noted “wherein the endothelial exosome is isolated from a ….” is product by process language which appears to define the endothelial exosome. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113. In the instant case, it does not appear any structural or chemical properties are imparted via said product by process language.
Thus, the claim is obvious and is properly rejected.
Claims 4 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Raso and further in view of Zhou (WO 2021007515 A1, EFD 7/10/2020; PTO 892).
In regards to claims 4 and 60, Zhang and Raso teach the loaded exosome of claim 1. Zhang and Raso do not teach wherein the loaded exosome comprises miR1, miR133, miR208, and miR499-5p.
As noted in the rejection of claim 1, Zhang and Raso teach of an exosome comprising miR148a-3p for the treatment of cardiovascular disease or disorders. Thus, Zhang and Raso have established loading exosomes with miRNA to treat cardiovascular disease or disorders.
Zhou teaches methods for generating induced cardiomyocytes by expression of selected miRNAs (Abstract). Zhou teaches cardiac reprogramming as a strategy to create new cardiomyocytes leading to improved heart function in patients diagnosed with or at risk for cardiomyopathy, heart failure or other cardiac pathologies [0004]. Zhou teaches microRNA can be introduced directly into cells via an exosome comprising the microRNA [0201]. Zhou teaches a method for enhancing the direct reprogramming of cells into cardiomyocyte cells or tissue by one or more microRNA oligonucleotides, comprising contacting the cells with an exosome comprising one or more miRNA oligonucleotides selected from the group consisting of… miR-1, miR-133, miR-208, miR-499-5p (claim 39, [0201]). Thus, Zhou teaches exosomes comprising miR-1, miR-133, miR-208, miR-499-5p to treat cardiovascular disease or disorders.
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Zhang and Raso with the teachings of Zhou. It would have been obvious, and a POSITA would have been motivated, to combine the exosome comprising miRNA 148a-3p of Zhang and Raso with the exosome comprising miR-1, miR-133, miR-208, and miR-499-5p of Zhou due to all teaching of treating cardiovascular disease via exosomes loaded with miRNA. A POSITA would have had a reasonable expectation of success in treating cardiovascular disease or disorder via said combination due to all studying miRNA and cardiovascular related treatments.
In regards to claim 60, as noted supra, Raso teaches miRNA-148a-3p.
Thus, claims 4 and 40 are obvious and are properly rejected.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Raso and further in view of Heineke.
In regards to claim 10, the above-cited references teach the loaded exosome of claim 2. The above cited references do not teach wherein said mammalian exosome is a C166 mammalian exosome. Zhang teaches mammalian exosomes can be derived from a variety of exosome producing mammalian cells, for example, endothelial cells [0172]. Zhang does not teach the murine endothelial cell line C166.
Heineke teaches of cardiac disease and in particular teaches chronic heart failure is a common and deadly disease. Further, Heineke teaches endothelial cells communicate with cardiomyocytes and regulate growth and function of cardiomyocytes. Heineke teaches endothelial cells relay specific signals and also shed small vesicles like exosomes and thereby transfer microRNAs to cardiomyocytes [0008]. Heineke teaches exosomes are useful for diagnostic and therapeutic purposes, since they can be used as drug delivery vehicles [0020]. Moreover, Heineke teaches exosomes isolated from C166 cells [0141] and teaches said cells are mouse endothelial cells [0136].
Thus, as Zhang/Raso teach of mammalian endothelial exosomes for the treatment of cardiac disease and/or disorder and Heineke teaches of mammalian exosomes isolated from C166 mouse endothelial cells for the treatment of cardiac disease and/or disorder, it therefore would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the mammalian endothelial exosomes of Zhang/Raso for the mammalian C166 endothelial exosomes of Heineke for the treatment of heart disease. The skilled artisan would have had a reasonable expectation of successfully substituting said exosomes. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claim is obvious and is properly rejected.
Claim Rejections - 35 USC § 112(d)
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.
Claim 62 is rejected under 35 U.S.C. 112(d), 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 62 depends from claim 61, which depends from claim 2, which depends from claim 1. Claim 1 requires the endothelial exosome to be isolated from an endothelial cell. Claim 2 requires the exosome to be mammalian. Claim 61 requires the endothelial cell from which the exosome is isolated from to be a primary human endothelial cell. Claim 62 then states the endothelial exosome may be isolated from, for example, a C166 cell, i.e., a mouse cell.
Thus, claim 62 is not further limiting of claim 61. Claim 62 is broader in scope in that the exosome, which per claim 1 must be isolated from the endothelial cell and per claim 61 must be a human cell, states the cell may also be a mouse cell, i.e., C166. Thus, claim 62 comprises a broader range of cells from which the exosome may be isolated.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Applicant Remarks
RE: 103 Rejections
RE: Zhang in view of Raso
Point (i): The “simple substitution” rationale fails.
Applicant’s remarks state substituting Raso’s miR-148a into Zhang’s exosome is not a straightforward swap of equivalent elements. Applicant remarks note Raso teaches delivering said miR via AAV9 administered intravenously. Applicant further notes the teachings of Raso are entirely unrelated to exosome-mediated fibroblast-to-cardiomyocyte reprogramming as claimed. Applicant remarks state “simple substitution” requires that the substituted element serve the same function in the same context and substituting an AAV-delivered cardiac miRNA into a stroke-directed exosome to somehow yield a reprogramming exosome is not a predictable substitution.
Applicant remarks have been considered but have not been found persuasive. Examiner respectfully notes Applicant remarks stating “the teachings of Raso are entirely unrelated to exosome-mediated fibroblast-to-cardiomyocyte reprogramming as claimed” are directed to language that is not currently required by instant claim 1. Instant claim 1 requires (1) a loaded endothelial exosome and (2) at least one exogenous miR selected from the group consisting of miR1, miR133, miR138, miR148a-3p, miR206, miR208, miR499-5p. Instant claim 1 does not require the loaded exosome to mediate fibroblast to cardiomyocyte reprogramming. Instant claim 1 solely requires the exosome to be loaded with at least one of the miR listed above. As such, the simple substitution rationale holds.
As discussed in the previously filed OA, Zhang teaches of cardiovascular complications involved in stroke-related mortalities and teaches of the therapeutic delivery of microRNAs via administering a therapeutically effective amount of mammalian exosomes loaded with miRNAs. Zhang teaches said delivery of microRNAs improves or prevents symptoms of cardiovascular disease in a patient who has suffered a stroke. As Raso teaches of the delivery of microRNA-148a-3p for the suppression of ventricular dilation in heart failure and thus teaches improving or preventing symptoms of cardiovascular disease, it therefore would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the microRNA of Zhang for the microRNA of Raso. The skilled artisan would have had a reasonable expectation of successfully substituting said microRNAs for improving or preventing symptoms of cardiovascular disease as both Zhang and Raso teach.
Point (ii): No reasonable expectation of success
Applicant remarks state “There is no basis in the prior art to predict that substituting Raso’s miR-148a into Zhang’s stroke exosome would yield the claimed loaded exosome for fibroblast reprogramming.” Applicant remarks further state “A person of ordinary skill would have had no rational basis to predict that combining these disparate teachings would produce an exosome capable of reprogramming fibroblasts into cardiomyocytes.”
Applicant remarks have been considered but have not been found persuasive. Examiner respectfully notes Applicant remarks are directed to claim language that is not currently required by instant claim 1. Instant claim 1 does not require the claimed loaded exosome to yield fibroblast reprogramming. As such, the current claim language does not require a reasonable expectation of success in fibroblast reprogramming.
As discussed in the previously filed OA and noted above in regards to point (i), Zhang teaches of cardiovascular complications involved in stroke-related mortalities and teaches of the therapeutic delivery of microRNAs via administering a therapeutically effective amount of mammalian exosomes loaded with miRNAs. Zhang teaches said delivery of microRNAs improves or prevents symptoms of cardiovascular disease in a patient who has suffered a stroke. As Raso teaches the delivery of microRNA-148a-3p for the suppression of ventricular dilation in heart failure and thus teaches improving or preventing symptoms of cardiovascular disease, it therefore would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the microRNA of Zhang for the microRNA of Raso. The skilled artisan would have had a reasonable expectation of successfully substituting said microRNAs for improving or preventing symptoms of cardiovascular disease as both Zhang and Raso teach.
Point (iii): Improper Hindsight
In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the rejection of record clearly takes into account the disclosures of Zhang and Raso, disclosed at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure. The previously filed rejection of record points to specific disclosures in the cited prior art that describe the limitations of Applicant’s claimed method.
It is noted that the test for obviousness is what the combined teachings of references would have suggested to one of ordinary skill in the art. See In re Keller, 642 F.2d 413, 425 (CCPA 1981) (citing cases). Applicant is reminded that “[a] person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id., 82 USPQ2d at 1396 (see MPEP § 2141.03).
Point (iv): Unexpected results and secondary considerations
Applicant remarks have been considered but have not been found persuasive. Applicant remarks state “the specification discloses that miR-148a-3p unexpectedly enhances the reprogramming efficacy of the miR combination (miR-1, miR-133, miR-208, miR-499-5p) through down-modulation of MDFIC (MyoD Family Inhibitor Domain Containing)”. Applicant remarks further state “separately, and at equivalent delivered miRNA levels, C166-derived exosome delivery of the miR combination produced approximately 50% more reprogramming events than lipid transfection”. Additionally, Applicant remarks state “this mechanism, miR-148a-3p targeting MDFIC to relieve repression of reprogramming, is entirely unknown to Raso, which teaches that miR-148a targets gp130 in cardiomyocytes.” Applicant states “The divergent mechanistic teaching is tantamount to a teaching away: Raso teaches that miR-148a functions by suppressing gp130 in cardiomyocytes to prevent hypertrophic remodeling, whereas the present invention demonstrates that miR-148a-3p silences MDFIC in fibroblasts to enable direct reprogramming into cardiomyocytes-a fundamentally different mechanism, in a different cell type, producing a different biological outcome.”
Examiner respectfully notes the discussed unexpected results are directed to a limitation not required by the instant claim language. The language of instant claim 1 is not directed to reprogramming.
RE: Zhang in view of Heineke
Points (i) – (ii)
As discussed supra, the previously filed 103 rejection has been withdrawn. Thus, Applicant remarks regarding the failings in Heineke are moot in view of new 103 rejection combining Zhang, Raso and Heineke.
Point (iii): Unexpected results
Examiner respectfully notes the unexpected results to which Applicant remarks are directed are focused to claim language which is not currently incorporated into instant claim 1. Instant claim 1 does not require fibroblast reprogramming, nor does it require preferential fibroblast targeting. As such, Applicant remarks have been considered but have not been found persuasive.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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