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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/05/2026 has been entered.
Claims 1-10, 15, 16, 18-28, 33-43, 45-62 and 64 are pending in this application, Claims 1-9, 18-28, 34, 36, 38, 40, 42, 43 and 45-60 are acknowledged as withdrawn, Claims 10, 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 were examined on their merits.
The rejection of Claims 10, 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 are rejected under 35 U.S.C.§ 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, has been withdrawn due to the Applicant’s amendments to the claims filed 07/10/2026.
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.
Claims 10, 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 are 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.
Claim 10 now recites, " wherein the administered isolated extracellular vesicles or exosomes are obtained from a general population of isolated extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow, wherein the administered isolated extracellular vesicles or exosomes have at least 20% higher expression of a PK gene compared to the average level of the PK gene compared to the average level of the PK gene in all extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow, wherein said administering does not comprise administering extracellular vesicles of exosomes derived from bone marrow that do not have at least 20% higher expression of a PK gene compared to the average level of the PK gene in all extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow”.
It is unclear what constitutes an "average level of the PK gene in all extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow" as it is not defined from how many mesenchymal stromal cells the extracellular vesicles or exosomes are obtained from, or what the nature of the mesenchymal stromal cells is. That is, the “average” level would be different if obtained from 10 mesenchymal stromal cells as opposed to that obtained from several million mesenchymal stromal cells. Further, there would be expected variability in the % gene expression in extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow between healthy individuals and individuals with different disease states. It is not set forth how one will determine the percent expression. As the “average” level appears to be a valueless parameter with infinite variability, the ordinary artisan could not readily determine the metes and bounds of the claimed invention (e.g. 20% higher than a valueless parameter cannot be determined). As the ordinary artisan could not readily determine what characteristics or properties make up the comparison “average” level of expression the artisan would have no basis for determining if the "selected" sample population has a 20% higher expression of the PK gene or not. The Examiner has interpreted the claim as any population of administered, isolated extracellular vesicles or exosomes obtained from bone marrow MSC and expressing PK as meeting the claimed limitation. Claims 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 are rejected as being dependent upon rejected Claim 10.
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.
Claims 10, 15, 16, 33, 35, 37, 39, 41 and 62 are rejected under 35 U.S.C. §
102(a)(1) as being anticipated by Mitsialis et al. (WO 2015/179227 A1), as evidenced by
Lim (US 2014/0031256 A1), Norhammar et al. (2002), Mahmoud et al. (2019), Handley
et al. (2011), Chen et al. (2009), Gerber et al. (2015) and Ventura-Clapier et al. (2011),
all of record.
Mitsialis et al. teaches a method of treating a cardiovascular disorder comprising
administering to a subject having or at risk of having the cardiovascular disorder, a
therapeutically effective amount of an isolated exosome (Pg. 41, Claim 24);
wherein the exosome is isolated from an MSC (Pg. 42, Claim 33);
wherein the MSC is isolated from bone marrow ( Pg. 42, Claim 35);
wherein the cardiovascular disorder is myocardial infarction (Pg. 43, Claim 39),
and reading on Claims 10 and 62.
With regard to Claim 10, Lim ('256) evidences that isolated, MSC-derived exosomes express PK genes and have a PK activity of 5.5 U activity/µg protein (Pg. 4, Paragraph [0070] and Pg. 6, Paragraphs [0107]-[0113]. As Mitsialis et al. teaches isolated bone-marrow MSC derived exosomes, these exosomes would be expected to have the increased expression of PK, as evidenced by the MSC derived exosomes of Lim ('256).
With further regard to Claim 10, as Mitsialis et al. teaches isolated, bone-marrow MSC-derived exosomes, which are the same as those claimed, those exosomes would be expected to increase O₂ consumption by smooth muscle cells, increase global amino acid metabolism, boost mitochondrial efficiency, decrease mitochondrial damage, and ameliorate glucose oxidation as these are characteristic properties of the isolated, bone- marrow MSC derived exosomes when administered to an individual.
With regard to Claim 15, as Mitsialis et al. teaches isolated, bone-marrow MSC- derived exosomes, which are the same as those claimed, those exosomes would be expected to normalize glucose oxidation in lung tissue of the treated individual as this is a characteristic property of the isolated, bone-marrow MSC derived exosomes when administered to an individual.
With regard to Claim 16, as Mitsialis et al. teaches treating subjects with myocardial infarction, which is the same subject population as claimed, the subjects with myocardial infarction would be expected to have decreased mitochondrial glucose oxidation, as Norhammar et al. evidences that abnormal glucose metabolism is highly prevalent in patients with acute myocardial infarction (Pg. 2143, Column 1, Lines 33- 35). Thus, the reference evidences myocardial infarction is associated with decreased mitochondrial glucose oxidation.
With regard to Claim 33, Mitsialis et al. teaches the isolated exosome express one or more of: ALIX, FLOT1, CD81 and TSG101 (Pg. 43, Claims 42-43).
With regard to Claim 35, as Mitsialis et al. teaches isolated, bone-marrow MSC- derived exosomes, which are the same as those claimed, those exosomes would be expected to; upregulate GLUD1 and/or PDH gene expression, downregulate PDK4 gene expression, and/or downregulate SIRT4 gene expression in the treated subjects, as these are characteristic properties of the isolated, MSC derived exosomes as claimed, when administered to a subject.
With regard to Claim 37, as Mitsialis et al. teaches treating subjects with myocardial infarction, which is the same subject population as claimed, the subjects with myocardial infarction would be expected to have increased expression of TNF, as evidenced by Mahmoud et al. whom evidences that TNF is produced in large quantities within infarcted myocardium (Pg. 1, Column 1, Lines 9-11). As Mitsialis et al. teaches administering isolated, bone-marrow MSC-derived exosomes, which are the same as those claimed, to the same subject population, the exosomes would be expected to downregulate TNF gene expression in the treated individuals as this is a characteristic property of the isolated, MSC-derived exosomes when administered to a subject with a disease associated with mitochondrial dysfunction.
With regard to Claim 39, as Mitsialis et al. teaches subjects with myocardial infarction, which is the same subject population as claimed, the subjects would be expected to have increased proliferation of PASMC (pulmonary arterial smooth muscle cells), as evidenced by Handley et al. whom evidences that hypoxia is a characteristic of myocardial infarction (Pg. 640, Column 2, Abstract) and Chen et al. whom evidences that hypoxia promotes PASMC proliferation (Pg. L1151, Abstract). As Mitsialis et al. teaches administering isolated, bone-marrow MSC-derived exosomes, which are the same as those claimed, to the same subject population, the exosomes would be expected to downregulate the proliferation of PASMC in the treated subjects as this is a characteristic property of the isolated, MSC derived exosomes when administered to a subject with a disease associated with mitochondrial dysfunction, e.g. myocardial infarction.
With regard to Claim 41, as Mitsialis et al. teaches subjects with myocardial infarction (disease or condition associated with mitochondrial dysfunction), which is the same subject population as claimed, the myocardial infarction subjects would be expected to have decreased expression of TFAM, as evidenced by Gerber et al. whom evidences that heart failure is common after acute myocardial infarction which is considered to be one of its’ major precursors (Pg. 1, Column 1, Lines 1-3) and Ventura-Clapier et al. whom evidences that heart failure is associated with decreased expression of PGC-1α and its downstream transcription factor TFAM (Pg. 1364, Column 1, Lines 22-28).
As Mitsialis et al. teaches administering isolated, bone marrow MSC derived exosomes, which are the same as those claimed, to the same subject population, the exosomes would be expected to upregulate TFAM gene expression in the treated subjects as this is a characteristic property of the isolated, bone-marrow MSC-derived exosomes when administered to a subject with a disease associated with mitochondrial dysfunction, such as myocardial infarction.
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 10, 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 are rejected under 35 U.S.C.
103 as being unpatentable over Mitsialis et al. (WO 2015/179227 A1), as evidenced
by Lim (US 2014/0031256 A1), Norhammar et al. (2002), Mahmoud et al. (2019),
Handley et al. (2011), Chen et al. (2009), Gerber et al. (2015) and Ventura-Clapier et al.
(2011), as applied to Claims 10, 15, 16, 33, 35, 37, 39, 41 and 62 above, and further in
view of Tarnopolsky et al. (WO 2016/115632 A1), as evidenced by Shiels (US
2014/0234263 A1), and Gray et al. (2014), all of record.
The teachings of Mitsialis et al. were discussed above.
Mitsialis et al. did not teach wherein the disease or disorder is associated with a reduced expression of PK gene, or wherein the disease is Friedreich's ataxia,
as required by Claims 61 and 64.
Tarnopolsky et al. teaches a method of treating a mitochondrial disease in a mammal comprising administering to the mammal a composition comprising genetically modified exosomes (Pg. 66, Claim 21), wherein the disease is: cardiovascular diseases and Friedreich's ataxia (Pgs. 70-71, Claims 28 and 29),
and wherein the exosomes may be isolated from mesenchymal stem cells (MSC) (Pg. 13, Paragraph [0055]).
Gray et al. teaches that in mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, and mutations in any of the genes encoding proteins regulating pyruvate metabolism may lead to disease (Pg. 2577, Abstract),
the reference further teaches that pyruvate kinase (PK) catalyzes the dephosphorylation of phosphoenolpyruvate into pyruvate during the final, irreversible step of glycolysis an important source of energy for most cells in the body (Pg. 2580, Column 1, Lines 4-9). Thus, the ordinary artisan would recognize that the PK gene is one of several genes known to be associated with mitochondrial dysfunction.
Shiels evidences that myocardial infarction is a cardiovascular disease (Pg. 23, Paragraph [0147]).
It would have been obvious to those of ordinary skill in the art to modify the method of Mitsialis et al. of treating the cardiovascular disease (as evidenced by Shiels above) of myocardial infarction by administering a composition comprising an isolated exosomes having an increased expression of PK gene (as evidenced by Lim ‘256) derived from bone-marrow MSC to the treat a disease characterized by mitochondrial dysfunction such as the Friedreich's ataxia as taught by Tarnopolsky et al. because both references teach the use of isolated MSC derived exosomes to treat similar diseases/conditions which have a basis in mitochondrial dysfunction potentially caused by a defect in the PK gene (as taught by Gray). Those of ordinary skill in the art would have been motivated to make this modification in order to apply a known treatment for one disease with a basis in mitochondrial dysfunction to the treatment of another disease with a basis in mitochondrial dysfunction. There would have been a reasonable expectation of success in making this modification because at least both Mitsialis et al. and Tarnopolsky et al. are drawn to the same field of endeavor, that is, the use of isolated exosomes from MSC to treat diseases/conditions with a basis in mitochondrial dysfunction.
Response to Arguments
Applicant’s arguments, see Remarks, filed 07/10/2026, with respect to the above withdrawn rejection have been fully considered and are persuasive. The remaining arguments have been considered only insofar as they apply to the current rejections.
The Applicant argues that the claim amendments obviate the indefiniteness rejection (Remarks, Pg. 13, Lines 15-16).
This is not found to be persuasive for the reasoning provided in the above rejection.
The Applicant argues that Mitsialis does not teach or suggest the method of amended Claim 10. Applicant asserts that the reference can only administer exosomes which have an average level of PK gene and not the 20% higher expression as claimed (Remarks, Pg. 14, Lines 6-26 and Pg. 15, Lines 1-5).
This is not found to pe persuasive for the reasoning provided in the above rejections. Briefly, the new limitations are indefinite because the “average” expression parameter is valueless and arbitrary. The Examiner has interpreted the claim as any population of administered isolated extracellular vesicles or exosomes obtained from bone marrow MSC and expressing PK (such as the method of Mitsialis) as meeting the claimed limitation.
The Applicant argues that Tarnopolsky does not remedy the alleged deficiencies of Mitsialis (Remarks, Pg. 15, Lines 11-12).
This is not found to be persuasive for the reasoning provided in the above rejections.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm 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, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653 09/03/2026
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