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 .
Claims 1-10, 15, 16, 18-28, 33-43, 45-62 and 64 are pending in this application, Claims 1-9, 18-28, 38, 40, 42, 43 and 45-60 are acknowledged as withdrawn, Claims 10, 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 were examined on their merits.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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.
The claim(s) contains subject matter which was not described in the specification
in such a way as to reasonably convey to one skilled in the relevant art that the inventor
or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s),
at the time the application was filed, had possession of the claimed invention. Claim 10
now recites, " wherein the administered isolated extracellular vesicles or exosomes belong to a selected subpopulation selected from a general population of isolated extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow, wherein the selected subpopulation has at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population". There is insufficient support in the originally filed disclosure
for this new limitation. The Examiner notes that the Applicant has cited Figures 1A-C, 2A-C, 3B, the brief descriptions thereof and Examples 1.1-1.4. The Examiner notes that Figs. 1A-C, merely show respectively; the isolation of different exosome populations by size exclusion chromatography, an overlay of exosomes isolated by phospholipid concentration and A280 chromatogram and the effect of isolated exosomes in treating mice with hypoxia-induced PAH wherein EXM2 was effective and EXM1 was not. The Examiner notes that neither the figures or the descriptions thereof provide support for isolation of exosomes/EVs from a selected subpopulation of cells/EVs having at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population.
Figures 2A-C merely depict respectively; pyruvate kinase (PK) activity of various exosome populations plotted against RSVP fold change between hypoxia-treatment and hypoxia control groups, PK activity of various exosome populations plotted against change in RSVP and PK activity of “potent” exosome populations. The Examiner notes that neither the figures or the descriptions thereof provide support for isolation of exosomes/EVs from a selected subpopulation of cells/EVs having at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population. The Examiner notes that Fig. 3B depicts a western blot of PK (protein concentration not expression) of PK in two exosome populations (EXM2 and EXM1). The Examiner notes that neither the figure or the description thereof provides support for isolation of exosomes/EVs from a selected subpopulation of cells/EVs having at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population. Example 1.1 merely describes isolating and fractionating exosome populations from MSC conditioned media; Example 1.2 is drawn to treatment of a mouse model of PAH with unspecified exosomes to identify “potent” exosome populations based upon effective treatment of hypoxia induced mice, Example 1.3 is drawn to an immunological identification of “potent” exosome populations having “increased” concentrations of PK as compared to non-potent populations and determination of PK activity in the potent exosome population. The Examiner notes that the Examples do not provide either explicit or implicit support for isolation of exosomes/EVs from a selected subpopulation of cells/EVs having at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population as now claimed.
The Examiner notes the Specification as filed at Pg. 2 states:
“In some embodiments, the extracellular vesicles or exosomes comprise at least 10%, 20%, 30%, 50%, or 100% more expression of the expression products compared to the average level of the same expression product in all extracellular vesicles or exosomes obtained from the mesenchymal stromal cells”.
This is distinct from the claims which now require at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population. Claims 15, 16, 33, 35, 37, 39, 41, 61, 62 and 64 are rejected as being dependent upon rejected Claim 10.
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 belong to a selected subpopulation selected from a general population of isolated extracellular vesicles or exosomes obtained from mesenchymal stromal cells derived from bone marrow, wherein the selected subpopulation has at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population". It is unclear what constitutes a remaining "subpopulation" of the general population which can be a little as one exosome or what percentage expression of PK (if any) is required in the remaining subpopulation(s) or how one determines the percent expression. It is further unclear what the metes and bounds of a "subpopulation based on at least 20% higher expression of a PK gene as compared to 'a remaining subpopulation' of the general population" encompasses or constitutes or how it is selected as the “remaining” subpopulation from any other subpopulation which may be present in the general population of isolated exosomes. As the ordinary artisan could not readily determine what characteristics or properties make up the comparison subpopulation(s) the artisan would have no basis for determining if the “selected” sample subpopulation 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 expresses
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), all of record.
The teachings of Mitsialis et al. were discussed above.
Mitsialis et al. did not teach wherein the disease or disorder 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]).
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
exosome derived from bone-marrow MSC to the treat 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. 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 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 filed 02/05/2026 have been fully considered but they are not persuasive.
The Applicant argues that Mitsialis does not teach every element of the claimed invention reflected in the latest claim amendment (Remarks, Pg. 13, Lines 5-16).
This is not found to be persuasive for the reasoning provided in the above rejections. As set forth above, the ordinary artisan could not readily determine what characteristics or properties make up the comparison subpopulation(s), therefore the artisan would have no basis for determining if the “selected” sample subpopulation has a 20% higher “expression” of the PK “gene” or not. The Examiner notes that this “comparison” is arbitrary and can be based on comparing the “selected subpopulation” expression to any other “remaining subpopulation” with any amount of PK gene expression, such as 2% or 0% expression for example. The Examiner has interpreted the claim as any population of administered isolated extracellular vesicles or exosomes obtained from bone marrow MSC and expressing/comprising PK (or the gene thereof) as meeting the claimed limitation. 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); and wherein the cardiovascular disorder is myocardial infarction (Pg. 43, Claim 39). 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).
The Applicant argues that Fig. 1C provides evidence that exosome population EXM2 (potent) has a higher potency than EXM1 (representative of general population), and EXM2 has a higher expression of PK gene than EXM1 (Fig. 3B) (Remarks, Pg. 13, Lines 17-25).
This is not found to be persuasive for the following reasons, as discussed above, The Examiner notes that Fig. 1C, merely shows the effect of isolated exosomes in treating mice with hypoxia-induced PAH wherein EXM2 was effective and EXM1 was not. The Examiner further notes that Fig. 3B depicts a western blot of PK (protein concentration not gene expression) of PK in the two exosome populations (EXM2 and EXM1).
The Applicant cites Examples 1.1-1.4 as comparing “potent” EXM2 with EXM1, while the rest of the examples are directed to experiments using EXM2 which allegedly provide the claimed effects upon administration.
Applicant asserts that EXM2 corresponds to the claimed “selected subpopulation” having at least a 20% higher expression of PK that the remaining subpopulation of the general population (Remarks, Pg. 14, Lines 1-15).
This is not found to be persuasive for the following reasons, as discussed above, Example 1.1 merely describes isolating and fractionating exosome populations from MSC conditioned media; Example 1.2 is drawn to treatment of a mouse model of PAH with unspecified exosomes to identify “potent” exosome populations based upon effective treatment of hypoxia induced mice, Example 1.3 is drawn to an immunological identification of “potent” exosome populations having “increased” concentrations of PK as compared to non-potent populations and determination of PK activity in the potent exosome population. The Examiner notes that the Examples do not provide either explicit or implicit support for isolation of exosomes/EVs from a selected subpopulation of cells/EVs having at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population as now claimed. The Examiner notes the Specification as filed at Pg. 2 states:
“In some embodiments, the extracellular vesicles or exosomes comprise at least 10%, 20%, 30%, 50%, or 100% more expression of the expression products compared to the average level of the same expression product in all extracellular vesicles or exosomes obtained from the mesenchymal stromal cells”.
This is distinct from the claims which now require at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population. Thus, the disclosure does not provide adequate written description for the claimed subject matter.
The Applicant argues that Mitsialis only teaches a general population of exosomes and does not recognize the more “potent” subpopulation of exosomes having at least 20% higher expression of a PK gene compared to that of a remaining subpopulation of the isolated general population. Applicant asserts that while the general population of exosomes of the reference may comprise the “potent” subpopulation, administration would include the rest of the general population which is precluded by the claims (Remarks, Pg. 14, Lines 16-23).
This is not found to be persuasive for the following reasons, as discussed above,
the indefiniteness of the claim amendment with regard to what constitutes a remaining "subpopulation" of the general population which can be a little as one exosome or what percentage expression of PK (if any) is required in the unspecified remaining subpopulation(s) which constitute the general population or how one determines the percent expression. It is further unclear what the metes and bounds of a "subpopulation based on at least 20% higher expression of a PK gene as compared to 'a remaining subpopulation' of the general population" encompasses or constitutes or how it is selected as the “remaining” subpopulation from any other subpopulation(s) which may be present in the general population of isolated exosomes. The Examiner notes that this “comparison” is arbitrary and can be based on comparing the “selected subpopulation” expression to any other “remaining subpopulation” with any amount of PK gene expression, such as 2% or 0% expression for example.
As the ordinary artisan could not readily determine what characteristics or properties make up the comparison subpopulation(s) the artisan would have no basis for determining if the “selected” sample subpopulation 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, such as taught by Mitsialis above, as meeting the claimed limitation.
Applicant argues that the administered general population of exosomes of Mitsialis comprising the subpopulation of “potent” exosomes would be diluted by less potent exosomes and the ordinary artisan would not have expected the claimed results (Remarks, Pg. 14, Lines 24-28 and Pg. 15, Lines 1-5).
This is not found to be persuasive for the following reasons, Applicant’s assertion is speculatory and not based on any supporting evidence. Mitsialis et al. teaches isolated, bone-marrow MSC-derived exosomes, which are the same as those claimed, thus 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.
The Applicant argues that Tarnolpolsky does not remedy the alleged deficiencies of Mitsialis (Remarks, Pg. 15, Lines 14-15).
This is not found to be persuasive for the reasoning provided in the above rejections.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to 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
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653