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 .
Claim Status
Applicant’s submission filed 10/10/2025 has been received and entered. Claims 3, 53, 58-66, 148, and 153-155 have been cancelled. Claims 1, 4, 8- 14, 15, 18, 19, 31, 33, 35-37, 50-52, 54-57, 67, 117, 120, 122-124, 132-135 have been amended. Claim 156 has been newly added. Accordingly, claims 1, 4, 7-14, 16, 18-19, 31, 33, 35-37, 50-52, 54-57, 67, 117, 120, 122-124, 132-135 and 156 are pending and under current examination.
Instant claims are now directed to a method of treating a subject for a stroke and/or treating a cerebrovascular injury, the method comprising administering a combination comprising mammalian exosomes and tPA, wherein the combination of mammalian exosomes and tPA is administered in a therapeutically effective amount, and wherein the mammalian exosomes are administered prior to a dose of the tPA to enhance a fibrinolytic effect of the tPA. This shift from a product (a combination comprising mammalian exosomes and tPA) to a method of using the product was authorized by the office in the interview dated 10/2/2025.
Status of Prior Rejection/Response to Arguments
The rejection of claim 67 under 35 U.S.C. § 102(a)(1) over Webb et al. is withdrawn:
Instant claim 67 has been amended to depend upon claim 1, is directed to a method comprising administering a combination comprising mammalian exosomes and tPA, wherein a therapeutically effective amount of mammalian exosomes is administered prior to a therapeutically effective amount of the tPA. Webb et al. teach extracellular vesicles (EVs) derived from neural stem cell (NSC) and mesenchymal stem cell (MSC) in the treatment of stroke, state that the EVs can be used in conjunction with tPA and endovascular therapies (p537, left column), but do not teach the claimed method comprising administering a combination comprising mammalian exosomes and tPA, wherein a therapeutically effective amount of mammalian exosomes is administered prior to a therapeutically effective amount of the tPA. Therefore the amendment is effective to obviate the prior basis of the rejection, the rejection is withdrawn.
The rejection of claims 1, 4, 7-14, 31, 33, 35-37, 50-57, 64, 67, 148 and 153-155 under 35 U.S.C. § 103 over Webb et al. in view of Zhang et al. is withdrawn:
The rejection of claims 1, 4, 7-14, 16, 18-19, 31, 33, 35-37, 50-57, 64, 67, 148 and 153-155 under 35 U.S.C. § 103 over Webb et al. in view of Zhang et al. and Lapchak et al. is withdrawn:
The rejection of claims 1, 4, 7-14, 31, 33, 35-37, 50-57, 64, 67,117, 120, 122-124, 148 and 153-155 under 35 U.S.C. § 103 over Webb et al. in view of Zhang et al. and Marban et al. is withdrawn:
Instant claims have been amended to directed to a method of treating a subject for a stroke and/or treating a cerebrovascular injury, the method comprising administering a combination comprising mammalian exosomes and Tissue Plasminogen Activator (tPA), wherein the combination of mammalian exosomes and tPA is administered in a therapeutically effective amount, and wherein the mammalian exosomes are administered prior to a dose of the tPA to enhance a fibrinolytic effect of the tPA, therefore the administration time, order, route, and the therapeutically effective amount further limit the claimed method. Web et al. teach extracellular vesicles (EVs) derived from neural stem cell (NSC) and mesenchymal stem cell (MSC) in the treatment of stroke, state that the EVs can be used in conjunction with tPA and endovascular therapies (p537, left column), but do not teach the method of treating stroke or cerebrovascular injury using a combination comprising mammalian exosomes and tPA, as recited in instant claims (i.e., administration time, order, route, and the therapeutically effective amount of the mammalian exosomes and tPA). Zhang et al. review the function of exosomes (including exosomes derived from cerebral endothelial cells, neurons and glia, as well as stem cells such as MSCs) in the treatment of stroke, do not teach the method of treating stroke or cerebrovascular injury using a combination comprising mammalian exosomes and tPA, as recited in instant claims. Moreover, Lapchak et al. teach extracellular vesicles from human cardiosphere derived cells (CDC-EVs), do not teach tPA and the method of treating stroke or cerebrovascular injury using a combination comprising mammalian exosomes and tPA, as recited in instant claims. Marban et al. teach miRNAs expressing in exosomes, do not teach the method as recited in instant claims. Therefore Applicant’s amendment is effective to obviate the prior basis of the rejection. The rejection is withdrawn.
The rejection of claims 132 under 35 U.S.C. § 103 over Webb et al. in view of Yin et al. is withdrawn:
The rejection of claims 132-135 under 35 U.S.C. § 103 over Webb et al. in view of Yin et al. and Sun et al. is withdrawn:
Instant claim 132 and the dependent claims have been amended and depend upon claim 1. As stated above, Web et al. do not teach the claimed method. Yin et al. as well as Sun et al. teach angiogenesis-related miRNA-21 as well as the change of miRNA-21, do not teach the method of treating stroke or cerebrovascular injury using a combination comprising mammalian exosomes and tPA, as recited in instant claims. Therefore the amendment is to obviate the prior basis of the rejection. The rejection is withdrawn.
New grounds of rejection are necessitated by Applicant’s amendment.
New grounds of rejections
Claim Rejections - 35 USC § 112(a)
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 1, 4, 8- 14, 15, 18, 19, 31, 33, 35-37, 50-52, 54-57, 67, 117, 120, 122-124, 132-135 are newly 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. The rejection is necessitated by Applicant’s amendment.
From M.P.E.P. § 2163, the analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention from the standpoint of one of skill in the art at the time the application was filed. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For claims drawn to a genus, possession may be shown (for example) through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to
reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
Instant claims are directed to a method of treating a subject for a stroke and/or treating or preventing a cerebrovascular injury, the method comprising administering a combination comprising mammalian exosomes and Tissue Plasminogen Activator (tPA), wherein the combination of mammalian exosomes and tPA is administered in a therapeutically effective amount, and wherein the mammalian exosomes are administered prior to a dose of the tPA to enhance a fibrinolytic effect of the tPA. The claims cover a genus of mammalian exosomes, which are extracellular vesicles that are produced and secreted by different mammalian cells. Mammals are a huge group of vertebrate animals having hair/fur, warm-bloodedness, mammary glands (producing milk for the offsprings), a complex brain, three middle ear bones, and a specialized jawbone. Mammalian cells are specialized eukaryotic cells derived from these mammals, containing a distinct nucleus and membrane-bound organelles, the cells can be any cell types from any part of the body which carry various nucleic acids, proteins, lipids, and metabolites. Therefore the claim is extremely broad. The issue at hand is whether or not Applicant has possession of the full scope of the genus of CNS diseases and the treating or preventing said CNS diseases at the time the application was filed.
In the instant case, Applicant has failed to provide disclosure of species which are representative of the full scope of the genus of mammalian exosomes. The specification discloses working examples regarding exosomes derived from cerebral endothelial cells (CEC-exosomes) of rat (Example 1), the treatment using CEC-exosome in combination with tPA and thrombectomy treatment (Example 2), CEC-exosome cargo different miRNAs for the treatment (Examples 3 and 4), the administration method (intra-arterial administration) of CEC-exosome to rats (Example 5) and human (Example 6), the mechanism of CEC-exosomes in treatment of stroke such as increasing inflammatory and pro-thrombotic protein levels (Example 7) and block BBB leakage (Example 8 and Example 9), Example 9 also discloses the function of MSC-exosomes on reduction of BBB. Applicant does not disclose any other species of mammalian exosomes from other mammalian animals or other cell types from these mammalian animals.
Furthermore, Applicant has failed to provide disclosure of relevant, identifying characteristics, such as the functional characteristics (be able to treat a subject for a stroke and/or treating a cerebrovascular injury) coupled with known or disclosed structure of the combination comprising mammalian exosomes and tPA. In the claims, Applicant limits that the mammalian exosomes are administered prior to a dose of the tPA to enhance a fibrinolytic effect of the tPA, however, none of the working examples support this limitation. Therefore Applicant has failed to establish a known structure- function relationship wherein the genus of structures of the combination comprising mammalian exosomes and tPA wherein the mammalian exosomes is capable of enhance a fibrinolytic effect of the tPA in the treatment of stroke or cerebrovascular injury as claimed with any predictability. Thus, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicant was in possession of the invention, as claimed, at the time the invention was made.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
Claims 1, 4, 8- 14, 15, 18, 19, 31, 33, 35-37, 50-52, 54-57, 67, 117, 120, 122-124, 132-135 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a subject for a stroke and/or treating a cerebrovascular injury, the method comprising administering a combination comprising exosomes and Tissue Plasminogen Activator (tPA), wherein the exosomes are derived from cerebral endothelial cells or Mesenchymal stem cells (CEC-exosomes or MSC-exosomes) of human or rodents, does not reasonably provide enablement for preventing cerebrovascular injury by administration a combination comprising mammalian exosomes and tPA, as well we administering a combination comprising ANY mammalian exosomes tPA for the treatment of stroke and/or cerebrovascular injury. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The rejection is necessitated by Applicant’s amendment.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in Jn re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention and Breadth of the claims:
Instant claims are directed to a method of treating a subject for a stroke and/or treating a cerebrovascular injury, the method comprising administering a combination comprising mammalian exosomes and tPA, wherein the combination of mammalian exosomes and tPA is administered in a therapeutically effective amount, and wherein the mammalian exosomes are administered prior to a dose of the tPA to enhance a fibrinolytic effect of the tPA. The claims broadly embrace a genus of mammalian exosomes, which are extracellular vesicles that are produced and secreted by different mammalian cells. Mammals are a huge group of vertebrate animals having hair/fur, warm-bloodedness, mammary glands (producing milk for the offsprings), a complex brain, three middle ear bones, and a specialized jawbone. Mammalian cells are specialized eukaryotic cells derived from these mammals, containing a distinct nucleus and membrane-bound organelles, the cells can be any cell types from any part of the body which carry various nucleic acids, proteins, lipids, and metabolites. Moreover, the claims do not limit the scope of preventing any cerebrovascular injuries (e.g., stop or delay the onset of disease before it occurs). Cerebrovascular injury is broadly including any form of non-penetrating injury to the internal carotid and vertebral arteries, as well as high-energy trauma (blunt or penetrating) to the head or neck. Therefore the breadth of the claims is extremely broad.
Guidance of the Specification and The Existence of Working Examples:
The specification discloses working examples regarding exosomes derived from cerebral endothelial cells (CEC-exosomes)(Example 1), the treatment using CEC-exosome in combination with tPA and thrombectomy treatment (Example 2), CEC-exosome cargo different miRNAs for the treatment (Examples 3 and 4), the administration method (intra-arterial administration) of CEC-exosome to rats (Example 5) and human (Example 6), the mechanism of CEC-exosomes in treatment of stroke such as increasing inflammatory and pro-thrombotic protein levels (Example 7) and block BBB leakage (Example 8 and Example 9), Example 9 also discloses the function of MSC-exosomes on reduction of BBB. Applicant does not disclose any other species of mammalian exosomes from other mammalian animals or other cell types from mammalian animals.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The state of the prior art with respect to exosomes for treatment of a stroke or a cerebrovascular injury are summarized by Zhang et al. (J Clin Invest. 2016 Apr 1;126(4):1190-7), Web et al. (Transl Stroke Res. 2018 Oct;9(5):530-539) and Xin et al. (Front Cell Neurosci. 2014 Nov 10;8:377). Zhang et al. review advances and impacts of exosomes on promoting coupled brain remodeling processes after stroke (Abstract). Zhang et al. teach exosomes released from human and rodents (i.e., mouse) brain cells, especially endothelial cells such as glioblastoma cells (p1191, right column), cerebral endothelial cells (p1191, right column), neurons and glia(p1192, right column). Zhang et al. also teach exosomes released from cultured mesenchymal stem cells (p1193, right column), hematopoietic stem cells (p1194, right column). Web et al. teach the therapeutic potential of human neural stem cell-derived extracellular vesicles (EVs) in a highly relevant preclinical stroke model without immunosuppression (p531, left column). Web et al. use mice to evaluate the function of NSC EVs (p532). Web et al. also states that there are many indications that EV cargoes are cell type specific and the parental cell line plays a prodigious role in the biological properties of the resultant EV. Therefore, EVs derived from different sources (MSC vs. NSC cells) may have unique properties relative to cell type (p531, left column). Xin et al. discuss exosomes derived from MSCs, the biogenesis of MSC exosomes, cargo packaging (especially the miRNAs) and intercellular communication, and new opportunities in modifying exosomal cargo to develop exosome-based cell-free therapeutics for stroke (p2, left column). Xin et al. discuss MSCs derived from human (p2, right column), mouse (p3, left column) and rat (p5, left column). None of the arts teach that the treating stroke or cerebrovascular injury can be achieved by ANY mammalian exosomes given that different cell types have distinct properties (i.e., carrying various nucleic acids, proteins, lipids, and metabolites which have different biological feature and function), none of the arts teach that the mammalian exosomes are capable of preventing a cerebrovascular injury (i.e., trauma caused cerebrovascular injury). With respect to the problems as discussed in the arts and the absent of specific guidance, one skilled in the art before the effective filing date of the claimed invention would have to perform undue experimentation to determine how to make/use the method of using any combination of mammalian exosomes a tPA for treating stroke or cerebrovascular injury or preventing a cerebrovascular injury, without reasonable expectation of success.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled commensurate with full scope. An artisan of skill would have required undue experimentation to practice the invention with a reasonable expectation of success.
Claim Rejections - 35 USC § 112
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 7 is newly 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. This rejection is necessitated by Applicant’s amendment.
Instant claim 1, which claim 7 depends upon, is directed to a method of treating a subject for a stroke, which limits that the subject has/suffers a stroke. Therefore claim 7 fails to further limit the subject matter of claim 1.
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.
Related Prior Art
Instant claims are directed to a method of treating a subject for a stroke and/or treating a cerebrovascular injury, the method comprises administering a combination comprising mammalian exosomes and Tissue Plasminogen Activator (tPA), wherein the combination of mammalian exosomes and tPA is administered in a therapeutically effective amount, and wherein the mammalian exosomes are administered prior to a dose of the tPA to enhance a fibrinolytic effect of the tPA. The closet arts are Web et al. and Zhang et al. as stated in previous office actions. Web et al. state tPA is a one of FDA-approved stroke therapies, also state that EVs derived from neural stem cell (NSC) and mesenchymal stem cell (MSC) in the treatment of stroke, state that the EVs can be used in conjunction with tPA and endovascular therapies (p537, left column), but do not teach the method of treating stroke or cerebrovascular injury using a combination comprising mammalian exosomes and tPA, as recited in instant claims (i.e., administration time, order, route, and the therapeutically effective amount of the mammalian exosomes and tPA). Zhang et al. review the function of exosomes (including exosomes derived from cerebral endothelial cells, neurons and glia, as well as stem cells such as MSCs) in the treatment of stroke, do not teach the method of treating stroke or cerebrovascular injury using a combination comprising mammalian exosomes and tPA, as recited in instant claims. Therefore instant claims are considered art-free.
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.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699