*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 .
Applicant’s response dated October 24, 2025, is acknowledged.
Priority
This application is a 371 of PCT/US20/56899 filed on 10/22/2020, and claims benefit in
provisional application 62/925,129 filed on 10/23/2019.
Claim Status
Claims 1, 18, 19, 24, 26, 28, 29, 31-39, 47, and 48 and pending and examined. Claims 2-17, 20-23, 25, 27, 30, and 40-46 were canceled. Claims 1, 29, and 36 were amended. Claims 47 and 48 were newly added.
Withdrawn Claim Rejections — 35 USC § 112
Rejections of claims 17 and 36 are withdrawn because claim 17 was canceled; and claim 36 was amended by deleting “barely detectable” and adding “weight/weight” next to percent concentrations.
New Claim Rejections — 35 USC § 112
Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-ATA), 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 1, 18, 19, 24, 26, 28, 29, 31-39, 47, and 48 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.
Claims 1 and 29 were amended to require “CD63lo, CD81lo and/or CD9lo” which means low or barely detectable levels of CD63, CD81, and CD9 compared with other vesicles, such as exosomes. Western blotting and flow cytometry may be used to distinguish low, barely detectable, or absent expression of CD63, CD81, and CD9 in MBV (according to page 16 of the specification). The claim is indefinite because “low” and “barely detectable” are relative terms which render the claim indefinite. The terms “low” and “barely detectable” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification on page 16 states “In some embodiments, MBV expression of CD63 and/or CD81 and/or CD9 is considered low or barely detectable compared with other vesicles where the expression of CD63 and/or CD81 and/or CD9 in MBV is at least one standard deviation or at least two standard deviations below the mean expression of other vesicles, such as exosomes”. This teaching is not sufficient for providing a standard for ascertaining the degree because the teaching does not clearly define what is encompassed by “other vesicles”. The phrase “such as exosomes” only provides an exemplary “other vesicles” and it is not limiting in any way. Thus, the skilled artisan would not have known which values of the markers are considered “low” or “barely detectable” because the values of the markers of “other vesicles” are unknown.
Claims 18, 19, 24, 26, 28, 31-39, 47, and 48 are indefinite because they depend from an indefinite base claim.
Modified and New Claim Rejections — 35 USC § 103
Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 18, 19, 24, 26, 28, 29, 31-39, 47, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Lim (US 2014/0031256 A1 Published January 30, 2014) and Badylak (WO 2017/151862 Al — of record in IDS dated 04/15/2022).
The claims encompass methods of treating psoriasis in a subject in need thereof comprising administering to the subject via systemic administration a pharmaceutical preparation comprising a therapeutically effective amount of isolated matrix bound vesicles (MBV) derived from extracellular matrix, wherein the MBV do not express one or more of CD63, CD81, and/or CD9, or are CD63lo, CD81lo, and/or CD9lo as detected by flow cytometry, thereby treating the psoriasis in the subject.
The teachings of Lim a related to a method of detecting therapeutic exosomes and a method of detecting an activity of an exosome, wherein the activity is one of a-i. If the exosome is detected having one or more such activities, the exosome is likely to comprise a therapeutic exosome having therapeutic activity (Abstract). The therapeutic activity may be against one or more diseases selected from psoriasis (paragraph 0024). The exosomes include isolated exosomes (paragraph 0025). Therapeutic exosomes may be used to treat psoriasis (paragraph 0195). The therapeutic exosomes may be delivered to the human or animal body by any suitable means (paragraph 0199). Long term delivery of therapeutic exosomes may be employed using transdermal microinjection needles until the condition is resolved (paragraph 0210).
Lim does not teach systemic administration and Lim does not teach MBV that do not express one or more of CD63, CD81, and/or CD9, or are CD63lo, CD81lo, and/or CD9lo as detected by flow cytometry.
The teachings of Badylak are related to pharmaceutical compositions comprising isolated matrix bound nanovesicles and methods of use (Abstract). A composition is disclosed herein that includes isolated nanovesicles derived from an ECM and a pharmaceutically acceptable carrier. In some embodiments, the nanovesicles do not express CD63 and/or CD81 (page 2 lines 30-32). Extracellular vesicles are nanosized, matrix bound vesicles with diameters ranging from 50- 1,000 nm and are categorized into three main groups: nanovesicles, exosomes, and apoptotic bodies, based upon their size, origin, and mode of release (page 8 lines 14-17). It is disclosed herein that nanovesicles, specifically exosomes, are embedded within, and bound to, laboratory produced ECM bioscaffolds and commercially available ECM bioscaffolds. The content of these nanovesicles was determined, and it was documented that they differentially affect particular target cells (page 9 lines 11-14). Therapeutically effective amount is a quantity of a specific substance, such as a nanovesicle, sufficient to achieve a desired effect in a subject being treated. When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations (for example, in bone) that has been shown to achieve a desired in vitro effect (page 22 lines 3-6). Nanovesicles, such as exosomes, directionally home to specific target cells, dependent on the physical properties of their membranes. Thus, nanovesicles can be used for the delivery of their contents. In addition, matrix bound nanovesicles can be used to induce cell proliferation, differentiation, and migration of cells. They can also be used to maintain a cell in an undifferentiated state. The effect of the disclosed nanovesicles can be local, regional or systemic. Thus, these nanovesicles are of use both in vitro and in vivo (page 31 lines 21-26). In some embodiments, the ECM-derived nano vesicles can be included in a pharmaceutical composition, such as including a pharmaceutically acceptable carrier, and can be administered to
a subject by any method known to those of ordinary skill in the art. Examples include intravenously, nasally, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, directly into a heart chamber, directly injected into the organ or portion of organ or diseased site of interest, or by other method or any combination of these methods. Topical administration may be particularly advantageous for the treatment of the skin, such as cancer, to prevent chemotherapy-induced alopecia or other dermal hyperproliferative disorder. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. For in vivo uses, compositions can be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients. In some embodiments, the composition is formulated a liquid. In other embodiments, the composition is formulated a gel or a powder. In other embodiments, the composition is formulated as a mist, such as in a nebulizer. The further embodiments, the composition can be formulated as a gel or a timerelease capsule. For treatment of conditions of the lungs, aerosol delivery can be used. Volume of an aerosol is generally between about 0.01 ml and about 0.5 ml (page 34 lines 4-24). The compositions including ECM-derived nanovesicles, for use in the disclosed methods, are suitably contained in a pharmaceutically acceptable carrier. The carrier is non-toxic, biocompatible and is selected so as not to detrimentally affect the biological activity of the nanovesicle. The ECM-derived nanovesicle can be formulated into preparations for local delivery (i.e. to a specific location of
the body, such as skeletal muscle or other tissue) or systemic delivery, in solid, semi-solid, gel, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections allowing for oral, parenteral or surgical 25 administration (page 36 lines 18-25).
The composition may be administered to (or taken by) the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more times, or any range derivable therein, and they may be administered every 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours, or 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, 5 weeks, or 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12 months, 5 or any range derivable therein. The composition can be administered once daily, twice daily, three times daily, four times daily, five times daily, or six times daily (or any range derivable therein) and/or as needed to the patient. Alternatively, the composition can be administered every 2, 4, 6, 8, 12 or 24 hours (or any range derivable therein) to or by the subject. In some embodiments, the subject is administered the composition for a certain period of time or with a certain number of doses after experiencing symptoms. The actual dosage amount of a composition administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject (page 36 lines 1-16). Pharmaceutical compositions are thus provided for both local use and for systemic use, formulated for use in human or veterinary medicine. In some embodiments, the composition can be administered by injection or catheter (page 42 lines 10-12). In another embodiment, the ECM and ECM-derived nanovesicles are from different tissue sources. Thus, in some non-
limiting examples, both the ECM and the ECM-derived nanovesicles can be produced from esophageal tissue, urinary bladder, small intestinal submucosa, dermis, umbilical cord, pericardium, cardiac tissue, or skeletal muscle, or cells in culture from these tissues. In other non-limiting examples, the ECM-derived nanovesicles are produced from esophageal tissue, urinary bladder, small intestinal submucosa, dermis, umbilical cord, pericardium, cardiac tissue, or skeletal muscle cells, and the ECM is not from this tissue source. In further nonlimiting examples, the ECM-is produced from esophageal tissue, urinary bladder, small intestinal submucosa, dermis, umbilical cord, pericardium, cardiac tissue, or skeletal muscle, and the ECM derived nanovesicles are not from this tissue source (page 49 lines 24-33).
The teachings of Lim and Badylak are related to compositions comprising matrix bound vesicles such as exosomes and methods of treatment using said compositions, and it would have been obvious to have combined them because they are in the same field of endeavor.
Regarding claim 1, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have practiced a method of treating psoriasis in a human comprising delivering therapeutic isolated exosomes using transdermal microinjection needles until the condition is resolved, with a reasonable expectation of success because Lim teaches treating psoriasis in a human comprising delivering therapeutic isolated exosomes using transdermal microinjection needles until the condition is resolved. It would have been obvious to have administered the exosomes to a human in need of psoriasis treatment because the purpose of the method is to treat psoriasis.
Lim does not teach systemic administration of the exosomes and does not teach exosomes that do not express one or more of CD63, CD81, and/or CD9, or are CD63lo, CD81lo, and/or CD9lo as detected by flow cytometry.
It would have been prima facie obvious to a person skilled in the art to have modified Lim’s method by using extracellular matrix bound exosomes that do not express CD63 and CD81 as disclosed by Badylak and administering the exosomes via systemic administration because Badylak teaches systemically administering isolated matrix bound vesicles such as ECM-derived exosomes and further teaches that ECM-derived exosomes do not express CD63 and CD81.
To further clarify, according to Badylak, no positive bands were detected in all samples for CD63 or CD81, and this indicates that exosomes embedded within the ECM have different characteristics than circulating exosomes (page 60 lines 22-27). Thus ECM-embedded nanovesicles represent a unique class of exosomes with biologic properties and functions distinct from circulating exosomes, and mediate many of the inductive properties of ECM scaffolds associated with constructive, functional remodeling (page 65 lines 8-10). Therefore, ECM-derived exosomes do not express one or more of CD63 or CD81. One of skill in the art would have had reasonable expectation of success using Badylak’s ECM-derived exosomes in Lim’s method of treating psoriasis because Badylak teaches that ECM-derived exosomes increase M2 macrophages (anti-inflammatory) and decrease M1 macrophages (pro-inflammatory) (page 45 lines 5-25). Psoriasis is known as an inflammatory condition, thus there would have been reasonable expectation of success in treating psoriasis with ECM-derived exosomes that increase M2 and decrease M1 macrophages. Lim’s method modified in view of Badylak is a method of treating psoriasis by administering extracellular matrix bound exosomes that do not express CD63 and CD81, wherein said exosomes are known to increase M2 macrophages (anti-inflammatory) and decrease M1 macrophages (pro-inflammatory).
Combining prior art elements according to known methods to obtain predictable results supports obviousness. Lim teaches administering isolated therapeutic exosomes until the condition is resolved. It would have been obvious to have administered a therapeutically effective amount of ECM-derived exosomes because the purpose of administering is to treat a condition until the condition is resolved. A person skilled in the art would have been capable of determining amounts of therapeutic exosomes that are therapeutically effective at treating psoriasis. Furthermore, Badylak teaches administering a therapeutically effective amount of matrix bound vesicles such as ECM-derived exosomes in methods of treating a disease.
Claims 18 and 19 recite “wherein” clauses that describe the effects of the claimed method. It would have been reasonable to expect the prior art treatment method to have the same effects as claimed method, absent evidence to the contrary, because the "wherein” clauses simply express the intended result of a process step positively recited.
Regarding claim 24, it would have been obvious to have administered the ECM-derived exosomes intravenously, with a reasonable expectation of success because Badylak teaches intravenous administration as a suitable way to administer isolated matrix bound vesicles such as ECM-derived exosomes to a subject.
Regarding claim 26, the references do not teach a number of exosomes per kg of body weight per administration. However, it would have been obvious to the skilled artisan to arrive at suitable amount per kilogram through routine experimentation. Badylak teaches that the actual dosage amount of a composition administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route
of administration. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject (page 36 lines 11-16). On pages 34 and 35, Badylak further teaches administering the composition to a subject containing various ranges nanovesicles expressed in mass of nanovesicles per kg based on the patient’s weight. The claimed concentration range is obvious because a person skilled in the art would have arrived at the claimed ranges through routine experimentation. The specification was reviewed and there is no evidence that claimed range is critical.
Regarding claim 28, it would have been obvious to have administered the ECM-derived therapeutic exosomes 1-20 times, and where administering occurs every 1-4 weeks, with a reasonable expectation of success because Badylak teaches that the composition may be administered to the subject 1-20 times and every 1-4 weeks (page 36 lines 1-10). The claimed administration times are obvious because they overlap with the prior art times. For example, administering the exosomes for a total of 4 times once per week for 4 weeks would have resulted in the claimed embodiment of administering 1 time per week for 4 weeks.
Regarding claim 29, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have practiced a method of treating psoriasis in a human comprising delivering therapeutic isolated exosomes using transdermal microinjection needles until the condition is resolved, with a reasonable expectation of success because Lim teaches treating psoriasis in a human comprising delivering therapeutic isolated exosomes using transdermal microinjection needles until the condition is resolved. It would have been obvious to have administered the exosomes to a human in need of psoriasis treatment because the purpose of the method is to treat psoriasis.
Lim does not teach systemic administration of the exosomes and does not teach exosomes that do not express one or more of CD63, CD81, and/or CD9, or are CD63lo, CD81lo, and/or CD9lo as detected by flow cytometry.
It would have been prima facie obvious to a person skilled in the art to have modified Lim’s method by using extracellular matrix bound exosomes that do not express CD63 and CD81 as disclosed by Badylak and administering the exosomes via systemic administration because Badylak teaches systemically administering isolated matrix bound vesicles such as ECM-derived exosomes that do not express CD63 and CD81 in methods of treating a disease.
To further clarify, according to Badylak, no positive bands were detected in all samples for CD63 or CD81, and this indicates that exosomes embedded within the ECM have different characteristics than circulating exosomes (page 60 lines 22-27). Thus ECM-embedded nanovesicles represent a unique class of exosomes with biologic properties and functions distinct from circulating exosomes, and mediate many of the inductive properties of ECM scaffolds associated with constructive, functional remodeling (page 65 lines 8-10). Therefore, ECM-derived exosomes do not express one or more of CD63 or CD81. One of skill in the art would have had reasonable expectation of success using Badylak’s ECM-derived exosomes in Lim’s method of treating psoriasis because Badylak teaches that ECM-derived exosomes increase M2 macrophages (anti-inflammatory) and decrease M1 macrophages (pro-inflammatory) (page 45 lines 5-25). Psoriasis is known as an inflammatory condition, thus there would have been reasonable expectation of success in treating it with ECM-derived exosomes that increase M2 and decrease M1 macrophages. Lim’s method modified in view of Badylak is a method of treating psoriasis by administering extracellular matrix bound exosomes that do not express CD63 and CD81, wherein said exosomes are known to increase M2 macrophages (anti-inflammatory) and decrease M1 macrophages (pro-inflammatory).
Combining prior art elements according to known methods to obtain predictable results. Lim teaches administering isolated therapeutic exosomes until the condition is resolved. It would have been obvious to have administered a therapeutically effective amount of ECM-derived exosomes because the purpose of administering is to treat a condition until the condition is resolved. A person skilled in the art would have been capable of determining amounts of therapeutic exosomes that are therapeutically effective at treating psoriasis. Furthermore, administering a therapeutically effective amount of matrix bound vesicles such as exosomes was known from Badylak. The “thereby” clause describes an intended result of a performed method step and because prior art method teaches the same steps as claimed, and it would have been obvious to expect the prior art method of treat the psoriasis in the subject being treated. It would have been obvious to have derived the matrix bound vesicles from extracellular matrix because Badylak teaches matrix bound vesicles such as exosomes derived from an extracellular matrix, wherein the exosomes are useful for treating diseases.
Regarding claim 31, it would have been obvious to have administered the therapeutic ECM-derived exosomes locally, with a reasonable expectation of success because Badylak teaches locally administering extracellular matrix derived nanovesicles such as exosomes in the method of treating a disease. Thus, local administration of exosomes was known in the art and would have been obvious to practice Lim’s treatment method.
Claims 32-35, recite “wherein” clauses that describe the effects of the claimed method. It would have been reasonable to expect the prior art treatment method to have the same effects as claimed method, absent evidence to the contrary, because the "wherein” clauses simply express the intended result of a process step positively recited.
Regarding claim 36, Badylak does not teach phospholipid content of the ECM-derived exosomes. However, considering that ECM-derived exosomes are matrix bound vesicles, it would have been reasonable to expect at least one of the claimed phospholipids to be present in a concentration that is at least close enough to the claimed concentration ranges that the skilled artisan would have expected them to have the same properties. There would have been a reasonable expectation that phospholipid content in ECM-derived exosomes is close enough in number to the claimed content because ECM-derived exosomes are a subgenus of matrix bound vesicles according to Badylak. Badylak teaches that extracellular vesicles are nanosized, matrix bound vesicles with diameters ranging from 50-1,000 nm and are categorized into three main groups: nanovesicles, exosomes, and apoptotic bodies, based upon their size, origin, and mode of
Release (page 8 lines 14-17). It is readily apparent from this teaching that matrix bound exosomes are considered matrix bound vesicles. The specification was reviewed and there is no evidence that the claimed concentration ranges of phospholipids are critical.
Regarding claims 37 and 38, it would have been obvious to have derived the matrix bound vesicles, i.e. exosomes, from extracellular matrix because Badylak teaches matrix bound vesicles such as exosomes derived from an extracellular matrix are useful for treating diseases. It would have been obvious to have derived the vesicles from extracellular matrix of urinary bladder or small intestinal submucosa, with a reasonable expectation of success because Badylak teaches extracellular matrix of urinary bladder or small intestinal submucosa as suitable sources of vesicles useful for treating a disease.
Regarding claim 39, it would have been obvious to have isolated the exosomes from a human, a monkey, a pig, a cow, or a sheep, with a reasonable expectation of success because Badylak teaches that ECM a human, a monkey, a pig, a cow, and a sheep are useful sources of matrix bound vesicles.
Regarding claim 47, it would have been obvious to have practiced Lim’s method by administering ECM-derived exosomes intravenously, with a reasonable expectation of success because Badylak teaches that intravenous administration is suitable in the method of treating a disease.
Regarding claim 48, it would have been obvious to have practiced Lim’s method by administering ECM-derived exosomes topically, with a reasonable expectation of success because Badylak teaches that topical administration to the skin is suitable in the method of treating a disease.
Combining prior art elements according to known methods to obtain predictable results supports obviousness and the selection of a known material suitable for its intended purpose supports obviousness.
Response to Arguments
Applicant’s arguments submitted in the remarks dated October 24, 2025 were fully considered but are not persuasive for the following reasons.
Applicant argued that exosomes are distinct from presently claimed matrix bound vesicles because exosomes are known to express CD63 and CD81, while matrix bound vesicles do not express these proteins or have a marked decrease in these proteins. Applicant also stated that Badylak disclosed these differences and cited page 16 lines 31-32. Applicant referred to instant specification for teachings that describe differences between exosomes and MBVs.
Arguments related to differences between exosomes and claimed MBVs are not persuasive because it is apparent from Badylak that exosomes taught by Badylak are ECM-bound or ECM-embedded exosomes which is a category of matrix bound vesicles. Badylak teaches that extracellular vesicles are nanosized, matrix bound vesicles with diameters ranging from 50-1,000 nm and are categorized into three main groups: nanovesicles, exosomes, and apoptotic bodies, based upon their size, origin, and mode of release (page 8 lines 14-17). A person skilled in the art would have interpreted this teaching to mean that exosomes are a category of matrix bound vesicles. Badylak further states that nanovesicles, specifically exosomes, are embedded within, and bound to, laboratory produced ECM bioscaffolds and commercially available ECM bioscaffolds (page 9 lines 11-12). This teaching further confirms examiner’s interpretation that exosomes are bound to the extracellular matrix, which reads on matrix bound vesicles. Page 16 lines 22-33 define “nanovesicle derived from an ECM”, “matrix bound nanovesicle”, and “ECM-derived nanovesicle” and the definition states that these vesicles do not express CD63 or CD81 or express barely detectable levels of these markers. Badylak further teaches that CD63 and CD81 are amongst the most commonly used validation surface markers for exosomes. Using Western blot analysis (Figure 3E) no positive bands were detected in all samples for CD63 or CD81. This indicates that nanovesicles and exosomes embedded within the ECM have different characteristics then circulating exosomes (page 60 lines 22-27). Thus, ECM-embedded nanovesicles represent a unique class of exosomes with biologic properties and functions distinct from circulating exosomes, and mediate many of the inductive properties of ECM scaffolds associated with constructive, functional remodeling (page 65 lines 8-10). A person skilled in the art would have interpreted this teaching to mean that matrix bound exosomes are different from circulating exosomes and the distinction is in the absence of CD63 and CD81 makers from the matrix bound exosomes.
In view of these teachings it is apparent that Badylak’s therapeutic exosomes are matrix bound exosomes (vesicles) that do not express CD63 and CD81, which do not have the same properties as circulating exosomes. Badylak makes it clear that matrix bound exosomes are different from circulating exosomes. Present claims do not exclude matrix bound exosomes from the scope of “matrix bound vesicles”. Applicant did not persuasively argue that Badylak’s matrix bound exosomes are structurally different from claimed matrix bound vesicles.
The instant specification was reviewed, however the teachings about the differences between “exosomes” and “matrix bound vesicles” are not sufficient to obviate the rejections over Lim and Badylak because there is no evidence that Badylak’s matrix bound exosomes have the properties of exosomes reported by the applicant.
There would have been a reasonable expectation of success in using Badylak’s matrix bound exosomes in Lim’s method of treating psoriasis because Badylak teaches that matrix bound exosomes increase M2 macrophages (anti-inflammatory) and decrease M1 macrophages (pro-inflammatory) and it is known in the art that psoriasis is an inflammatory condition. Thus, there would have been a reasonable expectation of success in treating an inflammatory conditions such as psoriasis with a composition that increases anti-inflammatory macrophages and decreases pro-inflammatory macrophages.
Lim teaches psoriasis in a list of diseases that may be treated with exosomes, which is sufficient for an obviousness rejection. A prior art reference is not required to exemplify the claimed embodiment or describe it as preferred for a proper obviousness rejection.
Applicant’s arguments regarding unexpected results are not persuasive because applicant did not meet the requirements set forth in MPEP 716.02. Applicant stated that decreased production of IL-6 and TNF-alpha induced by MBV, as compared to exosomes, was unexpected and could not have been predicted based on the cited prior art. Lim provides no data regarding treatment of any condition. The present application provides evidence that MBV can be used to treat psoriasis. Applicant provided a declaration to present evidence that MBV and exosomes have different immunomodulatory properties.
Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In the instant case, applicant tested exosomes derived from plasma and matrix bound vesicles and concluded that MBVs produced downregulation of proinflammatory markers that was significantly greater compared to exosomes. Section 4 of the declaration shows the results. First, it is not clear why the applicant concluded that the observed results are unexpected. Second, one of skill cannot determine whether or not the results are statistically different because of poor resolution of data in the graph. Markings 4 and 5 represent exosome and MBV, respectively, and the log values and error bars are not clear and it cannot be determined if the values are in fact statistically different from each other. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance."
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In the instant case, it is unknown if the claimed matrix bound vesicles are commensurate in scope with the matrix bound vesicles tested by the applicant. The term “matrix bound vesicle” is a generic term that describes different types of vesicles. See for example Badylak page 8 lines 14-17.
Applicant did not test Badylak’s matrix bound exosomes. According to Badylak there is a difference between free circulating exosomes and matrix bound exosomes, as well as there are different sources of exosomes. The comparison provided by the applicant is not proper because it does not compare matrix bound exosomes to the claimed matrix bound vesicles. Instant claims are rejected over matrix bound exosomes described by Badylak.
An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness.
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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/ALMA PIPIC/
Primary Examiner, Art Unit 1617