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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/09/2024, 03/13/2025, and 09/16/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure is being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: “functional integrin on surface". There should be an article "the" in front of “surface”. Appropriate correction is required.
Claim 124 is objected because of the plural “of claims 107”. Please correct to “of claim 107”.
Claim Rejections - 35 USC § 112(b)
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.
Claim 1 is rejected as indefinite for “substantially devoid.” The threshold for what is considered “substantially devoid” is indefinite because the specification has not provided a quantifiable measure for when the threshold is met. Therefore, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claim. For the purposes of examination, “substantially devoid” will be interpreted according to the definition of “deficient” in the specification. Claim 1 is further rejected for “functional integrin” which is not a term of the art. The metes and bounds of the claim are unclear because one of ordinary skill in the art would not know what the function of the integrin would infringe of on the claim.
Claims 116 and 125 are rejected for “mild alkaline pH”. The relative language is indefinite because what is considered a “mild alkaline pH” has not been defined in the specification. Therefore, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claim.
Claims 119 and 124 are rejected for “alkaline pH” and “high pH”. The relative language is indefinite because what is considered an “alkaline pH” or “high pH” has not been defined in the specification. Therefore, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claim. For the purposes of claim interpretation, “alkaline pH” and “high pH” will be used interchangeably to refer to a pH greater than 7.4.
Claim 125 is rejected as indefinite for “open” because the specification has not provided a quantifiable measure for when the threshold is met. Therefore, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claim. For the purposes of examination, “open” will include both making the vesicle the slightly porous, as well as completely dismantling the vesicle.
Claim 125 is further rejected for lack of antecedent basis for “the mild alkaline pH”. For the purposes of examination, it will be interpreted as “the alkaline pH.”
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
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 109 is 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. Claim 109 is a dependent claim that recites that the MYD88 inhibitor of claim 108 is a small or large molecule. Under broadest reasonable interpretation, a “small or a large molecule” encompasses all sizes of molecules. Since it does not exclude any MYD88 inhibitor size, it fails to further limit the claim from which it depends.
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.
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 107-120, 123, 124, 125 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 enablement requirement. The specification is enabling for relieving, ameliorating, or inhibiting a variety of inflammatory conditions using vesicles generated from mammalian cells that are devoid of cytoplasmic content. However, the specification does not reasonably provide enablement for the preventing/curing of every inflammatory condition using vesicles generated from every type of eukaryotic cell.
MPEP 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claim 107 and its dependents 108-120 are drawn to vesicles generated from any type of eukaryotic cell that are substantially devoid of cytoplasmic content, comprise a functional integrin on their surface and comprise an anti-inflammatory agent. As written, this broadly encompasses vesicles, including man-made vesicles and isolated exosomes, derived from any eukaryotic cell. The specification does not limit what the functional integrin or anti-inflammatory agent must be.
Claim 123 recites a method of treating by administering the vesicles of Claim 107 to a subject. As defined in the specification, paragraph [0050], treating includes preventing, curing, relieving/ameliorating and inhibiting any inflammatory condition in any animal. The genus of inflammatory conditions is extremely broad, encompassing a variety of mechanistically different conditions, as well conditions localized to specific parts or systems of the body.
The level of one of ordinary skill
The level of one of ordinary skill is deemed to be high.
The state of the prior art
The state of the art teaches that while the structure of exosomes is conserved across eukaryotes (Ibrahim et al., page 4, last paragraph), their cargo (Ibrahim et al., page 5, last paragraph) and surface markers (Ibrahim et al., page 5, middle paragraph) depend on their parental cell origin.
Therefore, while it may be possible to generate vesicles from a variety of eukaryotic cells, clear their cytoplastic contents, and load them with a therapeutic agent, not all vesicle sources would have a reasonable expectation of success for treating inflammatory conditions because their surface markers would not be relevant to the subject (ex. Vesicles from plant cells). However, the state of the art does demonstrate that vesicles generated from a wide variety of mammalian cell types have been used for therapeutic applications (Fu et al., Table 1). Even though this is still a broad genus, the state of the art teaches the genus such that one of ordinary skill in the art to have a reasonable expectation of success.
Furthermore, vesicles have been explored as a therapeutic route for relieving or inhibiting countless inflammatory conditions. At the time of filing, the use of vesicles that were devoid of cytoplasmic contents was less common, but nonetheless still used to treat a variety of conditions. For example, Furman teaches mesenchymal stem cell (MSC) derived vesicles devoid of cytoplasmic contents (pg. 3294, left side, last paragraph) with functional integrins on its surface (Fig. 1, panel H) and comprising a functional an anti-inflammatory agent, treated cancer in mice (pg. 3251, left side, last paragraph). Go et al., using a different method to remove cytoplasmic content, also teaches the reduction of an inflammatory condition, namely systemic inflammatory response syndrome (SIRS), using vesicles derived from U937 cells (abstract). Given the state of the art for therapeutic applications of vesicles both with and without cytoplasmic content, one would have a reasonable expectation of success for a variety of inflammatory conditions.
The amount of direction provided by the inventor and existence of working examples
Applicant has demonstrated that extruded ghost nanovesicles (exgNVs) can reduce the level of pro-inflammatory cytokines in mice treated with E Coli. [00140]. Therefore, Applicant has demonstrated enablement for relieving/ameliorating and inhibiting a single inflammatory condition using exgNVs. There are no working examples directed toward Synthetic Extracellular Vesicles (SynEVs) preventing, curing, relieving/ameliorating or inhibiting any inflammatory condition.
Conclusion
Taking the aforementioned factors into consideration, one of ordinary skill in the art would be enabled for relieving, ameliorating, or inhibiting a variety of inflammatory conditions using vesicles generated from mammalian cells that are devoid of cytoplasmic content, and comprise a functional integrin on their surface as well as an anti-inflammatory agent. However, the specification, given the state of the art at the time of filing, is not enabling for curing or preventing an inflammatory condition using vesicles derived from any eukaryotic cell.
Claim 124 is further rejected under enablement scope of enablement. The specification, while enabling for sonication disruption, it is not enabling for serial extrusion disruption. Claim 124 recites “disrupting the eukaryotic cells followed by exposure to an alkaline pH prior to forming the vesicles” (emphasis added). The claim then further recites that the disruption is either serial extrusion or sonication. However, the specification also teaches that serial extrusion forms vesicles [0010]. Therefore, in the embodiment where disruption is serial extrusion, it would be impossible to form vesicles, followed by exposure to an alkaline pH prior to forming vesicles. Because one of ordinary skill in the art could not use the claimed invention, it is rejected.
Claims 107, 108, and 123-125 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.
MPEP 2163.05 recites: The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Claim 107, 124, and 125 recite vesicles generated from eukaryotic cells, which constitutes a vast genus of cell types for vesicle origin across both mammalian and plant species. In the human body alone, there are over 215 cell types (Mostafa, pg. 40, left side first paragraph). While all eukaryotic cells secrete exosomes, they differ in their structural proteins (Ibrahim et al., pg. 4, last paragraph) and molecular cargo (Ibrahim et al, pg. 5, last paragraph, second sentence) based on their source. Therefore, even vesicles generated from several different types of eukaryotic cells could not represent the breadth of distinct vesicles possible under this recited genus. The specification discloses that both extruded ghost nanovesicles (exgNVs) and synthetic extracellular vesicles (SynEVs) were derived from MSCs or HEK293 cells ([00134], [00179], [00184]). Since the disclosed embodiment of the invention does not constitute the genus of all eukaryotic cells, Applicant is not in possession of the claimed invention.
Claim 107 recites vesicles comprising a functional integrin on their surface. There are 24 different types of integrin subunits in mammals (Takada et al., Table 1) each with different ligand specificity (Takada et al., Table 1), expression pattern throughout the body, and function (pg. 4, left side, last paragraph). The specification and working examples only teach vesicles comprising two different functional integrins on their surface: lymphocyte function-associated antigen (LFA-1) and macrophage-1 antigen (Mac-1) ([00199]). Both of these functional integrins are part of a subcategory of integrins defined by α subunits that contain an “interactive domain,” which is pivotal in ligand binding and intercellular adhesion for these integrin types. However, mammalian integrins without the interactive domain govern binding through other means (Takada, pg. 5, right side, first two sentences of second paragraph). Therefore, the genus recited by “functional integrin” in Claim 1 includes a breadth of structurally and functionally distinct species, which the working examples of not fully representative of. Since the disclosed species of the invention do not constitute the genus of all functional integrins, Applicant is not in possession of the claimed invention.
Claim 107 is further rejected as lacking written description for “an anti-inflammatory therapeutic agent.” The broadest reasonable interpretation of “an anti-inflammatory agent” constitutes a vast genus of structurally and functional distinct species including both natural and synthetic molecules. For example, Dinarello teaches that glucocorticoids (pg. 3, middle paragraph), antibodies (pg. 5, first paragraph, 7 lines from bottom), and statins (abstract) can function as anti-inflammatory agents. Given the breadth and variety of species that this genus represents, it would be impossible for possession of one or even several embodiments of an anti-inflammatory agent to demonstrate possession of the entire genus. The working examples are drawn to the following embodiments of anti-inflammatory agents: small molecules T6167923 and Cyclosporin (CsA) [00135], and a large molecule anti-Myd88 peptide [00193]. Since the disclosed species of the invention do not constitute the genus recited, Applicant is not in possession of the claimed invention.
Claim 108 is rejected for lacking written description because each recited inhibitor and activator is itself its own genus of structurally distinct species. For example, “an inhibitor of Myeloid Differentiation Primary Response 88 (Myd88)” is a genus including small molecules, peptides, antibodies, vesicles engineered to express a ligand for MyD88, etc. which is a separate genus from “an inhibitor of a non-receptor tyrosine kinase” and so on. The inhibitors of Myd88 in the working examples, namely T6167923 [00135] and a large molecule anti-Myd88 peptide [00193], are not representative of the entire MyD88 inhibitor genus. Furthermore, the working examples do not teach a single species for the other genera, such as inhibitors non-receptor tyrosine kinase. While Applicant does list potential activators of glucocorticoid receptors on pages 16-19 of the specification, this disclosure is nothing more than a suggestion of embodiments for one of ordinary skill in the art to implement; it is not described in sufficient detail to show possession. Since the species for which the Applicant does show possession of do not constitute the genus of each type of inhibitor or activator, Applicant does not have possession of the claimed invention.
Claim 123 is rejected for lacking written description for “treating an inflammatory condition.” Applicant does not have possession of curing or preventing, which are included in the definition of treating according to the specification [0053], every inflammatory condition. Figures 3B shows that one embodiment of the claimed invention, extruded ghost nanovesicles (exgNVs), had an anti-inflammatory effect in vivo, by reducing the level of a pro-inflammatory cytokine. However, no embodiments of the claimed invention demonstrate that the administration of vesicles, including exgNVs or SynEVs, was able to prevent or cure an inflammatory condition. The specification also teaches that Synthetic Extracellular Vesicles (SynEVs) could adequately deliver peptides to target cells [00195]. Furthermore, the genus recited by “inflammatory condition” is extremely broad, encompassing mechanistically different as well as environmentally induced types of inflammation, for which even a plethora of species could not possibly represent. According to the specification, the only condition treated by administration of vesicles was E. coli induced inflammation which does not constitute the genus of inflammatory conditions. Therefore, Applicant does not have possession of treating every inflammatory condition nor the prevention/curing of said conditions.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 107, 116-121, and 123 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Furman et al., Reconstructed Stem Cell Nanoghosts: A Natural Tumor Targeting
Platform, 2013, Nano Lett., pgs. 3248-3255 (hereafter Furman).
Claims 107 and 116-120 are drawn to vesicles generated from eukaryotic cells comprising functional integrin on the surface, devoid of cytoplasmic contents, and containing an anti-inflammatory therapeutic agent. Note: claims 116-120 are interpreted as product by process claims; for these claims the prior art must read on the product itself, not the method steps by which the product is achieved. Claim 121 further limits that the vesicles are generated from MSCs. Claim 123 recites treating a subject with a therapeutically effective amount of vesicles.
Furman teaches human MSC-derived vesicles devoid of cytoplasmic contents (pg. 3294, left side, last paragraph) with functional integrins on their surface (Fig. 1, panel H) and comprising an anti-inflammatory agent. Furman further teaches treating cancer in mice (pg. 3251, left side, last paragraph) by a single dose of the vesicles.
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.
Claim(s) 108-111 is/are rejected under 35 U.S.C. 103 as being unpatentable over Furman, as applied above, in view of Toshchakov US8940703 (hereafter Toshchakov).
Furman teaches the limitations of Claim 1, from which Claims 108-111 depend.
While Furman teaches vesicles containing an anti-inflammatory agent, it does not teach specifically that the anti-inflammatory agent comprises a large molecule inhibitor of MYD88 comprising instant SEQ ID NO: 2.
Toshchakov teaches that Myd88 is an adaptor protein which is essential in assisting toll like receptors (TLRs) initiate the innate immune response. It also teaches that SEQ ID: 37, which is the same as instant SEQ ID NO: 2 (see below), is a peptide that can modify inflammatory signaling. Specifically, Toshchakov teaches that the MyD88 peptide is able to inhibit proinflammatory cytokines (Fig. 13).
Instant SEQ ID NO: 2
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It would have been obvious to one of ordinary skill in the art to substitute the anti-inflammatory agent within the vesicles in order to treat various disorders more effectively. One of ordinary skill in the art would have been motivated to combine the vesicles taught by Furman, with the therapeutic agent of SEQ ID NO: 2 to treat inflammatory conditions because of the successful results taught by Toshchakov.
Claim(s) 112 and 113 is/are rejected under 35 U.S.C. 103 as being unpatentable over Furman, as applied above, in view of Noguchi US8440630 (hereafter Noguchi).
Furman teaches the limitations of Claim 1, from which Claims 112-113 depend.
Furman does not teach that the anti-inflammatory agent is an inhibitor of AKT, comprising instant SEQ ID NO: 4.
Noguchi teaches that AKT is involved in cancer, inflammation, and more (Column 2, lines 15-20). It also teaches SEQ ID NO: 1, equivalent to instant SEQ ID NO: 4, which is a peptide for inhibiting AKT activity (Column 15, lines 21-26). See below:
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It would have been obvious to one of ordinary skill in the art to substitute the anti-inflammatory agent within the vesicles in order to treat various disorders more effectively. One of ordinary skill in the art would have been motivated to combine the vesicles taught by Furman, with the therapeutic agent of SEQ ID NO: 4 to treat inflammatory conditions because of the successful results taught by Noguchi.
Claim(s) 122 is/are rejected under 35 U.S.C. 103 as being unpatentable over Furman, as applied above, in view of Fu et al. NanoImpact, 2020 (hereafter Fu).
Furman teaches the limitations of Claim 107, from which Claim 122 depends.
Furman does not teach that the vesicles are generated from HEK 293 cells, but rather from MSCs.
Fu teaches that it was well known in the art to use vesicles from HEK 293 cells and load them with cargo for various therapeutic applications (Table 1).
It would have been obvious to one of ordinary skill in the art to substitute the origin cell of the vesicles for any mammalian cell type known in the art to be successful as therapeutic carrier. Simple substitution from one well-known vesicle source, namely MSCs taught by Furman, to another well-known vesicle source, namely HEK 293 cells taught by Fu, which are functionally equivalent would have a reasonable expectation of success to practice the claimed invention.
Claim 125 is/are rejected under 35 U.S.C. 103 as being unpatentable over Furman, as applied above, in view of Go et al, Advanced Healthcare Materials, 2019 (hereafter Go) in further view of Kim et al., Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cell, 2016, Nanomedicine, pgs. 655-664 (hereafter Kim).
Claim 125 recites a method of making vesicles of Claim 107 by exposing exosomes to an alkaline pH, such that the exosome opens but retains a functional integrin on the surface. It further recites incubating the exosomes with a therapeutic agent and closing exosomes by applying energy.
Furman teaches the limitations of Claim 107, as applied above.
Furman does not teach that the vesicles are exosomes. It also does not teach the vesicles are made by exposing exosomes to an alkaline pH, incubation with a therapeutic agent, or applying energy to close them.
Go teaches exposing U973 cells to an alkaline pH, such that the cells open but retain a functional integrin on the surface (abstract). It further teaches incubating the opened cells with a therapeutic agent (pg.3, left side, first sentence) and closing exosomes by applying energy (abstract).
Go does not teach that exosomes are the cells exposed to an alkaline pH.
Kim et al. teaches that exosomes efficiently accumulate in target cells due to their presence of adhesion proteins, tetraspanins, integrins, immunoglobulins, proteoglycans and lectins (pg. 663, left side, first paragraph, bottom third).
It would have been obvious to one of ordinary skill in the art to apply Go’s method directly to exosomes instead of U973 cells because of the motivation that exosomes already express an array of molecules that make their targeting and uptake particularly efficient. Kim, Furman, and Go are all in the same field of interest, namely therapeutic applications of vesicles. One would have a reasonable expectation of success combining a known method clearing out and then loading vesicles with a known successful vesicle carrier.
Claim(s) 126 is/are rejected under 35 U.S.C. 103 as being unpatentable over Go et al, Advanced Healthcare Materials, 2019 (hereafter Go).
Claim 126 recites vesicles that are produced from a human cell line genetically modified to express lymphocyte function-associated antigen-1 (LFA-1) or macrophage-1 antigen (Mac-1).
Go teaches vesicles that express LFA-1 on their surface (Fig. 2C), generated from U973 cells. U973 cells are a human cell line.
Go does not teach that the U973 parent cells were genetically modified to express LFA-1 or Mac-1.
However, Go provides an explicit suggestion to do so by stating that vesicles “can be easily modified to express targeting molecules by genetic engineering of the parental cells” (pg. 6, left side, middle of first paragraph). Based on this suggestion from Go, it would have been obvious to one of ordinary skill in the art to genetically engineer the cells from which the vesicles are derived, in order to impart desirable membrane proteins onto the vesicles.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 107 and 116-121 are provisionally rejected on the grounds of nonstatutory double patenting of Lötvall US 17642140 (hereafter Lötvall) Claims 1 and 11 in view of Go and in further view of Jang et al, Bioinspired Exosome-Mimetic Nanovesicles for Targeted Delivery of Chemotherapeutics to Malignant Tumors, 2013, ACS Nano, Vol. 7, No. 9, pgs. 7698-7710 (hereafter Jang).
Although they are not identical, they are not patentably distinct from each other. Lötvall Claims 1 and 11 recite a method of making vesicles deficient in cytoplasmic contents and containing a therapeutic agent, but do not recite that the vesicles comprise a functional integrin on their surface.
However, Go teaches exposing cells to an alkaline pH, purifying the plasma membrane sheets, and applying the energy through sonication to produce nanovesicles devoid of cytoplasmic contents (abstract). Go also teaches that the vesicles produced retained the functional integrins of the parent cell (Fig. 2C).
Go does not teach that the vesicles are formed prior to removing cytoplasmic contents, which is the first step in Lötvall Claim 1.
Jang et al. teaches disruption of cells via extrusion to produce vesicles (abstract). In Figure 2D, Jang et al teaches the vesicles formed had the same topology as their parent cells and maintained functional integrins like LFA-1.
Based on the teachings from Go and Jang, the method steps recited in Lötvall would have preserved the functional integrin on the surface of the vesicles produced, even though it is not specifically recited in the claim. Therefore, Lötvall Claims 1 and 11 read on instant claims 107 and 116-121. It would have been obvious to combine the methods of Jang and Go with Lötvall because they are all in the same field of interest, namely clinical applications of vesicles.
Claims 108-111 are provisionally rejected on the grounds of nonstatutory double patenting of Lötvall Claims 1, 11, and 20 in view of Go and Jang, as applied above, in further view of Toshchakov. Although they are not identical, they are not patentably distinct from each other. Lötvall teaches the limitations of instant claim 107, from which Claims 108-111 depend, as addressed above. Lötvall Claim 20 further teaches that the therapeutic agent comprises a peptide, but does not recite that the peptide is instant SEQ ID NO: 2.
Toshchakov teaches that Myd88 is an adaptor protein which is essential in assisting toll like receptors (TLRs) initiate the innate immune response. It also teaches SEQ ID: 37, which is the same as instant SEQ ID NO: 2 (see below), is a peptide that can modify inflammatory signaling. Specifically, Toshchakov teaches that the MyD88 peptide is able to inhibit proinflammatory cytokines (Fig. 13).
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It would be obvious to one of ordinary skill in the art would to combine a known anti-inflammatory peptide, namely instant SEQ ID NO: 2, with a known vesicle designed to comprise a therapeutic peptide to treat inflammatory conditions more effectively. Therefore, it would be obvious that Lötvall Claims 1, 11, and 20 read on Claims 108-111, without explicitly reciting that the therapeutic peptide is SEQ ID NO: 2.
Claims 112-113 are provisionally rejected on the grounds of nonstatutory double patenting of Lötvall Claims 1, 11, and 20 in view of Go and Jang, as applied above, in further view of Noguchi. Although they are not identical, they are not patentably distinct from each other. Lötvall teaches the limitations of instant claim 107, from which Claims 112-113 depend, as addressed above. Lötvall Claim 20 further teaches that the therapeutic agent comprises a peptide, but does not recite that the peptide comprises instant SEQ ID NO: 4.
Noguchi teaches that AKT is involved in cancer, inflammation, and more (Column 2, lines 15-20). It also teaches SEQ ID NO: 1, equivalent to instant SEQ ID NO: 4, which is a peptide for inhibiting AKT activity (Column 15, lines 21-26). See below:
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It would be obvious to one of ordinary skill in the art would to combine a known anti-inflammatory peptide, namely instant SEQ ID NO: 4, with a known vesicle designed to comprise a therapeutic peptide to treat inflammatory conditions more effectively. Therefore, it would be obvious that Lötvall Claims 1, 11, and 20 read on Claims 108-111, without explicitly reciting that the therapeutic peptide is SEQ ID NO: 4.
Claims 114-115 and 123 are provisionally rejected on the grounds of nonstutterer double patenting of Lötvall Claims 1, 11, and 70 in view of Go and Jang, as applied above. Although they are not identical, they are not patentably distinct from each other. Lötvall teaches the limitations of the instant claims, but semantically divided them between two separate independent claims (Claims 1 and 70); however, one of ordinary skill in the art would recognize that the independent claims are drawn to the same invention and that the “overlay” of Claims 1, 11, and 70 is patentability indistinct from the instant claims. In other words, the strategic division of limitations does not give rise to patentably distinct inventions.
Lötvall Claims 1 and 70 are independent claims that recite the exact same steps for making vesicles. Therefore, one of ordinary skill in the art would recognize that limitations applicable to Claim 1 also apply to Claim 70 and vice versa because they are drawn to the same thing.
Lötvall Claims 1 and 11 teach all the limitations of instant Claim 107, from which Claims 114-115 depend, in view of Go and in further view of Jang, as described previously.
Lötvall Claim 70 teaches all the limitations of instant Claims 114-115 and 123.
Claim 70 recites steps for making vesicles identical to those of Claim 1, but does not include a limitation that the vesicles comprise a therapeutic agent. Claim 70 also recites administering vesicles to a subject to reduce the level of a proinflammatory cytokine in a subject, wherein the cytokine comprises IL-6 or TNF-alpha. Therefore, Claim 70 reads on the limitations of instant claims 114-115 that Lötvall Claims 1 and 11 don’t explicitly recite. It would be obvious to one of ordinary skill in the art that Claims 1, 11, and 70 altogether teach Claims 114-115.
Claim 70 of Lötvall recites administering vesicles to a subject to reduce the level of a proinflammatory cytokine, while instant Claim 123 simply recites “administering a therapeutically effective amount” of vesicles. The instant specification defines therapeutically effective amount to include the reduction of symptom of a disorder (pg. 8, [0054]).
Claims 124 is provisionally rejected on the grounds of nonstatutory double patenting Lötvall Claim 1. Although they are not identical, they are not patentably distinct from each other. Lötvall Claim 1 recites steps for generating vesicles on instant Claim 124 except for the limitations that the vesicles comprise an enrichment of mitochondrial proteins or specifically recite that disruption step is sonication or serial extrusion.
As defined by the specification, the “ghost nanovesicles deficient in cytoplasmic proteins” of Lötvall Claim 1 do not need to be completely empty [0021]. In addition, there are no steps recited in Lötvall Claim 1 that would exclude mitochondrial components from being enriched. Since Lötvall discloses the same steps for making the vesicles, it would be obvious to one of ordinary skill in the art the Lötvall vesicles also contain enriched mitochondrial proteins, even though it is not explicitly recited in the claim.
Furthermore, the limitation of Lötvall that the disruption was specifically sonication or serial extrusion would have been obvious to one of ordinary skill in the art in view of Jang et al., which teaches that serial extrusion was a known method of disruption to generate vesicles (abstract).
It would have been obvious to one of ordinary skill in the art that to combine a known method of disruption. Therefore, Lötvall reads on the claimed invention even though it does not explicitly recite the disruption or mitochondrial enrichment limitations of instant claim 124.
Conclusion
Claims 114 and 115 are free of the art but rejected under 112a and 112b as being dependent from Claim 1, as well as double patenting. Examiner could not find evidence that vesicles devoid of cytoplasmic content have anti-inflammatory effects on their own. For example, Jang et al. (Figure 7), Go et al. (Fig. 3 Panel D), and Furman et al. (Figure 4) all demonstrate that their vesicles did not have an anti-inflammatory effect without a loaded agent inside.
Claim 124 is free of the art because it recites a limitation that the vesicles “comprise an enrichment of mitochondrial proteins”. The closest art that examiner could find is Goa et al., where eukaryotic cells are disrupted via N2 cavitation, followed by an exposure to an alkaline pH, but wherein the vesicles are devoid, not enriched, of mitochondrial proteins. However, Claim124 remains rejected under 112(a), 112(b) and double patenting.
No claims are allowed.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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