DETAILED ACTION
Disposition of Claims
Claims 1-4, 7-10, 12, 16-21, 23-24, and 26-28 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250152642A1, Published 05/15/2025.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Of note, there is not an attorney of record on file due to a lack of an official power of attorney of record. While a customer number has been provided on the ADS submitted 07/08/2024, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings are objected to because Fig. 7 refers to color in the drawings (see ¶[0028]). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The attempt to incorporate subject matter into this application by reference to WO 2019/198068 (¶[0004][0091]) is ineffective because the material necessary to describe “bioxomes” is essential subject matter to the claims and is improperly incorporated by reference to an international patent application. The claims recite MSC-derived bioxomes and methods involving oncolytic viruses encapsulated within MSC-derived bioxomes. The specification provides only a general description of a bioxome as an artificial particle comprising a cell membrane component, engineered to carry cargo, and designed to fuse with a target cell. The specification relies on WO 2019/198068 for artificial bioxome particles, methods for their production, and EV- or bioxome-encapsulated oncolytic viruses (OV) or OV-based vectors and methods for producing them. Because this material is necessary to describe and enable the claimed bioxome embodiments, it is essential material. Incorporation by reference of essential material to a foreign application, foreign patent, or publication is improper under 37 CFR 1.57(d). Applicant is required to amend the specification to include the essential material relied upon, accompanied by the required statement that the inserted material is the material previously incorporated by reference and that the amendment contains no new matter.
Claim Objections
Claim 1 is objected to because of the following informalities: the definition of the abbreviation “EV” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … extracellular vesicle (EV)...).
Appropriate correction is required.
Claim 8 is objected to because of the following informalities: the definition of the abbreviations “HSV”, “VACV”, “VSV” and “SFV” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … herpes simplex virus (HSV)...).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 contains the trademark/trade names “ONYX-015™” and “ONCORINE®”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe specific oncolytic viruses and, accordingly, the identification/description is indefinite.
Claims 16-19, 24, and 26 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.
The term “inhibited” in claims 16-19, 24, and 26 is a relative term which renders the claims indefinite. The term “inhibited” is 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. As the claims are drawn to genes or protein which are, or are not, “inhibited”, it is unclear if this “inhibition” refers to the actual inhibition of an activity of one of these proteins, or if the expression of the gene is prevented. It is unclear whether the claims require inhibition of gene transcription, mRNA expression, translation, protein expression, protein activity, downstream signaling, pathway activation, or some other biological property. It is also unclear what reference level is used to determine whether the gene or protein listed is “inhibited” or not.
For at least these reasons, the metes and bounds of the claims are unclear.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 is drawn to the method of claim 1, wherein the first active agent is administered intranasally to the brain of the patient. The claim is unclear because “intranasally” identifies administration through the nasal route, while “to the brain” appears to identify either the anatomical target of delivery or a required result after administration. It is unclear whether the claim requires administration to the nasal cavity with the brain as an intended target, actual delivery of the first active agent to the brain, application to olfactory nerve cells, transport through the olfactory pathway, or some other route or result. As claim 21, which depends upon claim 20, appears to clarify this issue, it is not included in the rejection.
For at least these reasons, claim 20 is rejected on the grounds of being indefinite.
Claim 24 and dependent claim 26 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 24 is drawn to a mesenchymal stem cell (MSC), wherein in the MSC the MAVS gene or protein or a gene or protein regulated by the MAVS gene or protein, is inhibited, an EV derived from the MSC, or a bioxome derived from the MSC. The claim is unclear because the “wherein” clause does not clearly identify the subject in which the recited gene or protein is inhibited. For example, it is unclear whether the claim requires inhibition in the MSC, inhibition in the source MSC from which the extracellular vesicle (EV) or bioxome is derived, inhibition within the extracellular vesicle or bioxome itself, or some other functional change in the composition. This ambiguity is material because EVs and bioxomes are not cells, and the claim does not explain how a gene is “inhibited” in those non-cellular alternatives. One suggestion is to rewrite the claim along the lines of the following:
“24. A composition comprising:
(a) a mesenchymal stem cell (MSC), wherein expression or activity of MAVS, or expression or activity of a MAVS-regulated gene or protein, is reduced in the MSC relative to a corresponding MSC in which MAVS expression or activity has not been modified;
(b) an extracellular vesicle (EV) derived from the MSC of (a); or
(c) a bioxome derived from the MSC of (a).”
This is merely a suggestion, as Applicant is free to amend the claims however they deem necessary to overcome the rejections.
For at least these reasons, the metes and bounds of the claim are unclear. Claim 26 is also rejected for depending upon claim 24, but not clarifying the metes and bounds of claim 24.
Claim 26 is 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.
The term “substantially pure” in claim 26 is a relative term which renders the claim indefinite. The term “substantially pure” is 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 does not provide an objective standard, numerical threshold, assay, marker profile, or other guidance for determining when a population of mesenchymal stem cells (MSCs) are “substantially pure”. It is unclear whether the phrase refers to purity with respect to the MSC identity, the percentage of cells having inhibited MAVS or inhibited MAVS-regulated gene/protein expression, the absence of non-MSC cells, the absence of unmodified MSCs, or some other property.
For at least these reasons, the metes and bounds of claim 26 are unclear.
Claim 27 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 is drawn to a method for treating a central nervous system (CNS) related disorder, the method comprising administering to the patient a mesenchymal stem cell (MSC), an MSC-derived EV, or an MSC-derived bioxome, wherein said administration is intranasal administration to the patient. The limitations of “the patient” in line 2 has unclear antecedent basis, as no patient has previously been mentioned in the claim. It is suggested that “the” preceding “patient” be modified to an indefinite article “a”, or that a “patient” be added to the preamble of the claim. For example:
“27. A method for treating a central nervous system (CNS) related disorder in a patient, the method comprising administering to the patient a mesenchymal stem cell (MSC), an MSC-derived EV, or an MSC-derived bioxome, wherein said administration is intranasal administration to the patient.”
For at least these reasons, the metes and bounds of the claim are unclear.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
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 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 1 already limits the “first active agent” to being either an oncolytic virus-based vector or an oncolytic virus, so claim 7 does nothing to further limit 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.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method for treating cancer in a patient, the method comprising the step of administering to the patient a first active agent, the first active agent selected from the group consisting of an oncolytic virus and an oncolytic virus-based vector, wherein the first active agent:
(i) is comprised in a mesenchymal stem cell (MSC), in an MSC-derived extracellular vesicle (EV), or in an MSC-derived bioxome, and
(ii) is administered intranasally to the patient.
Further limitations on the method of claim 1 are wherein the cancer is brain cancer (claim 2), wherein the brain cancer is glioblastoma (claim 3); wherein the cancer is a solid tumor, primary tumor, or metastatic tumor (claim 4); wherein the first active agent is an oncolytic virus-based vector or an oncolytic virus (claim 7), wherein the oncolytic virus-based vector is selected from the group consisting of an Adenovirus-based vector, a herpes simplex virus (HSV)-based vector, a vaccinia virus (VACV)-based vector, a vesicular stomatitis virus (VSV)-based vector, a Poliovirus-based vector, a Reovirus-based vector, a Seneca virus-based vector, an Echovirus-based vector, a Semliki Forest virus (SFV)-based vector, a Maraba virus-based vector, and an Enterovirus-based vector (claim 8), wherein the oncolytic virus-based vector is selected from the group consisting of ICOVIR-5 (Ad-DM-E2F-K-Δ24RGD), a Herpes simplex virus type 1 mutant 1716 (HSV-1716), Oncorine (H101), Onyx-15 (dl1520), ColoAd1, Talimogene laherparepvec (T-VEC), GL-ONC1, CV706, and GLV-1h68 (claim 9), wherein the oncolytic virus-based vector is ICOVIR-5 (claim 10), wherein the oncolytic virus is selected from the group consisting of a Herpes simplex virus (HSV), an Adenovirus, a Vaccinia virus (VACV), a Vesicular stomatitis virus (VSV), a Poliovirus, a Reovirus, a Senecavirus, an Echovirus, a Semliki Forest virus (SFV), a Maraba virus, and an Enterovirus (claim 12); wherein in the MSC:
(i) a Toll-like receptor selected from the group consisting of TLR1, TLR2, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10, gene or protein, is not inhibited,
(ii) the MyD88 gene or protein, is not inhibited, and/or
(iii) the MAVS gene or protein, is not inhibited (claim 16); wherein in the MSC:
(i) a Toll-like receptor selected from the group consisting of TLR1, TLR2, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10, gene or protein, is inhibited,
(ii) the MyD88 gene or protein, is inhibited, and/or
(iii) the MAVS gene or protein, is inhibited (claim 17), wherein in the MSC, TLR4, TLR9, and/or the MyD88 gene or protein, is inhibited (claim 18), wherein in the MSC, the MAVS gene or protein, is inhibited (claim 19); wherein the first active agent is administered intranasally to the brain of the patient (claim 20), wherein the first active agent is applied to the olfactory nerve cells of the patient (claim 21); and wherein the first active agent is administered by a vortical flow, controlled particle dispersion (CPD) device (claim 23).
Claim 24 is drawn to a composition comprising:
(a) a mesenchymal stem cell (MSC), wherein expression or activity of MAVS, or expression or activity of a MAVS-regulated gene or protein, is reduced in the MSC relative to a corresponding MSC in which MAVS expression or activity has not been modified;
(b) an extracellular vesicle (EV) derived from the MSC of (a); or
(c) a bioxome derived from the MSC of (a).
Claim 26 is drawn to a method for the production of a population of modified mesenchymal stem cells (MSCs), the method comprising:
(i) obtaining a sample comprising mesenchymal stem cells,
(ii) culturing the mesenchymal stem cells obtained in step (i), and
(iii) modifying the cultured mesenchymal stem cells of step (ii) to reduce expression or activity of MAVS, or expression or activity of a MAVS-regulated gene or protein, relative to corresponding cultured mesenchymal stem cells not subjected to the modifying step.
Claim 27 is drawn to a method for treating a central nervous system (CNS) related disorder in a patient, the method comprising administering to the patient a mesenchymal stem cell (MSC), an MSC-derived EV, or an MSC-derived bioxome, wherein said administration is intranasal administration to the patient.
Further limitations on the method of claim 27 are wherein said MSC, MSC-derived EV, or MSC-derived bioxome comprises an oncolytic virus or an oncolytic virus-based vector (claim 28).
Claim Rejections - 35 USC § 112(a); First Paragraph
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, 7-10, 12, 16-21, 23-24, and 26-28 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims describe “bioxomes” and “MSC-derived bioxomes”. The specification only describes “bioxomes” and “MSC-derived bioxomes” at high, generic levels, and relies on WO2019/198068 for bioxome particles, production methods, and bioxome-encapsulated oncolytic viruses or virus-based vectors. Since essential material may not be incorporated by reference from a WIPO publication in an application to issue as a U.S. patent, the disclosure presently of record does not adequately describe and enable the full scope of the claimed bioxome embodiments. The specification states that the active agent is “encapsulated and within” a cell, EV, or bioxome, but the specification relies on WO2019/198068 for EV- and bioxome-encapsulated OV or OV-based vectors and methods for producing them. The specification does not teach how to make the claimed MSC-derived bioxomes, load or encapsulate the OV or OV-based vector in the MSC-derived bioxome, preserve the function of the virus or vector, and use the bioxome product for the claimed intranasal treatment methods without undue experimentation.
Since this essential material is not adequately provided in the present specification, the disclosure does not enable the full scope of the claimed bioxome embodiments.
Claims 1-4, 7-10, 12, 16-21, 23-24, and 26-28 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.
The claims encompass MSC-derived bioxomes, including MSC-derived bioxomes comprising or containing oncolytic virus (OV) or an OV-based vector, and bioxomes derived from MSCs in which MAVS or a MAVS-regulated gene or protein is inhibited. However, the specification provides only a general description of a bioxome as an artificial particle comprising “a cell membrane component derived from a selected cellular or extracellular source, engineered to carry a cargo and designed to undergo fusion with a target cell.”(¶[0004]). And relies on WO2019/198068 for bioxome particles and methods for their production. The specification does not provide representative examples or sufficient identifying characteristics showing possession of the claimed MSC-derived bioxomes, including MSC-derived bioxomes carrying or encapsulating an oncolytic virus or oncolytic virus-based vector.
Accordingly, the specification does not reasonably convey that the applicant was in possession of the claimed bioxome embodiments at the time of filing.
Claims 1-4, 7-10, 12, 16-21, 23-24, and 26-28 are 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 intranasal administration of ICOVIR-5-infected mouse MSCs and ICOVIR-5-infected MAV knockout mouse MSCs in a murine GL261 glioblastoma model, does not reasonably provide enablement for all MSC-derived bioxomes comprising or encapsulating any oncolytic virus (OV) or any OV-based vector, or for using such MSC-derived bioxomes in the claimed treatment methods, wherein the MAVS gene/protein is inhibited in any manner. 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 legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to intranasal administration of an oncolytic virus (OV) or OV-based vector comprised in a mesenchymal stem cell (MSC), an MSC-derived bioxome for treating cancer, as well as composition and CNS-related treatment methods involving MSC-derived bioxomes.
The specification describes a bioxome as an artificial particle comprising a cell membrane component, engineered to carry cargo, and designed to fuse with a target cell (¶[0004]). The specification further states that the bioxome source may include MSCs (¶[0091-0101], esp. [0096]). Example 1 states that the first active agent is “encapsulated and within” a cell, extracellular vesicle (EV), or bioxome, but also states that EV- and bioxome-encapsulated OV or OV-based vectors and methods for producing them are known from WO2019/198068, which is incorporated by reference (¶[0159-0175][0183][0091]). The working examples in the specification are narrower, and describe OV-infected mouse MSC WT cells and conditioned media tested against GL261 cells (Example 6 at ¶[0176-0178]). Example 5 describes intranasal administration of mouse MSCs bearing ICOVIR-5 using a N2B device in a murine GL261 glioblastoma model, including ICOVIR-5-infected mouse MSCs and ICOVIR-5-infected MAV knockout mouse MSCs (¶[0173-0182]). Example 6 describes biodistribution of PKH26-labeled MSCs and PKH26-labeled MAV knockout MSCs after intranasal administration (¶[0176-0182]).
However, the pending claims are not limited to the disclosed MSC embodiments. The claims also encompass MSC-derived bioxomes comprising or encapsulating an OV or OV-based vector. Claim 27 further encompasses treatment of CNS-related disorders by intranasal administration of an MSC-derived bioxome, and claim 28 further requires that the MSC-derived bioxome comprises an OV or OV-based vector. The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, it was known that carrier cells could be used with OV. Fernandez Santidrian et. al. (US20200140824A1) describes cell-assisted viral expression systems including “(1) a cell, such as a carrier cell, that is permissive to viral infection and replication; (2) an oncolytic virus; and (3) at least one expressed immunomodulatory or therapeutic gene encoded by the virus expressed in the cell.”(¶[0006]). Fernandez Santidrian also states that “[t]he time period … depends on the particular oncolytic virus and/or carrier cell, and combination thereof, used in the system.”(¶[0006]). This shows that cell-based OV delivery was known, but it also shows that the operative conditions depended on the selected virus and selected carrier cell.
Fernandez Santidrian further describes MSCs as carrier cells for oncolytic virotherapy. Fernandez Santidrian states that “MSCs have been used as carriers of the oncolytic adenovirus ICOVIR-5 for the treatment of children with advanced metastatic neuroblastoma “(¶[0175]) and that MSCs are attractive carrier cells because they can support replication of OV, protect OV from immediate neutralization in the host, and can home to tumors (¶[0173]). However, this art concerns carrier cells, not MSC-derived bioxomes comprising or encapsulating OV or OV-based vectors.
The extracellular vesicle art also indicates that vesicle preparations and vesicle-associated functions were not simple or uniformly predictable. Thery et. al. (Théry C, et. al. J Extracell Vesicles. 2018 Nov 23;7(1):1535750.) states that EVs are “a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly (abstract)”. Thery also states that ascribing a specific function to EVs or EV subtypes requires “reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs.”(abstract). In general, the art identifies that there are significant isolation and standardization hurdles, with EVs being a diverse mixture of vesicles (e.g. (exosomes, microvesicles, apoptotic bodies) that vary widely in size and molecular cargo, and isolating a truly pure, uniform population is currently considered nearly impossible. Standard isolation techniques (like ultracentrifugation or size-exclusion chromatography) often co-isolate non-EV proteins or lipoproteins, which can obscure data or cause adverse reactions due to these contaminants (Lu S, et. al. Bioengineering (Basel). 2023 Mar 3;10(3):325.) Administration in therapeutic methods can also be a challenge, as some EVs can still elicit immune responses or alter immune cell function, as well as a large percentage of introduced EVs are quickly cleared by macrophages in the liver and spleen, limiting the amount that reaches the actual target site. EVs are sensitive to temperature and shear stress; developing formulations that allow them to be stored for long periods without degrading or losing their biological activity is a major logistical challenge, and harvesting sufficient quantities of therapeutic EVs from cell cultures is a slow and low-yield process, making large-scale manufacturing difficult and expensive (Zeng Y, et. al. Front Cell Dev Biol. 2022 Jun 24;10:816698.)
The prior art therefore supports that MSC carrier-cell OV-based systems were known, and that EV-type particles were recognized as heterogeneous and difficult to characterize properly. The art was not sufficiently predictable to support extrapolation from ICOVIR-5-infected mouse MSCs to MSC-derived bioxomes comprising or encapsulating an oncolytic virus or OV-based vector. Accordingly, the results obtained using ICOVIR-5-infected mouse MSCs would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with MSC culture, viral infection of carrier cels, OV assays, EV isolation, particle characterization, and animal models of glioblastoma. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional MSC-derived bioxomes would encapsulate or carry an OV or OV-based vector while retaining useful viral function to satisfy the claimed limitations.
One skilled in the art would also have been able to evaluate candidate particles by size, marker expression, cargo content, presence of virus/virus material, cell entry, and therapeutic activity; however, those assays would be used to screen and identify successful embodiments after preparation. They do not replace the missing teaching of how to make and use the full scope of the claimed MSC-derived bioxome embodiments.
Working examples. The specification provides working examples directed to ICOVIR-5-infected mouse MSCs, ICOVIR-5-infected MAV knockout mouse MSCs, intranasal administration of MSCs, and biodistribution of labeled MSCs (¶[0159-0182]). The specification does not provide working examples directed to an MSC-derived bioxome comprising any OV, nor does the specification provide working examples of any other MSC infected with any other OV targeting any other cancer cell type. The specification also does not provide a working example showing intranasal administration of any OV-containing MSC-derived bioxomes for treatment of cancer or any CNS-related disorder. The specification fails to show how any of the claimed genes are “inhibited” beyond full knockout (removal) of said genes. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding the general idea of using MSCs, MSC-derived EVs, or MSC-derived bioxomes as carriers. The specification also provides a general description of bioxomes as particles comprising a membrane component, engineered to carry cargo, and designed to fuse with a target cell (¶[0076-0118]). However, the specification does not provide sufficient guidance regarding how to prepare the claimed MSC-derived bioxomes comprising or encapsulating an OV or OV-based vector. The specification fails to provide any other guidance regarding encapsulating any other OV other than ICOVIR-5, or how to inhibit any of the noted genes/proteins other than knocking out said genes from the cellular genome. In particular, the specification does not explain how the OV or vector is loaded into the MSC-derived bioxome, how loading is confirmed, how the bioxome is distinguished from free virus or contaminating EVs, how viral infectivity is preserved, or how the bioxome product is formulated and administered intranasally to achieve the claimed therapeutic use.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to prepare MSC-derived bioxomes, prepare appropriate OV or OV-based vectors, load or encapsulate said OV or vectors into said bioxomes, separate the loaded bioxomes from free virus/other particles/other contaminants, confirm the cargo with the bioxomes, confirm the retained function of the OV, and test intranasal delivery and overall therapeutic activity. Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed carrier, OV cargo, delivery, and therapeutic limitations. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays. The relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional MSC-derived bioxomes to determine which embodiments contain or encapsulate an OV or OV-based vector and/or how to “inhibit” the genes/proteins as claimed and can be used in the claimed intranasal treatment methods.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes ICOVIR-5-infected mouse MSCs and ICOVIR-5-infected MAV knockout mouse MSCs administered intranasally in a murine glioblastoma model, but the claims also encompass MSC-derived bioxomes comprising or encapsulating any OV or any OV-based vector wherein said MSC-derived bioxomes can have a number of genes/proteins inhibited in any manner. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in the claims without undue experimentation.
Claims 1-4, 7-10, 12, 16-21, 23-24, and 26-28 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claim(s) 1-4, 7-10, 12, 16-21, 23-24, and 26-28 recite methods of treating cancer by intranasally administering an oncolytic virus (OV) or OV-based vector, wherein the virus or vector is comprised in an MSC, an MSC-derived EV, or an MSC-derived bioxome. Claim 24 recites an MSC in which the MAVS gene or protein, or a gene or protein regulated by MAVS, is inhibited, an EV derived from the MSC, or a bioxome derived from the MSC. Claim 26 recites a method for producing a substantially pure population of mesenchymal stem cells (MSC) according to claim 24. Claim 27 recites treating a CNS-related disorder by intranasally administering an MSC, an MSC-derived EV, or an MSC-derived bioxome, and claim 28 further recites that the MSC, MSC-derived EV, or MSC-derived bioxome comprises an OV or an OV-based vector.
The specification describes WO2019/198068 as describing “an artificial ‘bioxome’ particle comprising a cell membrane component derived from a selected cellular or extracellular source, engineered to carry a cargo and designed to undergo fusion with a target cell”(¶[0004]) and incorporates the document by reference (¶[0091]). The specification states that this document “describes artificial bioxome particles, and methods for their production”(¶[0091]). The specification also describes the acritical bioxome particle as comprising a cell membrane component, being designed to undergo fusion with a target cell, and being engineered to carry cargo comprising at least one predetermined active molecule (¶[0092-0093]). The specification further describes that the source of the bioxome may be selected from many different cellular, extracellular, tissue, fluid, and biological sources, including MSC (¶[0093-0098]). The specification also describes, in broad terms, an EV derived from a MAVS-inhibited MSc and a bioxome derived from a MAVS-inhibited MSC (¶[0119-0125]). The specification additionally states that pharmaceutical compositions may comprise an MSC-derived bioxome comprising the first active agent, and that the MSC-derived bioxome may comprise an OV or OV-based vector (¶[0126-0133]).
However, the scope of the claims is not limited to the embodiments described in the specification. The claim(s) broadly encompass MSC-derived bioxomes, including MSC-derived bioxomes that comprise or encapsulate any OV or OV-based vector, and bioxomes derived from MSCs in which MAVS or a MAVS-regulated gene or protein is inhibited. The specification does not provide a working example of an MSC-derived bioxome, an MSC-derived bioxome containing an OV, an MSC-derived bioxome containing an OV-based vector, or an MSC-derived bioxome derived from a MAVS-inhibited MSC.
The working examples, as noted supra in the 35 USC 112a enablement rejection, are directed to MSC-based experiments. Example 1 states that the first active agent is “encapsulated and within a cell, for example a mesenchymal stem cell (MSC); an EV, for example an MSC-derived EV; or a bioxome, for example an MSC-derived bioxome”(¶[0159]), but then states that EV- and bioxome-encapsulated OV or OV-based vectors and methods for producing them are known from WO2019/198068 (¶[0162]). Example 5 describes a pilot study in which mice were administered mouse MSCs bearing ICOVIR-5, an experimental oncolytic adenovirus derived from the human adenovirus serotype 5 and genetically altered to only replicate within tumor cells. This example includes ICOVIR-5-infected MAV knockout mMSCs, using an N2B (nose-to-brain) device, which is a specialized medical applicator designed to administer medication into the upper nasal cavity (¶[0173-0183]). These examples do not describe MSC-derived bioxomes carrying or encapsulating any OV or OV-based vector; nor do these examples describe the use of any other OV, such as an HSV, VSV, VACV, or enterovirus-based OV, nor does it state if or how said OV are to be attenuated, nor do these examples describe any other means for “inhibiting” the genes noted in claim 17.
The specification does not describe a sufficient number of species (e.g. MSC-derived bioxomes, OVs, inhibited genes) representative of the claimed scope. The specification also does not describe structural features common to the claimed genus which would allow one skilled in the art to recognize which additional species fall within the scope of the claimed invention. Instead, one skilled in the art would be required to select additional MSC-derived bioxomes not described in the specification, additional OV not described in the specification, or mutations to the target genes not described in the specification, and determine whether those additional embodiments satisfy the recited therapeutic and carrier limitations.
The claimed MSC-derived bioxomes are defined, at least in part, by the recited function of carrying cargo, fusing with a target cell, releasing cargo into a target cell, and comprising an OV or OV-based vector. However, the specification does not establish a correlation between the disclosed structural features and the recited function sufficient to identify the additional MSC-derived bioxomes falling within the scope of the claim. The specification describes the desired use of MSC-derived bioxomes in the claimed methods, but does not identify structural features common to the broader claimed genus (e.g. MSC-derived bioxomes containing OV or OV-based vectors) which would allow one skilled in the art to recognize other members of the genus. The disclosure of the desired function or result, without a sufficient description of the claimed genus (e.g. bioxome embodiments), does not demonstrate possession of the full scope of the claims.
The claims are further defined by “inhibition” or “non-inhibition” of certain TLRs or TLR-associated proteins, such as MyD88 and MAVS, and the example describes a knockout of MAV in MSCs infected with ICOVIR-5. However, the specification does not establish a correlation between the disclosed structural features and the recited function sufficient to identify the inhibition or non-inhibition of these components (e.g. genes/proteins) falling within the scope of the claim. The specification describes the desired inhibition or non-inhibition of these genes/proteins in the claimed methods, but does not identify structural features common to the broader claimed genus (e.g. mutations which lead to inhibition, use/expression of proteins or compounds which inhibit these proteins, etc.) which would allow one skilled in the art to recognize other members of the genus. Additionally, it is not clear what genes the OV will or will not have, as certain viruses which are claimed for use as OV have immunomodulatory genes that affect these specific targets. For instance, poxviruses such as vaccinia virus, encode immunomodulatory proteins such as A46 (encoded by A46R) that binds to toll like receptor (TLR) domain-containing adaptor molecules (such as, for example, MyD88, MAL, TRIF and TRAM) and inhibits the function of these proteins. In the “non-inhibited” systems, it is not clear which OV may be used and which native viral proteins must be present or absent. The disclosure of the desired function or result, without a sufficient description of the claimed genus, does not demonstrate possession of the full scope of the claims.
The specification describes treatment of a murine glioblastoma model using intranasal administration of ICOVIR-5-infected mouse MSCs and ICOVIR-5-infected MAV knockout mouse MSCs (Examples 5-7 starting at ¶[0173]). However, the claims broadly encompass methods using MSC-derived bioxomes comprising any recited oncolytic virus or OV-based vector. For instance, claim 21 has delivery of the MSCs and OVs directly to the olfactory nerve in order to bypass the blood/brain barrier; if said OV are not sufficiently attenuated, delivery of a neurotropic oncolytic virus, such as HSV, that is not sufficiently attenuated could have severe and deleterious effects on the subject. The disclosure of ICOVIR-5-infected MSCs does not reasonably convey possession of methods using MSC-derived bioxomes containing oncolytic viruses or oncolytic virus-based vectors.
Claim 27 additionally recites treating a CNS-related disorder using an MSC, an MSC-derived EV, or an MSC-derived bioxome by intranasal administration. The specification lists CNS-related disorders and possible clinical outcomes, but does not provide representative treatment examples using MSC-derived bioxomes for those CNS-related disorders (¶[0134-0147]). The disclosure of a broad wish to use MSC-derived bioxomes for CNS-related disorders does not reasonably convey possession of the full scope of claim 27.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in the claims at the time the application was filed.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-4, 7-10, 12, 16-20, 24, and 26-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fernandez Santidrian et. al. (US20200140824A1, Pub. 05/07/2020, hereafter “Fernandez Santidrian”.)
The Prior Art
Fernandez Santidrian teaches systems for potentiating cell-mediated oncolytic viral therapy, as well as modified viruses for such systems, and methods of treatment of cancers by administering such systems (entire document; see abstract.) Fernandez Santidrian teaches mesenchymal stem cells (MSCs) are attractive as oncolytic virus (OV) carrier cells because they are easily isolated from patients and expanded in vitro, they support the replication of OVs and their protection from immediate neutralization by the immune system, they can be engineered easily, and they inherently home to tumors in vivo due to the tumor-associated expression of inflammatory cytokines (¶[0173]). Fernandez Santidrian teaches that these MSCs can carry an oncolytic adenovirus (reference claims 1-2, 10-12) and would be used in methods of treatment of a subject who has a tumor or hematological malignancy, comprising administering the cell-assisted viral expression system (CAVES) of the MSC and OV (reference claim 28). Said system can be delivered intranasally (¶[0566]; instant claims 1, 7-8, 20).
Fernandez Santidrian teaches additional limitations of the instant claims, such as the use of the CAVES to treat solid tumors such as glioblastomas (¶[0585][0597]; instant claims 2-4, 27-28). Fernandez Santidrian teaches that MSCs have been used as carriers of the oncolytic adenovirus ICOVIR-5 for the treatment of children with advanced metastatic neuroblastoma (¶[0175]; instant claims 9-10, 12). Fernandez Santidrian teaches the CAVES can be pretreated with TLR antagonists (¶[0218]), engineered to express TLR antagonists (¶[0231]), such as A46, which is a poxvirus protein that binds directly to all four major TLR domain-containing adaptor proteins (MyD88, Mal (TIRAP), TRIF, and TRAM) and inhibits interaction between the TLR receptor and adaptor (¶[0376][0417-0419]; instant claims 17-18). As Fernandez Santidrian teaches the use of these compounds is an embodiment, this also means that embodiments where these are not used are also envisioned, leading these TLR-associated proteins to function normally (instant claim 16). Fernandez Santidrian teaches that MAVS may be engineered in the MSC to only be transiently expressed or permanently suppressed (¶[0228]; instant claims 19, 24). Fernandez Santidrian teaches isolation of MSC, culturing MSC, and then infecting said MSC with an OV (¶[0573][0173-0175][0228]; instant claim 26).
For at least these reasons, Fernandez Santidrian teaches every limitation of instant claims 1-4, 7-10, 12, 16-20, 24, and 26-28, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
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.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Fernandez Santidrian as applied to claims 1-4, 7-10, 12, 16-20, 24, and 26-28 above, and further in view of Hoekman et. al. (US20140014104A1; Pub. 01/16/2014; hereafter “Hoekman”.)
The Prior Art
The teachings of Fernandez Santidrian have been set forth supra. While Fernandez Santidrian teaches that the MSCs with the OV can be delivered intranasally, Fernandez Santidrian fails to explicitly teach that said delivery is directly to the olfactory nerve. However, such intranasal delivery targets would be obvious to a skilled artisan, given the teachings of Hoekman.
Hoekman teaches a compound delivery device for delivering a plume derived from a propellant and a drug formulation (entire document; see abstract.) Hoekman teaches that the drug formulation is in an intranasal dosage form in the form of powder, suspension, dispersion or liquid, and that the aerosolized intranasal dosage form passes through a nozzle, thus delivering a plume to the olfactory region of a user's nasal cavity (entire document; see abstract.) Hoekman teaches that delivery to the olfactory mucosa includes the olfactory epithelium, and olfactory neurons are present in said epithelium, allowing direct delivery of the drug compound via the olfactory nerves to the brain (¶[0126-0127]).
Given the teachings of Fernandez Santidrian, one of skill in the art would find it obvious to deliver the MSCs encapsulated with the OVs intranasally, especially to treat brain-related tumors or cancers. This would be an obvious route, given that Hoekman teaches that delivery of a drug directly to the olfactory epithelium allows for delivery to the olfactory neurons, which can transport the drug directly to the brain. Therefore, arriving at the limitations of instant claim 21 would be obvious to a skilled artisan, given the teachings of Fernandez Santidrian and Hoekman.
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Fernandez Santidrian in order to ensure delivery to the olfactory mucosa, thereby delivering the MSCs and OVs intranasally directly to the olfactory mucosa to allow said OV to bypass the blood/brain barrier. One would have been motivated to do so, given the suggestion by Hoekman that the olfactory mucosa allows direct access to the olfactory neurons to allow transport of drugs delivered there to be delivered directly to the brain. There would have been a reasonable expectation of success, given the knowledge that delivery of said MSC-OV compositions could treat brain tumors, such as glioblastomas, as taught by Fernandez Santidrian, and also given the knowledge that using Hoekman’s delivery methods, said MSC-OV composition could access the brain and the tumor(s) therein in a less invasive manner. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Fernandez Santidrian as applied to claims 1-4, 7-10, 12, 16-20, 24, and 26-28 above, and further in view of Giroux (US20030079742A1; Pub. 05/01/2003; hereafter “Giroux”.)
The Prior Art
The teachings of Fernandez Santidrian have been set forth supra. While Fernandez Santidrian teaches delivery of the MSC-OV compositions intranasally, and provides a general description that devices for delivery of the compositions are known in the art, Fernandez Santidrian fails to specifically teach any intranasal delivery devices such as vortical flow controlled particle dispersion (CPD) devices. However, such devices for intranasal delivery were known in the art, as evidenced by the teachings of Giroux.
Giroux teaches a nebulizer, wherein the nebulizer and breathing techniques are capable of delivering medicament into the sinus cavity of a user (entire document; see abstract.) Giroux teaches a nebulizer including a nasal adapter; a vortex chamber in communication with the nasal adapter; an outflow tube in communication with the dispersion chamber capable of causing a plurality of nebulized particles to move in a vortex within the internal channel of the nebulizer; and a housing, the housing having a medicine chamber in communication with the outflow tube (¶[0009]). Giroux teaches the nebulizer is capable of delivering nebulized particles far into the nasal cavity and the paranasal sinuses, and in one method of operation, the user uses the nebulizer in conjunction with a Controlled Particle Dispersion Breathing Technique (BT) to allow for the nebulized particles to reach deeply into the nasal cavity and paranasal sinuses (¶[0073][0075-0076]; reference claim 1.)
Given the teachings of Fernandez Santidrian, one of skill in the art would find it obvious to deliver the MSCs encapsulated with the OVs intranasally, and that devices for such delivery were known in the art. Given the teachings of Giroux, one would be apprised of at least one device for such an intranasal delivery of nebulized particles. Therefore, arriving at the limitations of instant claim 23 would be obvious to a skilled artisan, given the teachings of Fernandez Santidrian and Giroux.
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Fernandez Santidrian in order to ensure intranasal delivery was carried out with the proper device. One would have been motivated to do so, given the suggestion by Giroux that their nebulizer would allow for delivery of particles to all parts of the nasal mucosa. There would have been a reasonable expectation of success, given the knowledge that delivery of said MSC-OV compositions was previously done intranasally, as taught by Fernandez Santidrian, and also given the knowledge that using the nebulizer of Giroux that the device would utilize vortical flow and that Giroux teaches controlled particle dispersion breathing techniques to use with their nebulizer. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 17/046,058 (reference application) in view of Frey et. al. (US20180125940A1; Pub. 05/10/2018; hereafter “Frey.)
Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming bioxome particles. Both are claiming the bioxome may be derived from mesenchymal stem cells (MSCs). The main difference is that the ‘058 claims are drawn to the composition of the bioxome particles, while the instant claim is drawn to the bioxome being used to treat any CNS disorder via intranasal delivery. However, such a difference would be obvious, given the teachings of Frey. Frey teaches pharmaceutical compositions and methods for enhancing targeting of therapeutic compounds to the CNS applied via intranasal administration while reducing non-target exposure (entire document; see abstract.) Frey teaches that intranasal delivery of deferoxamine can treat CNS disorders, such as Parkinson’s Disease (reference claim 1). Therefore, the use of the bioxome particles of the ‘058 claims in the method of instant claim 27 would be an obvious use and delivery method of said particles, especially given the teachings of Frey.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Saari H, et. al. J Extracell Vesicles. 2020 Apr 17;9(1):1747206. Teaches the use of EV to deliver OV to a subject. Not utilized as rejection would be redundant to those set forth supra.
Dogrammatzis C, et. al. Front Cell Dev Biol. 2020 May 26;8:376. Teaches the use of EV to deliver OV to a subject. Not utilized as rejection would be redundant to those set forth supra.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights