singhNotice 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 .
DETAILED ACTION
This action is in response to the papers filed on May 18, 2022. Pursuant to preliminary
amendment filed on May 18, 2022, claims 2, 4-5, 7-8, and 12-13 have been amended, claim 6 has been canceled, and claim 15 newly added.
Therefore, claims 1-5 and 7-15 are currently under examination.
Priority
The present application, filed on May 18, 2022, is a 5 U.S.C. 371 national stage filing of the International Application No. PCT/EP2020/082891, filed November 20, 2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent European Patent Application EP19306495.3, filed November 21, 2019. Receipt is acknowledged of priority document EP19306495.3 required by 37 CFR 1.55.
Thus, the earliest possible priority for the instant application is November 21, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 18, 2022 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim objection
Claim 2 is objected to because of the following informalities: the Markush group contains a typo which results in improperly reciting chloroaluminum as a group:
“porphyrins, hydroporphyrins, chlorins, bacteriochlorins, purpurins, porphycenes, verdins, cyanines, merocyanines, phthalocyanines, chloroaluminum and phthalocyanines”
Additionally, phthalocyanines is recited twice.
Claim Rejections - 35 USC § 112(a)- scope of enablement
Claims 7 and 8 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 embodiments in which a photosensitizer formulated MSC-EV is locally administered to a defined body cavity such as the peritoneal or pleural space and light-activated to generate cytotoxic species that reduce tumor burden, does not reasonably provide enablement for the full scope of the claims across the genus of all body cavities, and all routes of delivery without undue experimentation. The specification therefore does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make or use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC § 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988).
Wands states on page 1404,
"Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skills of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims."
In the instant application, the specification is enabling only for intracavitary administration of photosensitizer loaded MSC-EVs, particularly for peritoneal and pleural malignancies, where light activation may be achieved by laparoscopic, coelioscopic, or thoracoscopic illumination. The working descriptions and cited art indicate that such localized activation in open or minimally invasive surgical settings can generate a reactive oxygen species (ROS) and promote tumor cell death intraperitoneally by laparotomy to administer the light within the abdominal cavity. Thus, the specification provides sufficient detail for these specific routes of administration and treatment settings (see instant specification, pg. 19, last para. through pg. 20, first para.).
However, to the extent that the claims encompass treating cancer in any body cavity, including pericardial, cranial, etc. by any route of administration, including systemic, or intrathecal, the disclosure lacks adequate direction or examples demonstrating how such administration could achieve selective accumulation of the photosensitizer loaded MSC-EVs or sufficient illumination within the respective anatomical environments. Each cavity differs substantially in tissue composition, light penetration, oxygenation, clearance kinetics, and safety considerations. This specification does not provide the necessary experimental data or operational parameters to guide a person of ordinary skill in the art across all claimed contexts.
Thus, due to lack of sufficient detail and working examples in the specification concerning all delivery routes and distinct body cavities, and cancer types, one of ordinary skill in the art would not recognize and would require undue experimentation to practice the full scope of the disclosure as claimed. The scope of the claims exceeds the scope of enablement provided in the specification, and neither the specification nor the art enables the claimed method to its entire scope. While the specification may reasonably enable treatment of cancers or tumors in the peritoneal or pleural cavities with MSC-EVs based photosensitizer delivery and light activation, it does not enable the broader genus of method directed to treating any cancer in any body cavity by any administration route.
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 1-2, 4, 8 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fuhrmann et al. (J Control Release. 2015 May 10:205:35-44. Epub 2014 Dec 4.).
Regarding claims 1-2, Fuhrmann discloses mesenchymal stem cell derived extracellular vesicles loaded with porphyrin photosensitizers (Abstract; Fig. 1-2; pg. 36, column 1, Section 2.1 Chemicals through Section 2.2 Cell culture and EV extraction; pg. 39, Section 3.2).
Regarding claim 4, Fuhrmann discloses where the extracellular vesicles are derived from mesenchymal stem cells, loaded with the photosensitizer, and analysis of populations thereof (pg. 37, column 2, Section: 3.1. Characterisation of EVs indicates their advantageous size distribution and storage stability).
Regarding claim 8, Fuhrmann discloses where the EVs were applied in a therapeutic model, and the therapeutic photosensitizer produced strong photodynamic effect through induction of reactive oxygen species (ROS) after light activation. In a cancer cell model, porphyrin-loaded EVs showed a massively increased cellular uptake and decreased cell survival. Fuhrmann additionally disclosed that EVs are highly versatile entities that can deliver therapeutics to target cells, and that innovative, smart and efficient methods of drug encapsulation are promising as a clinical approach (pg. 36, column 1, para. 1-2).
Regarding claim 14, Fuhrmann discloses the application of the exosomes or extracellular vesicle delivery vehicles in a pharmaceutical setting (pg. 39, para. 1-2).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7-8, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Fuhrmann et al. (J Control Release. 2015 May 10:205:35-44. Epub 2014 Dec 4.), in view of Millard et al (Drug Deliv. 2018 Nov;25(1):1790-1801; see IDS filed 05/18/2022, Cite No. 3), and further in view of Piffoux et al. (Adv Biosyst. 2017 May;1(5):e1700044. Epub 2017 Apr 18.), and Kusuzaki et al. (J Enzyme Inhib Med Chem. 2017 Jul 14;32(1):908–916; see IDS filed 05/18/2022, Cite No. 2).
Regarding claims 1-4, Fuhrmann teaches mesenchymal stem cell derived extracellular vesicles loaded with porphyrin photosensitizers (Abstract; Fig. 1-2; pg. 36, column 1, Section 2.1 Chemicals through Section 2.2 Cell culture and EV extraction; pg. 39, Section 3.2). Fuhrmann further teaches the analysis of populations of mesenchymal stem cell derived extracellular vesicles loaded with at least one photosensitizer (pg. 37, column 2, Section: 3.1. Characterisation of EVs indicates their advantageous size distribution and storage stability).
Fuhrmann does not teach wherein the at least one photosensitizer is meta-tetra hydroxyphenylchlorin (mTHPC).
However, Millard teaches the evaluation of photophysical and photobiological properties of meta-tetra hydroxyphenylchlorin (mTHPC) loaded in endothelial EVs as nanocarriers (Abstract). Millard teaches different porphyrins were known to be efficiently loaded in EVs and significantly improved cellular uptake and photodynamic therapy (PDT) efficiency compared with free and liposomes-encapsulated drugs with similar membrane composition (pg. 1791, column 1, para. 1; pg. 1798, column 2, para. 1; pg. 1798-1799, bridging para.).
Before the effective filing date, a person of ordinary skill in the art would have found it obvious to simply substitute loading of the mesenchymal stem cell derived extracellular vesicles with porphyrin photosensitizer payload, as taught by Fuhrman, with the payload of mTHPC, as taught by Millard. The ordinary artisan would have been motivated to do so as Millard teaches the favorable targeting properties of EVs, the loading of alternatives like porphyrins, and
“loading of EVs with mTHPC may provide enhanced drug delivery, thus decreasing toxicity and diminishing side effects, and as such representing the future for PDT of cancer.” (pg. 1798-1799; pg. 1800, column 1, Section: Conclusion)
Additionally, Fuhrman explicitly states:
“We provide evidence that model drugs with different degrees of hydrophobicity (i.e., porphyrins) can be loaded into EVs from various cell types.”
“The methods presented herein are both straightforward and easily applicable to other drugs and vesicles… The present work creates a basis for further explorations of the drug delivery abilities of EVs and aims to stimulate their further development in a pharmaceutical setting. (pg. 43, Section 4. Conclusions)”
Furthermore, the ordinary artisan would have recognized extracellular vesicles from various cell types were known in the art, optimized, and evaluated for their ability to deliver various payloads to therapeutic targets, further in view of the teachings of Piffoux and Kusuzaki.
Piffoux teaches methods of multifunctional theragnostic extracellular vesicle loading, including the mTHPC photosensitizer, chosen as cargo owing to its respective magnetic and light responsiveness (pg. 10, column 1, para. 1). Piffoux also explicitly states “mesenchymal stem cells have been used as nanoparticle transporters with remarkable tumor homing properties” (pg. 1, column 2, para. 1). Moreover, Kusuzaki teaches the effectiveness of photodynamic molecules as cancer therapeutics and increasing the therapeutic efficacy of photosensitizers by utilizing extracellular vesicles or exosomes to delivery photodynamic molecules, stating:
“Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules. We have recently shown the ability of human exosomes to deliver photodynamic molecules. Therefore, this review focused on extracellular vesicles as a novel strategy for the delivery of photodynamic molecules at cancer sites. This completely new approach may enhance the delivery and decrease the toxicity of photodynamic molecules, therefore, represent the future for photodynamic therapy for cancer treatment.”
Kusuzaki expressly teaches the utility of mesenchymal stem cells (MSC)-derived EVs for the targeted delivery of photosensizers, including porphyins (pg. 908, column 1, para. 2; pg. 909, column 2, para. 3; Table 1)
Thus, before the effective filing date of the instant application, in view of the combined teachings of Fuhrmann, Millard, Piffoux, and Kusuzaki, it would have been obvious to a person of ordinary skill in the art to formulate mesenchymal stem cell-derived extracellular vesicles (EVs) as delivery carriers for porphyrin-based photosensitizers to enhance photodynamic therapy. Fuhrmann establishes that EVs from mesenchymal stem cells can encapsulate photosensitizing molecules, while Millard demonstrates improved uptake and distribution of EV encapsulated porphyrins, motivating the substitution of EVs for MSC-EVs. Piffoux supports this rationale by specifically describing the use of extracellular vesicles as efficient carriers for photosensitizers to enhance therapeutic efficacy, and Kusuzaki further substantiates this by explicitly teaching mesenchymal stem cell derived vesicles for targeted delivery of photosensitizing agents such as porphyrins in cancer therapy. Collectively, these references provide motivation and the reasonable expectation of success for the ordinary artisan to combine known EV-based delivery techniques with porphyrin photosensitizers to improve targeting and therapeutic performance in photodynamic applications, see MPEP 2144.06.
Regarding claims 7-8, the combined teachings of Fuhrmann, Millard, Piffoux, and Kusuzaki render claim 1 and 4 obvious. Fuhrmann teaches where the EVs were applied in a therapeutic model, and the therapeutic photosensitizer produced strong photodynamic effect through induction of reactive oxygen species (ROS) after light activation. In a cancer cell model, porphyrin-loaded EVs showed a massively increased cellular uptake
and decreased cell survival. Fuhrmann teaches that EVs are highly versatile entities that can deliver therapeutics to target cells, and that innovative, smart and efficient methods of drug encapsulation are promising as a clinical approach (pg. 36, column 1, para. 1-2). Additionally, Millard teaches the application of photodynamic therapy (PDT) involving the administration of a photosensitizing agent or photosensitizer for the treatment of tumors by tumor eradication induced by PDT, demonstrating improved PDT efficacy in vivo in a murine cancer model after
direct intratumor injection (pg. 1790 through pg. 1791 column 1, para. 3).
Hence, before the effective filing date the ordinary artisan would have found it obvious to have applied the method of reducing tumor cell growth or treating cancer by administering mesenchymal stem cell-derived extracellular vesicles loaded with photosensitizers to a subject for tumor and cancer therapeutic applications. The person of ordinary skill in the art would have been motived to apply this therapeutic framework to achieve enhanced PDT efficacy by using MSC-EVs as efficacious, natural biocompatible carriers for photosensitizers, with a reasonable expectation of success in reducing tumor proliferation or treating cancer through light-activated ROS generation.
Regarding claim 14, the combined teachings of Fuhrmann, Millard, Piffoux, and Kusuzaki render claim 1 and 4 obvious. Additionally, Fuhrmann teaches the application of the exosomes or extracellular vesicle delivery vehicles in a pharmaceutical setting (pg. 39, para. 1-2)
Regarding claim 15, the combined teachings of Fuhrmann, Millard, Piffoux, and Kusuzaki render claim 1 and 2 obvious. Additionally, Kusuzaki teaches where extracellular vesicle is loaded with phthalocyanines for delivery and photodynamic therapeutic utility (Table 1; pg. 912, column 2, para. 2)
***
Claims 1 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Fuhrmann et al. (J Control Release. 2015 May 10:205:35-44. Epub 2014 Dec 4.), in view of Millard et al (Drug Deliv. 2018 Nov;25(1):1790-1801; see IDS filed 05/18/2022, Cite No. 3), , Piffoux et al. (Adv Biosyst. 2017 May;1(5):e1700044. Epub 2017 Apr 18.), Kusuzaki et al. (J Enzyme Inhib Med Chem. 2017 Jul 14;32(1):908–916; see IDS filed 05/18/2022, Cite No. 2), and further in view of Gazeau et al. (US 12,098,355 B2; PCT Pub. Date January 3, 2019; FR3068361B1 English translation provided).
Regarding claims 1 and 4, Fuhrmann teaches mesenchymal stem cell derived extracellular vesicles loaded with porphyrin photosensitizers (Abstract; Fig. 1-2; pg. 36, column 1, Section 2.1 Chemicals through Section 2.2 Cell culture and EV extraction; pg. 39, Section 3.2). Fuhrmann further teaches the analysis of populations of mesenchymal stem cell derived extracellular vesicles loaded with at least one photosensitizer (pg. 37, column 2, Section: 3.1. Characterisation of EVs indicates their advantageous size distribution and storage stability).
Fuhrmann does not teach wherein the at least one photosensitizer is meta-tetra hydroxyphenylchlorin (mTHPC).
However, Millard teaches the evaluation of photophysical and photobiological properties of meta-tetra hydroxyphenylchlorin (mTHPC) loaded in endothelial EVs as nanocarriers (Abstract). Millard teaches different porphyrins were known to be efficiently loaded in EVs and significantly improved cellular uptake and photodynamic therapy (PDT) efficiency compared with free and liposomes-encapsulated drugs with similar membrane composition (pg. 1791, column 1, para. 1; pg. 1798, column 2, para. 1; pg. 1798-1799, bridging para.).
Before the effective filing date, a person of ordinary skill in the art would have found it obvious to simply substitute loading of the mesenchymal stem cell derived extracellular vesicles with porphyrin photosensitizer payload, as taught by Fuhrman, with the payload of mTHPC, as taught by Millard. The ordinary artisan would have been motivated to do so as Millard teaches the favorable targeting properties of EVs, the loading of alternatives like porphyrins, and
“loading of EVs with mTHPC may provide enhanced drug delivery, thus decreasing toxicity and diminishing side effects, and as such representing the future for PDT of cancer.” (pg. 1798-1799; pg. 1800, column 1, Section: Conclusion)
Additionally, Fuhrman explicitly states:
“We provide evidence that model drugs with different degrees of hydrophobicity (i.e., porphyrins) can be loaded into EVs from various cell types.”
“The methods presented herein are both straightforward and easily applicable to other drugs and vesicles… The present work creates a basis for further explorations of the drug delivery abilities of EVs and aims to stimulate their further development in a pharmaceutical setting. (pg. 43, Section 4. Conclusions)”
Furthermore, the ordinary artisan would have recognized extracellular vesicles from various cell types were known in the art, optimized, and evaluated for their ability to deliver various payloads to therapeutic targets, further in view of the teachings of Piffoux, Kusuzaki and Gazeau.
Piffoux teaches methods of multifunctional theragnostic extracellular vesicle loading, including the mTHPC photosensitizer, chosen as cargo owing to its respective magnetic and light responsiveness (pg. 10, column 1, para. 1). Piffoux also explicitly states “mesenchymal stem cells have been used as nanoparticle transporters with remarkable tumor homing properties” (pg. 1, column 2, para. 1). Moreover, Kusuzaki teaches the effectiveness of photodynamic molecules as cancer therapeutics and increasing the therapeutic efficacy of photosensitizers by utilizing extracellular vesicles or exosomes to delivery photodynamic molecules, stating:
“Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules. We have recently shown the ability of human exosomes to deliver photodynamic molecules. Therefore, this review focused on extracellular vesicles as a novel strategy for the delivery of photodynamic molecules at cancer sites. This completely new approach may enhance the delivery and decrease the toxicity of photodynamic molecules, therefore, represent the future for photodynamic therapy for cancer treatment.”
Kusuzaki expressly teaches the utility of mesenchymal stem cells (MSC)-derived EVs for the targeted delivery of photosensizers, including porphyins (pg. 908, column 1, para. 2; pg. 909, column 2, para. 3; Table 1). Gazeau further teaches the production of extracellular vesicles from mesenchymal stem cells for therapeutic utility (column 1, para. 1-3; column 11, lines 14-18).
Thus, before the effective filing date of the instant application, in view of the combined teachings of Fuhrmann, Millard, Piffoux, Kusuzaki, and Gazeau, it would have been obvious to a person of ordinary skill in the art to formulate mesenchymal stem cell-derived extracellular vesicles (EVs) as delivery carriers for porphyrin-based photosensitizers to enhance photodynamic therapy. Fuhrmann establishes that EVs from mesenchymal stem cells can encapsulate photosensitizing molecules, while Millard demonstrates improved uptake and distribution of EV encapsulated porphyrins, motivating the substitution of EVs for MSC-EVs. Gazeau provides further evidence that the prior art recognized such EVs can be effectively engineered for targeted molecular delivery, supporting the predictable nature of such products in the art. Piffoux supports this rationale by specifically describing the use of extracellular vesicles as efficient carriers for photosensitizers to enhance therapeutic efficacy, and Kusuzaki further substantiates this by explicitly teaching mesenchymal stem cell derived vesicles for targeted delivery of photosensitizing agents such as porphyrins in cancer therapy. Collectively, these references provide motivation and the reasonable expectation of success for the ordinary artisan to combine known EV-based delivery techniques with porphyrin photosensitizers to improve targeting and therapeutic performance in photodynamic applications, see MPEP 2144.06.
Regarding claim 5, the combined teachings of Fuhrmann, Millard, Gazeau, Piffoux, and Kusuzaki render claims 1 and 4 obvious. Additionally, Gazeau teaches a method of preparation of extracellular vesicles from producer cells, including mesenchymal stem cells comprising an agitator causing turbulent flow, where the producer cell is adhered on the surface of microcarriers and the vesicles are collected (claim 1; column 1, para. 1-3; column 11, lines 14-18).
Therefore, before the effective filing date, the ordinary artisan would have found it obvious to apply the scalable EV production method of Gazeau to the preparation of mesenchymal stem cell derived EVs loaded with photosensitizers as taught by Fuhrmann, Millard, Piffoux, and Kusuzaki, since such adaptation represents a routine optimization of known culture and recovery techniques to obtain therapeutic EV formulations. The combined references provide both the motivation to produce the photosensitizer-loaded vesicles efficiently for therapeutic use. Also, the ordinary artisan would have had a reasonable expectation of success, as the methods of production taught by Gazeau were specifically designed to yield high quality EVs suitable for molecular delivery applications established in the prior art.
***
Claims 1, 4, and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Fuhrmann et al. (J Control Release. 2015 May 10:205:35-44. Epub 2014 Dec 4.), in view of Millard et al (Drug Deliv. 2018 Nov;25(1):1790-1801; see IDS filed 05/18/2022, Cite No. 3), and further in view of Piffoux et al. (Adv Biosyst. 2017 May;1(5):e1700044. Epub 2017 Apr 18.), and Kusuzaki et al. (J Enzyme Inhib Med Chem. 2017 Jul 14;32(1):908–916; see IDS filed 05/18/2022, Cite No. 2), and further in view of Pinto et al. (Pleura Peritoneum. 2018 Dec 18;3(4):20180124.).
Regarding claims 1 and 4, Fuhrmann teaches mesenchymal stem cell derived extracellular vesicles loaded with porphyrin photosensitizers (Abstract; Fig. 1-2; pg. 36, column 1, Section 2.1 Chemicals through Section 2.2 Cell culture and EV extraction; pg. 39, Section 3.2). Fuhrmann further teaches the analysis of populations of mesenchymal stem cell derived extracellular vesicles loaded with at least one photosensitizer (pg. 37, column 2, Section: 3.1. Characterisation of EVs indicates their advantageous size distribution and storage stability).
Fuhrmann does not teach wherein the at least one photosensitizer is meta-tetra hydroxyphenylchlorin (mTHPC).
However, Millard teaches the evaluation of photophysical and photobiological properties of meta-tetra hydroxyphenylchlorin (mTHPC) loaded in endothelial EVs as nanocarriers (Abstract). Millard teaches different porphyrins were known to be efficiently loaded in EVs and significantly improved cellular uptake and photodynamic therapy (PDT) efficiency compared with free and liposomes-encapsulated drugs with similar membrane composition (pg. 1791, column 1, para. 1; pg. 1798, column 2, para. 1; pg. 1798-1799, bridging para.).
Before the effective filing date, a person of ordinary skill in the art would have found it obvious to simply substitute loading of the mesenchymal stem cell derived extracellular vesicles with porphyrin photosensitizer payload, as taught by Fuhrman, with the payload of mTHPC, as taught by Millard. The ordinary artisan would have been motivated to do so as Millard teaches the favorable targeting properties of EVs, the loading of alternatives like porphyrins, and
“loading of EVs with mTHPC may provide enhanced drug delivery, thus decreasing toxicity and diminishing side effects, and as such representing the future for PDT of cancer.” (pg. 1798-1799; pg. 1800, column 1, Section: Conclusion)
Additionally, Fuhrman explicitly states:
“We provide evidence that model drugs with different degrees of hydrophobicity (i.e., porphyrins) can be loaded into EVs from various cell types.”
“The methods presented herein are both straightforward and easily applicable to other drugs and vesicles… The present work creates a basis for further explorations of the drug delivery abilities of EVs and aims to stimulate their further development in a pharmaceutical setting. (pg. 43, Section 4. Conclusions)”
Furthermore, the ordinary artisan would have recognized extracellular vesicles from various cell types were known in the art, optimized, and evaluated for their ability to deliver various payloads to therapeutic targets, further in view of the teachings of Piffoux and Kusuzaki.
Piffoux teaches methods of multifunctional theragnostic extracellular vesicle loading, including the mTHPC photosensitizer, chosen as cargo owing to its respective magnetic and light responsiveness (pg. 10, column 1, para. 1). Piffoux also explicitly states “mesenchymal stem cells have been used as nanoparticle transporters with remarkable tumor homing properties” (pg. 1, column 2, para. 1). Moreover, Kusuzaki teaches the effectiveness of photodynamic molecules as cancer therapeutics and increasing the therapeutic efficacy of photosensitizers by utilizing extracellular vesicles or exosomes to delivery photodynamic molecules, stating:
“Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules. We have recently shown the ability of human exosomes to deliver photodynamic molecules. Therefore, this review focused on extracellular vesicles as a novel strategy for the delivery of photodynamic molecules at cancer sites. This completely new approach may enhance the delivery and decrease the toxicity of photodynamic molecules, therefore, represent the future for photodynamic therapy for cancer treatment.”
Kusuzaki expressly teaches the utility of mesenchymal stem cells (MSC)-derived EVs for the targeted delivery of photosensizers, including porphyins (pg. 908, column 1, para. 2; pg. 909, column 2, para. 3; Table 1)
Thus, before the effective filing date of the instant application, in view of the combined teachings of Fuhrmann, Millard, Piffoux, and Kusuzaki, it would have been obvious to a person of ordinary skill in the art to formulate mesenchymal stem cell-derived extracellular vesicles (EVs) as delivery carriers for porphyrin-based photosensitizers to enhance photodynamic therapy. Fuhrmann establishes that EVs from mesenchymal stem cells can encapsulate photosensitizing molecules, while Millard demonstrates improved uptake and distribution of EV encapsulated porphyrins, motivating the substitution of EVs for MSC-EVs. Piffoux supports this rationale by specifically describing the use of extracellular vesicles as efficient carriers for photosensitizers to enhance therapeutic efficacy, and Kusuzaki further substantiates this by explicitly teaching mesenchymal stem cell derived vesicles for targeted delivery of photosensitizing agents such as porphyrins in cancer therapy. Collectively, these references provide motivation and the reasonable expectation of success for the ordinary artisan to combine known EV-based delivery techniques with porphyrin photosensitizers to improve targeting and therapeutic performance in photodynamic applications, see MPEP 2144.06.
Regarding claim 8, the combined teachings of Fuhrmann, Millard, Piffoux, and Kusuzaki render claim 1 and 4 obvious. Fuhrmann teaches where the EVs were applied in a therapeutic model, and the therapeutic photosensitizer produced strong photodynamic effect through induction of reactive oxygen species (ROS) after light activation. In a cancer cell model, porphyrin-loaded EVs showed a massively increased cellular uptake and decreased cell survival. Fuhrmann teaches that EVs are highly versatile entities that can deliver therapeutics to target cells, and that innovative, smart and efficient methods of drug encapsulation are promising as a clinical approach (pg. 36, column 1, para. 1-2). Additionally, Millard teaches the application of photodynamic therapy (PDT) involving the administration of a photosensitizing agent or photosensitizer for the treatment of tumors by tumor eradication induced by PDT, demonstrating improved PDT efficacy in vivo in a murine cancer model after direct intratumor injection (pg. 1790 through pg. 1791 column 1, para. 3).
Hence, before the effective filing date the ordinary artisan would have found it obvious to have applied the method of reducing tumor cell growth or treating cancer by administering mesenchymal stem cell-derived extracellular vesicles loaded with photosensitizers to a subject for tumor and cancer therapeutic applications. The person of ordinary skill in the art would have been motived to apply this therapeutic framework to achieve enhanced PDT efficacy by using MSC-EVs as efficacious, natural biocompatible carriers for photosensitizers, with a reasonable expectation of success in reducing tumor proliferation or treating cancer through light-activated ROS generation.
Regarding claims 9-13, the combined teachings of Fuhrmann, Millard, Gazeau, Piffoux, and Kusuzaki render claim 1, 4, and 8 obvious. The combined teachings of Fuhrmann, Millard, Gazeau, Piffoux, and Kusuzaki do not disclose the therapeutic is applied in the context of peritoneal carcinomatosis, pleural metastasis, or pseudomyxoma peritonei.
However, the ordinary artisan would have recognized that photodynamic therapy was utilized for the treatment of peritoneal metastasis, including pseudomyxoma peritonei, further in view of Pinto.
Pinto teaches that PDT has been extensively applied for the treatment of peritoneal and pleural metastases through the accumulation of photosensitizers within tumor tissues followed by light activation to generate reactive oxygen species that induce tumor cell death via necrosis, apoptosis microvascular damage, including where is applied to the colon and to tumors during laparotomy, and to the intraperitoneal or abdominal cavities (pg. 1-2, bridging para.; pg. 4, column 1, para. 2; pg. 10, column 2, para. 3; pg. 17, Table 3). Pinto further teaches that porphyrin-based photosensitizers, and mTHPC achieve significant antitumor efficacy and survival benefit for peritoneal carcinomatosis, and that light delivery can be accomplished through intraperitoneal or thoracoscopic illumination methods (pg. 4, column 2, para. 1-2; pg. 10, column 1, para. 1; pg.11, Table 2). Pinto also teaches where the illumination was repeated every 3-4 days, or at least 2 times (pg. 17, Table 2, row 2).
Thus, before the effective filing date of the instant application, the ordinary artisan would have found it obvious to have applied known PDT methods utilizing extracellular vesicle photosensitizer delivery, as taught by the combined teachings of Fuhrmann, Millard, Gazeau, Piffoux, and Kusuzaki, for the treatment of cancers occurring within body cavities, including peritoneal carcinomatosis, pleural metastasis, or pseudomyxoma peritonei, as taught by Pinto, with a reasonable expectation of success in achieving tumor reduction and therapeutic efficacy.
Conclusion
Claims 1-5 and 7-15 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOEL D LEVIN whose telephone number is (571)270-0616. The examiner can normally be reached Fulltime Teleworker.
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/J.D.L./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699