DETAILED ACTION
Claims 1-20 are currently pending and under examination in the instant application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/30/24 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed copy of the 1449 is attached to this action.
Claim Rejections - 35 USC § 112
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.
Claims 3-6 and 15-20 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 3 recites the composition 1, “wherein the PEVS are provided in a syringe that is configured to deliver the PEVs into the eye”. The phrase “are provided in a syringe” is confusing and indefinite. It is unclear whether the phrase “are provided in a syringe” refers to actual or intended use step of providing the PEVs into an eye using the syringe or whether the applicant intends that the composition comprises a syringe which comprises the PEV. Claim 1 is drawn to a composition comprising platelet derived extracellular vesicles that include mitochondria (PEV). While the claim recites an intended use for the PEV which is to treat an ocular disorder, the claim remains a product claim and is not a method claim for “providing” or “delivering” the PEVs to an eye. As such, the metes and bounds of the phrase “are provided in a syringe” cannot be determined. In the interests of compact prosecution, claim 3 has been given its broadest reasonable interpretation as a composition which includes a syringe.
Claim 4 recites the composition of claim 1, “wherein the PEVs are provided in a port delivery system that provides a PEV implant for prolonged delivery of the PEVs into the eye”. The “wherein” phrase is confusing and indefinite because is unclear whether the phrase “are provided in a port delivery system that provides a PEV implant for prolonged delivery of the PEVs into the eye” refers to step of providing the PEVs into an eye using a port delivery system or whether the applicant intends that the composition comprises a port delivery system which comprises the PEV. Claim 1 is drawn to a composition comprising platelet derived extracellular vesicles that include mitochondria (PEV). While the claim recites an intended use for the PEV which is to treat an ocular disorder, the claim remains a product claim and is not a method claim for “providing” or “delivering” the PEVs to an eye. As such, the metes and bounds of the phrase “are provided in a port delivery system …” cannot be determined. In the interests of compact prosecution, claim 4 has been given its broadest reasonable interpretation as encompassing the further inclusion of a port delivery system in the composition.
Claim 5 depends on claim and is indefinite in the recitation, “wherein the PEVs are administered into vitreous chamber of the eye”. The wherein clause appears to include a method step where the PEVs are in fact administered to the eye. However, claim 1 is drawn to a composition comprising platelet derived extracellular vesicles that include mitochondria (PEV). While claim 1 recites an intended use for the PEV which is to treat an ocular disorder, the claim remains a product claim and is not a method claim which includes a step of administration of the PEVs to an eye. As such, the recitation of an apparent method step in claim 5 conflicts with independent claim which is a product claim such that the metes and bounds of claim 5 cannot be determined. In the interests of compact prosecution, the wherein clause of claim 5 has been given its broadest reasonable interpretation as reciting an intended use for the composition.
Claim 15 depends on claim 1 and recites, “wherein the PEVs are administered in a manner that the PEVs contact at least one cell of the eye”. The wherein clause appears to include a method step where the PEVs are in fact administered to the eye. However, claim 1 is drawn to a composition comprising platelet derived extracellular vesicles that include mitochondria (PEV). While claim 1 recites an intended use for the PEV which is to treat an ocular disorder, the claim remains a product claim and is not a method claim which includes a step of administration of the PEVs to an eye. As such, the recitation of an apparent method step in claim 15 conflicts with independent claim which is a product claim such that the metes and bounds of claim 15 cannot be determined. Claims 16-17 depend on claim 15 and further recite either a functional effect of the administration step in claim 15 or recite a dosage of the cells that are administered and thus are indefinite for the same reasons as claim 15. In the interests of compact prosecution, the wherein clauses of claims 15-17 have been given their broadest reasonable interpretation as reciting an intended use for the composition.
Claim 18 depends on claim 13 which depends on claim 1 and recites the composition of claim 13, “wherein the PEVs are frozen while stored”. The wherein clause is confusing as neither claim 13 nor claim 1 refer to stored PEVs. Claim 1 simply refers to a composition comprising PEVs. Claim 13 refers to the storage of blood, not PEVs. As such, the reference to PEVs having been stored is confusing such that the metes and bounds of the claim cannot be determined. Claims 19-20 depend on claim 18 and thus are included in this rejection.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, and 5-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. Independent claim 1 recite a composition comprising platelet-derived extracellular vesicles that include mitochondria (PEV) produced by specific process involving collecting the PEVs from the blood. PEVs, however, are naturally released from platelets in vivo and are present in at least blood. Thus, the PEVs isolated from blood are a product of nature. Under the Supreme Court's ruling in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), simply isolating a product of nature does not make it patent-eligible because isolating the natural product, in this case PEVs, from blood does not change the fundamental genus or natural characteristics of PEVs. Further, the claimed PEVs have no apparent markedly different characteristics following their isolation, are not claimed as part of a practical application, and do not include additional elements that amount to significantly more.
Claims 2 and 5-17, which recite additional limitations regarding with the process for producing the PEVs, or additional limitation regarding the intended use of the product, are subject to the same analysis and the same conclusions as claim 1 set forth above.
Claim 18 recites PEVs which are frozen while stored. While this claim suffers from issues of indefiniteness regarding, in so far as the claim appears to encompass frozen PEVs, the following analysis applies. The PEVs themselves are a product of nature as discussed above. There is no evidence of record that simply freezing the PEVs changes the PEVs such that they have "markedly different characteristics" from their natural counterparts. The frozen PEVs are further not claimed as part of a practical application, and do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 5-7, and 9-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rousseau et al. (2015) PLOS One; doi:10.1371/journal.pone.0116812, pages 1-27, as evidenced by Marcoux et al. (2019) Transfusion, Vol. 59, 2403-2414.
The instant product claims are recited as product by process claims. Applicant is reminded that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
It is also noted that the product claims further recite various intended uses. Claim 1 recites that the composition is “for treating an ocular disorder, or a symptom of an ocular disorder”, which is an intended use of the composition. Dependent claims 5 and 15-17 further recite “wherein” clauses regarding administering the composition which have also been interpreted as an intended use for the composition as the claims are drawn to a composition, and not to a method of using the composition-see the rejection of these claims under 35 U.S.C. 112(b) above. Applicant is reminded that the use of a product for a particular purpose is not afforded patentable weight in a product claim where the body of the claim does not depend on the preamble for completeness but, instead, the structural limitations are able to stand alone. The MPEP states that, “.. in apparatus, article, and composition claims, intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.” In re Casey, 152 USPQ 235 (CCPA 1967); In re Otto , 136 USPQ 458, 459 (CCPA 1963)(MPEP 2111.02).
Rousseau et al. teaches methods of isolating extracellular vesicles from PRP comprising centrifuging citrated blood to obtain PRP followed by washing and centrifuging the PRP in Tyrode's buffer to generate a homogenous preparation of platelets (Rousseau et al., page 4). Alternatively, Rousseau et al. teaches that blood can be drawn into a tube comprising the anticoagulant acid citrate dextrose (ACD) and then mixed with Tyrode's buffer at pH 6.5 prior to centrifugation to obtain the PRP (Rousseau et al., page 5). Rousseau et al. teaches that homogenous preparation of platelets were counted and then diluted at 100X10-6 platelets/ml with Tyrode's buffer pH7.4 containing 5mM CaCl2 and then stimulated by the addition of 1 mg/ml of heat aggregated human IgG (Rousseau et al., page 4). Rousseau et al. further teaches to stop the stimulation by addition of EDTA followed by centrifugation to obtain a pellet containing the platelet microparticles (EVs) (Rousseau et al., page 4). Rousseau et al. further teaches to store the MPs by freezing them at -80oC (Rousseau et al., page 4). Further, in regards to claim 2, it is noted for the preparation of PEVs from mouse PRP, Rousseau et al. teaches that the blood was cardiac blood (Rousseau et al., page 5). Further in regards to the use of blood which has been previously stored for 4 or more days or up to a year as recited in claims 13-14, it is noted that Rousseau et al. does not teach whether or how long blood obtained from humas or mice was stored prior to processing to obtain PEVs. However, as discussed above, the instant claims are product by process claims, Rousseau et al. teaches PEVs made using the same process steps as recited in the claims. There is no evidence that storage of blood prior to processing affects the structure of the any PEVs obtained. As noted above, “[t]he patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
While Rousseau et al. does not teach that the obtained PRP-EVs include mitochondria, the presence of mitochondria in MPs obtained from stimulated PRP platelets was known at the time of filing. Marcoux et al., for example, teaches that platelets are rich in mitochondria and that extracellular vesicles including exosomes and microparticles obtained from stimulated platelets contain mitochondria (Marcoux et al., page 2402). Thus, Marcoux et al. provides evidence that the presence of mitochondria i PRP-EVs is an inherent property of PRP-EVs.
Therefore, by teaching PRP derived EVs comprising all the limitations of the claims as written, Rousseau et al. anticipates the instant invention as claimed.
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.
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, 3-4, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Rousseau et al. (2015) PLOS One; doi:10.1371/journal.pone.0116812, pages 1-27, in view of Marcoux et al. (2019) Transfusion, Vol. 59, 2403-2414, US Patent Application Publication No. 2019/0290696 (2019), hereafter referred to as De Miroschedji et al., Parenky et al. (2021), AAPS PharmSciTech, Vol. 22, 100; doi:10.1208/s12249-01949-4, pages 1-13, and Khanani et al. (2021) Exp. Opin. Drug Deliv., Vol. 18:11, 1571-1576.
The instant product claims are recited as product by process claims. Applicant is reminded that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
It is also noted that the product claims further recite various intended uses. Claim 1 recites that the composition is “for treating an ocular disorder, or a symptom of an ocular disorder”, which is an intended use of the composition. Applicant is reminded that the use of a product for a particular purpose is not afforded patentable weight in a product claim where the body of the claim does not depend on the preamble for completeness but, instead, the structural limitations are able to stand alone. The MPEP states that, “.. in apparatus, article, and composition claims, intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.” In re Casey, 152 USPQ 235 (CCPA 1967); In re Otto , 136 USPQ 458, 459 (CCPA 1963)(MPEP 2111.02).
Rousseau et al. teaches methods of isolating extracellular vesicles from PRP comprising centrifuging citrated blood to obtain PRP followed by washing and centrifuging the PRP in Tyrode's buffer to generate a homogenous preparation of platelets (Rousseau et al., page 4). Alternatively, Rousseau et al. teaches that blood can be drawn into a tube comprising the anticoagulant acid citrate dextrose (ACD) and then mixed with Tyrode's buffer at pH 6.5 prior to centrifugation to obtain the PRP (Rousseau et al., page 5). Rousseau et al. teaches that homogenous preparation of platelets were counted and then diluted at 100X10-6 platelets/ml with Tyrode's buffer pH7.4 containing 5mM CaCl2 and then stimulated by the addition of 1 mg/ml of heat aggregated human IgG (Rousseau et al., page 4). Rousseau et al. further teaches to stop the stimulation by addition of EDTA followed by centrifugation to obtain a pellet containing the platelet microparticles (EVs) (Rousseau et al., page 4). Rousseau et al. further teaches to store the MPs by freezing them at -80oC (Rousseau et al., page 4).
While Rousseau et al. does not teach that the obtained PRP-EVs include mitochondria, the presence of mitochondria in MPs obtained from stimulated PRP platelets was known at the time of filing. Marcoux et al., for example, teaches that platelets are rich in mitochondria and that extracellular vesicles including exosomes and microparticles obtained from stimulated platelets contain mitochondria (Marcoux et al., page 2402).
While Rousseau et al. teaches to stimulate the platelets obtained from PRP prior to collection of the EVs, Rousseau et al. does not teach to stimulate the obtained PRP derived platelets by freeze/thaw, or to prepare a composition of the PRP-EVs in an injection syringe or port delivery device. De Miroschedji et al. supplements Rousseau et al. by teaching a similar method of obtaining platelet-derived extracellular vesicles that include mitochondria (PEVs) from blood (De Miroschedji et al., paragraphs 18 and 40). De Miroschedji et al. teaches wherein the PEVs have been collected by obtaining blood from one or more donors, adding an anticoagulant to the blood, separating the mix into supernatant and platelet rich plasma (PRP) through centrifugation, collecting the PRP, and subjecting the collected PRP by freezing and thawing-cycles (-20°C and RT) such that platelets are broken up/cracked and release their inner contents into the surrounding liquid, and collecting the extracellular vesicles as the PEVs (De Miroschedji et al., paragraphs 31-32, 139-143, 156, and 183). In addition, De Miroschedji et al. teaches pharmaceutical preparations of the PRP-EVs for intraocular injection (De Miroschedji et al., paragraphs 17, 20, 67, 102, 129, and 188). Thus, De Miroschedji et al. provides the teaching and motivation that as part of methods of isolation of PRP-EVs, platelets obtained from PRP can be subjected to freeze/thaw cycles to release the EVs from the platelets. De Miroschedji et al. further provides the teachings and motivation to prepare a pharmaceutical composition of EVs, including compositions for intraocular injection.
Therefore, in view of the teachings and motivation provided by De Miroschedji et al. that as part of a process for preparing PRP-EVs, PRP platelets can be subjected to freeze/thaw cycles to release EVs into the surrounding liquid for further collection, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the methods of Rousseau et al. to include a step of stimulation by freeze/thaw cycles in order to collect PRP-EVs with a reasonable expectation of success.
While Rousseau et al. and De Miroschedji et al. teach preparations of PRP-EVs which inherently comprise mitochondria, and De Miroschedji et al. teaches pharmaceutical compositions for intraocular injection, neither Rousseau et al. nor De Miroschedji et al. teach to include the PRP-EVs in a syringe or an ocular port delivery device. Parenky et al. and Khanani et al. supplements Rousseau et al. and De Miroschedji et al. by teaching different methods of intraocular delivery of pharmaceuticals. Parenky et al. teaches that the standard of care for many eye diseases involves intravitreal injection using a syringe filled with a drug product (Parenky et al., pages 1-2). Khanani et al. also teaches that intravitreal injection is the standard for drug delivery to the eye but suffers from several drawbacks including the need for frequent reinjection, where each injection carries a risk of adverse effects such as endophthalmitis, intraocular inflammation, elevated intraocular pressure, retinal tears, and rhegmatogenous retinal detachment, and the requirement for a regular regimen of injections which is difficult for patients to maintain, resulting in possible sub-therapeutic administration of medications with resultant vision loss (Khanani et al., page 1571). Khanani et al. teaches a new delivery means using a port delivery device comprising refillable implant provides several benefits over traditional intravitreal injection including a single implant procedure, continuous delivery of the drug to the vitreous, and less frequent visits for non-invasive refill of the implant (Khanani et al., pages 1571-1572). Therefore, by teaching that intravitreous injection using a syringe is the standard for intraocular delivery, Parenky et al. and Khanani et al. provide motivation to prepare a pharmaceutical composition of PRP-EVs for intraocular injection according to De Miroschedji et al. by preparing a syringe comprising the PRP-EVs. Alternatively, by teaching the benefits of using a port delivery device over intravitreal injection, Khanani et al. provides motivation to prepare a pharmaceutical composition of PRP-EVs for intraocular injection according to De Miroschedji et al. by preparing a port delivery device comprising he PRP-EVs.
Therefore, based on the teachings of De Miroschedji et al. to prepare a pharmaceutical composition comprising PRP-EVs for intraocular delivery, the teachings of Parenky et al. that intravitreal injection using a syringe is the standard for delivery drugs to the eye, and the teachings and motivation provided by Khanani et al. for an improved intraocular delivery system using a port delivery device, it would have been prima facie obvious to the skilled artisan at the time of filing to prepare a composition for intraocular delivery which comprises a syringe filled with PRP-EVs made using the process disclosed by Rousseau et al., or Rousseau et al. in view of De Miroschedji et al., or a port delivery device comprising said PRP-EVs with a reasonable expectation of success.
Claims 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rousseau et al. (2015) PLOS One; doi:10.1371/journal.pone.0116812, pages 1-27, in view of Marcoux et al. (2019) Transfusion, Vol. 59, 2403-2414, and Bosch et al. (2016) Scientific Reports, Vol. 6, 36162;doi:10.1038/srep36162, page 1-11.
The instant product claims are recited as product by process claims. Applicant is reminded that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
It is also noted that the product claims further recite various intended uses. Claim 1 recites that the composition is “for treating an ocular disorder, or a symptom of an ocular disorder”, which is an intended use of the composition. Applicant is reminded that the use of a product for a particular purpose is not afforded patentable weight in a product claim where the body of the claim does not depend on the preamble for completeness but, instead, the structural limitations are able to stand alone. The MPEP states that, “.. in apparatus, article, and composition claims, intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.” In re Casey, 152 USPQ 235 (CCPA 1967); In re Otto , 136 USPQ 458, 459 (CCPA 1963)(MPEP 2111.02).
Rousseau et al. teaches methods of isolating extracellular vesicles from PRP comprising centrifuging citrated blood to obtain PRP followed by washing and centrifuging the PRP in Tyrode's buffer to generate a homogenous preparation of platelets (Rousseau et al., page 4). Alternatively, Rousseau et al. teaches that blood can be drawn into a tube comprising the anticoagulant acid citrate dextrose (ACD) and then mixed with Tyrode's buffer at pH 6.5 prior to centrifugation to obtain the PRP (Rousseau et al., page 5). Rousseau et al. teaches that homogenous preparation of platelets were counted and then diluted at 100X10-6 platelets/ml with Tyrode's buffer pH7.4 containing 5mM CaCl2 and then stimulated by the addition of 1 mg/ml of heat aggregated human IgG (Rousseau et al., page 4). Rousseau et al. further teaches to stop the stimulation by addition of EDTA followed by centrifugation to obtain a pellet containing the platelet microparticles (EVs) (Rousseau et al., page 4). Rousseau et al. further teaches to store the MPs by freezing them at -80oC (Rousseau et al., page 4).
Rousseau et al. differs from the instant claims in that while Rousseau et al. teaches to store the MPs by freezing them at -80oC, Rousseau et al. does not teach to include a cryoprotectant, or more specifically a cryoprotectant which is a saccharide or polysaccharide. Bosch et al. supplements Rousseau et al. by teaching that the polysaccharide trehalose stabilized preparations of EVs from a variety of cells and further prevents acts as a cytoprotectant by preventing cryodamage including preserving the integrity of the EVs after freezing and thawing (Bosch et al., page 2). Therefore, based on the teachings and motivation provided by Bosch et al. that trehalose stabilizes EV preparations and acts as a cryoprotectant for EVs during freezing, it would have been prima facie obvious to the skilled artisan at the time of filing to include trehalose in the preparation of MPs for freezing at -80oC as taught by Rousseau et al. with a reasonable expectation of success.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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