DETAILED ACTION
Claims 1-14, 16, 20-25 and 28-31 pending. Claims 15, 17-19, 26-27 and 32 are cancelled.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Invention Group I (claims 1-14, 16 and 20-21) in the reply filed on May 29, 2026 is acknowledged.
Claims 22-25 and 28-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention Groups II and III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 29, 2026.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US2022/031107, filed May 26, 2022, which claims the benefit of provisional application No. 63/194,770, filed May 28, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/13/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The use of the terms Corning®, Costar®, SnapwellTM, for example, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1-14, 16 and 20-21 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.
Regarding claim 1 and the recited “first layer” comprising PLGA, claim 1 further recites the limitation “…and a fiber diameter of at least about 150 nm” which renders claim 1 indefinite since it is unclear if it is the PLGA component that is a fiber, or if the fiber is an additional component of the first layer.
Appropriate correction is appreciated.
In the interest of compact prosecution, the fiber having a diameter of at least about 150 nm is considered to be a fiber comprising PLGA. However, despite the above interpretation, such treatment does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action. The rejection to claim 1 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, stands and must be addressed.
Since each of claims 2-14, 16 and 20-21 depend directly or indirectly from claim 1 they each inherit the deficiency thereof, and thus are rejected on the same basis.
Further regarding claim 4, claim 4 recites the limitation “…wherein the PLGA has an average pore size of…” which renders claim 4 indefinite since it is unclear if the claim means the first layer comprising PLGA layer has the recited pore size, or if the recited “the PLGA” is an additional PLGA component.
Likewise, regarding claim 5, claim 5 recites the limitation “…wherein the PLGA has a fiber diameter of ….” which renders claim 5 indefinite since it is unclear if the claim means the first layer comprising PLGA comprises PLGA fibers having the recited diameter, or if the recited “the PLGA” is an additional PLGA component.
Claim 21 recites the term snap-well culture system. It is noted said limitation is a commercial cell culture insert. Snapwell is a trademark/trade name. 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 a tissue culture permeable support for cell culture and, accordingly, the identification/description is indefinite.
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.
Claim(s) 1 and 6-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Milosevic et al., (Scientific Reports (2020) 10:11126, 12 pages; previously cited) (“Milosevic 2020”).
Milosevic 2020 teach a fibrous scaffold comprising 3 layers of electrospun fibers, wherein a PLGA layer is sandwiched between two polycaprolactone (PCL) layers and the scaffold provides prolonged drug release properties (Abstract).
Regarding claims 1 and 6, Milosevic 2020 teaches the fibrous scaffold is prepared by sequential electrospinning, where the first and third layers are fabricated using poly(є-caprolactone) (PCL). The second layer was produced by emulsion electrospinning using Rhodamine B fluorescent drug and poly(lactic-co-glycolic acid) (PLGA 65:35, correlates to a ratio of 1.86:1 and thus lies within the claimed range) (see Materials and methods, Preparation of a three-layered fibrous scaffold produced via emulsion/sequential electrospinning, page 2). It is further noted that, although claim 1 recites the PLGA layer as a first layer and the PCL layer as a second layer, the recitation of first and second layers is not recited in a manner that limits the claim to any specific sequence of layers, merely that the scaffold must comprise a PLGA layer (as specified) and a PCL layer (as specified) and the PCL layer is attached to the PLGA layer. Therefore, given Milosevic 2020’s PLGA layer is attached to the PCL layer, Milosevic 2020’s scaffold reads on the first and second layers as claimed.
Furthermore, as illustrated in Figure 1, the PCL fibers form closed loops where overlapping fibers cross and contact each other, forming an enclosed loop structure and based on the 20 µm scale, numerous loops structures have a diameter of at least 5 µm (claim 6).
Figure 1 further illustrates the PLGA layer has pore sizes as large 20 µm (i.e., at least about 0.2 microns in diameter) and fiber diameters ranging from 1 to 4.5 µm (i.e., at least 150 nm). Figure 4a of Milosevic 2020 illustrates the PLGA layer has the approximate dimensions of 80 µm x 90 µm (i.e., at least 5 microns in height). Thus, Milosevic 2020 anticipates claims 1 and 6.
As to claim 7 and the limitation “wherein the second layer is attached to the first layer using electrospinning or chemical etching.”, it is noted said limitation is directed to the manner by which the scaffold has been produced. Such a limitation is a product-by-process limitation which appears to define the scaffold. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the scaffold layers have been attached is not sufficiently detailed so as to impart any unique structural/chemical properties to the scaffold. Thus, any scaffold as recited in claim 1 where a layer of PLGA and a layer of PCL are in contact with each other would appear to read on the claimed scaffold. As such instant claim 7 does not further limit claim 1, and thus is included in the rejection of claim 1.
It is noted however, that Milosevic teaches attaching the layers via sequential electrospinning (Abstract).
As to claim 8 and the limitation “wherein the electrospinning comprises:
an electric field voltage of at least 5 kV, a gas ejection pressure of at least 10 kPa, a working distance between nozzle and PLGA scaffolds of at least 10 mm, and at least 2 minutes of electrospinning time.”, said limitations are directed to the manner by which the scaffold has been produced via electrospinning. Such limitations are product-by-process limitations which appear to define the scaffold. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, if the product by process limitations are considered, the process imparts the feature of PLGA fibers.
Thus, any scaffold as recited in claim 1 where the layer of PLGA comprises PLGA fibers would appear to read on the claimed scaffold.
Milosevic at Figure 1 illustrates the PLGA layer comprises PLGA fibers, thus anticipating claim 8.
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(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020, as applied to claims 1 and 6-8 above, and further in view of DiFrancesco et al., (Journal of Controlled Release 319 (2020) 201-212; see PTO-892) (“DiFrancesco”).
The teaching of Milosevic 2020 is set forth above and anticipates claims 1 and 6-8.
Regarding claim 2 and the limitation the PLGA layer has a height of about 5 to 40 microns (µm), Milosevic 2020 teaches a complete PCL/PLGA/PCL scaffold wherein the PLGA layer is 160 µm (microns) thick, and the PCL layers are 200 µm thick (Numerical and experimental results of drug release, page 5). Milosevic does not further comment on the PLGA layer (first layer) having a thickness/height of about 5 to about 40 microns. However, DiFrancesco discusses that PLGA is the most extensively used polymer for biomedical applications, particularly as implants for delivery of therapeutic agents (Introduction, left col, page 201) and the success of PLGA is attributed to its biodegradability, limited toxicity, and tunable release profile (Introduction, left col, page 202). DiFrancesco specifically teaches fabricating PLGA scaffolds having heights ranging from 5 µm to 10 µm (Fig. 1). DiFrancesco teaches that drug release from a polymeric matrix is attributed to multiple mechanisms, with diffusion from the matrix core (via erosion) to the surrounding aqueous environment being a dominating factor that is affected by (1) the molecular weight(MW) of the drug, as diffusion decreases with MW, and the size of the pores in the polymeric matrix, as diffusion decreases with a more compact matrix; and (2) the progressive infiltration of water molecules into the polymer matrix which occurs over a longer time frame (weeks to months), thus higher polymer density (i.e.: PLGA mass for a given volume) would tend to reduce the
size of the pores within the matrix, increase the overall hydrophobicity of the system and consequently slow down the release process (page 208, left col, second paragraph).
DiFrancesco teaches that, for CURC-loaded PLGA (has lower affinity for PLGA), an increase in PLGA height was associated with increased release, and for DEX-loaded PLGA (has higher affinity for PLGA) an increase in height was associated with a slower release (page 206, right col, last line to page 208, left col first paragraph).
Thus, DiFrancesco has demonstrated that PLGA scaffolds having heights ranging from 5-10 µm have been successfully employed for therapeutic drug delivery.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the height of the PLGA layer of Milosevic 2020 for the predictable result of optimizing the amount/quantity of therapeutic drug to be delivered, thus meeting the limitation of claim 2.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Milosevic 2020 and DiFrancesco because each of these teachings are directed at using PLGA scaffolds for drug release.
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020, as applied to claims 1 and 7-8 above, and further in view of Milosevic et al (Materials 2018, 11, 2416, pages 1-17; see PTO-892) (“Milosevic 2018”).
The teaching of Milosevic 2020 is set forth above and anticipates claims 1 and 6-8.
Regarding claim 3, it is noted that Milosevic 2020 teaches PLGA 65:35 (correlates to a ratio of 1.86:1). Milosevic 2020 does not further comment on the use of PLGA 1:1 (i.e., 50:50). However, Milosevic 2018 is directed to implants comprising PLGA for controlled and sustained drug release, e.g., Rhodamine B (Abstract; 2.1 Materials).
Milosevic 2018 teaches PLGA has been well recognized for its suitability in drug delivery due to its good biocompatibility and ability to achieve complete drug release as a result of degradation and erosion of the polymer matrix. Milosevic 2018 prepared PLGA1 (PLGA 65:35) and PLGA2 (PLGA 50:50, correlates to) scaffolds, and it was shown that PLGA 50:50 (PLA/PGA) exhibited a faster degradation than PLGA 65:35 due to preferential degradation of glycolic acid proportion. Milosevic 2018 further teaches that PLGA 65:35 shows faster degradation than PLGA 75:25, and so does PLGA 75:25 compared to PLGA 85:15, i.e., the degradation rate increases with the glycolic acid proportion. Milosevic 2018 teaches the quantity of glycolic acid is a critical parameter in tuning the hydrophilicity of the matrix and, thus, the degradation and drug release rate (page 2, second paragraph).
Therefore, Milosevic 2018 has established it was known that PLGA scaffolds for drug release can be optimized for faster or slower degradation and release by tuning/optimizing the ratios of lactide/glycolide. Milosevic 2018 has shown that PLGA 50:50 (lactide/glycolide ration of 1:1) exhibited a faster degradation than PLGA 65:35 and Milosevic 2018 teaches the concentration of glycolic acid effects the result of degradation and drug release, thus the glycolide concentration is a results effective variable.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the ratio of lactide/glycolide to a ratio of about 1:1 in order to increase degradation and drug release.
The person of ordinary skill in the art would have been motivated to modify the lactide/glycolide ratio of Milosevic 2020 to a ratio of 1:1, as taught by Milosevic 2018, for the predictable result of successfully optimizing the scaffold in cases where faster drug release is required, thus meeting the limitation of claim 3.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Milosevic 2020 and Milosevic 2018 because each of these teachings are directed at fibrous scaffold implants comprising PLGA and useful for drug release.
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020, as applied to claims 1 and 6-8 above.
The teaching of Milosevic 2020 is set forth above and anticipates claims 1 and 6-8.
Regarding claim 4 and the limitation the PLGA has an average pore size of about 0.2 to 2 microns, it is noted that Milosevic 2020 does not specifically comment on average pore size regarding the PLGA layer. However, it is noted that Figure 1a illustrates the porosity of the PLGA layer wherein, based on the 20 µm scale, the pore sizes appear to include those ranging from as small as 0.5 µm to as large 20 µm. Thus, the claimed range overlaps the prior art range. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020, as applied to claims 1 and 6-8 above, and further in view of Xie et al., (Pharmaceutical Research, Vol. 23, No. 8, August 2006, pages 18171826; see PTO-892) (“Xie”), Wei et al., (RSC Adv, 2014, 4, 28011-28019; see PTO-892) (“Wei”) and Chen et al., (Fibers and Polymers 2012, Vol. 13, No. 9, 1120-1125; see PTO-892) (“Chen”).
The teaching of Milosevic 2020 is set forth above and anticipates claims 1 and 6-8.
Regarding claim 5, Figure 1 of Milosevic 2020 illustrates the PLGA fiber diameters ranging from 1 µm to 4.5 µm. Milosevic 2020 does not further teach fibers prepared at diameters ranging from 150 nm to 650 nm as recited in claim 5. However, it is noted that Xie is directed to PLGA electrospun scaffolds comprising micro- and nanofibers for use as implants for sustained drug delivery, specifically delivery of paclitaxel. Xie teaches fabrication of PLGA electrospun fibers having controllable diameters ranging from 30 nm to 10 µm (claimed range lies within the prior art range) (see Abstract).
Wei is directed to drug-loaded electrospun scaffolds comprising PLGA 50:50/gelatin. Wei teaches the mean fiber diameters were 430 nm, 400 nm and 370 nm corresponding to the PLGA/GE, DOX/PLGA/ GE and DOX@mZnO/PLGA/GE electrospun fiber scaffolds, respectively (Characterization of composite nanofibers, page 28014; Fig. 3). Wei’s Fig. 6 illustrates the sustained release of DOX (doxorubicin) and CPT (camptothecin) and Wei’s Fig. 7 further illustrates the antitumor effect for release of DOX and CPT against HepG-2 cells.
Chen is directed to exploring the influence of electrospun fiber diameter on drug delivery, specifically from electrospun poly(lactic acid) (PLA) (Abstract). Table 1 of Chen teaches fiber diameters ranging from 0.35 µm (350 nm) to 2.45 µm (claimed range overlaps the prior art range). Specifically, Drug F-4 fiber having a fiber diameter of 0.35 µm (350 nm), Drug F-3 having a fiber diameter of 0.53 µm (530 nm) and Drug F-2 having a fiber diameter of 0.73 µm (730 nm). Chen’s Figure 4 illustrates Drug F-2 (350 nm) having a higher release profile compared to Drug F-3 (530 nm) and Drug F-2 (730 nm), and Drug F-3 having a higher release profile as compared to Drug F-2 (730 nm). Thus, Chen has established that fiber diameter is a results effective variable and fiber diameter can be optimized to affect the drug release profile.
Therefore, taking into hand the teachings of Xie, Wei and Chen, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the fiber diameter to nanometer ranges known to be useful for promoting drug-release, including fiber diameters of 350 nm, 370 nm, 400 nm, 430 nm, or 530 nm in order to promote degradation and sustained drug release.
The person of ordinary skill in the art would have been motivated to modify the fiber diameter of Milosevic 2020 to a range of 350 nm to 530 nm, as taught by Wei and Chen, for the predictable result of successfully providing scaffolds that promote sustained drug release, thus meeting the limitation of claim 5.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Milosevic 2020 and Xie, Wei and Chen because these teachings are directed at electrospun fibrous scaffold useful for drug delivery.
Claim(s) 9, 11-14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020, as applied to claims 1 and 6-8 above, and further in view of Bulumulla et al., (Translational Vision Science & Technology, 2020; 9(6):18, pages 1-9; see PTO-892) (“Bulumulla”), as evidenced by CORNING (Surface Areas and Guide for Recommended Medium Volumes for Corning® Cell Culture Vessels, 4 pages, retrieved from the internet; see PTO-892) (“CORNING”).
The teaching of Milosevic 2020 is set forth above and anticipates claims 1 and 6-8.
Regarding claims 9 and 11 and the limitation the scaffold further comprises a coating of a cellular adhesion protein (claim 9) and the scaffold further comprises retinal pigment epithelial (RPE) cells, photoreceptor progenitor (PRP) cells, or both RPE cells and PRP cells (claim 11), it is noted that Milosevic does not further comment on the drug-release scaffold further comprising RPE cells or PRP cells. However, Bulumulla teaches of investigating the effects of esterified Rhodamine B on retinal pigment epithelial (RPE) cell uptake in order to understand the intracellular distribution of drugs into RPE cells since such property is critical for identifying potential ocular therapies for RPE-based diseases (Abstract). Bulumulla specifically seeds the RPE cells (ARPE-19 cells) on collagen I-coated culture substrate, i.e., a coating of a cellular adhesion protein (Quantification Experiments, page 3).
Thus, Bulumulla has established it was well-known that RPE cells can be successfully cultivated on a cellular adhesion protein and Rhodamine B is useful for investigating intracellular distribution of therapeutic agents into RPE cells since such property is critical for identifying potential ocular therapies for RPE-based diseases.
Therefore, it would have been obvious to further include RPE cells on the scaffold of Milosevic 2020, wherein the scaffold includes a coating of a cellular adhesion protein, thus permitting cell-adhesion and further investigating the disclosed scaffold for potential ocular therapies for RPE-based diseases, e.g., age-related macular degeneration (AMD).
The person of ordinary skill in the art would have been motivated to modify the Rhodamine B containing drug-release scaffold of Milosevic 2020 to include RPE cells, as taught by Bulumulla, for the predictable result of successfully investigating the intracellular uptake of Rhodamine B and the scaffolds potential for ocular therapies for RPE-based diseases, thus meeting the limitation of claim 11.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Milosevic 2020 and Bulumulla because these teachings are directed at using Rhodamine B for assessing therapeutic drug delivery.
Regarding claim 12, Bulumulla teaches successfully culturing the RPE cells at a density of 70,000 cells per 96-well (Quantification Experiments, page 3) and CORNING evidences the Costar 96-well plate disclosed by Bulumulla has a growth area of 0.32 cm2. Thus, Bulumulla’s cell density is initially 218,750 cells/cm2, i.e. at least 100,000 cells/ cm2. Thus, Bulumulla has established it was well-known that RPE cells can be successfully cultivated at densities of at least 100,000 cells/ cm2, thus meeting the limitation of claim 12.
Regarding claim 13 and the limitation the RPE cells are macular, central and/or peripheral RPE cells, it is noted that said limitation is directed to the source, i.e., manner by which the claimed RPE cells are produced. Such limitations are product-by-process limitations which appear to define the RPE cells. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the RPE cells have been produced is not sufficiently detailed so as to impart any unique structural/chemical properties to the RPE cells. If the product by process limitations are considered, the process appears to impart the feature of mature/differentiated RPE cells. Thus, any mature RPE cell would appear to read on the claimed RPE cells. As such instant claim 13 does not further limit claim 11, and thus is included in the rejection of claim 11. Bulumulla teaches human RPE cells, i.e., ARPE-19 cells.
Likewise, regarding claims 14 and 16, claims 14 and 16 further recite limitations directed to the manner by which the RPE cells are generated. As discussed immediately above, such limitations are product-by-process limitations which appear to define the RPE cells. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, if the product by process limitations are considered, the process appears to impart the feature of mature/differentiated RPE cells. Thus, any mature RPE cell would appear to read on the claimed RPE cells. As such instant claims 14 and 16 do not further limit claim 11, and thus are included in the rejection of claim 11.
Bulumulla teaches human RPE cells, i.e., ARPE-19 cells.
Claim(s) 10 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020 and Bulumulla, as evidenced by CORNING, as applied to claims 9, 11-14 and 16 above, and further in view of McHugh et al., (Invest Ophthalmol Vis Sci. 2014; 55:1754-1762; see PTO-892) (“McHugh”), as evidenced by Corning® Transwell® Permeable Supports, Polycarbonate (PC) Membrane (retrieved from the internet, 15 pages; see PTO-892) (“Transwell”).
The teaching of Milosevic 2020 and Bulumulla, as evidenced by CORNING is set forth above.
Regarding claim 10 and the limitation the cellular adhesion protein is vitronectin, laminin, fibronectin, or combinations thereof, it is noted that the Bulumulla taught use of collagen as the cellular adhesion protein and did not further teach using vitronectin, laminin, fibronectin, or combinations thereof. However, McHugh is directed to porous polycaprolactone (PCL) scaffolds for cultivation and transplantation of retinal pigment epithelial cells (RPE) for treatment of age-related macular degeneration (AMD) (Abstract, entirety; page 1754, right col, last paragraph to page 1755, left col, second paragraph). McHugh specifically teaches the PCL scaffolds are mounted on transwell inserts that have been coated with laminin (Cell culture, page 1755).
Thus, McHugh acknowledges that laminin coated substrates are suitable for promoting adhesion and cultivation of RPE cell-laden PCL scaffolds.
Therefore, it would have been obvious to further include laminin as an additional cellular adhesion protein.
Combination of multiple products (i.e. cellular adhesion proteins) each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
The person of ordinary skill in the art would have been motivated to modify the prior art scaffold to include laminin, as taught by McHugh, for the predictable result of successfully promoting adhesion and cultivation of RPE cells, thus meeting the limitation of claim 10.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of McHugh with the cited prior art because each of these teachings are directed at cultivation of RPE cells for ocular therapies.
Further regarding claim 20, Transwell evidences McHugh’s disclosed transwell inserts comprise non-biodegradable porous polycarbonate membranes, thus meeting the limitation of claim 20.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Milosevic 2020, Bulumulla, and McHugh, as evidenced by CORNING and Transwell, as applied to claims 10 and 20 above, and further in view of Bharti et al., (US 2019/0290803; see PTO-892) (“Bharti”), Clegg et al., (US 2015/0175964; see PTO-892)(“Clegg”) and Amirpour et al., (International Journal of Preventative Medicine, Vol 4, No 11, November 2013, pages 1243-1250; see PTO-892) (“Amirpour”).
The teaching of Milosevic 2020, Bulumulla and McHugh, as evidenced by CORNING and Transwell, are set forth above.
Milosevic teaches the scaffold of claim 1.
Bulumulla renders obvious the cultivation of RPE (committed RPE cells) cells on drug-release scaffolds for the purpose of investigating intracellular distribution of therapeutic agents into RPE cells since such property is critical for identifying potential ocular therapies for RPE-based diseases.
McHugh acknowledges that laminin coated substrates, i.e., transwell inserts, are suitable for promoting adhesion and cultivation of RPE cell-laden PCL scaffolds and McHugh’s disclosed transwell inserts comprise non-biodegradable porous polycarbonate membranes.
The combined prior art does not further teach a snap-well culture system, a PTFE O-ring, retinal induction media, retinal differentiation media, retinal maturation media, retinal media, pluripotent stem cells, RPE progenitor cells, committed RPE cells, immature RPE cells and PRP cells.
However, although McHugh teaches cultivation using transwell inserts, Bharti further teach successful cultivation of RPE cells on PLGA scaffolds using Snapwell or Transwell inserts ([0269]) and the Snapwells include a sterile Teflon (PTFE) O-ring so it is flush and watertight with the scaffold ([0270]).
Bharti is directed to tissue engineering for treatment of retinal degeneration, e.g., macular degeneration and teaches it has been demonstrated in animal models that photoreceptor rescue and preservation of visual function may be achieved by transplantation of retinal pigment epithelial (RPE) cells (Abstract; [0005], [0057]). Bharti further teaches the RPE cells are derived from pluripotent stem cells or induced pluripotent stem cells ([0045]; [0117]) and Bharti teaches the induced pluripotent stem cells can be derived from somatic cells including progenitor cells (RPE progenitor cells), fetal RPE cells (immature RPE cells), or adult RPE cells (mature RPE cells) ([0118]).
Furthermore, Clegg is directed to differentiation of pluripotent cells into retinal pigment epithelial (RPE) cells and notes such a process includes cell culture media formulations for efficient maintenance, propagation and maturation of the RPE cells (Abstract). Clegg teaches initiating RPE production by initially culturing the pluripotent cells commence culture in Medium 1 ([0049]) (i.e., retinal induction medium). Thereafter, the medium in the culture vessel is switched to Medium 2 and may take place as early as 24 hours after the commencement of culture in Medium 1 to as late as 3 days after commencement of culture in Medium 1 and may be made in response to the first detectable expression or significant upregulation of any of the retinal progenitor markers Pax6, Rax, Lhx2, Six3 ([0050]). Clegg further teaches that Medium 2 is then switched for Medium 3 (i.e., differentiation media) as early as Day 2 to as late as Day 6, and may be made in response to detection of any other molecular, physiological, or morphological markers of retinal progenitor specification ([0052]). Thereafter, Medium 3 is switched to Medium 4 (i.e., maturation media) as early as Day 5 to as late as Day 8 and the differentiating cells may be maintained in Medium 4 with media changes every other day [0054]). Clegg teaches that any time after Day 10 X-Vivo medium may be utilized for the continued maturation and expansion of the differentiated RPE cells ([0062]).
Amirpour teaches of developing an in vitro co-culture model of RPE cells with retinal progenitor cells in order to assess the effects of the close contact of RPE cells on generation of neural photoreceptors (Abstract and Co-culture of RPCs with retinal pigment epithelium, page 1247). Amirpour teaches there is a close interaction between retinal pigment epithelium (RPE) and photoreceptors produced by long apical microvilli that surround the outer-segments of photoreceptors (INTRODUCTION).
Therefore, taking into hand the teachings of Bharti, Clegg and Amirpour it would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to collect these items into a single kit for the predictable result of providing the components for cultivating RPE cells that are useful for treating retinal degenerative disease, e.g., macular degeneration, in convenient packaging for further investigating the scaffold for potential ocular therapies for RPE-based diseases, e.g., age-related macular degeneration (AMD), thus meeting the limitations of claim 21. One of ordinary skill in the art would have been motivated to modify the combined prior art in order to provide the components in a manner that is convenient for saving time and provides easier access to the composition components; thus one would have had a reasonable expectation of successfully collecting these items into a kit for the predictable result of providing the composition in convenient packaging.
Conclusion
No claim is allowed.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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