DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s response filed 7/28/2026 has been received and entered into the application file. All arguments have been fully considered. Claims 20-25, 28-31, 33-35 and 37-52 are currently pending. Claims 20 and 30 are currently amended. Claims 37-52 are new. Claims 1-19, 26-27, 32 and 36 are cancelled.
REJECTION(S) WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claim 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement:
Applicant’s amendment submitted 7/28/2026 has cancelled claim 36. Therefore, the previous rejection of record is withdrawn.
Claim Rejections - 35 USC § 103
RE: Rejection of Claims 20-25, 28-30 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Liu;
Rejection of Claim(s) 31 under 35 U.S.C. 103 as being unpatentable over Lu, in view of Liu, in view of Fonseca and WO 2019/198086;
Rejection of Claim(s) 34-35 under 35 U.S.C. 103 as being unpatentable over Lu, in view of Liu, in view of Pennington:
The rejections have been withdrawn in view of Applicant’s amendment positively reciting the crosslinking is performed after air-drying the scaffold material solution. Previously cited reference to Lu taught crosslinking prior to drying. However, new grounds of rejection are set forth below, addressing the newly amended limitation.
NEW GROUND(S) OF OBJECTION/REJECTION, NECESSITATED BY AMENDMENT
Claim Objections
Claim 42 is objected to because of the following informalities: typographical.
Claim 42 recites the phrase “and any combination thereof” twice at the end of claim 42.
Further regarding claim 42, it appears the word “designed” should be “designated”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 52 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 52 recites the following:
52. The method of claim 20 wherein the method does not comprise a step of vacuum desiccation.
The limitation that the method does not comprise a step of vacuum desiccation
is not supported by the original disclosure; therefore, the limitation that the method does not comprise a step of vacuum desiccation is considered new matter.
As set forth at MPEP 2173.05(i):
Any negative limitation or exclusionary proviso must have basis in the original disclosure. If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977) ("[the] specification, having described the whole, necessarily described the part remaining."). See also Ex parte Grasselli, 231 USPQ 393 (Bd. App. 1983), aff’d mem., 738 F.2d 453 (Fed. Cir. 1984).
In the instant case, the disclosure does not ‘reasonably convey’ to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date. Upon review of Applicant’s specification, a skilled artisan would not understand a negative limitation to necessarily be present in Applicant’s disclosure to support exclusion of a vacuum desiccation step.
The original disclosure discloses the following regarding ‘drying’:
[032] The above-mentioned biological and synthetic materials can be processed
by crosslinking, drying, molding, casting, printing, vitrification, polymerization, compression, freeze-drying, laser ablation, laser patterning, melting, evaporation,
condensation or a combination of the above.
[036] In some preferred examples, the scaffold is made by air drying a collagen
solution, followed by crosslinking and rehydrating steps, which is somewhat similar to the process disclosed in patent application IL 269671, which relates to corneal endothelial cells, and not retinal pigment epithelium (RPE) cells; however, there are significant/non- trivial differences in the methodologies and use. Such as collagen source/type; thickness; concentration; crosslinker; crosslinking conditions; and thickness of the scaffold.
[037] The step of air drying the collagen is done by adding a predefined volume
of aqueous collagen solution to a mold, setting the desired environmental conditions, such as humidity, temperature, gas composition, gas flow rate and direction, and light radiation, and letting the solution dry for a predefined period of time.
[040] To produce the crosslinked, rehydrated collagen scaffolds, a controlled
environment during the drying process is used, which may include a 10%-99% relative humidity, air flow, 4 - 40-degree Celsius temperature range; and gas composition.
Additionally, an appropriately designed drying mold is required to produce a suitable and uniform scaffold, the mold having wetting properties that may be hydrophilic surface or having a hydrophobic surface; e.g. made of glass; plastic, such as PTFE; metal; ceramic, or combination thereof, and made of one or more parts. The mold may comprise coatings thereon. The mold may have a wide range of geometries (flat, concave, convex, etc.) that can be beneficial for interfacing. The mold may also be designed (e.g. with a nozzle, inlet tube or the like) to allow and/or support and/or direct air or gas flow to aid in the drying process.
The only reference to vacuum is in regard to using vacuum sockets for removal of the dried collagen from the mold if the scaffold adheres to the mold surfaces ([043]).
Thus, the original disclosure does not comment on any step of vacuum desiccation. The limitation that the method does not comprise a step of vacuum desiccation was introduced in new claim 52, added on 7/28/2026.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). Applicant is required to cancel the new matter in the reply to this Office Action.
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 38-39, 43, 47, 49 and 50 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 39, it is noted the term “slow-release” is a relative term which renders the claim indefinite. The term “slow-release” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the metes and bounds of the time period for releasing of the additional active substances is unclear.
Regarding claim 47, it is noted claim 47 indicates the cooling step to cryogenic temperatures is performed in the middle of the maturation period, however the term “middle” is a relative term which renders the claim indefinite. The term “middle” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification at [055] indicates that maturation can take place between 1 and 30 days of incubation and [059] notes there is a secondary maturation period that can take place anytime between 1 and 5 days. The specification at [064] discloses that maturation can take place anytime between 3 to 60 days, or maturation can take place between 21-28 days.
Thus, the metes and bounds of the “middle” of the maturation period is unclear in view of the numerous maturation time periods.
Further regarding claim 47 and the limitation “the maturation period”, it is noted there is insufficient antecedent basis for this limitation in the claim since claims 20 and 46 from which claim 47 depends, do not recite the phrase “a maturation period”.
Regarding claim 49, it is noted claim 49 indicates a step of slowly thawing said retinal graft, however the term “slowly” is a relative term which renders the claim indefinite. The term “slowly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification at [059] merely indicates “When needed, the graft can be slowly thawed…” and does not specifically define the time period encompassing “slowly”.
Thus, the metes and bounds of the time period encompassing “slowly thawing” is unclear.
Further regarding claim 38 and the limitation “…said RPE cells are positioned separately within the scaffold…”, it is noted this limitation renders the claim indefinite since it is unclear in what manner the cells are separately positioned. Does the claim mean that single cells are deposited in separate locations from each other and are not in physical contact with each other, or does the claim mean that clusters of cells are positioned at different locations from each other on the scaffold, or does the claim mean the cells are positioned separately from other components of the scaffold material?
Regarding claim 43, it is noted the limitation directed to air-drying said scaffold layer post (after) said step of crosslinking the thin scaffold layer renders the claim indefinite since claim 20, from which claim 43 depends, requires air-drying the scaffold layer before the step of crosslinking. Thus, it is unclear as to how the already dried scaffold is dried again after crosslinking.
Regarding claim 50, and the limitations “the PR layer” and “the native RPEs layer”, it is noted there is insufficient antecedent basis for these limitations in the claim since claim 20, from which claim 47 depends, does not recite the phrases “a PR layer” or “a native RPEs layer”.
It is further noted the limitation “to ensure the cells are positioned toward the PR layer after implantation, and not toward the native RPEs layer” is unclear as to the recited “the cells”. Does the limitation “the cells” refer to the seeded RPE cells or to additional cells, such as PR cells, seeded to the scaffold.
Appropriate clarification is appreciated.
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.
Claims 20-25, 28-30, 33, 39-43 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al., (Biomaterials 28 (2007) 1486-1497; see; previously cited) (“Lu”), in view of Doillon et al., (US Patent No. 7,476,398; see PTO-892) (“Doillon”), as evidenced by Interceptor® Vertical Laminar Flow Clean Bench (User & Operation Manual, 34 pages, March 2016, retrieved from the internet; see PTO-892) (“Interceptor”).
Lu is directed to the preparation of thin (e.g., 2 or 10 µm thick, claimed range overlaps the prior art range) collagen film scaffolds that mimic Bruch’s membrane, and are useful for retinal epithelial cell culture since collagen films have been used for implantation as surgical grafts (i.e., retinal graft) (Abstract).
Regarding claim 20 Lu, at 2.1 Preparation of collagen sheets, exemplifies: preparing collagen sheets comprising Vitrogen 100 collagen. The Vitrogen 100 collagen solution (3 mg/ml) was mixed in a 1:2 ratio with Dulbecco’s Phosphate Buffered Saline (DPBS) (i.e., preparing a scaffold material solution), the pH was adjusted to 7.0 and 0.75 ml of the collagen solution was subsequently pipetted into acrylic rings (1.9 cm in diameter and 1 cm in height) for a final liquid height of 2.5 mm. The films were cross-linked under a 254 nm UV lamp for 3.5 h (i.e., crosslinking the thin scaffold layer) and then vacuum-desiccated for 48 h with fresh Drierite (i.e., drying the scaffold material to form a thin scaffold). After desiccation, the collagen films were semi-hydrated (i.e., rehydrating the scaffold layer), cut to remove from the acrylic mold, sterilized under UV light prior to seeding of cells. Lu, at 2.2 Cell culture, teaches seeding ARPE-19 cells (retinal pigment epithelial cells) at a density of 90 cells/mm2 and cultured, wherein experiments were performed after 7-25 days of culture (i.e., applying retinal pigment epithelium (RPE) cells onto the scaffold layer, thereby providing a retinal graft). Lu teaches the thickness of the collagen films was under 5 µm (5. Conclusion) and averaged 2.4 µm (3.1 Film characterization, page 1489) (i.e., claimed range overlaps the prior art range).
Further regarding claim 20 and the limitations “air-drying the scaffold material” and “wherein crosslinking is performed after air-drying the scaffold material solution”, it is noted that Lu conducts crosslinking before vacuum desiccation drying and does not further comment on air-drying and crosslinking after air-drying.
However, Doillon is directed to thin biopolymer (e.g., collagen) membranes used as a cell supports for corneal implants (Abstract and col 3, lines 3-21) and said membranes are chemically crosslinked with EDC (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide) and NHS (N-hydroxysuccinimide) (col 3, lines 25-32; col 4, lines 12-15).
Example 3 (col 9) of Doillon teaches preparing the crosslinked membranes wherein a collagen solution and pNIPAAm polymer solution are mixed (1:1 vol/vol) with a 10% stock solution of EDC. The mixture is poured into a plastic dish or a mold and left to air dry under sterile conditions in a laminar flow hood for at least 2-3 days at room temperature. Upon air-drying to a constant weight, the collagen is crosslinked. Thus, Doillon teaches successfully crosslinking after air-drying the collagen containing scaffold. Doillon further teaches the air-dried and crosslinked membrane is suitable for supporting epithelial cells.
Thus, Doillon has established it was well-known that thin collagen containing membranes useful as cell supports could be successfully crosslinked after air-drying the scaffold.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to conduct crosslinking after air-drying the scaffold since Doillon teaches that collagen scaffolds that have been crosslinked after air-drying are suitable for supporting epithelial cells and successfully implanted to the eye. One of ordinary skill in the art would recognize this as simply substituting one type of crosslinking for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Additionally, it is noted that the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (see In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), MPEP 2144.04 (IV)(C)).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Doillon because each of these teachings are directed at tissue engineering ocular implants comprising collagen scaffolds.
Further regarding claim 20 and the limitations directed to the crosslinking step comprises introducing EDC (1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide) and NHS (N-hydroxysuccinimide) to the scaffold material solution, it is noted Doillon teaches crosslinking comprises introducing EDC (1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide) and NHS (N-hydroxysuccinimide) to the scaffold material solution (col 3, lines 25-32 and col 4, lines 12-15).
Regarding claims 21 and 22, claims 21 and 22 are directed to culturing, i.e., maturing, the retinal pigment epithelial cells for at least one week (claim 21), and at least three weeks (claim 22).
Lu teaches culturing, i.e., maturing, the seeded cell scaffolds for 9 and 25 days prior to immunohistochemistry analysis, thus meeting the limitations of claims 21-22.
Regarding claim 23, Lu teaches using Vitrogen 100 collagen (bovine collagen), thus meeting the limitation of claim 23.
Regarding claims 24-25, it is noted that Lu teaches using Vitrogen 100 collagen solution (bovine collagen) and does not further comment on sourcing the collagen from human collagen (claim 25), or human recombinant collagen (claim 24). However, Doillon, as discussed above, further teaches the thin membrane comprising collagen includes collagen that is human collagen and includes recombinant collagen (col 3, lines 15-20).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute human recombinant collagen for Vitrogen 100 collagen since both types of collagens are known for preparing bioengineered tissue scaffolds for ocular implantation. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of collagen for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Regarding claim 28, Doillon teaches drying is performed for 2-4 days (col 7, lines 53-58). 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
Regarding claim 29, Doillon teaches the drying surface included a mold (col 4, lines 12-15), thus the drying step comprised drying in a mold, thus meeting the limitation of claim 29.
Regarding claim 30, Lu teaches applying the retinal pigment epithelial cells onto the scaffold layer by seeding (2.2 Cell culture), thus meeting the limitation of claim 30.
Regarding claims 33 and 44, Lu teaches cutting the collagen scaffolds from the acrylic rings having a diameter of 1.9 cm (2.1 Preparation of collagen sheets), thus meeting the limitation of claims 33 and 44.
Regarding claim 39, it is noted that Lu teaches that the collagen membranes support nutrient flow through the membrane to the RPE layer (4.1 Feasibility of collagen I as a replacement for Bruch’s membrane, second paragraph, page 1491) and given that Lu teaches culturing of the ARPE-19 cells on the collagen membranes is conducted using culture medium DMEM/F12 that contains penicillin-streptomycin (2.2 Cell culture, page 1487), it is considered the additional active substances within the collagen scaffolds includes the culture medium that contains the antibiotics penicillin-streptomycin, thus meeting the limitation of claim 39.
It is additionally noted that Doillon teaches a variety of agents, e.g., drugs, can be introduced during the making of the membranes (Example 5).
Regarding claim 40, Example 3 of Doillon teaches the step of crosslinking is conducted at room temperature (15-22° C; col 7, lines 57-58), and after drying, crosslinks are formed, thereafter the membranes are removed from the mold for soaking in sterile buffered solution. Thus, it is reasonable to consider the crosslinking takes place within a time period of 1 minute to 24 hours, prior to removal from the mold and subsequent soaking.
Regarding claim 41, Example 3 of Doillon teaches the step of air-drying the collagen membranes is conducted in a laminar flow hood and by setting the environmental condition of temperature at room temperature (15-22° C; col 7, lines 57-58) and relatively constant humidity (Example 1).
Interceptor evidences that standard operating humidity in laminar flow hoods ranges from a relative humidity of 10% to 70% (Chapter 4, VLF Clean Bench Operation, page 4.1).
Thus, Doillon’s teaching meets the limitations of claim 41.
Regarding claim 42, Lu teaches drying takes place in an acrylic (plastic) mold that was placed on Teflon tape (2.1 Preparation of collagen sheets) and Doillon teaches the drying surface is plastic (Example 3), thus meeting the limitation of claim 42.
Regarding claim 43, Lu teaches drying can be conducted after crosslinking.
Regarding claim 52, Doillon teaches air-drying in a laminar flow hood and does not teach a step of vacuum desiccation.
Claim(s) 31 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Doillon, as applied to claims 20-25, 28-30, 33, 39-43 and 52 above, and further in view of Fonseca et al., (Chemical Reviews, Vol 120, Issue 19, 11093-11139, September 16, 2020; see; previously cited) (“Fonseca”) and WO 2019/198086 (published 17 October 2019; IDS 8/2/2023, previously cited) (“WO ‘086”).
The teaching of Lu, in view of Doillon is set forth above.
Regarding claim 31, Lu teaches applying the cells to the scaffold by manually seeding. Lu does not further comment on seeding of the cells using laser-induced forward-transfer (LIFT) technology. However, Fonseca is directed to an article discussing the generation of 3D cellular constructs using precise spatial positioning of cells using bioprinting technologies to engineer artificial tissue models for personalized medicine, human organogenesis, and for disease and drug screening efforts (Abstract). Figure 3 of Fonseca illustrates a variety of different irradiation techniques used in vat photopolymerization of tissue scaffolds, including LIFT (i.e., laser-induced forward-transfer, synonymous with laser-assisted bioprinting). Fonseca further teaches that, although LIFT is a less commonly applied form of bioprinting for in vitro tissue models, LIFT is viewed as one of the technologies developing fastest in the tissue engineering field. Fonseca further describes how the cells to be bioprinted are combined with hydrogel material and then deposited on a metal film. Fonseca teaches optimization of the intensity and extent of laser exposure in order to yield constructs with much greater cell viability (2.4. Laser-Assisted Bioprinting, page 111000).
WO ‘086 is directed to preparing bioengineered corneal grafts comprising crosslinked collagen methacrylate scaffolds that are further seeded with endothelial cells (i.e., bioink) using printing technology (Abstract; [0008]-[0010], [0117]-[0118]; FIG. 1).
WO ‘086 teaches the step of depositing the cells (i.e., bioink) is performed by Laser-Induced Forward Transfer (LIFT) printing ([0085], [0090], [0139] and [0143]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute Laser-Induced Forward Transfer (LIFT) printing for manual cell seeding since both techniques are known for delivering cells to bioengineered scaffolds. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of cell seeding technique for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Additionally, given that Fonseca teaches LIFT cell seeding uses precise spatial positioning of cells to engineer artificial tissues, one would be motivated to substitute LIFT cell seeding for manual cell seeding for the predictable result of delivering cells to precise positions on the scaffold.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu with Fonseca and WO ‘086 because each of these teachings are directed at tissue engineering.
Claim(s) 34-35, 37-38 and 45-49 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Doillon, as applied to claims 20-25, 28-30, 33, 39-43 and 52 above, and further in view of Pennington et al., (US 2020/0077641; previously cited) (“Pennington”).
The teaching of Lu, in view of Doillon is set forth above.
Regarding claims 34-35, 37-38, 46-47 and 49, Pennington is directed to cryopreservation of cell-seeded (e.g. retinal pigment epithelial (RPE), photoreceptor(PR) cells) substrates (i.e., cooling said retinal graft to cryogenic temperatures, claim 46) (Abstract; [0012], [0067]; FIG. 1; claim 20) Pennington teaches cryopreservation of the cell-seeded substrates allows for long-term storage and later use in cell therapy after thawing of the cell-seeded construct ([0011]; [0013]). Pennington teaches cryopreserving of the RPE cells that are seeded on a substrate when optimal characteristics are achieved, which are observed between 2 and 10 days after seeding (i.e., middle of maturation period, claim 47) and include over 50% of the cells having a cobblestone morphology ([0067]).
Pennington teaches thawing by warming the cell seeded substrate to a target temperature using a temperature ramp-up heating rate (i.e., slowly thawing) to obtain thawed cells seeded on the substrate, and subsequently culturing (i.e., incubating, maturation incubation) the cell-seeded substrate for an additional period of time, e.g., 5-10 days (i.e., secondary maturation incubation period of 1-5 days, claim 49), to reach a mature state prior to implantation (i.e., thawed for further maturation, claims 34 and 47) ([0020] and [0076]).
Pennington, at FIG. 12, further illustrates attaching or integrating photoreceptor cells to the RPE cells, wherein the RPE cells are arranged as a monolayer with physical connection and biological interactions between the RPE cells (claims 37-38).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to include cryopreserving the graft in the middle of maturation and comprising RPE cells and PR cells, subsequently slowly thawing and culturing (incubating, secondary maturation incubation period) to promote further maturation prior to implantation since Pennington teaches cryopreservation of the cell-seeded substrates allows for long-term storage and later use in cell therapy ([0011]; [0013]).
The person of ordinary skill in the art would have been motivated to modify the method of Lu to include cryopreserving the graft, subsequently slowly thawing and culturing (incubating, maturation) prior to implantation, as taught by Pennington, for the predictable result of successfully permitting fabrication and long-term storage of cell-seeded scaffolds suitable for ocular implantation, thus meeting the limitation of claims 34-35, 37-38, 46-47 and 49.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Pennington because each of these teachings are directed at tissue engineering ocular implants comprising RPE cells.
Regarding claim 45 and the limitation “wherein said RPE cells are allowed to settle and attach to the scaffold for approximately 0.5 to 6 hours”, it is noted that Pennington teaches that, when two cell layers are grown on the first substrate layer simultaneously, with the first cell layer of RPE cells being seeded onto the substrate first and the second cell layer of photoreceptors being seeded onto the substrate on top of the RPE cells at a subsequent time, the photoreceptor cells are seeded approximately 1 to 10 days after the seeding of the RPE cells in order to allow the RPE cells the appropriate time to adhere to the substrate before the photoreceptor cells are added ([0057]).
Although Pennington does not teach the time period for adhering of the RPE cells is 0.5 to 6 hours Pennington recognizes that a brief time period, e.g., 1 day/24 hours, for RPE adherence is necessary to permit the RPE cells to adhere first to the substrate, before the PR cells are added, and thus the time period parameter is recognized as a result-effective variable which achieves the recognized result of permitting the RPE cells to time to adhere to the substrate before PR cells are added. It would be obvious to one of ordinary skill that, in cases where fewer RPE cells are seeded, less time (0.5 to 6 hours) would be sufficient for RPE cells to settle and attach to the substrate as there would be greater surface area of the substrate available for RPE attachment. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). It would therefore have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to modify the prior art method to optimize the time period for RPE cells to settle and attach first to the substrate to achieve the predictable result of permitting RPE cells time to adhere to the substrate before PR cells are added.
Regarding claim 48, Pennington further teaches conducting a cryo-hibernation protocol wherein, following initial controlled temperature ramp-down phase, and once the temperature is below the latent heat release (0° C to −20° C), the cells are placed/held at temperatures below the latent heat release temperature, including -80°C (i.e., placing in a -80°C freezer), for a time period of 12 hours to 28 days in order to acclimate the cells to a cryopreserved stated thus preventing microtears from forming in the substrates ([0093]-[0094]), thus meeting the limitation of claim 48.
Claim(s) 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Doillon, as applied to claims 20-25, 28-30, 33, 39-43 and 52 above, and further in view of Sadeer B. Hannush (Perfecting Posterior Corneal Grafts, Review of Ophthalmology, September 2016, 9 pages, retrieved from the internet; see PTO-892) (“Hannush”) and Kristine Brennan (DMEK: New Insights, Emerging Advances, Review of Ophthalmology 2018, 9 pages, retrieved from the internet; see PTO-892) (“Brennan”).
The teaching of Lu, in view of Doillon is set forth above.
Hannush teaches that one way to achieve the correct orientation of a tissue implant is the marking method, wherein the stromal side of the implant is marked with a letter S to aid in subsequent placement in the eye. The marking is made by a stamper that is colored with a gentian violet surgical pen (page 4 of 9, Unscrolling the tissue and achieving successful tamponade).
Brennan further teaches that one of the main causes of graft failure is an upside-down graft, however marking a graft with an ‘S’ or an ‘F’ helps avoid that complication and the S-stamp saves time and gives the surgeon confidence that what they’re doing is correct. The stromal side is stamped with an ‘S’ so when you’re looking at it, if you see the letter ‘S,’ the graft is oriented correctly, thus eliminating the number-one cause of graft failure: putting a graft in upside down (Preloaded Tissue, pages 2-3 of 9).
Thus, taking into hand the teachings of Hannush and Brennan, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include marking the retinal graft by staining with a gentian violet marking to differentiate the orientation of the graft, thus meeting the limitations of claims 50-51.
The person of ordinary skill in the art would have been motivated to modify the method of the prior art to include markings the easily identify graft orientation, as taught by Hannush and Brennan, for the predictable result of avoiding graft failure due to an upside-down graft.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu, in view of Doillon, with Hannush and Brennan because each of these teachings are directed at ocular grafts.
Response to Remarks
Rejection(s) under 35 USC 103:
As set forth above, Applicant’s amendment submitted 3/16/2026 has amended claim 1 to now require the limitations previously recited in claim 26 (now cancelled). As discussed in the previous Office action, Lu did not teach crosslinking comprising introducing EDC and NHS molecules to the scaffold material solution. Therefore, the previous rejection under 35 USC 102(a)(1) has been withdrawn. However, Applicant’s amendment has necessitated new grounds of rejection as set forth below.
Applicant has traversed the rejection of record on the grounds that claim 20 requires the drying step is performed prior to crosslinking, and the cited reference to Lu teaches drying is conducted after crosslinking, as discussed at Applicant’s remarks (page 8).
Applicant’s remarks have been carefully considered, but are not found persuasive given that there are no additional limitations as to the order of steps. Listing of the method steps does not impart that the steps are performed in that order. See MPEP 2144.04 IV C and 2111.01 (II). MPEP 2144.04 IV C notes "selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results " In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), and MPEP 2111.01 (II) indicates it is improper to import claim limitations from the specification.
Additionally, it is noted that Applicant has provided no evidence of new or unexpected results regarding the order of steps.
As to Applicant’s remarks regarding the limitation of air drying and Lu’s teaching of drying by vacuum-desiccation for 48 h with fresh Drierite, said drying technique exposes the scaffold to air, absent evidence to the contrary.
As to Applicant’s remarks regarding the cited reference to Fonseca, cited to address claim 31 and the limitation regarding seeding of the cells using laser-induced forward-transfer (LIFT) technology, Applicant has traversed the rejection of record on the grounds that Fonseca teaches additional seeding options but does not point to a specific reason or technological advantage to choose LIFT over the other disclosed options for seeding of cells, as discussed at Applicant’s remarks (page 8).
Applicant’s remarks have been carefully considered, but are not found persuasive.
In response, it is noted, as discussed in the previous rejection of record,
Fonseca taught that LIFT is viewed as one of the technologies developing fastest in the tissue engineering field and Fonseca teaches the intensity and extent of laser exposure can be optimized in order to yield constructs with much greater cell viability (2.4. Laser-Assisted Bioprinting, page 111000).
Moreover, regarding Applicant’s remarks that Fonseca teaches multiple bio-printing options, the optional seeding techniques cited in Fonseca are a finite number of identifiable techniques that are well known, predictable options in the bio-printing arts.
As noted in KSR International Co. v Teleflex, Inc., 82 USPQ2d 1385, 1397 (U.S. 2007), “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.”
As to Applicant’s remarks that Fonseca teaches away from LIFT bio-printing since it is recognized the technique exposes cells to high thermal energy, as discussed at Applicant’s remarks (page 8), Applicant’s remarks have been carefully considered, but are not found persuasive.
In response, it is noted that a reference may be relied upon for all that it would have necessarily suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). MPEP 2123(I)
Furthermore, it is noted that the prior art teaches away “when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken” in the claim. Galderma labs., L.P. v Tolmar, Inc., 737 F.3d 731, 728 (Fed. Cir. 2013). In the instant case, Fonseca provides the skilled artisan the knowledge to optimize and adjust the LIFT parameters of laser intensity and extent of laser exposure in order to improve cell viability, which does not discourage one from following the path and instead informs one of appropriate modifications to successfully carry out the technique.
As to Applicant’s remarks regarding the rejection of claims 34-35, as discussed at Applicant’s remarks (page 9), Applicant’s remarks have been fully considered, but are not found persuasive.
In response, Applicants rely on the arguments used in traversing the rejection of claims 20-25, 28-30 and 33, relying on Lu et al, to also traverse this rejection without additional arguments. However, as explained above, the previous rejection stands. Therefore, the response set forth above to arguments also applies to this rejection.
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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