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 .
Claim Status
1. The amendment filed 01/21/2026 has been entered. Claims 1, 3 – 7, 9 – 20, and 22 – 25 remain pending. Claim 21 has been canceled. Claims 1, 3 – 6, and 22 – 25 are under consideration.
Priority
2. This application claims the benefit of the filing date of U.S. provisional application 63/211,906 filed on 06/17/2021.
Election/Restrictions
3. Applicant’s election without traverse of Group I (claims 1 – 6) in the reply filed on 10/02/2023 is acknowledged.
4. Claims 7 – 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/02/2023.
Withdrawn Claim Objections
5. The objections to claim 1 are withdrawn in view of Applicant’s amendment to the claim.
6. The objection to claim 25 is withdrawn in view of Applicant’s amendment to the claim.
Withdrawn Duplicate Claims Warning
7. The duplicate claims warning is withdrawn in view of Applicant’s cancellation of claim 21.
Withdrawn Claim Rejections
8. The rejection of claims 1, 3 – 6, and 22 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
9. The rejection of claim 21 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancelation of the claim.
10. The rejection of claim 23 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
11. The rejection of claim 24 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
12. The rejection of claim 25 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
13. The rejection of claim 21 on the ground of nonstatutory double patenting as being unpatentable over claims 20 – 36 of U.S. Patent No. 12257365 is rendered moot in view of Applicant’s cancellation of the claim.
14. The rejection of claim 21 on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 18 of copending Application No. 18558837 is rendered moot in view of Applicant’s cancellation of the claim.
15. The rejection of claim 21 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24 and 27 – 31 of copending Application No. 19278964 is rendered moot in view of Applicant’s cancellation of the claim.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
16. Claims 1, 3 – 6 and 22 – 25 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20 – 36 of U.S. Patent No. 12257365. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by patent claims 20 and 29.
Patent claim 20 recites a composition for corneal transplantation comprising a Descemet’s Membrane Endothelial Keratoplasty graft. Patent claim 27 recites an injector comprising the composition of claim 20. Patent claim 29 recites a composition for corneal transplantation comprising a Descemet’s Membrane Endothelial Keratoplasty graft. Patent claim 36 recites an injector comprising the composition of claim 29. Therefore, patent claim 20 and 29 are in essence a “species” of the generic invention of instant claim 1 that recites broadly a genus of “a corneal graft” and “a modified Jones tube or tissue injector”. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention.
17. Claim 1, 3 – 6, and 22 – 25 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 18 of copending Application No. 18558837 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by copending claims 1.
Copending claim 1 recites a graft injector assembly. Instant claim 1 recites a corneal graft carrier comprising a modified Jones tube or tissue injector. Therefore, copending claim 1 is in essence a “species” of the generic invention of instant claim 1 that recites broadly a genus of “a corneal graft carrier”. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18. Claims 1, 3 – 6, and 21 – 25 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24 and 27 – 31 of copending Application No. 19278964 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by copending claim 24.
Copending claim 24 recites a composition comprising an isolated Descemet’s Membrane. Instant claim 1 recites a corneal graft carrier comprising a corneal graft. Therefore, copending claim 24 is in essence a “species” of the generic invention of instant claim 1 that recites broadly a genus of “a corneal graft”. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Interpretation
19. For the purpose of applying prior art, “resazurin” of claims 5 and 24 will be interpreted as comprising Alamar Blue as Applicant’s specification states that “Alamar blue cell viability reagent is an exemplary ready-to-use resazurin-based solution” (page 10, lines 15 – 16; page 4, lines 1 – 5).
20. For the purpose of applying prior art, claim 5 is interpreted as the fluid solution of claim 1 comprises Alamar Blue.
Rejections Necessitated by Amendment
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.
21. Claims 1, 3 – 6 and 22 – 25 are rejected under 35 U.S.C. 103 as being unpatentable over Schallhorn (Schallhorn, Julie M., et al. Cornea 35.3 (2016): 377-382; previously cited), hereinafter Schallhorn which is cited on the IDS filed 01/24/2024 in view of Binner (US-20220183818-A1; Filed 02/20/2020; Published 06/16/2022; previously cited), hereinafter Binner in view of Haggins (US-10443032-B2; Filed 04/19/2017; Published 10/15/2019), hereinafter Haggins in view of Gloeckner (Gloeckner, Herma, et. al. Journal of immunological methods 252.1-2 (2001): 131-138; previously cited), hereinafter Gloeckner which is cited on the IDS filed 01/24/2024 as evidenced by O’Brien (O'Brien, John, et al. European journal of biochemistry 267.17 (2000): 5421-5426.), hereinafter O’Brien.
Regarding claim 1, 3, and 4, Schallhorn teaches a corneal graft tissue carrier comprising a first end and a second end (“corneal graft carrier comprising a lumen, a first end, and a second end” of claim 1) containing a corneal endothelial cell graft in a scroll configuration in the lumen of the carrier (“corneal graft in a conformation comprising a curved surface disposed within the lumen of the corneal graft carrier” of claim 1 and “corneal endothelial cell graft” of claim 3) and BSS (“fluid solution” of claim 1) or Optisol (“corneal preservation solution” of claim 4 and 23) (page 378, right col.; Figure 1; page 379, left col. para. 1; page 381, left col. para. 2 and right col. para. 3). Schallhorn does not teach “at least one perfusion assembly”, “at least one pump”, “at least one flow control valve”, “at least one fluid control valve” or “cell viability assay compound” of claim 1.
Regarding claim 6, Schallhorn teaches the modified Jones tube has an average volume of 0.41 ± 0.08 cm3 and the Viscoject has an average volume of 0.13 ± 0.004 cm3 (page 380, left col. last para.). Schallhorn teaches submerging the Viscoject cartridge into BSS, removing all air bubbles and loading the graft into the cartridge (page 378, right col. para. 2). Schallhorn teaches filling the modified Jones tube with BSS, removing air bubbles and drawing the graft into the tube (page 379, left col. para. 1). Therefore, Schallhorn teaches the fluid solution is present in a range of 200 µL to 400 µL.
Schallhorn does not teach “at least one perfusion assembly” comprising “at least one pump configured to pump fluid into the lumen of the corneal graft carrier via the first end”, “at least one flow control valve in fluid communication with the pump and the lumen of the corneal graft carrier and configured to regulate flow of fluid from the pump to the lumen of the corneal graft carrier via the first end”, “at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen of the corneal graft carrier” or “cell viability assay compound” of claim 1 or “resazurin” of claim 5 or “peristaltic pump” of claim 22 or “the concentration of resazurin is 40 µm to 100 µm” of claim 24 or the corneal graft carrier comprises a polymer coating of claim 25. However, Schallhorn teaches after injection into the carriers, the grafts were then injected onto a staining well and unfurled and stained with calcein (“cell viability assay compound”) and imaged to evaluate endothelial cell damage after passage through the carriers (page 379, left col. para. 2 – 4; Abstract). Schallhorrn teaches because the grafts were opened via manipulation with viscoelastic, this method may have induced a small amount of trauma and cell loss (page 381, right col. para. 3). Schallhorn teaches attaching a syringe to the modified Jones tube with connector tubing for filing the graft carrier with fluid and for suctioning the graft into the carrier (“fluid communication with the corneal tissue carrier lumen”) (page 379, left col. para. 1). Schallhorn teaches grafts injected with both injectors had cell loss that were not visible before injection and are likely due to contact zones between the endothelium and the injector wall as the graft passes through (page 380, left col. para. 1; Figure 3D). Schallhorn teaches a significant portion of cell loss during DMEK surgery would come from graft preparation and injection, which suggest that proportionately less cell loss is attributable to the intraocular manipulation of the graft (page 381, left col. para. 3). Schallhorn teaches specular techniques have an inherent bias to count cells suggesting that postpeel specular microscopy has limited utility in graft evaluation (page 381, left col. para. 4). Schallhorn teaches any fluid dynamics that might influence how the graft interacts with the injector were not accounted for (page 381, right col. para. 3).
Regarding “at least one perfusion assembly” comprising “at least one flow control valve” and “configured to regulate flow of fluid from the pump to the lumen of the corneal graft carrier via the first end” and “cell viability assay compound” of claim 1, Binner teaches a corneal tissue graft carrier (10 in Figure 11) with attached tubing in fluid communication with the lumen of the tissue graft carrier through the first end of the carrier (1 in Figure 2) and either a “Y” shaped 2-way extension line with tube clamps (27 in Figure 11) or a 3-way stopcock (“at least one flow control valve” and “configured to regulate flow of fluid from the pump to the lumen of the corneal graft carrier via the first end”) for washing and staining a tissue graft housed in the carrier (Figure 11; page 10, 0113; page 20, 0272; page 21, 0273 – 0275; page 3, 0019; page 10, 0113; page 4, 0023; page 21, 0276 – 0281). Binner teaches trypan blue (“cell viability assay compound” of claim 1) staining for quality control of the tissue graft and is especially used for ophthalmological interventions (page 10, 0115). Binner teaches due to cell toxicity issues, the tissue graft should not be exposed to trypan blue for a long time so the tissue graft is usually stained and washed prior to implantation (page 10, 0115). Binner teaches the staining and washing is most preferably performed in the graft carrier in order to decrease the tissue graft manipulation which could result in tissue graft damage (page 10, 0115). Binner teaches a washing assembly for washing and staining a tissue graft inside of the graft carrier prior to ejection (e.g. implantation into an eye) (page 10, 0113). Binner teaches the tube clams can be used to interrupt the flow inside a tube used in the washing assembly (page 11, 0134; page 12, 0156 – 0158; page 13, 0158 and 0161 – 0162). Binner teaches the 3-way stopcock is equipped with connections for attaching the graft carrier and syringes where one syringe is filled with BSS and another syringe is filled with staining solution (“fluid solution comprising a cell viability assay compound” of claim 1) (page 11, 0134 – 0136; page 12, 0155). Binner teaches the 3-way stopcock is adjusted for allowing filling the graft carrier with BSS or staining solution (page 12, 0156; page 13, 0158 and 0161 – 0162; page 21, 0273 – 0274). Therefore, Binner teaches a perfusion assembly (tubing and syringes) in fluid communication with the graft carrier lumen and regulation of flow of fluid into the lumen of the graft carrier via the first end with a flow control valve (3-way stopcock), but does not teach “at least one pump” of claim 1.
Regarding “ the corneal graft carrier comprises a polymer coating” of claim 25, Binner teaches the inner surface comprises a hydrophobic coating that may be a polymer coating that smooths the surface and prevents the implant to touch the surface while bien in solution (page 6, 0054 – 0058).
Binner does not teach “at least one pump” or “at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen of the corneal graft carrier” of claim 1 or “resazurin” of claim 5 or “peristaltic pump” of claim 22 or “the concentration of resazurin is 40 µm to 100 µm” of claim 24. However, Binner teaches in Figure 6 that the second end (4 in Figure 6C) of the carrier can be connected to tubing (5 in Figure 6B) that is in fluid communication with the second end of the carrier (2 in Figure 6) containing a graft (11 in Figure 6) (page 20, 0267). Binner teaches the current state of the art methods suggest graft handling by aqueous flow (“no touch”) (page 1, 0005). Binner teaches endothelial keratoplasty methods are widely used when the whole cornea does not need to be replaced but also results in graft rejection (page 1, 0003). Binner teaches success of transplantation surgery strongly depends on the quality of the graft (page 1, 0006). Binner teaches because of the high probability of transport-associated damage there is growing demand to evaluate the implant in the operating room prior to implantation in order to prevent implant miscarriage (page 2, 0006). Binner teaches new ways of graft processing, evaluation, delivery, and transplantation have to be developed (page 2, 0007). One would have been motivated to combine the teachings of Schallhorn and Binner because both teach “no touch” methods for manipulating the corneal graft in the corneal graft carrier using syringes and tubing and Schallhorn teaches the method for measuring cell viability may have induced a small amount of trauma and cell loss and Binner teaches a “no touch” method for determining cell viability.
Regarding “at least one pump” or “at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen of the corneal graft carrier” of claim 1 and “peristaltic pump” of claim 22, Haggins teaches a perfusion assembly comprising three peristaltic pumps (60, 60a, and 80 in Figure 14) (“at least one pump” of claim 1 and “peristaltic pump” of claim 22) and check valves (88 and 90) and a microcontroller (64 in Figure 14) that regulate the flow of fluid into and out of a device (8a in Figure 14) (“at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen of the corneal graft carrier” of claim 1) housing a cornea in a conformation comprising a curved surface disposed within the lumen of the device (col. 8, lines 12 – 25 and 52 – 67; col. 9, lines 1 – 27). Haggins teaches the peristatic pump (80 in Figure 14) is situated between the device housing the cornea and the collection tube (72 in Figure 14) and introduces a compression point in the tubing (70 in Figure 14) that when the pump is “off” fluid movement within the tubing is prevented thus blocking fluid spillage from the device housing the cornea to the collection tube or vice versa (col. 8, lines 14 – 25). Haggins teaches the perfusion assembly includes two reagent reservoirs (56 and 56a in Figure 14) that allow the delivery of two distinct reagents, one-at-a-time, via a “Y” type tubing connector (86 in Figure 14) (col. 8, lines 64 – 67; col. 9, lines 1 – 15). Haggins teaches the perfusion system allows for programmed delivery of each reagent (col. 9, lines 16 – 27). Haggins does not teach “resazurin” of claim 5 or “the concentration of resazurin is 40 µm to 100 µm” of claim 24. One would have been motivated to combine the teachings of Schallhorn, Binner, and Haggins because all three teach “no touch” methods of manipulating cornea grafts.
Regarding “resazurin” of claim 5, Gloeckner teaches monitoring cell viability using Alamar Blue (“resazurin” of claim 5) in a perfusion assembly where Alamar Blue is perfused using a peristaltic pump (page 132, left col. para. 1 – 3 and right col. para. 2; page 134, left col. para. 1; Figure 1). Gloeckner teaches if Alamar Blue is not removed from cells, it can cause growth inhibition (Abstract). Gloeckner teaches the bioreactor and pump allows Alamar Blue to be delivered to the cells where it is reduced and released from the cell into the medium compartment (Abstract). Gloeckner teaches the bioreactor/pump set-up minimizes handling steps since no cell sample needs to be taken for readout of viability and thus is a non-invasive way to monitor cell viability in a closed system (Abstract; page 137, right col. last para.). Gloeckner teaches Alamar Blue is regarded as non-toxic for corneal endothelial cells (page 137, left col. para. 2). Gloeckner teaches the Alamar Blue assay shows good correlation with trypan blue assay (page 132, left col. para. 2).
Regarding “the concentration of resazurin is 40 µm to 100 µm” of claim 24, Gloeckner teaches 2.5% AlamarBlue was perfused but also teaches additional AlamarBlue concentrations of 5%, 10%, and 20% based on the number of cells and that the method was optimized by varying the number of cells and the AlamarBlue concentration (page 132, right col. last para.; page 133, left col. para. 1; page 134, left col. para. 1 and right col. para. 1; Figure 3). A 10% AlamarBlue solution is approximately 44 µM and a 20% AlamarBlue solution is approximately 88 µM as evidenced by O’Brien (page 5423, left col. para. 1 – 2 ).
It would have been obvious prior to the effective filing date of the invention as claimed for the person or ordinary skill in the art to combine the teachings of Schallhorn regarding a composition comprising a corneal graft carrier comprising a lumen, a corneal graft comprising a curved surface in the carrier, and a fluid solution with the teachings of Binner regarding a corneal graft carrier for in-carrier washing and staining with a “Y” shaped 2-way extension line with tube clamps or 3-way stopcock and tubing connected to the graft carrier at the first end and tubing connected to the second end for fluid communication with the lumen of the corneal graft carrier with the teachings of Haggins regarding a cornea perfusion assembly comprising multiple peristaltic pumps, check valves, a “Y” connector, a microcontroller and multiple reagent reservoirs for regulating the flow of fluid into and out of the lumen of a lumen comprising a cornea in a curved conformation with the teachings of Gloeckner regarding a perfusion assembly for monitoring cell viability of cells in a lumen with Alamar blue to arrive at the claimed composition comprising a corneal graft carrier comprising a lumen, a first end, and a second end; at least one perfusion assembly in fluid communication with the corneal graft carrier lumen, the at least one perfusion assembly comprising; at least one pump configured to pump fluid into the lumen of the corneal graft carrier via the first end; at least one flow control valve in fluid communication with the pump and the lumen of the corneal graft carrier and configured to regulate flow of fluid from the pump to the lumen of the corneal graft carrier via the first end; and at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen of the corneal graft carrier; a corneal graft in a conformation comprising a curved surface disposed within the lumen of the corneal graft carrier; and a fluid solution comprising a cell viability assay compound. One would have been motivated to combine the teachings of Schallhorn, Binner, Haggins, and Gloeckner in a non-toxic composition to determine cell viability of corneal grafts for transplantation with minimal manual manipulation of the graft as Schallhorrn teaches because the grafts were opened via manipulation, this method may have induced a small amount of trauma and cell loss and Schallhorn teaches any fluid dynamics that might influence how the graft interacts with the injector were not accounted for and Binner teaches because of the high probability of transport-associated damage there is growing demand to evaluate the implant in the operating room prior to implantation in order to prevent implant miscarriage and Binner teaches new ways of graft processing, evaluation, delivery, and transplantation have to be developed and Binner teaches the current state of the art methods suggest graft handling by aqueous flow (“no touch”). One would have a reasonable success in combining the teachings as Binner teaches the staining and washing is most preferably performed in the graft carrier in order to decrease the tissue graft manipulation which could result in tissue graft damage and Haggins teaches the assembly includes multiple reagent reservoirs and allows for programmed delivery of two distinct reagents, one-at-a-time, and Gloeckner teaches perfusion assembly minimizes handling steps since cells do not need to be taken for readout of viability and thus is a non-invasive way to monitor cell viability in a closed system and Gloeckner teaches Alamar Blue is regarded as non-toxic for corneal endothelial cells.
Applicant’s Arguments/ Response to Arguments
22. Applicant Argues: On page 8, last paragraph and page 10, paragraph 1 and pages 13 – 14, Applicant asserts that amended claim 1 is patentable over the combination of Schallhorn, Binner, and Gloeckner because a person of ordinary skill in the art could not have combined the teachings of the cited documents and obtained nor more than predictable results. On page 9, para. 4, Applicant asserts that Binner fails to cure the deficiencies of Schallhorn with respect to amended claim 1.
Response to Arguments: The prior rejections of the claims have been withdrawn and a new rejection set forth above necessitated by the amendment to claim 1 using the teachings of Schallhorn, Binner, Haggins, and Gloeckner. Binner teaches in Figure 6 the corneal graft carrier in fluid communication at the first and second ends with tubing (5 in Figure 6B) attached to the second end. Binner does not teach “at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen”. Haggins teaches a perfusion assembly comprising three peristaltic pumps (60, 60a, and 80 in Figure 14) (“at least one pump” of claim 1 and “peristaltic pump” of claim 22) and check valves (88 and 90) and a microcontroller (64 in Figure 14) that regulate the flow of fluid into and out of a device (8a in Figure 14) (“at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen of the corneal graft carrier” of claim 1) housing a cornea in a conformation comprising a curved surface disposed within the lumen of the device (col. 8, lines 12 – 25 and 52 – 67; col. 9, lines 1 – 27). Haggins teaches the peristatic pump (80 in Figure 14) is situated between the device housing the cornea and the collection tube (72 in Figure 14) and introduces a compression point in the tubing (70 in Figure 14) that when the pump is “off” fluid movement within the tubing is prevented thus blocking fluid spillage from the device housing the cornea to the collection tube or vice versa (col. 8, lines 14 – 25). Therefore, Haggins cures the deficiencies of Schallhorn and Binner regarding amended claim 1 requiring “at least one fluid control valve in fluid communication with the second end of the corneal graft carrier and configured to regulate flow of fluid out of the lumen”.
Applicant Argues: On page 9, para. 3, Applicant asserts that the Office Action mischaracterizes the teachings of Gloeckner. On page 10, para. 1, Applicant asserts that the Office Action overgeneralizes the teachings of Gloeckner and the alleged motivation to combine and expectation of success combining Gloeckner with the teachings of Schallhorn and Binner are lacking. On page 10, last para. and page 11, para. 1, Applicant asserts that it is not readily apparent how a person of ordinary skill in the art would modify the combination of Schallhorn and Binner and Gleckner is concerned with small volume cell culture. On page 11, para. 1, Applicant asserts that the “non-invasiveness” taught in Gloeckner is in the context of removing a cell culture sample from a small volume and the teaching of Gloeckner has absolutely no relation to the maintaining the quality of a corneal graft that can affect the success of a corneal transplant. On page 11, para. 2, Applicant asserts that nothing in Gloeckner applies to monitoring viability of a corneal graft and the difficult problem of monitoring viability of a corneal graft in a conformation that includes a curved surface and Gloeckner is limited to endothelial cells in culture.
Response to Arguments: This is not found persuasive because Schallhorrn teaches because the grafts were opened via manipulation when measuring cell viability, this method may have induced a small amount of trauma and cell loss (page 381, right col. para. 3). Binner teaches the staining with trypan blue and washing is most preferably performed in the graft carrier in order to decrease the tissue graft manipulation which could result in tissue graft damage (page 10, 0115). Binner teaches the current state of the art methods suggest graft handling by aqueous flow (“no touch”) (page 1, 0005). Binner teaches success of transplantation surgery strongly depends on the quality of the graft (page 1, 0006). Binner teaches because of the high probability of transport-associated damage there is growing demand to evaluate the implant in the operating room prior to implantation in order to prevent implant miscarriage (page 2, 0006). Binner teaches new ways of graft processing, evaluation, delivery, and transplantation have to be developed (page 2, 0007). Haggins teaches a perfusion assembly with multiple pumps and reagent reservoirs that allows the programmed delivery of different reagents to a cornea in a curved configuration in a carrier (Figure 14). Gloeckner teaches the perfusion assembly minimizes handling steps since no cells need to be taken for readout of viability and thus is a non-invasive way to monitor cell viability in a closed system (Abstract; page 137, right col. last para.). Gloeckner teaches Alamar Blue is regarded as non-toxic for corneal endothelial cells (page 137, left col. para. 2). Gloeckner teaches the Alamar Blue assay shows good correlation with trypan blue assay (page 132, left col. para. 2). Therefore, one would have been motivated to combine the teachings of Schallhorn, Binner, and Gloeckner in an assembly for monitoring cell viability of corneal grafts in situ because Schallhorn teaches ejection of the graft from the graft carrier to measure cell viability and this process caused cell loss and Binner teaches the current state of the art methods suggest graft handling by “no touch” and Gloeckner teaches the perfusion assembly minimizes handling steps since the sample in the lumen does not need to be removed to measure cell viability. One would have a reasonable expectation of success in combining the teachings as Binner teaches performing staining and washing is most preferably performed in the graft carrier to decrease graft damage due to graft manipulation and Haggins teaches the assembly includes multiple reagent reservoirs and allows for programmed delivery of two distinct reagents, one-at-a-time and Gloeckner teaches Alamar Blue is regarded as non-toxic for corneal endothelial cells and Gloeckner teaches the Alamar Blue assay shows good correlation with trypan blue assay.
Applicant Argues: On page 11, last para. and page 12, Applicant asserts that the feature recited in claim permit a previously uncontemplated method to be performed. Applicant asserts that previous methods for evaluating corneal graft tissue included slit lamp examination and vital dye staining which required flattening of the graft for imaging and usually resulted in cytotoxicity due to the vital dyes. Applicant asserts that previous to Applicant’s disclosure, those of skill in the art did not contemplate performing cell viability assay in a corneal tissue carrier that could be performed on a graft in a configuration with a curved surface.
Response to Arguments: In response, Schallhorrn teaches because the scrolled grafts were first ejected from their carrier and were opened via manipulation with for staining with calcein, this method may have induced a small amount of trauma and cell loss (page 381, right col. para. 3). Schallhorn teaches a significant portion of cell loss during DMEK surgery would come from graft preparation and injection, which suggest that proportionately less cell loss is attributable to the intraocular manipulation of the graft (page 381, left col. para. 3). Schallhorn teaches specular techniques have an inherent bias to count cells suggesting that postpeel specular microscopy has limited utility in graft evaluation (page 381, left col. para. 4). Binner teaches trypan blue staining for quality control of the tissue graft and is especially used for ophthalmological interventions (page 10, 0115). Binner teaches due to cell toxicity issues, the tissue graft should not be exposed to trypan blue for a long time so the tissue graft is usually stained and washed prior to implantation (page 10, 0115). Binner teaches the staining and washing is most preferably performed in the graft carrier in order to decrease the tissue graft manipulation which could result in tissue graft damage (page 10, 0115). Therefore, Schallhorn teaches the method of calcein staining causes cell loss in corneal grafts and Binner teaches trypan blue can be toxic to corneal grafts and Binner teaches it is preferable that the staining and washing is performed in the graft carrier to decrease tissue graft manipulation and minimize the exposure time of the graft to trypan blue. The teachings of Schallhorn and Binner regarding a growing demand to evaluate the implant in the operating room prior to implantation in order to prevent implant miscarriage (page 2, 0006) and Binner teaches new ways of graft processing, evaluation, delivery, and transplantation have to be developed (page 2, 0007) provides motivation for staining scrolled corneal grafts in their carrier with a nontoxic stain. Haggins and Gloeckner provide a reasonable expectation of success because Haggins teaches a perfusion assembly to control the flow of different reagents into and out of a lumen containing a curved cornea and Gloeckner teaches a noninvasive method for in situ Alamarblue staining to measure cell viability and teaches Alamar Blue is regarded as non-toxic for corneal endothelial cells and the Alamar Blue assay shows good correlation with trypan blue assay. Therefore, one of ordinary skill in the art would have a reasonable expectation of success in combining the teachings of Schallhorn, Binner, Haggins, and Gloeckner to arrive at the claimed composition for monitoring cell viability of curved corneal endothelial grafts.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632