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 .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed July 8, 2024 is acknowledged. Claims 3-11, 18 and 23 are canceled. Claims 12, 14 and 30-31 are amended. Claims 1-2, 12-17, 19-22 and 24-37 are pending in this application. Claims 1-2, 19-22 and 25-26 are withdrawn without traverse (filed 2/22/22) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 2, 2022.
3. Claims 12-17, 24 and 27-37 are under examination in this office action.
4. Applicant’s arguments filed on July 8, 2024 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
5. The rejection of claims 30-31 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in response to Applicant’s amendment to the claims.
The rejection of claims 12, 32 and 34-35 under 35 U.S.C. 102(a)(1) as being anticipated by Xie’2012 (Invest Ophthalmol. Vis. Sci. 2012; 53:279-286. DOI:10.1167/iovs.11-8441) is withdrawn in response to Applicant’s amendment to the claims.
The rejection of claims 12, 32 and 34-35 under 35 U.S.C. 102(a)(1) as being anticipated by Xie’2011 (Stem Cells, 2011; 29:1874-1885) is withdrawn in response to Applicant’s amendment to the claims.
The rejection of claims 12, 18, 32 and 34-35 under 35 U.S.C. 103 as being unpatentable over either Xie’2012 (Invest Ophthalmol. Vis. Sci. 2012; 53:279-286) or Xie’2011 (Stem Cells, 2011; 29:1874-1885) in view of Zhang et al. (US2017/0233698) is withdrawn in response to Applicant’s amendment to the claims.
New Grounds of Rejection Necessitated by the Amendment
The following rejections are new grounds of rejections necessitated by the amendment filed on July 8, 2024.
Claim Objections
6. Claim 12 is objected to because of the following informalities: The recitation “1:5 to 5.1” in the last line of the claim is objected to because the ratio range should be “1:5 to 5:1”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
7. 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 14-17, 24, 28-29, 31, 33 and 36-37 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 pre-AIA the applicant regards as the invention.
Claims 14-17, 24, 28-29, 31, 33 and 36-37 are indefinite because:
i. Independent claim 14 recites a method of preparing a multilayer cell composition but the claim also recites “a) depositing a uniform first layer comprising a plurality of limbal derived stromal cells (LSCs) and thrombin on the corneal or ocular surface of an individual….”, which means that there is no physical multilayer cell composition prepared in vitro as claimed in the preamble because the cells are directly deposited on the corneal or ocular surface of the individual. Dependent claims also recite “the composition” which contradicts the result of depositing cells directly on the corneal or ocular surface of the individual in vivo, which renders the claims indefinite.
ii. Claim 14 recites the limitation "the corneal or ocular surface of an individual" in line 4 of the claim. There is insufficient antecedent basis for this limitation in the claim.
iii. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
8. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 15-17, 24, 29, 31 and 33 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 15-17, 24, 29, 31 and 33 recite “the composition” that is prepared in vitro and also depend on independent claim 14 that does not recite preparing a multilayer cell composition in vitro. Thus, claims 15-17, 24, 29, 31 and 33 fail to further limit the subject matter of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
9. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 12, 32 and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over either Xie’2012 (Invest Ophthalmol. Vis. Sci. 2012; 53:279-286, cited previously) in view of Zhang et al. (US2017/0233698, cited previously) and Funderburgh et al. (The Ocular Surface, 2016; 14:113-120, cited previously).
Claims 12, 32 and 34-35 as amended is drawn to a method of preparing a cell composition for use in treating non-healing corneal epithelial defect or persistent corneal epithelial defect, the method comprising: mixing a plurality of limbal derived stromal cells (LSCs) and a plurality of limbal derived epithelial cells (LECs) to produce a mixed population of cells, wherein the LSCs and the LECs are present in the composition at a ratio ranging from 1:5 to 5:1; wherein the LSCs express CK3+12, ABCG2, PAX6 and VIMENTIN; and wherein the composition further comprises thrombin and fibrinogen at a ratio ranging from 1:5 to 5:1.
Xie’2012 teaches a method of preparing a cell composition comprising mixing a plurality of human limbal stromal mesenchymal cells (i.e. human LSCs) and a plurality of human limbal epithelial stem/progenitor cells (LECs) at a ratio of 1:4 and culturing the mixed cells at a density of 5x105 cells/cm2 in 3D Matrigel containing MESCM (modified embryonic stem cell medium) for 10 days, which meets the limitations “mixing a plurality of LSCs and a plurality of LECs to produce a mixed population of cells, wherein the LSCs and the LECs are present in the composition at a ratio of 1:4 (within the range of ranging from 1:5 to 5:1)” (see p. 280, 1st col., section: coated, 2D and 3D Matrigel Culture and Treatment; p.280, 1st col., 1st paragraph-2nd paragraph; p. 279, 2st col., Results to p. 285, 2nd col.). The human LSCs disclosed by Xie’2012 express CK12, PAX6 and VIMENTIN (Vim+) and thus are the limbal stromal mesenchymal stem cells or limbal derived stromal cells (LSCs) as instantly claimed (p. 279, abstract; p.281, 1st col-2nd col.; figure 2).
But Xie’2012 does not explicitly teach that LSCs also express CK3+12 and ABCG2 or the composition further comprising thrombin and fibrinogen at a ratio ranging from 1:5 to 5:1 as in claim 12.
Zhang et al. (US2017/0233698) teach a method of preparing a cell composition comprising a plurality of limbal stem cells and a plurality of limbal corneal epithelial cells for treating different ocular damage or diseases or ocular surface impairment including corneal ulcers including stromal ulceration, peripheral ulcerative or inflammatory keratitis, comprising obtaining cultured limbal stem cells (LSCs) which comprise limbal stromal stem cells (LSSCs) and limbal epithelial stem cells (LESCs), dissociating to single cells, placing the isolated LCSs in and/or on a matrix or extracellular matrix to form 3D cell culture and culturing LSCs on a tissue base in an enriched medium or in a LSC differentiation medium to differentiate LSCs to corneal epithelial cells (CECs), wherein the matrix or extracellular matrix includes fibrinogen and thrombin and wherein the tissue base includes a fibrin gel comprising corneal stromal fibroblasts, derivatives of mesenchymal tissue, and epithelial cells, such as corneal epithelial cells (see paragraphs [0105]; [0140]; [0144]; [0148]; [0150]-[0153]; [0127]; [0250]-[0253]; [0255]-[0256]; [0162]-[0165]; [0181]-[0187]; [0225]; [0209]-[0237]). Zhang teaches that the LSCs express PAX6, ABCG2, CK3+12 (K3 and K12) (see paragraphs [0105]; [0140]; [0144]; [0148];[0162]). Zhang also teaches 3D differentiation by embedding dissociated single stem cells in Matrigel® at 2x104 cells/50ul gel and that 3-D structures were formed after 14-18 day culture in a differentiation medium CnT-30 (limbal stem cell differentiation) (see paragraph [290]). Zhang also teaches cell transplantation by using 5x105 rabbit GFP-labeled LSCs, PAX6+ SESCs or shPAX6 LSCs cells mixed with fibrin (25 mg/ml) and thrombin (25 U/ml) (i.e. fibrin: thrombin=1:1) and seeded onto the exposed stromal bed of a recipient cornea and limbal area (see paragraph [0311]).
Funderburgh teaches limbal stromal stem cells expressing ABCG2, PAX6 (p. 114, figure 1; p. 115, 1st col. section C. Tissue localization of stromal stem cells). Funderburgh teaches that the proximity of corneal stromal stem cells (CSSCs) and limbal epithelial stem cells (LESCs) in vivo suggests the possibility that each of these populations provides symbiotic support for maintenance of the stem cell phenotype of the other (see p. 117, 1st col., lines 13-16). Funderburgh teaches that in vitro, limbal fibroblasts supported expansion of LESCs better than 3T3 cells or scleral fibroblasts, and this ability was enhanced by expansion of the CSSCs in culture conditions that maintain the stem-like phenotype of the CSSCs. When CSSCs and LESCs were co-isolated in clusters using collagenase digestion, the LESCs expanded more rapidly and formed more holoclones, than without the niche cells (see p. 116, 1st col., D. Function of Corneal stromal stem cells in vivo) and that CSSCs in vitro can produce collective tissue in composition and structure to that of human stroma and can be used for corneal bioengineering applications (p. 118, 1st co., IV. Summary and Conclusions).
A person of ordinary skill in the art would have recognized that selecting and applying the known LSCs expressing CK3+12, ABCG2, PAX6 and VIMENTIN, the known composition comprising LSCs and LECs, and the known technique of transplanting a composition comprising LSCs and LECs on the corneal or ocular surface of an individual disclosed by Zhang and Funderburgh to the method of Xie’2012 would have yielded the predictable result of preparing a cell composition for use in treating non-corneal epithelial defect or persistent corneal epithelial defect by mixing a plurality of LSCs and a plurality of LECs at a ratio of 1:5 to 5:1 in the composition to generate a mixed population of cells wherein the LSCs express CK3+12, ABCG2, PAX6 and VIMENTIN and wherein the composition further comprises thrombin and fibrinogen at a ratio of 1:5 to 5:1, and resulted in better production of a cell composition comprising LSCs and LECs for use in treating non-corneal epithelial defect or persistent corneal epithelial defect and better formation of limbal epithelial tissue and integration into the recipient cornea and limbal area.
Using or transplanting the known LSCs expressing CK3+12, ABCG2, PAX6 and VIMENTIN, the known composition comprising LSCs and LECs on the corneal or ocular surface of an individual disclosed by Zhang and Funderburgh in the method of Xie’2012 would expand application of the method of Xie’2012, and produce and integrate limbal epithelial tissue into the recipient cornea and limbal area, and would increase patient’s satisfaction with recommended treatment of limbal epithelial stem cell defect or ocular diseases using a cell composition comprising LSCs and LECs.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known LSCs expressing CK3+12, ABCG2, PAX6 and VIMENTIN, the known composition comprising LSCs and LECs, and the known technique of transplanting a composition comprising LSCs and LECs on the corneal or ocular surface of an individual disclosed by Zhang and Funderburgh to the method of Xie’2012 to transplant and layer the composition comprising LSCs and LECs on the corneal or ocular surface of an individual, and yield the predictable result of better generation and integration of limbal epithelial tissue into the recipient cornea and limbal area. See KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007); In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992), Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) and In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) and also see MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
10. Claims 14, 16-17, 24, 27-29, 33 and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Xie’2012 in view of Zhang (US2017/0233698) and Funderburgh et al. (2016) as applied to claims 12, 32 and 34-35 above, and further in view of Deng et al. (US2015/0175965) and Basu et al. (Sci. Transl. Med. 2014; 6:266ra172, as in IDS).
Claims 14, 16-17, 24, 27-29, 33 and 36-37 as amended are directed to a method of preparing a multilayer cell composition for use in treating non-healing corneal epithelial defect or persistent corneal epithelial defect, the method comprising: a) depositing a uniform first layer comprising a plurality of limbal derived stromal cells (LSCs) and thrombin on the corneal or ocular surface of an individual; and b) depositing directly onto the first layer a uniform second layer comprising a plurality of limbal derived epithelial cells (LECs) and fibrinogen, such that the LECs in the second layer directly contact the LSCs in the first layer, and wherein the LSCs express markers CK3+12, ABCG2, PAX6 and VIMENTIN.
Xie’2012, Zhang and Funderburgh are set forth above, and also teach the limitations “wherein the ratio of LSCs to LECs ranges from 1:5 to 5:1” and intended use for use as in claims 16, 33 and 36-37 (see p. 1877, 1st col., section Sphere Culture and Treatment to 2nd col., section: colony forming assay in Xie’2012 and paragraphs [0225]; [0209]-[0237] in US2017/0233698), the limitation “wherein the ratio of thrombin to fibrinogen ranges from 1:5 to 5:1” as in claim 17 (paragraphs [0311]; [0152]; [0164]; [0250]; claims 70-71 in US2017/0233698), the limitation “wherein the cell composition is layered on the corneal or ocular surface of an individual” as in claims 24 and 29 (paragraph [0311] in US2017/0233698).
But Xie’2012, Zhang and Funderburgh do not teach preparing a multilayer cell composition comprising depositing a uniform first layer: LSCs and thrombin on the corneal or ocular surface of an individual, and depositing a uniform second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer as in claim 14 or steps of removing a portion of the limbal derived epithelial cells and differentiating the portion into limbal derived stromal cells as in claims 27-28.
While Xie’2012 and Zhang do not teach a multilayer cell composition comprising a first layer: LSSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LESCs and fibrinogen, wherein the second layer is deposited directly over the first layer as in claim 14 or steps of removing a portion of the limbal derived epithelial cells and differentiating the portion into limbal derived stromal cells as in claims 27-28, Funderburgh, Deng et al. (US2015/0175965) and Basu et al. teach these limitations and provide motivation and an expectation of success because Deng and Basu teach a cell composition comprising two layers: LECs and LSCs and the benefits of including LSCs and fibrinogen and thrombin in cell composition to provide rapid expansion and development of LECs and for use in corneal bioengineering applications.
Funderburgh teaches that the proximity of corneal stromal stem cells (CSSCs) and limbal epithelial stem cells (LESCs) in vivo suggests the possibility that each of these populations provides symbiotic support for maintenance of the stem cell phenotype of the other (see p. 117, 1st col., lines 13-16).
Deng teaches a method of preparing a multilayer cell composition comprising: disposing human limbal stem cells (LSCs) including human limbal epithelial stem cells (LECs) in the first cell culture compartment, disposing human feeder cells including human limbal stromal stem cells (LSCs) in the second cell culture compartment, wherein the human feeder cells include limbal stromal cells (LSCs) including limbal stromal mesenchymal stem cells(LSMSCs) or human limbal fibroblasts (HLFs), wherein the human feeder cells are below the human limbal stem cells (LSCs), which are related to instant claims (see [0016]; [0011]-[0016]; [0032]-[0039]; [0041]; [0077]-[0089]; Examples 1-2). Deng also teaches steps of harvesting the limbal derived epithelial cells; removing a portion of the limbal derived epithelial cells and differentiating the portion into limbal derived stromal cells as in claims 27-28 (see paragraphs [0016]; [0032]-[0034]
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Basu teaches a cell culture of collagenase treated limbal biopsies comprising both epithelial and mesenchymal stem cells (p. 2, figure 1). Basu also teaches human limbal biopsy-derived stromal stem cells (LBSCs) embedded in a fibrin gel to the surface of a healing mouse wound by applying 5x104 LBSCs in a solution of fibrinogen (p. 2, 2nd col. Human LBSCs engraft in murine cornea in vivo to p. 3; p. 1, 2nd col to p. 2, 2nd col. to p. 3; p.5-6, figures 4-6) and also teaches that after wounding, 0.5 ml of thrombin was added to the wound bed, followed immediately by 1 ml of fibrinogen (with or without LBSCs), and after 1 to 2 min, the fibrinogen had gelled, and a second round of thrombin and fibrinogen was added and the corneal epithelium closed the wound in 24-36 hours, which relates to preparing a multilayer composition comprising a uniform first layer: limbal derived stromal cells (LSCs) and thrombin; and a uniform second layer comprising limbal derived epithelial cells (LECs) and fibrinogen (see p. 8, 2nd col., Fibrin gel and LBSC application).
A person of ordinary skill in the art would have recognized that selecting and applying the known technique of preparing a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer and the known steps of removing a portion of the limbal derived epithelial cells and differentiating the portion into limbal derived stromal cells as in claims 27-28 disclosed by Funderburgh, Deng, and Basu to the method of Xie’2012, Zhang and Funderburgh would have yielded the predictable result of preparing a multilayer cell composition comprising a first layer: LSSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LESCs and fibrinogen, wherein the second layer is deposited directly over the first layer, and resulted in an improved method of preparing a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer, and wherein the LSCs express CK3+12, ABCG2, PAX6 and VIMENTIN.
Using and preparing a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer and wherein the LSCs express CK3+12, ABCG2, PAX6 and VIMENTIN disclosed by Deng and Basu in the method of Xie’2012, Zhang and Funderburgh would expand application of the method of Xie’2012, Zhang and Funderburgh, and provide benefits of rapid expansion and development of LECs and for treating non-corneal epithelial defect or persistent corneal epithelial defect and better formation of limbal epithelial tissue and integration into the recipient cornea and limbal area, and would also increase patient’s satisfaction with recommended treatment of using a multi-layer cell composition for producing limbal epithelial tissue and treatment of non-corneal epithelial defect or persistent corneal epithelial defect.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known technique of preparing a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer and the known steps of removing a portion of the limbal derived epithelial cells and differentiating the portion into limbal derived stromal cells as in claims 27-28 disclosed by Funderburgh, Deng, and Basu to the method of Xie’2012, Zhang and Funderburgh to prepare and generate a multiplayer cell composition, and yield the predictable result of preparing a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer with the claimed ratios, and provide rapid expansion and development of LECs and for treating non-corneal epithelial defect or persistent corneal epithelial defect and better formation of limbal epithelial tissue and integration into the recipient cornea and limbal area. See KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007); In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992), Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) and In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) and also see MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
11. Claims 12-13, 15-17 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Xie’2012 in view of Zhang (US2017/0233698), Funderburgh et al. (2016), Deng et al. (US2015/0175965) and Basu et al. (2014) as applied to claims 14, 16-17, 24, 27-29, 33 and 36-37 above, and further in view of Claeyssens et al. (US2015/0118197), Frank et al. (US11129854) and Omoto et al. (Invest. Ophthalmol. Vis. Sci. 2009; 50:2019-2115. DOI:10.1167/iovs.08-2262).
Xie’2012, Zhang, Funderburgh, Deng and Basu are set forth above but do not teach a cell range that is exactly identical to the claimed range of 4000-5000 cells/ul (=4-5x106/ml) as in claims 13 and 15 or a ratio of cell range of LSCs to LECs or a ratio of thrombin to fibrinogen that is exactly identical to the claimed range of 1:5 to 5:1 as in claim 12 and 16-17 or 100ul of LSCs and 200ul of LECs combined with 50ul thrombin and 50ul fibrinogen as in claims 30-31.
While Xie’2012, Zhang, Funderburgh, Deng and Basu do not teach cell ranges that are exactly identical to the claimed ranges, Claeyssens et al. (US2015/0118197), Frank et al. (US11129854) and Omoto et al. teach these limitations and provide motivation and an expectation of success because Claeyssens, Frank and Omoto teach different cell ranges and ratios that are either within or overlapping the claimed ranges.
Claeyssens teaches an electrospun scaffold comprising limbal stem cells and mesenchymal stem cells for treatment of ocular injury (see paragraphs [0030]-[0033], [0107]-[0108]; claims 29-38), and also teaches that rabbit limbal fibroblasts were seeded on the scaffolds at a concentration of 1x105cells/ring, 8x104 cells/well and 25x104 or 5x104 cells and epithelial cells were seeded at a concentration of 5x104 cells/ring or 5x104 cells (i.e. 2:1 or 1:1 or 5:1 or 1.6:1) (see paragraphs [0168]; [0139]-[0142]) and microfabricated scaffolds treated with 10ul fibrin +10ul thrombin (see paragraph [0170]).
Frank teaches 1-107 cells, 10-107, 10-106, 10-105,10-104, 10-102, 10, 102, 103, 104, 105, 106, 107 or more of ABCB5(+) limbal stem cells (LSCs) including LESCs and LSSCs and ABCB5(+) retinal epithelial stem cells are prepared and administered in a form of preparation or graft for treatment of limbal stem cell deficiency (LSCD) or ocular diseases (col. 9, lines 1-30; 11, lines 1-39).
Omoto teaches the use of a density of 105 cells/well, 2.5x104cells/cm2 and 1000 human limbal epithelial cells (see p. 5, 1st col), and also teaches engineering of human or rabbit epithelial cell sheets by coating cell culture inserts with 300ul fibrin, seeding 5x105 feeder cells at the bottom of well and adding 2x104 cells/cm2 human limbal epithelial cells (i.e. 25:1) for transplantation (see p. 5, 2nd col. 2nd paragraph).
A person of ordinary skill in the art would have recognized that selecting and applying the known cell range (i.e. 4000-5000 cells/ul=4-5x106/ml), the known ratio of LSCs to LECs, the known ratio of thrombin to fibrinogen (i.e. 1:5 to 5:1) for treatment of limbal stem cell deficiency (LSCD) or specific ocular diseases and the known technique disclosed by Claeyssens, Frank and Omoto to the method of Xie’2012, Zhang, Funderburgh, Deng and Basu would have yielded the predictable result of generation of a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer with the claimed cell ranges and ratios for thrombin to fibrinogen.
The use of the known cell range of 4000-5000 cells/ul, the known ratio of 1:5 to 5:1 for the LSCs to LECs, the known ratio of 1:5 to 5:1 for the thrombin to fibrinogen for treatment of limbal stem cell deficiency (LSCD) or specific ocular diseases and the known technique disclosed by Claeyssens, Frank and Omoto in the method of Xie’2012, Zhang, Funderburgh, Deng and Basu would expand application of the method of Xie’2012, Zhang, Funderburgh, Deng and Basu, and generate a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer with the claimed ratios, and provide rapid expansion and development of LECs for treating non-corneal epithelial defect or persistent corneal epithelial defect and better formation of limbal epithelial tissue and integration into the recipient cornea and limbal area, and for treatment of limbal stem cell deficiency (LSCD) or specific ocular diseases.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known cell range of 4000-5000 cells/ul, the known ratio of 1:5 to 5:1 for the LSCs to LECs, the known ratio of 1:5 to 5:1 for the thrombin to fibrinogen for treatment of limbal stem cell deficiency (LSCD) or specific ocular diseases and the known technique disclosed by Claeyssens, Frank and Omoto to the method of Xie’2012, Zhang, Funderburgh, Deng and Basu to generate a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer with the claimed ratios, and yield the predictable result of generating a multilayer cell composition comprising a first layer: LSCs and thrombin deposited on the corneal or ocular surface of an individual, and a second layer: LECs and fibrinogen, wherein the second layer is deposited directly over the first layer with the claimed ratios; and provide rapid expansion and development of LECs for treating non-corneal epithelial defect or persistent corneal epithelial defect and better formation of limbal epithelial tissue and integration into the recipient cornea and limbal area, and for treatment of limbal stem cell deficiency (LSCD) or specific ocular diseases. See KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007); In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992), Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) and In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) and also see MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
Further, routine optimization of cell ranges of LSCs to LECs or ratios of thrombin and fibrinogen disclosed by the method of Xie’2012, Zhang, Funderburgh, Deng and Basu would have led to the claimed range of 4000-5000 cells/ul=4-5x106/ml or the claimed ratio of cell range of LSCs to LECs at 1:5 to 5:1 or the ratio range of thrombin to fibrinogen at 1:5 to 5:1 for treatment of limbal stem cell deficiency (LSCD) or specific ocular diseases because Claeyssens, Frank and Omoto teach different cell ranges and ratios are either within or overlapping the claimed ranges including 1x105cells/ring, 8x104 cells/well and 25x104 or 5x104 cells and epithelial cells were seeded at a concentration of 5x104 cells/ring or 5x104 cells (i.e. 2:1 or 1:1 or 5:1 or 1.6:1), 1-107 cells, 10-107, 10-106, 10-105,10-104, 10-102, 10, 102, 103, 104, 105, 106, 107 or more of ABCB5(+) limbal stem cells including LECs and LSCs and ABCB5(+) retinal epithelial stem cells are prepared and administered in a form of preparation or graft or engineering of human or rabbit epithelial cell sheets by coating cell culture inserts with 300ul fibrin, seeding 5x105 feeder cells at the bottom of well and adding 2x104 cells/cm2 human limbal epithelial cells (i.e. 25:1), which achieve a multilayer cell composition comprising two layers: LECs and LSCs mixed with fibrinogen and thrombin for treatment of ocular injury or transplantation or ocular disease desired in Xie’2012, Zhang, Funderburgh, Deng and Basu. The person of ordinary skill in the art would have found it obvious to optimize within the range taught by Claeyssens, Frank and Omoto because Claeyssens, Frank and Omoto teach that this entire range can form the claimed multilayer cell composition for treatment of ocular injury or transplantation or ocular disease, and also teaches how to optimize the multilayer cell composition comprising two layers: LESCs and LSSCs mixed with fibrinogen and thrombin and the cell ranges and ratios for LESCs and LSSCs and the ratios for fibrinogen and thrombin.
Note that
“[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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”; “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert.denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP § 2144.05.
Conclusion
12. NO CLAIM IS ALLOWED.
13. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kureshi et al. (Sci. Rep. 2015; 5:16816. DOI:10.1038/srep16186) teach a method of preparing a cell composition comprising mixed human limbal derived stromal cells (LSCs)/corneal stromal stem cells (CSSC) and human limbal derived epithelial cells (LECs)/limbal epithelial stem cells (LESCs), wherein the limbal derived stromal cells and the limbal derived epithelial cells are present in the composition (see 6-7).
14. 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 extension fee 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 date of this final action.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chang-Yu Wang whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:30pm EST.
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Chang-Yu Wang
November 13, 2024
/CHANG-YU WANG/Primary Examiner, Art Unit 1675