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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 submission filed on 01/12/2026 has been entered.
Claims 31, 38, 40, 43, 44, 47, 49, 53, 54, 58, 59, and 61 have been amended.
Claims 62-71 have been newly added and claims 34-35, 37, 39, 41, 50-51, 55-56, and 60 have been newly canceled.
Claims 31-33, 38, 40, 42-49, 52-54, 57-59, and 61-71 are currently pending and have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 63-68 are 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. (New Matter Rejection)
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.
Claims 63-68 all recite the term "simultaneously” with regard to the cell marker expression. There is insufficient support in the disclosure as originally filed for this limitation; thus it is being considered new matter.
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 introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See, e.g., Fujikawa V. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 31-33, 38, 40, 42-49, 52-54, 57-59, and 61-71 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al (US 2012/0288482) in view of Koizumi et al (WO 2015/016371 published 2/5/2015-from IDS filed 10/20/2020 using US 2016/0266114 as a translation-also from IDS filed 10/20/2020), Lupatov et al (Cell Technologies in Biology and Medicine, Feb 2015-from IDS filed 02/09/2024) and Deng et al (Journal of Biomedicine and Biotechnology, 2012-newly cited).
Regarding claims 31-32, 40, 42, 44-49, 52-54, 57-59, and 61-71, Takahashi teach a method of treating corneal endothelial dysfunction by administering human functional corneal endothelial cells capable of eliciting a human corneal functional property when infused into an anterior chamber of a human eye (page 16 claims 9-10, page 2 para 10-part 12 to para 11-part 30, page 7 para 69-71, page 9 para 88, page 11 para 113) in suspension (non-attached) (page 8-9 para 86). Takahashi teach wherein the corneal endothelial dysfunction includes bullous keratopathy, corneal edema as well as other corneal endothelial dysfunctions (page 6 para 64, page 9 para 88). Takahashi teach wherein the cells are administered by a cell infusion vehicle comprising a ROCK inhibitor (also known as compound (1a))(page 1 para 3, pages 1-2 para 9, page 9 para 87).
Takahashi are silent with regard to the markers used to identify human corneal endothelial cells.
Koizumi teach a cell population of normal human functional corneal endothelial cells that is positive for CD 166 and is in contrast to transformed corneal endothelial cells which express CD26, CD44, CD73, CD105, CD133 and CD200 (page 2 para 23-25, page 6 para 114, page 20, para 243-244).
Koizumi teach that the purpose of their invention is to provide a method of purification and preparation of cultured corneal endothelial cells, and in particular to provide cell surface markers for use in corneal endothelial cells not including transformed cells. Koizumi state this is for distinguishing between normal corneal endothelial cells and transformed corneal endothelial cells. The cell surface marker CD73 is used to remove the transformed cells by sorting and that it becomes possible to improve the purity of a normal cultured corneal endothelium. By using normal corneal endothelial surface marker such as CD166, or by combined use with the transformed cell surface marker, it becomes possible to provide a means for verifying the purity of a prepared corneal endothelium (abstract).
This combination of using the markers for normal cells and the markers for transformed cells allows the skilled artisan to arrive at a purified normal corneal endothelial population that must then be CD166+ and negative for CD26, CD44, CD73, CD105, CD133 and CD200.
Koizumi teach wherein their normal human functional corneal endothelial cells are purified (abstract, pages 22-23 para 264-267) and define purified as by at least 95% (page 10 para 143). The normal isolated corneal endothelial cells are taught to be used for eye therapy where they are infused into the anterior chamber (page 28 para 339). Since these cells are indicated as “normal” they are deemed without karyotype aneuploidy. Koizumi teach wherein their normal human corneal endothelial cells are suitable for use as pharmaceuticals (page 29, para 341) and is deemed capable of eliciting a human corneal functional property when infused into an anterior chamber of the human eye baring evidence to the contrary. Koizumi do indicate that their endothelial cells can be used with a carrier and can be administered as an infusion or injection into the eye as a cell suspension (non-attached)(page 28 para 339).
Koizumi teach that in contrast to the normal cells that the transformed cells have a fibroblast-like shape and are not polygonal, but have an elongated fibroblast-like shape (page 4 para 97) and have a high level of expression for CD73 (page 4 para 101, para 104)
One of ordinary skill in the art would have been motivated to use the human corneal endothelial cells of Koizumi with enhanced purity (such as at least 90%, or as close as possible to 100%) to optimize their effects in the method of Takahashi because Koizumi teach that their cells are suitable for use in methods of treating corneal endothelial dysfunction by injection of these cells (page 28 para 339). One of ordinary skill in the art would have had a reasonable expectation of success because both Koizumi and Takahashi suggest the use of human corneal endothelial cells that replicate normal function and have positive expression of barrier function ZO-1 positive and pumping function Na+/K+ ATPase.
However, even if the corneal endothelial cells of Koizumi are not the same as the claimed cells due to the issue of CD24 expression or non- expression, the teachings of Lupatov and Deng would have rendered the claimed corneal endothelial cells an obvious choice from the corneal endothelial population of Koizumi.
Lupatov teach that cells that were positive to for CD73, CD90, and CD105 markers were fibroblast cells or fibroblast-like cells and included a subpopulation that co-expressed CD24 and CD90 or CD24 and CD54 (page 537, abstract, page 539-542). Therefore, CD24 would be expected to be found on fibroblast-like cells and non- fibroblastic cells would be expected to be negative for CD24.
Deng disclose the CD24 is overexpressed in glioma cells in vitro and in vivo (abstract). Deng teach that accumulating evidence indicates that CD24 is an important marker for cancer diagnosis and prognosis. For various metastatic tumors, most studies have reported that the overexpression of CD24 protein might contribute to metastasis and by consequence poor prognosis (page 5). Various cancers in various tissues all have high expression of CD24 including breast cancer, non-small cell lung cancer, hepatocellular carcinoma, esophageal cancer, pancreatic cancer, cholangiocarcinoma, urothelial carcinoma, ovarian cancer and prostate cancer (pages 5-6).
Since the Koizumi corneal endothelial cells are CD73 negative and non-fibroblastic with a normal polygonal shape (see para 101 of Koizumi) and preferred for further use, one of ordinary skill in the art would have been motivated to select those cells of Koizumi that are CD24 negative because Lupatov suggest that non-fibroblast cells are preferred and that non-fibroblast cells are CD24 negative and CD73 negative. Additional motivation to avoid CD24 positive cells is provided by Deng which teach that CD24 expression is found in many different cancerous tissues and CD24 expression correlates with tumor lymph node metastasis, tumor grade and survival time (pages 5-6). One of ordinary skill in the art would have had a reasonable expectation of success because Koizumi indicate the preferred corneal endothelial cells are CD73 negative and non-fibroblastic and demonstrate their marker expressions by flow cytometry.
Regarding claim 33, Takahashi is silent with regard to the cell density for administration of human corneal endothelial cells to a human eye.
However, Takahashi teach wherein a cell density for administration of rabbit corneal endothelial cells to the anterior chamber of a rabbit bullous keratopathy model is 2.0 x 105 in 200 ul (page 15 para 168).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to use the cell density for administering rabbit cells described by Takahashi as a starting point for the optimization of the cell density for human cell administration because Takahashi teach and suggest that their method is also performed with human cells for human patients.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of aclaim 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) (MPEP 2144.05).
The selection of specific cell densities for human cells for administration to a human patient clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the therapeutic effect of the cells on the damaged tissue would be affected by the cell density administered.
Regarding claim 43, Takahashi are silent with regard to the expression of ZO1 and Na+/K+ ATPase in human endothelial cells.
However, Takahashi teach wherein the rabbit corneal endothelial cells combined with compound (1) express ZO-1 and Na/K ATPase and that these are indicative of cells with corneal endothelium barrier function and corneal endothelium pumping function which are desirable and beneficial functional properties and necessary for cells used in transplantation (pages 14-15, para 163-165).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to use human corneal endothelial cells with compound (1) that positively express ZO-1 and Na/K ATPase in the method of Takahashi because Takahashi teach and suggest that these positive protein expressions are beneficial and desirable for corneal endothelial cell function and needed in corneal endothelial cells when used for transplantation.
Regarding claims 38, Takahashi teach that when the subject is human that autologous transplantation is preferred (page 11 para 114) and this would have ensured that the cell population administered did not induce an allogeneic rejection upon infusion into the anterior chamber of a human eye or elicit an increased amount of serum inflammatory cytokines after in vivo administration. Optimizing the method of Takahashi to avoid an increased amount of serum inflammatory cytokines would have been an obvious tactic as inflammation would have negative effects on the therapeutic effect of the method as well.
Therefore, the combined teachings of Takahashi et al, Koizumi et al, Lupatov et al and Deng et al render obvious Applicant’s invention as claimed.
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.
Claims 31-33, 38, 40, 42-49, 52-54, 57-59, and 61-71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-60 of copending Application No. 19/259, 847 in view of Takahashi et al, Koizumi et al, Lupatov et al. and Deng et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the copending application are drawn to a population of human functional corneal endothelial cells for use in therapeutic methods for corneal dysfunction that are 99% positive for CD166 and weakly positive for CD105 (90%), negative for CD24 (95%) and low for CD44 (90%) in a method used for treating corneal endothelial dysfunction.
Regarding claims 31-32, 40, 42, 44-49, 52-54, 57-59, and 61-71, Takahashi teach a method of treating corneal endothelial dysfunction by administering human functional corneal endothelial cells capable of eliciting a human corneal functional property when infused into an anterior chamber of a human eye (page 16 claims 9-10, page 2 para 10-part 12 to para 11-part 30, page 7 para 69-71, page 9 para 88, page 11 para 113) in suspension (non-attached) (page 8-9 para 86). Takahashi teach wherein the corneal endothelial dysfunction includes bullous keratopathy, corneal edema as well as other corneal endothelial dysfunctions (page 6 para 64, page 9 para 88). Takahashi teach wherein the cells are administered by a cell infusion vehicle comprising a ROCK inhibitor (also known as compound (1a))(page 1 para 3, pages 1-2 para 9, page 9 para 87).
Takahashi are silent with regard to the markers used to identify human corneal endothelial cells.
Koizumi teach a cell population of normal human functional corneal endothelial cells that is positive for CD 166 and is in contrast to transformed corneal endothelial cells which express CD26, CD44, CD73, CD105, CD133 and CD200 (page 2 para 23-25, page 6 para 114, page 20, para 243-244).
Koizumi teach that the purpose of their invention is to provide a method of purification and preparation of cultured corneal endothelial cells, and in particular to provide cell surface markers for use in corneal endothelial cells not including transformed cells. Koizumi state this is for distinguishing between normal corneal endothelial cells and transformed corneal endothelial cells. The cell surface marker CD73 is used to remove the transformed cells by sorting and that it becomes possible to improve the purity of a normal cultured corneal endothelium. By using normal corneal endothelial surface marker such as CD166, or by combined use with the transformed cell surface marker, it becomes possible to provide a means for verifying the purity of a prepared corneal endothelium (abstract).
This combination of using the markers for normal cells and the markers for transformed cells allows the skilled artisan to arrive at a purified normal corneal endothelial population that must then be CD166+ and negative for CD26, CD44, CD73, CD105, CD133 and CD200.
Koizumi teach wherein their normal human functional corneal endothelial cells are purified (abstract, pages 22-23 para 264-267) and define purified as by at least 95% (page 10 para 143). The normal isolated corneal endothelial cells are taught to be used for eye therapy where they are infused into the anterior chamber (page 28 para 339). Since these cells are indicated as “normal” they are deemed without karyotype aneuploidy. Koizumi teach wherein their normal human corneal endothelial cells are suitable for use as pharmaceuticals (page 29, para 341) and is deemed capable of eliciting a human corneal functional property when infused into an anterior chamber of the human eye baring evidence to the contrary. Koizumi do indicate that their endothelial cells can be used with a carrier and can be administered as an infusion or injection into the eye as a cell suspension (non-attached)(page 28 para 339).
Koizumi teach that in contrast to the normal cells that the transformed cells have a fibroblast-like shape and are not polygonal, but have an elongated fibroblast-like shape (page 4 para 97) and have a high level of expression for CD73 (page 4 para 101, para 104)
One of ordinary skill in the art would have been motivated to use the human corneal endothelial cells of Koizumi with enhanced purity (such as at least 90%, or as close as possible to 100%) to optimize their effects in the method of Takahashi because Koizumi teach that their cells are suitable for use in methods of treating corneal endothelial dysfunction by injection of these cells (page 28 para 339). One of ordinary skill in the art would have had a reasonable expectation of success because both Koizumi and Takahashi suggest the use of human corneal endothelial cells that replicate normal function and have positive expression of barrier function ZO-1 positive and pumping function Na+/K+ ATPase.
However, even if the corneal endothelial cells of Koizumi are not the same as the claimed cells due to the issue of CD24 expression or non- expression, the teachings of Lupatov and Deng would have rendered the claimed corneal endothelial cells an obvious choice from the corneal endothelial population of Koizumi.
Lupatov teach that cells that were positive to for CD73, CD90, and CD105 markers were fibroblast cells or fibroblast-like cells and included a subpopulation that co-expressed CD24 and CD90 or CD24 and CD54 (page 537, abstract, page 539-542). Therefore, CD24 would be expected to be found on fibroblast-like cells and non- fibroblastic cells would be expected to be negative for CD24.
Deng disclose the CD24 is overexpressed in glioma cells in vitro and in vivo (abstract). Deng teach that accumulating evidence indicates that CD24 is an important marker for cancer diagnosis and prognosis. For various metastatic tumors, most studies have reported that the overexpression of CD24 protein might contribute to metastasis and by consequence poor prognosis (page 5). Various cancers in various tissues all have high expression of CD24 including breast cancer, non-small cell lung cancer, hepatocellular carcinoma, esophageal cancer, pancreatic cancer, cholangiocarcinoma, urothelial carcinoma, ovarian cancer and prostate cancer (pages 5-6).
Since the Koizumi corneal endothelial cells are CD73 negative and non-fibroblastic with a normal polygonal shape (see para 101 of Koizumi) and preferred for further use, one of ordinary skill in the art would have been motivated to select those cells of Koizumi that are CD24 negative because Lupatov suggest that non-fibroblast cells are preferred and that non-fibroblast cells are CD24 negative and CD73 negative. Additional motivation to avoid CD24 positive cells is provided by Deng which teach that CD24 expression is found in many different cancerous tissues and CD24 expression correlates with tumor lymph node metastasis, tumor grade and survival time (pages 5-6). One of ordinary skill in the art would have had a reasonable expectation of success because Koizumi indicate the preferred corneal endothelial cells are CD73 negative and non-fibroblastic and demonstrate their marker expressions by flow cytometry.
Regarding claim 33, Takahashi is silent with regard to the cell density for administration of human corneal endothelial cells to a human eye.
However, Takahashi teach wherein a cell density for administration of rabbit corneal endothelial cells to the anterior chamber of a rabbit bullous keratopathy model is 2.0 x 105 in 200 ul (page 15 para 168).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to use the cell density for administering rabbit cells described by Takahashi as a starting point for the optimization of the cell density for human cell administration because Takahashi teach and suggest that their method is also performed with human cells for human patients.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of aclaim 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) (MPEP 2144.05).
The selection of specific cell densities for human cells for administration to a human patient clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the therapeutic effect of the cells on the damaged tissue would be affected by the cell density administered.
Regarding claim 43, Takahashi are silent with regard to the expression of ZO1 and Na+/K+ ATPase in human endothelial cells.
However, Takahashi teach wherein the rabbit corneal endothelial cells combined with compound (1) express ZO-1 and Na/K ATPase and that these are indicative of cells with corneal endothelium barrier function and corneal endothelium pumping function which are desirable and beneficial functional properties and necessary for cells used in transplantation (pages 14-15, para 163-165).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to use human corneal endothelial cells with compound (1) that positively express ZO-1 and Na/K ATPase in the method of Takahashi because Takahashi teach and suggest that these positive protein expressions are beneficial and desirable for corneal endothelial cell function and needed in corneal endothelial cells when used for transplantation.
Regarding claims 38, Takahashi teach that when the subject is human that autologous transplantation is preferred (page 11 para 114) and this would have ensured that the cell population administered did not induce an allogeneic rejection upon infusion into the anterior chamber of a human eye or elicit an increased amount of serum inflammatory cytokines after in vivo administration. Optimizing the method of Takahashi to avoid an increased amount of serum inflammatory cytokines would have been an obvious tactic as inflammation would have negative effects on the therapeutic effect of the method as well.
Therefore, the combined teachings of the copending claims, Takahashi et al, Koizumi et al, Lupatov et al and Deng et al render obvious Applicant’s invention as claimed.
Koizumi teach a cell population of normal human functional corneal endothelial cell that is positive for CD 166 and is in contrast to transformed corneal endothelial cells which express CD73, CD133 and CD44 (page 6 para 114, page 20, para 243-244), thus deemed to be negative for CD73, CD133 and CD44. This cell population is deemed a normal corneal endothelial cell population and is thus deemed capable of eliciting a human corneal functional property when infused into an anterior chamber of the human eye baring evidence to the contrary. Koizumi teach wherein their normal human functional corneal endothelial cells are purified (abstract, pages 22-23 para 264-267) and define purified as by at least 95% (page 10 para 143). The normal isolated corneal endothelial cells are taught to be used for eye therapy where they are infused into the anterior chamber (page 28 para 339). Since these cells are indicated as “normal” they are deemed without karyotype aneuploidy.
Koizumi teach wherein barrier function ZO-1 positive and pumping function Na+/K+ ATPase indicate normal function of the corneal endothelial cells (Page 28, para 336-337). Koizumi teach wherein transformed human corneal cells express CD90 in contrast to normal human corneal endothelial cells and therefore the normal cells are deemed to be negative for CD90 (page 26, Example 1, Table 1-2, para 314-315). Koizumi teach wherein their normal human corneal endothelial cells are suitable for use as pharmaceuticals (page 29, para 341). Koizumi suggest beneficially including a rho kinase (ROCK) inhibitor to the cells (page 13 para 161-162), such as Y-27632 (page 13 para 164).
Okumura teach that cell surface markers can be used to characterize the phenotype of corneal endothelial cells destined for tissue engineering therapy and allow for purification of functional cells (page 7610, abstract). Flow cytometry analysis demonstrated that CD98, CD166 and CD340 are elevated in human corneal endothelial cells of non-fibroblastic phenotype, while CD9, CD49e, CD44 and CD73 are markers of fibroblastic phenotype. Cells that are CD73-negative exhibited normal hexagonal morphology and expressed functional markers, whereas cells that sorted as CD73-positive exhibited the fibroblastic phenotype (page 7610, abstract, page 7613 entire page).
Lupatov teach that cells that were positive to for CD73, CD90, and CD105 markers were fibroblast cells or fibroblast-like cells and included a subpopulation that co-expressed CD24 and CD90 or CD24 and CD54 (page 537, abstract, page 539-542). Therefore, CD24 would be expected to be found on fibroblast-like cells and non-fibroblastic cells would be expected to be negative for CD24.
Since the Koizumi corneal endothelial cells are CD73 negative and non-fibroblastic with a normal polygonal shape (see para 101 of Koizumi) and preferred for further use, one of ordinary skill in the art would have been motivated to select those cells claimed by the copending application that are CD24 negative because Okumura and Lupatov suggest that non-fibroblast cells are preferred and that these non-fibroblast cells are CD24 negative and CD73 negative. One of ordinary skill in the art would have been motivated to use human corneal endothelial cells that are CD166 positive, CD105 negative, CD24 negative, CD44 negative for administering into an anterior chamber of a human eye because Koizumi, Okumura and Lupatov suggest that these are cell types beneficial for therapeutic treatment of corneal dysfunction. One of ordinary skill in the art would have had a reasonable expectation of success because Koizumi and Okumura indicate the preferred corneal endothelial cells are CD73 negative and non-fibroblastic and demonstrate the marker expressions by flow cytometry.
The properties of the claimed cells with regard to their capability of eliciting normal function when infused into an anterior chamber of a human eye and producing a normal karyotype are deemed to be inherent to the cell markers expression and as demonstrated by Koizumi which report their normal function and morphology (para 101).
Therefore, the combined teachings of the copending claims, Takahashi et al, Koizumi et al, Lupatov et al and Deng et al render obvious Applicant’s invention as claimed.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 01/12/2026 have been fully considered but they are not persuasive. Applicant’s arguments have been addressed in so far as they relate to the new rejections above.
Applicant’s amendments to the claims have allowed for the previous new matter rejection under 35 USC 112a to be withdrawn. However, the recent amendment to the claims has required the addition of a new rejection under 35 USC 112a to be included as recited above.
Claim rejection 35 USC 103
Applicant argues that the cited references do not teach or suggest the recited marker combination. Applicant asserts that nowhere do these references alone or in combination disclose or suggest the particular combination of markers recited in the claims nor do they provide any motivation to select for a population of cHCECs with this phenotype.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Takahashi specifically disclose using human corneal endothelial cells in a method of treating corneal endothelial dysfunction or disease but are silent regarding the marker expression. Koizumi teach a cell population of normal human functional corneal endothelial cell that is positive for CD 166 and is in contrast to transformed corneal endothelial cells which express CD73, CD133 and CD44 (page 6 para 114, page 20, para 243-244), and thus the normal human corneal endothelial cells are also deemed to be negative for CD73, CD133 and CD44. This cell population is deemed a normal corneal endothelial cell population and is thus deemed capable of eliciting a human corneal functional property when infused into an anterior chamber of the human eye baring evidence to the contrary. Koizumi teach wherein their normal human functional corneal endothelial cells are purified (abstract, pages 22-23 para 264-267) and define purified as by at least 95% (page 10 para 143). The normal isolated corneal endothelial cells are taught to be used for eye therapy where they are infused into the anterior chamber (page 28 para 339).
The expression of CD24 in the normal human corneal endothelial cell population of Koizumi is also deemed to be and obvious selection based on the evidence provided by Deng and Lupatov as described above.
Applicant argues that Applicant’s own data confirm that morphologically normal cell populations obtained using the methods of Koizumi and Okumura remain heterogenous and can include CD24 positive and CD44 highly positive cells, underscoring that morphology-based enrichment does not inevitably yield cells of the claimed marker profile at a 75% purity threshold.
This is not found persuasive. Morphological observations are not the only criteria used to select the cells in Koizumi as described above.
Applicant argues that choosing cHCEC populations of their precise phenotypic identity species and purity level for treatment of endothelial dysfunction is not taught or suggested and would require undue picking and choosing.
This is not found persuasive because Koizumi specifically teaches and suggests the beneficial purification of corneal endothelial based on the picking and choosing of desired cell surface markers as described above.
Applicant argues that there is no reasonable expectation of success as Takahashi lacks data using cultured cells and Okumura and Koizumi provide no clinical efficacy data and expressly call for further studies.
This is not found persuasive. Koizumi specifically teaches and suggests the beneficial purification of corneal endothelial based on the picking and choosing of desired cell surface markers as described above which provides the details needed in the Takahashi reference method to identify and isolate the desired normal cell type for therapeutic purposes.
Applicant argues that Applicant’s data showed that cell populations with a high proportion or percentage of cells having the recited cell surface marker phenotype was unexpectedly found to be particularly efficacious in the clinics. Applicant asserts that the cel population claimed by Applicant achieves unexpected and clinically superior effects
This is not found persuasive. The prior art indicates that normal human corneal endothelial cells are expected to provide better therapeutic results the more they are purified and free of transduced abnormal fibroblast-like cells as suggested by Koizumi.
Applicant argues that Takahashi does not recognize any CD-immunophenotype as a variable for achieving corneal endothelial function after anterior chamber administration. Applicant argues that Takahashi gives no basis for selecting a particular CD profile for the administered corneal endothelial cells.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The teachings of the secondary references provide the suggestion and motivation to select those specific normal corneal endothelial cells expected to be beneficial for therapeutic use with desirable cell markers indicative of normal corneal endothelial cells as described above.
Applicant argues that it was known in the art that cultured human corneal endothelial cell populations comprise heterogenous mixtures of multiple subpopulations of cells and point to their specification and the declaration of Dr. Lacoste. Applicant argues that evidence from their Specification shows that their claimed cells are distinct from the cells of Okumura and Koizumi and that the normal cells of these references do not have the same marker expression as the claimed cells. Applicant points to paragraphs 310-314 and 372 and Table 1Ga as evidence that the cells cultured according to the method of Okumura produced cells that were CD166+, CD24+ and CD44+.
This is not found persuasive. Koizumi do not rely on morphological observation alone for the purification of normal corneal endothelial cells. Koizumi indicates that the markers for normal cells and the markers for transduced cells are used together to obtain a purified normal corneal endothelial cell population suitable for transplantation as described above.
Applicant argues that Takahashi does not provide the required details necessary for the claimed invention.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Takahashi specifically disclose using human corneal endothelial cells in a method of treating corneal endothelial dysfunction or disease but are silent regarding the marker expression. Koizumi teach a cell population of normal human functional corneal endothelial cell that is positive for CD 166 and is in contrast to transformed corneal endothelial cells which express CD73, CD133 and CD44 (page 6 para 114, page 20, para 243-244), and thus the normal human corneal endothelial cells are also deemed to be negative for CD73, CD133 and CD44. This cell population is deemed a normal corneal endothelial cell population and is thus deemed capable of eliciting a human corneal functional property when infused into an anterior chamber of the human eye baring evidence to the contrary. Koizumi teach wherein their normal human functional corneal endothelial cells are purified (abstract, pages 22-23 para 264-267) and define purified as by at least 95% (page 10 para 143). The normal isolated corneal endothelial cells are taught to be used for eye therapy where they are infused into the anterior chamber (page 28 para 339).
Applicant argues that the data of Koizumi show that the morphologically normal samples of cHCECs have enhanced expression of table 2 markers and decreased expression of Table 3 markers and does not show necessary presence of markers disclosed in Table 2 in every normal cell or necessary absence of markers disclosed in Table 3 in every normal cell. Applicant asserts that nothing in Koizumi teaches that its normal cells necessarily, inevitably have a phenotype positive for any specific marker in Table 2 and negative or weakly positive for any specific marker in Table 3. Applicant asserts that no conclusion can be made based on the data in Koizumi regarding co-expression or lack thereof of CD166, CD105, CD24, and CD44 in any cell or even 75% of the cells. Applicant also points out that Koizumi is silent with regard to the expression of CD24 nor does Koizumi teach any negative expression for any markers for normal cells.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Koizumi indicates that the markers for normal cells and the markers for transduced cells are used together to obtain a purified normal corneal endothelial cell population suitable for transplantation as described above.
Applicant argues that Koizumi is silent with regard to the CD24 expression of the corneal endothelial cells.
This is not found persuasive because Lupatov and Deng provide the motivation to select cells that are negative for CD24 expression as described above.
Applicant argues that Koizumi does not necessarily teach that markers like CD166 are necessarily present in each normal cell and markers like CD44, CD105 and CD24 are necessarily absent from each normal cell. Applicant asserts that at best Koizumi discloses a large genus of markers and does not teach or suggest the species of the combination of four markers recited in Applicant’s claims or selecting cells based on such four markers.
This is not found persuasive. Koizumi indicates that the markers for normal cells and the markers for transduced cells are used together to obtain a purified normal corneal endothelial cell population suitable for transplantation as described above.
Applicant argues that the Okumura reference does not teach or suggest the claimed invention.
This is not found persuasive because the Okumura reference is no longer relied upon for the current rejections.
Applicant argues that Lupatov provides no reason or motivation to focus on CD24 as a marker for HCEC selection and there is nothing obvious based on the combined discloses of Lupatov, Okumura and Koizumi in selecting CD24 negative as one of the four markers for identifying desired functional human corneal endothelial cells.
This is not found persuasive. First Okumura is no longer relied upon in the new rejections above. Second, both Lupatov and Deng provide motivation to avoid the use of cells that are positive in expression for CD24 due to the correlation of this cell marker with abnormal cancerous tissue as described above.
Applicant argues that a prima facie case of obviousness has not been established and cite the MPEP 2142 and KSR Int’l Co. v. Teleflex Inc and Restem LLC v. Jadi Cell, LLC as evidence. Applicant asserts that their claim invention shows unexpected results.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The teachings of the secondary references provide the suggestion and motivation to select those corneal endothelial cells expected to be beneficial for therapeutic use with desirable cell markers indicative of normal corneal endothelial cells as described above.
Applicant’s evidence is deemed insufficient to overcome the obviousness rejection because the prior art specifically teaches and suggests that the purification of normal human corneal endothelial cells is expected to provide superior therapeutic results over cell populations that are contaminated with transformed fibroblast-like cells as described above.
Applicant argues that Takahashi, Koizumi and Lupatov each do not include all the limitations of the claimed invention.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The teachings of the secondary references provide the suggestion and motivation to select those corneal endothelial cells expected to be beneficial for therapeutic use with desirable cell markers indicative of normal corneal endothelial cells as described above.
Applicant argues that the many surface markers identified in Koizumi and Okumura could be combined in ways that lead to a myriad of marker combinations. Applicant argues that the marker combinations suggested by Koizumi and Okumura to identify fibroblastic and non-fibroblast cells are different from those specified in Applicant’s claims. Applicant points to Koizumi paragraph 316 and Example 4 and Okumura abstract and pages 7613, 7614, 7617 as evidence that these references do not use the same markers as Applicant. Applicant asserts that there is no mention of CD105 or CD24 in the list of markers disclosed by Okumura.
This is not found persuasive. First Okumura is no longer relied upon in the new rejections above. Second, Koizumi indicates that the markers for normal cells and the markers for transduced cells are used together to obtain a purified normal corneal endothelial cell population suitable for transplantation as described above. Third, both Lupatov and Deng provide motivation to avoid the use of cells that are positive in expression for CD24 due to the correlation of this cell marker with abnormal cancerous tissue as described above.
Applicant argues that the deficiencies of Koizumi, Okumura and Lupatov are not cured by Laughlin.
This is not found persuasive as Koizumi, Okumura and Lupatov are not deemed to be deficient as discussed above.
Double Patenting
Applicant argues that the double patenting rejection over application 17/802824 should be withdrawn because it has a later filing date and because it is the only rejection remaining.
This is not found persuasive because it is not the only rejection remaining. However, this particular double patenting rejection has been withdrawn due to the latest amendments filed in application 17/802824.
Applicant requests withdrawal of the provisional double patenting rejection upon Applicant’s express abandonment of the copending Application No. 19/259859.
This is found persuasive and this rejection has been withdrawn.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Miyata et al., “Effect of Donor Age on Morphologic Variation of Cultured Human Corneal Endothelial Cells”, Cornea, 2001, 20(1): 59–63.
(page 62, Discussion- In summary, cultured HCEC displayed greater heterogeneity with older donor age. These results suggest that the use of HCEC from younger donors may be preferable to maximize the benefits of HCEC transplantation.)
Peh et al., “Optimization of human corneal endothelial cell culture: density dependency of successful cultures in vitro”, BMC Research Notes, 2013, 6:176, pp. 1-9.
(abstract- Results demonstrated a density dependency in the culture of primary human corneal endothelial cells. Sub-optimal seeding density results in a decrease in cell saturation density, as well as a loss in their proliferative potential. A seeding density of not less than 10,000 cells per cm2 for regular passage of primary human corneal endothelial cells is proposed.
Li et al., “Clinical Value of CD24 Expression in Retinoblastoma”, Journal of Biomedicine and Biotechnology, 2012, Volume 2012, Article ID 158084, pp. 1-6.
(abstract- This is the first correlation between CD24 expression and histopathology in human retinoblastoma. The study showed increased expression of CD24 in high risk tumors compared to low risk tumors.)
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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