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 .
This action is responsive to papers filed 07/13/2026.
Claims 31, 32, 35-36, 39, 41-42, 54, 60-61, 69-88 are currently pending.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. 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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 31, 32, 35-36, 39, 41-42, 54, 60-61, 69-88 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature judicial exception without significantly more.
The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
Regarding independent claims 31, 77, and 79: The claims are directed to cultured human endothelial cells that are capable of eliciting a human corneal endothelial functional property when infused into an anterior chamber of a human eye, wherein the cells express CD166+, CD105 negative to CD105 weakly positive, CD24 negative, and CD44 negative to CD44 weakly positive.
Dependent claims are drawn to limitations of intended use, additional markers and functional properties that appear to be inherent to the cells.
The claim is directed to a composition, which is a statutory category of invention
(Step 1: YES).
The claimed cells are considered a nature-based product as human functional corneal endothelial cells are naturally occurring cell types.
The corneal endothelium is a single layer of cells that covers the posterior cornea and is organized in a characteristic honeycomb pattern. The most frequently used markers Na+/K+ ATPase and zonula occludens-1 (ZO-1) as evidenced by Van den Bogerd et al (TVST, 2019, page 1). Van den Bogerd also state that healthy human corneal endothelial cells are positive for CD166, but this marker has been challenged and not been widely adopted by other groups to date (page 7).
Non-cultured corneal endothelial cells are discussed by Ting (Cells 2025, abstract and page 19) as a suitable alternative to cultured corneal endothelial cells as they provide the benefits of less manipulation with potentially fewer regulatory hurdles. This suggests that the cultured cells are not significantly different from freshly isolated corneal endothelial cells that have not been cultured and thus differences from cells in nature are questionable.
Thus, the claim is not considered markedly different than natural human cornea endothelial cells, the claim is considered to read on a product of nature judicial exception (Step 2A, Prong 1: YES).
The claim does not integrate the product into a practical application because the claim is to the product human functional corneal endothelial cells, per se, not a method of use. (Step 2A, Prong 2: NO).
Regarding dependent claims 32, 35-36, 39, 41-42, 54, 60-61, 69-76, 78, 80-88: None of the features/limitations of claims 32, 35-36, 39, 41-42, 54, 60-61, 69-76, 78, 80-88 represent significant structural or physical differences between the claimed product and natural human functional corneal endothelial cells. None of dependent claims 32, 35-36, 39, 41-42, 54, 60-61, 69-76, 78, 80-88 are patent eligible either.
On balance the relevant factors weigh against eligibility and claims do not qualify as eligible subject matter under 35 U.S.C. § 101.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 31, 32, 35-36, 39, 41-42, 54, 60, 69-88 are rejected under 35 U.S.C. 103 as being unpatentable over Koizumi (WO 2015/016371 published 2/5/2015-from IDS filed 11/26/2018-using US 2016/0266114 as translation-also from IDS filed 11/26/2018) in view of Lupatov et al (Cell Technologies in Biology and Medicine, Feb 2015) and Deng et al (Journal of Biomedicine and Biotechnology, 2012-newly cited).
Regarding claims 31-32, 35-36, 70-76, 77-88, 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)
The Koizumi reference is silent with regard to CD24 expression.
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 claims 35-36, 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).
Regarding claims 39, 41-42, 54, 69-70, Koizumi is silent with regard to these claim limitations or only teaches some of them with CD166 positive expression and CD26, CD44, CD73, CD90, CD105, CD133 negative expression (page 6 para 114, page 9 para 134). Baring evidence to the contrary, normal corneal endothelial cells that are CD166+ and CD26, CD44, CD73, CD90, CD105, CD133 negative expression are deemed to include these limitations as well.
Regarding claims 75-76, 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).
Therefore, the combined teachings of Koizumi et al, Lupatov et al and Deng et al render obvious Applicant’s invention as claimed.
Claim 62 is are rejected under 35 U.S.C. 103 as being unpatentable over Koizumi (WO 2015/016371 published 2/5/2015-from IDS filed 11/26/2018-using US 2016/0266114 as translation-also from IDS filed 11/26/2018) in view of Lupatov et al (Cell Technologies in Biology and Medicine, Feb 2015) and Deng et al (Journal of Biomedicine and Biotechnology, 2012-newly cited) as applied to claims 31, 32, 35-36, 39, 41-42, 54, 60, 69-88 above, and further in view of Laughlin et al (US 2004/0258670-previously cited).
Regarding claim 62, Koizumi include albumin (BSA) and ascorbic acid combined with their cultured endothelial cells (page 24, para 295, page 25, para 300, para 306), but do not specify that they are excipients. 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 (page 28 para 339).
Laughlin teach methods of cell-based therapies of treating damaged tissue by the administration of cell-based formulations (abstract). A therapeutically effective amount of cells (endothelial cells or mesenchymal stem cells) can be suspended in a pharmaceutically acceptable carrier or excipient such as one including serum albumin (page 8 para 82). Ascorbic acid is also indicated as a beneficial additive to a cell suspension carrier for preservation against contamination (page 8 para 84).
One of ordinary skill in the art would have been motivated to include albumin and ascorbic acid as carriers/excipients for the endothelial cell suspension of Koizumi because Laughlin suggests that these are both beneficial and desirable for the suspension of cells, particularly endothelial cells for administration as a pharmaceutical and Koizumi is using their endothelial cells as a pharmaceutical suspension as well. One of ordinary skill in the art would have had a reasonable expectation of success because Koizumi is also using albumin and ascorbic acid for combination with their endothelial cells for other purposes.
Therefore, the combined teachings of Koizumi et al, Lupatov et al, Deng et al and Laughlin 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, 32, 35-36, 39, 41-42, 54, 60, 62, 69-88 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 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 also drawn to a population of human functional corneal endothelial cells that are 75% or 95% positive for CD166 and negative to weakly positive for CD105 (75% and 95%), negative for CD24 (75% and 95%) and negative/ low for CD44 (75% and 80%) in a method of using for treating corneal endothelial dysfunction.
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).
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).
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 the copending claims 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.
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, Koizumi et al, Lupatov et al, Deng et al and Laughlin et al render obvious Applicant’s invention as claimed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 06/12/2026 have been fully considered but they are not fully persuasive. Applicant’s arguments have been addressed in so far as they relate to the new rejections above.
Applicant argues that Applicant’s own data confirm that morphologically normal cell populations obtained using the methods of Koizumi 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 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 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. 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 there is no reason to believe that any of the normal cells of Koizumi necessarily have the claimed CD marker identity at 75% or more particularly considering known heterogeneity of cHCEC populations. Applicant argues that the phenotype makeup of Koizumi’s HCEC samples tested in Example 1 is unknown and yet they do disclose selection of candidate markers that may potentially be used for sorting and purification of normal cells from phenotypically heterogenous cell mixtures (pointing to example 1 para 303 of Koizumi). Applicant argues that while Koizumi disclose using absence of CD73 to sort and purify for normal cells that they do not specifically use the same marker combination as claimed by Applicant. Applicant argues that the phenotype of Applicant’s claims is at best a species selection to the genus disclosed in Example 1 of Koizumi.
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. The teachings of Lupatov and Deng provide substantial motivation to select cells that are CD24 negative for use of normal cells in transplantation as described above.
Applicant argues that evidence from their Specification shows that their claimed cells are distinct from the cells of Koizumi and that the normal cells of these references do not have the same marker expression as the claimed cells. Applicant asserts that it was surprising to find that cells were visible phenotypes for non-fibroblastic cells and stained for CD24+, CD26+ or CD44+. Applicant argues that morphological judgment alone may not be sufficient to distinguish heterogenous subpopulations present in cHCECs. Applicant also points to Examples 1 and 3, and paragraphs 326, 373-377 in their Specification as evidence that the claimed cells are different from the reference cells.
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.
Toda disclose the production of homogenous cultured human corneal endothelial cells (HCEC) by a method comprising taking a Descemet’s membrane with corneal endothelial cells from donor corneas, digesting with collagenase, seeding the HCECs on a collagen coated plate and culturing them. The culture medium was prepared according to published protocols and included OPTIMEM-I, fetal bovine serum, gentamicin, and an MSC-conditioned medium (page 2012, column 1). The MSC-conditioned medium is indicated as not playing a critical role in improving the E-ratio of the cultured HCECs (page 2013), however the addition of a ROCK-inhibitor Y-27632 is indicated as providing E-ratios of approximately 90% or greater and the contaminating SPs were scarcely found in the cultured CHECs (page 2015). The E-ratio is defined as the proportion of SPs with CD44-, CD166+, CD24-, CD26-, CD105- (page 2013, column 1).
The cells of Koizumi are produced by taking a Descemet’s membrane with human corneal endothelial cells from donor corneal tissue, digesting with collagenase, seeding on a plate coated with FNC coating mix (contains collagen) and culturing them. The culture medium contains OPTIMEM-I, fetal bovine serum, gentamicin and Y-27632 (page 24 para 290). A similar culture medium is also disclosed with additional ingredients in the culture medium (page 25 para 306).
Applicants’ Specification disclose their method of culturing the HCECs that produce the claimed cells (pages 241-242, para 600-601) which is similar to those used by Koizumi and Toda.
Since the normal, non-fibroblastic HCECs of Koizumi are prepared in a similar manner as Toda and Applicant and includes the use of the ROCK inhibitor Y-27632, which Toda indicates is sufficient to produce HCEC with the expression of CD44-, CD166+, CD24-, CD26-, CD105- at greater than 90%, that the Koizumi HCECs have many cells with the same expression of these cell markers as well.
Applicant argues that Lupatov and Deng do not provide a motivation to select CD24 negative cultured corneal endothelial cells. Applicant argues that Lupatov and Deng are not directed to the claimed corneal endothelial cells and are directed to entirely different fields.
This is not found persuasive. First, in response to applicant's arguments against the references individually, 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).
Second, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Lupatov and Deng are cited in the obviousness rejection to demonstrate that no one of ordinary skill in the art would expected to find CD24 expression in a normal healthy corneal endothelial cell and thus one of ordinary skill in the art would have been motivated with a reasonable expectation of success to select cells that were negative for CD24 expression as explained above.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
The current rejections are based entirely on the teachings of the cited references and thus do not rely on impermissible hindsight reasoning to arrive at the claimed invention.
Applicant argues that the deficiencies of Koizumi, Lupatov and Deng are not cured by Laughlin.
This is not found persuasive as Koizumi, Lupatov and Deng are not deemed to be deficient as discussed above.
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 and point to their specification at paragraphs 335, 332, Example 6, paragraph 480, Figure 47, Example 10 and the Ueno 2022 reference as evidence of these unexpected results. Applicant points to Exhibit B, the Ueno 2022 reference which they have submitted for this evidence.
This is not found persuasive. The claimed cell population is not limited to therapeutic use and can be used for various other applications such as research models and drug studies which would not necessarily produce any unexpected results. In addition, 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.
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.
Tuft et al., "The Corneal Endothelium", Eye (1990), Vol. 4, pp. 389-424.
(Tuft disclose the development, structure and function of the corneal endothelium)
Yoshihara et al. “Discovery of Molecular Markers to Discriminate Corneal Endothelial Cells in the Human Body”, PLoS One, 2015, pp. 1-14.
(Yoshihara disclose the molecular markers used to identify corneal endothelial cells.)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached on 8:30-5:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
Prosecution Insights