DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 17 March 2026 have been entered. Claims 2-16, 18-22, and 24-27 were previously pending in the application. Claims 6 and 15 have been cancelled, and new claim 28 has been added by Applicant. Claims 2-5, 7-14, 16, 18-22, and 24-28 are currently pending in the application. Claims 24, 25, 26, and 28 are independent claims.
The election of Group IV, drawn to a method of producing a neural retina sheet, remains in effect in the instant application. The following election of species remains in effect in the instant application:
Single tissue marker: A) brain: a. telencephalon.
Claim 24 remains withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claims 2-5, 7-14, 16, 18-22, and 25-28 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2020/011254, filed 13 March 2020, which claims priority to Japan 2019-046505, filed 13 March 2019. Filing of a certified copy of the Japan 2019-046505, filed 13 March 2019 is acknowledged.
Thus, the earliest possible priority for the instant application is 13 March 2019.
Specification
The objection to the specification of the disclosure for the Brief Description of the Drawings not including a description of each panel in Figures 8, 9, and 14, and for the use of trade names and/or marks used in commerce without the accompanying marks and/or generic terminology, is withdrawn.
Claim Objections
The objections to amended claims 3, 5, 16, and 25 for multiple informalities is withdrawn in view of the amendment to claims 3, 5, 16, and 25.
**The following new objections are necessitated by amendments to the claims.
Amended claim 11 is newly objected to because of the following informalities: the line break between “the” and “transplant” comprises an indentation which appears to be a typographical error in that an indentation breaking up an indefinite article and the noun which it modifies is an improper format. Appropriate correction is required.
Amended claim 16 is newly objected to because of the following informalities: claim 16 has an extra space between “at” and “different” in line 16. Appropriate correction is required.
New claim 28 is newly objected to because of the following informalities: claim 28 recites “determined as being applicable as the transplant neural retina by step (d)” in lines 15-16, which improperly references step (d) as the determining step given that step (e) is the determining step and (d) is the detecting step. Appropriate correction is required.
Claim Interpretation
Amended and new independent claims 25, 26, and 28 recite “a neural retina sheet having an epithelial structure” (claim 25 line 1, claim 28 line 1), “a neural retina having an epithelial structure” (claim 25 lines 3-4, claim 26 lines 3-4, claim 28 lines 3-4), and/or “a continuous epithelium structure”. Additionally, claims 8, 9, 10, 11, 12, 21, 22, and 27 each recite, “epithelial tissue”.
The instant specification defines “epithelial tissue” and “epithelial structure” in paragraph [0040]:
‘The "epithelial tissue" is a tissue formed by covering the body surface or the surface of a lumen (digestive tract, etc.), body cavity (pericardial cavity, etc.) or the like with cells without any space. The cells forming the epithelial tissue are referred to as epithelial cells. The epithelial cells have a polarity in the apical-basal direction. The epithelial cells can mutually and firmly join via adherence junction and/or tight junction to form a layer of the cells. A tissue formed from a single layer or dozen layers overlapping of this layer of the cells is the epithelial tissue. In a tissue capable of forming the epithelial tissue, retinal tissue, brain and spinal cord tissue, eyeball tissue, neural tissue or the like of a fetal stage and/or an adult is also included. In the specification, the neural retina is also the epithelial tissue. The "epithelial structure"
means a structure characteristic of the epithelial tissue, such as apical surface or basal membrane.’
Therefore, “epithelial structure” has been interpreted to encompass any structure exhibited by any epithelial cells even when the structure is present in non-epithelial cells. Additionally, “epithelial tissue” has been interpreted to encompass any epithelial or neural tissues, including retinal tissue (such as a neural retina), brain and spinal cord tissue, other eye tissue, and other neural tissue.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, original, and cancelled claims 2-16, 18-22, and 25-27 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn over cancelled claims 6 and 15 and maintained in modified form over amended, previously presented, and original claims 2-5, 7-14, 16, 18-22, and 25-27, and newly applied to new claim 28.
Applicant amended the claims to address most of the identified issues of indefiniteness. However, the amendments have not satisfactorily addressed the following issues and/or have introduced new issues of indefiniteness, as discussed below.
Amended independent claim 25 has multiple issues of indefiniteness.
Amended independent claim 25 now recites, “a cell aggregate” in lines 3, 5, and 6, which is indefinite because it is unclear whether these are meant to be the same cell aggregate.
Additionally, claim 25 recites, “sampling a part of a cell aggregate as a neural retina sheet” in line 5, “sampling the part of a cell aggregate as a sample for quality determination” in line 6, which is indefinite because it is unclear how the part of a cell aggregate is sampled both as a neural retina sheet and as a sample for quality determination in that “the part” indicates that the same part is sampled. As such, it is unclear whether Applicant intends for the “a part” which is sampled in line 5 to refer to the portion of the aggregate that is “sampled”/removed to become the neural retina sheet or whether Applicant intends for “sampling” to encompass removing a part of the “a part” recited in line 6, such that “a part of a cell aggregate” (line 5)/ “the part of a cell aggregate” (line 6) is a portion of the cell aggregate from which two sub-parts are removed/sampled to obtain the neural retina sheet and the sample for quality determination.
Further, claim 25 recites, “determining that the neural retina sheet in the same cell aggregate as the sample for quality determination is applicable as the transplant neural retina”, which is indefinite in that the neural retina sheet is the same part of a cell aggregate as the sample for quality determination, and (d) requires that the sample for quality determination be used for detecting expression of a neural retina-related cell-related gene and a non-neural retina-related cell-related gene. As such, it is unclear what is meant to be encompassed by reciting that the neural retina sheet is in the same cell aggregate as the sample for quality determination. It is further unclear how the neural retina sheet can be applicable as the transplant neural retina after it has been used/consumed in the (d) detecting step.
Also, recitation of ”the expression” in lines 7 and 9, “the same cell aggregate” in line 11, and “the transplant neural retina” in lines 11-12 and 13 lack antecedent basis as claim 25 has no prior recitations of an expression, a same cell aggregate, or a transplant neural retina.
Recitation of “the neural retina sheet” in lines 16, 30, and 34-35 lack antecedent basis in that claim 25 has prior recitations of “a neural retina sheet” in line 5, “the neural retina sheet” in lines 10 and 13, and “the selected neural retina sheet” in line 15. Therefore, it is unclear to which neural retina sheet “the neural retina sheet” of lines 16, 30, and 34-35 are referring.
Recitation of “the non-neural retina-related cell-related gene” in lines 35 and 54 lacks antecedent basis because claim 25 has prior recitation of “a non-neural retina-related cell-related gene” in both lines 7-8 and 33, as well as a prior recitation of “the non-neural retina-related cell-related gene” in line 10.
As such, the metes and bounds of the claim still cannot be determined.
In the interest of compact prosecution, lines 5-6 have been interpreted to encompass (b) sampling a first part of the cell aggregate obtained in (a) to obtain a neural retina sheet, and (c) sampling a second part of the cell aggregate obtained in (a) to obtain a sample for quality determination.
Amended claim 4 recites, “the non-neural retina-related cell-related gene” in lines1-2, which lacks antecedent basis because claim 25, upon which claim 4 depends, now recites “a non-neural retina-related cell-related gene” in both lines 7-8 and 33, as well as a recitation of “the non-neural retina-related cell-related gene” in line 10. As such, the metes and bounds of the claim cannot be determined.
Amended claim 7 now recites, “the transplant neural retina is located continuous or adjacent at least partially to the part consisting of the sample for quality determination in the same cell aggregate” in lines 4-6, which is indefinite because claim 25 recites “sampling the part of a cell aggregate as a sample for quality determination” such that the part of a cell aggregate which is a neural retinal sheet is the same part of a cell aggregate which is a sample for quality determination. As such, the metes and bounds of the claim cannot be determined.
Previously presented claim 8 still recites, “wherein the transplant neural retina is contained in the same epithelial tissue as that of the sample for quality determination” in lines 1-2. There is still insufficient antecedent basis for “the same epithelial tissue”. None of claims 8 nor 7 or 25, upon which claim 8 depends, have any prior recitations of any epithelial tissue.
Additionally, it is unclear what is meant to be encompassed by reciting that the transplant neural retina, which is both the neural retina sheet and the sample for quality determination as recited in claim 25, is contained in the same epithelial tissue as that of the sample for quality determination, thereby saying that it is contained in the same tissue as itself. Further, it is unclear in what way the transplant neural retina is contained in the epithelial tissue. For example, it is unclear whether the neural retina is required to be completely surrounded by the epithelial tissue or whether the neural retina merely needs to be in contact with, adjacent to, or near the epithelial tissue, or whether the neural retina is meant to be a portion of the epithelial tissue.
As such, the metes and bounds of the claims cannot be determined.
Amended claim 9, which is dependent on claim 8, still recites “the transplant neural retina contains the center of the same epithelial tissue” in line 2, which is indefinite because it is still unclear how the transplant neural retina in contained in the same epithelial tissue (as recited in claim 8) and also contains the center of the same epithelial tissue. Regarding “the center”, it is still unclear which dimension(s) “the center” is referring to, such as the vertical center, the center of length, the center of depth, a center of a surface area, and/or a volumetric center. As such, the metes and bounds of the claims cannot be determined.
Amended claim 11 now recites, “the cell aggregate contains first epithelial tissue containing the transplant neural retina”, which is still indefinite because it is unclear how a first epithelial tissue “contains” a neural tissue. For example, it is unclear whether the neural retina is required to be completely surrounded by the epithelial tissue or whether the neural retina merely needs to be in contact with, adjacent to, or near the epithelial tissue, or whether the neural retina is meant to be a portion of the epithelial tissue.
Further, “the cell aggregate” lacks sufficient antecedent basis because claim 7, upon which claim 11 depends, recites, “the same cell aggregate” but does not recite any “a cell aggregate”. Claim 25, upon which claim 7 depends, recites “a cell aggregate” in lines 3, 5, and 6, and “the same cell aggregate” in line 11. Therefore, it is unclear to which cell aggregate “the cell aggregate” of claim 11 is referring.
Additionally, it is unclear how “the sample for quality determination is a part present between the second epithelial tissue and the transplant neural retina” (lines 8-9) in that the transplant neural retina is the neural retina sheet which is the same part as the sample for quality determination, as recited in claim 25.
As such, the metes and bounds of the claim still cannot be determined.
Previously presented claim 14 recites, “the non-neural retina-related cell-related gene” in lines 2-3, which now lacks sufficient antecedent basis in that claim 25, upon which claim 14 depends, now recites, “a non-neural retina-related cell-related gene” in both lines 7-8 and 33, as well as a recitation of “the non-neural retina-related cell-related gene” in line 10. As such, the metes and bounds of the claim cannot be determined.
Amended claim 16 recites, “non-neural retina-related cell-related gene” in lines 4-5, which is indefinite because it is unclear whether it is meant to be the same non-neural retina-related cell-related gene recited in claim 25 lines 7-8, 10, or 33 or a distinct non-neural retina-related cell-related gene.
Additionally, claim 16 recites, “the non-neural retina-related cell-related gene” in line 12, which now lacks sufficient antecedent basis in that claim 25, upon which claim 14 depends, now recites, “a non-neural retina-related cell-related gene” in both lines 7-8 and 33, as well as a recitation of “the non-neural retina-related cell-related gene” in line 10. As such, the metes and bounds of the claim cannot be determined.
Amended claims 18-22 each depend on claim 25 and each newly recite, “the neural retina sheet” in lines 1-2 (claims 18-21) and line 1 (claim 22), which lacks antecedent basis. Claim 25 has prior recitations of “a neural retina sheet” in line 5, “the neural retina sheet” in lines 10, 13, and 16, and “the selected neural retina sheet” in line 15. Therefore, it is unclear to which neural retina sheet “the neural retina sheet” of claims 18-21 are referring.
Additionally, amended claim 21 recites, “the continuous epithelial tissue” in lines 3-4 and “the cell aggregate” in line 4, which lack sufficient antecedent basis. Neither claim 21 nor claim 25 have any prior recitation of a continuous epithelial tissue. Additionally, claim 21 recites “a cell aggregate” in line 2 and claim 25 recites “a cell aggregate” in lines 3, 5, and 6, and “the same cell aggregate” in line 11. Therefore, it is unclear to which cell aggregate “the cell aggregate” of claim 21 line 4 is referring.
Claim 22 recites, “the cell aggregate” in line 4, which lack sufficient antecedent basis. Claim 22 recites “a cell aggregate” in line 2, and claim 25 recites “a cell aggregate” in lines 3, 5, and 6, and “the same cell aggregate” in line 11. Therefore, it is unclear to which cell aggregate “the cell aggregate” of claim 22 line 4 is referring.
Claim 22 also recites “a human neural retina” in line 4, which is indefinite because it is unclear whether the human neural retina recited in claim 22 line 4 is meant to be the same neural retina layer recited in claim 25.
As such, the metes and bounds of the claims cannot be determined.
Amended independent claim 26 now recites, “the sample for quality determination being a part of the each of the cell aggregate” in line 4. There is insufficient antecedent basis for “the sample for quality determination” in the claim. Claim 26 line 2 recites, “sampling a sample for quality determination from each of at least 2 to not more than 800 cell aggregates”, as such, it is unclear which of the at least 2 to not more than 800 samples for quality determination “the sample for quality determination” is referring to.
Further, “being a part of the each of the cell aggregate” is unclear language which renders the claim indefinite.
Independent claim 26 still recites, “the neural retina in the same cell aggregate as the cell aggregate containing the sample for quality determination being the part” in lines 9-11, which has multiple issues of indefiniteness. Firstly, there is insufficient antecedent basis for this limitation in the claim. Claim 26 recites “sampling a sample for quality evaluation from each of 2 or more and 800 or less cell aggregates” in lines 2-3. Therefore, it is unclear which cell aggregate “the cell aggregate” in line 10 is referring to, and it is unclear which of the samples for quality determination “the sample for quality determination” is referring to. Additionally, claim 26 recites “sampling a sample for quality determination from each of at least 2 to not more than 800 cell aggregates” in lines 2-3, “detecting an expression” of genes “in the sample for quality determination” [lines 5-6], and then determining based on the detecting that the neural retinal is applicable as the transplant neural retina. Therefore, it is unclear how the cell aggregate can contain the sample for quality determination following the sampling and detection of genes within the sample. As such, the metes and bounds of the claim cannot be determined.
Additionally, “the sample for quality determination being a part of the each of the cell aggregate” is further indefinite in that it is not clear whether each individual cell aggregate is meant to produce an individual sample for quality determination or whether samples from each of the cell aggregates are meant to be combined into a single sample for quality determination.
Claim 26 also newly recites, “the cell aggregate” in line 18, which lacks sufficient antecedent basis because claim 26 has a prior recitation of “at least 2 to not more than 800 cell aggregates”, and as such, it is unclear which cell aggregate “the cell aggregate” is referencing.
As such, the metes and bounds of the claim cannot be determined.
Claim 27 still recites, “the cell aggregate” in line 2 and line 10. There is insufficient antecedent basis for this limitation in the claim. Claim 27 is dependent on independent claim 25. Claim 25 recites “a cell aggregate” in lines 3, 5, and 6, and “the same cell aggregate” in line 11. Therefore, it is unclear which cell aggregate “the cell aggregate” of claim 27 line 2 is referring to.
Claim 27 also recites “a human neural retina” in line 4, which is indefinite because it is unclear whether the human neural retina recited in claim 27 line 4 is meant to be the neural retina layer recited in claim 25.
Claim 27 still recites, “the transplant neural retina contains a region on the first epithelial tissue” in lines 11-12, which is indefinite because it is unclear how the transplant neural retina can contain a region on the first epithelial tissue. Specifically, claim 27 also recites, “wherein the first epithelial tissue contains a human neural retina” in lines 3-4, and so it is unclear how the first epithelial tissue can contain the neural retina while the neural retina itself contains a region on the first epithelial tissue. further, it is unclear in what way the first epithelial tissue contains the neural retina, such as whether the neural retina is required to be completely surrounded by the epithelial tissue or whether the neural retina merely needs to be in contact with, adjacent to, or near the epithelial tissue, or whether the neural retina is meant to be a portion of the epithelial tissue. As such, the metes and bounds of the claim cannot be determined.
As such, the metes and bounds of the claim still cannot be determined.
New independent claim 28 recites, “a cell aggregate” in lines 3, 5, and 6, which is indefinite because it is unclear whether the “a cell aggregate” of each recitation is meant to be the same cell aggregate.
Additionally, claim 28 recites, “sampling a part of a cell aggregate as a neural retina sheet” in line 5, “sampling the part of a cell aggregate as a sample for quality determination” in line 6, which is indefinite because it is unclear how the part of a cell aggregate is sampled both as a neural retina sheet and as a sample for quality determination in that “the part” indicates that the same part is sampled. As such, it is unclear whether Applicant intends for the “a part” which is sampled in line 5 to refer to the portion of the aggregate that is “sampled”/removed to become the neural retina sheet or whether Applicant intends for “sampling” to encompass removing a part of the “a part” recited in line 6, such that “a part of a cell aggregate” (line 5)/ “the part of a cell aggregate” (line 6) is a portion of the cell aggregate from which two sub-parts are removed/sampled to obtain the neural retina sheet and the sample for quality determination.
Further, claim 28 recites, “determining the neural retina sheet as applicable as the transplant neural retina”, which is indefinite in that the neural retina sheet is the same part of a cell aggregate as the sample for quality determination, and (d) requires that the sample for quality determination be used for detecting expression of a neural retina-related cell-related gene and a non-neural retina-related cell-related gene by quantitative PCR, which is destructive to the sample used. Thus, it is unclear how the neural retina sheet can be applicable as the transplant neural retina after it has been used/consumed in the (d) detecting step.
Also, recitation of ”the expression” in lines 7 and “the transplant neural retina” in lines 9 and 15 lack antecedent basis as claim 28 has no prior recitations of an expression or a transplant neural retina.
Recitation of “the neural retina sheet” in line 18, 31, and 35 lack antecedent basis in that claim 28 has prior recitations of “a neural retina sheet” in line 5, “the neural retina sheet” in lines 9 and 15, and “the selected neural retina sheet” in line 17. Therefore, it is unclear to which neural retina sheet “the neural retina sheet” of lines 18, 31, and 35 are referring.
Recitation of “the non-neural retina-related cell-related gene” in lines 35 and 38 lack antecedent basis because claim 28 has prior recitation of “a non-neural retina-related cell-related gene” in both lines 7-8 and 34, as well as a prior recitation of “the non-neural retina-related cell-related gene” in line 13-14.
Claim 28 recites, “determining the neural retina sheet as being applicable as the transplant neural retina when the following reference 1 and reference 2 are satisfied:
reference 1: the difference between the threshold cycle (Ct) value of the neural retina-related cell-related gene and the Ct value of an internal standard gene (ΔCt value) is 10 or less, and
reference 2: the difference between the Ct value of the non-neural retina-related cell-related gene and the Ct value of the internal standard gene (ΔCt value) is 5 or more”.
Further, claim 28 recites “an expression of a neural retina-related cell-related gene is found and expression of a non-neural retina-related cell-related gene being not found in the neural retina sheet” in lines 34-35. Therefore, claim 28 requires that the neural retina-related cell-related gene be “found” in the neural retina sheet and the non-neural retina-related cell-related gene be “not found” in the neural retina sheet.
However, the limitations of the (e) determining step in lines 9-14 not only allow for the non-neural retina-related cell-related gene to be present in the sample, but also allow for the non-neural retina-related cell-related gene to be present at a higher level than the neural retina-related cell-related gene (e.g., when the internal standard gene is more abundant than either the neural retina-related cell-related gene and the non-neural retina-related cell-related gene, wherein the difference is calculated by subtracting the standard gene Ct from the neural or non-neural gene Ct, and wherein the ΔCt for the non-neural retina-related cell-related gene is lower than the ΔCt for the neural retina-related cell-related gene, such as for the non-neural retina gene to have a ΔCt of 5 and the neural retina gene to have a ΔCt of 10). Note that as written, the “difference between” does not specify which term is the greater term, and the ΔCt values of 10 or less encompass all negative values for ΔCt obtained when the larger Ct value is subtracted from the smaller Ct value.
As such, the metes and bounds of the claim still cannot be determined.
In the interest of compact prosecution, lines 5-6 have been interpreted to encompass (b) sampling a first part of the cell aggregate obtained in (a) to obtain a neural retina sheet; and (c) sampling a second part of the cell aggregate obtained in (a) to obtain a sample for quality determination.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 2-16, 18-22, and 25-27 under 35 U.S.C. 103 as being unpatentable over Nasonkin [US20210155895A1, filed 4 April 2017 with priority to U.S. Provisional Application Nos. 62/318,210, filed 4 April 2016, 62/354,806, filed 26 June 2016, and 62/465,459, filed 1 May 2017]; in view of Singh et al. [2015, Stem Cells & Development, 24(23), 2778-2795]; Mandai et al. [2017, New England Journal of Medicine, 376, 1038-46]; Sanchez-Freire et al. [2012, Nature Protocols, 7(5), 829-838]; Karlen et al. [2007, BMC Bioinformatics, 8, 131, 1-16]; and Sabin & Jones [2008, Nonlinear Systems Biology and Design: Surface Design, 54-65, Acadia Conference 10.52842/conf.acadia.2008.054], is withdrawn over cancelled claims 6 and 15, maintained over amended, previously presented, and original claims 2-5, 7-14, 16, 18-22, and 25-27, and newly applied to new claim 28. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the claims to address issues of indefiniteness.
Additionally, regarding amendments to independent claim 25, Nasonkin was cited for teaching a method for producing a neural retinal sheet/tissue slice, the method comprising:
(a) obtaining a cell aggregate differentiated from pluripotent stem cells and comprising a neural retina having an epithelial structure [0003, 0010-0011, 0145, 0187-0190, Figure 1, 9, 10, 16];
(b) sampling a part of a cell aggregate as a neural retina sheet [0145, 0286, Figure 10, 16];
(c) sampling a cell aggregate to obtain a sample for quality determination [0188, 0272-0273, 0276, 0278, 0281-0285, 0293, 0302-0303];
(d1) detecting the expression of neural retina-related genes and non-neural retina-related genes [0188, 0272-0273, 0276, 0278, 0281-0285, 0293, 0302-0303], such that the sampled neural retina demonstrates expression of neural retina-related genes (e.g., PAX6, EZRIN, CRX, BRN3B) [0285, 0293] and does not express non-neural retina-related genes (e.g., NANOG, OCT3, and markers of cerebrospinal tissues such as markers of astrocytes, or oligodendrocytes) [0302-0303];
(d2) determining the quality of a cell aggregate for suitability for transplantation [0003, 0010-0011, 0145, 0187-0190, 0285];
(e) selecting a transplant neural retina determined as being suitable for transplantation [0010, 0147, 0273]; and
(f) isolating the selected transplant neural retina sheet [0068. 0120].
Nasonkin was also cited for teaching wherein the neural retina sheet
(1) is obtained from a pluripotent stem cell [title, abstract, 0003, Figure 33];
(2) has a three-dimensional structure [0003];
(3) comprises a neural retinal layer having a plurality of layer structures including a photoreceptor layer and an inner layer [0011, 0039, 0121]; wherein the inner layer is adjacent to the photoreceptor layer [0011, Figures 1, 9, 10, 16];
(4) the photoreceptor layer comprises one or more cells selected from the group consisting of a photoreceptor precursor cell and a photoreceptor cell [0011, 0039];
(5) the inner layer comprises one or more cells selected from the group consisting of a retinal precursor cell, a ganglion cell, an amacrine cell, and a bipolar cell [0012, 0066, 0077],
(6) a surface of the neural retinal layer is an apical surface [0074, 0094, 0189, Figure 1];
(7) the photoreceptor layer is located along the apical surface [0011, 0122, 0187, Figure 1, 9, 10, 16];
(8) the area of the neural retinal layer is 50% or more with respect to the total area of the surface of the neural retinal sheet [Figure 10, 16, 33];
(9) the area of a continuous epithelium structure is 80% or more with respect to the total area of the apical surface of the neural retinal layer [Figure 1, 9, 15, 16, 26]; and
(10) an expression of a neural retina-related cell-related gene(s) is found [0014-0023, Figure 20, 33] and expression of non-neural retina-related cell-related gene(s) being not found in the neural retina sheet, wherein the non-neural retina-related cell-related gene(s) comprise one or more genes selected from the group consisting of cerebrospinal tissue marker gene and eyeball-related tissue marker gene, and wherein the non-neural retina-related gene comprises one or more genes selected from the group consisting of brain or spinal cord marker genes and eyeball-related tissue marker genes [0026-0027, 0141-0142, 302-303, claims 14-15].
Nasonkin does not explicitly recite using the same aggregates which were sampled for gene expression analysis as a source of neural retinal sheet for transplantation.
Mandai teaches the pre-transplantation quality assessment of iPSC-derived RPE sheets, such that the autologous iPSC-derived RPE cells were assessed for quality and safety before transplantation according to their protocol, and whole-genome sequencing, whole-genome methylation profiling, and expression analyses were also performed [column 4 ¶ 2]. Mandai goes on to teach the quality standard and assessment of iPSC-RPE sheet includes no contamination of other cell types, the positive expression of RPE markers (e.g., BEST1, RPE65, MERTK, and CRALBP), and the lack of expression of an iPSC marker (e.g., LIN28) [supplemental protocol page 12-13, 5.3.1 Flowchart]. Madai further teaches that quality testing occurs both at the stage following purifying differentiated RPE cells and at the stage following purification of RPE cell sheets, such that assessment of RPE cell sheets on shipping comprises quality test of RPE cells and cell sheets and detection of stem cell markers [page 13, 5.3.1. Flowchart]. Mandai also teaches the expression of RPE markers in the iPSC-RPE and the absence of neural stem cell marker NES (e.g., a cerebrospinal progenitor cell marker) [Table S5, Figure S4, S6].
Therefore, given the teachings of Mandai for assessing the quality of a transplant RPE sheet prior to transplantation into the retina of a patient to ensure suitability and safety of the transplanted sheet, including assessment of gene expression to determine expression of desired cell type-specific genes and lack of expression of undesired cell-type specific genes, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to sample a prepared cellular sheet prior to transplantation to assess the quality of the sheet and to ensure the safety and suitability of the sheet for subsequent transplantation.
Regarding independent claim 26, claim 26 was amended to address issues of indefiniteness without altering the scope of the claim sufficiently to overcome a finding of obviousness over the cited art references.
Regarding new claim 28, new independent claim 28 incorporates a combination of limitations from independent claims 25 and 26 as well as limitations from previously presented claim 14 and cancelled claim 15, which were each addressed above and/or in the previous action.
Accordingly, Applicant’s amendments do not overcome a finding of obviousness under 35 U.S.C. 103 over Nasonkin, Singh, Mandai, Sanchez-Freire, Karlen, and Sabin.
Applicant argues that:
The combination of the cited references does not teach or suggest the claimed sampling step for quality determination in that Nasonkin is silent regarding any sampling a part of a cell aggregate, hESC-3D retinal tissue, as a sample for quality determination or any evaluation method for transplant neural retina without destroying any of the transplant neural tissue, and further in that, and as such, the combination of cited references fails to teach or suggest sampling a part of a cell aggregate and detecting the expression of genes in the sample for quality determination as set forth in the present claims; and
Mandai teaches the assessment only of iPSC-derived RPE cells, not the 3D retina tissue or cell aggregate as set forth in the present claims, nor any idea for sampling a part of a cell aggregate to qualify the transplant neural retina derived from the cell aggregates, such that in reading Mandai, one of ordinary skill in the art would have no reason to incorporate Nasonkin’s hESC-3D retinal tissue, which is not iPSC-derived RPE cells, in Mandai’s assessment method.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that 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). 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). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, 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).
Specifically, regarding Applicant’s argument 1), note that Nasonkin was not cited for teaching every limitation of the claimed invention. As discussed above and in the prior action, Nasonkin was cited for teaching a method for producing a neural retinal sheet/tissue slice for transplantation in a cell-based therapy for retinal degeneration. As discussed above, Nasonkin teaches all the limitation of independent claims 25 and 26 except for sampling from the same cell aggregate as the cell aggregate from which the transplant neural retina is isolated. Note that independent claims 25 and 28 each recite “(b) sampling a part of a cell aggregate as a neural retina sheet, (c) sampling the part of a cell aggregate as a sample for quality determination”, thereby requiring that the neural retina sheet and the sample for quality determination be the same sample part. As such, the subsequence limitations indicating that the neural retina sheet and the sample for quality determination are meant to be alternative parts of the cells aggregate are in conflict with the limitations recited for (b) and (c). To the extent that the limitations for (b) and (c) are meant to indicate sampling different parts of the same cell aggregate (e.g., sampling a first part of a cell aggregate to obtain a neural retina sheet and sampling a second part of the cell aggregate to obtain a sample for quality determination), as discussed above and in the prior action, Mandai was cited for providing the teachings and motivations for sampling a cellular sheet prior to transplantation to ensure the safety and suitability of the sheet for subsequent transplantation [Table S5, Figure S4, S6].
Regarding Applicant’s argument 2), although the cellular sheet of Mandai is an RPE sheet instead of a slice of a cellular aggregate comprising a neural retina sheet, both the RPE sheet of Mandai and the neural retinal sheet of the instant invention are intended for transplantation into the posterior eye to treat retinal degenerations and accordingly have comparable safety and suitability concerns. For example, both products require that the cells be properly differentiated from the pluripotent stem cells from which they were produced, such that cell-type specific gene expression patterns are present which are specific to the desired cell types (i.e., neural retinal cells for the instant invention or RPE cells for Mandai) and further that the samples lack undesirable cell types (e.g., undifferentiated stem cells, insufficiently differentiation precursor cells, and/or alternatively differentiated cells). Therefore, the quality testing taught by Mandai to ensure safety and suitability of the RPE sheet for transplantation is highly relevant for the neural retinal sheet of the instant application. As such, an ordinarily skilled artisan would have been motivated by the teachings of Mandai to test a cellular sheet following purification of the cellular sheet and prior to shipping of the cellular sheet to the intended recipient for proper gene expression profiles to determine the suitability of the cellular sheet for transplantation into the eye of a patient, and therefore would have been motivated to apply the quality testing method of Mandai to the transplant neural retina sheet of Nasonkin with a reasonable expectation of success for evaluating the quality of the transplant neural retina sheet.
Accordingly, Applicant’s amendments and arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Nasonkin, Singh, Mandai, Sanchez-Freire, Karlen, and Sabin, and the rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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