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 .
Restriction/Election
Applicant’s election of Group II (Claims 28-30), without traverse, in the reply filed on 28 October 2025 is acknowledged.
Claims 1-12, 14, 16-18, 21-23, 26, 55 and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Groups I, III and IV there being no allowable generic or linking claim. It is noted that Applicant added new claims 74-90 which are dependent on independent claim 28.
Election was made without traverse, in the reply filed on 28 October 2025 to the Restriction/Election Office Action mailed on 28 April 2025.
Status of Claims
Claims 1-12, 14, 16-18, 21-23, 26, 55 and 63 show incorrect status identifiers. Applicant is reminded that claims 1-12, 14, 16-18, 21-23, 26, 55 and 63 should be labeled: “(Withdrawn)”; remaining claims should be identified appropriately (MPEP 714 (II)(C)(A)) (See 37 CFR 1.121 (c)).
Appropriate correction is required.
Applicant is required to provide a new claim set showing correct status identifiers in the response to this Office Action.
Claims 1-12, 14, 16-18, 21-23, 26, 28-30, 55, 63 and 74-90 are pending.
Claims 28-30 and 74-90 are rejected.
Claims 28-30 and 76-85 are objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. This application is a 371 of PCT/US2021/034930, filed on 05/28/201, which claims benefit of 63/032,358, 05/29/2020.
Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c).
Claims 28-30 and 74-90 have the effective filing date of 29 May 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 28 November 2023, 09 October 2024, 01 November 2024, 27 December 2024, 04 April 2025, 22 July 2025, 12 August 2025, 18 September 2025 and 13 November 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the Examiner.
However, the following individual documents are not being considered for reasons specific to the cited references, as follows:
Foreign patent document citation B26 “EP1044024” on the IDS received 04 April 2025 is not being considered because no copy was provided.
It is not clear if this was an error by the Office or Applicant. Applicant may provide copies of the missing references in response to this Office action for consideration without the necessity of filing an additional IDS statement under the provisions of 37 CFR 1.97(f).
Drawings
The drawings were received on 28 November 2022. These drawings are objected to.
It is noted that Figure 6 is shown as a figure represented by two separate sheets ("FIG. 6 CONTINUED").
MPEP 608.02 (V) Drawing standards
37 CFR 1.84 (u) Numbering of views. (1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
(2) Numbers and letters identifying the views must be simple and clear and must not be used in association with brackets, circles, or inverted commas. The view numbers must be larger than the numbers used for reference characters.
Therefore, Figure 6 should be labelled as 'Fig. 6A' and 'Fig. 6B'.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) (and/or appropriate amendment to the specification) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
(1) The title contains a typographical error.
The application title reads: "Retinal Pigmented Epithelium and Photoreceptor Dual Cell Aggregates and Method of Use thereof", which should read: "Retinal Pigment Epithelium and Photoreceptor Dual Cell Aggregates and Method of Use thereof", 'retinal pigment epithelium' being the art accepted term for such epithelium.
Appropriate correction is required.
(2) The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1), MPEP 608.01(o), MPEP 608.01(l) and MPEP 2173.03. See also MPEP 2163.06 (III). Correction of the following is required:
The specification recites: "For further differentiation of the RPE cells, the cells are preferably cultured in RPE Maturation Medium (RPE-MM). Exemplary RPE-MM media are shown in Table 3" (originally-filed specification, pg. 36, para. [00159]).
However, there is no Table 3 presented in the disclosure.
The medium formulations are listed in Table 1.
In order to provide proper antecedent basis, Applicant should indicate where in the specification this concept is explained, described or defined, or submit an appropriate amendment to the specification which provides clear antecedent basis for the term in the specification as it relates to limitations in the claimed subject matter, without introducing new matter (MPEP 608.01 (o) and MPEP 2163.06 (III)).
Claim Objections
Claims 28-30 and 76-85 are objected to because of the following informalities:
The claims recite the terms "RPE and PR/PRP" or "RPE" or "PR/PRP" or "PR/PRP to RPE" or "RPE and/or the PR/PRP".
These abbreviations should be followed by the term 'cells' to indicate that the various seedings and other culture manipulations are performed with cells and not tissue sections (e.g., sections of RPE epithelium).
For example, the claims (apart from claim 28, which should also recite the full name of each cell type- see 112(b) rejection below) should read, for example: "RPE cells and PR/PRP cells " or "RPE cells" or "PR/PRP cells" or "PR/PRP cells to RPE cells" or "RPE cells and/or PR/PRP cells".
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
35 U.S.C. § 112(a)
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.
35 U.S.C. §112(a) and pre-AIA 35 U.S.C. §112, first paragraph require that the specification include the following (MPEP 2161 (I)):
(A) A written description of the invention;
(B) The manner and process of making and using the invention (the enablement requirement); and
(C) The best mode contemplated by the inventor of carrying out his invention.
Claim 89 is 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. The claim(s) contain(s) 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 89 fails to comply with the written description requirement because it contains new matter.
Claim 89 recites: "The method of claim 28, wherein the culturing is for at least 1 day."
However, there is no support in the original disclosure nor in the originally-filed claims for the culturing step lasting for at least 1 day.
The specification recites: "In some aspects, the culturing is for at least 10 days, such as for at least 2 weeks, 3 weeks, 1 month, or two months" (originally-filed specification, pg. 4, para. [0022]).
That is, there is no support in the specification for culturing less than 10 days, which would be included in the limitation 'at least 1 day'. For example, there is no support for those days between 1 and 10.
In addition, it is also noted that claim 48 of the originally-filed claims submitted on 28 November 2022 recites: "..., wherein the culturing is for at least 10 days."
To overcome this rejection, Applicant may attempt to demonstrate (by means of argument or evidence) that the original disclosure establishes that he or she was in possession of the new claim, the claim may be amended to recite a culturing time that is supported by the specification or the claim may be canceled.
35 U.S.C. § 112(b)
The following is a quotation of 35 U.S.C. §112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. §112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28-30 and 74-90 are rejected under 35 U.S.C. §112(b) or 35 U.S.C. §112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
[Claims 29, 30 and 74-90 are dependent on claim 28, contain the limitations of claim 28, and, therefore, are rejected for the same reason.]
Claims 75 and 88 are indefinite, because they recite insufficient, improper or unclear antecedent basis for the limitations in the claim(s).
(1) Claim 75 recites: "The method of claim 31, wherein the Y-27632 is added at a concentration of 10 μM."
However, claim 31 has been canceled.
For the purpose of compact prosecution, claim 75 will be interpreted to read: "The method of claim 74, wherein the Y-27632 is added at a concentration of 10 μM."
(2) Claim 88 recites: "The method of claim 28, wherein culture medium is RPE-maturation media (MM) media."
However, it is not clear whether the culture medium described in claim 88 is the same as the culture medium as described in claim 28.
For the purpose of proper antecedent basis, claim 88 will be interpreted to read: "The method of claim 28, wherein the culture medium is RPE-maturation media (MM) media."
(Compare to the wording in claims 86 and 87.)
Claims 28-30 and 74-90 are indefinite because the metes and bounds of the claimed subject matter are not clear.
(3) Claim 28 recites: "A method for producing the dual cell aggregate composition of claim 1 comprising seeding RPE and PR/PRP in culture medium..."
However, it is not clear what the acronyms 'RPE' and 'PR/PRP' stand for, within the context of the claimed subject matter. The specification defines the acronyms to mean 'retinal [pigment] epithelial cells' and 'photoreceptor cells and/or photoreceptor precursor cells' (originally-filed specification, pg. 1, para. [0002]). However, in order to avoid misinterpretation of the acronyms ‘RPE' and 'PR/PRP', the full name for which each abbreviation stands should be incorporated into the claim text at the first recitation of 'RPE' and 'PR/PRP'.
For the purpose of compact prosecution, claim 28 will be interpreted to read: "A method for producing a dual cell aggregate composition comprising seeding retinal pigment epithelium (RPE) cells and photoreceptor and/or photoreceptor precursor (PR/PRP) cells in culture medium..."
(4) Claims 29 and 30 recite the relative term "essentially".
Claim 29 recites: "..., wherein the RPE and PR/PRP are seeded as essentially single-cell suspensions."
Claim 30 recites: "..., wherein the RPE are seeded as an essentially single-cell suspension..."
The specification recites: "The term 'essentially' is to be understood that methods or compositions include only the specified steps or materials and those that do not materially affect the basic and novel characteristics of those methods and compositions" (originally-filed specification, pg. 9, para. [0054]).
However, it is not clear that this definition explains what type of cell suspensions would be considered to be 'essentially single-cell' suspensions.
Therefore, the term 'essentially', as used in claims 29 and 30, is considered to be a relative term which renders the claim indefinite. The specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There is no definition, explanation or description given for the term 'essentially' as it relates to a single-cell suspension (MPEP 2173.05 (b)(I)).
For example, it is not clear how many of the RPE and/or PR/PRP cells need to be in single cell form in order for the entire suspension to be considered to be an essentially single-cell suspension.
This term will be defined by its plain meaning at the discretion of the Examiner, as it applies to the claim language (see MPEP 2111.01).
For the purpose of compact prosecution, the claims will be interpreted to read: Claim 29- "..., wherein the RPE and PR/PRP are seeded as single-cell suspensions"; and Claim 30- "..., wherein the RPE are seeded as a single-cell suspension..."
Claim Interpretations
(1) Claims 76-78, 83 and 84 recite the relative term "about".
For example, claim 76 recites: "..., wherein the ratio of PR/PRP to RPE is about 2:1 to about 500: 1..."
Claim 83 recites: "..., wherein the RPE and PR/PRP are seeded at a density of about 1 million cells/mL to about 10 million cells/mL."
The specification recites: "The term 'about' means, in general, within a standard deviation of the stated value as determined using a standard analytical technique for measuring the stated value. The terms can also be used by referring to plus or minus 5% of the stated value" (spec., pg. 10, para. [0057]).
(2) Claim 88 recites: "..., wherein culture medium is RPE-maturation media (MM) media."
The specification recites: "For further differentiation of the RPE cells, the cells are preferably cultured in RPE Maturation Medium (RPE-MM). Exemplary RPE-MM media are shown in Table 3 (spec., pg. 36, para. [00159]). However, there does not appear to be a "Table 3" in the specification. Table 1, however, does show formulations for various RPE-maturation media, e.g., RPE-MM, RPE-MM XF and RPE-MM + PGE-2 (spec., pg. 47, cont. Table 1 thru pg. 50).
For the purpose of examination, prior art which shows medium for the propagation of RPE cells which comprises the main components of medium RPE-MM, as described on pg. 47, will be considered to be RPE-maturation medium.
(3) Claim 79 recites the abbreviation "PGE-2".
The specification recites: "In further aspects, the culture medium further comprises prostaglandin E2 (PGE-2). In some aspects, the RPE were previously cultured in the presence of PGE-2" (originally-filed specification, pg. 4, para. [0018]).
Claim Rejections - 35 U.S.C. § 102
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 the appropriate paragraphs of 35 U.S.C. §102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 28-30, 74, 75, 81-82, 86-87 and 89-90 are rejected under 35 U.S.C. §102(a)(1)/(a)(2) as being anticipated by Takahashi et al. (Pub. No. WO 2019/050015 A1; see Takahashi et al., Pub. No. US 2020/0206387 A as the English translation of the WO document).
[Takahashi et al. cited in the Restriction/Election Office Action mailed 28 April 2025.]
Takahashi et al. addresses the limitations of claims 28, 29, 30, 74, 75, 81, 82, 86, 87, 89 and 90.
Regarding claim 28, pertaining to a method for producing the dual cell aggregate composition comprising retinal pigment epithelium (RPE) cells and photoreceptor and/or photoreceptor progenitor (PR/PRP) cells,
Takahashi et al. shows a sphere-like cell aggregate comprising: a core part containing neural retina (NR); and a covering part containing retinal pigment epithelium (RPM) in contact with each other. In the neural retina, a neural retinal layer includes at least a photoreceptor layer which is formed from one or more types of cells selected from a group which includes, minimally, photoreceptor (PR) cells and photoreceptor progenitor (PRP) cells (pg. 1, para. [0014]-[0019]).
Further regarding claim 28, pertaining to seeding RPE and PR/PRP in culture medium comprising a ROCK inhibitor and culturing for a period of time sufficient to produce the dual cell aggregate composition,
Takahashi et al. shows the separate preparation of RPE cells and NR [which includes, minimally, PR cells] from human embryonic stem (ES) cells (pg. 14, para. [0199]). Human ES cells were cultured in the presence of a ROCK inhibitor (10µM) (pg. 14, para. [0201]). The human ES cells dispersed into single cells were suspended in serum-free medium in a non-cell-adhesive 96-well culture plate (pg. 14, para. [0203]). At the start of suspension culture Y27632 (ROCK inhibitor, final concentration 20µM) was added to the above serum-free medium (pg. 14, para. [0204]). On day 15 or 18, the aggregates were then long-term cultured on a culture dish in serum medium (DMEM/F12 medium) supplemented with taurine (pg. 14, para. [0205]). On the day 38 after the start of suspension culture, observation was performed with a microscope and a fluorescence microscope. As a result, RPE preparation efficiency was good and the preparation efficiency of the cell aggregate containing neural retina containing CRX positive photoreceptor progenitor cells was good (pg. 14, para. [0205]-[0206]). NR and RPE cells prepared as just described were seeded onto a low-adhesive plate. One hour after the seeding, observation was performed with a microscope and a fluorescence microscope. As a result, it was confirmed that single-cell dissociated RPE cells were sunk to the bottom of the well and gathered around NR (pg. 15, para. [0212]). Cell aggregates of NR-RPE cells at day 50 after adhesion were immobilized with 4% PFA and frozen sections were prepared (pg. 15, para. [0215]; and Figs. 2A and 5A).
Regarding claim 29, Takahashi et al. shows that RPE cells, after being washed with PBS were then single-cell dissociated by pipetting (pg. 15, para. [0210]). NR and RPE cells prepared as just described were seeded onto a low-adhesive plate (pg. 15, para. [0212]; and Figs. 2A and 5A).
Regarding claim 30, RPE cells, after being washed with PBS were then single-cell dissociated by pipetting (pg. 15, para. [0210]). NR was collected in a tube, coated with iMatrix 511 or Matrigel and washed with PBS (pg. 15, para. [0211]). NR and RPE cells prepared as just described were seeded onto a low-adhesive plate (pg. 15, para. [0212]; and Figs. 2A and 5A).
Regarding claims 74 and 75, human ES cells dispersed into single cells were then seeded in a Laminin 511-E8 coated plastic culture dish and cultured in the presence of Y27632 (ROCK inhibitor, 10μM) in StemFit medium (pg. 14, para. [0201]). At the start of suspension culture, Y27632 (ROCK inhibitor, final concentration 20μM) was added to the above serum-free medium (pg. 14, para. [0204]).
Regarding claims 81 and 82, the term 'retinal cell' means a cell constituting each retinal layer in a retina in vivo or a progenitor cell thereof. Specific examples of the retinal cells include, but are not limited to, minimally, photoreceptor cells (rod photoreceptor cells, cone photoreceptor cells) (pg. 3, para. [0069]).
Regarding claim 86, pertaining to taurine,
Takahashi et al. shows that the aggregates were long-term cultured on a low-adhesive culture dish in serum medium supplemented with 10% fetal bovine serum, 1 % N2 supplement and Taurin [sic], sometimes referred to as NucT0 medium (pg. 14, para. [0205]).
Regarding claim 87, pertaining to serum-free media,
Takahashi et al. shows that at the start of suspension culture, Y27632 (ROCK inhibitor, final concentration 20 μM) was added to the above serum-free medium (pg. 14, para. [0204]).
Regarding claim 89, on the day 38 after the start of suspension culture, observation was performed with a microscope and a fluorescence microscope. As a result, RPE preparation efficiency was good. The preparation efficiency of the cell aggregate containing neural retina containing CRX positive photoreceptor progenitor cells was good (pg. 14, para. [0205]-[0206]).
Regarding claim 90, the treatment drug or pharmaceutical composition according to one embodiment of the described invention can be produced as a cell suspension by suspending the sphere-like cell aggregate or a portion of the cell aggregate in an appropriate physiological aqueous solvent. If necessary, after addition of a cryopreservation agent, the cell suspension may be cryopreserved, thawed upon use, washed with a buffer, and used for transplantation therapy (pg. 13, para. [0193]).
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. §103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 28-30, 74-78 and 81-90 are rejected under 35 U.S.C. §103 as being unpatentable over Takahashi et al. (Pub. No. WO 2019/050015 A1; see Takahashi et al., Pub. No. US 2020/0206387 A as English translation of the WO document).
[Takahashi et al. cited in the Restriction/Election Office Action mailed 28 April 2025.]
Takahashi et al. addresses the limitations of claims 28-30, 74-75, 81-82, 86-87 and 89-90 above in the 35 U.S.C. §102(a)(1)/(a)(2) rejection.
Takahashi et al. does not explicitly show: 1) the ratio of PR/PRP to RPE is about 2:1 to about 500:1 or about 1:1 to 100:1 or about 2:1 to 50:1 at the time of assembly of the dual cell aggregate composition [Claims 76, 77 and 78]; 2) the RPE and PR/PRP are seeded at a density of about 1 million cells/mL to about 10 million cells/mL or about 5 million cells/mL [Claims 83 and 84]; 3) the RPE and/or the PR/PRP have been previously cryopreserved [Claim 85]; and 4) the culture medium is RPE-maturation media (MM) media [Claim 88].
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for producing a dual cell aggregate composition comprising seeding RPE cells and PR/PRP cells in a culture medium and culturing for a period of time to produce the dual cell aggregate, as shown by Takahashi et al., by formulating the dual cell composition to comprise a ratio of PR/PRP to RPE that is about 2:1 to about 500:1 or about 1:1 to 100:1 or about 2:1 to 50:1 (at the time of assembly of the dual cell aggregate composition) [Claims 76-78], with a reasonable expectation of success, because one of ordinary skill in the art of (mammalian) cell culture propagation would have understood that when combining two types of cells in one culture medium, it would have been obvious, barring a showing of criticality for the specific limitation(s), to have combined the two cell types in a specific ratio (e.g., PR/PRP to RPE at about 2:1 to about 500:1 or about 1:1 to 100:1 or about 2:1 to 50:1), as part of a routine optimization protocol, depending on the desired cell content of the resulting dual cell composition or the growth rate differences between the two cell types (MPEP 2144.05 (II)(III) and MPEP 2144.05 (II)).
Takahashi et al. shows in Figures 2A and 5A that the relative ratio of RPE cells and NR (as an aggregate) can be envisioned (Figs. 2A and 5A).
It would have been further obvious to have seeded the RPE and PR/PRP cells at a density of about 1 million to about 10 million cells/mL or at a density of about 5 million cells/mL [Claims 83 and 84], with a reasonable expectation of success, because one of ordinary skill in the art of (mammalian) cell culture propagation would have understood that when combining two types of cells in one culture medium, it would have been obvious, barring a showing of criticality for the specific limitation(s), to have seeded the two cell types in at a specific concentration (e.g., at a density of about 1 million to about 10 million cells/mL or at a density of about 5 million cells/mL), as part of a routine optimization protocol, depending on the type of substrate being used to propagate the cell combination or the desired time for the cells to come to confluence on the substrate or the number of cells available to perform the co-culture propagation step (MPEP 2144.05 (II)(III) and MPEP 2144.05 (II)).
Takahashi et al. shows in Figures 2A and 5A that the seeding density of RPE cells and NR (as an aggregate) can be envisioned (Figs. 2A and 5A).
It would have been further obvious to have used RPE and/or the PR/PRP cells that had been previously cryopreserved [Claim 85], with a reasonable expectation of success, because Takahashi et al. shows that final dual cell aggregate composition can be cryopreserved then thawed and used in a subsequent transplantation therapy (pg. 13, para. [0193]; and above in the 102 rejection). Therefore, it would have been obvious to one of ordinary skill in the art of (mammalian) cell propagation to have considered using previously cryopreserved RPE and/or PR/PRP cells in a culture protocol after thawing, with the reasonably predictable expectation that the cells would have been viable and capable of successfully being cultivated (MPEP 2143 (I)(G)).
It would have been further obvious to have selected a specific type of culture medium, such RPE-maturation media (MM) media [Claim 88], with a reasonable expectation success, because Takahashi et al. teaches that specific examples of a culture medium used for culturing animal cells as a basal medium include a medium, such as, minimally, Glasgow MEM (GMEM) medium, Improved MEM Zinc Option medium, Medium 199 medium, Eagle MEM medium, and aMEM medium (pg. 6, [0096]) (MPEP 2143 (I)(G)).
Takahashi et al. also shows that fetal bovine serum can be added to a culture medium for propagating cell aggregates as well as taurine (pg. 14, para. [0205]). The major components of RPE-MM medium are: MEM alpha or aMEM and fetal bovine serum along with taurine (originally-filed specification, pg. 47, RPE-MM table). Therefore, one of ordinary skill in the art of propagating mammalian cells would have expected that the RPE-MM medium, per instant claim 88, would have supported the propagation of RPE cells and PR/PRP cells as shown by Takahashi et al. which cites alpha MEM, FBS and taurine ingredients (MPEP 2143 (I)(B)(3)). That is, one of ordinary skill in the art would have expected that the two different media would have been functionally interchangeable, barring a showing of criticality for the specific limitation (MPEP 2144.05 (II)(III) and MPEP 2144.05 (II)).
One of ordinary skill in the art would have been motivated to have made those modifications, because the routine optimization of cell culture, particularly for mammalian cells which tend to be environmentally fastidious, is critical for several reasons, particularly with regard to the production of a specific mammalian cell composition, such as the described dual cell aggregate.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 79 is rejected under 35 U.S.C. §103 as being unpatentable over Takahashi et al., as applied to claims 28-30, 74-78 and 81-90 above, and further in view of May-Simera et al. (Cell Reports, 2018, 22: 189-205).
Takahashi et al., as applied to claims 28-30, 74-78 and 81-90 above, do not show: 1) the RPE were previously cultured in the presence of PGE-2.
Regarding claim 79, May-Simera et al. teaches that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation and that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells (pg. 189, column 1, Abstract). Prostaglandin E2 (PGE2), an eicosanoid, enhances ciliogenesis by increasing intraflagellar transport (pg. 192, column 1, para. 1). The described data confirmed that experimentally enhanced ciliogenesis via culturing RPE cells in PGE2 generates fully mature and polarized iPSC-RPE cells (pg. 192, column 2, para. 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for producing a dual cell aggregate composition comprising seeding RPE cells and PR/PRP cells in a culture medium and culturing for a period of time to produce the dual cell aggregate, as shown by Takahashi et al., as applied to claims 28-30, 74-78 and 81-90 above, by selecting RPE cells that had been previously cultured in the presence of PGE-2 [Claim 79], as shown by May-Simera et al., with a reasonable expectation of success, because May-Simera et al. shows that culturing RPE cells in PGE2 generates fully mature and polarized iPSC-RPE cells (MPEP 2143 (I)(G)).
One of ordinary skill in the art would have been motivated to have made that modification, because one of ordinary skill in the art of propagating RPE cells would have optimized the medium for culturing RPE cells so that it contains reagents which would promote and enhance the biochemical/biophysical functions of said cells, especially cells to be used for therapeutic purposes. May-Simera et al. shows that ciliogenesis is a mechanism with which to mature iPSC-derived RPE and lung epithelia. The described work of May-Simera et al. has helped develop mature and polarized iPSC-RPE for autologous cell therapy of AMD patients and also highlights other considerations when developing treatment strategies for retinal degeneration in ciliopathy patients; that a combined defect in RPE and photoreceptors likely underlies the mechanism for ciliopathy-induced retinal degeneration (pg. 203, column 1, para. 3).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 80 is rejected under 35 U.S.C. §103 as being unpatentable over Takahashi et al., as applied to claims 28-30, 74-78 and 81-90 above, and further in view of Akhtar et al. (Stem Cell Res. 2019, 39: 1-11).
Takahashi et al., as applied to claims 28-30, 74-78 and 81-90 above, do not show: 1) the PR/PRP express Recoverin.
Akhtar et al. provides information from which one of ordinary skill in the art of propagating photoreceptor (PR) cells in culture, as shown by Takahashi et al., would have been motivated to have used the cell marker recoverin to identify PR cells to be used in the method, by way of addressing the limitations of claim 80.
Akhtar et al. teaches that retinal organoids (ROs) derived from human-induced pluripotent stem cells recapitulate the three-dimensional structure of retina, mimic human retinal development. The described study involves the contact of primary mouse RPE (retinal pigment epithelium) cells with ROs in co-culture conditions at different time points. unknown. Primary mouse RPE cells were contact co-cultured with ROs at different time points. The described results revealed that the RPE cells accelerated photoreceptor differentiation in ROs. Overall, an improved co-culture system based on modeling of human retina-RPE dynamics during retinogenesis for the evaluation of ocular therapies is shown (pg. 1, Abstract [nexus to Takahashi et al.- co-culture of RPE and PR cells]).
Regarding claim 80, retinal organoids (ROs) derived from human-induced pluripotent stem cells (hiPSCs), are three-dimensional (3D) retina-like structures which recapitulate the cell type and differentiation process of human fetal retina (pg. 1, column 2, para. 1 [nexus to Takahashi et al.- differentiate stem cells into RPE and PR cells]). Neural retina and retinal pigment epithelium (RPE) are two adjacent structures in vertebrate eye, which interact with each other and play essential roles to maintain visual functions (pg. 1, column 1, para. 1 [nexus to Takahashi et al.- co-culture RPE cells and PR-containing NR cells]). To investigate the differentiation process of ROs, the gene expression profiles of differentiated ROs at week 8 (W8), W15, and W25 were analyzed using photoreceptor progenitor markers CRX and RCVRN, rod photoreceptor markers NRL, GNAT1 and RHO, and cone photoreceptor marker OPN1LW/MW (pg. 3, column 2, para. 3 [RCVRN = recoverin]). The expression of RCVRN transcript increased at W15 and W25 (Fig. 1C) (pg. 3, column 2, para. 3; and pg. 4, Fig. 1C thru pg. 5, legend).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for producing a dual cell aggregate composition comprising seeding RPE cells and PR/PRP cells in a culture medium and culturing for a period of time to produce the dual cell aggregate, as shown by Takahashi et al., as applied to claims 28-30, 74-78 and 81-90 above, by selecting PR/PRP cells that express recoverin [Claim 80], as shown by Akhtar et al., with a reasonable expectation of success, because Akhtar et al. shows that the cell surface marker recoverin (RCVRN) is considered to be a photoreceptor progenitor cell marker (MPEP 2143 (I)(G)).
Therefore, it would have been obvious to have used PR/PRP cells which express recoverin in the method for producing a dual cell aggregate, as shown by Takahashi et al., because the use of these cells would ensure that the selected cells would, in fact, differentiate into or mature as photoreceptor cells, as part of the dual cell aggregate.
One of ordinary skill in the art would have been motivated to have made that modification, because Akhtar et al. shows that the differentiation of hiPSCs (human induced pluripotent stem cells) into photoreceptors is a long, tedious, labor-consuming, and expensive process. In the described study, the differentiation efficiency of hiPSCs into photoreceptors was improved. The efficiency may be further improved potentially by combining with other methods (pg. 8, column 1, para. 1 thru column 2, lines 1-2). That is, in order to produce a dual cell aggregate, PR cells are initially required, and so one would have been motivated to have employed a method to efficiently prepare PR cells which exhibited cell markers (such as recoverin) indicative of what would eventually become fully mature photoreceptor cells.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
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/SMP/ Examiner, Art Unit 1651
/MELENIE L GORDON/ Supervisory Patent Examiner, Art Unit 1651