Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restriction
Applicant’s election, without traverse, of Group II, claims 13 and 14, drawn to a method of treating a retinal disease comprising administering a composition which comprises Muller cells that were derived from culturing stem cells with a ROCK inhibitor and a WNT inhibitor, in the reply filed on 03/23/2026 is acknowledged.
Claims 12, 15-16 and 35-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 12-16 and 35-36 are pending.
Claims 12, 15-16 and 35-36 are withdrawn.
Claims 13-14 are considered on the merits.
Priority
This application is a 371 of PCT/GB2020/052756 (filed on 10/30/2020), which claims benefit from foreign application GB1915803.9 (filed on 10/31/2019). The priority claim of the instant application has been granted and the earliest benefit date is 10/31/2019 from the application GB1915803.9.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/06/2022, 06/09/2022 and 09/04/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Objections
Claim 13 is objected to because of the following informalities:
Claim 13 recites the terms “Muller” cells and the “Müller” cells in line 4. It is recommended to only use one form for consistency.
Furthermore, Claim 13, step (a), recites the term “medium” in line 1. It is recommended to change to “a medium”. Additionally, there is no punctuation mark at the end of step (a). It is recommended to add a comma (,) after the phrase “a Wnt inhibitor”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 13-14 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 (d) recites the limitation of culturing said cells “until retinal organoids are visible”. A claim may be rendered indefinite by reference to term of an object that is variable (see MPEP 2173.05(b), II; see, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989). In instant case, the recited timing of “until retinal organoids are visible” is variable since neither the claims nor the specification specify how the retinal organoids are visualized, e.g., with the naked eye or under a microscope, with or without any staining, etc. Thus, the timing needed for the retinal organoids to be visible is highly variable depending on examining approaches used, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 14 is rejected as being dependent from claim 13 but not resolving the ambiguity.
Claim Rejections - 35 USC § 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.
Claims 13-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
SCOPE OF THE INVENTION
Independent claim 13 encompasses a genus of method of treating a retinal disease or condition comprising administering a pharmaceutical composition comprising a population of Muller cells that are obtained from a method comprising culturing stem cells in a medium supplemented with a genus of “synthetic cell adhesion promoter” (see step (b)) and a genus of “synthetic enriched growth factor” (see step (c)). Dependent claim 14 encompasses the stem cells being human embryonic stem cells.
It is noted that the cited genus of “synthetic cell adhesion promoter” and “synthetic enriched growth factor” are extremely broad. For example, “synthetic cell adhesion promoter” encompasses coating the container with synthetic ECMs or peptide fragments, treating the container surface with vacuum gas plasma to make synthetic hydrophilic surface, or genetically modifying the cells with synthetic constructs to overexpress cell-surface adhesion receptors or to secrete synthetic ECM proteins, and “synthetic enriched growth factor” encompasses any synthetic purified small molecule, hormone, or recombinant protein that is capable of supporting cell growth.
However, regarding the broad genus of “synthetic cell adhesion promoter”, the specification only describes a single species of “synthetic vitronectin or synthetic vitronectin-based substrate” (see specification, p. 10, para 2). It is noted that only Matrigel is used in the working examples (e.g., specification, p. 35), which is not even synthetic. Regarding the genus of “synthetic enriched growth factor”, the specification does not provide any species of a synthetic enriched growth factor. The only growth factor taught and used in the working examples is Human Platelet Lysate (HPL), which is not synthetic. Thus, the specification does not provide any working example on the claimed “synthetic cell adhesion promoter” or “synthetic enriched growth factor”.
ACTUAL REDUCTION TO PRACTICE
Accordingly, Applicant did not demonstrate a reduction to practice a genus of “synthetic cell adhesion promoter” or a genus of “synthetic enriched growth factor”, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of using the claimed invention is not well established. As stated supra, the Applicant has provided no working examples to use the genus of “synthetic cell adhesion promoter” or the genus of “synthetic enriched growth factor” to differentiate stem cells into retinal organoids comprising Muller cells. Thus, using any synthetic cell adhesion promoter and any synthetic enriched growth factor to differentiate stem cells into retinal organoids comprising Muller cells, is highly unpredictable, and is not well established.
To the extent that the specification lacks teaching or working examples of using the claimed genus, the prior art is treated as enabling as the specification. Prior art Reichman et al., (Stem Cells. 2017;35:1176-1188) teaches using the truncated recombinant human vitronectin as synthetic substrate, which supports pluripotency of hESCs and hiPSCs in a xeno-free defined medium and enables the generation of self-forming neuroretinal structures and Muller cells (p. 1186, left col, “Discussion” section, and p. 1178, left col, “Results” section, para 1). Prior art Nakano et al., (Cell Stem Cell. 2012; 10: 771-785. Cited in IDS 06/06/2022) teaches using CHIR99021 or Wnt3a to support stem cell growth and differentiation into retinal organoids (e.g., p. 783, left col, subsection “Retinal Differentiation from hESCs”, para 2), which is a synthetic purified small-molecule (CHIR99021) or a recombinant thus synthetic purified protein (Wnt3a).
Applicant has claimed a genus of method of treating a retinal disease or condition comprising administering a population of Muller cells that are obtained from a method comprising culturing stem cells in a medium supplemented with a genus of “synthetic cell adhesion promoter” and a genus of “synthetic enriched growth factor”, yet the specification has not disclosed such supplements, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of synthetic cell adhesion promoter or synthetic enriched growth factor. Furthermore, the state of the art indicated that a method of using any synthetic cell adhesion promoter and any synthetic enriched growth factor to differentiate stem cells into retinal organoids comprising Muller cells, is highly unpredictable and is not well established, and would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed outcome of obtaining Muller cells according to the claimed genus of method using the claimed genus of synthetic cell adhesion promoter and synthetic enriched growth factor.
CONCLUSION
The Examiner concludes that there is insufficient written description of the instantly claimed genus of synthetic cell adhesion promoter and synthetic enriched growth factor. Specifically, Applicant has only provided one single species of synthetic cell adhesion promoter but does not provide any species of synthetic enriched growth factor, nor provide any working examples using any of the claimed genus. Thus, the specification does not provide sufficient number of species to represent the entire scope of the claimed extremely broad genus of cell adhesion promoter and growth factor. Therefore, the Examiner concludes that there is insufficient written description to show that Applicant was in possession of the claimed genus of synthetic cell adhesion promoter and synthetic enriched growth factor.
Claim Rejections - 35 USC § 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, 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 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Wan et al., (Vision Res. 2008;48(2):223-34) in view of Nakano et al., (Cell Stem Cell. 2012; 10: 771-785. Cited in IDS 06/06/2022) and Reichman et al., (Stem Cells. 2017;35:1176-1188).
With respect to claim 13, Wan teaches a method of intravitreal transplantation of Muller cells (5-10 x 104 cells in 2 µl volume) into damaged retina in adult rat to regenerate photoreceptors to provide a therapeutic strategy for retinal degenerative diseases (e.g., abstract and p. 224, right col, last paragraph before the “Results” section, and p. 231, subsection “3.6. Transplanted Muller glia produced rhodopsin in MNU-damaged Retina” and see Figs 9-10), thus teaches a method of treating a retinal disease (e.g., damaged retina) comprising administering (e.g., intravitreal transplanting) a pharmaceutical composition (5-10 x 104 Muller cells in 2 µl volume) to a patient in need thereof, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier (i.e., the 2 µl solution) and a population of Muller cells.
However, Wan teaches the Muller cells are isolated and cultured from mouse retinas (see p. 224, right col, para. 3), but is silent on the Muller cells being obtained from a method comprising the cited steps (a) through (e) from culturing stem cells.
Nakano teaches a method of generating an optic cup structure and stratified neural retina (i.e., equivalent to a retinal organoid) by self-organization in human embryonic stem cell (ESC) culture (e.g., abstract). Nakano acknowledges that the mESC-derived neural retina (NR) epithelium grows into a stratified NR tissue with six kinds of NR cells (photoreceptors, bipolar cells, ganglion cells, horizontal cells, amacrine cells, and Muller cells) (p. 771, last para.). Thus, one of ordinary skill in the art would have immediately expected that Nakano’s hESC-derived stratified neural retina would have had Muller cells as well.
Regarding step (a), Nakano teaches culturing human ESCs (i.e., stem cells) in low-cell-adhesion 96-well plates (i.e., in suspension in a plate-based system) in retinal differentiation medium containing Y-27632 (i.e., a ROCK inhibitor) and IWR1e (i.e., a Wnt inhibitor) (e.g., p. 783, left col, subsection “Retinal Differentiation from hESCs”).
Regarding step (b), Nakano teaches “Matrigel (growth-factor-reduced) was added from day 2 to day 18” (e.g., p. 783, left col, subsection “Retinal Differentiation from hESCs”), thus teaches step (b) supplementing the medium of step (a) with a cell adhesion promoter and culturing said cells. It is noted that Nakano is silent on the cell adhesion promoter being synthetic, which is taught by Reichman below.
Regarding step (c), Nakano teaches from day 15 to day 18, CHIR99021 (or Wnt3a) and SAG (or recombinant human Shh) are added to differentiation medium (e.g., p. 783, left col, subsection “Retinal Differentiation from hESCs”, para 2), thus teaches step (c) supplementing the medium of step (b) with a synthetic enriched growth factor (e.g., CHIR99021 or Wnt3a) and an agonist of Smoothened protein of the hedgehog signaling pathway (e.g., SAG or Shh) and culturing said cells. It is noted that “a synthetic enriched growth factor” is not specially defined in the specification, thus is reasonably examined as a synthetic factor that is purified and has growth function. Both CHIR99021 (a synthetic small-molecule with certain purity) and Wnt3a (a recombinant thus synthetic protein with certain purity) satisfy this limitation.
Regarding step (d), Nakano teaches from day 18 or 24, the neural retinas are cultured in a medium comprising retinoic acid in the long-term culture study for NR layer formation until day 126 for detecting visual pigments (e.g., p. 783, right col, para 1, under the subsection “Long-Term NR Culture”), thus teaches step (d) culturing said cells from step (c) and supplementing the medium of step (c) with retinoic acid until retinal organoids are visible (i.e., having visual pigments).
Regarding step (e), as stated supra, Nakano’s hESC-derived stratified neural retina would have had Muller cells. Nakano teaches a step of dissociating aggregates into single cells for FACS analysis (see supplemental page 18, para 1).
Reichman teaches a method of generation of retinal organoids and RPE from human induced pluripotent stem cells in xeno-free conditions (e.g., abstract). Reichman teaches “the emergence of Muller glial cells was also observed at later time points, as shown by RT-qPCR with the induction of specific markers GLAST1 and RLBP1 (Fig. 4M) and by the identification of cells co-expressing the Glutamine Synthetase (GS) and SOX9 (Fig. 4G)” (p. 1181, right col, para 2, Fig 4M showing Muller cells from Day 84). Thus, Reichman teaches retinal organoids derived from human pluripotent stem cells have Muller cells that could be identified by specific markers, related to step (e). Reichman further teaches a step of dissociating retinal organoids using papain into single cells, related to step (e), for either culturing (see Fig 5I, 5J, 5M, 5N) or cryopreservation (see Fig 5K, 5L, 5O, 5P) (see p. 1184, left col).
In regard to a “synthetic” cell adhesion promoter in step (b), Reichman teaches the protocol avoids the use of Matrigel (used by Nakano) in xenogeneic condition, and uses the truncated recombinant human vitronectin as synthetic substrate, which supports pluripotency of hESCs and hiPSCs in a XF defined medium and enables the generation of self-forming neuroretinal structures and RPE cells (p. 1186, left col, “Discussion” section, and p. 1178, left col, “Results” section, para 1).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a retinal disease by administering Muller cells isolated from mouse eyes disclosed by Wan, by substituting with Muller cells obtained from differentiating human pluripotent stem cells comprising the cited steps of (a) through (e) as suggested by Nakano and Reichman with a reasonable expectation of success. Since Nakano teaches differentiating human pluripotent stem cells into retinal tissue enables large-scale preparation of clinical-grade retinal tissues (e.g., abstract), and since Reichman teaches human pluripotent stem cells can generate an unlimited source of retinal cells for cellular therapies and protocols using defined conditions free of nonhuman derivatives are preferred for clinical translation (p. 1176, section “Significance Statement”), one of ordinary skill in the art would have had a reason to substitute Muller cells obtained from differentiating human pluripotent stem cells for the Muller cells isolated from mouse eyes in order to take advantage of the unlimited source of clinical-grade retinal cells. One of ordinary skill in the art would have had a reason to substitute synthetic human vitronectin as suggested by Reichman for Matrigel (extracted from mouse sarcoma) in order to facilitate clinical translation. Furthermore, since both Nakano and Reichman teach a method of dissociating retinal organoids and Reichman further teaches Muller cells could be identified by specific markers, one of ordinary skill in the art would have had a reasonable expectation of success in performing step (e) dissociating the retinal organoids to isolate Muller cells, e.g., using the specific markers by FACS, as suggested by Nakano and Reichman.
With respect to claim 14 directed to the stem cells being human embryonic stem cells, as stated supra, Nakano teaches differentiating human embryonic stem cells (hESCs) (e.g., abstract), and Reichman acknowledges protocols for generating retinal cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) (e.g., p. 1177, para 1).
In regard to the limitation “optionally RC-9 human embryonic stem cells”, Applicant is reminded that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04 I.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (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.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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