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 .
Claims status
Applicants reply filed 10/1/1025 is acknowledged.
Claims 2, 5, 8 is/are cancelled. Claims 1, 3, 4, 6, 7, 9-12 is/are currently pending and is/are under examination.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 112(b) - Withdrawn
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.
Rejection of Claims 9-11 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in light of amendment to claim 9 that now makes it an independent claim and cancellation of claim 8.
Claim Rejections - 35 USC § 112(a) - Withdrawn
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.
Written Description
Rejection of Claims 1-5, 7-12 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 is withdrawn because claims 1 and 9 are limited to a cell aggregate derived from PSC in vitro.
Scope of Enablement
Rejection of Claims 1-5, 7-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification did not enable the full scope of the claim, is withdrawn because claims 1 and 9 are limited to a cell aggregate derived from PSC in vitro.
Claim Rejections - 35 USC § 102 – Maintained, updated to address claim amendments
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.
Rejection of Claim(s) 2, 5, 8 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kodani et al (JP 2018011527 A, Published 2018/01/25; Machine translation provided in IDS dated 7/8/2024) as evidenced by Suga et al (Self-formation of functional adenohypophysis in three-dimensional culture. Nature, 2011) and Zimmer et al (Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells. Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024) is moot due to claim cancellation.
Rejection of Claim(s) 12 under 35 U.S.C. 102(a)(1) as being anticipated by Kodani et al (JP 2018011527 A, Published 2018/01/25; Machine translation provided in IDS dated 7/8/2024) as evidenced by Suga et al (Self-formation of functional adenohypophysis in three-dimensional culture. Nature, 2011) and Zimmer et al (Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells. Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024) is withdrawn because claim is amended to depend from claim 9 that was rejected under U.S.C. 103. Claim 12 is instantly rejected with claim 9 below.
Claim(s) 1, 3, 4, 6, 7 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kodani et al (JP 2018011527 A, Published 2018/01/25; Machine translation provided in IDS dated 7/8/2024; ref of record) as evidenced by Suga et al (Nature, 2011; ref of record) and Zimmer et al (Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024; ref of record).
Regarding claims 1, Kodani discloses a method comprising separating cells that express EpCAM from a cell aggregate containing adenohypophysis precursor tissue and hypothalamic neuroepithelial tissue (Figure 12, 14, 16).
Kodani teaches deriving the cell aggregate from inducing differentiation of pluripotent stem cells ([0022, 0034, 0083, 0123, 0167]) wherein the cell aggregate comprises adenohypophysis precursor tissue and hypothalamic neuroepithelial tissue (as evidenced by Suga, Figure 1g which shows Rx+ is a marker for hypothalamic neuroectoderm/ neuroepithelium and Pitx1/2+ is a marker for oral ectoderm which are progenitors of adenohypophysis. Suga uses neuroectoderm and neuroepithelium synonymously as evidenced by the description of Figure 1g in the text “Importantly, a layer of Pitx1/2+ epithelium reproducibly formed on the surface of the ES cell aggregates, adjacent and exterior to the Rx1+ neuroepithelia, which formed inner layers (Fig. 1f, g).”).
Rx of Suga and Rax of Kodani are synonyms for the same marker and this was known. See Kodani “[0003] Conventionally, such purification has been performed by hetero knocking-in the GFP gene into the Rax gene (also referred to as Rx), which is a marker gene for hypothalamic progenitor cells”.
Figures 12, 14 and 16 in Kodani and their associated description in [0188, 189, 191, 194] show that EpCAM+ cells were separated from Rax+ cells i.e. Kodani’s aggregate comprises hypothalamic neuroepithelial tissue.
Regarding claims 3 and 4, Kodani discloses dispersing the cell aggregate before contacting the anti-EpCAM antibody which comprises treatment with Accumax followed by pipetting to break up the cell aggregate (= shredding, as claimed in claim 4; Example 1; [0051, 0157]).
Regarding claims 6, Kodani teaches embodiments wherein the pluripotent stem cells are induced pluripotent stem cells from humans [0022, 0034, 0083, 0123].
Regarding claim 7, since Kodani teaches deriving the cell aggregate from inducing differentiation of pluripotent stem cells ([0022, 0034, 0083, 0123, 0167]) wherein the cell aggregate comprises adenohypophysis precursor tissue pituitary placode or Rathke’ pouch (as evidenced by Suga, Figure 1g).
Although Kodani uses EpCAM as a negative selection tool in order to separate EpCAM -ve hypothalamic precursors from the cell aggregate, Kodani’s method anticipates the claimed method since it comprises the disclosed method steps and, in the process of separating EpCAM -ve hypothalamic precursors, inherently separates EpCAM +ve cells that are the pituitary-hormone producing cell. This inherent property is also evidenced by Zimmer that shows that pituitary-hormonal cells produced from cells aggregates containing adenohypophysis and hypothalamic neuroepithelial tissue generated from induced PSC express CD326 (=EpCAM) at a very high level on the cell surface (Figure S6).
Therefore, Kodani anticipates the claimed method.
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.
Rejection of Claim(s) 9-11 under 35 U.S.C. 103 as being unpatentable over Kodani as applied to claim 8 above, and further in view of Zimmer et al (Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells. Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024) is withdrawn because the rejection depended on Kodani’s teachings as applied to now cancelled claim 8 and thus the rejection of claim 8 is withdrawn.
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over et al Kodani et al (JP 2018011527 A, Published 2018/01/25; Machine translation provided in IDS dated 7/8/2024; ref of record) as evidenced by Suga et al (Nature, 2011; ref of record), and in view of Zimmer et al (Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024; ref of record).
Regarding claims 9, 10 and 11, Kodani teaches a cell aggregate from inducing differentiation of pluripotent stem cells ([0022, 0034, 0083, 0123, 0167]) wherein the cell aggregate comprises adenohypophysis precursor tissue and hypothalamic neuroepithelial tissue (as evidenced by Suga, Figure 1g which shows Rx+ is a marker for hypothalamic neuroectoderm/ neuroepithelium and Pitx1/2+ is a marker for oral ectoderm which are progenitors of adenohypophysis. Suga uses neuroectoderm and neuroepithelium synonymously as evidenced by the description of Figure 1g in the text “Importantly, a layer of Pitx1/2+ epithelium reproducibly formed on the surface of the ES cell aggregates, adjacent and exterior to the Rx1+ neuroepithelia, which formed inner layers (Fig. 1f, g).”).
Kodani teaches the dispersion of cell aggregate using Accumax followed by pipetting to break up the cell aggregate (= shredding, as required for claim 9-step (A) and claim 11; Example 1; [0051, 0157]).
Regarding claim 9-Step (C) and claim 10, Kodani teaches reaggregation of a selected population after separation [0161, 0162].
Since Kodani uses EpCAM as a negative selection tool in order to separate EpCAM -ve hypothalamic precursors from the cell aggregate, Kodani does not explicitly teach reaggregation of the EpCAM +ve pituitary hormone producing cells, as required by claim 9-step (C) and claim 10.
However, Zimmers teaches that EpCAM is a cell surface marker for pituitary-hormone producing cells produced from cells aggregates containing adenohypophysis precursors and hypothalamic neuroepithelial tissue generated from induced PSC (Figure S6).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to collect and reaggregate the EpCAM+ve cells separated in Kodani’s method. Such cells are inherently pituitary hormone producing cells and thus produce one or more of the hormones required in claim 12. An ordinary artisan would be motivated to collect and reaggregate the EpCAM+ve cells separated in Kodani’s method because it would allow for collection of pituitary-hormonal cells since Zimmer teaches that EpCAM is a cell surface marker for pituitary-hormonal cells. An ordinary artisan would reasonably expect to collect and reaggregate the EpCAM+ve cells separated in Kodani’s method because Kodani teaches methods for collection and reaggregation of separated cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Rejection of Claim(s) 2, 5 and 8 under 35 U.S.C. 103 as being unpatentable over Zimmer et al (Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells. Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024) in view of Kodani et al (JP 2018011527 A, Published 2018/01/25; Machine translation provided in IDS dated 7/8/2024) is moot due to claim cancellation.
Claim(s) 1, 3, 4, 6, 7, 9-12 remain rejected under 35 U.S.C. 103 as being unpatentable over Zimmer et al (Stem Cell Reports, Vol. 6, 858–872, June 14, 2016; IDS dated 7/8/2024; ref of record) in view of Kodani et al (JP 2018011527 A, Published 2018/01/25; Machine translation provided in IDS dated 7/8/2024; ref of record).
Zimmer teaches a method of generating pituitary-hormone producing cells from a cell aggregate comprising adenohypophysis or its precursor pituitary placode and a hypothalamic neuroepithelial tissue (Figures 2, 3; as required for claim 7), wherein the cell aggregate is derived from differentiating human induced pluripotent cells (Experimental Procedures: Human Pluripotent Stem Cell culture and Differentiation, Supplemental Experimental Procedures: ESC differentiation, as required for claim 6) and the resultant pituitary hormone producing cells are in the form of a cell sheet and produce pituitary hormones such as ACTH, GH, PRL, FSH (Figure 4; as required for claims 10, 12).
Zimmer characterized the expression of cell surface markers on their pituitary-hormone producing cells using a cell surface marker screening kit that comprises anti-CD326 (=EpCAM) antibody and identified EpCAM as a marker that labels nearly 100% of the cells (Figure S6B). Prior to labeling the cells with anti-CD326 antibody, Zimmer dispersed the cell aggregate using Accutase followed by pipetting to break up the cell aggregate (= shredding, Figure S6A, Supplemental Experimental Procedures: Cell Surface Marker Screen; as required for claims 3, 4, claim 9-step (A) and claim 11).
Although Zimmer teaches that EpCAM is a cell-surface marker that labels nearly 100% of the pituitary-hormone producing cells, Zimmer does not separate these EpCAM +ve cells (as recited in claim 1, claim 9-step (B) and thus does not reaggregate these separated cells (as recited in claim 9-step (C), claim 10).
However, methods for separating cells labeled with desirable cell-surface markers were known in the art. Kodani teaches separating cells labeled with cell-surface markers including EpCAM (Example 1, [0158], Figure 12, 16; as required for claims 1, claim 9-step (B)). Kodani also teaches that selected cells after separation can be reaggregated [0161, 0162] (as required for claim 9-step (C), claim 10) .
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to collect and reaggregate the EpCAM+ve cells of Zimmer using Kodani’s method. An ordinary artisan would be motivated to collect and reaggregate the EpCAM+ve cells produced by Zimmer because Zimmer teaches that EpCAM is a strong cell surface marker for pituitary-hormonal cells. An ordinary artisan would reasonably expect to collect and reaggregate the EpCAM+ve cells produced by Zimmer because methods to collect and reaggregate cells using cell surface marker expression were taught by in Kodani.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 3, 6, 7, 9-10, 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 22, 24 of copending Application No. 18/696,610 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1, 9 are directed to a method for separating/producing pituitary hormone producing cells by separating EpCAM expressing cells from a cell aggregate comprising adenohypophysis or its precursor. The cell aggregate comprising adenohypophysis or its precursor comprises hypothalamic neuroepithelial tissue (instant claim 2) and precursors of adenohypophysis such a pituitary placode and Rathke’s pouch (instant claim 7). The cell aggregate comprising adenohypophysis or its precursor is derived from hiPSC (instant claim 6). The step of separation is preceded by a dispersion of cell aggregate step (instant claim 3, 9-step A). Finally, the separated cells are reaggregated in an aggregate or sheet form (instant claim 9-C, 10). The separated/produced pituitary hormone producing cells comprise at least one of the pituitary hormone producing cell types recited in instant claim 12.
The method claims in `610 are not patentably distinct from the instant claims because:
Claims 2, 8 of `610 are directed to a method for separating/producing pituitary hormone producing cells by separating EpCAM expressing cells from a cell aggregate comprising adenohypophysis or its precursor (same as instant claims 1, 9). The cell aggregate comprising adenohypophysis or its precursor are known to comprise hypothalamic neuroepithelial tissue (rendered obvious by claims 1, 7 of `610) and precursors of adenohypophysis such a pituitary placode and Rathke’s pouch (rendered obvious by claims 6 of `610; required for instant claim 7). The cell aggregate comprising adenohypophysis or its precursor could be derived from IPSC and use of human species is obvious to an ordinary artisan to derive human pituitary hormone producing cells (rendered obvious by claims 5 of `610; required for instant claim 6). Dispersion of cell aggregate prior to separation is taught in claims 3, 11, 22 of `610 (required for instant claim 3, 9-step A). Finally, reaggregation of the separated cells is taught in claims 9, 10 of `610 and that the produced cell could be in aggregate or cell sheet form is taught in claim 14 of `610 (required for instant claim 9-C, 10). The separated/produced pituitary hormone producing cells comprise at least one of the pituitary hormone producing cell types recited in instant claim 12 (taught in claim 13, 24 of ‘610).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4, 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 22, 24 of copending Application No. 18/696,610 in view of Kodani.
Instant claim 4 and 11 require the dispersion steps of claim 1, 9 to be performed by shredding or physical incision. As detailed in the DP rejection above, Claims 2, 8, 3, 11, 9, 10, 14 of `610 teach instant claims 1 and 9. Specifically, dispersion of cell aggregate prior to separation is taught in claims 3, 11, 22 of `610 (required for instant claim 3, 9-step A). `610 does not teach that the dispersion could be performed by shredding or physical incision. Kodani teaches dispersion of cell aggregate using Accumax followed by pipetting to break up the cell aggregate (= shredding, Example 1; [0051, 0157]). Therefore, it would be obvious to an ordinary artisan to perform the dispersion step taught by `610 using method taught by Kodani. Such a combination would not require inventive ingenuity.
This is a provisional nonstatutory double patenting rejection.
Claim 1, 3, 6, 7, 9-10, 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 7, 8, 9, 13, 16, 18, 19 of copending Application No. 18/697,382 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1, 9 are directed to a method for separating/producing pituitary hormone producing cells by separating EpCAM expressing cells from a cell aggregate comprising adenohypophysis or its precursor. The cell aggregate comprising adenohypophysis or its precursor comprises hypothalamic neuroepithelial tissue and precursors of adenohypophysis such a pituitary placode and Rathke’s pouch (instant claim 7). The cell aggregate comprising adenohypophysis or its precursor is derived from hiPSC (instant claim 6). The step of separation is preceded by a dispersion of cell aggregate step (instant claim 3, 9-step A). Finally, the separated cells are reaggregated in an aggregate or sheet form (instant claim 9-C, 10). The separated/produced pituitary hormone producing cells comprise at least one of the pituitary hormone producing cell types recited in instant claim 12.
The method claims in `382 are not patentably distinct from the instant claims because:
Claims 7 of ‘382 are directed to a method for separating/producing pituitary hormone producing cells by separating EpCAM expressing cells from a cell aggregate comprising adenohypophysis or its precursor (same as instant claims 1, 9). The cell aggregate comprising adenohypophysis or its precursor comprises hypothalamic neuroepithelial tissue (claim 7 of `382) and pituitary placode and Rathke’s pouch are known precursors of adenohypophysis (rendered obvious by claim 7 of `382; required for instant claim 7). The cell aggregate comprising adenohypophysis or its precursor is derived from IPSC and use of human species is obvious to an ordinary artisan to derive human pituitary hormone producing cells (rendered obvious by claims 7 of `382; required for instant claim 6). Dispersion of cell aggregate prior to separation is taught in claims 8 of `382 (required for instant claim 3, 9-step A). Finally, reaggregation of the separated cells using suspension culture is taught in claims 7, 13 of `610 and that the produced cell could be in aggregate form is taught in claim 1, 16 of `382 (required for instant claim 9-C, 10). The separated/produced pituitary hormone producing cells comprise at least one of the pituitary hormone producing cell types recited in instant claim 12 (taught in claim 16, 18, 19 of ‘382).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4, 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 7, 8, 9, 13, 16, 18, 19 of copending Application No. 18/697,382 in view of Kodani.
Instant claim 4 and 11 require the dispersion steps of claim 1, 9 to be performed by shredding or physical incision. As detailed in the DP rejection above, Claims 7, 8, 16 of `382 teach instant claims 1 and 9. Specifically, dispersion of cell aggregate prior to separation is taught in claims 8 of `382 (required for instant claim 3, 9-step A). `382 does not teach that the dispersion could be performed by shredding or physical incision. Kodani teaches dispersion of cell aggregate using Accumax followed by pipetting to break up the cell aggregate (= shredding, Example 1; [0051, 0157]). Therefore, it would be obvious to an ordinary artisan to perform the dispersion step taught by `382 using method taught by Kodani. Such a combination would not require inventive ingenuity.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 10/1/2025 regarding the U.S.C. 102 rejection of claims 1-8, 12 as anticipated by Kodani have been fully considered but they are not persuasive.
Applicant argue that amendment to claim 1 by introducing a limitation from now cancelled claim 2 i.e. “wherein the cell aggregate comprises a hypothalamic neuroepithelial tissue” overcomes Kodani because “Kodani et al., Suga et al., and Zimmer et al. do not teach or suggest isolating only pituitary cells from a cell aggregate comprising a hypothalamic neuroepithelial tissue using EpCAM expression as an indicator” (page 15-16, bridging para). Further, Applicant argue that “the disclosure of Kodani et al. relates to "hypothalamus precursor cells," which are separate and distinguishable from the claimed "hypothalamic neuroepithelial tissue." (page 16, para 3). Applicant point to a definition provided by Kodani which states that the hypothalamic precursor cells of Kodani have the ability to self-renew and differentiate into cells constituting the hypothalamus (page 16, last para). Applicant allege that the claimed “hypothalamic neuroepithelial cells” are distinct from Kodani’s hypothalamic precursor cells because “the "hypothalamic neuroepithelial tissue" of the present invention includes not only self-renewing hypothalamus precursor cells, but also neural progenitor cells that have differentiated from the self-renewing hypothalamus precursor cells and have lost their self- renewal capacity” (page 17, para 2). In other words, Applicants appear to be arguing that the claimed hypothalamic neuroepithelial cells comprise cells same as Kodani’s cells but also cells that maybe at a more advanced stage of differentiation. Applicant point to [0068] in the specification as evidence (page 17, last para).
In response, it should be noted that para [0068] does not provide a restrictive definition for this argued claim term and the description in [0068] states that the ratio of progenitor and differentiated cells vary depending on degree of differentiation. Thus, the hypothalamic neuroepithelial cells of the claim could comprise any ratio of progenitors and differentiated cells. This is expected since precursor populations such as of Kodani or instant claims comprise some cells that are in more advanced stages of differentiation, unless differentiation is actively being restricted by some culture condition. Critically, [0068] identifies Rx+ as a marker for hypothalamic neuroepithelium which is the same as Kodani and the prior art. See evidence from at least Suga. Thus argument pertaining to distinction between Kodani’s cells and claimed cells are unpersuasive. Furthermore, as noted in the rejection, Zimmer explicitly evidences that EpCAM labels pituitary cells in cell aggregates that comprise hypothalamic neuroepithelium.
Next the Applicant argue that “Since Kodani et al. merely discloses that EpCAM is not expressed in hypothalamus precursor cells, and since Kodani et al. does not recognize that EpCAM is not expressed in all cells that constitute the hypothalamic neuroepithelial tissue (i.e., not only hypothalamic progenitor cells, but also differentiated neurons and glial cells that have lost self-renewal potential), Kodani et al. does not disclose or reasonably suggest a method for separating or producing pituitary hormone-producing cells and/or progenitor cells thereof by separating cells that express EpCAM from a cell aggregate containing an adenohypophysis and/or a precursor tissue thereof, wherein the cell aggregate comprises a hypothalamic neuroepithelial tissue, as required by the pending claims” (page 18, para 2). Applicant also argue that “Suga et al. and Zimmer et al. do not recognize that EpCAM is not expressed in all cells that constitute the hypothalamic neuroepithelial tissue (i.e., not only hypothalamic progenitor cells, but also differentiated neurons and glial cells that have lost self-renewal potential). As a result, Suga et al. and Zimmer et al. do not provide any teaching or motivation to modify the disclosure of Kodani et al. so as to arrive at the claimed invention, which requires separating cells that express EpCAM from a cell aggregate containing an adenohypophysis and/or a precursor tissue thereof, wherein the cell aggregate comprises a hypothalamic neuroepithelial tissue” (page 18-19, bridging para).
In response, as discussed above, no distinction between Kodani’s hypothalamus precursor cells and claimed “hypothalamic neuroepithelial tissue” is established. Furthermore, Kodani explicitly identifies EpCAM as a “NON-hypothalamic progenitor cell” marker and as the cells ectodermal cells that give rise to the hypothalamic neural tissue mature they remain Rax+ and become EpCAM -ve [0189]. In other words, Kodani teaches that as hypothalamic precursor cells mature, for example as they differentiate into neural cells such as neurons and glia, they become EpCAM -ve. So even in conditions wherein Kodani’s hypothalamus precursor cells comprise some cells that more differentiated, these cells are expected to remain EpCAM -ve. Kodani’s method separates these EpCAM -ve cells from the EpCAM +ve cells thus anticipating the claimed method. Zimmer provides evidence that the EpCAM +ve cells are pituitary hormone producing cells.
MPEP 2111,02 (II) guides that “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963) (The claims were directed to a core member for hair curlers and a process of making a core member for hair curlers. The court held that the intended use of hair curling was of no significance to the structure and process of making.)” Similarly, “In re Cruciferous Sprout Litig., 301 F.3d 1343, 1346-48, 64 USPQ2d 1202, 1204-05 (Fed. Cir. 2002) (A claim at issue was directed to a method of preparing a food rich in glucosinolates wherein cruciferous sprouts are harvested prior to the 2-leaf stage. The court held that the preamble phrase "rich in glucosinolates" helps define the claimed invention, as evidenced by the specification and prosecution history, and thus is a limitation of the claim (although the claim was anticipated by prior art that produced sprouts inherently "rich in glucosinolates")).
In the instant case, the intended use/result of the method wherein EpCAM +ve cells are separated is mentioned in the preamble as “for separating pituitary hormone-producing cells and/or progenitor cells thereof”. This does not provide any additional structural limitation to the claim since the claim results in separating EpCAM +ve cells and the preamble merely identifies them as “pituitary hormone-producing cells and/or progenitor cells thereof”. The claimed method is structurally limited by the recited active steps each of which are taught by Kodani.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 9-11 as unpatentable over Kodani in view of Zimmer have been considered but are moot because the new ground of rejection necessitated by claim amendments. Arguments pertinent to instant U.S.C. 103 rejection these claims are addressed below.
Applicant argue that the claims would not be “obvious over Kodani et al. in view of Zimmer et al., for the reasons described above with respect to the anticipation rejection” (page 19, last para).
In response, these arguments were addressed above and were unpersuasive.
Next, Applicants argue that “Kodani et al. does not disclose or reasonably suggest that pituitary cells express EpCAM, much less recognize that EpCAM expression is exclusive to pituitary cells in a cell aggregate comprising a hypothalamic neuroepithelial tissue (i.e., not only hypothalamic progenitor cells, but also differentiated neurons and glial cells that have lost self-renewal potential)” (page 20, para 1) and “Zimmer et al. does not teach or suggest that EpCAM expression is exclusive to pituitary cells in a cell aggregate comprising a hypothalamic neuroepithelial tissue (i.e., not only hypothalamic progenitor cells, but also differentiated neurons and glial cells that have lost self-renewal potential).” (page 20, para 2). Thus, the Applicant conclude that owing to the alleged deficiencies in Kodani and Zimmer, an ordinary artisan would not reasonably expect to separate pituitary hormone producing cells (page 20, para 3).
In response, these arguments are not materially distinct from the arguments addressed above. The argument pertaining to distinction between Kodani’s hypothalamic precursor cells and claimed “hypothalamic neuroepithelium cells” were unpersuasive. On contrary, due to the expression of the same cell marker Rx, Kodani’s hypothalamic precursor cells and claimed “hypothalamic neuroepithelium cells” are the same. Kodani teaches separating EpCAM +ve and -ve cells. Zimmer explicitly teaches that EpCAM labels pituitary cells in cell aggregates and thus providing sufficient motivation to reaggregate the EpCAM+ve cells from Kodani. Both Zimmer and Kodani teach method to reaggregate and thus an artisan would reasonably expect to reaggregate any separated cell population.
Applicant's arguments filed 10/1/2025 with respect to the U.S.C. 103 rejection of claim(s) 1-12 as unpatentable over Zimmer in view of Kodani have been fully considered but they are not persuasive.
Applicant argue that “As described above with respect to the anticipation and obviousness rejections based on Kodani et al., neither Kodani et al. nor Zimmer et al. teaches or suggests that EpCAM expression is exclusive to pituitary cells in a cell aggregate comprising a hypothalamic neuroepithelial tissue (i.e., not only hypothalamic progenitor cells, but also differentiated neurons and glial cells that have lost self-renewal potential)” (page 21, para 5) and “Since Kodani et al. and Zimmer et al. do not teach or suggest that EpCAM expression is exclusive to pituitary cells in a cell aggregate comprising a hypothalamic neuroepithelial tissue (i.e., not only hypothalamic progenitor cells, but also differentiated neurons and glial cells that have lost self-renewal potential), a person of ordinary skill in the art would not have had a reasonable expectation of success in isolating pituitary cells from a cell aggregate containing a hypothalamic neuroepithelial tissue using EpCAM expression as an indicator “(page 21, para 6).
In response, these arguments are not materially distinct from the arguments addressed above. In the instant rejection is based on Zimmer in view of Kodani. Zimmer explicitly teaches that EpCAM labels pituitary cells in cell aggregates derived from PSC comprising adenohypophysis precursors and hypothalamic cells (Figure 3, S6). Although Zimmer does not separate these cells and thus does not reaggregate them, Kodani teaches methods to separate cells based on marker expression and also methods to reaggregate them.
Applicant's arguments filed 10/1/2025 with respect to the Double Patenting rejections have been fully considered but they are not persuasive. Applicant’s request that the rejection be held in abeyance is acknowledged (page 22, para 3). 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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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632