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
Claims 1 and 3-9 are pending
Claims 1, 3 and 9 are newly amended.
Claim 2 is newly cancelled.
Claims 1 and 3-9 are examined on the merits.
Withdrawn Objections & Rejections
Applicant's response filed 08/22/2025 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 06/02/2025 are hereby withdrawn due to amendment.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
The rejection of the claims under 35 U.S.C. 102 and 103 are discussed below.
Claim Rejections - 35 USC § 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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 1 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rezania et al (Diabetes (2011)60:1-9); cited in the IDS filed on 09/19/2022).
This rejection is a new rejection based on the claim amendments filed 08/22/2025.
Regarding claim 1: The claim recites “a dissolved oxygen concentration in a culture solution is controlled to be 20% or more when a saturated dissolved oxygen concentration in the culture solution at 37°C at 1 atm is 100%”. The broadest reasonable interpretation of “20% or more” includes every value greater than and including 20%.
Claim 1 step (a) recites “endodermal cell”. The instant specification defines “endodermal cell” as cells that “have the ability to differentiate into the tissues of organs such as the digestive tract, the lung, the thyroid gland, the pancreas, and the liver, the cells of secretory glands opening onto the digestive tract, and the peritoneum, the pleura, the larynx, the auditory tube, the trachea, the bronchi, and the urinary tract (most of the bladder and the urethra, and part of the ureter).” (p15/16 ln23-25/1-3). The endodermal progenitor cells disclosed by Rezania have the ability to differentiate into pancreatic α-cells and thus read on endodermal cell of the instant invention.
Claim 1 step a recites “primitive gut tube” cells. The instant specification defines “primitive gut tube cell” as cells that “form the foregut, the midgut and the hindgut” (p16 ln11). Because the pancreas is an organ derived from the foregut, foregut progenitors read on cells that form the foregut. Thus the foregut progenitor cells of Rezania would have formed from “primitive gut tube cells" and read on the PGT of the instant claim 1, as early in primitive gut tube development primitive gut tube cells must have been present to give rise to the foregut progenitors.
Claim 1 step b recites “pancreatic endocrine precursor cells”. The instant specification defines “pancreatic endocrine precursor cell” as cells “that are differentiated from pancreatic progenitor cells, the cells being able to differentiate to pancreatic endocrine cells (α cells, β cells, δ cells, є cells, PP cells, etc.)” (p17 ln10-15). Rezania do not explicitly name a cell stage “pancreatic endocrine precursor cells”. The endocrine precursor cells of Rezania differentiate into pancreatic endocrine cells (α-cell), however, and thus read on pancreatic endocrine precursor cell of the instant invention.
Claim 1 step c recites “pancreatic α cells”. The instant specification defines pancreatic α-cells as follows “pancreatic α-cells are cells that are differentiated from pancreatic endocrine precursor cells, the cells secreting glucagon” (p17 ln 20-21). Thus cells positive for glucagon read on pancreatic α-cells.
Claim 1 step c defines 100% dissolved oxygen concentration as the concentration of oxygen dissolved in the culture solution at 37ºC 1 atm.
The claims are examined with the interpretations as described supra.
Rezania teach differentiation of human embryonic stem cells (pluripotent stem cells) to functional glucagon-producing α-cells (pancreatic α-cells) (abstract). Rezania teach culturing endodermal cells (endoderm progenitor cells) which have been induced to differentiate from pluripotent stem cells (ES cells) (Fig 1A).
Rezania further teach cells are differentiated to foregut progenitor cells by culture of the endodermal cells with a BMP inhibitor (noggin) and retinoic acid (RA) which result in differentiation of PGT cells (foregut progenitor cells) (Figure 1A).
Rezania further teach step 1C of the instant invention; culture of the primitive gut tube cells (foregut progenitor cells) to induce differentiation into pancreatic endocrine precursor cells (endocrine precursor) (Fig 1A).
Rezania do not teach use of ascorbic acid in any step of the method (Fig 1A; Supplemental Data) and thus read on the claim limitation “step (b) and the step (c) are performed in the absence of ascorbic acid”.
Rezania are silent on the oxygen supply condition for the cell culture, however one of ordinary skill in the art would understand that in the absence of explicit cell culture conditions, mammalian cell culture is typically performed at 37ºC using atmospheric oxygen levels at 1 atm (sea level). Thus, it is reasonable to conclude that the oxygen supply condition of the cell culture disclosed by Rezania is 100% per the definition of 100% dissolved oxygen concentration as discussed supra.
MPEP 2131.03 reads “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated' if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”
Thus the disclosure of Rezania reads on the claim limitation of 20% or more dissolved oxygen concentration.
While the developmental stages from pluripotent stem cells to pancreatic α-cells as disclosed by Rezania are not identical to those of the instant invention, one of ordinary skill in the art would understand that cell development occurs on a continuum. Thus (for example) one of ordinary skill in the art would understand that the addition of the BMP signaling inhibitor and retinoic acid which is included in the “foregut progenitor” stage disclosed by Rezania, encompasses culturing of endodermal cells in the presence of the BMP inhibitor and RA because at the initial stage of the PGT differentiation stage the cells are endodermal cells which will become foregut progenitor cells due to the specific culture conditions disclosed by Rezania.
Regarding claim 5: The claim recites a “wherein” clause. MPEP 2111.04 states “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… The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.”
Claim 5 does not recite any active steps, the claim describes precedent conditions that are not required to be performed.
Furthermore, the endodermal cells cited by claim 5 are considered product-by-process. M.P.E.P. § 2113 reads “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps”
No structure or manipulation is required or imparted on the endothelial cells by the wherein clause of claim 5. In absence of evidence to the contrary, the endodermal cells taught by Yabe (p70 col 2 para 2) read on the endodermal cells of claim 5.
Thus Rezania anticipates the invention as claimed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Rezania et al (Diabetes (2011)60:1-9); cited in the IDS filed on 09/19/2022) as applied to claim 1 above, and further in view of Al-Ani et al (PLOS one (2018)1-13).
This rejection is a new rejection based on the claim amendments filed 08/22/2025.
Regarding claim 3: The teachings of Rezania are discussed supra. Rezania do not teach the oxygen supply condition is 20%-50%.
Al-Ani teach dissolved oxygen in an incubator under atmospheric oxygen (18.6%) at 37ºC ranges from 175uM-205uM (p7 para 2) and that 5% CO2 reduces the partial pressure of oxygen by 11% (p7 Table 2). Thus it is reasonable to estimate that at standard cell culture conditions of 37ºC 5% CO2, cultures comprise a dissolved oxygen concentration of approximately 155-182uM and reads on an “oxygen supply condition”.
20-50% of the dissolved oxygen concentration in the culture solution at 37ºC would be approximately 35uM-100uM (0.035-0.10mM). Al-Ani teach that in liquid cell culture the oxygen concentration across a media column varies, and that at typical culture depth (Fig 1 center) the dissolved oxygen concentration ranges from 0-~0.2mM depending on location in the media column. This reads on a dissolved oxygen concentration of 0.035-0.10mM as the ranges overlap and Al-Ani teach that the dissolved oxygen concentration varies depending on oxygen partial pressure, culture density, media depth, location in the media column, and elevation (p5 fig1).
Furthermore, with regard to the concentration of oxygen in the cell culture medium, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05).
The selection of a specific oxygen concentration clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the amount and viability of the cells cultured would have been affected by these conditions.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Rezania et al (Diabetes (2011)60:1-9); cited in the IDS filed on 09/19/2022) as applied to claim 1 above, and further in view of Takebe et al (2019 US 10,370,638 B2).
This rejection is a new rejection based on the claim amendments filed 08/22/2025.
Regarding claim 4: The teachings of Rezania are discussed supra. Rezania do not teach step (a), culturing endodermal cells in the presence of a ROCK inhibitor to induce differentiation into primitive gut tube cells.
Takebe teach differentiation of human pluripotent stem cells to endodermal cells capable of generating pancreatic cells (Fig 1, col1 ln 5-11).
Figure 3 teaches addition of ROCK inhibitor when passaging definitive endoderm (DE), which are endodermal cells derived from human pluripotent stem cells (Fig 1). Thus, the addition of ROCK inhibitor taught by Rezania reads on the addition of ROCK inhibitor during step 1a of the instant invention, culturing endoderm cells which have been induced to differentiate from pluripotent stem cells.
Takebe further teach addition of ROCK inhibitor enhanced the survival and adhesion of cells (col15 ln 15-20, Fig 3) and that cell numbers in ROCK inhibitor groups suggested treatment with the ROCK inhibitor enhanced cell proliferation (col 15 ln20-26, Fig 3).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Rezania drawn to generating pancreatic α-cells by including a ROCK inhibitor when culturing endodermal cells as taught by Takebe.
One would have been motivated to include a ROCK inhibitor as taught by Takebe in the culture of endodermal cells derived from pluripotent stem cells to increase cell survival, adhesion and proliferation.
One would have had a reasonable expectation of success because both methods are drawn to the differentiation of pancreatic cells from pluripotent stem cells and address analogous developmental phases of the cells to generate the desired functional cells.
Claims 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Rezania et al (Diabetes (2011)60:1-9); cited in the IDS filed on 09/19/2022) as applied to claim 1 above, and further in view of Yabe et al (Regenerative Therapy(2019)10:69-76; cited in the IDS filed on 09/19/2022) and Habener et al (Islets (2012) 4:3;188-198).
This rejection is a new rejection based on the claim amendments filed 08/22/2025 but is substantially similar to a previous rejection.
Regarding claim 6: The teachings of Rezania are discussed supra. Rezania do not teach culturing of primitive gut tube cells in the presence of a PKC activator to induce differentiation into posterior foregut cells. Rezania also do not teach culturing the posterior foregut in the presence of retinoic acid to induce differentiation into pancreatic progenitor cells. Rezania do not teach culturing pancreatic progenitor cells with a Notch signaling inhibitor and a Rock signaling inhibitor to generate endocrine precursor cells.
Yabe teach the development pancreatic cells derived from pluripotent stem cells (abstract). The invention of Yabe drawn to generating pancreatic β-cells, however the method of Yabe also generates glucagon expressing cells, which read on pancreatic α-cells according to the claim interpretation discussed supra (p73 Fig2 e). Thus the method of Yabe reads on generation of both pancreatic α- and β-cells.
Yabe teach 6 stages of development; definitive endoderm, primitive gut tube, posterior fore gut, pancreatic progenitor, endocrine progenitor, and the functional pancreatic cell (Fig 1A).
Yabe teach culturing primitive gut tube cells in the presence of indolactam V (a PKC activator) to differentiation to posterior foregut (p70 col2 para 4). This reads on culturing primitive gut tube cells in the presence of a PKC activator to induce differentiation into posterior foregut cells, as required by the claim (step b1).
Yabe also teach culture of posterior foregut cells in the presence of a retinoic acid analog (EC23) to induce differentiation into pancreatic progenitor cells (step b2 of the instant claim) (p70 col2 para 5).
Yabe also teach culturing of pancreatic progenitor cells with a ROCK inhibitor (Y27632) and Notch inhibitor (DBZ) to induce differentiation to endocrine progenitor cells (p70 col2 para 6).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to combine the method of Rezania with method of Yabe to include because it would have been obvious to combine prior art elements according to known methods to yield predictable results.
Habener teach pancreatic alpha cells share lineage development with pancreatic beta cells, and may be direct progenitors of beta-cells (p188 col1 para1, Figure 2). Figure 2 of Habener teach both pancreatic alpha cells and pancreatic beta cells arise from primitive gut tube cells that differentiate to endocrine precursors before developing into either fully-differentiated alpha or beta cells (p190). Both Rezania and Yabe teach differentiation of pancreatic alpha cells that comprise the differentiation of pluripotent stem cells through the same developmental steps to produce functional endocrine cells.
Both Yabe and Rezania teach culture of primitive gut tube to posterior foregut cells, posterior foregut cells to pancreatic progenitor cells, and pancreatic progenitor cells to pancreatic endocrine precursor cells (Yabe Fig 1 and claim interpretation supra).
Thus, combining the method of Rezania with the method of Yabe by using components taught by Yabe for early differentiation of pluripotent stem cells to pancreatic progenitor cells would have led to predictable results with a reasonable expectation of success because both method are drawn to generating functional endocrine precursor cells from pluripotent stem cells, and both methods generate functional glucagon producing pancreatic alpha cells.
Regarding claim 7: The teachings of Rezania are discussed supra. Rezania do not teach culturing the pancreatic endocrine precursor (EP) cells in the presence of an insulin receptor signaling activator, transferrin, and selenous acid.
Yabe teach stage 6 of culture in which pancreatic endocrine precursor cells are cultured in the presence of ITS-X (insulin, transferrin and selenium solution) (p70 para 7; abbreviations).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to combine the method of Rezania with method of Yabe to include because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Combining the method of Rezania with the method of Yabe would have led to predictable results with a reasonable expectation of success because both method are drawn to generating functional (glucagon secreting) pancreatic α-cells.
Regarding claims 8 and 9: The teachings of Rezania are discussed supra. Rezania do not teach the cells are cultured in suspension or that cells are cultured under stirring conditions.
Yabe teach the culture protocol is modified to adjust for suspension culture (p70 col 1 para 3) and that that dissociated cells are seeded in a spinner type reactor (p70 col2 para 1).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to combine the method of Rezania with method of Yabe to include because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Combining the method of Rezania with the method of Yabe would have led to predictable results with a reasonable expectation of success because both method are drawn to generating functional (glucagon secreting) pancreatic α-cells.
Response to Arguments
The responses are in regards to the Arguments filed 8/22/2025 as they relate to the new rejections that were necessitated by the amendments.
Regarding Arguments over 35 U.S.C. § 103:
Applicant’s arguments filed 8/22/2025 have been fully considered but they are not persuasive.
Applicant argues the proposed combination of references can only be made by the improper use of hindsight.
This argument is moot in view of the new rejections due to the amendments, as discussed supra, which does not in any way rely on Ibuki
for any teaching or matter specifically challenged in the argument.
Applicant argues that Yabe teach cells with low glucagon and thus do not read on differentiation of pancreatic α-cells, and that the expression of glucagon is only from cells transplanted into mice.
While Yabe does teach glucagon expression in a minority of cells (Fig2g), glucagon is expressed and this reads on pancreatic α-cells as defined in the instant specification and discussed supra in the claim interpretation (p17 ln20-21).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., high glucagon expression) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The cells which Yabe teach that express glucagon are have not been transplanted in mice; Figure 2 shows representative spheroids at the end of the final stage which does not include transplantation (Fig2e).
The rejection is maintained.
Applicant argues that Al-Ani do not suggest controlling the dissolved oxygen concentration under the conditions recited in claim 1 for the purpose of claim 1.
Regarding the conditions recited in claim 1, claim 1 recites “a culture solution is controlled to be 20% or more when a saturated dissolved oxygen concentration in the culture solution at 37°C at 1 atm is 100%”. As discussed supra in the rejection over 35 U.S.C. § 103, the broadest reasonable interpretation of “20% or more” includes every value greater than and including 20%. Thus, tissue culture conducted under standard conditions (37ºC under 1 atm) reads on 100% saturated dissolved oxygen concentration per the definition of “100% saturated dissolved oxygen” as defined in the instant claim, and thus reads on the instant limitation of 20% or more dissolved oxygen concentration.
MPEP 2131.03 reads “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated' if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”
The rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631