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
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.
Election/Restrictions
Applicant’s election with traverse of Group I, claims 1-14, in the reply filed on May 27, 2026 is acknowledged. Claims 15 and 86-90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention. It is noted claim 15 directed to mesendoderm spheroids should have been included in Group II which is also directed to mesendoderm spheroids.
The traversal is on the grounds that the groups of inventions share the special technical feature. Specifically, the traversal is on the grounds that Silva does not teach mesendoderm spheroids containing both definitive endoderm and lateral plate mesoderm and instead teaches spheroids containing undifferentiated mesendoderm progenitors that subsequently undergo a differentiation process. Applicant argues that Silva has no teaching of FOXA2+ definitive endoderm at the spheroid stage or HAND1+ lateral plate mesoderm (Remarks pg. 5-6 bridging para.).
This is not found persuasive because Silva teaches mesendoderm spheroids which have the co-emergence of mesoderm and endoderm cell lineages (pg. 3 para. 1). One of ordinary skill in the art would have readily understood that for the mesendoderm spheroids of Silva to form cardiac and gut organoids that the mesendoderm spheroids would form definitive endoderm and lateral plate mesoderm along the way as evidenced by Liu et al. (US 2019/0322987 A1) and Champeris et al. (Journal of Endocrinology, 2010). Liu reports that the mesendoderm is an embryonic tissue later that differentiates into mesoderm and endoderm (0094). Liu reports mesendoderm cells differentiate towards lateral plate mesoderm cells that expresses HAND1 (0019 and 0091). Liu teaches endodermal genes expressed include FoxA2 (0027). Champeris teaches that the TGF-β pathway is central to the generation of mesendoderm and DE (definitive endoderm) (pg. 16 Col. 1 last para.) and that in the developmental stages of pancreatic organoids the cells transition through mesendoderm to definitive endoderm (abstract).
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-14 are presented for examination on the merits.
Status of the Claims
Claims 1-15 and 86-90 are currently pending.
Claims 15 and 86-90 have been 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.
Claims 16-85 are cancelled.
Claims 1-14 have been considered on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. There is a list of reference in the Specification on pg. 65-68.
Drawings
The disclosure is objected to because of the following informalities:
The drawings are objected to because of the following informalities: illegible text in Figures 16 and 17.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) 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: the use of trademarks.
The use of the terms Matrigel® in 0126, 0131, 0133-0134; AggreWell™ plate in 0129; N2 B-27™ medium in 0129; Ultra-Low attachment™ 6-well plate in 0129; Parafilm® in 0131, which are a trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
The disclosure is objected to because of the following informalities:
Claim 1 is objected to because of the following informalities: the first time an acronym is utilized in a claim-set, said acronym should be spelled out in its entirety followed by said acronym in parenthesis (e.g. transforming growth factor-beta (TGF-b), bone morphogenetic protein (BMP), Wingless (Wnt), Forkhead Box A2 (FOXA2), Heart and Neural Crest Derivatives Expressed 1 (HAND1)).
Claim 5 is objected to in the recitation of “optionally wherein the TGF-b activator is TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, IDE2 and any combination thereof, optionally Activin A”, and in the interest of improving claim form, it is suggested that the recited phrase be amended to recite “optionally wherein the TGF-b activator is TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, IDE2 and any combination thereof
Claim 7 is objected to in the recitation of “optionally wherein the BMP activator is BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, IDE2 and any combination thereof, optionally BMP4”, and in the interest of improving claim form, it is suggested that the recited phrase be amended to recite “optionally wherein the BMP activator is BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, IDE2 and any combination thereof
Claim 9 is objected to in the recitation of “optionally wherein the Wnt activator is Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, TWS119 and any combination thereof, optionally CHIR99021”, and in the interest of improving claim form, it is suggested that the recited phrase be amended to recite “optionally wherein the Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, TWS119 and any combination thereof
Appropriate corrections are appreciated.
Claim Interpretation
It is noted that claim 1 recites that the serum supplement can optionally be fetal bovine serum and the term “optionally” does not require that the serum supplement be fetal bovine serum.
It is noted that claim 3 recites that step a) can optionally be performed for about 28 hours and the term “optionally” does not require that step a) be performed for about 28 hours.
It is noted that claim 4 recites that step b) can optionally be performed for about 44 hours and the term “optionally” does not require that step b) be performed for about 44 hours.
It is noted that claim 5 recites that the TGF-b activator can optionally be TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, IDE2 and any combination thereof and the term “optionally” does not require that the TGF-b activator be TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, IDE2 and any combination thereof.
It is noted that claim 7 recites that the BMP activator can optionally be BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, IDE2 and any combination thereof and the term “optionally” does not require that the BMP activator be BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, IDE2 and any combination thereof.
It is noted that claim 9 recites that the Wnt activator can optionally be Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, TWS119 and any combination thereof and the term “optionally” does not require that the Wnt activator be Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, TWS119 and any combination thereof.
It is noted that claim 10 recites that the Wnt pathway activator is optionally provided at a concentration of 9, 10, 11, or 12 µM and the term “optionally” does not require that the concentration of the Wnt pathway activator to be 9, 10, 11, or 12 µM.
It is noted that claim 12 recites that optionally the number of cells aggregated is, or is about 200-4000, 300-3000, 500-2000, 600-1500, or 750-1250 cells and the term “optionally” does not require that the number of cells aggregated be or be about 200-4000, 300-3000, 500-2000, 600-1500, or 750-1250 cells.
It is noted that claim 13 recites that keeping the cells in suspension can optionally be performed by shaking and the term “optionally” does not require that shaking be performed to keep the cells in suspension.
Claim Rejections - 35 USC § 112(a) written description
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 1-15 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 claims 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.
The instant claims are drawn to methods of activating a TGF-β pathway, a BMP pathway and a Wnt pathway in pluripotent stem cells. The activation of these pathways have a wide array of activities and/or effects, since the individual pathways could be activated at any point and by any means. Thus, the claims are broadly drawn to any compound, molecule, mechanism (e.g. cell density) or condition (e.g. hypoxia) which activates any point of a TGF-β pathway, a BMP pathway and a Wnt pathway. Therefore, the claims are considered genus claims that encompass a wide array of compounds, mechanisms and conditions. The claims encompass anything that activates a TGF-β pathway, a BMP pathway and a Wnt pathway which are not described by their function, structure or relation thereto. The genus for activators of a TGF-β pathway, a BMP pathway and a Wnt pathway is highly variant, inclusive to numerous structural variants because a significant number of structural differences between genus members is permitted and inclusive to numerous mechanisms or conditions.
For activating a TGF-b pathway, the specification describes TGF-b activators can include TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, and IDE2 (0020, 0188, 0199 of published application). The specification does not disclose the diverse genus. The specification does not disclose the diverse genus. The specification does not place any structure, chemical or functional limitations on the embraced by genus of “activating a TGF-b pathway”. The specification instead just lists some TGF-b pathway activators. The recitation of “activating a TGF-b pathway” does not convey a common structure, function, mechanism or condition and is not so defined in the specification. The specification does not disclose or suggest additional methods of activating a TGF-b pathway. In sum, specification and the claims do not provide any guidance on what activates a TGF-b pathway.
For activating a BMP pathway, the specification describes BMP activators can include BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, and IDE2 (0022, 0185, 0199 of published application). The specification does not disclose the diverse genus. The specification does not disclose the diverse genus. The specification does not place any structure, chemical or functional limitations on the embraced by genus of “activating a BMP pathway”. The specification instead just lists some BMP pathway activators. The recitation of “activating a BMP pathway” does not convey a common structure, function, mechanism or condition and is not so defined in the specification. The specification does not disclose or suggest additional methods of activating a BMP pathway. In sum, specification and the claims do not provide any guidance on what activates a BMP pathway.
For activating a Wnt pathway, the specification describes Wnt activators can include Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, and TWS119 (0024, 0183, 0199 of published application). The specification does not disclose the diverse genus. The specification does not disclose the diverse genus. The specification does not place any structure, chemical or functional limitations on the embraced by genus of “activating a Wnt pathway”. The specification instead just lists some Wnt pathway activators. The recitation of “activating a Wnt pathway” does not convey a common structure, function, mechanism or condition and is not so defined in the specification. The specification does not disclose or suggest additional methods of activating a Wnt pathway. In sum, specification and the claim do not provide any guidance on what activates a Wnt pathway.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad generics, with respect to all of the potential species of agonists that may exhibit one, all, of or any of the claimed activity. The possible variations of compounds are limitless with potentially thousands of compounds that may exhibit the claimed activities. The purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by them. A patent specification must describe an invention and do so in sufficient detail so that one skilled in the art can clearly conclude that the inventor invented the claimed invention. Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
The specification lacks sufficient variety of species of compounds, mechanisms and conditions for activating a TGF-β pathway, a BMP pathway and a Wnt pathway in pluripotent stem cells to reflect this variance in the genus since the specification does not provide any examples of such a genus of compounds, mechanisms and conditions. Accordingly, the specification fails to provide adequate written description for the genus of activating a TGF-β pathway, a BMP pathway and a Wnt pathway in pluripotent stem cells and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed had possession of the entire scope of the claimed invention. Moreover, the specification neither describes the complete structure of a representative number of species, nor describes a representative number of species in terms of partial structure and relevant identifying characteristics. Additionally, there is no description of other mechanism and conditions that activate the claimed pathways. Absent of such teachings and guidance as to the structure and function of these compounds, mechanisms and conditions, the specification does not describe the claimed activating a TGF-β pathway, a BMP pathway and a Wnt pathway in such full, clear, concise and exact terms so as to indicate that Applicant had possession of activity these pathways by all means possible at the time of filing of the present application. Thus, the written description requirement has not been satisfied.
Claim Rejections - 35 USC § 112(a) enablement
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 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
a method of producing mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm by
contacting pluripotent stem cells with a TGF-β pathway activator, a BMP pathway activator and a Wnt pathway activator for about 24 hours to about 48 hours; and
contacting the cells of step a) with a TGF-β pathway activator and a BMP pathway activator, without a Wnt pathway activator for about 24 hours to about 72 hours;
wherein the cells of step a) and/or step b) are contacted with a serum supplement;
wherein the serum supplement is optionally fetal bovine serum;
wherein the TGF-β pathway activator is TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, IDE2 and/or combinations thereof;
wherein the BMP pathway activator is BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, IDE2 and/or combinations thereof; and
wherein the Wnt pathway activator is Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, TWS119 and/or combinations thereof
does not reasonably provide enablement for producing mesendoderm spheroids by first activating a TGF-β pathway, a BMP pathway and a Wnt pathway by all means and at any point in the pathway in pluripotent stem cells and then activating a TGF-β pathway and a BMP pathway without activating a Wnt pathway by all means and at any point in the pathway in the cells.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of producing mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm by
activating a TGF-β pathway, a BMP pathway and a Wnt pathway for about 24 hours to about 48 hours; and
activating a TGF-β pathway and a BMP pathway, without a Wnt pathway, in the cells of step a) for about 24 hours to about 72 hours;
wherein the cells of step a) and/or step b) are contacted with a serum supplement;
wherein the serum supplement is optionally fetal bovine serum. Thus, the claims taken together with the specification imply that any kind of pluripotent stem cell can produce mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm by activating a TGF-β pathway, a BMP pathway and a Wnt pathway by any means and at any point of the pathway and then activating a TGF-β pathway and a BMP pathway, without a Wnt pathway in the cells by any means and at any point of the pathway with the instantly claimed method. In other words, any compound, mechanism or condition that activates these pathways at any point can result in mesendoderm spheroids from any type of pluripotent stem cell.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Inventions involving the differentiation of pluripotent stem cells (PSCs) into different cell types need to provide supporting evidence because of the unpredictability in culture conditions and the necessary amounts and timing of the differentiation inducing factors and culturing conditions. The standard of enablement is high for such inventions because as the state of the art stands, there is no generalized culture conditions or method for the differentiation of PSCs into mesendoderm spheroids such that recited in claim 1.
The prior art in general teaches differentiating PSCs into mesendoderm requires culturing the cells under particular culture conditions. For instance, (Cha et al. Macromolecular Research, 2015) reports that during EB (embryoid body) formation, polarized mesendoderm develops intermediately by an epithelial-to-mesenchymal transition and generates mesoderm and endoderm (pg. 245 para. 2) and that “the typical heterogeneity in the differentiation of EBs which hinders the production of defined cell types, which can be modulated by cell culture methods for EB formation” (pg. 246 Col. 1 para. 1). Additionally, Cha reports that culture time of EBs and EB sizes are important parameters for ESC (embryonic stem cell) differentiation (pg. 246 Col. 1 para. 1).
In further support, Wang et al. (Journal of Molecular Biology, 2016) teaches the transforming growth factor-β (TGF-β)/Activin signaling and Wnt signaling have been shown to be most critical ones for the differentiation of ES (embryonic stem) cells towards ME (mesendoderm) (abstract). Wang teaches that the activation of Wnt signaling promotes the differentiation of ES cells toward ME and its derivative tissues (pg. 1413 last para.) and that Activin A and Wnt3a accelerate ME formation and inhibition of either Activin or Wnt signaling blocks this process (pg. 1415 Col. 1 para. 1).
To further illustrate the unpredictability, Kempf et al. (Nature Communications, 2016) states “controlling the complex pathways” interplay during PSC differentiation is challenging. It depends on the concentration of respective growth combinations as well as their temporal supplementation patterns, and is often accompanied by the heterogeneity of differentiation outcomes lacking interexperimental reproducibility” (pg. 2 Col. 2 para. 5). Kempf indicates that cell density is important to differentiation especially in 3D cultures (pg. 10 Col. 1 para. 2).
Thus, as the state of the art stands, the method would be unpredictable depending on specific methods being used to activate a TGF-β pathway, a BMP pathway and a Wnt pathway in PSCs and how the Wnt pathway is not being activated in the second step to result in differentiation into mesendoderm. Additionally, the method would be unpredictable depending on the culturing conditions. The high degree of unpredictability associated with the claimed method underscores the need to provide teachings and/or examples in the specification that would provide the skilled artisan with specific differentiation conditions that achieve the differentiation of PSCs under conditions where the cells are not cultured at some point in mediums that do not contain TGF-β pathway activators, BMP pathway activators and a Wnt pathway activators. In addition, there are no teachings and/or examples in the specification for the cell types other than embryonic stem cells and induced pluripotent stem cells (see 0176-0177 of published application).
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The instant specification only provides guidance for instantly claimed method where the activating of the pathways is accomplished by culturing PSCs with activators of the pathways where the TGF-β pathway activator is TGF-beta 1, TGF-beta 2, TGF-beta 3, Activin A, Activin B, Nodal, a BMP, IDE1, IDE2 and/or combinations thereof; the BMP pathway activator is BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11, BMP15, IDE1, IDE2 and/or combinations thereof; and
the Wnt pathway activator is Wntl, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wntll, Wntl6, BML 284, IQ-1, WAY 262611, CHIR99021, CHIR 98014, AZD2858, BIO, AR-A014418, SB 216763, SB 415286, aloisine, indirubin, alsterpaullone, kenpaullone, lithium chloride, TDZD 8, TWS119 and/or combinations thereof (0004 and 0014-0029). Additionally, the Applicant’s working Example 2 demonstrates human iPSCs were used to form mesendoderm spheroids containing both definitive endoderm expressing FOXA2+ and lateral plate mesoderm expressing HAND1+ cells where it was determined that about 28 hours of Wnt activation was good for generating appropriate amount of both DE and LPM populations from iPSCs (0219 and Fig. 2A). However, there was no guidance has to how the activation was performed. Similarly, working Example 3 demonstrates Mesendoderm spheroids were generated first (Fig. 3A) (0220), however there is no description of the method used to form the mesendoderm spheroids.
Accordingly, the specification does not provide any guidance for the instantly claimed method where the activating of the pathways is accomplished by other means. The applicants have provided neither cell data nor any mechanism of action for activating a TGF-β pathway, a BMP pathway and a Wnt pathway in PSCs to give the skilled artisan any reason to expect that the method would be effective in differentiating PSCs into mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm under all circumstances of activation of these pathways. The Applicant has failed to disclose any other culture condition where other forms of activating the claimed pathways are used. There is no conclusive evidence in the instant disclosure to indicate that the instantly claimed method can be used to differentiate PSCs into mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm under all circumstances of activation of these pathways.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
It is the examiner’s position that one skilled in the art could not practice the invention commensurate in the scope of the claims without undue experimentation. Therefore, claim 1 and its dependents are rejected under 35 U.S.C. 112 (a), while being enabled for differentiating PSCs into mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm with specific activators of the claimed pathways, does not reasonably provide enablement for differentiating PSCs into mesendoderm spheroids containing FOXA2+ definitive endoderm and HAND1+ mesoderm under all circumstances of activation of these pathways.
Conclusion
No claims are allowed.
This Office action has an attached requirement for information under 37 CFR 1.105. A complete reply to this Office action must include a complete reply to the attached requirement for information. The time period for reply to the attached requirement coincides with the time period for reply to this Office action.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Champeris et al. "Generating pancreatic β-cells from embryonic stem cells by manipulating signaling pathways." Journal of Endocrinology 206.1 (2010): 13-26.
Champeris teaches that the TGF-β pathway is central to the generation of mesendoderm and DE (pg. 16 Col. 1 last para.). Champeris teaches that Wnt signaling is involved in mesendoderm-specific differentiation (pg. 17 Col. 1 last para.).
Jackson et al. "Differentiating embryonic stem cells pass through ‘temporal windows’ that mark responsiveness to exogenous and paracrine mesendoderm inducing signals." Plos One 5.5 (2010): e10706.
Jackson reports that BMP4 and Wnt3a are required between differentiation day 1.5 and 3 to most effectively induce Mixl1 expression in embryonic stem cells and Activin A induced Mixl1 expression in ESCs between days 2 and 4 (abstract). Jackson reports stimulation of ESCs with these factors at earlier or later times resulted in little Mix11 induction (abstract). Jackson reports that “the timing of growth factor activity is critical for the initiation of mesendoderm formation from ESCs and paracrine signaling contributes to mesendoderm development” (pg. 2 Col. 1 para. 1). Jackson reports that differentiation of ESCs into mesendoderm requires an integrated network of signaling molecules to maintain the process (pg. 10 Col. 2 para. 2).
Liu et al. (US 2019/0322987 A1)
Liu teaches the culture medium for deriving the primitive streak mesendoderm cells from pluripotent stem cells contains activin, a WNT-signaling activator and a fibroblast growth factor (0007). Liu teaches culturing the primitive streak or primitive streak-like mesendoderm cells to obtain lateral plate mesoderm cells on an extracellular matrix containing a fibroblast growth factor, a bone morphogenetic protein (BMP), a Rho-associated protein kinase (ROCK) inhibitor and follistatin (0093 and 0102). Liu teaches culturing the cells in a first lateral plate mesoderm cell culture medium for 1 to 24 hours and then in a second lateral plate mesoderm cell culture medium for 1 to 4 days (0103). Liu reports that HAND1 is a mesodermal gene (0014) and endodermal genes include FoxA2 (0027). Liu refers to the mesendoderm as an embryonic tissue later that differentiates into mesoderm and endoderm (0094). Liu reports that Activin is a member of the transforming growth factor-β (TGF-β) superfamily (0129).
Teo et al. "Activin and BMP4 synergistically promote formation of definitive endoderm in human embryonic stem cells." Stem Cells 30.4 (2012): 631-642.
Teo teaches that Activin and BMP4 increases the number of embryonic stem cells that differentiate into definitive endoderm (DE) cells (abstract). Teo teaches that combined Activin and BMP4 treatment leads to an increase in the expression of FOXA2 (abstract). Teo teaches that the TGF-B-related ligand Nodal is indispensable for the formation of DE in vertebrates (pg. 2 para. 2). Teo reports that the simultaneous addition of Activin A and WNT3A to hESC leads to increase DE formation after 2-4 days of differentiation.
Wang et al. "Signaling control of differentiation of embryonic stem cells toward mesendoderm." Journal of molecular biology 428.7 (2016): 1409-1422.
Wang reports that “mesendoderm (ME) refers to the primitive streak in mammalian embryos, which has the ability to further differentiate into mesoderm and endoderm” (abstract). Wang teaches the transforming growth factor-β (TGF-β)/Activin signaling and Wnt signaling have been shown to be most critical ones for the differentiation of ES (embryonic stem) cells towards ME (abstract). Wang reports FoxA2 is preferentially expressed in the anterior region of the primitive streak (pg. 1411 Col. 1 para.). Wang teaches the TGF-β superfamily includes TGF-β, Nodal, Activin, BMP, growth factors and others (pg. 1411 Col. 1-2 bridging para.). Wang teaches that the activation of Wnt signaling promotes the differentiation of ES cells toward ME and its derivative tissues (pg. 1413 last para.). Wang teaches a Activin A and Wnt3a accelerate ME formation and inhibition of either Activin or Wnt signaling blocks this process (pg. 1415 Col. 1 para. 1).
Zhang et al. "Wnt signaling promotes hindgut fate commitment through regulating multi-lineage genes during hESC differentiation." Cellular Signalling 29 (2017): 12-22.
Zhang reports that the “coordinated differentiation of the splanchnic mesoderm and posterior endoderm is well orchestrated through several major signaling pathways, including Hh, Wnt, FGF, BMP, and Retinoic Acid (RA)” (pg. 2 para. 3). Zhang teaches that mesoderm sends instructive signals through Wnt, FGF, RA and BMP to the endoderm to establish regional identities including FOXA2 (pg. 1 para. 1). Zhang teaches D7 spheroids expressing mesenchymal genes activated by Wnt signaling including HAND1 and that CXCR4+ CD117+ representing DE (definitive endoderm) and CXCR4- cells expressed HAND1 (pg. 8 para. 3). Zhang teaches that HAND1 is a mesoderm marker gene (pg. 11 para. 2) and that APLNR+ CXCR4+ are lateral plate mesoderm (pg. 11 last para.)
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
Request for Information under 37 CFR § 1.105
Applicant and the assignee of this application are required under 37 CFR § 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
This request is being made for the following reasons:
As of Aug. 21, 2026, 48 Information Disclosures (IDS)s have been submitted in this application which contain:
US Patent/PGPub documents: 412
Foreign Patent documents: 318
Non Patent Literature documents: 1,949
Total: 2,679
The requested information is required as being reasonably necessary for finding prior art within the submitted Non Patent Literature (NLP) documents. There is currently no system that allows submitted NPL documents to be searched by class or keyword.
See MPEP Section 704.11:
INFORMATION REASONABLY NECESSARY FOR FINDING PRIOR ART
The criteria stated in 37 CFR 1.105 for making a requirement for information is that the information be reasonably necessary to the examination or treatment of a matter in an application. The information required would typically be that necessary for finding prior art or for resolving an issue arising from the results of the search for art or from analysis of the application file. A requirement for information necessary for finding prior art is not a substitute for the examiner performing a search of the relevant prior art; the examiner must make a search of the art according to MPEP §§ 704.01 and 904 – 904.03.
The criteria of reasonable necessity is generally met, e.g., where:
(A) the examiner’s search and preliminary analysis demonstrates that the claimed subject matter cannot be adequately searched by class or keyword among patents and typical sources of non-patent literature, or
(B) either the application file or the lack of relevant prior art found in the examiner’s search justifies asking the applicant if he or she has information that would be relevant to the patentability determination.
In this case, criteria (A) stated in the MPEP has been met and the claimed subject matter cannot be adequately searched by class or keyword among the submitted NPL documents.
The information is required to enter in the record are the NPL documents specifically relevant to the examination and to the claimed invention listed in the submitted IDSs.
In response to this requirement, please provide the following information:
(A) The NPL documents listed in the IDSs related to the claimed invention, applicant’s disclosure, or the claimed subject matter.
The claimed invention is to a method of producing mesendoderm spheroids containing definitive endoderm and lateral plate mesoderm by first activating a TGF-β pathway, a BMP pathway and a Wnt pathway in pluripotent stem cells and then activating a TGF-β pathway and a BMP pathway without activating a Wnt Pathway. Therefore, relevant NPL documents would include those relating to mesendoderm spheroids or spheroids containing definitive endoderm and lateral plate mesoderm; methods of generating definitive endoderm and lateral plate mesoderm in culture by activating any of the TGF-β pathways, BMP pathways and/or Wnt pathways. Additionally, any NPL documents that might support the novelty of the claimed invention are requested. For example, these may include NPL documents that teach that activating the claimed pathways do not result in mesendoderm spheroids or spheroids containing definitive endoderm and lateral plate mesoderm.
In responding to those requirements that require copies of documents, where the document is a bound text or a single article over 50 pages, the requirement may be met by providing copies of those pages that provide the particular subject matter indicated in the requirement, or where such subject matter is not indicated, the subject matter found in applicant' s disclosure. Please indicate where the relevant information can be found.
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/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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