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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Jan. 29, 2026, has been entered.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/US2020/033876, filed on Nov. 19, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
In the reply filed Jan. 29, 2026, Applicant has amended claims 29-30, canceled claims 2-18 and 20-28, and filed new claims 43-45. Currently, claims 1 and 19 are withdrawn.
Applicant’s election without traverse of Group III (Claims 29-42), drawn to a composition comprising at least one BMP pathway activator and a plurality of PDX+ cells, in the reply filed on 12/17/2024 is acknowledged.
Claims 29-45 are under examination in this Office Action.
Specification
In response on December 1, 2025, Applicant’s filed amendments to the specification “Table 1: Resources” (see Amendments to the Specification, page 2) because the table labeled “Resources” that located on the specification page 77-79 does not have a corresponding Table number. The amendments to the specification is entered and the objection is withdrawn.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
Applicant is reminded that 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.
Claim Objections
Claims 29 and 30 are objected to because of the following informalities: the first recitation of the abbreviation are not spelled out in the claims (e.g. pancreatic and duodenal homeobox (PDX1)). Appropriate correction is required.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the labeling of “HOXA1, SHISA2 and HHEX” (see Drawings Fig.1D, page 4) and the drawings fail to show the labeling of “The absence of NKX6.1 and expression of the foregut markers HOXA1, SHISA2 and HHEX, suggest that these cells represent an early stage in pancreatic bud development (FIG. 1D, Table 1)” (Spec. para. 195) as described in the specification.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
In addition to Replacement Sheets containing the corrected drawing figure(s), applicant is required to submit a marked-up copy of each Replacement Sheet including annotations indicating the changes made to the previous version. The marked-up copy must be clearly labeled as “Annotated Sheets” and must be presented in the amendment or remarks section that explains the change(s) to the drawings. See 37 CFR 1.121(d)(1). Failure to timely submit the proposed drawing and marked-up copy will result in the abandonment of the application.
Specification
The disclosure is objected to because of the following informalities: the specification references: Appendices 1-3 and Tables 1-3 (see Specification page 9, lines 10-31, and page 10, lines 1-2), and there is an additional Table 1 (i.e. “Table 1: Resources” (see Amendments to the Specification, page 2)). The specification refers to Tables 1-3 throughout the specification (see e.g. page 9-10, 62-66); however, Table 1-3 are not present in the application as filed. Applicant is required to correct the specification by either suppling the missing tables, if originally omitted by Office error, or deleting all references thereto.
See MPEP 608.01(p) Incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. See MPEP 37 CFR 1.57(g).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 29-31, 33-36, 38-42, and 44-45 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
The claims are direct to: A composition comprising at least one bone morphogenetic protein (BMP) pathway activator and a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (see claim 29).
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019; and the October 2019 Update: Subject Matter Eligibility.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim)(Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B). (See MPEP § 210 6.05 for examples of integration of practical application).
Based upon an analysis with respect to the claim as a whole, the claims do not recite something significantly different than a judicial exception (i.e. product of nature). The rationale for this determination is explained below.
Step 1-Statutory Category: According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e. process, machine, manufacture, or composition of matter).
The claims are direct to a composition of matter comprising at least one bone morphogenetic protein (BMP) pathway activator and a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (see claim 29). Thus, the composition is a natural product and meets the requirements for step 1 of the analysis.
Next the claim is assessed to determine if it is directed to a judicial exception under step 2A.
Step 2A Judicial Exception-Prong 1 (claim is directed to a judicial exception): Regarding the first prong (l), the claim is directed to composition of matter comprising a bone morphogenetic protein (BMP) pathway activator and a plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+.
As described in the specification: “a composition comprising stem cell-derived endocrine cells” (see e.g. Spec. pg 55, lns. 9-10). Further, the specification discloses “In one embodiment, the term stem cell refers generally to a naturally occurring mother cell whose descendants (progeny) specialize, often in different directions, by differentiation, e.g., by acquiring completely individual characters, as occurs in progressive diversification of embryonic cells and tissues […] Some differentiated cells also have the capacity to give rise to cells of greater developmental potential, such capacity may be natural” (Spec. page 14).
Accordingly, the specification does not disclose that the claimed composition of endoderm cells with BMP are modified or changed their natural characteristics (see e.g. Spec. page 14). Rather the claimed composition of endoderm cells with BMP is expected that the claimed composition is substantially similar, if not identical, to the naturally occurring composition of endoderm cells with BMP in nature (e.g. differentiation of human embryonic stem cells). Thus, instant claim composition of endoderm cells with BMP that are identical (no difference in structural or functional characteristics) to naturally occurring endoderm cells with BMP. Further, there is no indication in the specification that the composition of endoderm cells with BMP results in the composition of endoderm cells with BMP having any characteristics (structural, functional, or otherwise) that are different from the naturally occurring cells in their natural state. Because there is no difference between the claimed and naturally occurring cells, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception.
Accordingly, the claims are directed to a composition using only a nature-based product, i.e., endoderm cells with BMP, this nature-based product is then analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, the claimed compositions are directed to a product of nature exception. Because the claimed compositions do not include any additional features that could add significantly more to the exception, the claimed endoderm cells (i.e. expressing PDX; HOXA1; SHISA2; and HHEX+) with BMP do not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
Because instant claims are directed to a nature-based product, i.e., endoderm cells with BMP, the nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. Thus, the naturally occurring counterpart of a plurality of cells expressing PDX; HOXA1; SHISA2; and HHEX+ with BMP of claim 29 is a plurality of endoderm cells expresses PDX; HOXA1; SHISA2; and HHEX+ at the foregut endoderm stage with BMP that are present in any known natural source of cells (e.g. human embryonic stem cells).
Applicant is directed to the publication of Funa, et al. (Stem Cell Reports 19.7: 973-992, published 2024, hereinafter as “Funa”), which discusses human embryonic stem cells specification to foregut endoderm lineages, and where “RNA-seq data disclosed that TGF-b1 may suppress BMP signaling in foregut progenitors by repressing BMP6 expression and inducing BMP antagonists”(see e.g. page 987). Funa discloses that it was well known that “endocrine differentiation towards pancreases specification expresses the pancreatic progenitor markers PDX1+ and NKX6-1+” (see e.g. page 974). Funa discloses that at “anterior-posterior (A-P) pattern specification and negative regulation of Wnt signaling identified human orthologs of genes (i.e. HHEX)(Figure 3) and Wnt pathway genes (i.e. SHISA2) after TGF-β treatment (Figure 3) suggesting that TGF-β anteriorizes endoderm by antagonizing Wnt signaling” (see e.g. page 979). Thus, Funa is evidence of endocrine differentiation having naturally occurring BMP, and foregut endoderm cells naturally expressing PDX1+, NKX6.1+, SHISA2, and HHEX, as discussed above. Moreover, the prior art of Bort, et al. (Development: 797-806, published 2004; hereinafter as “Bort”), discloses that “Hex (i.e. HHEX) is a homeobox-containing gene that is expressed in endoderm cells at embryonic day 7.0 of mouse gestation (E7.0) and subsequently in the ventral-lateral foregut (Thomas et al., 1998) that gives rise to the ventral pancreas and the liver” (page 798). Therefore, Bort provides further evidence that an endoderm cell would naturally express HEXX at the foregut endoderm stage. Additionally, the prior art of Agulnick (US2014/0271566A1, published 2014, cited IDS 12/17/2024) discloses cells expressing HOXA1+ is expressed in the dorsally-biased PDX1-positive foregut endoderm cells (see e.g. Table 1-2, page 16, para. 50). Thus, Agulnick provides further evidence that endoderm cells at the foregut endoderm cell stage would naturally express HOXA1+.
Regarding the dependent claims, the composition of endoderm cells with BMP further comprising the features of retinoic acid, Keratinocyte Growth Factor (KGF) and activin A are considered as features that are inherent or innate characteristic of composition of endoderm cells. The prior art of Lee DH, Chung HM. (Int J Stem Cells. 2011 Jun;4(1):35-42, published 2011, hereinafter as “Lee”), discloses that retinoic acid directs differentiation of activin-induced definitive endoderm of human ES cells into PDX1+ foregut endoderm cells (see e.g. page 38) and KGF furthers beta cell differentiation (see e.g. page 38). Further, Lee discloses human embryonic stem cells were induced to differentiate into functional insulin-producing cell in a serum-free system through definitive endoderm, pancreatic commitment, and insulin producing cells with activin A (see e.g. page 40). Therefore, as discussed above, the additional features of the claimed composition of endoderm cells with BMP further comprising retinoic acid, Keratinocyte Growth Factor (KGF) and activin A are considered as inherent or innate characteristic features of the naturally occurring counterpart. The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. Thus, in order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP2106.04(c)(II)(C)). The instant specification does not disclose the claimed composition of endoderm cells with BMP further comprising retinoic acid, Keratinocyte Growth Factor (KGF) and activin A has characteristic(s) that are different from the naturally occurring MSC or the inventor caused any change to the composition of endoderm cells with BMP further comprising retinoic acid, Keratinocyte Growth Factor (KGF) and activin A from the nature. Thus, the claimed composition of endoderm cells with BMP further comprising retinoic acid, Keratinocyte Growth Factor (KGF) and activin A is not significantly different from the naturally occurring counterpart, endoderm cells (i.e. at the foregut endoderm stage).
Therefore, the claimed composition of matter comprising a bone morphogenetic protein (BMP) pathway activator, and a plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (i.e. endoderm cells) are directed to a product of nature because they are found in nature. As such, the claim is directed to a judicial exception. Furthermore, the endoderm cells with BMP further comprising retinoic acid, Keratinocyte Growth Factor (KGF) and activin A of claims 31, 33-36, 38-42, and 44-45 were not subjected to any modification that would markedly distinguish them from their natural occurring counterparts. Moreover, the claimed endoderm cells expressing PDX; HOXA1; SHISA2; and HHEX+ with BMP in the claims of 29-31, 33-36, 38-42, and 44-45 recite no structural or functional feature that would distinguish the claimed endoderm cells with BMP different from those that occur in nature.
Because there is no difference between the composition of endoderm cells with BMP used in the claimed composition, the claimed composition of endoderm cells with BMP do not have markedly different characteristics, and thus are a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, the claimed compositions are directed to an exception. Because the claimed compositions do not include any additional features that could add significantly more to the exception, the claimed composition of endoderm cells with BMP do not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
Thus, the instant claimed invention is a composition that comprises only a naturally occurring products, which are directed to a judicial exceptions, and in the instant case these naturally occurring products are the endoderm cells (i.e. foregut endoderm cells) with a BMP. It noted that only the recited limitations in the claims are examined under 101 and not aspects such as what the cells are capable of being used for. In this case, only endoderm cells with BMP are examined with respect to their status as a judicial exception. It is emphasized that the claimed invention is a composition and not a method.
Step 2A Judicial Exception-Prong 2 (Judicial exception is integrated into a practical application): An examination of Step 2B, the answer is no with respect to the claimed invention. There are no other additional elements recited in the claims that would amount to significantly more than the judicial exceptions. This is because while the claimed invention is drawn to endoderm cells (i.e. foregut endoderm cells with BMP), there are no additional components which impart any additional element or structural limitations to the recited cells. The endoderm cells (i.e. foregut endoderm cells with BMP) of the claims are indistinguishable from endoderm cells with BMP that exist in nature in differentiating human embryonic stem cells. The endoderm cells (i.e. foregut endoderm cells with BMP) of the claims have the same capability as those that exist in nature and the fact that they are present in an isolated population or produced by a specific method does not change the composition of endoderm cells (i.e. foregut endoderm cells with BMP) in a significant or meaningful way to amount to more than the judicial exception.
The only factors which can be examined under 101 in the claimed composition are those that are recited in the claimed composition comprising at least one bone morphogenetic protein (BMP) pathway activator and a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (i.e. endoderm cells with BMP). How the composition comprising endoderm cells with BMP are obtained and the knowledge of using the composition comprising endoderm cells with BMP are not considered with respect to a composition, it is only the judicial exceptions themselves that are analyzed under 101 and in this case all of the components in the claimed composition are naturally-occurring products and thus qualify as a judicial exception.
This judicial exception is not integrated into a practical application because there is no additional element that integrate the claimed product into a practical application. It is noted that merely an intended use of the claimed invention or a field of use limitation cannot integrate a judicial exception. See MPEP2106.04(d)(2).
Step 2B Significantly More: The "significantly more" analysis determines that a claim is patent eligible if the claims recite structures or functions that transform the natural product in a manner that make the product markedly different from the judicial exception. The nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state.
Claim 29 does not recite any additional elements, modification(s) or transformation(s) that are significantly more or place a meaningful limitation on the composition comprising at least one bone morphogenetic protein (BMP) pathway activator and a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (i.e. endoderm cells with BMP). As discussed above, the claim recites “at least one BMP and the prior art of Funa, et al. discloses that BMP signaling is present in human embryonic stem cells specification to foregut endoderm lineages (see e.g. page 973). Therefore, the recitation of “at least one BMP” does not impart a marked enough distinction to distinguish it from its natural counterpart. Thus, the claim encompasses endoderm cells with BMP that are identical to the natural counterpart of endoderm cells with BMP. Therefore, claim 29 does not meet the requirement of step 2B and therefore claim 29 and its dependent claims 29-31, 33-36, 38-42, and 44-45 do not meet patent subject matter eligibility requirements. It is noted that the dependent claims 32, 37 and 43, are directed to Sant1, which is hedgehog pathway inhibitor and not a natural product, and therefore deemed patent eligible.
Under the holding of Myriad, the Courts decided that an isolated but otherwise unchanged nucleic acid was not patent eligible subject matter because it was not different enough from what exists in nature to avoid improperly tying up the future use and study of naturally occurring nucleic acid. Thus, the endoderm cells with BMP of the claim is analogous to the isolated nucleic acid in Myriad. Moreover, the claimed endoderm cells with BMP can be interpreted as being an isolated composition of endoderm cells with BMP that is otherwise unchanged.
Thus, the claims does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements other than the therapeutically effective amount of composition comprising at least one bone morphogenetic protein (BMP) pathway activator and a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (i.e. endoderm cells with BMP). Regarding the limitations directed to the intended use in the dependent claims, the limitations are considered as well-understood, routine and conventional activity of using the claimed cells that does not amount to an inventive concept.
In conclusion, claims 29-31, 33-36, 38-42, and 44-45 do meet all the requirements of the 2019PEG and therefore deemed patent ineligible.
Claim Rejections - 35 USC § 112
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 29-45 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is a new rejection as necessitude by amendments to the claims.
In amended cases, subject matter not disclosed in the original application is occasionally added and a claim directed thereto. Such a claim is rejected on the ground that it recites elements without support in the original disclosure under 35 U.S.C. 112, first paragraph, Waldemar Link, GmbH & Co. v. Osteonics Corp. 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 2163.06- § 2163.07(b) for a discussion of the relationship of new matter to 35 U.S.C. 112, first paragraph. New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific compounds after a broader original disclosure. See MPEP § 608.04 to §608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05for guidance in determining whether the addition of specific compositions after a broader original disclosure constitutes new matter.
The instant specification, as well as the PCT and/or provisional specifications to which the instant application claims priority, as originally filed does not provide support for the invention as now claimed: a composition comprising at least one bone morphogenetic protein (BMP) pathway activator and a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ (claim 29), and the composition of claim 29, wherein the composition comprises a plurality of cells, wherein each of the cells in the plurality of cells expresses PDX; NKX6.1; HOXA1; SHISA2; and HHEX+ (claim 30).
When determining if a newly added recitation by amendment has adequate written description, the specification and claims, as originally filed, are examined to determine if they provide an explicit or implicit disclosure of the newly added recitation.
The closest disclosure found in the specification is as follows:
“Early in vitro differentiation is linear and uniform, whereas late differentiation gives rise to heterogeneous populations: At the end of the first stage, marked by SOX17 expression, all cells analyzed primarily use an EP comprised of other definitive endoderm genes including CER1 and LEFTY2, whereas by the end of the second stage they primarily use an EP corresponding to foregut endoderm (HHEX, TTR) (FIGS. 1D-lE, FIG. 5C, FIG. 5F, and Table 1). Almost all cells analyzed at the end of the third stage, when PDX1 is activated, use an EP that contains additional pancreatic-bud markers such as GATA4, ONECUT1 and ONECUT2 (FIGS. 1D-lE, FIG. 5F, and Table 1). The absence of NKX6.1 and expression of the fore gut markers HOXA1, SHISA2 and HHEX, suggest that these cells represent an early stage in pancreatic bud development (FIG. 1D, Table 1)” (see Specification page 62).
In the instant case, the specification recites that table 1 is directed to the reagents or resources used in the specification (see Spec. and Drawings as discussed above, and Spec. page 77-78). Therefore, table 1 does not disclose wherein each of the cells in the plurality of cells expresses PDX, HOXA1, SHISA2, and HHEX+ and wherein each of the cells in the plurality of cells expresses PDX, NKX6.1, HOXA1, SHISA2, and HHEX+ (see claims 29-30). Furthermore, it is noted that figure 1D does not disclose SOX17 or HHEX expression but does disclose PDX1 and NKX6-1 expression. Additionally, figure 1 and 5 are directed to a heterogenous population of cells (see section title) and is directed to genes expressed at certain developmental stages (see spec. page 62). Further, it is noted that figure 5F shows “relative expression levels of the top genes in each of the major 8 expression profiles 20 (rows), across all cells in a heterogenous population of cells” (see Drawings page 28). Also, it is noted that the epithelial progenitors in figure 5F appears to show expression of SHISA2 appear at stage 2 as definitive endoderm cell type and showing expression of HOXA1 appearing at stage 1 and 2 as pancreatic bud cell type. Therefore, there is no support in the specification in figures 1, 5 and table 1 for each of the cells in a composition comprising a plurality of cells that expresses PDX; HOXA1; SHISA2; and HHEX+ and PDX; NKX6.1; HOXA1; SHISA2; and HHEX+.
Thus, the instant claims now recite limitations which were not disclosed in the specification as-filed, and now change the scope of the instant disclosure as-filed. Such limitations recited in the present claims, which did not appear in of the instant specification, nor in the PCT and/or provisional applications to which priority is claimed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. § 112. Therefore, the specification does not provide sufficient disclosure for wherein each of the cells in the plurality of cells expresses (i.e. PDX; HOXA1; SHISA2; and HHEX+ and PDX; NKX6.1; HOXA1; SHISA2; and HHEX+), nor direction for the claimed composition encompassing the above-mentioned limitations, as currently recited.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 31, and 43-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 31, the recitation of “BMP2/BMP6, BMP2/BMP7, and BMP4/BMP7,” renders the claims indefinite because the claim includes elements not actually disclosed, thereby rendering the scope of the claims unascertainable. See MPEP2173.05(h). In the instant case, the dash in the claim is a relative term “and/or” which renders the claim indefinite. Further, terms “BMP2/BMP6, BMP2/BMP7, and BMP4/BMP7” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Further, the claim recites “wherein the BMP pathway activator is selected from the group consisting of BMP2, BMP7, BMP9, GDF5, BMP2/BMP6, BMP2/BMP7, and BMP4/BMP7”, which is a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 31 recites the broad recitation of “is selected from the group”, and the claim also recites “BMP2 and BMP7” which is the narrower statement of the range/limitation. Thus, the claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. In the interest of compact prosecution, the dash will be interpreted as “BMP2 or BMP6, BMP2 orBMP7, and BMP4 or BMP7”.
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 29-31, 33-34, 36, 38-42, and 44-45 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Agulnick et al., (US20140271566A1, published 2014, cited IDS 12/17/2024, previously presented) as evidence by Filipe, et al., (Dev Dyn 235, 2567-2573, published 2006, hereinafter as “Filipe”), Bort, Roque, et al. (Development;797-806, published 2004, hereinafter as “Bort”), D’Amour et al., (US8,647,873B2, published 2014, hereinafter as “D’Amour”).
This is a new rejection as necessitated by amendments to the claims submitted on the 29th of January 2026. Any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 29-30, Agulnick discloses a composition comprising at least one bone morphogenic protein (BMP) pathway activator (i.e. BMP2, BMP5, BMP6, BMP7, BMP8 and BMP4)(see e.g. para. 41 and 205, fig. 44-45) and a plurality of cells (e.g. endoderm cell) (see e.g. para. 6, 11, 13, 29, 31-32, 37, 41, 68, 179 and 285; fig. 25-28, and 44-45). Agulnick discloses wherein the composition comprises a plurality of PDX and NKX6.1 cells (see e.g. para. 41, fig. 2, 9, 13, 14, 18, 24, 31, 33, and 44-45). Further, Agulnick discloses HOXA1+ is expressed in the dorsally-biased PDX1-positive foregut endoderm cells (see e.g. Table 1-2, page 16, para. 50). Therefore, Agulnick discloses each cell in a plurality of cells expressing PDX, NKX6.1, and HOXA1.
Regarding claim 29-30, Agulnick does not explicitly disclose wherein a plurality of cells, each cell express SHISA2 (i.e. WGAR9166) and HHEX(i.e. Hex).
However, it appears that applicant has claimed the same composition of a foregut endoderm cells as taught by Agulnick. Thus, in order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP2106.04(c)(II)(C)). In the instant case, the composition of foregut endoderm cells as taught by Agulnick reads on the claimed platelet production promoting factor as evidence the prior art of Filipe discloses SHISA2+ (i.e. mShisa) is inherently expressed in the endoderm lining of the foregut during mouse development (see e.g. fig. 2). Therefore, Agulnick inherently discloses a plurality of foregut endoderm cells, each cell express SHISA2 (i.e. WGAR9166).
Regarding claim 29-30, Agulnick does not explicitly disclose the marker HHEX+.
However, it appears that applicant has claimed the same composition of a foregut endoderm cells as taught by Agulnick. Thus, in order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP2106.04(c)(II)(C)). In the instant case, the foregut endoderm cell composition as taught by Agulnick reads on the claimed platelet production promoting factor. As evidence the prior art of Bort which discloses that foregut endoderm cells inherently express HHEX (i.e. HEX) (see e.g. abstract, page 797-198 and fig. 2,5). Therefore, Agulnick inherently discloses a plurality of foregut endoderm cells, each cell express the marker HHEX+.
Regarding claim 29-30, as stated supra, Agulnick et al. does not explicitly disclose wherein each cell in a plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ and PDX; NKX6.1; HOXA1; SHISA2; and HHEX+.
However, Agulnick et al. discloses methods to purify the endocrine cells by using fluorescent (see e.g. Example 24, para. 453), and as evidence the prior art of D’Amour disclose isolating and purifying foregut endoderm cells by fluorescent-activated cell sorting (FACS) (see e.g. col. 57-58, Example 23), which reads on the claim limitation of each cell in a plurality of cells expresses PDX; HOXA1; SHISA2; and HHEX+ and PDX; NKX6.1; HOXA1; SHISA2; and HHEX+.
As discussed above, it appears that applicant has claimed the same composition of a foregut endoderm cells as taught by Agulnick. Thus, in order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP2106.04(c)(II)(C)). In the instant case, the composition of foregut endoderm cells as taught by Agulnick inherently discloses a composition of plurality of foregut endoderm cell with a BMP each expressing PDX; HOXA1; SHISA2; and HHEX+ and PDX; NKX6.1; HOXA1; SHISA2; and HHEX+.
Regarding claim 31, as discussed above, Agulnick discloses wherein the BMP pathway activator is selected from the group consisting of BMP2, BMP5, BMP6, BMP7, BMP8 and BMP4(see e.g. para. 41 and 205, fig. 44-45).
Regarding claim 33, 36, and 44, Agulnick discloses wherein the composition further comprises retinoic acid (see e.g. para. 14, 37-41, 152, 271-273, figs. 43-45, table 2, Example 8).
Regarding claim 34, 36, and 45, Agulnick discloses wherein the composition further comprises and keratinocyte growth factor (KGF)(see e.g. para. 210, 268, 271, 283, 330-333, Example 1, Table 8, Fig. 44-45).
Regarding claim 38-42, Agulnick discloses wherein the composition further comprises activin A (see e.g. para. 11, 13, 16, 24-29, 31-34, 49, 267, figs. 43-45).
In conclusion, the prior art of Agulnick anticipates the instant claims because it inherently discloses all the required limitations.
Response to Traversal:
Applicant argues that the prior art of “Agulnick is cited as allegedly disclosing that dorsally-biased PDX1 + foregut endoderm cells may express HOXA1. Applicants argues that the cells referenced in the prior art document are not all at the same developmental stages (e.g., foregut endoderm vs. definitive endoderm)”(Remarks, page 4-5).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the cited prior art all discloses endoderm cells, as discussed above.
In response to applicant's argument that Agulnick is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, the prior art are all directed to endoderm cells, as discussed above. Contrary to Applicants assertion the claim is directed to “a composition” and does not disclose a specific cell type, time period, or endoderm stage during differentiation just that the cells have to express PDX, HOXA1, SHISA2, and HHEX (see claim 1).
Applicant argues that the “Office has not pointed to any evidence of a single population of cells where each cell expresses all of PDX, HOXA1, SHISA2, and HHEX” (Remarks, page 4-5).
In response to applicants’ argument a single population of cells where each cell expresses all of PDX, HOXA1, SHISA2, and HHEX, please see 112 rejection above regarding the claim limitation of “wherein each of the cells in the plurality of cells.” Contrary to Applicants assertion the claim is directed to a composition and does not have a claim limitation directed to a single population of cells. Furthermore, the claims read on “comprising” (see MPEP 2111.03), which does not exclude other embodiments, such as a composition that has a cell population that is differentiating during a period of time.
Applicant argues that the prior art of Agulnick and the pending application note that definitive endoderm cells would not be expected to express PDX1 (Agulnick at paragraphs [0187]-[0189]; and the pending application at paragraph [0195])(Remarks, page 5).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicants’ argument, the prior art citations of Agulnick cited does not teach away from PDX1 expression and instead discusses PDX1 positive and negative cells. Further, it appears that Agulnick does at least a few cells have PDX1 expression at stage 2 (i.e. day 6)(see fig. 2H). Contrary to applicants’ assertion the pending application does teach away from definitive endoderm cells not expecting to express PDX1. The paragraph cited suggests that “almost all cells analyzed at the end of the third stage, when PDX1 is activated” (Spec. para. 195), which does not teach that definitive endoderm cells are not expected to express PDX1.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 32, 35, 37, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Agulnick et al., (US20140271566A1, published 2014, cited IDS 12/17/2024, previously presented) as evidence by Filipe, et al., (Dev Dyn 235, 2567-2573, published 2006, hereinafter as “Filipe”), Bort, Roque, et al. (Development;797-806, published 2004, hereinafter as “Bort”), D’Amour et al., (US8,647,873B2, published 2014, hereinafter as “D’Amour”) as applied to claims 29-31, 33-34, 36, 38-42, and 44-45 above, and further in view of Rezania et al., (US2013/0330823A1, published 2013, previously presented).
This is a new rejection as necessitated by amendments to the claims submitted on the 29th of January 2026. Any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Agulnick et al, apply here as indicated above.
Regarding claims 32, 34-35, 37, and 43, Agulnick discloses wherein the composition further comprises and keratinocyte growth factor (KGF)(see e.g. para. 210, 268, 271, 283, 330-333, Example 1, Table 8, Fig. 44-45). Agulnick discloses wherein the composition further comprises retinoic acid (see e.g. para. 14, 37-41, 152, 271-273, figs. 43-45, table 2, Example 8). Agulnick discloses wherein the composition further comprises and keratinocyte growth factor (KGF)(see e.g. para. 210, 268, 271, 283, 330-333, Example 1, Table 8, Fig. 44-45). Further, Agulnick discloses wherein the composition further comprises activin A (see e.g. para. 11, 13, 16, 24-29, 31-34, 49, 267, figs. 43-45).
Agulnick is silent regarding the composition further comprises the agent Sant1.
However, the prior art of Rezania discloses a composition further comprises Sant1 (see e.g. abstract, claims 10, 12, 21, Examples 1-3).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the composition as taught by Agulnick and incorporate the agent Sant1 as taught by Rezania because both Agulnick and Rezania disclose compositions that can be differentiated into a beta-cell lineage composition (see e.g. abstracts, respectively). Further, Rezania discloses methods to promote differentiation of endoderm cells to pancreatic endocrine rich clusters and to enhance insulin expression in hormone-expressing cells (see e.g. abstract). Thus, a person of ordinary skill in the art would have had a reasonable expectation of success because both disclose methods for investigating the endodermal cell lineage and pancreatic cell types, as discussed above. Furthermore, an artisan of ordinary skill in the art of (i.e. endocrine cells) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007). Moreover, a person of ordinary skill in the art would have combined similar pancreatic endoderm cell methods, which would have led to predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the prior art of Agulnick or Rezania do not discloses treating a PDX+ cell (or PDX, HOXA1, SHISA2, and HHEX) with a BMP inhibitor (Remarks, page 5).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as discussed above, Agulnick discloses a composition comprising at least one bone morphogenic protein (BMP) pathway activator (i.e. BMP2, BMP5, BMP6, BMP7, BMP8 and BMP4)(see e.g. para. 41 and 205, fig. 44-45) and a plurality of cells (e.g. endoderm cell) (see e.g. para. 6, 11, 13, 29, 31-32, 37, 41, 68, 179 and 285; fig. 25-28, and 44-45). Agulnick discloses wherein the composition comprises a plurality of PDX and NKX6.1 cells (see e.g. para. 41, fig. 2, 9, 13, 14, 18, 24, 31, 33, and 44-45). Further, Agulnick discloses HOXA1+ is expressed in the dorsally-biased PDX1-positive foregut endoderm cells (see e.g. Table 1-2, page 16, para. 50). 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., same developmental stage) are not recited in the rejected claims. 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).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Xu, Xiaofang, Victoria L. Browning, and Jon S. Odorico. ("Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells." Mechanisms of development 128.7-10: 412-427, published 2011).
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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