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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 24th of November 2025 has been entered.
Priority
This application was filed 13th of December 2019 and is a 371 application of PCT/EP2018/065779 filed on 14th of June 2018, which claims benefit to the foreign application LU100320 filed on 14th of June 2018.
Claim Status
In Applicants response filed on the 24th of November 2025, amended claim 1 and cancelled claims 12-14, 19-20, and 22.
Claims 1-11, 15-18 and 21 are pending in this application and are under consideration in this office action.
Information Disclosure Statement
Applicant is reminded of 37 CFR §1.56, which details Applicant's duty to disclose all information known to be material to patentability.
It is noted that the disclosure statements filed lists a “Search Reports”. The list of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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.
Claim Objections
Claim 3 is objected to because of the following informalities: punctuation marks (i.e. comma and semicolon) in claim 3d before the word “or”, line 5. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 103 (c) for any potential 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103 (a).
Claims 1, 2, 4-11, 15-18 and 21 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kelly et al. (WO2009/131568A1; cited IDS 12/13/2019), Benvenisty et al. (WO2012/070014A2; cited IDS 12/13/2019), Sharivkin et al. (Molecular & Cellular Proteomics, published Sept. 1, 2012), Morrison et al. (Cell Stem Cell 3.4: 402-415, published 2008, prior art of record), Cheng, et al., (Cell stem cell 10.4: 371-384; published 2012; cited IDS 12/13/2019).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on May 23, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
[AltContent: textbox ([img-media_image1.png][img-media_image2.png]
Adapted from fig 1. (top) and table 1 (bottom) of Kelly.)]Regarding claim 1, 2, and 21, Kelly teaches five stages of differentiation of the hESCs - (ES) through mesendoderm (ME), ME to definitive endoderm (DE or PDX1-negative definitive endoderm)(stage 1), DE to primitive gut tube (PG or PDX1 negative foregut endoderm) (stage 2, CyT203), PG to posterior foregut (PF or PDX1-positive foregut endoderm)(stage 3), PF to pancreatic endoderm (PE)(stage 4, CyT49), and PE to endocrine (EN cells)(stage 5, CyT203)(see fig. 1, Example 1, table 1). Kelly teaches a method of purifying pancreatic progenitor cell population derived from a population of pluripotent stem cells (e.g. embryonic stem cells)(see e.g. abstract and claim 1), corresponding to the claim limitation of exposing an initial population of cells that comprises the pancreatic progenitor cells at the definitive endoderm (DE) stage that express Cerberus (CER1)(i.e. DE to primitive gut tube (PG or PDX1 negative foregut endoderm) (stage 2, CyT203)(see e.g. para. 63-71, 97, and 105, fig. 1).
Further, Kelly teaches CD177 is positively expressed at stage 2 (endodermal lineage screen), late stage 4/early stage 5 (pancreatic endoderm and endocrine screen), and stage 5 (pancreatic endoderm and endocrine screen) )(see p. 41, table 1). Further, Kelly teaches that the antibodies from Table 1 (i.e. CD177)(p. 41) may be used either alone or in combination with each other to separate human embryonic stem cells (hES)-derived endoderm populations at various stages of differentiation of pancreatic progenitor cells (see Table 1, p. 45, para. 147). Thus, Kelly discloses the endodermal lineage, where CD177 is positively expressed (Example 1, Table 1,see fig. 1), corresponding to the claim limitation of wherein the pancreatic progenitor cell comprises CD177 on the cell surface. Kelly discloses separating the initial population from cells derived from pluripotent stem cells which do not bind to the ligand, thereby purifying said pancreatic endoderm cell (i.e. a product cell population enriched relative to the initial population of cells for pancreatic progenitor cells that bind to the ligand (see e.g. para. 114, claims 11, 16, 21, p. 61). Further, Kelly teaches the differentiation of the hESCs – (ES) through mesendoderm (ME), ME to definitive endoderm(DE) (DE or PDX1-negative definitive endoderm)(stage 1), and DE to primitive gut tube (PG or PDX1-negative foregut endoderm) (stage 2)(see e.g. fig. 1).
Kelly does not explicitly disclose exposing a pancreatic progenitor cell population to a ligand which binds surface CD177.
However, the prior art of Benvenisty et al. teaches that the two significant points along the differentiation process for pancreatic progenitor cells are the definitive endoderm (DE) stage, having the expression of SRY box 17 (SOX 17), which is the earliest stage, and the pancreatic progenitor stage, having the pancreatic and duodenal homeobox 1 (PDX1), which is the earliest commitment stages towards the pancreas (page 2, lin. 12-18). Further, Benvenisty discloses sorting and isolating SOX17 and PDX1 populations by methods known in the art such as, fluorescence-activated cell sorting (FACS) (see e.g. p. 37, 52, 81, 155, 212-213, claim 39, fig. 2). Further, Benvenisty discloses CD177 is a marker positively associated with definitive endoderm cells (claim 28, p. 9-10, 18, 90, 132, 235, and Example 3). Additionally, the prior Sharivkin discloses using CD177 ligand (e.g. antibody) to capture hESC-derived CXCR4+ endoderm cells (see e.g. abstract, p. 588, table 1, fig. 1, supplemental table 1). Further, Sharivkin discloses method for sub-fractionating the early definitive endoderm compartment of cells (i.e. CXCR4+) into discrete subsets that exhibit unique properties (see e.g. abstract, p. 588 and 591).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the method of purifying a pancreatic progenitor cell population, as taught by Kelly, to expose an initial population of cells with CER1 and a CD177 ligand, as taught by Kelly, Benvenisty, and Sharivkin, with a reasonable expectation of success because one of ordinary skill in the art would know that CER1 and D177 ligands would obtain anterior definitive endoderm cells, which are the earliest pancreatic progenitor cell stage that are committed towards the pancreatic fate (as taught by Kelly, see fig. 1; Benvenisty, see Example 1; and Sharivkin, see p. 586). Further, Sharivkin et al. teaches the need for more information on progenitor-specific cell surface markers, and that the resources for determining them are readily available (see e.g. page 593). Therefore, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success of using a CER1 and CD177 ligands in order to obtain a population of pancreatic progenitor cells at the anterior definitive endoderm (ADE) stage. Furthermore, an artisan of ordinary skill in the art of (i.e. purifying pancreatic progenitor cell populations) 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).
Kelly et al. does not explicitly state differentiation the pancreatic progenitor cells that bind to the ligand, express CER1, and are at the ADE stage to provide a population of glucose-responsive β-like cells.
However, Kelly discloses differentiation the pancreatic progenitor cells to a mature endocrine cell (e.g., a pancreatic beta cell), which is sensitive to glucose (para. 61-68, p.9-11). Further, the prior art of Benvenisty teaches differentiation of cells towards pancreatic beta cells (see e.g. p. 211). Further, Morrison discloses pancreatic progenitor cells from embryonic stem cells to anterior definitive endoderm cells (see e.g. p. 404, fig. 1-3) and discloses CER1 as an anterior definitive endoderm (ADE) marker, which can be expanded and undergo differentiation towards pancreatic fates (see e.g. abstract, page 408-410, fig. 6). Moreover, the prior art of Cheng discloses the surface marker CD177 was known in endodermal progenitor (EP) cells and that CD177 suggests a functionally superior population glucose-responsive pancreatic β-like cells from endodermal progenitor (EP cells) that reflect biological features related to the developmental timing of pancreatic endoderm production in vivo (See e.g. abstract, page 379, 382, fig. 3, 6).
MPEP 2111.04 states “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.” Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instant case, the claims are drawn to an invention employing the same process steps but the product(s) is(are) alleged to be different. Applicant is required to recite the missing steps to form the alleged different product(s) in view of the above-cited decision. If this is the case, Applicant is required to recite the missing steps.
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the method of purifying a pancreatic progenitor cell population, as taught by as taught by Kelly, Benvenisty, and Sharivkin, to incorporate the differentiation the pancreatic progenitor cells that bind to the ligand, express CER1, and are at the ADE stage to provide a population of glucose-responsive β-like cells, as taught by Morrison and Cheng, with a reasonable expectation of success because one of ordinary skill in the art would know that the endodermal progenitor (EP) cells-derived β-cells are “functionally responsive to the physiologic stimulus (D-glucose) for insulin release in a manner similar to that of adult islets in vitro” (as taught by Cheng, page 379). Furthermore, Cheng teaches that endodermal progenitor (EP) cells represent a powerful tool to study endoderm specification and offer a potentially safe source of endodermal-derived tissues for transplantation therapies (see abstract of Cheng). Therefore, incorporating the endodermal progenitor lines as taught by Cheng with the methods of purifying pancreatic progenitor cells as taught by Kelly et al. would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. definitive endoderm differentiation) 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).
Regarding claim 4, Kelly et al. discloses that the ligand is an antibody or binding fragment (claim 2).
Regarding claim 5, Kelly et al. discloses a monoclonal antibody (claim 3).
Regarding claim 6, Kelly et al. discloses the detection of an amplified nucleotide acids resulting from PCR primers can be conjugated to a detectable label. (page 27, para. 108)
Regarding claim 7, Kelly et al. discloses a method of quantitating expression of markers that are produced by marker genes is through the use of quantitative PCR (page 27, para 105, 166, and Table 10)
Regarding claims 8 and 10, Kelly et al. discloses that the staining intensity of cells can be monitored by flow cytometry, where lasers detect the quantitative levels of fluorochrome (which is proportional to the amount of cell surface marker bound by specific reagents, e.g. antibodies). Further Kelly et al. discloses that flow cytometry, or FACS, can also be used to separate cell populations based on the intensity of binding to a specific reagent, as well as other parameters such as cell size and light scatter (page 31, para. 115, Examples 2-5; Table 11).
Regarding claim 9, Kelly et al, discloses separating includes affinity chromatography (p. 30, para. 114).
Regarding claim 11, Kelly et al. discloses using human embryonic stem cells as the starting material (page 24, para 101).
Regarding claims 15-17, Kelly et al. discloses that ligands can be soluble or can be immobilized on the capture medium as indicated by the assay format, e.g., antibody affinity chromatography (see e.g. p. 17, para. 84). Further Kelly et al., discloses the method for enriching, depleting, isolating, separating, and sorting and/or purifying the cell population include antibody-coated magnetic beads, affinity chromatography and "panning" with antibody attached to a solid matrix or solid phase capture medium, e.g. plate, column or other convenient and available technique (see e.g. p. 30, para. 114).
Regarding claim 18, Kelly is silent regarding the product cell population comprises at least 50% pancreatic progenitor cells that bind to CD177, express CER1, and are at the ADE stage.
However, Benvenisty et al. teaches that an isolated population of pancreatic progenitor cells, comprising at least about 50% of cells PDX1+ (page 53). Further, the prior art of Morrison discloses the cells expressing “Cer1, Foxa2, and E-cadherin, but not Oct4 (Figure 6C), indicating these cells represent a form of ADE progenitor. To confirm that these cultures were predominantly ADE, we quantitated the percentage of cells expressing these markers and found that 79% (±1.4) expressed Cer1” (page 409, fig. 6).
Further, the following is noted from the MPEP: MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the method of purifying a pancreatic progenitor cell population, as taught by as taught by Kelly, Benvenisty, and Sharivkin, to incorporate the product cell population comprises at least 50% pancreatic progenitor cells that bind to CD177, express CER1, and are at the anterior definitive endoderm (ADE) stage, as taught by Benvenisty and Morrison, with a reasonable expectation of success because one of ordinary skill in the art would have known that the marker CER1 is expressed at about 79% at the ADE (as taught by Morrison, p. 409, fig. 6). Furthermore, an artisan of ordinary skill in the art of (i.e. methods or purifying cell populations) 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).
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 initial population of cells comprises the pancreatic progenitor cell population that expresses Cerberus 1 (CER1) and is at the anterior definitive endoderm (ADE) stage” (remarks, p. 6).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive because contrary to Applicants arguments the claims also recites “exposing an initial population of cells derived from pluripotent stem cells, induced pluripotent stem cells and/or embryonic stem cells” (claim 1, lines 3-4). Further, absent evidence to the contrary, Kelly discloses that the pancreatic progenitor cells ,derived from pluripotent stem cells, at the definitive endoderm (DE) stage that express Cerberus (CER1)(i.e. DE to primitive gut tube (PG or PDX1 negative foregut endoderm) (stage 2, CyT203)(see e.g. para. 63-71, 97, and 105, fig. 1) and teaches CD177 is positively expressed at stage 2 (endodermal lineage screen), as discussed above (see fig. 1, table 1) Further, as stated supra, the definitive endoderm (DE) stage encompasses the anterior definitive endoderm (ADE) stage absent evidence to the contrary.
Applicant argues that Kelly et al. states that all stages of hES-derived cells tested in Table 1 are positive for CD177, which would inform the skilled artisan that CD177 binding would be a very poor choice for providing a product cell population that are at the ADE stage as required by the present claims (remarks, p. 6). Applicants argue that like Kelly et al., the prior at of Benvenisty et al. does not teach CD177 as characterizing definitive endoderm cells (remarks, p. 7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments regarding Kelly and Benvenisty, the MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Contrary to Applicants assertion Kelly does not discloses that all stages of hES-derived cells in Table 1 are positive for CD177 (table 1, example 1). As discussed above, Kelly teaches CD177 is positively expressed at stage 2 (endodermal lineage screen), late stage 4/early [AltContent: textbox ([img-media_image3.png]
Adapted Page 226 of Benvenisty)]stage 5 (pancreatic endoderm and endocrine screen), and stage 5 (pancreatic endoderm and endocrine screen)(see p. 41, table 1). Further, Benvenisty discloses CD177 is a marker positively associated with definitive endoderm cells (see e.g. claim 28, Table 1, and see p. 226 to the right). Further, as stated supra, Kelly et al discloses the definitive endoderm (DE) stage, which encompasses the anterior definitive endoderm (ADE) stage absent evidence to the contrary.
Applicant argues that the prior art of Sharivkin would also inform the skilled artisan that CD177 binding would be a very poor choice for providing a product cell population that are at the ADE stage because Sharivkin et al. demonstrates that CD177 is "detected" but that it is not "differentially expressed” (i.e. Table 1)(remarks, p. 8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). 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, Sharivkin is cited for using CD177 and CD51 ligands (e.g. antibody) to capture hESC-derived CXCR4+ endoderm cells (see e.g. abstract, p. 588, table 1, fig. 1, supplemental table 1), and suggesting a method for sub-fractionating the early definitive endoderm compartment of cells (i.e. CXCR4+) into discrete subsets that exhibit unique properties (see e.g. abstract, p. 588 and 591). The prior art of Kelly is cited for teaching that CD177 is differentially expressed at stage 2 (endodermal lineage screen)(see p. 41, table 1).
Applicant argues that the prior art of Kelly, Benvenisty, and Sharivkin would naturally teach away from exposing an initial population of cells with CER1 and CD177 ligand as taught by Kelly to isolate the anterior definitive endoderm stage as taught by Benvenisty and Sharivkin in order to obtain the earliest pancreatic progenitor cell stage that is committed toward the pancreas (remarks, p. 9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant's argument, it is unclear how the prior art of Kelly, Benvenisty, and Sharivkin would naturally teach away from the claimed invention. As discussed above, As discussed above, Kelly et al., teaches CER1 and CD177 that can be used to enrich or purify the indicated cell type at each stage (see e.g. p. 6, 41, table 1 and fig. 1). Additionally, the prior art of Benvenisty discloses CD177 is a marker positively associated with definitive endoderm cells (claim 28, p. 9-10, 18, 90, 132, 235, and Example 3). Furthermore, the prior art of Morrison discloses pancreatic progenitor cells from embryonic stem cells to anterior definitive endoderm cells (see e.g. p. 404, fig. 1-3) and discloses CER1 as an anterior definitive endoderm (ADE) marker, which can be expanded and undergo differentiation towards pancreatic fates (see e.g. abstract, page 408-410, fig. 6). Further, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instant case, the prior art of Morrison discloses the cells expressing “Cer1, Foxa2, and E-cadherin, but not Oct4 (Figure 6C), indicating these cells represent a form of ADE progenitor”. Therefore, it was well known in the art that CER1 identified ADE stage. Additionally, Cheng is cited for disclosing the surface marker CD177 in endodermal progenitor (EP) cells and providing a population glucose-responsive pancreatic β-like cells (See e.g. abstract, page 379, 382, fig. 3). Further, the arguments regarding prior art of and Kelly et al., are not persuasive, see CD177 is positively expressed at stage 2 (endodermal lineage screen)(page 44, para. 145 and 146, Table 1), and the marker of CER (i.e. CER1, see page 23, par. 97) are expressed in definitive endoderm cells (see e.g. abstract, page 9, para. 63; Figure 1). 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.
Applicant argues that the prior art of Cheng discloses endodermal progenitor cells, which are not the same as the anterior definitive endoderm cells of the present invention (remarks, p. 9). Applicant argues that Cheng combined with the prior art of Kelly, Benvenisty, Morrison, and Sharivkin would not teach a skilled artisan to use a CD177 ligand and are the ADE stage (remarks, p. 9).
In response to applicant's argument that Cheng is non-analogous 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, Cheng discloses definitive endoderm progenitor lines from embryonic stem cells and induced pluripotent stem cells (see p. 371). Therefore, it is unclear how the endodermal progenitor cells as taught by Cheng are not the same as the the anterior definitive endoderm cells of the present invention (remarks, p. 9).
Further, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instance, Cheng is cited for disclosing that the surface marker CD177 was known in endodermal progenitor (EP) cells and that CD177 suggests a functionally superior population glucose-responsive pancreatic β-like cells from endodermal progenitor (EP cells) that reflect biological features related to the developmental timing of pancreatic endoderm production in vivo (See e.g. abstract, page 379, 382, fig. 3, 6). Therefore, absent evidence to the contrary the method as taught by Kelly, Benvenisty, Morrison, Sharivkin, Cheng et al., naturally provide a population of glucose-responsive beta-like cells.
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 3 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kelly et al. (WO2009/131568A1; cited IDS 12/13/2019), Benvenisty et al. (WO2012/070014A2; cited IDS 12/13/2019), Sharivkin et al. (Molecular & Cellular Proteomics, published Sept. 1, 2012), Morrison et al. (Cell Stem Cell 3.4: 402-415, published 2008, prior art of record), Cheng, et al., (Cell stem cell 10.4: 371-384; published 2012; cited IDS 12/13/2019), as applied to claims 1, 2, 4-17, and 21 above, and further in view of Brafman et al. (Cell Death Differ, 2013, prior art of record) and Holtzinger et al., (Development. Dec 15;142(24):4253-65, 2015).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on May 23, 2025, therefore 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 Kelly et al., apply here as indicated above.
Regarding claim 3, as stated supra, Kelly et al., teaches five stages of differentiation of the hESCs - (ES) through mesendoderm (ME), ME to definitive endoderm (DE or PDX1-negative definitive endoderm)(stage 1), DE to primitive gut tube (PG or PDX1 negative foregut endoderm) (stage 2, CyT203), PG to posterior foregut (PF or PDX1-positive foregut endoderm)(stage 3), PF to pancreatic endoderm (PE)(stage 4, CyT49), and PE to endocrine (EN cells)(stage 5, CyT203)(see fig. 1, Example 1, table 1). Further, Kelly et al. teaches purification of endoderm cells using the pancreatic and duodenal homeobox 1 (PDX1) marker for pancreatic endoderm cells (Example 3) and a definitive endoderm cell with a ligand (e.g. antibody) that is a marker for the definitive endoderm stage (see e.g. para. 63-71, 97, 105, 114, Example, 1, table 1, fig. 1). As discussed above, Kelly et al., teaches CER1 and CD177 that can be used to enrich or purify the indicated cell type at each stage (see e.g. p. 6, 41, table 1 and fig. 1). Additionally, the prior art of Benvenisty discloses CD177 is a marker positively associated with definitive endoderm cells (claim 28, p. 9-10, 18, 90, 132, 235, and Example 3). Furthermore, the prior art of Morrison discloses pancreatic progenitor cells from embryonic stem cells to anterior definitive endoderm cells (see e.g. p. 404, fig. 1-3) and discloses CER1 as an anterior definitive endoderm (ADE) marker, which can be expanded and undergo differentiation towards pancreatic fates (see e.g. abstract, page 408-410, fig. 6). Moreover, the prior Sharivkin discloses using CD177 and CD51 ligands (e.g. antibody) to capture hESC-derived CXCR4+ endoderm cells (see e.g. abstract, p. 588, table 1, fig. 1, supplemental table 1). Further, Sharivkin discloses method for sub-fractionating the early definitive endoderm compartment of cells (i.e. CXCR4+) into discrete subsets that exhibit unique properties (see e.g. abstract, p. 588 and 591).
Kelly et al. does not explicitly teach exposing the initial population of cells to a second ligand that binds to CD51.
However, the prior art of Holtzinger discloses that the marker CD51 (ITGAV) can be used to monitor endoderm development (see e.g. p. 4253 and 4262) and cites the prior art of Brafman for teaching obtaining human embryonic stem cell (HESC)-derived definitive endoderm (DE) cells with increased CD 51 expression, which were sorted by flow cytometry and differentiated into the primitive gut tube (PGT) stage (stage 3 or posterior foregut, PF or PDX1-positive foregut endoderm)(see e.g. Figure 5). Further, Brafman et al. teaches that ITGA5 (CD51) and ECMP-integrin interactions are required for hESC differentiation into functionally mature cells (abstract).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the method of purifying a pancreatic progenitor cell population, as taught by as taught by Kelly, Benvenisty, and Sharivkin, to incorporate exposing the initial population of cells pancreatic progenitor cells to a second ligand which binds by CD51 (ITGA5) or CD275, as taught by Sharivkin, Holtzinger, and Brafman, with a reasonable expectation of success because one of ordinary skill in the art would know that CD51 (ITGAV) can be used to monitor endoderm development (as taught by Holtzinger, see e.g. p. 4253 and 4262) and that CD275 is . Further, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because methods of purifying endoderm progenitor cells from differentiation human embryonic stem cells using CD51 (ITGAV) were known (see Brafman, fig. 5). Thus, adding a second ligand which binds to CD51 (ITGAV) a known viable marker for pancreatic progenitor cells and using it to purify the pancreatic progenitor cell population (as taught by and Kelly et al.) to obtain a product cell population that is enriched relative to the initial population of cells that bind to the ligand, express CER1, and are at the ADE stage would have led to a reasonable expectation of success because Sharivkin suggests for a person of ordinary skill to sub-fraction early definitive endoderm compartment of cells (i.e. CXCR4+) into discrete subsets that exhibit unique properties (see e.g. abstract, p. 588 and 591). Therefore, a person of ordinary skill in the art would have combined similar pancreatic progenitor cell purification techniques, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of endodermal progenitor (EP) cell culture methods 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).
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 Brafman does not resolve the deficiencies of the cited prior art (i.e. Kelly, Benvenisty, Morrison, and Sharivkin), and submits that no prima facie case of obviousness exists (remarks, p. 10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. The arguments addressed to the cited prior art. Kelly, Benvenisty, Morrison, Sharivkin and Cheng have been addressed above. It is noted that the prior art of Brafman is cited for disclosing human embryonic stem cell (HESC)-derived definitive endoderm (DE) cells with increased CD 51 expression (see e.g. fig. 5). Further, in response to applicant's argument, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
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
No claim is allowed.
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Josephine Gonzales PhD
Examiner
Art Unit 1638
/JOSEPHINE GONZALES/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
