DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
This action is responsive to papers filed 05/13/2026.
Claims 2, 9, 20, 32, 37, 42, and 52 have been amended. Claims 33-35 have been newly canceled and claims 53-55 have been newly added.
Claims 2-9, 19-32, and 36-55 are currently pending.
Claims 50-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/13/2026.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendments. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claims 2-9, 19-32, 36-49, and 52-55 have been examined on their merits.
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 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 2, 4-6, 8, 20-22, 26-27, 38, 40, 42, 46-47, 52 and 55 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Parenteau (US 2006/0121605-newly cited) in view of Fisk (US 2003/0138948-previously cited), Rulifson et al (PNAS 2007-previously cited), Crosnier et al (Nature Reviews/ Genetics, 2006-from IDS filed 11/19/2018 and in parent) and Fuchs et al (US 2006/0172304) and as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018).
Regarding claims 2, 4-6, 8, 20-22, 26-27, 38, 40, 52 and 55, Parenteau disclose methods of culturing primary progenitor cells wherein the progenitor cells are derived from pancreatic tissue (page 2 para 14, 21-22, page 5 example 2). The tissue the cells are derived from can be adult tissue (non-transformed) (page 1 para 8, page 5 para 49). The progenitor cells derived from human tissue are established from enzymatically dissociated tissue or from mincing to form tissue explants (tissue fragments) (page 4 para 43). Organotypic differentiation upon changing the culture conditions to an environment that may contain factors that promote and/or support development and growth of differentiating cells is suggested (page 5 para 47). The formation of suspended cell clusters (organoids) is suggested (page 8 para 89). The isolated pancreatic tissue contains stem cells which give rise to the progenitor cells (page 2 para 23).The growth factors used in the culture of the isolated cells include epidermal growth factor (EGF), keratinocyte growth factor (KGF) and fibroblast growth factor (FGF) (mitogenic growth factors)(page 4 para 40, page 6, para 62). In a preferred embodiment the cultures are maintained in the presence of an extracellular matrix component such as collagen (page 2 para 13) that assists the formation of cellular complexes (organoids) and cluster formation (organoids)(page 4 para 41, page 5 para 47 para 53).
While Parenteau is silent with regard to the expression of Lgr5 in their pancreatic progenitor cells, it is shown in the art that pancreatic stem cells inherently include Lgr5 (see Clevers et al., US 2010/0275280, page 6 Table 1, para 94, page 63 claim 5). In addition, the culture of pancreatic epithelial stem cells with a Wnt agonist will also inherently stimulate the expression of Lgr5+ as evidenced by Applicant’s Specification para 195, para 201, para 204).
Parenteau does not specifically teach including a BMP inhibitor in their culture medium in a mixture with EGF and a Wnt agonist. Parenteau does not specifically teach including Noggin as a BMP inhibitor along with WNT3a and Notch in the culture medium, nor the inclusion of nicotinamide.
Fisk teach that Noggin is an islet (pancreatic cell) differentiation factor (page 2 para 22) that is beneficially used with mitogens (such as EGF and bFGF) to differentiate stem cells to pancreatic cells (page 3 para 28). Fisk include a step for withdrawing Noggin and adding nicotinamide for later stages of differentiation to end-stage islet cells (pancreatic cells) (page 3 para 28). Factors for differentiation of islet cells from stem cells include Exendin-4, nicotinamide, Gastrin, EGF, and KGF (aka FGF7) (page 7 Table 1). FGF10 is listed as an alternative to FGF7 and bFGF (page 8 para 80).
Rulifson teach that Wnt signaling stimulates islet beta cell proliferation and that the addition of Wnt3a protein leads to increased beta cell proliferation in vitro (abstract, page 6250 column 2 Discussion to page 6251 column 1).
Crosnier et al describe evidence regarding key regulatory signals for epithelial stem cells and how feedback loops involving BMP and Wnt pathways define and localize the stem cell niche (page 349, column 1, 2nd paragraph). Crosnier teach that the Noggin protein (BMP inhibitor) along with Wnt assist in the proliferation of epithelial cells by protecting the cells from inhibition (page 352). Wnt makes epithelial cells competent for secretory fates (page 354) and Wnt and Notch are essential for the proliferation of epithelial cells, including the stem cells (page 355-356). Wnt proteins include WNT3 (page 352) and WNT3A (page 357, Box 4).
Fuchs teach methods of modulating an epithelial stem cell lineage and teach wherein BMP inhibitors, such as Noggin and a Wnt protein, such as Wnt3a, can be used to modulate epithelial stem cell lineage, specifically stimulate epithelial bud formation (abstract, pages 1-2, para 9, page 3 para 17).
Therefore, one of ordinary skill in the art would have been motivated to select Noggin, WNT3A, and Notch as mitogens for the culture of epithelial stem cells in the method of Parenteau because Fisk and Rulifson describe the use of Noggin and Wnt3a in the culture of pancreatic cells and Crosnier and Fuchs teach that Noggin, WNT proteins such as WNT3A and Notch assist in the culture of epithelial cells. One of ordinary skill in the art would have been motivated to include nicotinamide in the cell culture medium because Fisk teach and suggest that nicotinamide aids in the differentiation to end-stage islet cells (pancreatic cells) (page 3 para 28). One of ordinary skill in the art would have had a reasonable expectation of success because Parenteau, Fisk, Rulifson, Crosnier and Fuchs are all drawn to the optimization of the growth and/or culture of epithelial progenitor/stem cells.
The use of various combinations of growth factors in a first medium and a second medium is deemed to be obvious as a matter of routine optimization and experimentation in order to optimize the growth of the cells. Therefore, it is deemed to be obvious to remove factors, such as Noggin, from subsequent culture media in order to preserve cell morphology, conserve resources and reduce cost and when further proliferation of epithelial cells is no longer required. One of ordinary skill in the art would have been motivated as well with a reasonable expectation of success by the suggestion of Fisk to remove Noggin at the end stages of differentiation.
Regarding claim 42, Parenteau disclose wherein the cultures are incubated for at least 14 days (2 weeks) (page 8 para 79).
Regarding claims 46-47, Parenteau disclose wherein the mitogenic growth factor is present in the culture medium at less than 10 ng/ml (page 3 para 32, page 4 para 44), which overlaps with the claimed range and thus renders it obvious. In one example the EGF is described specifically as 10 ng/ml of EGF (page 6 para 64).
Therefore, the combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al and Fuchs et al render obvious Applicant’s invention as claimed.
Claims 3, 23-25, 36-37, 49 and 53 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Parenteau (US 2006/0121605-newly cited) in view of Fisk (US 2003/0138948-previously cited), Rulifson et al (PNAS 2007- previously cited), Crosnier et al (Nature Reviews/ Genetics, 2006-from IDS filed 11/19/2018 and in parent) and Fuchs et al (US 2006/0172304) and as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018) as applied to claims 2, 4-6, 8, 20-22, 26-27, 38, 40, 42, 46-47 and 52 above, and further in in view of Yoon (US 2007/0059829).
Regarding claims 3, 23-25, 36-37, 49 and 53, The combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al and Fuchs et al render obvious Applicant’s invention as described above, but do not specifically include any one of R-spondin 1- R-spondin 4 for stimulating the Wnt signaling pathway.
Yoon teach that R-spondins stimulate the Wnt signaling pathway, specifically R-spondin 2 and 3 (page 1 para 1, para 4, para 8-10). The Wnt signaling pathway is one of the key pathways in controlling cell proliferation, differentiation and morphogenesis and breakdown of the pathway results in various disease states (page 1 para 4).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to include R-spondins in the method of Parenteau in addition to the Wnt 3A protein because Yoon teach that R-spondins stimulate the Wnt signaling pathway, specifically R-spondin 2 and 3 (page 1 para 1, para 4, para 8-10) and that the Wnt signaling pathway is one of the key pathways in controlling cell proliferation, differentiation and morphogenesis and breakdown of the pathway results in various disease states (page 1 para 4) and Rulifson teach the importance of the Wnt pathway in the culture of pancreatic cells. The combination of agents known for the same purpose is deemed to be prima facie obvious.
Regarding claim 37, The use of various combinations of growth factors in a first medium and a second medium is deemed to be obvious as a matter of routine optimization and experimentation in order to optimize the growth of the cells. Therefore, it is deemed to be obvious to remove factors, such as Noggin, from subsequent culture media in order to preserve cell morphology, conserve resources and reduce cost and when further proliferation of epithelial cells is no longer required. One of ordinary skill in the art would have been motivated as well with a reasonable expectation of success by the suggestion of Fisk to remove Noggin at the end stages of differentiation.
Therefore, the combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al and Yoon render obvious Applicant’s invention as claimed.
Claims 7, 9, 19, 29-31, 39 and 54 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Parenteau (US 2006/0121605-newly cited) in view of Fisk (US 2003/0138948- previously cited), Rulifson et al (PNAS 2007- previously cited), Crosnier et al (Nature Reviews/ Genetics, 2006-from IDS filed 11/19/2018 and in parent) and Fuchs et al (US 2006/0172304) and as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018) as applied to claims 2, 4-6, 8, 20-22, 26-27, 38, 40, 42, 46-47 and 52 above, and further in in view of Robins et al (US 2008/0113433-from IDS filed 11/19/2018).
Regarding claims 7, 9, 19, 29-31, 39 and 54, The combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al and Fuchs et al render obvious Applicant’s invention as described above, but do not specifically teach the inclusion of a Rock (Rho-kinase) inhibitor.
Robins et al teach that a Rock inhibitor, such as Y-27632, can be added to a cell suspension as an inhibitor of apoptosis and that it provides the benefit of improved cell viability (page 19 para 166-167). Robins et al also teach that the cell medium can include supplements such as N2, B27, additional factors such as fibronectin, EGF, noggin, gremlin, Cerberus, Dan, Notch activator and WNT factor (pages 13-14, para 119).
Therefore, one of ordinary skill in the art would have been motivated to add a Rock inhibitor to the method of Parenteau because Robins et al teach that it is an inhibitor of apoptosis and provides the benefit of improved cell viability. One of ordinary skill in the art would have been motivated to add N2 and/or B27 to the culture conditions of Tsao because Robins indicate that these supplements are also beneficial and also used with EGF, Noggin and Wnt. One of ordinary skill in the art would have had a reasonable expectation of success because Robins et al is also directed to cell compositions containing adult stem cells from epithelial tissue (page 5 para 57).
Therefore, the combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al and Robins et al render obvious Applicant’s invention as claimed.
Claims 28 and 54 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Parenteau (US 2006/0121605-newly cited) in view of Fisk (US 2003/0138948- previously cited), Rulifson et al (PNAS 2007- previously cited), Crosnier et al (Nature Reviews/ Genetics, 2006-from IDS filed 11/19/2018 and in parent) and Fuchs et al (US 2006/0172304) and Yoon (US 2007/0059829) and as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018) as applied to claims as applied to claims 2-6, 8, 20-22, 26-27, 36-38, 40, 42, 46-47, 49 and 52 above, and further in in view of Robins et al (US 2008/0113433-from IDS filed 11/19/2018).
Regarding claims 28 and 54, The combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al and Yoon render obvious Applicant’s invention as described above, but do not specifically teach the inclusion of a Rock (Rho-kinase) inhibitor.
Robins et al teach that a Rock inhibitor, such as Y-27632, can be added to a cell suspension as an inhibitor of apoptosis and that it provides the benefit of improved cell viability (page 19 para 166-167). Robins et al also teach that the cell medium can include supplements such as N2, B27, additional factors such as fibronectin, EGF, noggin, gremlin, Cerberus, Dan, Notch activator and WNT factor (pages 13-14, para 119).
Therefore, one of ordinary skill in the art would have been motivated to add a Rock inhibitor to the method of Parenteau because Robins et al teach that it is an inhibitor of apoptosis and provides the benefit of improved cell viability. One of ordinary skill in the art would have had a reasonable expectation of success because Robins et al is also directed to cell compositions containing adult stem cells from epithelial tissue (page 5 para 57).
Therefore, the combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al, Yoon and Robins et al render obvious Applicant’s invention as claimed.
Claims 32, 41, and 48 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Parenteau (US 2006/0121605-newly cited) in view of Fisk (US 2003/0138948- previously cited), Rulifson et al (PNAS 2007- previously cited), Crosnier et al (Nature Reviews/ Genetics, 2006-from IDS filed 11/19/2018 and in parent) and Fuchs et al (US 2006/0172304) and as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018) as applied to claims 2, 4-6, 8, 20-22, 26-27, 38, 40, 42, 46-47 and 52 above, and further in in view of Herlyn et al (US 2004/0175367-from IDS filed 11/19/2018).
Regarding claims 32, 41 and 48, The combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al and Fuchs et al render obvious Applicant’s invention as described above, but do not specifically teach wherein the epithelial stem cells are obtained from a pancreatic adenoma.
Herlyn et al teach that an alternative source of epithelial stem cells can be derived from an adenoma or carcinoma (page 4 para 42).
Therefore, one of ordinary skill in the art would have been motivated to use pancreatic epithelial stem cells from a pancreatic adenoma tissue in the method of Parenteau because Herlyn et al teach and suggest that an alternative source of epithelial stem cells can be derived from an adenoma source (page 4 para 42). One of ordinary skill in the art would have had a reasonable expectation of success because Parenteau and Herlyn are both culturing epithelial stem cells.
Therefore, the combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al and Herlyn et al render obvious Applicant’s invention as claimed.
Claims 43-45 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Parenteau (US 2006/0121605-newly cited) in view of Fisk (US 2003/0138948- previously cited), Rulifson et al (PNAS 2007- previously cited), Crosnier et al (Nature Reviews/ Genetics, 2006-from IDS filed 11/19/2018 and in parent) and Fuchs et al (US 2006/0172304) and as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018) as applied to claims 2, 4-6, 8, 20-22, 26-27, 38, 40, 42, 46-47 and 52 above, and further in in view of Lelkes et al (US 2008/0112890-from IDS filed 01/28/2019).
Regarding claims 43-45, The combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al and Fuchs et al render obvious Applicant’s invention as described above, but do not specifically teach the inclusion of FGF-10.
Lelkes et al teach that FGF-10 enhance epithelial budding and proliferation (page 3 para 23).
Therefore, one of ordinary skill in the art would have been motivated to include FGF-10 in the culture method of Parenteau because Lelkes et al teach that FGF-10 is a beneficial mitogen for culture of epithelial cells and enhance epithelial budding and proliferation. Additional motivation is provided by Fisk which teach and suggest that FGF10 is an alternative to FGF7 or bFGF for differentiation of pancreatic cells (page 8 para 80). One of ordinary skill in the art would have had a reasonable expectation of success because both Lelkes et al and Parenteau are drawn to the proliferation of epithelial progenitor/stem cells.
Therefore, the combined teachings of Parenteau, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al and Lelkes et al render obvious Applicant’s invention as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 2-6, 20-27, 32, 42, 46-49, 52-53 and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-12 of U.S. Patent No. 9,752,124 in view of Parenteau (US 2006/0121605-newly cited) as evidenced by Clevers et al (US 2010/0275280-from IDS filed 11/19/2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent are drawn to an epithelial organoid that includes the adenoma epithelial stem cells and the same culture conditions.
Parenteau disclose methods of culturing primary progenitor cells wherein the progenitor cells are derived from pancreatic tissue (page 2 para 14, 21-22, page 5 example 2). The tissue the cells are derived from can be adult tissue (non-transformed) (page 1 para 8, page 5 para 49). The progenitor cells derived from human tissue are established from enzymatically dissociated tissue or from mincing to form tissue explants (tissue fragments) (page 4 para 43). Organotypic differentiation upon changing the culture conditions to an environment that may contain factors that promote and/or support development and growth of differentiating cells is suggested (page 5 para 47). The formation of suspended cell clusters (organoids) is suggested (page 8 para 89). The isolated pancreatic tissue contains stem cells which give rise to the progenitor cells (page 2 para 23). The growth factors used in the culture of the isolated cells include epidermal growth factor (EGF), keratinocyte growth factor (KGF) and fibroblast growth factor (FGF) (mitogenic growth factors)(page 4 para 40, page 6, para 62). In a preferred embodiment the cultures are maintained in the presence of an extracellular matrix component such as collagen (page 2 para 13) that assists the formation of cellular complexes (organoids) and cluster formation (organoids)(page 4 para 41, page 5 para 47 para 53).
Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use pancreatic epithelial stem cells from an adult tissue source, such as an adenoma, in the method of the patent because Parenteau suggest that these are suitable pancreatic stem cells for the production of a three-dimensional ductal cell type (organoid). In addition, it is shown in the art that pancreatic stem cells inherently express Lgr5 (see Clevers et al., US 2010/0275280, page 6 Table 1, para 94, page 63 claim 5). In addition, the culture of pancreatic epithelial stem cells with a Wnt agonist will also inherently stimulate the expression of Lgr5+ as evidenced by Applicant’s Specification para 195, para 201, para 204).
Therefore, the combined teachings of the claims of the patent and Parenteau render obvious the claims of the current application.
Response to Arguments
Applicant’s amendments to the claims have overcome the rejections under 35 USC 112 first paragraph, 35 USC 112 second paragraph and 35 USC 103 and therefore, these rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Parenteau (US 2006/0121605) as described above.
Applicant’s arguments have been addressed in so far as they relate to the references that remain in the rejections above.
Applicant acknowledges that claims 50-51 were withdrawn from consideration as being directed to a non-elected invention.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant argues that Fisk relates to methods of producing islet cells, not organoids and is limited to culturing human embryonic stem cells and not pancreatic tissue or primary adult pancreatic cells. Applicant asserts that Fisk does not describe the formation of pancreatic organoids or culturing the starting material as recited in the claims.
This is not found persuasive.
Applicant argues that Fisk does not teach that Noggin is a differentiation factor that is beneficially used with mitogens such as EGF and bFGF to differentiate stem cells into pancreatic cells in a way that is consistent with the use of Noggin in the present invention.
This is not found persuasive.
Applicant asserts that Fisk is limited to a 3-step protocol for producing islet cells from embryonic stem cells. Applicant argues that Fisk describes the use of Noggin and mitogens in a step that moves endoderm cells from the endoderm stage towards the pancreas progenitors and that this is in contrast to the present invention which uses Noggin for the purpose of proliferation of already existing pancreas progenitors in primary pancreatic tissue and subsequent formation of pancreatic organoids by the proliferation.
This is not found persuasive.
Applicant argues that Rulifson is directed to the role of Wnt signaling in the proliferation of differentiated pancreatic beta cells and cannot be applied to primary pancreatic epithelial stem cells derived from pancreatic tissue. Applicant asserts that Rulifson is limited to a transformed cell line and cannot be applied to the primary pancreatic epithelial stem cells of the present claims. Applicant argues that Rulifson uses differentiated islet cells for their experiments and not cells from primary tissue as required by the claims.
This is not found persuasive. 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).
Rulifson teach that Wnt signaling stimulates islet beta cell proliferation and that the addition of Wnt3a protein leads to increased beta cell proliferation in vitro (abstract, page 6250 column 2 Discussion to page 6251 column 1). This teaching combined with the teaching of Crosnier which suggest the use of Wnt for the culture of epithelial stem cells are what lend motivation and a reasonable expectation of success to select Wnt proteins for use in the Parenteau method as described above.
Applicant argues that Crosnier does not teach methods of in vitro culturing an epithelial stem cell. Applicant asserts that Crosnier is limited to in vivo development pathways and does not relate to exogenous components and their ability in in vitro culture methods.
This is not found persuasive. 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).
Crosnier et al describe evidence regarding key regulatory signals for intestinal stem cells and how feedback loops involving BMP and Wnt pathways define and localize the stem cell niche (page 349, column 1, 2nd paragraph). Crosnier teach that the Noggin protein (BMP inhibitor) along with Wnt assist in the proliferation of epithelial cells by protecting the cells from inhibition (page 352). Wnt makes epithelial cells competent for secretory fates (page 354) and Wnt and Notch are essential for the proliferation of epithelial cells, including the stem cells (page 355-356). Wnt proteins include WNT3 (page 352) and WNTS3A (page 357, Box 4). Crosnier also refer to culture methods as a source of information (page 351, Box 1, page 357, column 2, end of first paragraph, Box 4). Therefore, Crosnier is deemed to be related to the study and manipulation of cells in culture. It is the combination of Crosnier with Rulifson and Fuchs that lend motivation and a reasonable expectation of success to select BMP inhibitors and Wnt proteins for the method of Parenteau as described above.
Applicant argues that the teachings of Fuchs are not related to the pancreas. Applicant asserts that the teaching of Fuchs is entirely different from methods of culturing pancreatic epithelial stem cells and thus they cannot be combined with the cited references.
This is not found persuasive. 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).
Fuchs teach methods of modulating an epithelial stem cell lineage and teach wherein BMP inhibitors, such as Noggin and a Wnt protein, such as Wnt8a, can be used to modulate epithelial stem cell lineage, specifically stimulate epithelial bud formation (abstract, pages 1-2, para 9, page 3 para 17). It is the combination of Fuchs with Crosnier and Rulifson that lend motivation and a reasonable expectation of success to select BMP inhibitors and Wnt proteins for the method of Parenteau.
Applicant argues that the secondary references of Yoon, Robins, Herlyn and Lelkes do not remedy the deficiencies of the cited references Tsao, Fisk, Rulifson, Crosnier and Fuchs.
This is not found persuasive because Parenteau, Fisk, Rulifson, Crosnier and Fuchs are not deemed to be deficient as described above.
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 claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Roberts, Penelope, “Human Pancreatic Epithelial Progenitor cells and Methods of Isolation and Use Thereof”, WO 01/77300 A2,
(Roberts describes methods of isolating and culturing pancreatic progenitor cells.)
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631
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