DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/08/2025 has been entered.
Claims 2, 9, 20, and 32 have been amended. Claims 50-52 have been newly added and no claims have been newly canceled.
Claims 2-9 and 19-52 are currently pending.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Newly submitted claims 50-51 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
The claims originally elected for examination were drawn to the in vitro culturing of pancreatic epithelial stem cells, isolated pancreatic tissue fragments comprising pancreatic epithelial stem cells, the method comprising incubating the cells with an extracellular matrix; and culturing the cells for a length of time sufficient to be able to observe formation of a pancreatic organoid, in the presence of a culture medium comprising a BMP inhibitor, a mitogenic growth factor and a WNT agonist and obtaining from the culture medium a pancreatic epithelial organoid.
The methods of claims 50-51 require steps for culturing to obtain new organoids and steps for culturing organoids which the other claims do not require. The methods of the originally examined claims require an isolated pancreatic tissue fragment or a pancreatic epithelial adenoma stem cell which claims 50-51 do not require.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits.
Accordingly, claims 50-51 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 2-9, 19-49, and 52 have been examined on their merits.
Information Disclosure Statement
The information disclosure statement filed 08/08/2025 complies with 37 CFR 1.97(c) and has been considered.
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 20 and 32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The 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.
Applicants have entered the limitation “culturing a non-transformed Lgr5+ adult pancreatic epithelial stem cell” and “derived from the non-transformed pancreatic epithelial adenoma stem cell” in claims 20 and 32 respectively. There is insufficient support in the disclosure as originally filed for this limitation; thus it is being considered new matter. The disclosure as originally filed does not disclose the status of the cultured stem cells, specifically the Lgr5+ adult pancreatic stem cells, with regard to whether they are transformed or not.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). Applicant is required to cancel the new matter in the reply to this Office Action.
The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir.1996).
Applicant is hereby notified that the insertion of new matter into the claims has necessitated the removal of the 103 rejection over claims 20 and 32. However, removal of new matter will result in the reinstatement of the 103 rejection.
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.
Claim 32 is 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.
Claim 32 recites the limitation "the non-transformed pancreatic epithelial adenoma stem cell”" in line 10 of the claim. There is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of a non-transformed pancreatic epithelial stem cell in the claim and thus the meets and bounds of the claim are unclear and indefinite.
Appropriate correction is required.
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 and 52 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tsao et al (US 2003/0003088-from IDS filed 11/19/2018) 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, 46-47 and 52, Tsao teach that there is a need to determine how a human pancreatic stem cell line can be used to form three-dimensional organoids to use as a means to use in treatments in diabetic patients (page 2 para 14). Tsao suggest that such a cell line containing pancreatic epithelial stem cells is cultured on Matrigel (an extracellular matrix) and that they develop a ductal-like structure and express ductal cell markers (page 14 para 111). Tsao also teach the use of epidermal growth factor (EDF or EGF), bFGF (mitogenic growth factors) and nicotinamide (page 6, para 52), specifically 5 ng/ml of epidermal growth factor (EDF or EGF) (page 10 para 75). Tsao et al teach that nicotinamide is a beneficial agent to add to the culture media of pancreatic cells (epithelial) because it promotes the differentiation of pancreatic cells (page 6 para 52, page 13 para 103 and page 14 para 111 and para 113). Tsao also include keratinocyte growth factor (KGF) and fibroblast growth factor (FGF) as well (page 7, para 57).
Tsao does not specifically teach including a BMP inhibitor in their culture medium in a mixture with EGF and a Wnt agonist. Tsao does not specifically teach including Noggin as a BMP inhibitor along with WNT3a and Notch in the culture medium.
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).
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 Tsao 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. Also, 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). One of ordinary skill in the art would have had a reasonable expectation of success because Tsao, Fisk, Rulifson, Crosnier and Fuchs are 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, Tsao do not specifically describe wherein the stem cells are cultured for at least 2 weeks, but the length of culture time is deemed to be an optimizable parameter as the amount and size of the final product would be affected by the culture time. One of ordinary skill in the art would have been motivated to culture the epithelial stem cells of Tsao for at least 2 weeks in order to increase the number of organoids produced for future use.
Therefore, the combined teachings of Tsao et al, 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 and 49 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tsao et al (US 2003/0003088-from IDS filed 11/19/2018) 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 and 49, The combined teachings of Tsao et al, 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 Tsao 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 Tsao et al, 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 and 39 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tsao et al (US 2003/0003088-from IDS filed 11/19/2018) 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 and 39, The combined teachings of Tsao et al, 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 Tsao et al 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 Tsao et al, Fisk et al, Rulifson et al, Crosnier et al, Fuchs et al and Robins et al render obvious Applicant’s invention as claimed.
Claim 28 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tsao et al (US 2003/0003088-from IDS filed 11/19/2018) 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 claim 28, The combined teachings of Tsao et al, 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 Tsao et al 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 Tsao et al, 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 32-35, 41, and 48 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Tsao et al (US 2003/0003088-from IDS filed 11/19/2018) 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 32-35, 41 and 48, The combined teachings of Tsao et al, 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 established epithelial cell line, such as an adenoma or carcinoma cell line (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 stem cell line in the method of Tsao because Herlyn et al that an alternative source of epithelial stem cells can be derived from an established epithelial cell line, such as an adenoma or carcinoma cell line (page 4 para 42).One of ordinary skill in the art would have had a reasonable expectation of success because Tsao suggest the use of cell lines in their methods and both Tsao and Herlyn are culturing epithelial stem cells.
Therefore the combined teachings of Tsao et al, 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 Tsao et al (US 2003/0003088-from IDS filed 11/19/2018) 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 Tsao et al, 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 Tsao because Lelkes et al teach that FGF-10 is a beneficial mitogen for culture of epithelial cells and enhance epithelial budding and proliferation. One of ordinary skill in the art would have had a reasonable expectation of success because both Lelkes et al and Tsao are drawn to the proliferation of epithelial progenitor/stem cells.
Therefore the combined teachings of Tsao et al, 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 2-9 and 19-49 and 52 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 Tsao (US 2003/0003088) and 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.
Tsao suggest that a cell line containing pancreatic epithelial stem cells is cultured on Matrigel (an extracellular matrix) they develop a ductal-like structure and express ductal cell markers (page 14 para 111). Tsao also teach the use of epidermal growth factor (EDF or EGF), bFGF and nicotinamide (page 6, para 52), specifically 5 ng/ml of epidermal growth factor (EDF or EGF) (page 10 para 75). Tsao et al teach that nicotinamide is a beneficial agent to add to the culture media of pancreatic cells (epithelial) because it promotes the differentiation of pancreatic cells (page 6 para 52, page 13 para 103 and page 14 para 111 and para 113). Tsao also include keratinocyte growth factor and fibroblast growth factor as well (page 7, para 57).
Therefore one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use pancreatic epithelial stem cells in the method of the patent because Tsao 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 claims of the patent render obvious the claims of the current application.
Response to Arguments
Applicant's arguments filed 08/08/2025 have been fully considered but they are not persuasive.
Applicant argues that a prima facie case of obviousness has not been made because there is no reason to modify the disclosure of the cited references to arrive at the claimed invention and no reasonable expectation of success for making the modifications proposed by the Office. Applicant asserts that they have made a showing of secondary considerations in the forms of unexpected results relating to the claimed invention. Applicant asserts that the totality of their evidence weighs in favor of non-obviousness of the pending claims.
This is not found persuasive. The office has provided a rationale for the selection and the combination of the claimed culture medium agents as all the cited references indicate that the claimed agents are beneficial for the culture of epithelial stem cells, in some cases specifically pancreatic stem cells. The MPEP states that the selection of a known material based on its suitability for its intended use is sufficient support for a prima facie obviousness determination (see MPEP 2144.07 Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)). “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.” 325 U.S. at 335, 65 USPQ at 301.). The Examiner has determined that the evidence of obviousness outweighs any evidence provided towards non-obviousness as explained in the prior office action.
Applicant argues that Tsao uses the word “organoids” in the context of an immortalized cell line. Applicant asserts that the mere use of the general term “organoid” does not imply that Tsao teaches or suggest the organoids of the present invention. Applicant argues that immortalized cells are not the same as non-transformed cells. Applicant points to paragraph 189 for support of the requirement of non-transformed cells in their claimed method.
This is not found persuasive. The claims are drawn to a method for obtaining an organoid. Therefore, as long as the prior art teaches or suggests the claimed method steps the requirements of the claims are deemed to be met. In addition, Tsao disclose that their disclosed methods are drawn to obtaining a three-dimensional organoid (para 50, para 58, para 59) by culturing their cells under specific culture conditions. Tsao does not indicate that an immortalized cell line is an organoid. Also only amended claims 20 and 32 recite non-transformed cells and these claims have been deemed to contain new matter as Applicant’s Specification as filed does not support the requirement of non-transformed cells as described above. Also, the paragraph of 189 is the source of Applicant’s quote in the PGPUB of the application. This recitation is found at paragraph 199 in Applicant’s Specification as filed and Applicant is supposed to be using this form of the Specification for reference.
Applicant argues that Tsao is limited to differentiating immortalized pancreatic stem cells and does not include Lgr5+ adult epithelial stem cells.
This is not found persuasive. Most of Applicant’s claims do not require the exclusion of immortalized pancreatic stem cells as described above. 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).
Applicant argues that Tsao does not teach a culture media for culturing epithelial stem cells as recited in the instant claims with a BMP inhibitor and a Wnt agonist. Applicant argues that there are differences between the features of claims 2 and 20 and Tsao.
This is not found persuasive. Tsao specifically describe culturing pancreatic epithelial stem cells (HPDE cells) on Matrigel with nicotinamide and hepatocyte growth factor to produce insulin producing cells (page 14 para 111). Tsao teach that there is a need to determine how a human pancreatic stem cell line can be used to form three- dimensional organoids to use as a means to use in treatments in diabetic patients (page 2 para 14). Tsao also suggest many of Applicant’s claimed growth factors as useful and beneficial in their method as described above. Also, the addition of a BMP inhibitor and a Wnt agonist is taught and suggested by the secondary references recited in the 103 rejection above and claim 2 does not recite non-transformed cells.
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).
Applicant argues that Fisk teaches the skilled artisan to remove Noggin, EGF and FGF from the medium. Applicant asserts that Fisk relates to a different purpose from Tsao. Applicant asserts that Fisk is limited to a 3-step protocol for producing islet cells from embryonic stem cells. Applicant asserts that Fisk does not motivate the skilled person to use the claimed medium and therefore the skilled person would not be motivated to modify the method of Tsao which is limited to an immortalized pluripotent pancreatic epithelial cell line in view of Fisk. Applicant also argues that Fisk is silent with regard to a Wnt agonist.
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).
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). This is not deemed to be a teaching away from Tsao or the claimed method. In addition, both Fisk and Applicant disclose withdrawing Noggin later in the culture method (see claim 37 of the current application).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that Rulifson does not teach methods of culturing stem cells. Applicant asserts that Rulifson is limited to methods of culturing pancreatic beta cells which are differentiated cells. Applicant argues that because Rulifson is different from Tsao and Fisk it cannot be relied upon to provide any insight into the effect of Wnt on an immortalized pluripotent pancreatic epithelial cell line such as HPDE6c7. Applicant asserts that the skilled person would not be motivated to include Wnt agonists in Tsao’s methods based on Rulifson.
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 Tsao method.
Applicant argues that Crosnier does not teach methods of culturing an epithelial stem cell as alleged by the Office. Applicant argues that Crosnier is not even directed toward in vitro cell culture. 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 Tsao.
Applicant argues that the teachings of Fuchs are not related to the pancreas. Applicant asserts that the teaching of Fuchs is entirely different from Tsao and thus they cannot be combined.
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 Tsao.
Applicant asserts that the claimed methods are inventive over the cited art because they yield unexpected results. Applicant asserts that the combination of a BMP inhibitor, a mitogenic growth factor and a Wnt agonist in cell culture medium synergistically enhances robust expansions of defined, non-transformed adult pancreas progenitors over long periods of time that maintain the capacity to differentiate along the endocrine lineage. Applicant asserts that this result is surprising and unexpected. Applicant asserts that evidence of this surprising effect is shown in their Specification in examples 6-8. Applicant asserts that none of the prior art documents teach or suggest the method as claimed.
This is not found persuasive. An assertion that the examples in the specification provide unexpected results is insufficient (see MPEP 716.02). In addition, these examples are not commensurate in scope with the claims. Applicant’s assertion of synergy from a specific combination of mitogens at specific concentrations are not commensurate in scope with the current claims. Synergistic effects are known to be concentration dependent.
In submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964).
The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter "as a class" relative to the prior art subject matter "as a class." In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971); In re Hostettler, 429 F.2d 464, 166 USPQ 558 (CCPA 1970). See, also, In re Lindner, 457 F.2d 506, 173 USPQ 356 (CCPA 1972).
It should also be established that the differences in the results are in factunexpected and unobvious and of both statistical and practical significance. In reMerck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D'Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
Applicant argues that the secondary references of Yoon, Robins, Herlyn and Lelkes do not remedy the deficiencies of Tsao, Fisk, Rulifson, Crosnier and Fuchs.
This is not found persuasive because Tsao, 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.
Hubrecht Institut, “A method for identifying, expanding, and removing adult stem cells and cancer stem cells”, EP 2022848 A1
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631