DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
In the event the determination of the status of the application as subject to pre- AIA 35 U.S.C. 102 and 103 (or as subject to 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.
Status of the Claims
Claims 35, 37, 39, 65-72, 75-79, 83-85, and 88-92 are pending.
Claims 39,and 68-69 are newly amended.
Claims 70-72 and 78-79 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply received on 10/05/2015.
Claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 103 - maintained
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 35, 37, 39, 65-69, 75-77, 83-85, 89, and 91 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sato et al. (WO 2010/090513, on IDS 09/08/2015, previously cited) in view of Tseng et al. (US 2007/0010008, referred to as Tseng ‘008, previously cited) and Asahara et al. (US, previously cited).
In regards to claims 35, 65, 67, and 89, Sato teaches methods for inducing organoids (Title, Abstract; p13, lines 4-5, claims 2, 9 and 10). Sato teaches that tissue fragments comprising Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) are cultured in a medium comprising R-spondin 1 (which is known in the art as a Lgr5 agonist), a BMP inhibitor, and a mitogenic growth factor (claim 2).
Sato does not explicitly teach that the medium comprises one or more TGF-beta inhibitor wherein the TGF-beta inhibitor is an inhibitor of ALK5, ALK4 and/or ALK7 signaling.
However, Tseng ‘008 teaches that culturing animal cells, including gastrointestinal stem cells (of which Lgr5+ cells are a type) with a TGF-beta inhibitor (including SB-431542) allows for expansion of these cells while controlling differentiation of these cells (claim 1; paragraphs [0007, 0022, 0029]).
Additionally, Asahara teaches that TGF-beta inhibitors can be added to culture media to expand cells in vitro (paragraphs 0057, 0069]). Likewise, Asahara demonstrates that the TGF-beta inhibitor can be SB-431542 (paragraph [0030]).
It is noted that according to Applicant’s disclosure (page 12, Table 1 of Applicant’s as filed specification), mechanistically, SB-431542 reduces the activity of ALK5, ALK4 and ALK7.
A person of ordinary skill in the art would have been motivated to include a TGF-beta inhibitor because it would have promoted expansion of Lgr5+ stem cells in organoids.
Furthermore, because both Tseng ‘008 and Asahara demonstrate that TGF-beta inhibitors can promote expansion of cells, and Tseng ‘008 teaches that gastrointestinal stem cells (of which Lgr5+ stem cells are a type) can be expanded, it could have been done with predictable results and a reasonable expectation of success.
In regards to the structure of the organoid, Sato teaches that after culturing (which requires time) the organoid comprises a lumen lined by a crypt villus-like epithelium (p2, lines 26-34).
Sato teaches that, as a basic matter, crypts are polarized, with stem cells (Lgr5+ stem cells) residing at the base and most differentiated cells in the upper positions, and that stem cells serve as the source of these differentiated cells (p3, lines 1-19; p1, lines 23-25).
In regards to the organoids specifically, Sato teaches Lgr5+ stem cells within tissue fragments fuels growth of these organoids, that Lgr5+ stem cell hierarchy is maintained in organoids, and that all differentiated cell types are found (p2, lines 26-33; p42, lines 1-11; p19, lines 31-32, p20, lines 1-30; p42, lines 1-11).
Thus, crypt-containing tissue fragments, and organoids derived from them, already comprise Lgr5+ stem cells and differentiated cells that derive from Lgr5+ stem cells.
It is noted that while claims 35 and 89 require differentiated epithelial progeny it does not necessarily require that these cells differentiate from Lgr5+ over active method steps in claims 35 and 89.
Therefore, the organoids as taught by Sato that comprise stem cells and differentiated stem cells reads on the limitation of organoids that have a lumen surrounded by cells that (i) comprise a combination of Lgr5+ epithelial stem cells and differentiated epithelial progeny, and (ii) are derived from those Lgr5+ cells.
However, even if these claims did require that Lgr5+ stem cells differentiate during active method steps, while, as above Tseng ‘008 teaches that a TGF-beta inhibitor (including SB-431542) allows for expansion of these cells while controlling differentiation of these cells (claim 1; paragraphs [0007, 0022, 0029]), it is noted that “controlling” does not necessarily imply that no differentiation occurs.
Indeed, as taught by Asahara cell clusters will both expand and differentiate in media comprising a TGF-beta inhibitor (Example 2, paragraphs [007-0013, 0057-0058]; Figs. 2, 3, and 7). Indeed, Asahara explicitly teaches that differentiation is a matter of “degree” (paragraphs [0040, 0047]). Therefore, in actual reduction to practice, cell clusters will both expand and differentiate when exposed to a TGF-beta inhibitor.
Therefore, since, as taught by Sato, organoids comprising Lgr5+ stem cells continually replace themselves and differentiate over time, and since, as taught by Asahara, cell clusters exposed to TGF-beta both expand and differentiate over time, even if, as taught by Tseng ‘008 differentiation can be “controlled”, it would be expected that the cultured Lgr5+ stem cells as taught by Sato, and as modified by Tseng ‘008 and Asahara to include a TGF-beta inhibitor, would in fact still differentiate to some degree while still expanding.
In regards to claim 37 and 75-77, Sato teaches that the epithelial stem cells are attached to an extracellular matrix, preferably Matrigel (EHS mouse sarcoma cell matrix) (page 5 line 32 to page 6 line 27) which inherently interacts with the cellular membrane protein integrin according to Applicant's disclosure (page 102 lines 1-6 of Applicant's specification as filed) and as taught by Sato contains laminin (p6, lines 23-27).
In regards to claim 39, Tseng ‘008 teaches that removing compositions or conditions that downregulate TGF-b (i.e., the TGF-b inhibitor) can be used to promote differentiation of the cell (paragraph [0018]). Tseng ‘008 teaches that removing compositions or conditions that downregulate TGF-b (i.e., the TGF-b inhibitor) can be used to promote differentiation of the cell (paragraph [0018]). Therefore, a person of ordinary skill in the art would have been motivated to remove the TGF-beta inhibitor in order to promote differentiation of LGr5+ cells, and furthermore, because Tseng ‘008 explicitly teaches that it can be removed to promote differentiation, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 66, it would have been prima facie obvious to modify the method of Sato and include a TGF-beta inhibitor, as discussed above.
In regards to the concentrations of a TGF-beta inhibitor, Asahara teaches that suitable concentrations for the TGF-beta inhibitor SB-431542 are taught about 0.1-10 μM, preferably about 1 μM (page 3 para 30), which overlaps with ranges as in claim 66.
According to MPEP 2144.05(I), 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).
A person of ordinary skill in the art would have been motivated to use the TGF-beta inhibitor concentration of about 1 μM in the method of Sato because Asahara indicates that this is a suitable concentration for the expansion of cells in vitro. One of ordinary skill in the art would have had a reasonable expectation of success because Asahara teaches specific concentrations of SB-431542 that overlap with the claim as limited, and because Sato, Tseng, and Asahara are all drawn to the expansion of cells.
In regards to claim 68, Sato teaches that the medium may further comprise nicotinamide (p13, Lines 10-15).
In regards to claim 69, as above, Sato teaches that the medium comprises R-spondin 1 (which is known in the art as a Lgr5 agonist) and a mitogenic growth factor (claim 2). Sato also teaches that the mitogenic growth factor can be EGF (p10, lines 29-31). Furthermore, Sato teaches that the medium comprises a basal medium, gastrin, nicotinamide, and Wnt3a as a further Wnt agonist (in addition to R-spondin 1 which is both an agonist of Lgr5 and a Wnt agonist) (p2, lines 20-24; p13, lines 10-15; p15, lines 18-22).
In regards to claim 83, as above, Sato teaches that the medium comprises R-spondin 1 (which is known in the art as both a Lgr5 agonist and Wnt agonist). Sato also teaches that the mitogenic growth factor can be EGF (p10, lines 29-31). Furthermore, Sato teaches that the BMP inhibitor can be Noggin (p8, lines 4-5). In as much as claim 83 could require a Wnt agonist in addition to R-spondin, as above, Sato teaches that Wnt3a may be used as a further Wnt agonist (p15, lines 18-22).
In regards to claims 84-85, as above Sato teaches that the medium may comprise nicotinamide and gastrin (p13, Lines 10-15).
In regards to claim 91, as discussed above, Sato teaches methods for inducing organoids (Title, Abstract; p13, lines 4-5, claims 2, 9 and 10). Sato teaches that tissue fragments comprising Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) are cultured in a medium comprising R-spondin 1 (which is known in the art as a Lgr5 agonist), a BMP inhibitor, and a mitogenic growth factor (claim 2).
Sato does not explicitly teach that the medium comprises one or more TGF-beta inhibitor wherein the TGF-beta inhibitor is an inhibitor of ALK5, ALK4 and/or ALK7 signaling.
However, Tseng ‘008 teaches that culturing animal cells, including gastrointestinal stem cells (of which Lgr5+ cells are a type) with a TGF-beta inhibitor (including SB-431542) allows for expansion of these cells while controlling differentiation of these cells (claim 1; paragraphs [0007, 0022, 0029]).
Additionally, Asahara teaches that TGF-beta inhibitors can be added to culture media to expand cells in vitro (paragraphs 0057, 0069]). Likewise, Asahara demonstrates that the TGF-beta inhibitor can be SB-431542 (paragraph [0030]).
It is noted that according to Applicant’s disclosure (page 12, Table 1 of Applicant’s as filed specification), mechanistically, SB-431542 reduces the activity of ALK5, ALK4 and ALK7.
A person of ordinary skill in the art would have been motivated to include a TGF-beta inhibitor because it would have promoted expansion of Lgr5+ stem cells in organoids.
Furthermore, because both Tseng ‘008 and Asahara demonstrate that TGF-beta inhibitors can promote expansion of cells, and Tseng ‘008 teaches that gastrointestinal stem cells (of which Lgr5+ stem cells are a type) can be expanded, it could have been done with predictable results and a reasonable expectation of success.
In regards to the structure of the organoid, Sato teaches that after culturing (which requires time) the organoid comprises a lumen lined by a crypt villus-like epithelium (p2, lines 26-34).
Sato teaches that, as a basic matter, crypts are polarized, with stem cells (Lgr5+ stem cells) residing at the base and most differentiated cells in the upper positions, and that stem cells serve as the source of these differentiated cells (p3, lines 1-19; p1, lines 23-25).
In regards to the organoids specifically, Sato teaches Lgr5+ stem cells within tissue fragments fuels growth of these organoids, that Lgr5+ stem cell hierarchy is maintained in organoids, and that all differentiated cell types are found (p2, lines 26-33; p42, lines 1-11; p19, lines 31-32, p20, lines 1-30; p42, lines 1-11).
Thus, crypt-containing tissue fragments, and organoids derived from them, already comprise Lgr5+ stem cells and differentiated cells that derive from Lgr5+ stem cells.
However, it is noted that claim 91 explicitly requires that Lgr5+ cells differentiate during the culturing steps over time in the culture medium.
Therefore, even though a tissue sample, could comprise differentiated cells, and differentiated cells that derive from Lgr5+ stem cells, the limitation of “differentiation of a portion of Lgr5+ epithelial stem cells into differentiated epithelial cell progeny” does not refer to already differentiated cells in a tissue sample, but instead, again, to cells differentiated from Lgr5+ epithelial stem cells during the active method step of culturing these cells in the media over time.
While, as above Tseng ‘008 teaches that a TGF-beta inhibitor (including SB-431542) allows for expansion of these cells while controlling differentiation of these cells (claim 1; paragraphs [0007, 0022, 0029]), it is noted that “controlling” does not necessarily imply that no differentiation occurs.
Indeed, as taught by Asahara cell clusters will both expand and differentiate in media comprising a TGF-beta inhibitor (Example 2, paragraphs [007-0013, 0057-0058]; Figs. 2, 3, and 7). Indeed, Asahara explicitly teaches that differentiation is a matter of “degree” (paragraphs [0040, 0047]). Therefore, in actual reduction to practice, cell clusters will both expand and differentiate when exposed to a TGF-beta inhibitor.
Therefore, since, as taught by Sato, organoids comprising Lgr5+ stem cells continually replace themselves and differentiate over time, and since, as taught by Asahara, cell clusters exposed to TGF-beta both expand and differentiate over time, even if, as taught by Tseng ‘008 differentiation can be “controlled”, it would be expected that the cultured Lgr5+ stem cells as taught by Sato, and as modified by Tseng ‘008 and Asahara to include a TGF-beta inhibitor, would in fact still differentiate to some degree while still expanding.
Therefore, the combined teachings of Sato, Tseng ‘008, and Asahara renders the invention unpatentable as claimed.
Claims 88, 90, and 92 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sato et al (WO 2010/090513, on IDS 09/08/2015, previously cited) in view of Tseng et al (US 2007/0010008, referred to as Tseng ‘008, previously cited) as applied to claims 35, 89, and 91 above, and further in view of Tseng et al (US 2007/0128719, referred to hereafter as Tseng ‘719, previously cited) and McKay et al (US 2008/0242594, previously cited).
The rejection of independent claims 35, 89, and 91 are discussed above.
In regards to claims 88, 90, and 92, the combined method of Sato, Tseng ‘008, and Asahara does not explicitly teach adding a p38 inhibitor.
However, McKay teaches methods for promoting stem cell proliferation and survival (page 1 para 2). The term “proliferation” is taught to be interchangeable with “expansion” and typically includes wherein the cells do not differentiate to form mature cells, but divide to form more cells (page 4 para 42). Contacting stem cells or precursor (progenitor) cells with a p38 inhibitor is taught to increase survival and/or proliferation (expansion) of stem cells and precursor cells (page 1 para 2, para 7-8). The progenitor cells are taught to include epithelial cells such as those lining the gut (epithelial stem cells)(pages 12-13 para 134).
Additionally, Tseng ‘719 teaches methods for preventing differentiation while expanding animal cells by modulating and down-regulating TGF-beta signaling in the animal cells with TGF-beta inhibitors, including epithelial stem cells as the animal cells (page 2 para 13-16). Methods for expanding epithelial stem cells include using p38 inhibitors as well (page 2 para 13, para 19). Including at least one of downregulation of TGF-beta signaling to prevent cell differentiation during expansion, methods for controlling differentiation by inhibiting the p38 pathway, or combinations thereof is suggested (page 4 para 42) and thus a combination of a TGF-beta inhibitor and a p38 inhibitor is deemed to be a suggested option.
One of ordinary skill in the art would have been motivated to include a p38 inhibitor in the method of Sato because Tseng ‘008, McKay and Tseng ‘719 teach that its addition will promote the survival and expansion of stem and progenitor cells, specifically epithelial stem cells. One of ordinary skill in the art would have had a reasonable expectation of success because Sato, Tseng ‘008, Tseng ‘719l, and McKay are all drawn to the expansion of stem and progenitor cells, specifically epithelial stem cells.
Furthermore, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (MPEP 2144.06). Therefore, the combination of a TGF-beta inhibitor and a p38 inhibitor would have been prima facie obvious as they are both taught in the prior art to be beneficial for the expansion of epithelial stem cells.
Therefore, the combined teachings of Sato, Tseng ‘008, Asahara, Tseng ‘719, and McKay render obvious Applicant’s invention as claimed.
Double Patenting - maintained
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 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,591,572 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 11,591,572 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 they are not patentably distinct because the claims of both inventions are drawn to culturing progenitor (stem) cells, which can be Lgr5+ epithelial stem cells in media comprising a TGF-beta inhibitor, which is an inhibitor of ALK5, ALK4 or ALK7 signaling, and Wnt inhibitors (such as R-spondin, which is also a Lgr5 agonist).
In specific embodiments, the method of U.S. Patent No. 11,591,572 B2 may comprise a BMP inhibitor such as Noggin (paragraph 52, lines 1-3), and used to obtain organoids (paragraph 51, lines 19-22).
A person of ordinary skill in the arts would have been motivated to produce organoids with Lgr5+ stem cells because Sato teaches that organoids comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Furthermore, they would have been motivated to include a BMP inhibitor such as Noggin because Sato teaches that it is either required or improves proliferation depending on cell type (p13, lines 25-29; p42, lines 30-34) and can synergistically increase the size of organoids cyst structure without affecting morphogenesis of organoids (p54, lines 15-20).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23), and that Noggin can be added to the culture medium (p8, lines 18-24), it could have been done with predictable results and a reasonable expectation of success.
Claims 35, 37, 39, 65-68, 75-77, 89, and 91-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,407,980 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 11,407,980 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-68, 75-77, 89, and 91 they are not patentably distinct because the claims of both inventions are drawn to media comprising R-spondin 1 (which is both a Wnt agonist and an Lgr5 agonist), a BMP inhibitor, and a TGF-beta inhibitor, for the culturing of organoids.
In specific embodiments, the medium of U.S. Patent No. 11,407,980 B2 may comprise a mitogenic growth factor (paragraph 2, lines 5-10), and the organoids may be derived from Lgr5+ stem cells (paragraph 16, lines 50-55).
A person of ordinary skill in the art would have been motivated to include a mitogenic growth factor in order to improve proliferation of cells. They would have been motivated to produce organoids with Lgr5+ stem cells because Sato teaches that organoids comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Furthermore, since Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) and that mitogenic growth factors can be added to cell media for producing organoids (p2, lines 15-25; claim 1), it could have been done with predictable results and a reasonable expectation of success.
Claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,760,978 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 11,760,978 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-68, 75-77, 89, and 91 they are not patentably distinct because the claims of both inventions are drawn to methods for producing organoids comprising culturing epithelial stem cells in media comprising a Wnt inhibitor (such as R-spondin, which is also a Lgr5 agonist), a TGF-beta inhibitor, a BMP inhibitor, a mitogenic growth factor (such as FGF2).
In specific embodiments, the method of U.S. Patent No. 11,760,978 B2 may comprise forming organoids from Lgr5+ stem cells (paragraph 16, lines 43-52) and suggests that these cells form lumina (paragraph 1, lines 52-67).
A person of ordinary skill in the arts would have been motivated to produce lumen organoids with Lgr5+ stem cells because Sato teaches that organoids with lumina comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) it could have been done with predictable results and a reasonable expectation of success.
Claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9,765,301 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 9,765,301 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 they are not patentably distinct because the claims of both inventions are drawn to culturing Lgr5+ epithelial stem cells from tissue fragments in media comprising mitogenic growth factors (such as EGF), R-spondin (which is both a Wnt agonist and an Lgr5 agonist), a TGF-beta inhibitor, and nicotinamide for producing organoids.
In specific embodiments, the method of U.S. Patent No. 9,765,301 B2 may comprise a BMP inhibitor such as Noggin (paragraph 2, lines 33-35; paragraph 3, lines 14-21) and that the organoids have lumina (paragraph 27, lines 22-40).
A person of ordinary skill in the arts would have been motivated to produce lumen organoids with Lgr5+ stem cells because Sato teaches that organoids with lumina comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Additionally, a person of ordinary skill in the art would have been motivated to add a BMP inhibitor such as Noggin because Sato teaches that it is either required or improves proliferation depending on cell type (p13, lines 25-29; p42, lines 30-34) and can synergistically increase the size of organoids cyst structure without affecting morphogenesis of organoids (p54, lines 15-20).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23), and that Noggin can be added to the culture medium (p8, lines 18-24), it could have been done with predictable results and a reasonable expectation of success.
Claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,034,935 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 11,034,935 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 they are not patentably distinct because the claims of both inventions are drawn to culturing epithelial stem cells in a media comprising a mitogenic growth factor (such as EGF), a TGF-beta inhibitor, and a Wnt agonist (which can be R-spondin1, which is also a Lgr5 agonist).
In specific embodiments, the method of U.S. Patent No. 11,034,935 B2 the culture method may be for the generation of organoids with lumina (Title, Abstract; paragraph 27, lines 25-28) comprised of Lgr5+ stem cells (paragraph 28, lines 60-64), the media may comprise a BMP inhibitor such as Noggin (paragraph 2, lines 38-41; paragraph 3, lines 19-25) and that the organoids have lumina (paragraph 27, lines 22-40).
A person of ordinary skill in the arts would have been motivated to produce lumen organoids with Lgr5+ stem cells because Sato teaches that organoids with lumina comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Additionally, a person of ordinary skill in the art would have been motivated to add a BMP inhibitor such as Noggin because Sato teaches that it is either required or improves proliferation depending on cell type (p13, lines 25-29; p42, lines 30-34) and can synergistically increase the size of organoids cyst structure without affecting morphogenesis of organoids (p54, lines 15-20).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23), and that Noggin can be added to the culture medium (p8, lines 18-24), it could have been done with predictable results and a reasonable expectation of success.
Claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,725,184 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 11,725,184 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-68, 75-77, 89, and 91 they are not patentably distinct because the claims of both inventions are drawn to media comprising an Lgr5+ agonist, a TGF-beta inhibitor, a mitogenic growth factor (such as EGF), and a BMP inhibitor (such as Noggin)
In specific embodiments, the medium of U.S. Patent No. 11,725,184 B2 may may be used to produce organoids with lumina comprising Lgr5+ cells (paragraph 28, lines 3-55).
A person of ordinary skill in the arts would have been motivated to produce lumen organoids with Lgr5+ stem cells because Sato teaches that organoids with lumina comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) it could have been done with predictable results and a reasonable expectation of success.
Claims 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,834,681 B2 in view of Sato et al. (WO2010090513A2, 2010, on IDS 09/08/2015, previously cited).
While the conflicting claims of U.S. Patent No. 11,834,681 B2 are not identical to the currently prosecuted claims 35, 37, 39, 65-68, 75-77, 89, and 91 they are not patentably distinct because the claims of both inventions are drawn to methods for producing organoids from epithelial stem cells in media comprising mitogenic growth factor (such as FGF2), a TGF-beta inhibitor, a BMP inhibitor, and a Wnt agonist (which can be R-spondin1, which is also a Lgr5 agonist).
In specific embodiments, the method of U.S. Patent No. 11,834,681 B2 comprise forming organoids from Lgr5+ stem cells (paragraph 16, lines 43-52) and suggests that these cells form lumina (paragraph 1, lines 52-67).
A person of ordinary skill in the arts would have been motivated to produce lumen organoids with Lgr5+ stem cells because Sato teaches that organoids with lumina comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) it could have been done with predictable results and a reasonable expectation of success.
Claim 35, 37, 39, 65-69, 75-77, 83-85, and 88-92 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9-19 of copending Application No. 18/843.858 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both inventions are drawn to methods for producing organoids comprising culturing tissues in a medium comprising a Wnt agonist (such as R-spondin which is also a Lgr5 agonist), a TGF-beta inhibitor, a mitogenic growth factor (such as EGF), and a BMP inhibitor.
In specific embodiments the method of copending Application No. 18/843.858 can be used to produce organoids (paragraph [0008]) comprising epithelial stem cells (paragraph [0016]).
A person of ordinary skill in the arts would have been motivated to produce lumen organoids with Lgr5+ stem cells specifically because Sato teaches that organoids with lumina comprising Lgr5+ cells and comprising Lgr5+ and differentiated cell types (p2, lines 26-34; p2, lines 26-33; p42, lines 1-11; p42, lines 1-11) is are useful in regenerative medicine, for example as implants after resection of the pancreas or as part of a treatment for diabetes (p23, lines 1-5), or as models, such as intestinal models for drug screening (p70, lines 4-16).
Furthermore, because as above, Sato teaches that organoids can be produced form Lgr5+ epithelial stem cells (claim 2; p28, lines 5-22; p45, lines 18-23) it could have been done with predictable results and a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues that Tseng ‘008 teaches that TGFb inhibitors prevent differentiation (citing paragraphs[0007. 0022] and claim 1 of Tseng ‘008; Remarks, p10).
In regards to Tseng ‘008’s statement that “cell whose differentiation state is controllable by modulating TGF-β signaling” means that differentiation is either is prevented or differentiation is promoted based on TTGFb signaling (Remarks, p11). Therefore, Applicant argue that this does not equate to a disclosure that inhibiting TGFb signaling allows for both expansion of differentiation of cells or that inhibiting TGFb allows for controlling the degree of differentiation of cells (Remarks, p11). As a result, Applicant argues that the type of cells used does not equate to a disclosure that inhibiting TGF-β signaling allows for both expansion and differentiation of cells or that inhibiting TGF-β signaling allows for controlling the degree of differentiation of cells (Remarks, p12-13).
Relatedly, Applicant argues that in a method where differentiation is necessary, one of ordinary skill in the art would be motivated by Tseng ‘008 to remove the TGFb inhibitor (Remarks, p13).
Therefore, Applicant concludes that a person of ordinary skill in the art would not have been motivated by Tseng ‘008 to add a TGFb inhibitor to a culture medium where differentiation of cells is necessary, and would have no reasonable expectation that the addition of a TGFb to a culture medium for a method of culturing organoids would successfully allow for the combined expansion and differentiation of Lgr5+ cells which is a unique feature of organoid formation and culture (Remarks, p14).
Applicant’s arguments filed 12/17/2025 have been fully considered but are not found persuasive.
As the method steps “comprise” culturing a single Lgr5+ epithelial stem cell, a population of Lgr5+ stem cells, or an isolated tissue fragment comprising a single Lgr5+ epithelial stem cell or population of Lgr5+ epithelial stem cells in a culture medium comprising an agonist of Lgr5, one or more TGFb inhibitor, a BMP inhibitor, and a mitogenic growth factor, the method steps may contain additional steps not recited in the claims and therefore, do not necessarily suggest that differentiation of at least one Lgr5+ epithelial stem occurs in the presence of a TGFb inhibitor. Instead, the claim only requires that these cells are contacted for some time.
This interpretation is supported throughout the specification.
According to paragraph [0040], “The culture media, supplements, methods, compositions and uses according to this invention may also be optimised by routine experimentation. For example, if a culture medium, supplement or composition fails to give the desired level of stem cell expansion, variables such as the amount of each ingredient in the culture medium or supplement, seeding densities, culture conditions, culture periods, etc. can be altered in further experiments. The amount of each of the ingredients described herein can be optimised independently of the other ingredients by routine optimisation or one or more ingredients can be added or removed” (emphasis added).
Continuing, paragraph [0133] states, “In some embodiments, the culture medium is placed on top of the ECM. The culture medium can then be removed and replenished as and when required. In some embodiments, the culture medium is replenished every 1, 2, 3, 4, 5, 6 or 7 days. If components are ‘added’ or ‘removed’ from the media, then this can in some embodiments mean that the media itself is removed from the ECM and then a new media containing the ‘added’ component or with the ‘removed’ component excluded is placed on the ECM.”
In regards to a TGFb inhibitor specifically, the states, “a method of obtaining differentiated cells or organoids may comprise culturing epithelial cells in a culture method of the invention which comprises a TGF-beta and/or p38 inhibitor to enable the cells to survive and/or proliferate (i.e. expansion medium) and then continuing to culture the cell and replenish the media, wherein the replenished media does not comprise a TGF-beta inhibitor and/or p38 inhibitor (i.e. differentiation medium) (paragraph [0300], emphasis added).
This is confirmed by paragraph [0303] which states that “the invention provides a method for expanding a single stem cell or a population of stem cells, preferably to generate an organoid, wherein the method comprises culturing the single stem cell or population of stem cells in a culture medium according to the invention, wherein the method comprises: culturing the stem cell, population of stem cells or tissue fragments in a first expansion medium; continuing to culture the stem cell, population of stem cells or tissue fragments and replenishing the medium with a differentiation medium, wherein the differentiation medium does not comprise one or more of . . . a TGF-beta inhibitor, etc.” (emphasis added).
Thus, the specification explicitly envisions that “a culture medium” is a generic term which can refer to both expansion and differentiation media, that components of the culture medium (including specifically, a TGFb inhibitor) can be replaced over time, and therefore, the scope of the claim does not necessarily require a TGFb inhibitor for the duration of the culturing step and the claim is broad enough to allow its removal.
Therefore, assuming arguendo that Applicant’s interpretation of Tseng ‘008 is correct, that the effect of a TGFb inhibitor is binary, that “either differentiation is prevented, or differentiation is promoted” (Remarks, p11) or that TGFb inhibitors result in an “on” or “off” state Remarks, p12) (which is noted the Examiner is not conceding), it does not overcome the teachings of Tseng ‘008 because the scope of the claim is broad enough to allow for the removal of a TGFb inhibitor from the media.
Therefore, as discussed above, a person of ordinary skill in the art would have been motivated to include a TGF-beta inhibitor because it would have promoted expansion of Lgr5+ stem cells in organoids. As taught by Tseng ‘008 as discussed above, culturing animal cells, including gastrointestinal stem cells (of which Lgr5+ cells are a type) with a TGF-beta inhibitor (including SB-431542) allows for expansion of these cells while controlling differentiation of these cells (claim 1; paragraphs [0007, 0022, 0029]).
Additionally, as taught by Asahara as discussed above, TGF-beta inhibitors can be added to culture media to expand cells in vitro (paragraphs 0057, 0069]). Likewise, Asahara demonstrates that the TGF-beta inhibitor can be SB-431542 (paragraph [0030]).
Furthermore, because both Tseng ‘008 and Asahara demonstrate that TGF-beta inhibitors can promote expansion of cells, and Tseng ‘008 teaches that gastrointestinal stem cells (of which Lgr5+ stem cells are a type) can be expanded, it could have been done with predictable results and a reasonable expectation of success.
In regards to Asahara, Applicant argues that there is no teaching in Asahara that would lead one of ordinary skill in the art to re-interpret Tseng ‘008’s teaching that TGFb inhibitors prevent differentiation and instead teaching that Tseng ‘008 as teaching that TGFb inhibitors allow for both expansion and differentiation of cells and allow for the control of the degree of different cells (Remarks, p13).
Applicant’s arguments filed 12/17/2025 have been fully considered but are not found persuasive.
Asahara is not relied upon to provide any teaching about differentiation, but rather only, as above, the demonstrate that it was known in the prior art that a TGFb inhibitor, such as SB-431542, was known to be able to be added to culture media to expand cells in vitro (paragraphs 0057, 0069]).
Applicant argues that there was no reasonable expectation of success based on the prior art in its entirety (Remarks, p14). Applicant argues that Tseng ‘008 “teaches away” from the claimed invention because Tseng ‘008 clearly discourages the use of a TGFb inhibitor in a method where differentiation is necessary (Remarks, p14-15).
Continuing, Applicant argues that the entirety of the prior art shows inconsistent results, as discussed in the Declaration on 10/27/2019 (Remarks, p14).
According to Applicant, “The state of the art at the time of filing (here represented by Hatzfeld) therefore suggests that inhibiting the action of TGF-beta would promote differentiation as evidenced by Hatzfeld et al. (US 2009/0325289) (Remarks, p14).
Applicant’s arguments filed 12/17/2025 have been fully considered but are not found persuasive.
In regards to a method that requires differentiation, as discussed above, while the claim requires differentiation of at least on Lgr5+ stem cell, the claim does not necessarily require that differentiation occurs when the cell is exposed to a TGFb inhibitor, but rather, as discussed above, the claim is broad enough to allow removing reagents from the culture medium including a TGFb inhibitor.
In regards to Applicant’s arguments that Tseng ‘008 “teaches away” from a TGFb inhibitor in a method that requires differentiation of cells, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”) (see MPEP 2145(X)(D)(1)).
In the instant case, Tseng ‘008 does not criticize, discredit, or otherwise discourage the solution claimed, in this case, specifically allowing Lgr5+ cells to differentiate. As above, Tseng ‘008 at least teaches that that removing compositions or conditions that downregulate TGF-b (i.e., the TGF-b inhibitor) can be used to promote differentiation of the cell (paragraph [0018]), which is not only within the scope of the claims, but suggests that cells contacted with a TGFb inhibitor can still be differentiated.
In regards to Hatzfeld, assuming arguendo that Hatzfeld supports Applicant’s argument that “The state of the art at the time of filing . . . suggests that inhibiting the action of TGF-beta would promote differentiation”, it undermines Applicant’s argument that the use of a TGFb inhibitor is necessarily binary, that it is either off/on as argued by Applicant above, but suggests that a person of ordinary skill in the art would have known that at least some cells may differentiate in the presence of a TGFb inhibitor, even if most are expanding.
Furthermore, it is noted that Hatzfeld explicitly teaches a method for maintaining human embryonic stem cells in a non-differentiated state while allowing cell division of the stem cells comprising an “an anti-inhibitor of cell proliferation” which is an “anti-TGFβ” (claim 1), which “neutralizes” TGFβ (paragraph [0094]) (and thus, is a TGFβ inhibitor). Thus, Hatzfeld teaches that TGFb inhibitors promote expansion while controlling differentiation.
Applicant argues that the disclosure demonstrates unexpected results (Remarks, p15). In particular, Applicant argues that the invention promotes improved organoid formation (as shown or described in at least FIG. 2B, post-filing data submitted with the Office Action response dated June 21, 2018, and the Declaration); and Allow for long-term culture of organoids (as shown or described in at least Example 1, paragraph [0717], and paragraph [0718]) (Remarks, p15).
Specifically, Applicant argues that according to the Declaration, based on the state of the art at the time of the experiments, there would have been no reasonable way to predict the effect of a TGF-β inhibitor on organoid formation and culture length of organoids and that none of the cited references teach or suggest that a TGF-β inhibitor would have any role in organoid culture, let alone promote organoid formation and increase the length of time that organoids can be cultured (Remarks, p15).
Applicant’s arguments filed 12/17/2025 have been fully considered but are not found persuasive.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (see MPEP 716.02(d)).
Specifically, Applicant’s assertions of unexpected results are not commensurate in scope with the claims.
In particular, the results in Fig. 2A appear dependent on at least the presence of nicotinamide which is not required by the claims.
Furthermore, these appears limited to the specific colonic organoids as demonstrated in Fig. 2A, since organoid formation does not appear significant until a TGF-beta inhibitor, nicotinamide, and a p38 inhibitor are included in the media for Barret’s esophagus organoids as demonstrated in Fig. 5B.
It is noted however, that Figs. 2A and 5B appear to demonstrate synergistic effects when stem cells are cultured in the WENRg media when also cultured with nicotinamide, TGF-beta inhibitor A83-01 and p38 inhibitor p38. However, none of the claims require this specific embodiment.
Additionally, as explicitly stated in the specification, for organoids derived from Lgr5+ stem cells (i.e., colon, liver and pancreas), “very few differentiated cells are present in the expansion medium. Only once the expansion medium is replaced with a differentiation medium, do the cells begin to differentiate. At this stage, the organoids also start to lose their stem cells (paragraph [0307]). Therefore, a step that actively removes the TGFb inhibitor from the culture medium appears necessary to achieve any effects.
Applicant requests to hold the double-patenting rejections in abeyance (Remarks, p16-17).
Applicant’s request is noted. However, Applicant’s request is not a proper response to the rejections of record as it neither traverses the grounds of rejection by providing specific arguments, nor indicates that a terminal disclaimer has been filed to overcome the rejection. As such, the rejections of record stand.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631