DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/26/2026 has been entered.
Claims 1, 41 and 42 have been amended. Claim 44 has been newly added and no claims have been newly canceled.
Claims 1-8, 10-11, 15-18, 21, 28-29, 32-33, and 39-44 are currently pending.
Claims 4, 6-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected specie, there being no allowable generic or linking claim. Election of the specie of pancreas for the target tissue (target internal organ) was made without traverse in the reply filed on 12/09/2020.
Claims 1-3, 5, 10-11, 15-18, 21, 28-29, 32-33, and 39-44 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 62/518,380 and Application No. 62/664,694, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Claim 1 requires “wherein the second hydrogel has a viscoelasticity from 250 to 800 Pa”. The prior filed applications do not disclose a viscoelasticity range of 250 to 800 Pa and thus the claimed invention is not entitled to the filing date of these applications.
The non-provisional application does provide support for the amended claims and therefore claim 1 and dependent claims 2-3, 5, 10-11, 15-18, 21, 28-29, 32-33, and 39-40 have been examined with the effective filing date of the non-provisional which is 06/12/2018.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5, 10-11, 15-18, 21, 28-29, 32-33, 39-43 are rejected under 35 U.S.C. 103 as being unpatentable over Mooney et al (US 2008/0044900-from IDS filed 11/14/2018) in view of Reid et al (US 2014/0301985-previously cited), Ghosh et al (Biomaterials, 2007-from IDS filed 02/17/2021) and Hanjaya-Putra et al (US 2012/0225814-from IDS filed 11/14/2018).
Regarding claims 1-3, 5, 10-11, 40, Mooney teach a cell transplantation device that contains a mixture of cells and can be used for organ and tissue regeneration (page 3 para 17) repair and augmentation of function of a mammalian bodily tissue (page 3 para 19). The mixed cells may include stem cells such as mesenchymal stem cells (MSCs, early lineage stage cell-ELSMCs) and pancreatic stem cells (epithelial stem cells) (page 3 para 17 and page 6 para 44). As per Applicant’s disclosure, MSCs are early lineage stage cells capable of expressing and secreting MMPs (see page 36 lines 14-21 of Applicant’s specification). This device includes a scaffold composition which incorporates or is coated with a bioactive composition, the device regulates the egress of resident cells through the physical or chemical characteristics of the scaffold. The scaffold can be differentially permeable, allowing cell egress (migration) only in certain physical areas of the scaffold. The permeability of the scaffold composition is regulated by selecting or engineering a material for viscoelasticity (page 1 para 6). This would render obvious a material configured to inhibit cell migration towards an undesired direction, away from the target tissue and towards the backing material.
Mooney include wherein their polymeric carriers include a mesh (pages 12-13 para 79) and specifically wherein the scaffold is porous (page 2 para 16, page 7 para 49) and fabricated from a variety of polymers including a hydrogel and hyaluronic acid (hyaluronan) (page 8 para 51-52).
The scaffold is biocompatible and biodegradable (page 2 para 13). The cells incubated in the scaffold are educated and induced to migrate out of the scaffold to directly affect a target tissue, e.g. an injured tissue site (page 7 para 47-48). The cells may include a hydrogel medium that contains factors required to maintain the multipotent nature of stem cells (maintain sternness) (page 10 para 68-69) and/or inhibit differentiation (para 11, page 7 para 48, para 81, para 85, para 93). Suitable hydrogels are taught to be well known in the art (page 10 para 66) and include hydrogels with hyaluronic acid (hyaluronan) (page 8 para 52, page 13 para 82).
Mooney disclose wherein MMP-sensitive substrates are used to allow cells to exit when the seeded cells have secreted sufficient MMP to begin degradation of the matrix (page para 46). This provides for wherein at least the first hydrogel is configured to allow the mixed cell population to produce an amount of MMPs sufficient to allow the cells to exit the hydrogel and facilitate engraftment of cells into target internal organs.
Mooney does not specifically disclose an embodiment wherein the target internal organ is brought into contact with the device delivering mesenchymal stem cells and epithelial stem cells into the target internal organ nor an embodiment wherein the target internal organ is the pancreas.
Reid teach a method of treating a pancreatic disfunction by administering cells, specifically a mixture of cells, including pancreatic stem cells, mesenchymal stem, progenitor cells and biomaterials such as hyaluronan to pancreatic tissue (pages 2-3, para 14-16). The grafting technologies that involve the delivery of transplanted cells as an aggregate on or in scaffolds that can be localized to the diseased tissue to promote proliferation and engraftment is explicitly taught (page 6 para 47). Applicant’s specification indicates that cell organoids include cell aggregates (page 28).
One of ordinary skill in the art would have been motivated to select the pancreatic organ as the target tissue injured by diseases such as diabetes in the method of Mooney because Reid suggest that such injured pancreatic organ tissue is in need of repair and would benefit from delivering a mixture of cells, such as pancreatic stem cells, mesenchymal stem, progenitor cells and biomaterials such as hyaluronan (pages 2-3, para 14-16). One of ordinary skill in the art would have had a reasonable expectation of success in applying the method of Mooney to injured pancreatic tissue and administering MSCs and pancreatic stem cells directly to the pancreas because Mooney suggests that damaged pancreatic tissue is a suitable organ tissue type for their method and Mooney also includes the use of a mixture of cells, such as stem, progenitor and pancreatic stem cells in their composition as well and that they are capable of ensuring that the cells included in their device maintain their stemness.
Mooney teach wherein the mixed cells may include adult stem cells, mesenchymal stem cells (MSCs, early lineage stage cell), pancreatic stem cells, pancreatic islet cells, epithelial cells (page 3 para 17 and page 6 para 44).
Reid suggest that such injured pancreatic organ tissue is in need of repair and would benefit from delivering a mixture of cells, including pancreatic stem cells, mesenchymal stem, progenitor cells and biomaterials such as hyaluronan (pages 2-3, para 14-16) providing motivation to deliver the cell mixture directly to the pancreatic organ tissue. Reid also teach that biliary tree stem cells (BTSCs) can give rise to either liver or pancreas (page 3 para 24) and thus these cells would be obvious for use in the repair of pancreatic tissue as pancreatic progenitor cells or pancreatic stem cells. One of ordinary skill in the art would have also been motivated to include BTSCs in Mooney with a reasonable expectation of success because Mooney also suggest the inclusion of adult stem cells in their method that give rise to the pancreas as well.
Regarding step c of claim 1, Mooney teach addition of a first and second hydrogel coating (page 10 para 69) and compartment layers (pages 10-11 para 70-71) to control the cells. The release profiles from the scaffold devices are controlled (configured) by both factor diffusion and polymer degradation, the dose of the factor loaded in the system and the composition of the polymer (page 12 para 78). With migration away from the target tissue being discouraged, the addition of a third hydrogel layer on the opposite side (serosal surface) of the backing away from the cells would be obvious to reinforce the backing of the scaffold and prevent cells from migrating away from the target tissue. One of ordinary skill in the art would have had a reasonable expectation of success because Mooney specifically suggests adding layers to regulate cell locomotion (migration) (page 3 para 18) and outer coverings (backings) (page 24 para 154). The mere duplication of parts has no patentable significance unless a new and unexpected result is produced (MPEP 2144.04 VI).
With regard to the inhibition or prevention of adhesions by or from other tissues, this property is deemed to be present when using the same polymer (hyaluronan) and designed to have a viscoelasticity to inhibit migration of the cells away from the target tissue baring evidence to the contrary. Mooney teach that they utilize materials with a relatively low elastic modulus, e.g., 0.1-100, 1-100kPa (e.g. 100 Pa, 1,000 Pa are included at the low end of these ranges) and that this is why they include hydrogels and elastomeric polymers (page 24 para 154). Applicant’s Specification states that a hyaluronan hydrogel with a viscoelasticity of approximately 106 Pa has a level of rigidity that it served to further minimize adhesions from neighboring tissues (see page 77 lines 15-19 of Applicant’s Specification).
Mooney also teach wherein the scaffold (backing) includes materials that have sufficient resilience to withstand mechanical forces, able to be tethered to a target organ or tissue and has sufficient flexibility to be tethered to locations with curvature (such as a liver) (page 7 para 49, page 24 para 154). Attachment (tethering) to the injured tissue site is disclosed and suggested (page 22 para 143).
Regarding claims 1, 39, Mooney teach that they utilize materials with a relatively low elastic modulus, e.g., 0.1-100, 1-100kPa (e.g. 100 Pa, 1,000 Pa are included at the low end of these ranges) and that stiff materials would not be suitable, as such materials would not conform to a wound and that this is why they include hydrogels and elastomeric polymers (page 24 para 154). Mooney discloses that the scaffold may be composed of multiple gel layers of various levels of rigidity and form a sandwich configuration” (pages 10-11 para 63-71).
Mooney do not explicitly recite the claimed viscoelasticities for the various layers.
Ghosh examines the effects of viscoelastic properties of hyaluronan/fibronectin hydrogels on cell behavior (Abstract). Ghosh discloses preparing hydrogels with viscoelasticity of 95, 550 and 4270 Pa and seeding human dermal fibroblasts (hDFs) on the hydrogels (Section 2.1,2.4). hDF migration speed significantly decreased as viscosity of the hydrogel increased (Section 3.3.1, Fig. 5). Ghosh suggests that softer hydrogels (e.g., 95 Pa) may be utilized to promote cellular migration, while viscosities of 550 Pa or higher promote cellular adhesion and proliferation (Section 3.3.1,4, Fig. 5).
Hanjaya-Putra teach the viscoelasticities of hydrogels (including hyaluronic acid) intended for use in regenerative medicine (page 2 para 10, para 17, page 3 para 35) and indicate that values of 650 +/- 180 Pa provide a rigid hydrogel, 75 +/-40 Pa for a firm hydrogel and 10+/-2 Pa for a yielding hydrogel (page 3 para 35). Cell migration is discussed as well (page 7 para 77, page 8 para 87, para 91, page 9 para 92, page 15 para 153, pages 18-19, para 180).
As Mooney, Ghosh and Hanjaya-Putra are all directed to hyaluronan based hydrogels and cellular migration therein by modulating physical characteristics of the hydrogel, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated with a reasonable expectation of success to utilize the viscoelasticities suggest by Ghosh and Hanjaya-Putra because they fall within the range of viscoelasticities suggested by Mooney to both promote and inhibit cellular migration within the hydrogel. Softer hydrogels of about 95 Pa would be utilized in the first hydrogel where cell migration toward the target tissue is desired (configured to allow the mixed population comprising MSCs and BTSCs to produce an amount of MMPs in the first hydrogel sufficient to facilitate engraftment of the BTSCs into the target tissue).
More firm hydrogels of about 500 Pa would be more desirable for the second and third hydrogels so that they can prevent egress of the administered cells away from the target tissue. A third hydrogel with a viscoelasticity of about 500 Pa would also inherently inhibit adhesions by or from other tissues or organs as per Applicant’s Specification (see page 61 lines 1-9, page 68 lines 9-16, page 77 lines 15-19).
Regarding claims 15-17, 40, Mooney suggests wherein the hydrogels are made from hyaluronic acid (hyaluronan)(page 8 para 51-52).
Regarding claim 18, the cells may include a hydrogel medium that contains factors required to maintain the multipotent nature of stem cells (maintain sternness) (page 10 para 68-69).
Regarding claims 21, Mooney teach wherein the mixed cells may include adult stem cells, mesenchymal stem cells (MSCs, early lineage stage cell), pancreatic stem cells, pancreatic islet cells, epithelial cells (page 3 para 17 and page 6 para 44). Reid suggest that such injured pancreatic organ tissue is in need of repair and would benefit from delivering a mixture of pancreatic stem cells, mesenchymal stem, progenitor cells and biomaterials such as hyaluronan (pages 2-3, para 14-16) providing motivation to deliver the stem cells directly to the pancreatic organ tissue. Reid also teach that biliary tree stem cells (BTSC) can give rise to either liver or pancreas (page 3 para 24) and thus these cells would be obvious for use in the repair of pancreatic tissue as pancreatic progenitor cells or pancreatic stem cells.
Regarding claim 28, Mooney teach wherein the cells are autologous or allogeneic (page 14 para 92).
Regarding claim 29, Mooney teach wherein the cells are programmed/reprogrammed (genetically modified) (page 15 para 97).
Regarding claim 32, Mooney teach wherein the scaffold (backing) comprises a nonporous material such as metals and silk (page 2 para 13, page 24 para 154).
Regarding claim 33, Mooney teach wherein the scaffold (backing) includes materials that have sufficient resilience to withstand mechanical forces, able to be tethered to a target organ or tissue and has sufficient flexibility to be tethered to locations with curvature (such as a liver) (page 7 para 49, page 24 para 154).
Regarding claims 41-43, Mooney does not specifically teach including organoids in their method and are silent with regard to the number of cells included in their cell mixture.
Reid teach a method of treating a pancreatic disfunction by administering a mixture of pancreatic stem cells, mesenchymal stem, progenitor cells and biomaterials such as hyaluronan to pancreatic tissue (pages 2-3, para 14-16). The grafting technologies that involve the delivery of transplanted cells as an aggregate on or in scaffolds that can be localized to the diseased tissue to promote proliferation and engraftment are explicitly taught (page 6 para 47). Applicant’s specification indicates that cell organoids include cell aggregates (page 28). The type of aggregate that Reid refers to in their disclosure is one that has ultrastructural, electrophysiological and functional characteristics of neoislets (pancreatic tissue organs)(pages 5-6 para 45, 47). This is interpreted to mean that Reid is referring to cell aggregates that are more than just clusters of cells, but cells that have organized to form a tissue structure (tissue organoid) suitable for use in the repair of damaged in vivo tissue, in this particular case a damaged pancreas. Reid also teach that biliary tree stem cells (BTSCs) can give rise to either liver or pancreas (page 3 para 24) and thus these cells would be obvious for use in the repair of pancreatic tissue as pancreatic progenitor cells or pancreatic stem cells.
While Mooney and Reid are silent with regard to the total number of cells and cell aggregates to include in their administered cell graft compositions, these cell and organoid numbers would have been a matter of routine optimization and experimentation. The optimal cell and organoid amount would have been dependent upon the size of the subject and the size and severity of the damaged organ tissue. Target damaged organs from larger mammals would require larger amounts of cells than lab animals such as mice. The fact that Mooney includes an example wherein their scaffold is seeded with 107 cells/ml (page 21 para 138) is suggestive that scaffolds with at least 107 cells would be appropriate. The number of aggregates (organoids) from these cells would be affected by the need to keep the aggregates of a small size in order to avoid cell necrosis that occurs when cell aggregates get too large and thus a larger number of aggregates from 107 cells (at least 100,000 aggregates or organoids) would be appropriate.
With regard to the concentrations of cells in the composition, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05).
The selection of specific concentrations clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the amount and viability of the cells would have been affected by these concentrations.
The combined teachings of Mooney et al, Reid et al, Ghosh et al and Hanjaya-Putra et al render obvious Applicant’s invention as claimed.
Claim(s) 41-44 are rejected under 35 U.S.C. 103 as being unpatentable over Mooney et al (US 2008/0044900-from IDS filed 11/14/2018) in view of Reid et al (US 2014/0301985-previously cited), Ghosh et al (Biomaterials, 2007-from IDS filed 02/17/2021) and Hanjaya-Putra et al (US 2012/0225814-from IDS filed 11/14/2018) as applied to claims 1-3, 5, 10-11, 15-18, 21, 28-29, 32-33, 39-43 above, and further in view of Khurgel et al (WO 2007/089798).
Regarding claim 41-44, the combined teachings of Mooney et al, Reid et al, Ghosh et al and Hanjaya-Putra et al render obvious Applicant’s invention as described above, and render obvious the use of cell organoid aggregates in the methods and device of Mooney as described above, but are silent with regard to how the organoids (cell aggregates) are formed.
Khurgel disclose methods for making and using multicell aggregates (organoids) by forming these cell aggregates (SOMBs) on low attachment plates with a variety of media types, including serum-free culture medium (page 4 line 23-page 5 line 31, page 49 lines 1-28) for further use in regenerative therapies to repair damaged tissue (page 30 lines 23-28 to page 31 line 1, page 31 lines 11-31). A culture dish or plate are both indicated to be suitable alternatives for a solid support for maintaining cells in a tissue culture (page 25 lines 25-30). Khurgel disclose that their formed cell aggregates (SOM-Bs) can then be seeded with/onto scaffolds of matrix/polymers and can be used for administration to a subject in need (page 31 lines 11-31, page 6 lines 26-30). The cell aggregates (SOMBs) can be used for administration to repair the pancreas (page 30 lines 23-30).
One of ordinary skill in the art would have been motivated to include organoids formed from culture on low attachment dishes in serum-free conditions in the method and devices of Mooney because Khurgel teach and suggest that multicell aggregates (organoids) that are formed in this manner are beneficially included in regenerative therapies for the treatment of damaged tissue. One of ordinary skill in the art would have had a reasonable expectation of success because both Mooney and Khurgel disclose that mixed cells that include adult stem cells (stromal stem cells) and other regenerative cells intended for damaged tissue, such as a pancreas, are beneficially cultured and prepared for administration with a carrier material such as a polymer or matrix.
The combined teachings of Mooney et al, Reid et al, Ghosh et al, Hanjaya-Putra et al and Khurgel 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 10-11, 15-18, 21, 28-29, 32-33, and 39-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-27, 29-43, and 45-48 of copending Application No. 17/867135 in view of Mooney et al (US 2008/0044900-from IDS filed 11/14/2018), Reid et al (US 2014/0301985), Ghosh et al (Biomaterials, 2007-from IDS filed 02/17/2021), Hanjaya-Putra et al (US 2012/0225814-from IDS filed 11/14/2018) and Khurgel et al (WO 2007/089798).
The claims of the copending application are drawn to methods of engrafting cells into a target tissue comprising contacting the target tissue with a patch graft composition comprising a mixed population having two or more cell types, including early lineage stage cells capable of expressing MMPs in a medium in a first hydrogel having viscoelasticity sufficient to allow for migration of the mixed population into the target tissue and a backing comprising a biocompatible, biodegradable material having a viscoelasticity sufficient to inhibit a migration of the mixed population away from the target tissue.
The copending claim does not specifically include all the claimed features in one embodiment and wherein the cells include biliary tree stem cells or organoids formed after culturing on low attachment dishes and under serum-free conditions.
Mooney and Reid render obvious pancreatic tissue as a target tissue for a patch graft, the inclusion of multiple cell types and multiple layers and suggest the inclusion of biliary tree stem cells as described above. Mooney and Reid also render obvious the inclusion of aggregates (organoids), organoid number and a cell number of at least 107 cells as described above.
Gosh and Hanjaya-Putra render obvious the ranges of viscoelasticity in the hydrogel layers as described above.
Khurgel render obvious the use of organoids formed after culturing on low attachment dishes and under serum-free conditions as described above.
Therefore, the combined teachings Mooney et al, Reid et al, Gosh et al, Hanjaya-Putra et al and Khurgel et al and the copending claims render obvious Applicant’s invention as claimed.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 06/26/2026 have been fully considered but they are not fully persuasive.
Applicant argues that the presently claimed invention is not taught or suggested by the cited references. Applicant asserts that none of the cited references teach or suggest a multilayered patch graft where each layer has a distinct structure and function and the combination of layers results in a patch graft that engrafts stem cells into an internal organ and facilitate functional recovery of a diseased condition. Applicant argues that Mooney and Reid are directed to different inventions and that Ghosh and Hanjaya-Putra are irrelevant. Applicant asserts that only the present application demonstrates the successful engraftment of stem cells into internal organs by using a patch graft and point to Figures 3-6 of their Specification as evidence.
This is not found persuasive. First, 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).
Second, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the current case, the obviousness rejection is based on the modification of the Mooney reference method as motivated by the teachings of Reid, Ghosh and Hanjaya-Putra as described above. Mooney and Reid are both directed to the use of cells for administration to a subject with damaged tissue and thus are both related to cell therapy. Mooney teaches that their method and device are suitable for multiple cell types and a viscoelasticity range that overlaps with Gosh. Ghosh suggests that softer hydrogels (e.g., 95 Pa) may be utilized to promote cellular migration, while viscosities of 550 Pa or higher promote cellular adhesion and proliferation (Section 3.3.1,4, Fig. 5). Hanjaya-Putra teach the viscoelasticities of hydrogels (including hyaluronic acid) intended for use in regenerative medicine (page 2 para 10, para 17, page 3 para 35). Clearly Gosh and Hanjaya-Putra are not irrelevant to the claimed subject matter.
In addition, Mooney does in fact demonstrate successful engraft of transplanted cells into internal organs (paragraph 147).
Applicant argues that the cited references do not teach or suggest the configuration of the first hydrogel as claimed. Applicant asserts that Reid does not teach or suggest a method of treating pancreatic insufficiency by administering a mixture of pancreatic stem cells, mesenchymal stem cells and progenitor cells and biomaterials such as hyaluronan to pancreatic tissue as described by the Examiner. Applicant asserts that Reid is limited to cells that may be biliary tree stem cells or their descendants, committed progenitors or mesenchymal stem cells for both liver and pancreas or hepatic stem cells or committed progenitors for liver or pancreatic stem cells or their committed progenitors for pancreas. Applicant asserts that Reid only teaches these cell types in the alternative and does not teach cell mixtures and asserts that this is the same reason why Reid cannot teach organoids.
This is not found persuasive. First, 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).
Second, the obviousness rejection is based on the modification of the Mooney reference method, not the Reid method. One of ordinary skill in the art would have been motivated to select the pancreatic organ as the target tissue injured by diseases, such as diabetes, in the method of Mooney because Reid suggest that such injured pancreatic organ tissue is in need of repair and would benefit from delivering a mixture of cells, such as pancreatic stem cells, mesenchymal stem, progenitor cells and biomaterials such as hyaluronan (pages 2-3, para 14-16).
Applicant argues that aggregates are not the same as organoids. Applicant asserts that aggregates is a general term covering any mixture of cells attached to each other in some way. Applicant asserts that their specification refers to a particular cellular aggregate of donor epithelial cells with mesenchymal cells which is not taught or suggested by Reid.
This is not found persuasive. The type of aggregate that Reid refers to in their disclosure is one that has ultrastructural, electrophysiological and functional characteristics of neoislets (pancreatic tissue organs)(pages 5-6 para 45, 47). This is interpreted to mean that Reid is referring to cell aggregates that are more than just clusters of cells, but cells that have organized to form a tissue structure suitable for use in the repair of damaged in vivo tissue, in this particular case a damaged pancreas. This is why the type of aggregate described in Reid is deemed to meet the type of cell aggregate/organoid that Applicant intends for their application.
Applicant argues that Reid does not mention matrix metalloproteinases (MMPs). Applicant argues that while MSCs can express and secrete MMPs, that the expression of MMPs from MSCs depends on the differentiation status of the MSCs and points to paragraph 135 as evidence. Applicant argues that the working examples of their specification demonstrate the engraftment of epithelial stem cells into internal organs by using a mixed population comprising ELSMCs and BTSCs to produce an amount of MMPs in the first hydrogel sufficient for engraftment of the BTSCs into the target internal organ which is without precedent in the literature.
This is not found persuasive. The claims require early lineage stage MSCs and biliary tree stem cells that express membrane-associated and/or secreted MMPs. The obviousness rejection relies on the modification of the Mooney method by Reid to provide a method that combines these two cell types in a hydrogel scaffold and therefore it is expected, baring evidence to the contrary, that these cells will express or secrete MMPs and provide the effects of MMPs in the final result.
Applicant argues that the Office Action reliance on Ex parte Obiaya is misplaced. Applicant asserts that Ex parte Obiaya only applies where the claimed structure and the prior art structure are substantially identical such that a newly recognized benefit is inherent in the prior art. Applicant asserts that in the current case that the structural differences between the presently claimed patch graft and the prior art are not merely cosmetic, but that they are fundamental and directly tied to the claimed MMP functionality.
This is not found persuasive. The MPEP states that Ex parte Obiaya is relevant in an obviousness rejection specifically because a “prima facie obviousness is not rebutted by merely recognizing advantages or latent properties present but not recognized in the prior art” (see MPEP 2145, II). In essence, the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention. In the current case, the prior art teaches and suggests the combination of the claimed cell types in a layered hydrogel scaffold (patch) with optimized viscoelasticities for application to a damaged organ as described above. The description of additional advantages of this combination does not render this combination patentable
Applicant argues that Ex parte Obiaya does not apply because the prior art does not teach or suggest the claimed structural configuration. Applicant argues that Mooney’s teaching is fundamentally different than Applicant’s because Mooney includes MMP-sensitive substrates as a release mechanism to allow cells to exit after degradation of the matrix while the present claims require a hydrogel configured to allow the mixed population to produce MMPs sufficient to facilitate engraftment into the target organ. Applicant asserts that Mooney’s matrix degradation for cell release is not equivalent to and does not inherently result in the claimed MMP-facilitated engraftment into organs like pancreas and liver.
This is not found persuasive. The obviousness rejection relying on Mooney, Reid, Ghosh and Hanjaya-Putra does address all the structural claim limitations as described above, and baring evidence to the contrary, the functional limitations are deemed to follow when the structural limitations are combined as suggested by the prior art. It is unclear what specific “configuration” is required that Applicant asserts is lacking from the prior art teachings. There is no evidence on the record that the prior art cell/hydrogel combination is unable to express or secrete the required MMPs. If this were the case the claims would have to further include a structural configuration that produces this effect.
Applicant argues that the claimed MMP functionality is not merely an inherent property that flows naturally from the prior art structure because the prior art does not possess the claimed structure. Applicant asserts that Ex parte Obiaya addresses situations where a known structure is found to have a previously unrecognized benefit. Applicant argues that the structure itself -a patch graft as claimed is not taught by the prior art. Applicant points to paragraphs 285-287 of their specification as evidence that the 100% engraftment efficiency in porcine models with functional recovery including insulin-producing islet cells in pancreas is not a latent property of Mooney’s wound-repair scaffold.
This is not found persuasive. As explained above, the obviousness rejection provides the necessary motivation and reasonable expectation of success to combine the claimed structural features and thus renders the structure obvious. Applicant’s assertions of a necessary “configuration” seem to rely on a disclosure in their specification of a specific embodiment at paragraphs 285-287 and this is insufficient. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, if a specific configuration disclosed in the Specification is required for a claimed effect then this specific configuration would need to be recited in the claims as an essential feature for claim enablement.
Applicant argues that the Office Action conflates matrix degradation with engraftment facilitation. Applicant asserts that Mooney’s MMP-sensitive substrates are designed to undergo degradation to allow cell release- the substrate is consumed. Applicant asserts that this is in contrast to the present claims which require the facilitation of engraftment of the cells into the target organ. Applicant asserts that the MMPs produced by the claimed mixed population serve an entirely different purpose than Mooney’s substrate degradation and facilitate the active migration, invasion and integration of stem cells into target organ tissue and point to paragraph 135 of their specification as evidence for an entirely new role of MMPs.
This is not found persuasive. Matrix degradation is not the opposite of engraftment facilitation. In fact, as the matrix degrades, this allows for the cells to migrate more easily from their original location. The components of the administered composition can serve more than one purpose and provide more than one advantage. In addition, Applicant’s claims do not require the exclusion of matrix degradation. The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
Applicant argues that Mooney’s device serves a completely different purpose as compared to the presently claimed patch graft. Applicant asserts that Mooney’s devices are primarily designed to differentiate the stem cells in the device and Mooney does not teach or suggest engrafting undifferentiated stem cells. Applicant asserts that Mooney’s devices are meant to differentiate the stem cells and control temporal and spatial release of cells, not maintaining stemness or engrafting stem cels to internal organs.
This is not found persuasive. Mooney specifically teaches that their cells are induced to migrate out of their scaffold to directly affect a target tissue (page 7 para 47- 48) and may include a hydrogel medium that contains factors required to maintain the multipotent nature of stem cells (maintain stemness and prevent differentiation) (page 10 para 68-69).
Applicant argues that because the Office action has acknowledged that Mooney does not specifically disclose an embodiment where the target internal organ is brought into contact with the device delivering mesenchymal stem cells and epithelial stem cells into the target organ that Mooney does not teach or suggest wherein the first hydrogel is tethered to the subject’s target organ by using the backing.
This is not found persuasive. Mooney teach wherein the scaffold (backing) includes materials that have sufficient resilience to withstand mechanical forces, able to be tethered to a target organ or tissue and has sufficient flexibility to be tethered to locations with curvature (target organs)(page 7 para 49, page 24 para 154). Attachment (tethering) to the injured tissue site is disclosed and suggested (page 22 para 143).
Applicant argues that Reid does not teach or suggest a patch graft that is tethered as claimed. Applicant asserts that Reid is only limited to tethering to a surface of bile ducts at paragraph 96 and does not mention tethering as claimed. Applicant asserts that Mooney is silent to any tethering. Applicant asserts that a person of ordinary skill in the art would not be motivated to combine the teachings of Mooney and Reid because Mooney has a different function compared to Applicant’s claims and is silent to any type of tethering.
This is not found persuasive. The obviousness rejection is based on the modification of the Mooney reference method, not Reid’s method. Mooney is not silent to tethering as described above. In addition, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the current case, the Reid reference provides the motivation to include the claim limitations that are missing from the Mooney reference as described above.
Applicant argues that Mooney does not provide any guidance for selecting viscoelasticity of a hydrogel as recited in the claims. Applicant asserts that Mooney is limited to soft materials described at paragraph 154 within Example 3 and transplanting of myoblasts in this specific example.
This is not found persuasive. First, the obviousness rejection is based on the combination of references and not on the teaching of Mooney alone. Second, Mooney discloses that a scaffold may be composed of multiple gel layers of various levels of rigidity and form a sandwich configuration (pages 10-11 para 63-71). Third, Mooney also specifically states that while their invention has been particularly shown and described with reference to preferred embodiments that it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention. Therefore, the method of Mooney is not limited to their disclosed examples.
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 Ghosh and Hanjaya-Putra are not relevant to the claimed invention. Applicant asserts that Gosh is limited to developing hydrogels for wound repair and only shows the different viscoelastic properties of hydrogels on dermal fibroblasts and Mooney does not provide sufficient guidance for selecting biomaterials and appropriate viscoelasticity ranges for pancreas or liver. Applicant argues that because Gosh only measures cell migration within the hydrogel in their example at page 54 that they cannot be applied to Applicant’s claims which recite cell migration out of the hydrogel and into the target organ or tissue. Applicant asserts that the success of cellular migration out of the hydrogel into the target depends on the characteristic of the hydrogels to maintain cellular MMP expression, which is not taught or suggested by Gosh. Applicant asserts that because of this that Gosh is not relevant to the claimed invention and cannot provide the missing teaching of Mooney.
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).
Mooney teaches that their method and device are suitable for multiple cell types and a viscoelasticity range that overlaps with Gosh. Ghosh suggests that softer hydrogels (e.g., 95 Pa) may be utilized to promote cellular migration, while viscosities of 550 Pa or higher promote cellular adhesion and proliferation (Section 3.3.1,4, Fig. 5).
The Mooney reference specifically indicates that their method uses the softer hydrogels (page 24 para 154) and that the cells egress (migration) from the hydrogel is to be controlled (page 1 para 6). Applicant has not provided any evidence that the references are missing any essential limitation recited by the claims.
Applicant argues that Gosh teaches at page 9 that AHDF (fibroblast) numbers increased significantly on the stiffest hydrogels while those on the softest ones underwent a decline suggesting inhibition in cell adhesion or death or both. Applicant asserts that Gosh is both not relevant and teaches away from the claimed invention.
This is not found persuasive. First, Ghosh teach that their data shows that stiff substrates induce strong cellular traction and that tractional force correlates inversely with cell migration speed (page 9, 2nd paragraph). Second, the Mooney reference specifically indicates that their method uses the softer hydrogels (page 24 para 154) and that the cells egress (migration) is to be controlled (page 1 para 6). Third, even if Gosh could be construed as a teaching of a cell decline with regard to the use of softest hydrogels it would be with regard to fibroblasts and not any and all cells contacted with such soft hydrogels as suggested by Mooney.
Applicant argues that Hanjaya-Putra cannot provide the missing teaching of Mooney and Reid because Hanjaya-Putra is limited to methods and compositions for vascularization and point to the abstract and claims as evidence. Applicant argues that the teaching of Hanjaya-Putra can only be used for varying stiffness of hydrogels for varying kinetics of EPC tubulogenesis and cannot be used for the treatment of liver, pancreas or other organ diseases as recited by the present claims.
This is not found persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Hanjaya-Putra teach the viscoelasticities of hydrogels (including hyaluronic acid) intended for use in regenerative medicine (page 2 para 10, para 17, page 3 para 35) and indicate that values of 650 +/- 180 Pa provide a rigid hydrogel, 75 +/-40 Pa for a firm hydrogel and 10+/-2 Pa for a yielding hydrogel (page 3 para 35). Cell migration is discussed as well (page 7 para 77, page 8 para 87, para 91, page 9 para 92, page 15 para 153, pages 18-19, para 180). The Mooney reference specifically indicates that their method uses the softer hydrogels (page 24 para 154) and that the cells egress (migration) is to be controlled (page 1 para 6). Hanjaya-Putra provides the necessary information regarding hydrogel viscosities required by Mooney in order to optimize the administration of therapeutic cells to damaged target tissue.
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 the Office Action’s obviousness analysis improperly relies on hindsight reconstruction rather than the teachings and suggestions of the prior art itself.
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).
In the current case the obviousness analysis relies completely upon the teachings and suggestions of the prior art references as described above.
Applicant argues that each of the cited references in the obviousness rejection is directed to a different purpose and application.
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).
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the current case, the obviousness method is based on the modification of the Mooney method and not the modification of the Ghosh method. Second, Mooney, Ghosh and Hanjaya-Putra are all directed to hyaluronan based hydrogels and cellular migration therein by modulating physical characteristics of the hydrogel, it would have been obvious to one of ordinary skill in the art that the references could be combined. The selection of a softer hydrogel for the first hydrogel would have been obvious to allow for cell migration to the damaged tissue and harder hydrogels for the second and third hydrogels to reduce cell migration away from the target tissue. A skilled artisan would be motivated with a reasonable expectation of success to utilize the viscoelasticities suggest by Ghosh and Hanjaya-Putra because they fall within the range of viscoelasticities suggested by Mooney to both promote and inhibit cellular migration within the hydrogel.
In response to Applicant’s request to hold the double patenting rejection in abeyance, this request cannot be granted at this time. The “provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in one of the applications. See MPEP 822.01
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.
Alimperti et al., “Serum-Free Spheroid Suspension Culture Maintains Mesenchymal Stem Cell Proliferation and Differentiation Potential”, Biotechnology Progress, 2014, Vol. 30, No. 4, pp. 974-983.
Alimperti disclose methods of forming MSC organoids on low attachment plates in serum-free conditions (page 975).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached on 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631
