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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/4/2026 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-5, 7-13, 15, 18, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites, “at least one dissociated human pluripotent stem cell”.
The term “dissociated” is a relative term which renders the claim indefinite. The term “dissociated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. When a human pluripotent stem cell described as “dissociated”, it means it has been dissociated from something. As such, “dissociated” is relative to that something from which the pluripotent stem cell is dissociated. However, the recitation renders the claim indefinite because one does not known from what the human pluripotent stem cell is dissociated. Further, the claim also recites, “each dissociated cell is encapsulated within a…hydrogel”. As such the dissociated is associated within a hydrogel. As such, it is not apparent how a human pluripotent stem cell can be considered both dissociated and “encapsulated within” (i.e. associated by encapsulation within) a hydrogel. As such, the metes and bounds of the claim are indefinite.
Claims 4-5 and 7-10 depend upon claim 1. As such, these dependent claims also have the above indefinite recitation.
Claim 11 recites, “at least one dissociated human pluripotent stem cell”.
The term “dissociated” is a relative term which renders the claim indefinite. The term “dissociated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. When a human pluripotent stem cell described as “dissociated”, it means it has been dissociated from something. As such, “dissociated” is relative to that something from which the pluripotent stem cell is dissociated. However, the recitation renders the claim indefinite because one does not known from what the human pluripotent stem cell is dissociated.
Claims 12-13, 15, 18, and 20 depend upon claim 11. As such, these dependent claims also comprise the indefinite recitation.
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, 4-5, 7-10, as amended, originally presented, or previously presented, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, of U.S. Patent No. 11,591,564. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims discloses a species of the instant claims.
Regarding instant claim 1, patent claim 1 states a composition for use in propagating human pluripotent stem cels from single human pluripotent cells, comprising biocompatible, naturally-derived, crosslinked hydrogel linked to polypeptides comprising cell-binding sequence of an epithelial cadherin extracellular domain for use with human pluripotent stem cells, wherein the cell-binding sequence is at least one of LFSHAVSSNG (HAV10, SEQ ID NO: 2); SHAVSS (HAV6, SEQ ID NO: 3); QGADTPPVGV (ADT10, SEQ ID NO: 4), and ADTPPV (ADT6, SEQ ID NO: 5), and wherein the polypeptide is linked directly to the hydrogel by an amide bond. It does not expressly state that the pluripotent stem cell is encapsulated by the hydrogel. However, it would be obvious to choose placing human pluripotent stem cells into the hydrogel substrate to grow the cells (i.e. encapsulate) from a finite number of possible means of culturing/using a hydrogel with human pluripotent stem cells to predictably arrive at the limitations of instant claim 1.
The amendments to instant claim 1 further specify that the hydrogel is a carboxylated polysaccharide hydrogel and that the polypeptide of comprising an epithelial cadherin extracellular domain is cross-linked to the carboxylated hydrogel. Patent claim 1 does not expressly teach these limitations. However, patent claim 1 does teach that the polypeptide, which are the same polypeptide as recited in instant claim 1, are linked by an amide bond (i.e. crosslinked by an amide bond). Crosslinking of the polypeptide by an amide bond in patent claim 1 inherently requires that the hydrogel of the patent be one that is a carboxylated hydrogel for the amide bond to form. As such, inherently patent claim 1 teaches a carboxylated hydrogel. Patent claim 1 does not specify that the carboxylated hydrogel is a carboxylated polysaccharide hydrogel. However, prior to the patent claim 1, carboxylated polysaccharide hydrogels such as alginate were commonly being used with human pluripotent stem cells. As such, it would have been obvious to choose a carboxylated polyssacharide hydrogel from a finite number of predictable hydrogel species to arrive at limitations for the hydrogel in instant claim 1.
Further regarding instant claim 1, patent claim 2 discloses a carboxylated polysaccharide hydrogel as claimed. As such, patent claim 2 also teaches the limitations of instant claim 1 for reasons discussed above.
Further patent claim 7 uses the hydrogel of patent claim 1 in a culture method to propagate human pluripotent stem cells. Thus also teaching the limitations of instant claim 1 for reasons discussed above
Regarding claim 4, patent claim 3 specifies the hydrogel as alginate.
Regarding claim 5, patent claim 8 specifies an embryonic stem cell. Patent claim 9 specifies an induced pluripotent stem cell. Patent claim 1 and 10 specify human pluripotent stem cells.
Regarding claims 7, patent claim 1 discloses the sequences of SEQ ID NOS:2-5. Patent claim 4 discloses sequences having at least five consecutive aa of SHAVSS or ADTPPV. Both disclose a sequence comprising the AA sequence HAV or ADT.
Regarding claim 8, patent claim 1 teaches directly linkage by an amide bond.
Regarding claim 9, patent claim 5 discloses the pendent free limitations of claim 9.
Regarding claim 10, patent claim 6 discloses the composition is anionic and is in the form of capsules formed with a divalent cation.
In the remarks, Applicant submit a terminal disclaimer, if appropriate, upon withdrawal of the statutory rejections. In response, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
(1) Claims 1, 4-5, 9 and 10, as amended, originally presented, or previously presented, is/are rejected under 35 U.S.C. 103 as being obvious over Banerjee (Disclosure for grant on 6/16/15; abstract; pp 1-2; of record in IDS) in view of Darrabie (Darrabie et al. Journal of Microencapsulation, September 2006; 23(6): 613–621).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding claim 1, Banerjee teaches that in this work, the investigators propose to overcome these shortcomings through the design of novel biomimetic hydrogel capsules for scalable culture of hPSCs. Specifically, they propose to incorporate synthetic bioactive peptides mimicking cadherin and non-cadherin cell-cell interactions within three dimensional (3D) microporous hydrogel capsules, for encapsulating and propagating hPSCs (i.e.- composition for use in propagating pluripotent stem cells). These peptide-conjugated hydrogel capsules (i.e. - a biocompatible hydrogel, optionally synthetic or naturally derived) will be designed to mimic the cellular microenvironment by synthetically recreating cell-cell contacts through epithelial-cadherin (E-cadherin) (i.e. - linked to a polypeptide comprising a cell-binding sequence of an epithelial cadherin, optionally human epithelial cadherin, extracellular matrix). Alternate peptide designs and combinations will be screened in an alginate array platform to select for those supporting short-term viability and proliferation. Further, macroporous capsules will be synthesized from the designed peptide-conjugated alginate to facilitate homogeneity in hPSC aggregates (i.e. a biocompatible, naturally derived, crosslinked, biocompatible carboxylated polysaccharide hydrogel as claimed). The capsule design will also prevent coalescence of the aggregates. hPSCs propagated in alternate capsule designs will be characterized for long-term viability, pluripotency and scalability. Recreating cell-cell contact is expected to significantly enhance single cell viability and clonal expansion over current state-of-art of inhibiting Rho associated coiled coil protein kinase (ROCK) pathway. Furthermore, hydrogel encapsulation will protect the cells from bioreactor hydrodynamic stresses, hence removing shear-induced variations in the culture (p. 2, last paragraph of abstract).
Claim 1, as amended, specify the composition as “a cell culture composition”. However, the cell culture composition does not comprise an structures that specific to cell culture. As such, the breath of describing the composition as a “cell culture composition” in the preamble includes interpreting “cell culture” as the intended use for the composition and thus does not impart any further structural limitations to the claimed composition.
Claim 1, as amended, specifies “the hydrogel linked on an inner surface to a polypeptide comprising a cell-binding sequence”. Banerjee does not expressly teach the linkage on “an in surface”. However Banerjee does teach that the hydrogel is in capsule formation, the human pluripotent stem cells are inside the capsule interacting with the polypeptides comprising the cell-binding sequence, and the polypeptide is linked to the hydrogel. As such, the peptide has to be linked on the inner surface of the hydrogel capsule to have such interactions with the human pluripotent stem cells as taught by Bannerjee.
Banerjee is silent as to whether the alginate hydrogel is crosslinked. However, almost a decade before the effective filing date of the instant application, Darrabie teaches microencapsulation and immunoisolation of cells for transplantation in alginate microcapsules. Although soluble in monovalent cationic solutions, alginate, when introduced to certain divalent cations, such as Ba++ and Ca++, forms cross-linkages between its polymer chains. The microencapsulation procedure entraps tissue in a semi-permeable gel sphere. Applying a cationic polyaminoacid layer such as poly-L-lysine selectively allows insulin, glucose and other nutrients to traverse the microcapsule membrane, while preventing immune system components such as immunoglobulins from destroying the encapsulated tissue. Once the perme-selective coating is performed, the inner alginate gel core can in some cases be liquefied by chelation of the gelling cation, such as Ca++. (p. 613-614).
As such, it would have been obvious to an artisan of ordinary skill before the effective filing date to use known an alginate hydrogel crosslinked with divalent, Ca++ or Ba++ taught by Darrabie in forming the alginate microcapsule encapsulating pluripotent stem cells taught by Banerjee to predicably arrive at the limitations of claim 1. The artisan would have a reasonable expectation of successfully making such a variant because Darrabie teaches that long before the time effectively filing microcapsules for encapsulating cells that are made of crosslinked alginate were successfully being made and used in the prior art. Further, Darrabie teaches that that this crosslinked alginate allowed for immunoisolation along with nutrient passage into the microcapsule without immune system components destroying the encapsulated cells. As such, Banerjee in view of Darrabie render claim 1 obvious.
Regarding claim 4, both Banerjee and Darrabie teach alginate, meeting the limitations of claim 4. As such, Banerjee in view of Darrabie teaches renders claims 2-4 obvious.
Regarding claim 5, Banerjee discloses pluripotent stem cells as claimed. Thus Banerjee in view of Darrabie render claim 5 obvious.
Regarding claim 9, Banerjee does not disclose the claimed ranges of free carboxylate groups, wherein 99% of less….1% or less of monomers of the hydrogel. However, the ranges claimed essentially encompass all possible carboxylate groups except 100%. As such, it would have been obvious to an artisan of ordinary skill that Banerjee would have to fall somewhere within this range because the disclosed ranges cover all possibilities of free carboxylate groups. Thus Banerjee in view of Darrabie renders claim 9 obvious.
Regarding claim 10, Banerjee in view of Darrabie teaches the composition is anionic and is in the form of capsules formed with a divalent cation as discussed above.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. The claimed method was known in the art at the time of filing as indicated by Banerjee in view of Darrabie. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
(2) Claims 7-8, a previously or originally presented, is/are rejected under 35 U.S.C. 103 as being obvious over Banerjee (Disclosure for grant on 6/16/15; abstract; pp 1-2; of record in IDS) in view of Darrabie (Darrabie et al. Journal of Microencapsulation, September 2006; 23(6): 613–621), as applied to claims 1-5, 9 and 10, in further view of Brinchman (WO 2008/157324), Sinaga (Sinaga et al. Pharm Res 19(8):1170-1179, 2002: of record in IDS) and Li (Li et al. Cell Adhesion and Migration 60:59-79, 2012; of record in IDS).
Regarding claims 7-8, Banerjee in view of Darrabie teaches the composition comprising pluripotent stem cells encapsulated by a crosslinked alginate hydrogel comprising a linked polypeptide comprising a cell-binding sequence of E-cadherin extracellular domain as discussed above. Banerjee in view of Darrabie does not the claimed species of the E-cadherin polypeptide in claim 7. Banerjee also does not tach the polypeptide is linked by an amide bond (claim 8).
However, Brinchman teaches biostructures comprising modified alginates entrapping one or more stem cells. The modified alginates comprise at least one alginate chain section to which is bonded by covalent bonding (amide bond) at least one cell attachment peptide (p. 2, lines 22-25). Further, Brinchman teaches that these attachment polypeptide allows for development of polymers onto which these adhesive peptides can be conjugated to facilitated stem cell adhesion (p. 1, line 12-30).
Sinaga teaches peptide derived from the bulge (HAV-peptides) and groove (ADT-peptides) regions of the extracellular 1 (EC-1) domain of human E-cadherin (abstract). Sinaga more specifically discloses HAV-10 (SEQ ID NO:2); Hav-6 (SEQ ID NO:3); ADT10 (SEQ ID NO:4); and ADT6 (SEQ ID NO:5). See page 1172, Table I). Sinaga further teaches that both the groove and bulge regions of the EC-domain are important for cadherin-cadherin interactions (abstract).
Further, Li teaches that E-cadherin mediate cell-cell cohesion plays an important role in the survival and self-renewal of hESC (p. 61 sentence bridging paragraph 1 and 2).
As such, it would have been obvious to the artisan of ordinary skill at the time of effective filing to covalently link via an amide bone the species of HAV and/or ADT e-cadherin cell-binding sequences, as taught by Sinaga, to the alginate hydrogel capsule, taught by Banerjee in view of Darrabie, using the means taught by Brinchman, to predictably arrive at the alginate hydrogel linked to a polypeptide comprising a cell-binding sequence of an human e-cadherin EC domain as claimed. An artisan would have a reasonable expectation of success because both Brinchman provides a successful means of covalently linked cell-binding sequences to alginate polymers for stem cell culture and the e-cadherin cell-binding sequences were known in the art, as taught by Sinaga. Further, an artisan would be motivated to include these human e-cadherin cell binding sequences, taught by Sinaga, to the alginate polymer capsule of Banerjee in view of Darrabie because Brinchman teaches that the cell adhesion polymers provide improved environment for the stem cells, and Li more particularly teaches that E-cadherin mediate cell-cell cohesion which plays an important role in the survival and self-renewal of hESC. Thus, Banerjee in view of Darrabie in further view of Brinchman, Sinaga, and Li render the claims obvious.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. The claimed method was known in the art at the time of filing as indicated by Banerjee in view of Darrabie in further view of Brinchman, Sinaga, and Li. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
(3) Claim(s) 1, 4-5, 7-13, 15, 18, and 20, as amended, previously presented, or originally presented, is/are rejected under 35 U.S.C. 103 as being unpatentable over Maguire (US 2009/0311765 Pub date:12/17/2009; of record in IDS) in further view of Brinchman (WO 2008/157324), Sinaga (Sinaga et al. Pharm Res 19(8):1170-1179, 2002: of record in IDS) and Li (Li et al. Cell Adhesion and Migration 60:59-79, 2012; of record in IDS).
Regarding claim 1, Maguire teaches a single cell suspension of embryonic stem cells encapsulated within an alginate polyelectrolyte microenvironment (p, 10; claim 1). These teachings encompass the limitations a composition comprising at least one pluripotent stem cell encapsulated within a 3D biocompatible hydrogel.
Maguire does not teach that the hydrogel is linked to a polypeptide comprising a cell-binding sequence of an epithelial cadherin extracellular domain. Maguire teaches that the embryonic stem cells can be of human origin ([0033]).
Brinchman teaches biostructures comprising modified alginates entrapping one or more stem cells. The modified alginates comprise at least one alginate chain section to which is bonded by covalent bonding (amide bond) at least one cell attachment peptide (p. 2, lines 22-25). Further, Brinchman teaches that these attachment polypeptide allows for development of polymers onto which these adhesive peptides can be conjugated to facilitated stem cell adhesion (p. 1, line 12-30).
Sinaga teaches peptide derived from the bulge (HAV-peptides) and groove (ADT-peptides) regions of the extracellular 1 (EC-1) domain of human E-cadherin (abstract). Sinaga more specifically discloses HAV-10 (SEQ ID NO:2); Hav-6 (SEQ ID NO:3); ADT10 (SEQ ID NO:4); and ADT6 (SEQ ID NO:5). See page 1172, Table I). Sinaga further teaches that both the groove and bulge regions of the EC-domain are important for cadherin-cadherin interactions (abstract).
Further, Li teaches that E-cadherin mediate cell-cell cohesion plays an important role in the survival and self-renewal of hESC (p. 61 sentence bridging paragraph 1 and 2).
As such, it would have been obvious to the artisan of ordinary skill at the time of effective filing to covalently link via an amide bone the species of HAV and/or ADT e-cadherin cell-binding sequences, as taught by Sinaga, to the alginate hydrogel capsule, taught by Maguire, using the means taught by Brinchman, to predictably arrive at the alginate hydrogel linked to a polypeptide comprising a cell-binding sequence of an human e-cadherin EC domain as claimed. An artisan would have a reasonable expectation of success because both Brinchman provides a successful means of covalently linked cell-binding sequences to alginate polymers for stem cell culture and the e-cadherin cell-binding sequences were known in the art, as taught by Sinaga. Further, an artisan would be motivated to include these human e-cadherin cell binding sequences, taught by Sinaga, to the alginate polymer capsule of Maguire because Brinchman teaches that the cell adhesion polymers provide improved environment for the stem cells, and Li more particularly teaches that E-cadherin mediate cell-cell cohesion which plays an important role in the survival and self-renewal of hESC. Thus, Maguire view of Brinchman, Sinaga, and Li render the claims obvious.
Regarding claims 4, Maguire teaches an alginate capsule as discussed above.
Regarding claim 5, Maguire teaches an embryonic stem cell as discussed above.
Regarding claims 7-8, Maguire does not teach the specific species of E-cadherin polypeptides (claims 7) linked to the hydrogel by an amide bond. However, Brinchman, Sinaga, and Li teach these missing limitations in Maguire and provide reasonable expectation of success and motivation to combine these prior art elements as discussed above.
Regarding claim 9, neither Maguire nor the secondary references expressly teach the claimed ranges of free carboxylate groups, wherein 99% of less….1% or less of monomers of the hydrogel. However, the ranges claimed essentially encompass all possible carboxylate groups except 100%. However, it would have been obvious to an artisan of ordinary skill that both Maguire the secondary references would have to fall somewhere within this range because the recited ranges cover all possibilities of free carboxylate groups. Thus Maguire in view of Brinchman, Sinaga, and Li renders claim 9 obvious.
Regarding claim 10, Maguire teaches a single cell suspense of embryonic stem cells encapsulated with an alginate polyelectrolyte microenvironment ([0031]). The alginate polyelectrolyte microenvironment includes a divalent cation. Suitable divalent cations include Ca2+ or Ba2+ ([0032]). Alginate is anionic. As such, Maguire teaches the composition is anionic and is in the form of capsules formed with a divalent cation as claimed. As such, Maguire in view of Brinchman, Sinaga, and Li renders claim 10 obvious.
Regarding claim 11, Maguire teaches methods for producing encapsulated embryonic stem cells. In one embodiment, the method includes providing a single cell suspension of ES cells; and combining this single cell suspension of ES cells with an alginate solution to form a mixture. This method further includes subjecting the mixture to an electrostatic field to form electrostatic alginate droplets; and exposing the electrostatic alginate droplets to a divalent cation solution to form a bead about the ES cells ([0080]). As such Maguire in view of Brinchman, Sinaga, and Li render claim 11 obvious for reasons discussed above.
Regarding claim 12, Maguire teaches the divalent cation is Ca2+ or Ba2+ as discussed above. In the examples Ca2+ is used in the form of CaCl ([0087]). Therefore, Maguire in view of Brinchman, Sinaga, and Li renders claim 12 obvious.
Regarding claim 13, Maguire teaches embryonic stem cells not “induced pluripotent stem cells”. However, the claims do not recite any addition structural or functional limitations that would distinguish the induced pluripotent stem cell from the embryonic stem cell. As such, stating it is “induced” solely recites the means by which the pluripotent stem cell is made and does not necessarily impart additional structural or functional limitation to the claimed pluripotent stem cell. As such, the breadth of the claimed induced pluripotent cell encompasses any pluripotent cells such as the embryonic stem cell of Maguire. As such, Maguire in view of Brinchman, Sinaga, and Li teach the requisite limitations of the claim and render it obvious for reasons discussed above.
Regarding claim 15, Maguire does not teach the specific species of E-cadherin polypeptides linked to the hydrogel by an amide bond. However, Brinchman, Sinaga, and Li teach these missing limitations in Maguire and provide reasonable expectation of success and motivation to combine these prior art elements as discussed above.
Regarding claims 18, Maguire teaches an alginate hydrogel as discussed above.
Regarding claims 20, Maguire does not teach the specific species of E-cadherin polypeptides linked to the hydrogel by an amide bond. However, Brinchman, Sinaga, and Li teach these missing limitations in Maguire and provide reasonable expectation of success and motivation to combine these prior art elements as discussed above.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. The claimed method was known in the art at the time of filing as indicated by Maguire in view of Brinchman, Sinaga, and Li. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Response to Arguments
Applicant's arguments filed 5/4/2026 have been fully considered but they are not persuasive.
Applicant traverses this rejection on the grounds that the amendments are not taught by the prior art rejections. In response, Applicant’s arguments are not found persuasive because Applicant is not giving the claims their broadest reasonable interpretation. See the revised rejections above to see how the amendments are still taught by the prior art rejections of record.
Applicant seems to emphasize in their remarks that the prior arts does not teach “dissociated” human pluripotent stem cells as not being taught. In response, how this term in intended to further limit the claims is not completely clear. The claim does not specify from what the cells are dissociated and clearly if they are going to be in a hydrogel they are not dissociated but rather associated. However, it is further pointed out by the process of putting a cell into hydrogel encapsulated or otherwise the cells must be dissociated from the environment in which they were originally present (embryo, cell aggregate, petri dish, culture media, etc…). As such, the term “dissociated” does not particularly further limit the human pluripotent stem cells of the claims.
Additional arguments regarding the elements that the cited prior art do and do not teach were reiterated by Applicant, as was the teachings of the Declaration. All of these arguments have been previously address in prosecution. As such, Applicant is referred back to previous office action for their discussed as to why these arguments are not persuasive.
In conclusion, the prior art rejections of record are being maintained because the claims are still taught by the prior art cited, giving the claims their broadest reasonable interpretation.
No claims are allowed.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/ Primary Examiner, Art Unit 1632
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