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 .
Election/Restrictions
Claims 10-13 and 15-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05 December 2024.
The election of species as set forth in the Office action mailed on 07 October 2024 was withdrawn in the Official action mailed 17 June 2025.
Claim Status
Claim 1 is currently amended, claims 10-13 and 15-21 have been withdrawn from consideration as being drawn to a nonelected invention, claims 2 and 7-8 were previously canceled, claims 9 and 14 are newly canceled, and claims 1 and 3-6 have been considered on their merits.
Withdrawn Rejections
The rejections of claim 14, under 35 U.S.C. 112(b) and 35 U.S.C. 112(d), have been withdrawn due to Applicant canceling the claim.
The claim rejections under 35 U.S.C. 102(a)(1) and 103 have been withdrawn due to the amendment to the claims. However, upon further consideration, a new ground of rejection has been made in view of Yang, Miles, and Sarker.
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 (i.e., changing from AIA to pre-AIA ) 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 and 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (International Journal of Biological Macromolecules, published 08/03/2013 IDS ref., of record) in view of Miles et al. (Mol Reprod Dev. 2017;84:775-787) and Sarker et al. (International Journal of Biological Macromolecules 78 (2015) 72-78).
This is a new rejection, necessitated by applicants’ amendments to the claims. A response to Applicant’s traversal follows the rejection below.
Claim 1 recites a product-by-process limitation. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e. is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113.
In the instant case, the product as claimed is a homogenous crosslinked ADA/collagen hydrogel comprising cells embedded in said hydrogel and one or more further component selected from: antibiotic(s), cytokine(s), blood serum(s), and/or glycosaminoglycan(s) supplements; wherein the stiffness of the hydrogel is from about 0.1 to 20 kP; and wherein said cells are selected from neuronal cells, bone cells, stem cells, immortal cell lines, muscle cells, cells forming blood vessels, and cancer cells.
Yang teaches alginate dialdehyde (ADA) is used as the cross-linker to crosslink collagen hydrogel to culture chondrocytes for cell viability assays (claim 1 (i)) (Abstract and p. 491, section 3.6). Yang teaches their fabrication process could retain the self-assemble property of collagen and also brought in a covalent cross-linking between ADA and collagen (p. 488, 1st column). Yang teaches cross-sectional SEM images of the ADA-Col hydrogels showed homogeneous distribution and inter-connected fibrous structure at all ADA degree of oxidation percentages (p. 489, Section 3.2. Morphology observation). Yang teaches encapsulated chondrocytes within the ADA-collagen hydrogels were cultured in 1 mL α-minimum essential medium (α-MEM) (p. 489, section 2.9). The encapsulated chondrocytes read as cells embedded in said hydrogel (claim 1 (ii)), the embedded cells would necessarily result in the formation of a three-dimensional cell culture hydrogel. Yang teaches the mechanical properties of the hydrogel could be influenced by crosslink reaction (p. 491, section 3.5). Yang teaches the compressive modulus of collagen hydrogel was 3.97 kPa to 10.51 kPa depending on the percentage of ADA (p. 491, section 3.5). The modulus of Yang, 3.97 kPa to 10.51 kPa, falls within the claimed range of 0.1 to 20 kP. The limitation directed to the temperature range of 0 to 4°C is considered a product-by-process step and therefore is not limiting.
Yang does not teach the one or more further components of claim 1(iii), antibiotics, cytokines, blood serum, or glycosaminoglycan supplements or wherein the cells are neuronal cells, bone cells, stem cells, immortal cell lines, muscle cells, cells forming blood vessels, or cancer cells. However, Miles teaches alginate hydrogels for the culture of porcine blastocysts, which comprise stem cells, and Sarker teaches cell culture medium comprising DMEM supplemented with fetal bovine serum and antibiotics for culturing osteoblasts used for encapsulation in an alginate hydrogel.
Miles teaches within the field of tissue engineering, researches combine cells, scaffolds, and bioactive signals in an attempt to engineer a variety of tissues for therapeutic application, such as bone, cartilage, skin, nerves, cardiovascular tissues (p. 778, section 3). Miles teaches most tissue-engineered models are developed and constructed for a specific purpose using cells of many different types, scaffolds made of varying materials, and a wide range of bioactive signals (p. 778, section 3). Miles teaches hydrogels are three dimensional scaffolds for in vitro cell and tissue culture due to their ability to mimic the physical properties of native soft tissue (p. 778, section 4). Miles teaches alginate hydrogels are widely applied in tissue engineering because alginate is a biocompatible, naturally derived, linear polysaccharide produced as an ECM component and an external gelation process allows for gentle encapsulation of cells and tissues without negatively affecting cell viability (p. 778, section 4). Miles teaches alginate mechanical properties can be modulated, wherein, the compressive modulus for alginate hydrogels can range from less than 1-kPa to over 1,000-kPa and lower moduli can be used to mimic ECM for tissues like smooth muscle or higher moduli can be used for bone tissue engineering (p. 780, section 4.2). Miles teaches development of alginate hydrogels for the culture of porcine blastocysts, which comprise stem cells, which utilized a Young’s modulus ranging from 5 to 20-kPa (p. 780, section 4.2).
Miles teaches mammalian cells do not normally adhere to alginate polymers and interactions with extracellular ligands are necessary because cellular surface receptors bind to cell adhesion molecules (ECM molecules) such as collagens, fibronectin, laminin, and SPP1, resulting in physiological changes that support cell survival, migration, proliferation, and differentiation (p. 780, section 4.3). Miles teaches useful chemical modifications of alginate is sulfation, in which alginate is reacted with chlorosulfuric acid in formamide, said processes gives alginate a structural similarity to heparin (a glycosaminoglycan supplement) (p. 780, section 4.3). While Miles does not specifically teach a glycosaminoglycan supplement, the sulfation process suggests the benefit of such supplementation.
Miles teaches ECM molecules are easily blended within the alginate solution prior to cross-linking, thus incorporating them within the hydrogels and providing physiological changes to cells consistent with in vivo phenotypes (p. 780, section 4.3). Miles teaches when covalently linked to alginate, RGD peptide sites serve as ligands for cell-surface integrins, wherein, ligand density can be varied to produce desired degree of adhesion (p. 780, section 4.3). Miles teaches further investigation with the three-dimensional culture system will focus on the effects of certain growth factors, hormones, ligands, and ECM components on the interactions on the development of blastocysts (p. 784, section 6). Cytokines are a type of ligand.
Sarker teaches cell culture medium comprising DMEM supplemented with fetal bovine serum and antibiotics for culturing osteoblasts (bone cells) used for encapsulation in alginate-gelatin hydrogel (p. 73, section 2.2). Therefore, the cell culture medium of Sarker reads as one or more further component including antibiotics and blood serum.
Additionally, DMEM is widely used for culturing a variety of mammalian cells, including neurons (neuronal cells), and established cell lines like HeLa and 293 cells (immortal cell lines). Thus, suggesting the culture medium of Sarker would be suitable for many cell types, to include those required by claim 1.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the cells of Miles or Sarker and the blood serum and antibiotics of Sarker with the hydrogel of Yang with a reasonable expectation of success because all three references teach alginate hydrogels encapsulating cells. One would have been motivated to utilize the cells of Miles or Sarker with the hydrogel of Yang because Miles teaches and suggests several cell types, to include bone, cartilage, skin, nerves, cardiovascular cells, which could be cultured in an alginate-collagen hydrogel. One would have been motivated to utilize the serum and antibiotics of Sarker with the hydrogel of Yang because blood serum and antibiotics are routinely used in cell culture medium to support cell growth and prevent contamination, which could be used to culture a variety of cell types to include neuronal cells, bone cells, immortal cells lines among others. Additionally, Miles suggests the use of cytokines and glycosaminoglycan supplements as cytokines are ligands and glycosaminoglycan is part of the ECM.
Regarding claim 3, this claim recites a product-by-process limitation. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113. Therefore, claim 3 reads the same as instant claim 1. The limitations following “The cell culture system of claim 1” do not add structure to the claimed product, absent evidence to the contrary. Therefore, Yang in view of Miles and Sarker teach the limitations of claim 3.
Regarding claim 4, Yang teaches the hydrogel production wherein the collagen it type I collagen (p. 488, section 2.1).
Regarding claim 5 directed to the adjustable properties of the hydrogel, Yang teaches the degree of oxidation (DO) of the alginate alters the compressive modulus of the ADA-Collagen hydrogel (p. 491, section 3.5). Yang teaches three DO levels of the alginate, ADA1, ADA2, and ADA3 with varying degrees of compressive modulus (kPa) in Table 1 (p. 491, section 3.5 and Fig. 2). Yang teaches gel strength was mainly depended on the interaction between collagen molecules, and the adding of ADA provided more covalent links that may increase the compressive modulus (p. 491, section 3.5). The adjustable nature of the compressive modulus by varying levels of DO of the alginate read as the hydrogel has adjustable hydrogel stiffness, crosslinking degree, swelling kinetics, inter alia. Yang also teaches compressive modulus were correlated with the adding of ADA, cross-linking enhanced the mechanical strength of collagen hydrogels and resisted hydrogel contraction and degradation (degradation kinetics) (p. 492-493, section 3.6).
Regarding claim 6, Yang is silent to the hydrogel comprising further components selected from: growth factor(s), antibiotic(s), cytokine(s), blood serum(s), and glycosaminoglycan(s) supplements. However, Miles teaches cultured blastocysts using the alginate hydrogel encapsulation system with the addition of transforming growth factor-β (TGFB) (p. 783, section 5.3) and the teachings of Miles suggest a glycosaminoglycan supplement. Additionally, Sarker teaches culturing cells with antibiotics and blood serum. Therefore, for the same reasons set forth above, Yang in view of Miles and Sarker teach the limitations of the claim.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see remarks, filed 30 March 2026, with respect to the rejection(s) of claims 1, 3-6, 9, and 14 under 35 USC 102(a)(1) and 103 have been fully considered and are persuasive. Specifically, the references did not teach all of the limitations of the newly amended claim 1. Additionally, Applicant has canceled claims 9 and 14, which renders moot the rejection of record directed to those claims. Therefore, the rejections has been withdrawn.
Applicant’s arguments regarding Yang are all directed to the amendments to claim 1, which as been addressed in the rejection above.
Applicant’s arguments directed to Zhu, Fang, and Steiner, with respect to claims 1 and 3-6 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wright et al. (Journal of Biomedical Materials Research A, October 2014, Vol 102A, Issue 10)
Wright teaches oxidized alginate-collagen hydrogels comprising corneal extracellular matrix proteins were utilized to culture and encapsulate stem cells. Wright teaches cells were cultured in a medium comprising serum, growth factors, and antibiotics.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NICHOLAS A. HUMPHRIES whose telephone number is (703)756-5556. The examiner can normally be reached Monday - Friday, 7:30am - 4:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
Prosecution Insights