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 .
Status of the Claims
Claims 1-6 and 10-30 are currently pending.
Claim 1 is amended.
Claims 11-30 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 7-9 and 31-33 are cancelled.
Claims 1-6 and 10 have been considered on the merits.
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 10 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a limitation of “wherein the microcarrier is free of exogenous gelling polysaccharides or alginate hydrogels”. The specification does not appear to recite the terms “exogenous” or “exogenous gelling polysaccharide”. The specification does recite “functionalized digested decellularized tissue microcarriers 232 can be loaded into a pre-formed, growth factor-loaded scaffold, such as a pre-formed collagen, gelatin, alginate, or chitosan scaffold or a scaffold based on a decellularized matrix” (pg. 21, para 3). Claims 2-6 and 10 are included in this rejection for being dependent on claim 1.
This is a new matter rejection.
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.
Claims 1-6 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Shelby et al (2010/0028849) (Shelby) in view of Nasert et al (US2017/0049930), Pathak et al (US 20070254005) (Pathak), Lelkes et al (US 20080213389), and Kesti et al (US 2017/0348458) (Kesti), all of which are references or record.
With regards to claim 1, Shelby discloses a devitalized acellular matrix for cell culture [0004]. Shelby discloses the tissue is mammalian devitalized and acellular tissue, i.e., decellularized ([0016]), which can act as a scaffold for cellular ingrowth, i.e., a carrier for cell culture and expansion as required by claim 1. Shelby discloses the tissue is treated with a processing solution comprising trypsin or dispase, i.e. the newly amended limitation “wherein the decellularized mammalian tissue is digested and enzymatically-degradable;” as required by claim 1 ([0020]). Further, Shelby teaches that the microcarrier is treated with ozone ([0024]) to cross-link the tissue as required by claim 1. Shelby describes the crosslinking as happening on the devitalized and acellular tissue ([0024]). Shelby teaches that Shelby discloses ozone treatment mildly crosslinks the tissue after the tissue is soaked in processing solution to remove all cellular debris, leaving only the collagen structural matrix and associated proteins ([0021]/[0022]). Additionally, Shelby teaches that the microcarrier is free of exogenous gelling polysaccharides or alginate by omission of the terms alginate or gelatin in respect to the matrix. For clarity, Shelby does disclose the term “gelatin” when describing a study in the prior art at [0006] but does not connect gelatin to any methods of producing or characteristics of the devitalized acellular matrix.
Regarding claims 1, 2, and 4, Shelby teaches that the microcarrier can originate from a human ([0040]) and can be dermis tissue ([0004].
Regarding claim 6, Shelby also teaches that the tissue is micronized ([0024]).
Firstly, Shelby does not teach that the particle size ranges from about 10-600 microns as required by claim 1.
However, Nasert teaches cartilage particles ([0085]) which are comprised of a decellularized material ([0076]). Nasert discloses that the cartilage particles have a particle size of 50-212 microns ([0085]) as required by claim 1. Further, the particles of Nasert can be utilized as an implant for the delivery of cells and allowing for the ingrowth of tissue [0034]. Nasert discloses the decellularized mammalian tissue can be cross-linked collagen and which can be crosslinked to synthetic polymers ([0096]). Therefore, Nasert discloses a tissue which is crosslinked and “functionalized”, which requires the utilization of a functionalization agent.
It would have been obvious to one of ordinary skill at the effective filling date to modify the devitalized and acellular (“decellularized’) microcarrier of Shelby by choosing a particle size being about 10 micrometers (10 microns) to about 600 micrometers (600 microns) as disclosed by Nasert. One of ordinary skill would have been motivated to use the Nasert size particles in view of the teachings of Nasert that the particles of that size can be utilized as an implant for the delivery of cells and allowing for the ingrowth of tissue [0034]. One of ordinary skill would have had a reasonable expectation of success in using in particles 10 micrometers (10 microns) to about 600 micrometers (600 microns) as disclosed by Nasert view of the teachings of Nasert that the cartilage implants are a tissue-genic matrix ([0034]).
Further, Shelby does not teach that the tissue is from a human as required by claim 2. Shelby does not teach that the decellularized mammalian tissue can originate from a mature adult human donor as required by claim 3. Shelby does not teach that the tissue can originate from articular cartilage as required by claim 4. Shelby does not teach that the microcarrier is compatible with cells harvested from mammalian tissue of a same type as the decellularized mammalian tissue as required by claim 5.
Nasert discloses the tissue can be from a human [0035] as required by claim 2. Nasert discloses the decellularized mammalian tissue can originate from a mature adult human donor [0035] as required by claim 3. Nasert discloses [0035] the tissue can originate from articular cartilage as required by claim 4. Nasert discloses [0035] the cartilage particle can be obtained from cartilage fibers which are allogenic to the patient, i.e., “microcarrier is compatible with cells harvested from mammalian tissue of a same type as the decellularized mammalian tissue”, as required by claim 5.
It would have been obvious to one of ordinary skill at the effective filling date to modify the devitalized and acellular (“decellularized’) microcarrier of Shelby by including the tissue features as disclosed by Nasert. One of ordinary skill would have been motivated to use the tissue taught by Nasert because Nasert teaches that articular cartilage does not heal without surgical intervention however it can be repaired using auto/allograft techniques ([0004]). One of ordinary skill would have had a reasonable expectation of success in using the tissue features as disclosed by Nasert view of the teachings of Nasert that the cartilage implants are a tissue-genic matrix ([0034]).
Shelby and Nasert do not explicitly disclose acrylate functionalization as recited in claim 1.
However, Pathak discloses implantable tissue fixation methods and compositions (abstract). Pathak discloses tissues are fixed using variable length crosslinks (abstract). Pathak discloses the functionalization agent can be methacrylic anhydride ([0110]). Pathak discloses tissue is exposed to methacrylic anhydride in 1.0% triethanolamine ([0307]).
It would have been obvious to one of ordinary skill at the effective filling date to modify the method of Shelby and Nasert by functionalizing using an acrylate as suggested by Pathak. One of ordinary skill would have been motivated to use an acrylate, such as methacrylic anhydride as the functionalization agent in view of the teachings of Pathak that the crosslinked collagen sponge may have a higher degradation time as compared to uncrosslinked sponge and may be useful in tissue engineering applications especially in bone tissue engineering applications ([0117]). One of ordinary skill would have had a reasonable expectation of success in performing acrylate functionalization in view of the teachings of Pathak that methacrylic anhydride can be used to modify collagen particles [0117].
Shelby, Nasert, and Pathak do not teach that the microcarrier includes pores having an average size of about 2.5-20 micrometers including a honey comb microstructure as required by claims 1 and 10.
However, Lelkes discloses biologically active scaffolds ([0025]) obtained by lyophilization having pore sizes of about 20 microns or pores having an average diameter of about 10 microns as required by claim 10 ([0046]). Lelkes also discloses the scaffolds were highly porous (>80%) thereby disclosing the scaffold has the claimed “honeycomb microstructure” as required by claim 1 ([0025]). Lelkes teaches that the porosity and pore size helps to accommodate cells and direct cell growth and tissue regeneration ([0025]).
It would have been obvious to one of ordinary skill at the effective filling date to modify the microcarrier of Shelby and Nasert by forming a highly porous microstructure (“honeycomb microstructure”) having pore sizes of about 20 microns as suggested by Lelkes. One of ordinary skill would have been motivated to use microcarriers having high porosity in view of the teachings of Lelkes that the porosity and pore size helps to accommodate cells and direct cell growth and tissue regeneration ([0025]). One of ordinary skill would have had a reasonable expectation of success in utilizing microcarriers having a high porosity and 20-micron size pores in view of the teachings of Lelkes disclosing that neural cells were able to populate the scaffolds (microcarriers) and undergo neuronal differentiation [0025].
Shelby discloses crosslinking the decellularized mammalian tissue using ozone (see claims 5 and 9 of Shelby) however, Shelby, Nasert, Pathak, and Lekes do not teach that the functionalized decellularized mammalian tissue is crosslinked using calcium chloride as required by claim 1.
However, Kesti discloses (abstract) a graft scaffold for cartilage repair comprising particles, an aqueous solution of a gelling polysaccharide, mixing particles and the solution of the gelling polysaccharide and deposing the mix in a three-dimensional form. Kesti discloses the particles can be derived from cartilage ([0031]) and decellularized tissues ([0098]). Kesti discloses the polysaccharide can be alginate ([0061]). Kesti discloses an aqueous solution of a salt comprising monovalent, divalent and/or trivalent cations is added to the gelling polysaccharide to effect gelation, i.e., “multivalent solution” ([0038]). Kesti discloses the multivalent solution can comprise calcium chloride as required by claim 1 ([0127]).
It would have been obvious to one of ordinary skill to modify the microcarrier of Shelby, Nasert, and Pathak by crosslinking the mammalian tissue using a multivalent solution in view of the teachings of Kesti. One of ordinary skill would have been motivated to crosslink the functionalized decellularized mammalian tissue using calcium chloride in view of the teachings of Kesti that the mechanical properties of the microcarrier are highly dependent upon the cation concentration and the crosslinking time [0127]), and because Shelby teaches cross-linking employing alternative methods. One of ordinary skill would have had a reasonable expectation of success in crosslinking the functionalized decellularized mammalian tissue because Shelby teaches that the decellularized mammalian tissue is crosslinked (see claims 5 and 9 of Shelby) and Kesti teaches calcium chloride can be used for successful crosslinking.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filling date, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 8, last para) that Kesti fails to teach or suggest cross-linking acrylate functionalized decellularized mammalian tissue as required by claim 1 and that the CaCl2 that is disclosed in Kesti is added to “effect gelation” and not related to crosslinking.
In response, this argument is not found persuasive. Kesti specifically discloses calcium chloride as a crosslinking agent at the previously cited [0127] which states “the concentration of cations (black=calcium chloride and grey=strontium chloride) has similar effect on crosslinking despite the cationic source. It can be concluded that the mechanical properties are highly dependent on the cation concentration and crosslinking time.” Which is referring to Fig. 3 which demonstrates the effect of cationic concentrations using calcium chloride in relation to crosslinking.
Additionally, Kesti is only being relied upon to teach the use of CaCl2 as the agent in the cross-linking process. Shelby also teaches the cross-linking of decellularized material, however the cross-linking of Shelby is completed with ozone.
Further, 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). However, Kesti explicitly recites “In certain embodiments, either one of said printing mix and said polymer scaffold comprises reactive groups covalently attached thereto, particularly reactive groups facilitating linking of said printing mix, or its constituent components, to said particles, by crosslinking by spontaneous or externally triggered reaction, wherein reactive groups are present on at least one of the polymer, minced tissue and cells to reconstruct functional and native cartilage like tissue grafts” ([0097]). Kesti describes the cross-linking of the “minced tissue”, which includes tissue that is subjected to decellularization and Kesti teaches that decellularized tissues “have attracted interest as scaffold material alternatives to simpler approaches where the scaffold is composed of a single material” ([0098]). Kesti teaches that the agent for initiation cross-linking can be “a monovalent, divalent and trivalent cation, enzyme, hydrogen peroxide, horseradish peroxidase, radiation polymerizable monomers such as lithium phenyl-2,4,6-trimethylbenzoylphosphinate. In certain embodiments, crosslinking initiating groups are present in the printing mix, particularly selected from groups that participate in light exposure, cation-mediated crosslinking and enzyme-mediated crosslinking” ([0083]-[0084]). More specifically, Kesti teaches that the solution for cross-linking comprises Ca2+ ions ([0039]-[0040]), and Kesti employs an example of cross-linking with either calcium chloride or strontium chloride ([0127]). Kesti concludes that “the concentrations of cations (black=calcium chloride and grey=strontium chloride) has similar effect on crosslinking despite the cationic source” ([0127]). Thus, there would be a reasonable expectation of success in combining the methods regarding cross-linking taught in Kesti with Shelby, Nasert, Pathak, and Lekes.
Thus, the argument is not found persuasive.
Applicant argues (Remarks, pg. 9) that Shelby discloses ozone mediated crosslinking, Pathak discloses methacrylate-based polymerization and Kesti discloses Ionic alginate gelation and thus the combination of references would be an unsupported reconstruction of the chemistry in view of the prior art.
In response, the argument is not found persuasive. Shelby is relied upon to teach crosslinking of the functionalized decellularized mammalian tissue, but is deficient in teaching the crosslinking is performed with calcium chloride. This deficiency is remedied by Kesti. One of ordinary skill would have been motivated to crosslink the functionalized decellularized mammalian tissue using calcium chloride in view of the teachings of Kesti that the mechanical properties of the microcarrier are highly dependent upon the cation concentration and the crosslinking time [0127]), and because Shelby teaches cross-linking employing alternative methods. One of ordinary skill would have had a reasonable expectation of success in crosslinking the functionalized decellularized mammalian tissue because Shelby teaches that the decellularized mammalian tissue is crosslinked (see claims 5 and 9 of Shelby) and Kesti teaches calcium chloride can be used for successful crosslinking.
Additionally, dual-crosslinked hydrogels are a known concept in the art, thus the combination of Pathak disclosing methacrylate based crosslinking in addition to the crosslinking taught by the combination of Shelby and Kesti would not be an unsupported reconstruction of the chemistry nor provide substantial unpredictability. Applicant’s arguments do not appear to identify what specific unpredictability would have discouraged a person of ordinary skill in the art from combining the cited crosslinking methods. 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).
Thus, the argument is not found persuasive.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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