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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/19/26 has been entered.
Claim Status:
Claims 3, 6, 8, 13 and 16-18 are cancelled.
Claims 1, 2, 4, 5, 7, 9-12, 14, 15 and 19-20 are pending.
Claims 11, 12, 15 and 19-20 are withdrawn.
Claims 1, 2, 4, 5, 7, 9, 10 and 14 are under examination.
Withdrawn rejections
Applicants’ amendments and arguments filed 7/19/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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, 2, 4, 5, 7, 9, 10 and 14 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 has been amended to recite: “A cartilage tissue engineering complex, which consists of…” MPEP 2111.03(II) states that the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. Claim 1 also recites: “wherein the cartilage gel comprises a cell population of chondrocytes…”. The term “comprises” allows for the addition of components. See MPEP 2111.03(I): “…is inclusive or open-ended and does not exclude additional, unrecited elements…”. However, claim 1 expressly excludes the addition of other unrecited elements. Consequently, the metes and bounds of the claim are indefinite because the terms “consists of” and “comprises” are in conflict. Dependent claims are rejected as indefinite because they are dependent upon an indefinite base claim. Correction is required.
A similar issue is presented in claim 2, which recites “comprise”. See MPEP 2111.03: A claim which depends from a claim which “consists of” the recited elements or steps cannot add an element or step. When the phrase “consists of” appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. Consequently, the scope of claim 2 conflicts with the scope of claim 1. Correction is required.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 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.
Claims 1, 2, 4, 5, 7, 9, 10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Masuda et al. (US20030229400) and Gomes et al. (US20040230303) and Vunjak-Novakovic et al. (US20050064042).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a tissue engineering research scientist, as is the case here, then one can assume comfortably that such an educated artisan will have knowledge of and draw conventional ideas from biology, biomaterials science, and tissue engineering for regenerative medicine, with practical skills in areas like cell culture, biomaterial design, and 3D tissue handling— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1 and 14, Masuda et al. teach a transplantable osteochondral implant comprising engineered cartilage tissue attached to a biocompatible support scaffold comprising a plurality of pores, hence a cartilage tissue engineering complex that comprises a carrier comprising a porous frame structure, wherein the cartilage tissue is derived from chondrogenic cells cultured in vitro, the cells having a cell associated matrix (CM) that implicitly encapsulates the cell population (claimed component b), and wherein the scaffold is selected from the group consisting of at least one of natural cancellous bone, demineralized natural cancellous bone, collagen, and bone substitute material (claimed component a) (Claims 1-2 and 6; [0068]). While claim 1 of Masuda et al. is “comprising”, only claimed components a and b appear recited and thus claim 1 of Masuda et al. reads on a cartilage tissue engineering complex that consists of those components. It is the Examiner’s position that the associated matrix of the cartilage cells in the cartilage tissue reads on at least a gel in a gel state that encapsulates the cell population such that the chondrocytes are loaded on the carrier and form a more closely integrated structure with the carrier. See [0047-0051]. Furthermore, the “plurality of pores” of the biocompatible support scaffold implicitly is a porous frame structure that is a carrier made of a biocompatible material having a certain number of pores on its surface and interior to facilitate the attachment of cartilage gel or cartilage sheet inoculated thereon. Alternatively, Masuda et al. also teach adding a gel (Claim 19) and having 1 or 2 or more layers of cartilage tissue or cells can be cultured as a monolayer [0066], which would appear to read on sheets of cartilage.
Regarding the product-by-process limitations (“formed by”; “undergoing”; “obtained by”; “prepared by”) of claim 1 and claims dependent therefrom, please note that in product-by-process claims, “once a product appearing to be substantially identical is found and a 35 U.S.C. 102/103 rejection [is] made, the burden shifts to the applicant to show an unobvious difference.” See MPEP 2113 Product-by-Process Claims [R-08.2017] I. PRODUCT-BY-PROCESS CLAIMS ARE NOT LIMITED TO THE MANIPULATIONS OF THE RECITED STEPS, ONLY THE STRUCTURE IMPLIED BY THE STEPS “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claims 1-2, Masuda et al. teach: “The chondrogenic cells can
be isolated directly from pre-existing cartilage tissue, for example, hyaline cartilage, elastic cartilage, or fibrocartilage.” ([0034]; see also [0053]). Thus, the chondrogenic cells can comprise elastic cartilage cells, fibrocartilage cells and hyaline cartilage cells. It is the Examiners position that the artisan can obtain the pre-existing tissue in the form of shavings/sheets and then mince those sheets into pieces for culture/extraction of chondrogenic cells.
Regarding claims 9-10, Masuda et al. teach that the scaffold can be selected from the group consisting of at least one of natural cancellous bone, demineralized natural cancellous bone, collagen, and bone substitute material (Claim 1) where that the bone substitute material has a thickness of at least about 2 mm or at least about 10 mm or even greater depending upon the anatomy of the joint into which the implant will be surgically inserted (Claim 5; [0008, 0024, 0058]). The limitation of “at least about 10 mm” is reasonably interpreted to be “at least 10 mm” or “about 10 mm” and “at least 10 mm is open ended and includes greater values such as 0.3-0.8 cm. The term “demineralized natural cancellous bone” is reasonably interpreted to read upon a “decalcified bone matrix”.
Regarding claim 1, Vunjak-Novakovic et al. teaches that it is common to have milled/minced cartilage pieces in a carrier repair assembly with chondrocytes (Claims 1-8; 12-13).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Masuda et al. is that Masuda et al. do not expressly teach minced cartilage sheet pieces, a cell density of chondrocytes of at least 1.0 X 108 cells/ml or 1.0 X 108 cells/g with a cell adhesion rate of ≥ 90% or ≥ 95%.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make the implant of Masuda et al. with minced cartilage sheet pieces, a cell density of chondrocytes of at least 1.0 X 108 cells/ml or 1.0 X 108 cells/g with a cell adhesion rate of ≥ 90% or ≥ 95% and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because for the following sound articulated reasoning with rational underpinning based upon the evidence. Masuda et al. teach: “cells with a reestablished CM are further cultured in medium on the biocompatible support scaffold for a length of time effective for allowing formation of a cohesive cartilage matrix. An effective time of culture is typically at least about 3 days under standard culture conditions.” [0064] While Masuda et al. is silent on the adhesion rate, the ordinary artisan would desire the highest adhesion rate possible such as 100% and thus achieving an adhesion rate of the cartilage gel of ≥ 90% or ≥ 95% is obvious to the ordinary artisan. While Masuda et al. is silent on the cell density, Gomes et al. teach that in the cartilage repair art (Abstract; claims 1-48; Figures 1-9 and accompanying text) and that: “cells include allogenic or autologous, bone marrow cells, stem cells and chondrocyte cells. The cellular density of the cells preferably ranges from 1.0 x l08 to 5.0 x l08 or from about 100 million to about 500 million cells per cc of putty or gel mixture.” Consequently, having at least 1.0 x 108 cells/ml or 1.0 x 108 cells/g in the implant of Masuda et al. is obvious in view of the combined references. With regard to the limitation of mincing a cartilage sheet to provide cartilage pieces, it is the Examiner’s position that Masuda et al. render obvious a cartilage sheet, as explained above, and the time to culture such as sheet is at the discretion of the ordinary artisan with no change to the structure of the implant. Cutting/mincing the sheet into pieces, thus it is no longer a sheet but just a bunch of particulate pieces of cartilage chondrocytes to provide the chondrocytes for the scaffold/carrier of Masuda et al. appears to be a routine and conventional in this art, as taught by Vunjak-Novakovic et al., which will provide chondrocytes for application to the carrier/scaffold with a reasonable expectation of success.
The difference between the instant application and Masuda et al. is that Masuda et al. do not expressly teach obtaining a cartilage gel obtained by gelation culture for 3-5 days or a cartilage sheet by gelation culture for 10-15 days or wherein the gelation medium contains the following components: high-glucose DMEM medium containing 4 to 5 wt% glucose, 10% PBS (v/v) and 100 U/ml penicillin-streptomycin. However, the instantly claimed sheet is ultimately minced into pieces and is no longer a sheet and Masuda et al. teach and suggest obtaining chondrogenic cells from any tissue that contains the cell [0034] and isolating by any suitable method [0037], which would include mincing a shaving/sheet of the tissue and exposing to a culture medium. A culture time of 3-5 days for a gel and 10-15 days for a sheet is at the discretion of the ordinary artisan to obtain the desired chondrogenic cells. Indeed, Masuda et al. teach: “crosslinks in particular show a large increase in concentration after two weeks of culture” [0052], which would provide a reasonable starting point for culture periods for gels and sheets within that time frame. Selection of a gelation medium as claimed is part of the product-by-process limitation and at the discretion of the ordinary artisan.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicants’ arguments filed 1/30/26 have been carefully considered but are not persuasive.
Applicant submits that the structure and composition of the cartilage tissue engineering complex as claimed in the present invention are significantly different from that of the cartilage tissue engineering complex of the prior art, on the basis of the different process as defined in claims. This argument was presented previously. Applicant asserts that: “the present application adopts a technical system completely distinct from that disclosed by Masuda et al. The prior art taught by Masuda et al. relies on the classic tissue engineering strategy of "cells plus material carriers (such as agarose or sodium alginate)". In contrast, the present application establishes a carrier- free pure cell high-density culture system, representing two entirely different technical approaches.” However, claim 1 requires the addition of a carrier comprising a porous frame structure… wherein the porous frame structure is a carrier made of a biocompatible material having pores on its surface and interior to facilitate the attachment of the cartilage gel or cartilage sheet inoculated thereon.” Thus, claim 1 requires the combination of a carrier with the cartilage gel/sheet. A carrier free pure cell high-density culture system is not the composition of matter that is under examination. Applicant’s arguments have been carefully considered but are not persuasive.
Applicant asserts: “Since the technical system of Masuda et al relies on exogenous materials, its product (the engineered cartilage tissue, chondrocytes with CM) inevitably contains residual materials. In contrast, the product of the present application (cartilage gel or cartilage sheet) consists solely of cells and cell-secreted extracellular matrix. It can be seen that the two products are fundamentally different in composition and structure.” Respectfully, the Examiner does not discern how the two products are fundamentally different in composition and structure. It is speculation by Applicant that the system of Masuda et al. inevitably contains residual materials. No residual materials are pointed out by Applicant. Even if residual material impurities are present, those would not affect the scope of the transitional phrase. See MPEP 2111.03(II) states: “The transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. In re Gray, 53 F.2d 520, 11 USPQ 255 (CCPA 1931)” and "closing the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith". Applicant’s arguments have been carefully considered but are not persuasive.
On pages 8-9 of remarks, Applicant discusses the method of Masuda et al. and points out that Masuda et al. teach: “In another embodiment, the culture medium for the chondrocytes further includes at least one exogenously added specific growth factor.” However, that is another embodiment of Masuda et al. that further limits the invention of Masuda et al. In fact, Masuda et al. teach that the growth factors are optional [0063]. Additionally, a composition of matter is under examination; not a method/process claim. Applicant has not persuasively argued any structural difference between the final product produced by Masuda et al. and that which is claimed.
On pages 9-10, Applicant provided a comparative table again. Previously, the Examiner stated: “However, the table is misleading because the density of 2-6 X 104 cells/ml stated by Applicant is actually broader because Masuda et al. teach “at least about 104 cells/ml” [0042], which is open ended. Furthermore, the cells were cultured for 5 days to form a cell-associated matrix (CM) [0042], which means the actual density is larger due to proliferation of the cells in the cell culture medium. The table points out a 3 day culture for the instant application and 5 days for Masuda et al. However, the claim 5 recite: “wherein the cartilage gel is obtained by gelation culture for 3-5 days.” So, Masuda et al. is within the claimed limitation. What conditions and how the culture is recovered is not material to the examination of a composition of matter claim. Especially when Masuda et al. suggest that the chondrocytic cells are cultured in a suitable growth medium [0063].” Applicant’s comparative table does not provide any evidence that the product of Masuda et al., as modified by the combined references, is any different from that which is claimed. A composition of matter claim is under examination, not a process claim.
On page 10 of remarks, Applicant repeats their previous assertion: “It can be seen that the preparation of the cartilage gel of the present application is more simple, and the cartilage gel is more pure. The preparation of the cartilage gel of the present application does not involve the use of agarose and sodium alginate in culture and their removal.” However, “the preparation…is more simple” and “The preparation of the cartilage gel…” speak to the method of producing the cartilage gel and not the product obtained. A composition of matter claim is under examination, not a process claim. There is no agarose or sodium alginate in the product of Masuda et al. (See the claims of Masuda et al.) Plus, Masuda et al. teach that the chondrocytes are removed from the matrix materials: “Recovery of cultured chondrocytes with a CM can be accomplished by solubilizing alginate beads after an effective culture period, using known techniques. The resulting cell suspension is centrifuged, separating the cells with their CM into the pellet away from components of the further removed matrix which remain in the supernatant.” [0055]. Applicants’ concerns about the presence of alginate or agarose appear unfounded.
Applicant argues that Masuda et al. does not teach inoculating chondrocytes at a density of 106 cells/ml and the obtained cartilage gel containing at least 108 cells/ml. However, Masuda et al. teach the inoculation density is "at least about 104 cells/ml", which is open ended and overlaps the claimed range. Plus, the Examiner has asserted: “While Masuda et al. is silent on the cell density, Gomes et al. teach that in the cartilage repair art (Abstract; claims 1-48; Figures 1-9 and accompanying text) and that: “cells include allogenic or autologous, bone marrow cells, stem cells and chondrocyte cells. The cellular density of the cells preferably ranges from 1.0 x l08 to 5.0 x l08 or from about 100 million to about 500 million cells per cc of putty or gel mixture.” Consequently, having at least 1.0 x 108 cells/ml or 1.0 x 108 cells/g in the implant of Masuda et al. is obvious in view of the combined references.” Masuda et al. is not read in a vacuum. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In view of the combined references, the claimed cell density is obvious. Applicants have failed to demonstrate any criticality of the claimed density of cells. Thus, it is merely routine optimization by the ordinary artisan within the scope taught by Masuda et al. with a reasonable expectation of success. Applicant’s supplied references 1 and 2 have been reviewed but are not controlling. Applicants’ arguments are not persuasive.
On page 13 of remarks, Applicant argues: “Masuda et al. are silent on the cartilage sheet pieces of present application. The cartilage sheet of the present application is also obtained under the same gelation culture conditions for culturing the cartilage gel. Then the cartilage sheet is milled or minced to obtain the said cartilage sheet pieces of present application.” As stated above, “Cutting/mincing the sheet into pieces, thus it is no longer a sheet but just a bunch of particulate pieces of cartilage chondrocytes to provide the chondrocytes for the scaffold/carrier of Masuda et al. appears to be a routine and conventional in this art, as taught by Vunjak-Novakovic et al., which will provide chondrocytes for application to the carrier/scaffold with a reasonable expectation of success.” This is merely a conventional technique known to the ordinary artisan and within their skill set with no inventive advantage obtained. In other words, Applicant has not shown with objective evidence any criticality to having cartilage sheet pieces whatsoever. Applicants’ arguments are not persuasive. Nothing has been presented by Applicant that would demonstrate that the engineered cartilage tissue of Masuda et al. is structurally different from that which is claimed.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after review of all the facts, Applicant’s arguments are not persuasive. The Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts, which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
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