DETAILED ACTION
The receipt is acknowledged of applicants’ amendment filed 08/14/2025.
Claims 1-20 are pending and subject of this office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), 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 pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 4-12, 19-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over the combination of Hu et al. (US 2007/0178074, IDS filed 04/11/2024), Seyedin et al. (US 2006/0275273, IDS filed 11/04/2022), and the article by Bravenboer et al. (“Improved cartilage integration and interfacial strength after enzymatic treatment in a cartilage transplantation model”, IDS filed 11/04/2022).
Applicant Claims
Claim 1 is directed to a cryopreserved cartilage product comprising a partially digested cryopreserved natural cartilage collagen matrix isolated from a subject, wherein:
the collagen matrix contains viable cells embedded within the collagen matrix that are native to the collagen matrix and that were embedded in the collagen matrix when the collagen matrix was isolated from the subject;
at least 70% of the embedded cells native to the collagen matrix are viable in the cryopreserved cartilage product; and
the partially digested collagen matrix retains interaction between the collagen matrix and the native cells.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Hu teaches compositions for providing graft recipients with chondrocytes. The compositions provide for populations of chondrocytes that may be isolated from a patient and cultured in vitro to generate a proliferating population of chondrocytes that exhibit great proliferation capacity up to 40 times, and differentiation to produce cartilage, e.g. hyaline cartilage. The chondrocytes are isolated from the cartilage of a patient, to generate a proliferating population of chondrocytes (abstract; ¶¶ 0011-0012, 0060- 0062). Growth factors include basic fibroblast growth factor (bFGF) and transforming growth factor B (TGF-B) (¶¶ 0015, 0058). Chondrocytes are isolated autologous chondrocytes (¶ 0018). The cultured chondrocytes are added to a natural or synthetic biocompatible matrix that does not produce an adverse, or allergic reaction when administered to the recipient host. Such matrix can be made from collagen of Type II (¶ 0068). The cultured chondrocytes are minced and digested with enzymes to prepare the culture medium (¶¶ 0072-0073). On digesting the chondrocytes to prepare a culture medium would inevitably release its growth factors into the culture medium, i.e. autologous and native to the material.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While Hu teaches viability of chondrocytes in presence of growth factors up to 40 times that in absence of growth factors, the reference does not explicitly teach 70% of native chondrocytes are viable as claimed by claim 1.
Hu does not teach the cartilage material is cryopreserved and partially preserved as claimed by claim 1. The “cryopreserved” and “partially digested” limitation fall in the preamble of the claim. However for completeness of record this two limitation will be addressed as will be set forth infra.
Seyedin teaches composition, method and device for treatment degenerative intervertebral disc. The composition comprises chondrocytes expressing type II collagen (abstract). Chondrocytes can be obtained from articular cartilage, hyaline cartilage, costal cartilage, epiphyseal plate or any other cartilage (¶¶ 0004, 0015). The chondrocytes are extracted from human cartilage while the chondrocytes remain viable (¶¶ 0005, 0041). The extracted chondrocytes are grown in vitro with growth factors prior to implantation to a recipient (¶ 0007). The reference teaches after removal of the cartilage, the cartilage is minced, digested, or dissociated into single cells or small groups of cells, and cryopreserved. The cells are cryopreserved in cryopreservation medium at temperature 2-8oC (¶¶ 0042, 0043, 0072-0076). The viability of chondrocytes in the cryopreserved composition was ~80% (¶ 0080).
Bravenboer teaches that enzyme treatment of cartilage wounds increases histological integration and improves biomechanical bonding strength, and represent a promising addition to the current techniques for articular cartilage repair (see the entire document, and in particular the abstract and conclusion).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art at the time of the present invention to provide natural cartilage composition for implant comprising collagen, chondrocytes as taught by Hu, and cryopreserve the implant taught by Hu as taught by Seyedin. One would have been motivated to do so because Seyedin teaches cryopreservation of cartilage provides chondrocyte viability of ~80% suitable for cartilage regeneration. One would reasonably expect formulating cryopreserved natural cartilage implant suitable for cartilage regeneration comprising collagen and chondrocytes having chondrocyte viability of ~80%.
Further, one having ordinary skill in the art would have partially digest the cryopreserved natural cartilage taught by the combination of Hu and Seyedin as taught by Bravenboer because Bravenboer teaches that enzyme treatment of cartilage increases histological integration and improves biomechanical bonding strength, and represent a promising addition to the current techniques for articular cartilage repair.
Regarding the limitation of claim 1 that the partially digested collagen matrix retains interaction between the collagen matrix and the native cells, this is an expected property inseparable from the partially digested cartilage taught combination of the cited references.
Regarding claim 4 that the collagen matrix comprises viable chondrocytes, combination of the cited references teaches that limitation.
Regarding claim 5 that the collagen matrix comprises a bioactive factor that is native to the collagen matrix, Hu teaches the collagen matrix comprises growth factors.
Regarding claim 6 that cartilage matrix comprises a cryopreservation medium, Seyedin teaches cryopreservation medium.
Regarding claim 7 that cartilage is devoid of subchondral bone or cartilage, Hu and Seyedin imply this limitation because the references teach cartilage, and do not teach subchondral bone or cartilage.
Regarding claim 8 that the cartilage is depleted of immunogenic cells, and claim 9 that the cartilage does not comprise macrophages, enzymatic treatment of the cartilage expected to remove immunogenic cells and macrophages because this is the process applicants used to remove immunogenic cells and macrophages.
Regarding claim 10 that the cartilage comprises layer of bone that is native to the collagen matrix, based on the intended use of the cartilage matrix and its site of application, one having ordinary skill in the art would have determined to include layer of bone if needed.
Regarding claim 11 that the partially digested collagen matrix is substantially intact relative to an undigested collagen matrix, this is expected property inseparable from the cartilage based on the enzyme used.
Regarding claim 12 that the partially digested collagen matrix comprises extracellular matrix protein fragments, this is suggested by Hu.
Regarding nominal method of use the cartilage as claimed by claims 19 and 20, this is expected eventual method to administer the cartilage matrix implant at the site of removed injured cartilage. In any event, thawing and administering the cartilage to the patient is directed to the method of use of the cartilage implant that does not impart patentability to composition claims.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the present invention.
Claim 13 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over the combination of Hu, Seyedin and Bravenboer as applied to claims 1, 4-12, 19-20 above, and further in view of Davisson et al. (2007/0299517, IDS filed 04/11/2022).
Applicant Claims
Applicant’s claim 13 is directed to the cartilage material comprises a radial layer, a transitional layer, and a tangential layer.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The combined teachings of Hu, Seyedin and Bravenboer are previously discussed in this office action.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While the combination of the above references teaches natural structure of the cartilage is preserved, and it is expected that the natural cartilage to have radial layer, transitional layer and tangential layer, the references however do explicitly teach this structure of the cartilage as claimed by claim 13.
Davisson teaches method to the repair of articular cartilage in joints using articular cartilage graft. The articular cartilage graft comprises a collagen portion with structure or architecture similar to, or substantially the same as, native human articular cartilage (abstract; (¶¶ 0013, 0027). The articular cartilage comprises three-dimensional structure comprising collagen type II (¶¶ 0030, 0032). The articular cartilage collagen matrix is unique. It forms a pattern of overlapping leaves that are arranged vertically close to the bone and then curve to become parallel to the joint surface as the collagen moves away from the bone. The collagen fibers are arranged vertically in the intermediate zone and curve near the superficial zone to become parallel to the joint surface. The collagen in the graft should have at least one of the following arrangements: a curved-leaf structure similar to that found in native human articular cartilage; a substantially vertical arrangement in the intermediate zone with curving near the superficial zone; and a similar split-line orientation as the native human articular cartilage. In some embodiments, the graft contains collagen structure which is similar to all three arrangements. In other embodiments, the graft contains collagen structure which is similar to only two of these arrangements. In other embodiments, the graft contains collagen structure which is similar to only one of these arrangements (¶¶ 0029, 0031). The reference teaches articular cartilage graft obtained from a portion of a joint from a human cadaver, where the removed joint portion comprises cartilage and attached bone. The graft maintains substantially the same three dimensional collagen scaffold structure as the articular cartilage in the native human cadaver joint (¶¶ 0014, 0015, 0028). The articular cartilage grafts may include intact condyle, which is the end protruded area at the end of some bones, or the bone portion may be removed and only cartilage is used as graft (¶ 0016). The native articular cartilage having the three dimensional structure is advantageous because it provides an articular cartilage graft that can potentially restore normal joint function without an immune response (¶¶ 0033, 0037). The reference teaches preserving the three dimensional collagen structure (¶¶ 0033, 0099). The bone portion of the graft is demineralized, and calcium is removed (¶¶ 0054), and slightly devitalized (¢ 0061). Bacteria is removed from the graft using solvents (¶ 0059). Biological agents including growth factor is added to the graft (¶¶ 0079-0080).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art at the time of the invention to provide cartilage implant as taught by the combination of Hu, Seyedin and Bravenboer, and use articular cartilage comprising collagen matrix having three dimensional structure that comprises the collagen fibers are arranged vertically in the intermediate zone and curve near the superficial zone to become parallel to the joint surface, and has curved-leaf structure similar to that found in native human articular cartilage; a substantially vertical arrangement in the intermediate zone with curving near the superficial zone as taught by Davisson. One would have been motivated to do so because Davisson teaches that native articular cartilage having this three dimensional structure is advantageous because it provides an articular cartilage graft that can restore normal joint function without an immune response. One would reasonably expect formulating native three dimensional cartilage graft comprising the structure described by Davidson wherein the graft can restore normal joint function without an immune response.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 2, 3, 14-18 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over the combination of Hu, Seyedin and Bravenboer as applied to claims 1, 4-12, 19-20 above, and further in view of Steinwachs et al. (EP 1784117, IDS filed 04/11/2022).
Applicant Claims
Applicant’s claim 2 and 3 are directed to the thickness of the cartilage matrix claimed by claim 1. Claims 14-18 are directed to structure of the collagen matrix: comprising channels (claim 14), extending through the entire structure of the cartilage (claim 15), cylindrical channels (claim 16), channel density (claim 17), and diameter of channels (claim 18).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The combined teachings of Hu, Seyedin and Bravenboer are previously discussed in this office action.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
The combined teachings of the references does not teach the specific thickness and structure of the cartilage matrix as claimed by claims 2, 3, 14-18.
Steinwachs teaches implant for cartilage repair comprising natural cartilage matrix comprising viable cells that can be differentiated into chondrocytes. Chondrocytes are autologous (abstract; ¶¶ 0009, 0011). The implant have channels having diameter between 0.5-2 mm to enhance cells, e.g. chondrocytes, migration into within the implant. Further the implant adapted to the shape of cartilage defect can be disc shaped to serve repairing defect in articular cartilage. The matrix having thickness of 0.5-3 mm that is not larger than thickness of the articular cartilage to be repaired, and having diameter of 0.5-30 mm (¶¶ 0010, 0017, 0018, 0026; Figure 1).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art at the time of the invention to provide cartilage implant as taught by the combination of Hu, Seyedin and Bravenboer, and design the cartilage implant in the form of circular desk having thickness 0.5-3 mm and cavities as taught by Steinwachs. One would have been motivated to do so because Steinwachs teaches that disc shaped implant having such a thickness is adapted to the shape of cartilage defect e.g. articular cartilage, and the cavities serve to increase the surface of the implant and enhancing cell migration into the implant. One would reasonably expect formulating natural cartilage implant comprising collagen, chondrocytes and growth factor in the form of disc having thickness of 0.5-3 mm and cavities so that the implant is adapted to the shape of the articular cartilage and enhancing cell migration into the implant.
Regarding the thickness of the collagen matrix of 0.2-2.0 mm and 1 to 1.5 mm as claimed by claims 2 and 3, respectively, Steinwachs teaches the thickness of the implant is 0.5-3 mm that overlap with claimed thickness. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5].
Regarding the channels claimed by claim 14, and the channels that extend through the entire thickness of the cartilage as claimed by claim 15, Steinwachs teaches channels extending through the entire thickness of the implant, see also Figure 1 of the reference.
Regarding the cylindrical shape of the channels as claimed by claim 16, this is taught by Steinwachs, see Figure 1.
Regarding density of the channels as claimed by claim 17, one having ordinary skill in the art would have determined the density of channels according to specific site of use and intended use.
Regarding the diameter of the channels of 0.6-1 mm as claimed by claim 18, Steinwachs teaches diameter between 0.5-2 mm that overlap with the claimed diameter. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5].
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,406,735. Although the claims at issue are not identical, they are not patentably distinct from each other because the subject matter claimed in the instant application is fully claimed and disclosed in the issued patent and would be covered by any patent granted on the present application since the issued claims and the instant application are claiming common subject matter as follows: cryopreserved cartilage material comprising cartilage matrix and viable chondrocytes. The issued claims anticipate the pending claims.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,413,373 in view of Hu et al. The issued claims and the instant application are claiming common subject matter as follows: cryopreserved cartilage material comprising collagen matrix, and viable chondrocytes. The issued claims anticipate the pending claims.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12,268, 797. The issued claims and the instant application are claiming common subject matter as follows: cryopreserved cartilage material comprising collagen matrix, and viable chondrocytes. The issued claims anticipate the pending claims.
Response to Arguments
Applicant's arguments filed 08/14/2025 have been fully considered but they are not persuasive.
The Claims are Patentable Over Hu, Seyedin, & Bravenboer
Applicants argue that the cited portions of the Hu, Seyedin, and Bravenboer, alone or in combination, fail to disclose a cryopreserved cartilage product comprising a partially digested natural collagen matrix with native, embedded cells, at least 70% of which remain viable post- cryopreservation.
In response to this argument, it is argued that all the elements of the claimed product are taught by combination of the cited references. Seyedin teaches cryopreservation of cartilage provides chondrocyte viability of ~80% suitable for cartilage regeneration, and Bravenboer teaches that enzymatic treatment of cartilage to increase histological integration and improves biomechanical bonding strength, and represent a promising addition to the current techniques for articular cartilage repair. Therefore, unlike applicant’s assertion, all the limitation of the claims are taught by the cited references. The cells are cultured and grown in the collagen matrix, therefore, the cells are native to the collagen matrix as claimed.
Applicants argue that the cited references do not disclose or suggest a cryopreserved cartilage product that preserves the native architecture of the cartilage matrix with viable, native, embedded cells. Hu is directed to “methods and compositions for providing graft recipients with chondrocytes. Specifically, the methods and compositions of the invention provide for populations of chondrocytes that may be isolated from a patient and cultured in vitro to generate a proliferating population of chondrocytes that exhibit great proliferation capacity.” Hu at Abstract; see also Hu at ¶ [0002] (“The present invention relates to cell culture compositions such as compositions for culturing chondrocytes. The present invention also relates to methods for culturing chondrocytes and cell cultures comprising chondrocytes.”).
In response to this argument, it is argued that Hu teaches composition comprising chondrocytes that isolated from a patient, and chondrocytes are isolated
autologous chondrocytes, i.e. native to the cartilage. The reference teaches
digesting the chondrocytes to prepare a culture medium, i.e. autologous and native to the material. Hu teaches extracellular matrix, chondrocytes isolated from the same person receiving the implant.
Applicants argue that Hu does not teach cryopreserved or partially digested cartilage material. While Hu discloses that cultured chondrocytes can be added to a natural or synthetic biocompatible matrix, Hu also does not teach or suggest a natural cartilage collagen matrix isolated from a subject, where the collagen matrix contains any number of viable cells native to the collagen matrix that were embedded in the collagen matrix when the collagen matrix was isolated from the subject. Rather, the chondrocytes in Hu are enzymatically dissociated from their native extracellular matrix and cultured in vitro, a process that inherently disrupts native cell- matrix interactions, such that Hu’s natural or synthetic biocompatible matrix to which cultured chondrocytes are later added is fundamentally distinct from Applicant’s collagen matrix containing viable cells embedded within it at the time of isolation from the subject.
In response to this argument, it is reiterated that Hu teaches cartilage matrix comprising chondrocytes that isolated from a patient, i.e. autologous chondrocytes that is native to the cartilage, unlike applicant’s assertion. Even if Hu teaches enzymatic dissociation of the matrix, applicants used partial enzymatic digestion to the matrix that is taught by Bravenboer. Cryopreservation is taught by Seyedin. Therefore, all the limitation of the cited product are taught by combination of the cited references. One cannot attack the references individually wherein obviousness is based on combination of the references. The cartilage matrix taught by combination of the cited references suggests cartilage matrix comprising about 80% viable cells. The cells are embedded at the time of the isolation, because it was actually present in the cartilage at the time of isolation. Whether the cells are present at the time of isolation or embedded at the time of the isolation, applicants failed to show unexpected results of one over the other, the ultimate result is obtained.
Applicants argue that the embedded cells in isolated collagen matrix are endogenously integrated into the extracellular matrix (ECM) during tissue development. These cells are naturally positioned within the matrix architecture, maintaining native cell-matrix interactions, signaling pathways, and mechanical responsiveness. The embedded cells are phenotypically stable, having developed in situ under physiological conditions, with expression profiles and functional behaviors that are aligned with their native tissue roles. In contrast, cultured chondrocytes added to a biocompatible matrix are exogenously introduced. Their integration depends on artificial seeding techniques, which often result in non-uniform distribution, limited penetration, and altered cell-matrix signaling. Additionally, cultured cells often undergo dedifferentiation during expansion, losing their native phenotype, and re-differentiation upon seeding is unpredictable.
In response to this argument, it is argued that the chondrocytes taught by Hu are native to the matrix and expected to behave the same way when cultured in the autologous cartilage matrix. Applicants failed to show unexpected result obtained from the chondrocytes of the present invention versus of the prior art that is cryopreserved and partially digested. Embedding the chondrocytes into the cartilage is directed to a method step of making the cartilage and does not impart patentability to the claims especially the product taught by combination of the cited references contain about 80% viable cells as applicants desired to achieve.
Applicants argue that Hu does not disclose or suggest the use of a natural cartilage matrix that retains native embedded cells, nor does it teach or suggest cryopreservation of such a matrix. Furthermore, Hu does not disclose any viability threshold for native cells post-cryopreservation, nor does it address the preservation of native cell-matrix interactions following enzymatic treatment or freezing.
In response to this argument, it is argued that Hu teaches cartilage matrix that contains the native cells, regardless how or when the chondrocytes included in the matrix. Cryopreservation and viability of the cells are taught by Seyedin and partial enzymatic degradation is taught by Bravenboer. One cannot show non-obviousness by attacking the references individually wherein obviousness is based on combination of the references.
Applicants argue that Seyedin fails to remedy Hu’s failure to disclose cryopreserved or partially digested cartilage material. However, Seyedin is directed to chondrocytes obtained from human subjects that are grown in vitro to provide a treatment for degenerative disc disease. Seyedin at Abstract, ¶ [0007]. While Seyedin describes the use of cadaveric chondrocytes and their cryopreservation, the reference is limited to isolated cells that are cultured in vitro and subsequently introduced into a biocompatible carrier. Like Hu, Seyedin does not teach or suggest cryopreservation of a natural cartilage matrix containing native, embedded cells. The reference does not address the viability of cells embedded within a collagen matrix post-cryopreservation, nor does it disclose or suggest a partially digested matrix that retains native cell-matrix interactions. Seyedin does not teach or suggest cryopreserving a natural cartilage collagen matrix isolated from a subject. The cryopreservation protocols in Seyedin are directed to isolated cells, not to intact cartilage matrix, and thus do not implicate the unique biophysical and biochemical challenges associated with preserving viable cells within a cartilage matrix that would lead one of skill in the art to expect substantially reduced cell viability.
In response to this argument, it is argued that Seyedin is relied upon for teaching cryopreservation. In construing the rejection, the examiner did not replace the native chondrocytes of Hu by the cadaveric chondrocytes of Seyedin, rather used the cryopreservation taught by Seyedin on the viable cartilage matrix comprising native chondrocytes taught by Hu. Seyedin addresses viability of chondrocytes that are obviously viable, or they will not be revived. If Seyedin was to teach cryopreservation, the reference may have considered for anticipation,
Applicants argue that Seyedin discloses only that chondrocyte cells can be cryopreserved. Cryopreservation of isolated chondrocyte cells and cryopreservation of a cartilage matrix containing embedded chondrocytes are fundamentally different processes with distinct implications for cell viability, tissue integrity, and post-thaw functionality. While cryopreservation of isolated chondrocyte cells is a well-controlled, optimized process that ensures high post-thaw viability, cryopreservation of cartilage matrix containing embedded chondrocytes introduces multiple biophysical and biochemical challenges that can compromise cell survival. Cryopreservation protocols for isolated chondrocytes allow for uniform exposure to cryoprotective agents. These agents permeate the cell membrane efficiently, minimizing intracellular ice formation and osmotic stress. By comparison, dense cartilage matrix can act as a barrier to cryoprotective agent diffusion, resulting in heterogeneous distribution and incomplete protection of embedded cells due to, e.g., increased risk of ice crystal formation, mechanical damage, and osmotic injury during freezing and thawing. A person skilled in the art would therefore expect substantially reduced cell viability in cryopreserved cartilage tissue compared to isolated chondrocytes.
In response to this argument, applicant’s attention is directed to the scope of the present claims that are directed to a product, and all the elements of the claimed product are taught by combination of the cited references. Applicants did not show that cryopreservation of cartilage matrix of Hu comprising native cells did not work. The cryopreserved materials or cells are used after reconstitution, Seyedin ¶ [0085]. Therefore, cartilage containing native viable cells of Hu when cryopreserved by the process of Seyedin, will be reconstituted prior to use, and no ice will be present in the reconstituted material. Viability of the cells are increased by cryopreservation as taught by Seyedin. Further, It has been held that it is obvious to combine prior art elements according to known methods to yield predictable results. A finding that the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference, was held obvious by the court. The examiner believes all the elements of the claimed product are taught by combination of the cited references.
Applicants argue that Hu and Seyedin, alone or in combination, do not disclose or suggest a cryopreserved cartilage product comprising natural collagen matrix with native, embedded cells, at least 70% of which remain viable post-cryopreservation. Bravenboer does not remedy these deficiencies of Hu and Seyedin. Bravenboer describes enzymatic treatment of cartilage explants to improve integration but does not disclose or suggest cryopreservation of the treated cartilage, nor does it address the viability of native cells following such treatment. The reference is silent on the retention of native cell-matrix interactions and does not quantify or even mention post- treatment cell viability. Bravenboer’s focus is on improving integration of cartilage grafts, not on preserving viable native cells within a partially digested and cryopreserved matrix. None of the references, alone or in combination, teach or suggest the claimed cartilage product’s unique combination of features.
In response to this argument, again applicants attacking the references individually wherein in obviousness is based on combination of the references. If any of the cited references was to teach all the elements of the claims, such a reference would have been an anticipatory reference. Bravenboer’s as applicants noted focus is on improving integration of cartilage grafts, not on preserving viable native cells within a partially digested and cryopreserved matrix. Bravenboer is relied upon for teaching the partial digestion of the matrix. Combination of the cited references teaches the claimed cartilage product. The rationale to modify the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art and the reason to modify the reference may often suggest what the applicant has done.
The obviousness does not require absolute predictability of success all that is required is a reasonable expectation of success. See In re Kubin, 561 F.3d at 1360. The Court has held that "the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965). "There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. v. Interdigital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir.1997). An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
The Claims are Patentable Over Hu, Seyedin, Bravenboer, & Davisson
Applicants argue that claim 13 was rejected under 35 U.S.C. § 103 as allegedly being unpatentable over Hu, Seyedin, and Bravenboer in view of US Pat. Pub. No. 2007/0299517 (“Davisson’’). Claim 13 ultimately depends from claim 1. As explained above, claim 1 is patentable over Hu, Seyedin, and Bravenboer. The Office has not shown that Davisson would supply the deficiencies of Hu, Seyedin, and Bravenboer.
In response to this argument, it is argued that claim 1 is unpatentable for the reasons discussed above. Claim 13 is further unpatentable over the above references and Davisson as set forth in this office action. Davisson is relied upon for teaching articular cartilage comprising collagen matrix having three dimensional structure that comprises the collagen fibers are arranged vertically in the intermediate zone and curve near the superficial zone to become parallel to the joint surface, and has curved-leaf structure similar to that found in native human articular cartilage; a substantially vertical arrangement in the intermediate zone with curving near the superficial zone. Davisson teaches that native articular cartilage having this three dimensional structure is advantageous because it provides an articular cartilage graft that can restore normal joint function without an immune response. The reference satisfies the purpose for which it was applied.
The Claims are Patentable Over Hu, Seyedin, Bravenboer, and Steinwachs
Applicants argue that claims 2, 3, and 14-18 ultimately depend from claim 1. Claim 1 is patentable over Hu, Seyedin, and Bravenboer. The Office has not shown that Steinwachs would supply the deficiencies of Hu, Seyedin, and Bravenboer.
In response to this argument, it is argued that claim 1 is unpatentable for the reasons discussed above. Claims 2, 3, 14-18 are further unpatentable over the above references and Steinwachs as set forth in this office action. Steinwachs is relied upon for teaching cartilage implant in the form of circular desk having thickness 0.5-3 mm. Steinwachs teaches that disc shaped implant having such a thickness is adapted to the shape of cartilage defect e.g. articular cartilage, and the cavities serve to increase the surface of the implant and enhancing cell migration into the implant. The reference satisfies the purpose for which it was applied.
Double Patenting Rejections
The examiner acknowledges applicants request to hold these rejections in abeyance until the Office identifies patentable subject matter in the application. Therefore, the rejections are maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/ISIS A GHALI/Primary Examiner, Art Unit 1611 /I.G./