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 Claims
Claims 1-10 are pending. This is the first office action on the merits.
Information Disclosure Statement
No Information Disclosure Statement has been filed. Applicants are reminded of their duty to disclose.
Election/Restrictions
Applicant’s election of Group I (claims 1-6) in the reply dated April 30, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicants did not reply to the species election in the reply dated May 23, 2025, however, upon further consideration the species election is hereby withdrawn.
Claims 7-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 April 30, 2025.
Claims 1-6 are examined on their merits.
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 of this title, 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.
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 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kandel US 2002/0111695 (8/15/2002) in view of Min et al. Characterization of subpopulated articular chondrocytes separated by Percoll density gradient, In Vitro Cellular & Developmental Biology-Animal 38.1 (2002): 35-40, Kang et al. WO 2012/033352 (3/15/2012) and Nagatoshi et al. Bioengineered chondrocyte sheets may be potentially useful for the treatment of partial thickness defects of articular cartilage, Biochemical and Biophysical Research Communications, Volume 349, Issue 2, 20 October 2006, pp 723-731.
Kandel teaches a biological material comprising a continuous layer of cartilaginous tissue reconstituted in vitro which contains components associated with cartilage mineralization. (See Abstract). The mineralized biological material is characterized by having a biochemical composition and physiological organization substantially similar to the deep and contiguous calcified cartilage zones of articular cartilage found in animals in vivo. Kandel also teaches methods for preparing the biological materials. (See Abstract).
Kandel teaches a method for producing a mineralized biological material comprising (a) isolating chondrocytes from the deep zone of articular cartilage tissue; (b) forming a layer of the chondrocytes on a substrate and (c)(i) curing the chondrocytes in growth media under suitable conditions so that the chondrocytes accumulate matrix and form cartilaginous tissue which contains components associated with cartilage mineralization; and culturing the cartilaginous tissue in the presence of a mineralizing agent to form a continuous layer of mineralized cartilaginous tissue having a biochemical composition and physiological organization substantially similar to the deep and contiguous calcified cartilage zones of articular cartilage found in animals in vivo, or (ii) culturing the chondrocytes in growth media in the presence of a mineralizing agent under suitable conditions so that the chondrocytes from a continuous layer of mineralized cartilaginous tissue having a biochemical composition and physiological organization substantially similar the deep and contiguous calcified cartilage zones of articular cartilage found in animals in vivo. (See [0013] and Kandel claims 16 and 8).
Kandel claim 16:
A method for producing a reconstituted mineralized cartilaginous tissue comprising (a) isolating chondrocytes from the deep zone of articular cartilage tissue, (b) forming a layer of the chondrocytes on a substrate, (c) culturing the chondrocytes in growth media under suitable conditions so that the chondrocytes accumulate matrix and form cartilaginous tissue in the presence of a mineralizing agent, to form a reconstituted mineralized cartilaginous tissue characterized by (i) mineralized biological material comprising a continuous layer of cartilaginous tissue having a biochemical composition and physiological organization substantially similar to the deep and contiguous calcified cartilage zones of articular cartilage found in vivo; and (ii) a mid and superficial non-mineralized layer adjacent to and continuous with the mineralized biological material, wherein the mid and superficial non-mineralized layer has a biochemical composition and physiological organization substantially similar to the mid and superficial zones of articular cartilage found in animals in vivo.
The step of (a) isolating chondrocytes from the deep zone of articular cartilage tissue is the step of providing a cartilage sample from a subject as called for in instant claim 1(a) and isolating chondrocytes from the cartilage sample in 1(b). Kandel’s step (b) of forming a layer of the chondrocytes on a substrate reads on the step in 1(c) of seeding the chondrocytes.
The step of (c)(i) curing the chondrocytes in growth media under suitable conditions so that the chondrocytes accumulate matrix and form cartilaginous tissue which contains components associated with cartilage mineralization; and culturing the cartilaginous tissue in the presence of a mineralizing agent to form a continuous layer of mineralized cartilaginous tissue having a biochemical composition and physiological organization substantially similar to the deep and contiguous calcified cartilage zones of articular cartilage found in animals in vivo is the seeding the deep zone chondrocytes, and seeding the middle zone chondrocytes and the seeding the superficial zone chondrocytes called for in instant claims 1(c), 1(d), 1(e). e
Kandal teaches that forming a continuous layer of mineralized cartilaginous tissue having a biochemical composition and physiological organization substantially similar to the deep and contiguous calcified cartilage zones of articular cartilage found in animals in vivo is mid and superficial layers substantially similar to the mid and superficial zones of articular cartilage.
Kandel teaches using articular cartilage as called for in instant claim 2. (See claims 1, 6 and 8).
Kandel teaches that the chondrocytes are seeded on the substrate at a cell density of about 1 x 105 to 8 x 106 cells/cm2. (See [0041]). The chondrocytes seeded on the coated or uncoated substrate are grown in suitable culture conditions. Examples of suitable culture media are known in the art such as Ham’s F12 and/or Dulbecco’s modified Eagle’s medium (DMEM). Preferably DMEM is used after 4-5 days in culture. The culture medium may contain serum, for example fetal bovine serum in a concentration range of about 2-20% and may further contain growth factors, and optionally ascorbic acid. The culture media is applied above and below the substrate. The cells may be cultured at 37˚C in a humidified atmosphere supplemented with CO2. A cofactor for lysyl oxidase to cross-linked collagen, for example copper sulfate, may be used to retain more collagen and provide thicker collagen. (See [0041]).
A cell density of about 1 x 105 to 8 x 106 cells/cm2 overlaps with the 1 x 104 to 5 x 104 cells/cm2 called for in instant claim 4.
Kandal does not teaches using a density gradient centrifugation to isolate the chondrocytes and does not teach culturing until reaching 90-100% cell confluence. Kandal also does not expressly teach using three layer human chondrocyte sheets. These deficiencies is made up for with the teachings of Min et al., Kang et al. and Nagatoshi et al.
Min et al. (Min) teaches a method for the fractionation of articular chondrocytes. (See Abstract). The method comprises isolating chondrocytes from articular cartilage and then fractionating the isolated chondrocytes by centrifugation in a Percoll density gradient that resulted in cell fractions in which chondrocytes from the deep layer of the articular cartilage were in a separate fraction that chondrocytes from the superficial layer of cartilage. The use of density gradient centrifugation to isolate the chondrocytes into superficial zone chondrocytes, middle zone chondrocytes and deep zone chondrocytes is called for in instant claim 1b. Min teaches that its method provides ready separation of articular chondrocytes and using Percoll density gradient centrifugation permits clear separation of chondrocytes and allows distinguishing of chondrocytes from the different layers of articular cartilage. (See Abstract).
Kang et al. (Kang) teaches equine amniotic fluid derived multipotent stem cells and to a production method therefor, and more specifically related to amniotic fluid derived multipotent stem cells and have the ability to differentiate into chondrocytes. (See Abstract and Kang claim 12).
Kang teaches culturing for a period of three weeks (See Example 4). Three weeks overlaps with the culturing time of for 1 to 3 weeks called for in instant claim 5. Kang teaches that the culturing medium can contain various additives. (See Example 4 ). Kang teaches incubation of 1 x 105 cells that are incubated until 90-100% confluency (See Example 4-3). This overlaps with the culturing until reaching 90-100% cell confluence called for in claim 1c, 1d and 1e. Kang teaches that its chondrocytes are very useful for treating tendon and muscular injuries. (See Abstract).
Nagatoshi et al. (Nagatoshi) teaches that three layer chondrocyte sheets are able to maintain the cartilaginous phenotype and can be attached to the sites of cartilage damage which acts as a barrier to protect the joints from catabolic factor.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention following the Kandel method of making a zonal layered chondrocyte composition by (a) isolating chondrocytes from the deep zone, middle zone and superficial zone of articular cartilage tissue using density gradient centrifugation as taught by Min in light of Min’s teaching that its method of using density gradient centrifugation allows for the clear separation of chondrocytes and allows distinguishing of chondrocytes from the different layers of articular cartilage and then (b) seeding the deep layer chondrocytes by forming a layer of the chondrocytes on a substrate with a cell density of about 1 x 105 to 8 x 106 cells/cm2 and culturing for a period of time of three weeks until reaching 90-100% as taught by Kang in order to have chondrocytes that are very useful for treating tendon and muscular injuries as taught by Kang.
It would be obvious for one of ordinary skill in the art before the effective filing date of the claimed invention following the Kandel method of making a zonal layered chondrocyte composition to, after seeding and culturing the deep layer chondrocytes, seed the middle layer chondrocytes by forming a layer of the middle chondrocytes on a substrate that is the deep layer chondrocyte layer (therefore seeding and culturing to form a layer on top of the deep chondrocyte layer) with a middle chondrocyte cell density of about 1 x 105 to 8 x 106 cells/cm2 and culturing for a period of time of three weeks until reaching 90-100% as taught by Kang in light of Kandel’s teaching that it is beneficial for the mineralized cartilaginous tissue to have a biochemical composition and physiological organization substantially similar to the cartilage zones of articular cartilage found in animals in vivo. The cartilage zones of articular cartilage found in animals in vivo have superficial zone chondrocytes on top of middle zone chondrocytes on top of deep zone chondrocytes.
It would be obvious for one of ordinary skill in the art before the effective filing date of the claimed invention following the Kandel method of making a zonal layered chondrocyte composition to, after seeding and culturing the middle layer chondrocytes, seed the superficial layer chondrocytes by seeding with a superficial chondrocyte cell density of about 1 x 105 to 8 x 106 cells/cm2 forming a layer of the superficial chondrocytes on a substrate that is the middle layer chondrocyte layer (therefore seeding and culturing the superficial chondrocytes to form a superficial chondrocyte layer on top of the middle chondrocyte layer) and culturing for a period of time of three weeks until reaching 90-100% as taught by Kang in light of Kandel’s teaching that it is beneficial for the mineralized cartilaginous tissue to have a biochemical composition and physiological organization substantially similar to the cartilage zones of articular cartilage found in animals in vivo.
There would have been a motivation to make a three layer chondrocyte sheet with the superficial chondrocyte layer on top of the middle chondrocyte layer which is in turn on top of the deep layer chondrocytes in light of the teachings of Nagatoshi that three layer chondrocyte sheets are known to be useful for treating cartilage damage and Kandel’s teaching that it is beneficial for the mineralized cartilaginous tissue to have a biochemical composition and physiological organization substantially similar to the cartilage zones of articular cartilage found in animals in vivo.
The step of 1(c)(i) of curing the chondrocytes in growth media under suitable conditions so that the chondrocytes accumulate matrix and form cartilaginous tissue which contains components associated with cartilage mineralization; and culturing the cartilaginous tissue in the presence of a mineralizing agent to form a continuous layer of mineralized cartilaginous tissue having a biochemical composition and physiological organization substantially similar to the deep and contiguous calcified cartilage zones of articular cartilage found in animals in vivo is the seeding the deep zone chondrocytes, and seeding the middle zone chondrocytes and the seeding the superficial zone chondrocytes called for in instant claims 1(c), 1(d), 1(e). e
Claims 6 is rejected under 35 U.S.C. 103 as being unpatentable over Kandel US 2002/0111695 (8/15/2002) in view of Min et al. Characterization of subpopulated articular chondrocytes separated by Percoll density gradient, In Vitro Cellular & Developmental Biology-Animal 38.1 (2002): 35-40, Kang et al. WO 2012/033352 (3/15/2012) and Nagatoshi et al. Bioengineered chondrocyte sheets may be potentially useful for the treatment of partial thickness defects of articular cartilage, Biochemical and Biophysical Research Communications, Volume 349, Issue 2, 20 October 2006, pp 723-731 as applied to claims 1-5 and further in view of Chen et al. US 2008/0077251 (3/27/2008).
The teachings of Kandel in view of Min, Kang and Nagatoshi are described supra. Kandel in view of Min, Kang and Nagatoshi does not teach suramin in the culturing medium. This deficiency is made up for with the teachings of Chen et al.
Chen et al. (Chen) teaches that its invention is directed to a cleaned, disinfected and derivatized cartilage graft. (See Abstract). Chen teaches that the extracting solution comprises sodium suramin which is a detergent which makes the cartilage acellular (devitalized) and is a useful additive in culturing media. (See [0069]). Suramin is called for in instant claim 6.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention following the Kandel in view of Min, Kang and Nagatoshi method of making a zonal layered chondrocyte composition by (a) isolating chondrocytes from the deep zone of articular cartilage tissue; (b) forming a layer of the chondrocytes on a substrate with a cell density of about 1 x 105 to 8 x 106 cells/cm2 and culturing for a period of time of three weeks until reaching 90-100% and repeating this process on top of the deep chondrocyte layer with the middle chondrocytes to form a middle chondrocyte layer and then repeating this process with superficial chondrocytes on top of the middle chondrocyte layer to form a superficial chondrocyte layer to use sodium suramin in the culturing medium in light of Chen’s teaching that sodium suramin makes the cartilage acellular and is a useful additive in culturing medium.
Conclusion
No claims are allowed.
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SARAH CHICKOS
Examiner
Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619