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 .
Claim Status
Claims 1-6 are currently pending in this application.
Claim Objections
Claims 2-3 are objected to because of the following informalities:
Claim 2 recites the term “mol%”, which would be clearer if first defined before used as an abbreviation, such as mole percent (mol%). Appropriate correction is requested for improved clarity.
Claim 3 recites the phrase “n represents a number of 1 to 50”, which would be clearer if expressed as “n represents an integer from 1 to 50.” Appropriate correction is requested for improved clarity.
Claim Interpretation
In claim 1, a “cartilage tissue” is interpreted as requiring at least two cell types, e.g., a chondrocyte and chondroblast or chondrocyte progenitor cell.
In claim 1, the “plurality of spots” is interpreted as being part of or on a surface of the substrate. Furthermore, in the claims, it is implied that the cartilage progenitor cells are contacting the plurality of spots during the cell culturing and aggregate culturing steps.
In claim 1, the “recurring unit” based on the monomer represented by formula (I) is interpreted as always being identical units, including at any polymer chain terminal. Similarly, the “recurring unit” based on the monomer represented by formula (II) is interpreted as always being identical units, including at any polymer chain terminal.
Claim 1 is interpreted as having an implied step of deriving human cartilage progenitor cells from human pluripotent stem cells prior to the seeding step.
In claim 1, the seeding step is interpreted merely as requiring contacting the substrate with the cells in such a way the cells remain near the substrate in an aqueous suspension as cell adhesion to the substrate may not occur or be minimal in strength or duration.
In claim 1, the step of culturing the cells or culturing the aggregates is interpreted as not necessarily comprising a cell culture medium, such as incubating the cells or aggregates in vivo or in an implant.
In claim 1, the property of the substrate having an ability to suppress adhesion of cells is interpreted as meaning any cell type, i.e., encompassing cells that are human cartilage progenitor cells or pluripotent stem cells.
Claim 3 is interpreted as requiring the “structural unit” to be present at least once, i.e. not necessarily recurring or reoccurring in the copolymer.
Claim 4 omits any requisite structural cooperative relationship(s) between the coating film, the part of a surface, the copolymer of claim 1, and the cells or aggregates during each culturing step of claim 1, such as whether the cells/aggregates are required to be in contact with the coating film or no more than the part of the surface thereof, whether the coating film is required suppress adhesion of cells comparably to the copolymer, whether the coating film between the cells and the copolymer affects the copolymer’s ability to suppress adhesion of cells, whether copolymer P is required to suppress adhesion of cells, and whether there is a requisite relationship between the cells/aggregates and the coated part of the surface during the culturing steps in order to produce the cartilage tissue. Thus, claim 4 is interpreted to require that at least the plurality of spots be coated with a film comprising the copolymer (P).
In claim 5, the culture medium containing agar is interpreted to be limited to a simple aqueous solution, i.e., the amount of agar is below the threshold of forming a complex hydrogel or solid.
Claim Rejections - 35 USC § 112(a), Written Description
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 are 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.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
In the instant case, the claims are directed to a method comprising a substrate comprising a copolymer comprising recurring units “derived” from two different monomers represented respectively by formula (I) and (II). However neither the claims nor the instant specification provides any standard for measuring a requisite minimum degree constituting “derived” as used in the claims and thus a person of ordinary skill in the art could read the claim wherein the recurring unit derived from a monomer represented by formula (i) or formula (II) encompasses unlimited deviations from the monomer, e.g., having alterations to reactive side chains and loss of dipole moments. Thus, claim 1 encompasses a vast variety of recurring units, which include chemical alterations, derivatizing reactions, etc. Moreover, no limitation in dependent claims 2-6 provides any restriction on the scope of the derived recurring units.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any clear description of a representative number of species for the broad genus of possible recurring units of claim 1.
The instant specification lacks a written description for a sufficient number of representative species for such broad reoccurring units, instead merely describing examples of monomers. The specification provides first monomer examples such as 2-N,N-dimethylaminoethyl methacrylate and N,N-dimethyl-aminomethyl methacrylate and second monomer examples as acrylic acid and methacrylic acid. There is no description of any derivative of such monomers. Due to unpredictability in the art regarding the ability of such broad genus of copolymers having the ability to suppress adhesion of cells, one skilled in the relevant art would not find Applicant was in possession of the full genus. The skilled artisan simply cannot envision the variety of possible copolymers and their properties when “derived” has no apparent limit to the retention of structure and/or function with regard to the monomer.
35 USC § 112(a) – Scope of Enablement
Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the claims are enabled for wherein the copolymer comprises recurring units of monomers represented by formula (I) and (II), the specification does not enable any person skilled in the art, to which it pertains or with which it is most nearly connected to, make any copolymer containing a recurring unit “derived” from a monomer represented by either formula (I) or (II).
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
In claim 1, the copolymer is broadly directed to ones containing recurring units derived from a monomer represented by formula (I) and a monomer represented by formula (II). Further, there is no limitation in dependent claims 2-6 which provides any restriction on the scope of said derived recurring units.
Although the prior art teaches methods of making polymers and copolymers via monomers using various polymerization reactions, e.g., using a reactive crosslinker, the prior art does not teach how to reliably provide the property of the “ability to suppress adhesion of cells” for a given set of monomer starting materials in such reactions from such a wide genus of any derivative thereof encompassing a vast variety of recurring units, which include chemical alterations, derivatizing reactions, changes in atoms and their bonds, etc.
Therefore extensive experimentation would be required to bridge these gaps to determine how to use all the species of recurring units to produce copolymers having the ability to suppress adhesion of cells. The examples provided, while extrapolatable to other highly similar chemical structures, without guidance or working examples in the instant application regarding untested species one of skill in the art would be unable to use the claimed method across the full scope recurring units. Thus, undue and unreasonable experimentation is required to determine how to make copolymers containing recurring units derived from monomers represented by formula (I) and formula (II), when the genus of derived species is vast and the resulting copolymer must have the function of suppressing adhesion of cells.
In addition, claim 1 recites a copolymer required to comprise two recurring units but nothing more despite being open-ended in claim form. As a most parsimonious case, the copolymer consists merely of the two recurring identical units, which is incompatible for when the polymer or polymer network has individual free ends and the end unit chemical differs from the recurring unit, e.g., at a polymer terminal as a result of a polymerization reaction using only one or both monomers. Thus extensive experimentation would be required to determine how to polymerize the recurring units such that the end units are identical to the interior units to form this particular arrangement. Such undue and unreasonable experimentation is required for such species encompassed by the instant claims.
Claim Rejections - 35 USC § 112(b)
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 1-6 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 pre-AIA the applicant regards as the invention.
The claims are interpreted as provided in a previous section.
Claim 1 recites the phrase “on a substrate having an ability to suppress adhesion of cells,” which is ambiguous, incoherent, or unclear as to whether (1) the second use of the term “substrate” has antecedent in the first occurrence of “substrate” and (2) what is on said substrate, e.g., are the plurality of spots on the first or second substrate. Claims 2-6 are included in the rejection for depending from indefinite claim 1. Furthermore, claim 1 recites a third use of the term “substrate” in the a step of seeding cells on “the substrate”, suggesting an ambiguous antecedent in one more or the substrate terms used previously within claim 1. In addition, claim 4 recites “the substrate having an ability to suppress adhesion of cells” with an ambiguous antecedent in claim 1 as explained above.
Claim 1 and 2 each recites the relative term “derived” with regard to two monomers; however, the specification does not provide some standard for measuring that degree “derived” and thus a person of ordinary skill in the art would not understand the metes and bounds of “derived” in the claim. Thus, the term is ambiguous and unclear as to what structure(s) of the monomer must be maintained and what may vary during the derivation, e.g., a polymerization reaction. Claims 3-6 are included in the rejection for depending from indefinite claim 1.
Claim 4 recites the substrate “has a coating film containing a copolymer (P)” and ends with “at least a part of a surface thereof”, which is ambiguous, incoherent, or unclear as to the relationship, if any, between (1) the copolymer (“P0”) (comprising recurring units derived from monomers represented by formulae (I) and (II)) and (2) copolymer (P) (comprising recurring units represented by formulae (a) and (b)), such as whether copolymer P0 must be created first and then a surface thereof is coated with copolymer P or if copolymer P need be in direct contact with copolymer P0, and as to the permissibility of presence of an unrelated intermediate layer between the two copolymers. For example, does the claim encompass wherein all surfaces of copolymer P0 are covered with said coating?
In claim 4, it is unclear what the “surface thereof” is referring to, such as any surface of the substrate or instead a certain subpart of the substrate like its plurality of spots comprising said first copolymer.
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 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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Tsumaki (US20180251732A1) in view of Lin (Lin et al. ACS Macro Letters 5: 1191-5 (2016)) and as evidenced by Peterson (Peterson et al., Dev Dyn 233: 811-21 (2005)).
The claims are interpreted as provided in a previous section.
Regarding claim 1, Tsumaki teaches a method of differentiating human pluripotent stem cells into chondrogenic lineages using induction agents in tissue culture to produce cartilage progenitor cells in the form of cultured human chondrocyte progenitor cells and chondrocytes which eventually form cartilage tissues in vitro (Abstract; [0054]; Examples 1-3 and 5; FIG. 4). Tsumaki teaches during this method the chondrocyte progenitor cells form cell aggregate clusters of chondrocytes (FIG. 1-2), termed iPSC cell-derived “cartilaginous particles” having diameters of no greater than 300 µm. Tsumaki teaches culturing these cartilage cell aggregates both in suspension and adhered to plastic tissue culture dishes, such as by seeding the cells/aggregates onto a substrate (e.g., an Iwaki or Sumitomo dish) (Examples 1-3). Tsumaki teaches transplanting these in vitro generated cartilage tissues into a subject (Example 4, FIG. 3)
Tsumaki does not teach wherein the substrate has a plurality of spots comprising a copolymer as recited in claim 1 or a specific step of seeding human cartilage progenitor cells which are PRRX1+ onto the plurality of copolymer spots of the substrate.
However Lin teaches a method of producing an artificial cartilage-like substrate (cross-linked hydrogel) for use in joint implants, the method comprising making a copolymer by polymerizing [2-(methacryloyloxy)ethyl] trimethylammonium, which is represented by formula (I), with acrylamide, which is represented by formula (II). Lin does not expressly teach this substrate has the ability to suppress adhesion of cells; however, this characteristic is inherent to the copolymer as positively recited in the claim (see MPEP 2112). Lin teaches this copolymer has both high mechanical properties and ultralow friction performance related to high load bearing, friction and wear of a human joint and thus provides an accurate mimic of an articular cartilage tissue structure of synovial joints (Abstract; Fig. 1e, 2-3; pg. 1194, right col., last para.).
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to use the copolymer of Lin as a substrate in the method of Tsumaki when producing an artificial cartilage for transplantation, e.g., for use at a synovial joint. One of ordinary skill in the art would be motivated by Lin to incorporate the articular cartilage tissue mimetic copolymer with the developing cartilage tissue of Tsumaki to produce an improved cartilage implant. It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to incorporate the copolymer of Lin into the developing cartilage tissue by combining the cartilage progenitor cells with the copolymer while the cells differentiate to form cartilage tissues in conditions taught by Tsumaki in connected organization with the copolymer mimetic. Further, it would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to use the copolymer of Lin in the form of spots which only need accommodate a few cells or cell aggregates of no more than 300 µm as taught by Tsumaki to produce an array of artificial cartilage tissue aggregates. One of ordinary skill in the art would be motivated to produce larger amounts of artificial cartilage tissue than obtainable from a single developing cartilaginous particle, and thus would simultaneously produce a series of cartilaginous particles, such as for amassing or grouping together into larger implantable structures, such as by a method taught by Tsumaki (Example 5; FIG. 4).
While Tsumaki and Lin do not expressly teach wherein the cartilage progenitor cells are PRRX1+ (Prx1), as evidenced by Peterson, cartilage progenitor cells in culture (prechondrocytes and during chondrogenesis) are inherently PRRX1+ (Fig. 1-2; pg. 813, mid. col., last para., to right col.). Thus, the in the method of Tsumaki, the stem cells differentiating into chondrogenic lineages inherently comprise PRRX1+ cartilage progenitor cells that would be present in the cells seeded on the substrate for culturing.
Thus, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary.
Claims 1 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Tsumaki in view of Lin and Peterson as applied above, and further in view of Gong (Gong et al., J Biomed Mater Res B Appl Biomater 82: 192-204 (2007)) as evidenced by Suzuki (Suzuki et al., Food Science and Technology Research 7: 280-4 (2001)).
Regarding claims 5-6, the combination of Tsumaki, Lin and Peterson does not teach wherein the method comprises a culture medium containing agar, such as at 1% (w/v) with an average molecular weight between 10,000-60,000.
However Gong teaches scaffolds comprising agar for use in cartilage tissue engineering and that when culturing chondrocytes with less than 2% (w/v) agar increases chondrocyte viability and that agar can function to promote chondrogenesis, e.g., specifically at 1% (w/v) (pg. 194, right col., last para.; Fig. 4 and 7; Table I; Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing to use 1% agar (e.g., MW 20,000) or less in the artificial cartilage production method of Tsumaki when culturing the chondrocyte progenitor cells (e.g., in aggregates), chondrocytes and/or later stage cartilage tissues in vitro. One of ordinary skill in the art would be motivated by Gong teaching agar promotes chondrogenesis and improves chondrocyte viability at such low agarose concentrations.
Although Gong does not expressly teach the average molecule weight of the agar is in the range of 10,000-60,000, Gong teaches sourcing the agar from Bio Basic (pg. 193, right col., 1st para.; pg. 194, left col., 2nd para.). As evidenced by Suzuki, the average molecule weight of agar can vary from about 10,000 to over 60,000 (Fig. 2). Thus, it would have been prima facie obvious to one of ordinary skill in the art to use a 1% agar concentration wherein the average molecular weight of agar polymer components is inherently between 10,000-60,000 as evidenced by Suzuki.
Thus, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638