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 .
Priority
The instant claims herein are examined utilizing the accepted effective filing date of 1/19/2017 for the basis of any prior art rejections.
Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 recites “iPSCs”, “EBs” and “OG”. Applicant is requested to spell out the acronyms followed by the abbreviations in parentheses.
Appropriate correction is required.
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 1-10 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.
Claims 1, 2, 5, and 10 recite the limitation "outgrowth cells". The specification does not clearly define what an “outgrowth cell” is. Where applicant acts as his or her own lexicographer to specifically define a term of a claim, the written description must clearly define the claim term and set forth the definition so as to put one reasonably skilled in the art on notice of applicant’s claim term. Thus, the claims are indefinite. For purposes of compact prosecution, the examiner is interpreting the outgrowth cells to be a cell resultant from the culturing step as claimed (i.e., cultured embryoid bodies results in outgrowth cells absent evidence to the contrary).
Claims 1 and 2 both recite “gelatin-coated medium.” It is unclear how a liquid medium could be coated, thus, the claim is indefinite.
Claim 3 recites the limitation "containing the att attachment sequence of bacteriophage lambda". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of any att attachment sequence in the claim or in claim 1. Thus, the claim is indefinite.
Claim 4 recites the limitation "containing the att attachment sequence of bacteriophage lambda". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of any att attachment sequence in the claim or in claim 1. Thus, the claim is indefinite.
Claim 8 recites the limitation "containing the att attachment sequence of bacteriophage lambda". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of any att attachment sequence in the claim or in claim 2. Thus, the claim is indefinite.
Claim 9 recites the limitation "containing the att attachment sequence of bacteriophage lambda". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of any att attachment sequence in the claim or in claim 2. Thus, the claim is indefinite.
Please note that claims 3-10 are also included in this rejection for their dependency on indefinite claims.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to rejections made based on said interpretations. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 101 – Product of Nature
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 6-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (natural product) without significantly more. This judicial exception is not integrated into a practical application and does not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below:
Claim interpretation: Under the broadest reasonable interpretation (BRI), the terms of the claims are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art (see MPEP 2111). The specification indicates on page 2 that chondrocytes that are cells specially differentiated so as to be distributed between cartilage matrices and chondrocytes serve to create and maintain articular cartilage. Page 12 of the specification states that when chondrogenic pellet of the invention is transplanted into cartilage, cartilage regeneration ca be effectively exhibited (i.e., has same function of creating and maintaining cartilage). As such, under BRI, the claims encompass naturally occurring chondrocyte. The examiner notes that instant claim 6 and 7 recites “produced by the method of claim 1” and “produced by the method of claim 2”, respectively. However, as per MPEP 2113, 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.
Step 1 (Statutory Category): This part of the eligibility analysis evaluates whether the claim falls within any statutory category. Here, the claims recite “A chondrocyte produced by the method of claim 1” and “A chondrocyte produced by the method of claim 2”. This is a composition of matter; therefore, the claims fall within a statutory category. [Step 1: YES]
Step 2A (Judicial Exceptions), Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. A claim “recites” a judicial exception when the exception is “set forth” or “described” in the claim (see MPEP 2106.04(II)). Because the claims recite nature-based product limitations, the markedly different characteristics analysis is used to determine if the nature-based product limitations are a product of nature exception (see MPEP 2106.04(c)(I)). This analysis is performed by comparing the nature-based product limitations in the claims to its naturally occurring counterparts to determine if it has markedly different characteristics (see MPEP 2106.04(c)(II).
The appropriate natural counterpart to the claimed chondrocyte is a chondrocyte as found in its natural state. The second step in the analysis requires identifying appropriate characteristics to compare. In this case, the appropriate characteristics pertain to expressing type 2 collagen, as well as creating and maintaining cartilage.
Otero et al (Methods Mol Biol. 2012; 806:301-36) describes characterization of articular chondrocytes (title). The reference discusses that mature articular chondrocyte embedded in the cartilage matrix is a resting cell with no detectable mitotic activity and a very low synthetic activity (1). The markers of mature articular chondrocytes are type II collagen (COL2A1), other cartilage-specific collagens IX (COL9) and XI (COL11), and the large aggregating proteoglycan aggrecan (ACAN) (Table 1). Chondrocytes also synthesize a number of small proteoglycans such as biglycan and decorin and other specific and nonspecific matrix proteins both in vivo and in vitro. As the single cellular constituent of adult articular cartilage, chondrocytes are responsible for maintaining the cartilage matrix in a low turnover state of equilibrium.
Thus, the embodiments of the claims encompass naturally occurring chondrocytes. Thus, the claims recite a judicial exception, a natural product. [Step 2A, Prong 1: YES]
Therefore, the analysis proceeds to Step 2A Prong 2.
Step 2A (Judicial Exceptions), Prong 2: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claims beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claims as a whole integrate the exception into a practical application. The recited chondrocyte is a product of nature, and the claims do not recite additional elements that impose a practical use or application of the claimed natural products. In this regard, the claims fail to recite additional elements that integrate the judicial exception natural products into a practical application. [Step 2A, Prong 2: NO]
Step 2B (Significantly More): This part of the eligibility analysis evaluates whether the claims as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05).
Again, the claims at issue do not recite any additional element or combination of elements that add an inventive concept to the claim. As such, none of these limitations impose a practical use or application of the claimed natural products as stated in Step 2A2, and thus do not add significantly more to the exception. [Step 2B: NO]
The claims fail to recite additional elements that are sufficient to amount to significantly more than the judicial exception. Therefore, the claims do not qualify as eligible subject matter under 35 USC 101.
Examiner’s Note
Claim 1 and 2 recite “iv) inducing differentiation of the OG cells transduced in step iii) into chondrocytes; and v) obtaining the chondrocytes produced by differentiation induction in step iv),” and “so that the OG cells are induced to differentiate into chondrocytes; and vi) obtaining the chondrocytes produced by differentiation induction in step v).” respectively. The examiner is interpreting that the induction and obtaining steps are intended results of the active transduction and culturing steps (i.e., flow from the active steps) as one of ordinary skill would understand that contacting embryoid bodies with the chondrogenesis factor(s) BMP-2 and/or TGF-B3 induces chondrocyte formation.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 6-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Otero et al (Methods Mol Biol. 2012; 806:301-36).
Otero describes characterization of articular chondrocytes (title). The reference discusses that mature articular chondrocyte embedded in the cartilage matrix is a resting cell with no detectable mitotic activity and a very low synthetic activity (1). The markers of mature articular chondrocytes are type II collagen (COL2A1), other cartilage-specific collagens IX (COL9) and XI (COL11), and the large aggregating proteoglycan aggrecan (ACAN) (Table 1). Chondrocytes also synthesize a number of small proteoglycans such as biglycan and decorin and other specific and nonspecific matrix proteins both in vivo and in vitro. As the single cellular constituent of adult articular cartilage, chondrocytes are responsible for maintaining the cartilage matrix in a low turnover state of equilibrium. As per MPEP 2113, 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) (citations omitted)
Thus, absent evidence to the contrary, Tsumaki anticipates instant claim 6 and instant claim 7.
Claim(s) 6-7 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Tsumaki (US20160251623 A1, 10/31/2014; published 9/01/2016).
Tsumaki teaches an induced chondrocyte from a pluripotent stem cell, the chondrocyte having at least 100-fold increase in COL2A1 gene expression compared with that in the pluripotent stem cell, at least 250-fold increase in SOX9 gene expression compared with that in the pluripotent stem cell, and no foreign gene introduced therein (except for foreign genes used for iPS cell production) (see claim 15 of Tsumaki). As per MPEP 2113, 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) (citations omitted)
Thus, absent evidence to the contrary, Tsumaki anticipates instant claim 6 and instant claim 7.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to w0hich 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.
Claim(s) 1-2, 5-7, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Athanasiou et al (US20090136559 A1, 7/8/2005; published 5/28/2009) in view of Tsumaki (US20160251623 A1, 10/31/2014; published 9/01/2016).
Athanasiou teaches chondrocyte differentiation from stem cells (abstract). It teaches a method for inducing differentiation of human embryonic stem cells into chondrocytes comprising aggregating undifferentiated human embryonic stem cells to form embryoid bodies; and culturing the embryoid bodies, or cells dissociated from the embryoid bodies, in a culture medium, wherein the culture medium comprises a growth factor that induces chondrogenic differentiation of the embryoid bodies, or of the cells (see claim 1 of Athanasiou). It teaches that the growth factor is chosen from one or more of TGF-β1, IGF-I, TGF-β3, BMP-2, and BMP-4 (see claim 9 of Athanasiou). The undifferentiated cells can be derived from induced pluripotent stem cells (see para 0036). The EBs were cultured on agarose coated plates (see para 0079). This reads on “a method for producing chondrocytes obtained by differentiation induction from stem cells comprising culturing induced pluripotent stem cells to generate embryoid bodies, culturing the EBs generated in step (i) in a gelatin-coated medium, to obtain outgrowth cells . . . either or both of. . . . BMP-2 . . . TGF-β3” as in instant claim 1 in-part and “culturing induced pluripotent stem cells to generate embryoid bodies, culturing the EBs generated in step (i) in a gelatin-coated medium, to obtain outgrowth cells . . . BMP-2 . . . TGF-β3” as in instant claim 2 in-part.
The reference differs from the instant invention in that it does not teach that the cells are transduced with a vector containing BMP-2 and/or TGF-β3 (instant claim 1 in-part and instant claim 2 in-part).
Tsumaki teaches a novel chondrocyte induction method from pluripotent stem cells utilizing BMP-2 and TGF-β (see abstract and claim 1 of Tsumaki). Of note, the reference teaches that the reprogramming vectors can be introduced into the cells via viral vectors such as retroviral, lentiviral, adenoviral, and adeno-associated vectors (see para 42 of Tsumaki). When the culturing step is performed to produce the mature chondrocytes, the medium used is a basal medium for animal cell culture, such as EMEM, DMEM, Ham’s F12, etc. (see para 80-81). The medium can contain serum or no serum and may contain one or more serum substitutes such as albumin, transferrin, KnockOut Serum Replacement (KSR) (serum substitute for FBS in ES cell culture), N2 supplement, B27 supplement, fatty acids, insulin, collagen progenitors, trace elements, 2-mercaptoethanol, and 3′-thiolglycerol, as well as one or more substances such as lipids, amino acids, L-glutamine, GlutaMAX, nonessential amino acids (NEAAs), vitamins, growth factors, low-molecular-weight compounds, antibiotics, antioxidants, pyruvic acid, buffering agents, and inorganic salt (para 81). The culture period for this step may be 20 days or more and is preferably 28 days or more (see para 82). The reference is silent to the use of recombinant growth factors in this culture step, reading on “wherein the step of inducing differentiation of the OG cells into chondrocytes is performed by culturing the OG cells in a medium containing no recombinant growth factor for 3 to 30 days” as in instant claim 5 and “wherein the step of inducing differentiation of the OG cells into chondrocytes is performed by culturing the OG cells in a medium containing no recombinant growth factor for 3 to 30 days” as in instant claim 10. The resulting induced chondrocytes can have increased expression of COL2A1 and SOX9 50-fold or more (see para 85-86) (“a chondrocyte produced by the method of claim 1” as in instant claim 6; “a chondrocyte produced by the method of claim 2” as in instant claim 7). The resulting chondrocytes are high-quality, and can be successfully grafted into an animal model (para 12). This shows that pluripotent stem cells can be successfully transformed into chondrocytes using vector transduction with BMP-2 and TGF-β3.
Neither Athanasiou nor Tsumaki explicitly tach that the BMP-2 and TGF-β transduction occurs in separate steps and the resulting transduced cells are mixed together to form chondrocytes as in instant claim 2 in-part. However, given that both references individually teach that BMP-2 and TGF-β are responsible for induction of chondrocytes, it is prima facie obvious to combine two methods, each of which is taught by the prior art to be useful for the same purpose, in order to form a third method to be used for the very same purpose (see MPEP 2144.06) for the advantageous purpose of forming chondrocytes. [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (see MPEP 2144.06).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to induce chondrocytes from induced pluripotent stem cells as taught by Athanasiou, where BMP-2 and TGF-β is introduced via vector as taught by Tsumaki, to arrive at the instantly claimed invention. Tsumaki shows that chondrocytes can successfully be produced from induced pluripotent stem cells via vector transduction of reprogramming factors BMP-2 and TGF-β. One of ordinary skill would have been motivated to simply substitute one known element [medium containing reprogramming factors BMP-2 and TGF-β] for another [vectors containing BMP-2 and TGF-β] to obtain the predictable result of advantageously producing induced chondrocytes having increased expression of COL2A1 and SOX9 50-fold or more as taught by the prior art.
Examiner’s Note
SEQ ID NO: 1 and 2, required by instant claims 3-4 and 8-9, respectively, are free of prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 7-3.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632