Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 29 May 2025 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 29 May 2025.
CLAIMS UNDER EXAMINATION
Claims 22-31 have been examined on their merits.
PRIORITY
The Applicant claims priority to Provisional Application 62/639,442 (06 March 2018),
62/700,210 (18 July 2018), 62/730,454 (12 September 2018) and 62/733,526 (09 September 2018).
Claim 22 has been amended to recite iPSC-derived MSCs obtained “under conditions to activate the Wnt signaling pathway” and “characterized by expression of CD73, CD90, CD105, CD34 and CD45 surface markers”. Provisional Applications 62/639,442 (06 March 2018), 62/700,210 (18 July 2018) do not provide support for the recited surface markers. None of the Provisional Applications provide support for conditions to activate the Wnt signaling pathway. The Non Provisional Application filed on 04 September 2020 does not provide support for conditions to activate the Wnt signaling pathway. The earliest priority is the claims filed on 29 May 2025.
WITHDRAWN REJECTIONS
The arguments made in the response filed on 25 October 2024 are acknowledged. The previous grounds of rejection have been withdrawn due to claim amendment.
NEW REJECTIONS
New grounds of rejection have been necessitated by claim amendment.
Claim Rejections - 35 USC § 112
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 22-31 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 claims contain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 22 has been amended to recite iPSC-derived MSCs are “characterized by expression of CD73, CD90, CD105, CD34, and CD45 surface markers”. In the response filed on 29 May 2025, the Applicant states support for the amendments is found at [0235], [0255] and [0257]. The Applicant states the claims recite the iPSC-derived MSCs are CD73+/CD90+/CD105+/CD34+/CD45+.
Examiner notes [0235] discloses a process for differentiating MSCs to produce chondrocytes. It does not disclose iPSCs derived MSCs obtained by differentiating single-cell iPSCs under conditions to active the Wnt signaling pathway. It does not disclose MSCs that are positive for the surface markers recited in claim 22.
Examiner notes [0255] discloses a process for differentiation of iPSCs into MSCs. It does not disclose iPSCs derived MSCs obtained by differentiating single-cell iPSCs under conditions to active the Wnt signaling pathway. It does not disclose MSCs that are positive for the surface markers recited in claim 22.
Examiner notes “Wnt” or “Wnt signaling pathway” do not appear in a text search of the specification. This is new matter.
The specification filed on 04 September 2020 discloses the following:
[0256] The expansion medium was replenished every 3-4 days. Cells were passaged upon subconfluency, at a 1:3 split ratio. The second passage (P2) was used for the tri-lineage differentiation evaluation and flow cytometry analysis.
[0257] Flow cytometry markers included the following surface markers: CD73, CD90, CD105, CD34 and CD45
While the specification discloses the “flow cytometry makers” used for analysis, it does not disclose MSCs that are positive for the surface markers recited in claim 22.
This is new matter.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 22-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 22 has been amended to recite “characterized by expression of CD73, CD90, CD105, CD34 and CD45” and “characterized by” expression aggrecan and/or collagen II. The specification does not define the term “characterized”. It is unclear if the claim means the claim means the cells are positive for these makers, or if the claim is referring to the process by which the cells properties are measured. The metes and bounds of the claim are unclear. All dependent claims are included in this rejection. Appropriate correction is required. In the interest of compact prosecution, the claims have been rejected under 35 USC 112a.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 30-31 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 30 recites the composition comprises iPSC-derived MSCs. The claim is not further limiting because the base claim has been amended to require iPSC-derived MSCs. Claim 31 is included in this rejection because it depends from claim 30.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
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.
Claims 22-31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more as evidenced by Fellows et al. (previously cited; Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for cartilage Repair. Front Genet. 2016 Dec 20;7:213), Xia et al. (previously cited; Altered function in cartilage derived mesenchymal stem cell leads to OA-related cartilage erosion. Am J Transl Res. 2016 Feb 15;8(2):433–446) and Mafi et al. (cited below).
Question 1: Are the claims directed to a process, machine manufacture or composition of matter? Yes, claim 22 is directed to a composition of matter.
Question 2A: Are the claims directed to a product of nature, a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)?
Prong 1. Yes, claim 22 is directed to a nature-based product limitation. The limitation in the claim that sets forth a nature based product is: Claim 22 has been amended to recite a composition comprising iPSC-derived MSCs and iPSC-derived chondrocytes.
As evidenced by Fellows et al., mesenchymal stem cells can be derived from multiple tissues, including adipose tissue, bone marrow, cartilage, periosteum, muscle, articular cartilage and synovial membranes (see Abstract; see page 2, left column, last sentence of first full paragraph). As evidenced by Xia et al., mesenchymal stem cells can be derived from cartilage (Abstract). As evidenced by Xia, chondrocytes can be isolated from cartilage (see text of Figure 1). Said cells are obtained from male and female patients at a hospital (see page 435, right column, “Sample Collection”). Therefore the cells are human. The closest naturally occurring counterpart to the claimed composition is human cartilage.
The nature based product lacks markedly different characteristics (and thus is a product of nature exception) because:
When the composition is compared to its counterpart, it does not have different chemical characteristics. Claim 1 recites each of the claimed cell types are derived from an induced pluripotent stem cell. The specification does not disclose any differences between chondrocytes and MSCs derived from iPSCs and naturally occurring chondrocytes and MSCs derived from human cartilage. The instant specification refers to the claimed chondrocytes as “mature chondrocytes” ([0110]). The instant specification discloses naturally occurring chondrocytes produce cartilage [0003]. Therefore the claimed chondrocytes have the same characteristics as their naturally occurring counterparts. While the specification discloses the claimed iPSCs can be distinguished from bone-marrow derived MSCs by expression of CXCR4, CXCR7, CCL5 (RANTES), IDO1, A2M, EGFL6, BMP2, BMP4, BMPR1B, IGF2, CILP2, COL2A1 genes ([0025]), it does not disclose any differences between the claimed MSCs and those derived from natural human cartilage. As evidenced by Mafi et al. (cited below), human MSCs are most commonly positive markers are CD105, CD90, and CD73, and negative for CD34, and CD45. The specification does not distinguish the claimed MSCs from naturally occurring human MSCs.
Prong Two: Do the claims recite additional elements that integrate the judicial exception into a practical application? No. The claims are directed to a product (i.e. a composition) and not a method of administration to a subject.
Question 2B: Do the claims recite any additional elements that amount to significantly more than the judicial exception?
Are there any additional elements recited in the claim beyond the exception identified above?
Yes.
(b) Do the additional elements, taken individually and as a combination result in significantly more? No.
Regarding claim 22: The claim has been amended to recite 1) the MSCs are obtained by differentiation single cell iPSCs under conditions to activate the Wnt signaling and 2) the chondrocytes are obtained by differentiating iPSC-derived MSCs under chondrogenic conditions. These are product by process limitations that do not distinguish the claimed MSCs and chondrocytes from their naturally occurring counterpart. The instant specification discloses HLA typing is used to determine the HLA type of an individual ([0171 of PG Pub). This is a process by process limitation that does not impart a markedly different characteristic that distinguishes the claimed MSCs and chondrocytes from those present in natural human cartilage. While the claim recites the composition is allogeneic, this does not impart a chemical limitation that distinguishes the claimed composition from one found in a human.
Regarding claims 23-24: The limitations are directed to how the claimed cells are administered. The limitations do not result in something markedly different than the claimed cells.
Regarding claims 25-26: The instant specification indicates cells are frozen for storage ([0198] [0201] PG Pub) and thawed for later use (Example 2). The instant specification does not indicate freezing and thawing cells produces a markedly different characteristic in any of the claimed cells.
Regarding claims 27-29: The claims recite the composition is stored or retrieved from an indexed biorepository. The limitations are directed to storage. The claims are directed to a product. Limitations directed to where the cells are stored do not produce something markedly different than the claimed judicial exceptions.
Claim 30 further limits claim 22. As set forth above, the specification does not distinguish the claimed MSC from a naturally occurring cartilage MSC.
Claim 31 recites the iPSC-derived MSCs comprise transcripts from one or more of the claimed genes. The specification does not disclose any data that distinguishes the claimed MSCs from those present in natural human cartilage.
Therefore, claims 22-31 are not eligible subject matter under 35 USC 101.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 29 May 2025 are acknowledged. The Applicant argues at least in view of the limitations “an allogeneic composition for treating a subject thereof, the iPSCs are allogenic and have been characterized by HLA typing to be compatible”, the claim recites a personalized cell composition for treating a subject in need thereof. The Applicant argues the claim requires i) iPSC-derived MSCs produced under Wnt-activation and defined by the surface-maker profile CD73+/CD90+/CD105+/CD34+/CD45+ (ii) iPSC-derived chondrocytes that must
first be obtained from those MSCs and exhibit at least one cartilage-specific marker (Aggrecan or Collagen II) and (iii) HLA compatibility. Therefore the Applicant argues the claimed cells do noy have the same chemical characteristics as their naturally occurring counterparts.
In response: The claims do not recite cells that are CD73+/CD90+/CD105+/CD34+/CD45+. The claims only recited they are characterized by expression of these markers. The specification does not define “characterized” as meaning the cells are positive for the markers recited in claim 22. Therefore the claim is interpreted to mean the claims are analyzed for expression of these markers.
The claims are not directed to a method of treatment. While the claim recites the cells are allogenic have been characterized by HLA typing, this is a product by process limitation that does not distinguish the claimed cells from naturally occurring cells.
Therefore the arguments are not persuasive.
The Applicant states Table 2 shows the claimed iPSC derived MSCs have significantly higher expression of the genes recited in claim 31 compared to bone marrow derived MSCs. The Applicant argues Fellows and Xia don’t teach MSCs that are CD73+/CD90+/CD105+/CD34+/CD45+.
In response: Neither the claims or specification disclose MSCs that are CD73+/CD90+/CD105+/CD34+/CD45+. The analysis does not compare the claim composition to MSCs from bone marrow. The analysis compares the claimed composition to cartilage. Therefore the arguments are not persuasive.
The Applicant states FIGS. 9, 10, 12(b) and 14(d)-(g) of the specification show
compositions comprising both iPSC-derived MSCs and iPSC-derived chondrocytes have unexpectedly additive therapeutic effects when compared to MSCs from bone marrow, FGF18, or compositions comprising only iPSC derived MSCs or iPSC-derived chondrocytes.
In response: The Applicant acknowledges the claimed compositions has an additive effect. Examiner notes a synergistic effect, and not additive, is evidence of an unexpected result. The Applicant has not provided evidence of a synergistic effect that occurs as the result of combining the two claimed cell types.
The Applicant points to experiments that analyze iPSC derived MSCs or chondrocytes. The claimed composition comprises iPSC derived MSCs and chondrocytes. As set forth above, the closest naturally occurring counterpart are the cells present in natural human cartilage. The specification does not provide any evidence the claimed composition is markedly different than natural cartilage (which contains MSCs and chondrocytes)..
The Applicant argues the claimed iPSC-derived MSCs are distinguishable from natural bone-marrow MSCs based on levels of the genes recited in claim 31. It is well known that MSCs can be derived from other tissues, included cartilage. The specification does not disclose any data that distinguishes the claimed cells from MSCs found in natural cartilage. The specification does not disclose significantly higher expression of said genes in iPSC-derived MSCs and chondrocytes when compared to those found in natural cartilage. Therefore the arguments are not persuasive.
The Applicant argues an allogenic composition that is HLA typed recites something significantly more than a judicial exception.
In response: The claims are drawn to a product. HLA typing is a process. The product by process limitation recited in claim 22 does not distinguish the claimed product is different from natural cartilage containing MSCs and chondrocytes. While the claims recite the composition is allogeneic for treating a subject, the claims are not directed to treating a human. “Allogeneic” does not impart a chemical characteristic that distinguishes the claimed composition from cartilage in a human.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 22-31 are rejected under 35 U.S.C. 103 as being unpatentable over D’Lima et al. (Systems and methods to repair tissue defects. US20230233058A1 with benefit of PCTUS2017034539 filed on 25 May 2017) in view of Xia et al. (previously cited; Altered function in cartilage derived mesenchymal stem
cell leads to OA-related cartilage erosion. Am J Transl Res 2016;8(2):433-446) and Mafi et al. (Adult mesenchymal stem cells and cell surface characterization - a systematic review of the literature. Open Orthop J. 2011;5(Suppl 2):253-60).
D’Lima teach a method of repairing an internal tissue defect or a chondral defect using bioprinting (Abstract). The tissue can be cartilage ([0002]). The art bioprints a bio-ink ([0002]). The bio-ink may comprise a plurality of cells ([0002]).
In some embodiments, the plurality of cells comprises chondrocytes ([0004]). D’Lima teaches in some embodiments, the bio-ink composition comprises a plurality of iPSC-derived chondrocytes ([0051]). The chondrocytes can be derived from mesenchymal stem cells (MSCs) ([0051]). In some embodiments, the bio-ink composition comprises a plurality of MSC-derived chondrocytes ([0051]). D'Lima teaches a plurality of chondrocytes derived from precursors that express one or more markers selected from: aggrecan, Collagen II, collagen type 2A1, Collagen IV, and SOX9 ([0053]).
In some embodiments, the plurality of cells is a plurality of mesenchymal stem cells (MSCs) ([0004]). D’Lima teaches in some embodiments, the bio-ink comprises a plurality of MSCs, wherein the MSCs are derived from induced pluripotent stem cells (iPSCs) ([0056]). D’Lima teaches at least 85% positive for CD73 and CD105 ([0053]).
D’Lima teaches the plurality of cells is selected from chondrocytes, MSCs, MSC-like cells, hESCs, iPSCs or a combination thereof ([0004]).
D’Lima teaches the use of allogeneic cells obtained from a genetically non-identical donor ([0004] [0025]). D’Lima teaches allogeneic cells are extracted from a donor and returned back to a different, genetically non-identical recipient ([0025])
D’Lima teaches the composition can comprise chondrocytes and mesenchymal stem cells. The cells can be derived from iPSCs. The art does not explicitly teach an embodiment comprising both cells. D’Lima teaches MSCs that are positive for CD73 and CD105. The art is silent regarding other markers.
Xia et al. teach mesenchymal stem cells (Abstract) and chondrocytes (see text of Figure 1) are present in human cartilage (supra).
Mafi teaches summarize all the available information about the cell surface characterization of adult human MSCs. Mafi teaches “we have found that the most commonly reported positive markers are CD105, CD90, CD44, CD73, CD29, CD13, CD34, CD146, CD106, CD54 and CD166”. The most frequently reported negative markers are CD34, CD14, CD45, CD11b, CD49d, CD106, CD10 and CD31 (see Abstract).
It would have been obvious to use chondrocytes and MSCs in the bio-ink taught by D’Lima. One would have been motivated to do so since D’Lima teaches a composition comprising cells that are used to replace cartilage and Xia teaches chondrocytes and MSCs are found in cartilage. The skilled artisan would use both cell types since they are present in cartilage. One would have had a reasonable expectation of success since Xia teaches both cell types are combined in cartilage. One would have expected similar results since both references are directed to cartilage.
Claim 22 recites 1) MSCs are obtained by differentiating single-cell iPSCs under conditions to activate the Wnt signaling pathway and 2) chondrocytes are obtained by differentiating iPSC-derived MSCs under chondrogenic conditions. These are product by process limitations. D’Lima teaches the claimed cell types. D’Lima teaches they are used to repair cartilage. The recited product by process limitations do not distinguish the claimed cells from the MSCs and chondrocytes derived from iPSCs in D’Lima. See MPEP 2113.The examiner concludes the burden has been shifted to the applicant to show an unobvious difference between the claimed product and the prior art product.
It would have been obvious to characterize MSCs by expression of CD73, CD90, CD105, CD34 and CD45 surface markers. Mafi teaches MSCs can be characterized by positive expression of CD73, CD90, CD105, and negative expression of CD34 and CD45. One would use these markers to identify MSCs. One would have had a reasonable expectation of success since Mafi teaches these markers can be used to characterize MSCs. One would have expected similar results since D’Lima and Mafi are directed to the same cell type.
While Instant claim 22 recites said cells are derived from iPSCs “characterized by HLA typing” this limitation does not impart a specific chemical characteristic to the claimed cells. This is a product by process limitation that does not distinguish the cells recited in claim 22 from the allogenic cells taught in D’Lima. Therefore claim 22 is rendered obvious.
D’Lima teaches the bio-ink may comprise a combination of cells (supra). The cells can be present in a fluid ([0045]). Because the claimed combination of the claims cells is rendered obvious, it is interpreted to be injectable. Therefore claim 23 is included in this rejection. D’Lima teaches the composition can be implanted ([0073]). Therefore claim 24 is included in this rejection. D’Lima teaches in some embodiments, the plurality of cells is frozen ([0049]). Therefore claim 25 is included in this rejection. D’Lima teaches in some embodiments, the plurality of cells is previously frozen (hence, thawed; [0049]). Therefore claim 26 is included in this rejection. Claims 27-29 are directed to a method of storage. The claims are directed to a product. Claims 27-29 does not recite a chemical limitation that further limits the claimed product. Therefore claims 27-29 are included in this rejection. D’Lima teaches iPSC-derived MSCs (supra). Therefore claims 29-30 are included in this rejection. Because D’Lima teaches the use of iPSCs-derived MSCs, they would be expected to have a transcriptome that comprises transcripts of one or more of the genes recited in claim 31. Therefore claim 31 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 29 May 2025 are acknowledged.
The Applicant argues D’Lima does not teach iPSC-derived chondrocytes and iPSC-derived MSCs that are obtained as recited in claim 22. The Applicant argues Xia does not teach cells obtained by differentiating iPSCs under conditions to activate Wnt signaling. The Applicant argues Xia does not teach the claimed surface markers.
In response: New grounds of rejection have been set forth above. Xia is not relied upon to teach the claimed differentiation conditions. Xia is relied upon because it teaches chondrocytes and MSCs occur together in cartilage. D’Lima is relied upon because it teaches a composition comprising chondrocytes and MSCs which can be derived from iPSCs. The arguments are not persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653