DETAILED ACTION
Claims 1-9 are currently pending.
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
Acknowledgement is made of the instant application being a Divisional of co-pending Application No. 16/593,462 (US Patent No. 12,024,720), filed on October 4, 2019. Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application No. PCT/JP2018/011392, filed on March 22, 2018. Acknowledgment is further made of applicants' claim for foreign priority to Japanese Patent Application No. 2017-075828, filed on April 6, 2017. A certified copy of the foreign priority document is present in the application file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/16/2024, 6/10/2024 and 6/25/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Interpretation
Claim 1 recites the following:
Cultivated cells being produced by a cultivation method including: cultivating primary cultured kidney cells which are dedifferentiated in a state of being non-adherent to a culture vessel for a period of 5 days or longer, forming aggregates of the kidney cells during the cultivation period, then cultivating the kidney cells in a state of having formed aggregates, during a portion of the period, and thereby restoring physiological functions of the kidney cells, the primary cultured kidney cells including primary cultured renal proximal tubular epithelial cells, and a percentage of the primary cultured renal proximal tubular epithelial cells in the primary cultured kidney cells being 83% or more.
It is initially noted that claim 1 is directed to a cell product. As to the limitations directed to cultivating primary cultured kidney cells which are dedifferentiated in a state of being non-adherent to a culture vessel for a period of 5 days or longer, forming aggregates of the kidney cells during the cultivation period, then cultivating the kidney cells in a state of having formed aggregates, during a portion of the period, and thereby restoring physiological functions of the kidney cells, the primary cultured kidney cells including primary cultured renal proximal tubular epithelial cells, it is noted these limitations are directed to the manner by which the cell product has been produced. Such limitations are product-by-process limitations which appear to define the cultivated cells. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, if the product by process limitations are considered, the process imparts the feature of an aggregation of primary cultured renal proximal tubular epithelial cells (RPTECs), and the portion of the RPTECs are a concentration of 83% or more and have restored physiological functions.
Further regarding claims 2 and 5-8, it is noted these claims recite limitations directed to the manner by which the aggregation of primary cultured renal proximal tubular epithelial cells (RPTECs) has been prepared by further defining culture duration (claim 2) and culture vessel conditions (claims 5-8), but these limitations do not further limit the structure of the claimed cells.
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 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) an aggregation of primary renal proximal tubular epithelial cells (RPTECs) which are not markedly different from the product’s naturally occurring counterpart in its natural state.
The rationale set forth below conforms to current Office practice for examination of claims under § 101.
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. All of the claims are directed to a statutory category, e.g., a composition (Step 1: YES).
The next part of the analysis involves whether the claimed invention recites or is directed to one or more judicial exceptions (Step 2A, prong one).
Claim 1: As set forth above at Claim Interpretation, it is noted Claim 1 is directed to an aggregation of primary renal proximal tubular epithelial cells (RPTECs).
As is recognized by the instant specification (paragraph [0016]), renal proximal tubular epithelial cells are native to the kidney.
Bondue (see PTO-892), at Figure 2, evidences that native proximal tubule epithelial cells exist in vivo as an aggregation of cells within the proximal tubule of the kidney and KidneyPathology.com (see PTO-892) further provides histology images to evidence the native aggregation of proximal tubular epithelial cells (see Figure 1).
Thus, the claim as currently drafted encompasses a natural product.
Further regarding the limitation directed to the amount of proximal tubular epithelial cells, it is noted this limitation does not limit the claimed composition in such a way that is markedly different in structure or biological and/or pharmacological function from their natural counterparts and Bondue clearly shows the tubule lining comprises 100% proximal tubule epithelial cells.
Accordingly, the claim is directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
Claims 2 and 5-8, as set forth above at Claim Interpretation these claims recite limitations directed to the manner by which the aggregation of primary cultured renal proximal tubular epithelial cells (RPTECs) has been prepared by further defining culture duration (claim 2) and culture vessel conditions (claims 5-8), however, these limitations do not further limit the structure of the claimed cells a way that is markedly different in structure or biological and/or pharmacological function from their natural counterparts.
Claims 3-4 and 9: claims 3-4 and 9 depend directly from claim 1 and further define the amount of cells present (claim 3), cell size (claim 4) and restored physiological functions (claim 9). These limitations do not limit the claimed composition in such a way that is markedly different in structure or biological and/or pharmacological function from the natural counterpart. Specifically regarding claim 9, it is noted the instant specification recognizes that removal of the proximal tubular epithelial cells from the native environment causes dedifferentiation and reduces native physiological functions ([0016]-[0017] and [0101]), thus the native environment maintains physiological functions.
The next part of the analysis involves whether the claimed invention recites additional elements that integrate the judicial exception into a practical application (Step 2A, prong two).
Given the claims are directed to a composition, the claims do not recite additional steps that integrate the judicial exception into a practical application (Step 2A, prong two: No).
The final part of the analysis involves whether the claimed invention, as a whole, recite something “significantly more” than the judicial exceptions (Step 2B).
In view of the above and considered as a whole, the claimed composition does not have markedly different characteristics from what occurs in nature and such elements discussed above are not significantly more than the indicated judicial exceptions. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101 (Step 2B: NO).
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.
Claim(s) 1-2 and 5-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lewis et al., (Kidney International, Vol. 49 (1996), pp. 48-58; IDS 4/16/2024) (“Lewis”).
Regarding claim 1, Lewis teaches of isolating proximal tubular epithelial cells, the cells being 90% or greater proximal tubular epithelial cells (Methods, Cell culture, left col, first paragraph, page 49; Results, Characterization of rat renal cell cultures, right col, page 50) wherein the cells were further plated in 8-chamber slides and cultured to confluence (i.e., aggregation) for immunohistochemical analysis (Methods, Characterization of cells, right col, page 49).
Regarding claims 2 and 5-8, it is noted as set forth above at Claim Interpretation, these claims recite limitations directed to the manner by which the aggregation of primary cultured renal proximal tubular epithelial cells (RPTECs) has been prepared by further defining culture duration (claim 2) and culture vessel conditions (claims 5-8), but these limitations do not further limit the structure of the claimed cells. As such instant claims 2 and 5-8 do not further limit parent claim 1, and thus are included in the rejection of claim 1.
Claim(s) 1-2 and 4-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Prange et al., (Pflugers Arch – Eur J Physiol (2016) 468: 739-750; IDS 4/16/2024) (“Prange”).
Regarding claims 1 and 4, Prange teaches evaluating the formation of microtissues (i.e., forming aggregates) from primary human proximal tubular epithelial (HRPTEpiC) cells alone (i.e., 100% primary cultured renal proximal tubular epithelial cells), or in combination with fibroblasts, wherein low passaged (P3) pure HRPTEpiC were cultured for 8 days to form the pure aggregated microtissues having a size of 210 +/- 21 µm, and the high passage (P10) mono-cultures (pure) formed microtissues in 4 days having a size of 272 +/- 12 µm (Formation of microtissues from primary HRPTEpiC cells, page 742; Fig. 2). Thus, Prange anticipates claims 1 and 4.
Regarding claims 2 and 5-8, it is noted as set forth above at Claim Interpretation, these claims recite limitations directed to the manner by which the aggregation of primary cultured renal proximal tubular epithelial cells (RPTECs) has been prepared by further defining culture duration (claim 2) and culture vessel conditions (claims 5-8), but these limitations do not further limit the structure of the claimed cells. As such instant claims 2 and 5-8 do not further limit parent claim 1, and thus are included in the rejection of claim 1.
Regarding claim 9 and the limitation regarding restoring the physiological function of the kidney cells includes increasing an amount of expression of OAT1, it is noted that Prange does not further comment on expression of OAT1. However, Prange discloses the same aggregation of renal proximal tubular epithelial cells as disclosed in the instant specification, therefore although Prange does not comment on restored OAT1 expression, the fact that Prange discloses the same aggregation of renal proximal tubular epithelial cells as the instant application ([0137]) means the cell product of the applicant and the prior art are the same, whether recognized at the time of publication or not. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). MPEP 2112.01
Claim(s) 1-2 and 5-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by King et al., (Frontiers in Physiology, March 2017, vol. 8, Article 123, 18 pages; see PTO-892) (“King”).
King is directed to methods of 3D Proximal Tubule tissues for recapitulating renal physiology for the purpose of enabling nephrotoxicity testing (Title).
Regarding claims 1 and 9, King teaches of developing a fully cellular human in vitro model of the proximal tubule interstitial interface comprising renal fibroblasts, endothelial cells, and primary human renal proximal tubule epithelial cells (RPTECs) to enable more accurate prediction of tissue-level clinical outcomes. King used Organovo's proprietary 3D bioprinting platform to develop the 3D model (Abstract).
King, at Figure 1, shows a schematic diagram of the multicellular 3D model.
King teaches that one of the primary goals of tissue engineering is to use living cells and biomaterials to generate 3D tissues that recapitulate key aspects of the architecture and function of a native tissue or organ. (INTRODUCTION, right col, second paragraph, page 2).
King teaches the bioprinting technology created layered tissue models of the human PT (proximal tubule) that incorporate key interstitial cell types supporting RPTEC to facilitate both cell-cell interactions and paracrine signaling between renal fibroblasts, endothelial cells, and epithelial cells. The resulting engineered tissues were then characterized in three main areas: validation of key physiologic aspects of the native proximal tubule, confirmation of the ability to detect nephrotoxicity using the well-characterized nephrotoxin cisplatin, and demonstration of the utility of the model in evaluating renal fibrosis. (INTRODUCTION, right col, second paragraph, page 2).
King teaches combining the cultured renal fibroblasts and HUVEC in a 50:50 ratio and resuspending in thermo-responsive NovoGel® Bio-Ink, and then bioprinting onto 0.4 μm Transwell clear polyester membrane inserts in a 24-well plate. On culture day 3, primary RPTEC cells were added to the tissues in a suspension of 1.25 × 106 cells/ml in RPTEC media. Tissues were then maintained for up to 30 days in 3D PT culture media and 2.5% final v/v FBS, with media exchanges every other day (3D bioprinting and tissue culture, page 3).
King further teaches the 3D PT tissues cultured for 21 days were subjected to targeted proteomic analysis for OAT1, OAT3, OCT2, and P-gp and human serum albumin (HSA, internal standard), wherein the 3D PT tissues showed expression of OAT1 (LC-MS/MS-based detection of renal transporters, page 5; FIGURE 4).
Thus, King teaches cultivated cells comprising the aggregation of primary RPTEC cells (FIGURE 1) and the percentage of the primary RPTEC cells is 100%, thus anticipating claims 1 and 9.
Regarding claims 2 and 5-8, it is noted as set forth above at Claim Interpretation, these claims recite limitations directed to the manner by which the aggregation of primary cultured renal proximal tubular epithelial cells (RPTECs) has been prepared by further defining culture duration (claim 2) and culture vessel conditions (claims 5-8), but these limitations do not further limit the structure of the claimed cells. As such instant claims 2 and 5-8 do not further limit parent claim 1, and thus are included in the rejection of claim 1.
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 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.
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Prange, as applied to claims 1-2 and 4-9 above.
The teaching of Prange is set forth above.
Regarding claim 3, Prange does not further teach the number of cells constituting the HRPTEpiC aggregates (microtissues) is from 500-5,000. However, it is noted that Prange teaches testing the influence of cell density on velocity of microtissue formation, and specifically teaches using 500, 1000 and 2000 cells per drop (cpd) when seeding the HK-2 cells (claimed range overlaps the prior art range). Prange teaches cells seeded at 1000 cpd formed regular, solid microtissues in 10 days (Formation of microtissues from immortalized HK-2 cells, left col, page 742). Thus, Prange has established it was known that cells seeded at a range of 500-2000 was effective for forming the aggregated microtissues comprising HRPTEpiCs.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the same concentrations employed for forming the HK-2 microtissues for forming the HRPTEpiC microtissues since both cell types are known to form the aggregated microtissues. Therefore, one of ordinary skill in the art would recognize this as simply substituting one cell seeding concentration for another useful for the same purpose of forming aggregated microtissues ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Prange renders obvious cell concentrations ranging from 500-2000 kidney cells, that is, Prange teaches the limitations required by the current claims and as all limitations are found in one reference it is held that using cell concentrations ranging from 500-2000 cells is within the scope of the teachings of Prange, and thus renders the invention of claim 3 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to use cell concentrations ranging from 500-2000 cells for producing the aggregated microtissues. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Prange.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633
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