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 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 1,4,5,9,12 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 1,4,9,12 recite the trademark/trade name “Matrigel”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the composition and putative functions of its extracellular matrix material used during cell culture. However, identification/description of all components is incomplete and concentrations often vary batch to batch.
Claim 5 recites the limitation "the well plate" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim since there is no well plate present in claim 1.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1/7/8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1,18/17/14 of copending Application No. 17/995,114 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the instant application and claim 1,18 of the reference application both claim a method of generating specialized kidney organoids using kidney-derived decellularized extracellular matrix and additional extracellular components which form into hydrogels. Importantly both methods result in increased VEGF expression and formation of glomerulus structures displaying vascular structures. Claim 7 of the instant application and claim 17 of the reference application both specify that the method of kidney organoid creation (methods 1) must result in increased expression of 1 or more genes they specify. Importantly, both specify the gene could be PDK1. Claim 8 of the instant application and claim 14 of the reference application both specify that the kidney organoids generated in claims 1 come from pluripotent stem cells.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Low JH, et al 2019, Sun G, et al 2020, and Eremina, et al 2003, and Yang X, et al 2021.
Low JH, et al 2019 discloses a method of differentiating human pluripotent stem cells (hPSCs) into kidney organoids using Matrigel-coated plates and a media composition containing CHIR99021 (Glycogen Synthase Kinase 3 inhibitor aka GSK-3) (paragraphs 2 and 3 in the “Method Details” section). Importantly, they noticed consistently elevated levels of VEGF mRNA and secreted protein during differentiation. (Figure 1F-H). The newly differentiated kidney organoids displayed well organized vascular networks. However, network integrity/structure was severely compromised in the presence of VEGF inhibitors (Figure 1H). This is consistent with the observation that VEGF signaling is essential for the maturation and maintenance of renal vasculature, as supported by Eremina, et al 2003. Interestingly, single cell-transcriptomics revealed that the newly differentiated organoids contained several distinct subgroups of cells. Of particular note, a single group was expressing hemangioblast markers (FOXC2, ETV2, and SIX1) and more mature endothelial markers (PECAM1/CD31, CDH5, and FLT1) as exhibited by an endothelial lineage trajectory. (Figure 2I-K). Excitingly, when these organoids were implanted into the renal capsule of mice, they developed morphologically distinct glomerular capillary tufts (Figure 5A-G). The structural/organizational and cellular identity data presented in Figure 5 indicate implantation greatly facilitated complex structural and functional maturation of hPSC-derived kidney organoids.
Low JH, et al 2019 does not disclose the use of kidney-derived decellularized-extracellular matrix in the differentiation protocol. They also do not disclose the use of a TGF-beta inhibitor during differentiation. Finally, they do not disclose a method for preparing an organ model for modeling vasculopathy in Fabry disease comprising a GLA KO (knockout).
Sun G, et al 2020 discloses a method of differentiating stem cells (urine-derived stem cells (USCs)) into kidney organoids by adding kidney-derived decellularized-extracellular matrix to the media. “This study successfully sketched the optimized process of USC-organoid generation with kECM and proved that USC-organoids had similar morphology, histology, gene expression, and nephrotoxicity screening ability to renal organoids.” (paragraph 1, Discussion section). (See paragraph 2 of “kECM concentration optimization by Live/Dead staining” section for decellularization).
Yang X, et al 2021 show that TGF-beta expression/signaling induces a profibrogenic program characterized by excessive extracellular matrix deposition in iSPC-derived kidney organoids (Figure 2A-B). They go on to show that INT-767 effectively inhibits TGF-beta induced increase of p-SMAD3 and TAZ. Therefore, INT-767 preserved mature nephron architecture by inhibiting TGF-β1-driven organoid fibrosis (Figure 3).
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to differentiate human pluripotent stem cells into kidney organoids using the method of Low JH, et al 2019 wherein cells are cultured/differentiated using a composition containing Matrigel, the GSK inhibitor CHIR99021, and VEGF, and to incorporate the teachings of Sun G, et al 2020 by using kidney-derived decellularized-extracellular matrix (kECM) as a plate coating for cells to grow on during the differentiation process. The kECM composition maintains all the natural chemical components/signals (unlike synthetic membranes eg matrigel), and provides the mechanical support and spacial integrity derived from the basement membrane in vivo. These features are essential for correct development of 3D structures when forming multicellular organoid structures in vitro. They dictate the newly formed organoids exhibit architectures and functionalities that mimic in vivo organs. This renders claims 1-2,4-8,11 obvious.
It would also be obvious to as person of ordinary skill in the art, before the effective filing date, to supplement the aforementioned stem cell [Wingdings font/0xE0] kidney organoid differentiation methodology and compositions with a TGF-beta inhibitor as disclosed by Yang X, et al 2021. Aberrant TGF-beta overexpression during the differentiation process can result in structural scarring and fibrogenesis in the newly formed organoids, thereby reducing their therapeutic value and effectiveness, as supported by Yang X et al. 2021. This renders claim 3 obvious.
It would also be obvious to a person of ordinary skill in the art, before the effective filing date, to assemble all of the disclosed reagents and teachings provided above that are necessary to perform the method. The assembly of known reagents/components disclosed in the prior art into a “kit” and supplementing them with the written instructions and teaching of the prior art does not impart additional meaningful structural limitations to the claim in this scenario. Therefore, claims 9-10 are obvious as rationalized above.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Low JH, et al 2019, Sun G, et al 2020, and Eremina, et al 2003, and Yang X, et al 2021 as applied to claim 1 above and further in view of Kim Ky et al 2020.
As outlined above, using kidney decellularized extracellular matrix as a cell culture plate coating, as disclosed in Sun G, et al 2020, and adding a TGF-beta inhibitor would be obvious to include in the stem cell [Wingdings font/0xE0] kidney organoid differentiation method/protocol (aka claim 1). However, these disclosures do not teach the creation of an organoid model for studying vasculopathy in Fabry disease via the knockout of the alpha-galactosidase gene in the undifferentiated stem cells.
Kim Ky et al 2020 discloses the creation of GLA-KO hiPSCs. GLA-KO hiPSCs are normal human induced pluripotent stem cells which have had their alpha galactosidase gene knocked out via CRISPR-Cas9 editing. Importantly, under α-galactosidase A activity assay conditions the GLA-KO hiPSC line exhibited typical phenotypes of Fabry disease, such as a deteriorated GLA activity and Gb3 accumulation which is shown by immunostaining for Gb3 (Figure 1F,G and Table 1).
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to take the GLA-KO hiPSCs created by Kim Ky et al 2020 and use them in the method of stem cell [Wingdings font/0xE0] kidney organoid differentiation outlined above. This unique combination of components results in a high-fidelity genetic model of Fabry disease (alpha-galactosidase KO) and provides a differentiation process wherein the final organoid product naturally captures the endothelial pathology of Fabry, and recapitulates the glomerular capillary which allows the examination of how endothelial dysfunction manifests in the glomerulus. This type of fidelity is in drug model systems is indicative of significant translational value. Therefore, claim 12 is obvious.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (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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/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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