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
This application claims benefit of US provisional 63/385,873 (filed on 12/02/2022).
Election/Restrictions
Applicants’ election without traverse of invention group II filed on 06/02/206 is acknowledged. Claims 14-17 read on the elected invention.
Claims Status
Claims 14-17 are pending.
Claims 1-13 have been canceled with amendment filed on 06/02/2026.
Claims 14-17 have been examined on the merits.
Drawings
The drawings filed on 12/04/2023 are objected to because they contain color images, but there is no granted petition for color drawings.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because of the following informalities:
The use of the term Pluronic™, GlutaMAX™, B27™, mTeSR1™, and ReLeSR™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claim 14 is objected to because of the following informalities:
Claim 14 is objected to for improper format. Claim 14 references a table in the specification. MPEP 2173.05(s) states "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608 (bd. Pat. App. & Inter. 1993)(citation omitted). The information from the Table 1 pertinent to the claims does not qualify as an exception to circumstance. Therefore, the information from the table, a list of supplement composition, must be incorporated into the claims.
Also in claim 14, the full term ‘para-aminobenzoic acid’ should precede the first use of acronym, “PABA” in line 10.
Appropriate correction is required.
Claim Interpretation
For clarity of the record the following comments are made regarding claim interpretation under broadest reasonable interpretation:
None of the ‘optionally’ limitation are considered as required by the claims.
Regarding claim 14, claim 14 recites, “a first media supplement comprising…” in line 11, for compact prosecution this is being interpreted as, the first cell-culture media of the method comprises the reagents from Table 1.
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 14 -17 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 14 recites a limitation ii)…at least…reagents from Table 1…” in line 12. The table is meant to recite a list of supplement composition, the list comprises supplement names that are unclear and thus makes the limitation indefinite because it is unclear what is required by simply stating, ”ingredients of Table 1”. Supplement names that are unclear, 2) Glutathione reduced, 3) NO INSULIN (B27 normally has insulin), and 6) T3.
For compact prosecution, for claim 14, any media that is supplemented with at least 5 reagents from Table 1 (interpreting 2) as ‘reduced glutathione, 3) as B27 minus insulin, and 6) as Triiodothyronine (T3)).
Claim 14 recites, “…said first media supplement..” in lines 14 & 24 lacks antecedent basis. It is unclear which first media supplement is being referred to.
Claim 14 is further indefinite because it is unclear what the metes and bounds of “Mesoderm Induction Medium” are. Neither the specification nor art provides a specific definition/formulation.
Claim 14 is further indefinite because it is unclear if, in step c), i)-v) are alternative options, or if they are all required (at least those which are not “optional”). The problem stems from there being no conjunction (i.e. “or” or “and”) between iv) and v).
Claim 14 is further indefinite because it is unclear if steps b), c), d) and e) are each treating the same portion of hPSCs or different portions of hPSCs. This leads to confusion as to how/if steps b)-e) are related to one another, and what the method ultimately involves. If the steps are intended to build off one another, the claim should be amended to clarify, e.g. “c) treating at least a portion of said hPSC from step b) such that at least…..”… “d) treating a least a portion of said hPSC from step c) with either: ….”…. “e) incubating at least a portion of said hPSC from step d) such that…” Correction is required.
Finally, claim 14 contains trademarks/trade names: B27™ and GlutaMAX™. 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 names are used to identify human or humanized enzymes and, accordingly, the identification/description is indefinite.
Claim 17 recites the limitation "...wherein said lipids" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 17 is currently dependent on claim 15, which has no limitation that requires a lipid.
For compact prosecution, claim 17 is being interpreted as being dependent on claim 16, as claim 16 further comprises a lipid component in their limitations.
Claim 17 contains trademarks/trade name Pluronic™ and Tween®. 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 names are used to identify human or humanized enzymes and, accordingly, the identification/description is indefinite.
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 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lai et al (Stem cell reports, 2022); evidenced by Ludwig and Thomson (Current protocols in stem cell biology, Chapter 1, 2007), Thermofisher DMEM/F12 formulation sheet, and STEMCELL™ Technologies STEMdiff™ Mesoderm Induction Medium protocol.
Lai et al teaches a method to efficiently generate function quiescent induced hepatic stellate cells (iHSCs) from human embryonic stem cells (hESCs) or induced pluripotent stem cell (iPSC) differentiation, which includes mesoderm differentiation intermediatory step (See, Abstract).
Regarding claim 14, Lai et al teaches that the differentiation of hESCs and iPSCs into mesoderm cells was performed by dissociating the into single cells and plating them in mTeSR1 with ROCK inhibitor (Y27632), culturing them, such that cells reach 60% confluency. Then the cells are treated with STEMdiff™ mesoderm induction medium kit and following the manufacturer’s (STEMCELL™ Technologies) instructions (See, p2545 col 1 paragraph 3). This reads on, a) adding single cell suspension of hPSCs to a cell culture container containing a first cell culture media,… b) incubating at least a portion of said hPSCs such that at least about 10% confluence is… achieved.
The instructions provided by the manufacturer of STEMdiff™ states, cells are resuspended in DMEM/F12 or mTeSR™1 or TeSR™-E8™ with ROCK inhibitor (Y27632). The cells are culture to cell density of 20-50% confluency. This reads on, c) treating at least a portion of said hPSCs with: i) a second cell culture media comprising biotin, as all those media contain DMEM/F12 which comprises biotin (See, Thermofisher DMEM/F12 formulation). This also reads on, ii) a first media supplement comprising at least 5 reagents, because mTeSR™1 comprises DMEM/F12, reduced glutathione, pipecolic acid, sodium selenite, and human insulin; as taught by Ludwig and Thomson (See, p 9-10 mTesR culture medium and stock B), and DMEM/F12 comprises biotin and linoleic acid (See, Thermofisher DMEM/F12 formulation).
Then the addition of the STEMdiff™ mesoderm induction media is added for 4 days and on the 5th day they are mesoderm cells (See, STEMdiff™ Mesoderm Induction Medium protocol). This reads on, d) treating at least a portion of said hPSCs with… ii) Mesoderm Induction Medium; and e) incubating at least a portion of said hPSCs such that mesoderm cells are generated.
Therefore, claim 14 is anticipated by Lai et al (Stem cell reports, 2022); evidenced by Ludwig and Thomson (Current protocols in stem cell biology, Chapter 1, 2007), Thermofisher DMEM/F12 formulation sheet, and STEMCELL™ Technologies STEMdiff™ Mesoderm Induction Medium protocol.
Claims 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Coll et al (Cell Stem Cell, 2018; as cited in the IDS filed on 08/11/2025); evidenced by Ludwig and Thomson (Current protocols in stem cell biology, Chapter 1, 2007), Lim et al (International journal of stem cells, 2019), and Thermofisher DMEM/F12 formulation sheet.
Coll et al teaches a protocol to differentiate human pluripotent stem cells (hPSCs) into hepatic stellate cells (HSCs)-like cells or iPSC-HSCs that exhibit a quiescent phenotype (See, Abstract).
Regarding claims 14 and 15, Coll et al teaches, that hESCs were cultured in mTeSR™1 medium prior to differentiation being initiated (See, p e3 paragraph 2). This reads on, a) adding a single cell suspension of hPSCs to a cell culture container containing a first cell culture media,… and ii) a first media supplement comprising at least 5 reagents of claim 14, as mTeSR™1 comprises DMEM/F12, reduced glutathione, pipecolic acid, and sodium selenite; evidenced by Ludwig and Thomson (See, p 9-10 mTesR™ culture medium and stock B), and DMEM/F12 comprises biotin and linoleic acid (See, Thermofisher DMEM/F12 formulation).
Coll et al teaches that for HSC differentiation hPSCs are dissociated into single cells, seeded and cultured in E8™ medium until they reach 50% confluency. This reads on, b) incubating at least a portion of said hPSCs such that at least about 10% confluence…c)treating a portion of said hPSCs with : i) a second cell culture media comprising biotin of claim 14, as E8™ comprises DMEM/F12; evidenced by Lim et al (See, Table 2).
Coll et al then teaches that HSC differentiation medium contains DMEM low glucose, MCDB-201-water, linoleic-acid-BSA, insulin-transferrin-selenium, pen-strep, L-ascorbic acid, dexamethasone, and β-mercaptoethanol. Coll et al also teaches that BMP4 was added from day 0 to day 4, FGF1 was added from day 4 to 8, and finally retinol and palmitic acid were added from day 6 to 12 (See, p e4 paragraph 4).
The combination of the differentiation media with BMP4, from days 0-4, reads on, d) treating at least a portion of said hPSCs with either: i) said second cell-culture media, said first media supplement, and BMP4; and e) incubating at last a portion of the hPSCs such that mesoderm cels are generated of claim 14, as Figure 1A of Coll et al shows that the medium with BMP4 induces the differentiation of the hPSCs to mesoderm cells (See, Figure 1A and p103 col 1 paragraph 4).
The combination of differentiation media with BMP4 and FGF1, from days up to day 6 induce mesodermal progenitor cells with submesothelial phenotype (See, p103 col 1 paragraph 4 and Figure 1A). This reads on, f) treating a portion of said mesoderm cells with: a second cell culture media, said first media, BMP4, FGF1, insulin, transferrin, and selenite; and g) culturing .. such that mesodermal progenitor cells are generated of claim 15.
Therefore claims 14 and 15 are anticipated by Coll et al (Cell Stem Cell, 2018; as cited in the IDS filed on 08/11/2025); evidenced by Ludwig and Thomson (Current protocols in stem cell biology, Chapter 1, 2007) and Thermofisher DMEM/F12 formulation sheet.
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 an
d 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.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lai et al (Stem cell reports, 2022) as applied to claim 14 above, and further in view of Coll et al (Cell Stem Cell, 2018; as cited in the IDS filed on 08/11/2025) and Chen et al (Stem cells, 2012).
The teachings of Lai et al and Coll et al are set forth above.
Regarding claims 15, Lai et al teaches that HSC differentiation from mesoderm cells requires, dissociation into single cells then plated with ROCK inhibitor in basal medium (BM) consisting of DMEM/F12, Knockout serum (KOSR), GlutaMAX™, penicillin-streptomycin, FGF2, BMP4, VEGF, and HGF (See, p2545 col 1 paragraph 5). The cells are culture for 4 days, then the cells were exposed to BM containing B27, insulin-transferrin-selenium-ethanolamine, retinoic acid, rosiglitazone, and dexamethasone for 6 days to obtain HSCs (See, p2545 Methods col 1 paragraph 5). This reads on, f) treating at least a portion of said mesoderm cells with: said second cell-culture media, said first media, BMP4,…, insulin, transferrin, and selenite.
Lai et al does not teach the use of FGF1 in the differentiation process from mesoderm cells to HSC. Coll et al does teach the use of FGF1 in the differentiation process from hPSCs to HSC and that it results in mesodermal progenitor cells.
Chen et al teaches that thermally stable mutated FGF1 sustains human ESCs and supports differentiation protocols (See, Abstract).
Chen et al teaches that FGF1 derivatives were used to initiate differentiation in the presence of BMP4, and we found that thermal stability directly affected the cell differentiation to mesodermal-specific cells (See, p 6 paragraph 2 and Figure 4).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of mesoderm to HSC differentiation taught by Lai et al by including FGF1 during the differentiation process with BMP4 as taught by Coll et al to obtain mesodermal progenitor cells.
This conclusion of obviousness is based on the teaching, suggestion, or motivation rationale, one would have been motivated to do so because Chen et al teaches that FGF1directly affects cell differentiation to mesodermal specific cells in the presence of BMP4, which is the goal of the methods taught by both Lai et al and Coll et al. Further, one would have a reasonable expectation of success evidence by Coll et al differentiation to quiescent HSCs, such that method of including FGF1 and BMP4 results in mesodermal progenitor cells.
Regarding claims 16 and 17, following the discussion above, Lai et al teaches the cells are cultured for 4 days, then the cells were exposed to BM containing B27™, insulin-transferrin-selenium-ethanolamine, retinoic acid, rosiglitazone, and dexamethasone for 6 days to obtain HSCs (See, p2545 Methods col 1 paragraph 5). This reads on, h) treating at least a portion of mesodermal progenitor cells with: said second cell culture media, said first media, insulin, transferrin, selenite, lipids, and FGF2 of claim 16. This also reads on, wherein said lipids is…. linoleic acid of claim 17, as DMEM/F12 contains this lipid.
Lai et al teaches a method of differentiation of hESC and iPSC into cells with functional and phenotypic features of quiescent human primary cultured HSCs (See, p2544 col 2 paragraph 3).This reads on, h)culturing at least a portion of said mesodermal progenitor cells such that quiescent hepatic stellate cells (HSCs) are generated of claim 16.
Therefore, claims 15-17 are rendered obvious over Lai et al in view of Coll et al and Chen et al.
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 14-17 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 11,492,596 B2 in view of Coll et al (Cell Stem Cell, 2018; as cited in the IDS filed on 08/11/2025).
The teachings of Coll et al are set forth above.
Regarding claims 14-17, reference claims 1 and 4 recite a method of producing cells with a hepatic stellate cell phenotype, comprising (a) culturing pluripotent stem cells with BMP4, (b) culturing cells from (a) with FGF1 and FGF3, (c) culturing the cells obtained from (b) with retinol and palmitic acid, and (d) isolating the cells with hepatic stellate cell phenotype. The scope of the invention of the reference claims reads on the methods provided by instant application claims. US patent 11,492,596 B2 is silent on the method producing intermediary cell populations such as mesoderm cells, mesodermal progenitors, or that the HSCs are quiescent and that the pluripotent cells are human.
Coll et al teaches that by culturing human pluripotent stem cells with those factors with the appropriate medium, generates mesodermal cells, mesodermal progenitors, and in the end quiescent hepatic stellate cells.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of culturing pluripotent stem cells to HSC differentiation taught by reference Patent US11,492,596 B2 by using human pluripotent stem cells during the differentiation process as taught by Coll et al to obtain mesodermal cells, mesodermal progenitor cells, and quiescent HSCs.
This conclusion of obviousness is based on the teaching, suggestion, or motivation rationale, one would have been motivated to do so because both the reference patent and Coll et al methods for HSCs differentiation from pluripotent stem cells, the use of human pluripotent stem cells provides more efficacy for the protocol and its further use for information gather and potential as a therapeutic. Further, one would have a reasonable expectation of success evidence by Coll et al differentiation to quiescent HSCs, such that intermediary cell populations of mesodermal cells and mesodermal progenitors are generated and identified.
Therefore, claims 14-17 are rendered obvious and unpatentable over US patent 11,492,596 B2 in view of Coll et al in nonstatutory double patenting.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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