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 .
Claim Status
Claims 1-12, 17-21, 24-33, 36, 38-47 and 49-52 are pending.
Claims 38-47 are withdrawn.
Claims 1-12, 17-21, 24-33, 36, and 49-52 are under examination.
Election/Restrictions
Applicant’s election with traverse of the following invention
Invention
Group I, claims 1-12, 17-21, 24-33, 36, and 49-52, drawn to a method for promoting the directed differentiation of pluripotent stem cells (PSCs)
in the reply filed on 4th, February, 2026 is acknowledged.
Applicant’s traversal is on the grounds that “Applicant submits that Groups I, II and III are related to each other under category (3), "a product, a process specially adapted for the manufacture of the said product, and a use of the said product". Applicant argues “the present claims should be considered as having unity of invention under 37 CFR § 1.475(c)” (pg. 3-4).
In response this is not found persuasive because even if Groups I, II and III are related to each other under category (3), the technical feature shared between the groups is not novel and therefore the Groups Lack unity of Invention (see Lack of Unity Mailed on 8th December, 2025). The technical feature of a cell population which is not enriched or purified, comprising more than 90% of mature CD56+CD3-iNK cells does not make a contribution over the prior art in view of Knorr et al. (Stem Cells Transl Med. 2013 Apr;2(4):274-83. Epub 2013 Mar 20.; see IDS filed 6th, September, 2024; henceforth “Knorr”) (see Lack of Unity Mailed on 8th December, 2025 pg. 4-5).
Furthermore, as set forth previously, the groups do not fall under (3), "a product, a process specially adapted for the manufacture of the said product, and a use of the said product" because the product obtained by Group I is immature iNK cells. Group II is a product of mature iNK cells which are different than the immature iNK cells made by Group I, and Group III is a method of using the mature iNK cells. (see Lack of Unity Mailed on 8th December, 2025 pg. 4 which explains that Group I lacks unity with Groups II-III).
As set forth in the Lack of Unity Mailed on 8th December, 2025, as provided in 37 CFR 1.475(a), a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art. In the instant case, Group I lacks unity of invention with Groups II-III because the groups do not share the same or corresponding technical feature. Groups II-III require the technical feature of a cell population which is not enriched or purified, comprising more than 90% of mature CD56+CD3-iNK cells which is not required by Group I because Group I only requires immature iNK cells. Groups II-III lack unity of invention because even though the inventions of these groups require the technical feature of a cell population which is not enriched or purified, comprising more than 90% of mature CD56+CD3-iNK cells, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Knorr et al. (Stem Cells Transl Med. 2013 Apr;2(4):274-83. Epub 2013 Mar 20.; see IDS filed 6th, September, 2024; henceforth “Knorr”) (see Lack of Unity Mailed on 8th December, 2025 pg. 4-5).
Applicant argues “"[i]f the search and examination of an entire application can be made without serious burden, the Examiner must examine it on the merits even though it includes claims to distinct or independent inventions." Applicant respectfully submits that because of the relatedness discussed above, searches designed for Groups I-III would likely produce overlapping results. Therefore, it is believed that search and consideration of Groups I-III would not impose a serious burden on the Examiner” (pg. 4).
In response, this is not found persuasive because undue search burden are not a criteria for election/restriction purposes under 35 USC §121 and 35 USC § 372.
The requirement is still deemed proper and is therefore made FINAL.
Claims 38-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
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 3-10, 20 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 3 recites the phrase “discontinuously used throughout the step” which renders the scope of the claim indefinite because it is unclear how the media can be used “throughout” the step which includes the entire time, as well as “discontinuously” which requires it is not used the entire step.
Claim 4 recites the phrase “arbitrary order,” with no corresponding definition of the phrase. Since the plain and ordinary meaning of the term “arbitrary” encompasses chosen, decided, etc. seemingly at random or on a whim rather than in a reasoned or methodical way or based on or determined by individual preference or convenience rather than by necessity or the intrinsic value of something (see attached Merriam-Webster Definition), the term “arbitrary” encompasses subjective terminology an therefore, the scope of the claim is unclear. A claim may be rendered indefinite by reference to subjective phrase (see MPEP 2173.05(b), IV). Specifically, the phrase “target level” is a subjective phrase which renders the claim indefinite. The phrase " target level " is not defined by the claim, the specification does not provide a standard for some standard for measuring the scope of the phrase, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Furthermore, the scope of claim 4 is additionally unclear because it is unclear how the recited “another different basal medium” is used in the method because the fifth differentiation culture is recited in claim 1, upon which claim 4 depends, to use a single differentiation culture medium (“a fifth differentiation culture medium” in claim 1) whereas claim 4 recites the use of two basal mediums (“the basal medium supplemented with the combination of (i) nicotinamide-based compound, (ii) heparin-based compound, and (iii) human platelet lysate and an another different basal medium”).
By nature of its dependency on claim 4, claim 5 is also rejected because it does not clarify the issue.
Claim 6 recites “the same basal medium” which renders the scope of the claim indefinite. A “same basal medium” is not recited in claim 1, upon which claim 6 depends, and therefore there is improper antecedent basis for this term and it is unclear what the scope of the “same basal medium” encompasses.
Claim 6 is also indefinite because the phrase “same basal medium” is relative terminology. A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite. See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989). In the instant case the “same basal medium” is dependent on some reference basal medium, which is not sufficiently defined (see MPEP 2173.05(b)).
Claim 7 recites “a basal medium supplemented with (i) nicotinamide-based compound and (ii) heparin-based compound and without (iii) human platelet lysate is continuously used as the other of the basal medium of the fourth differentiation culture medium and the basal medium of the fifth differentiation culture medium” which includes “the other of the basal medium of the fourth differentiation culture medium and the basal medium of the fifth differentiation culture medium.” However, claim 1, upon which claim 7 depends, does not recite an “other of the basal medium of the fourth differentiation culture medium and the basal medium of the fifth differentiation culture medium,” and therefore it is unclear what the scope of this term encompasses and it is unclear how this basal medium is integrated into the method of claim 1, upon which claim 7 depends.
Furthermore, the scope of claim 7 is additionally unclear because it is unclear how the recited “one of the basal medium of the fourth differentiation culture medium” and “the other of the basal medium” are used in the method because the fourth differentiation culture or fifth differentiation culture is recited in claim 1, upon which claim 7 depends, uses a single differentiation culture medium (“fourth differentiation culture medium” or “fifth differentiation culture medium” in claim 1) whereas claim 7 recites the use of two basal mediums.
Claim 8 requires specific amounts of the nicotinamide-based compound. However, claim 1, upon which claim 8 depends, requires the nicotinamide-based compound alternatively in the fourth and/or fifth differentiation culture media. Therefore, it is unclear whether claim 8 is intended to require the nicotinamide-based compound in both the fourth and the fifth differentiation culture medium, or whether it is intended to limits the amounts in either of the fourth and the fifth differentiation culture medium.
Claim 9 requires specific amounts of the heparin-based compound. However, claim 1, upon which claim 9 depends, requires the heparin-based compound alternatively in the fourth and/or fifth differentiation culture media. Therefore, it is unclear whether claim 9 is intended to require the heparin-based compound in both the fourth and the fifth differentiation culture medium, or whether it is intended to limits the amounts in either of the fourth and the fifth differentiation culture medium.
Claim 10 requires specific amounts of the human platelet lysate. However, claim 1, upon which claim 9 depends, requires the human platelet lysate alternatively in the fourth and/or fifth differentiation culture media. Therefore, it is unclear whether claim 9 is intended to require the human platelet lysate in both the fourth and the fifth differentiation culture medium, or whether it is intended to limits the amounts in either of the fourth and the fifth differentiation culture medium.
Claim 20 recites “the concentration of the Wnt signaling pathway activator in the second differentiation culture medium is from 0 to 4 μM” which includes 0 μM of the Wnt signaling pathway activator while claim 17, upon which claim 20 depends, recites “the first and second differentiation culture media are further supplemented with a Wnt signaling pathway activator.” The scope of claim 20 is unclear because it is unclear how the value of 0 μM of the Wnt signaling pathway activator can further limit claim 17 because claim 17 requires the second differentiation culture media are further supplemented with a Wnt signaling pathway activator.
Claim Rejections - 35 USC § 112
Improper Markush
Claim 29 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of “IL-2, IL-10, IL-18, and SB431542” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The grouping is improper because “IL-2, IL-10, IL-18, and SB431542” includes SB431542, which is a TGFβ signaling inhibitor and does not share both a single structural similarity and a common use with IL-2, IL-10 and IL-18 which are cytokines and are structurally and functionally distinct from the TGFβ signaling inhibitor of SB431542.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
Provisional Non-Statutory Double Patenting
U.S. Co-Pending Application No. 18025588
Claims 1-5, 7-10, 17-21, 24-26 and 49-52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-9, 11-15, 19-21 of U.S. Co-pending Application No. 18025588 This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the method for promoting the directed differentiation of pluripotent stem
cells (PSCs) makes obvious the method of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 1, U.S. Co-pending App ‘588 claims method for promoting the directed differentiation of pluripotent stem cells (PSCs), comprising the steps of:
contacting the PSCs with a maintenance culture medium to form embryoid bodies (EBs) (claim 1);
contacting the EBs with a first differentiation culture medium, or with the first
differentiation culture medium and a second differentiation culture medium sequentially,
to form mesodermal cells (claims 1-2);
contacting the mesodermal cells with a third differentiation culture medium to
form hemogenic endothelial (HE) cells (claims 1-2).
contacting the HE cells with a fourth differentiation culture medium to form
hematopoietic progenitor (HP) cells (claim 2).
Regarding claim 1, U.S. Co-pending App ‘588 separately claims contacting the HP cells with a fifth differentiation culture medium to obtain immature iNK cells (claim 3) and it would be obvious to combine the separately claimed embodiments.
Regarding claim 1, U.S. Co-pending App ‘588 separately claims a basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate is used as a basal medium of the fourth differentiation culture medium and/or a basal medium of the fifth differentiation culture medium (claim 11) and it would be obvious to combine the separately claimed embodiments.
Regarding claims 2-4, further to the discussion of claim 1 above, as stated above, U.S. Co-pending App ‘588 claims a basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate is used as a basal medium of the fourth differentiation culture medium and a basal medium of the fifth differentiation culture medium (claim 11), using the basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate for both the fourth and the fifth differentiation encompasses both continuous use (instant claim 2) and discontinuous use (instant claim 3) one of ordinary skill would have at once envisaged either of these two options.
Regarding claim 4, both continuous use and discontinuous use meet the structural requirement of an “arbitrary order.” Regarding claim 4, one of ordinary skill would also not consider the use of “another different basal medium” to be inventive as this encompasses a wash step with basal medium which is well known in the art and further one of ordinary skill would not have considered the “different” basal medium to be inventive because basal mediums are well known in the art, and many different basal mediums would be usable with the claimed invention with no change in respective function and therefore simply substituting with another well-known basal medium would not be inventive.
Regarding claim 5, further to the discussion of claims 1 and 4 above, as stated above, U.S. Co-pending App ‘588 claims using the basal medium supplemented with the combination of (i) nicotinamide-based compound, (ii) heparin-based compound, and (iii) human platelet lysate for the fourth and fifth differentiation culture medium (claim 11), this media includes basal medium is
supplemented with a nicotinamide-based compound and one selected from a heparin-based
compound and a human platelet lysate as claimed. One of ordinary skill would not have considered the “different” basal medium to be inventive because basal mediums are well known in the art, and many different basal mediums would be usable with the claimed invention with no change in respective function and therefore simply substituting with another well-known basal medium would not be inventive.
Regarding claim 7, further to the discussion of claim 1 above, as stated above, U.S. Co-pending App ‘588 claims using the basal medium supplemented with the combination of (i) nicotinamide-based compound, (ii) heparin-based compound, and (iii) human platelet lysate for the fourth and fifth differentiation culture medium (claim 11), and it would be obvious to one of ordinary skill to use this medium for the duration of the culture step of both of the fourth and the fifth differentiation medias.
Regarding claim 8, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the concentrations of the nicotinamide-based compound in the fourth and fifth differentiation culture media are each from 0.5 to 20 mM (claim 12).
Regarding claim 9, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the concentrations of the heparin-based compound in the fourth and fifth differentiation culture media are each from 0.1 to 100 μg/mL (claim 13).
Regarding claim 10, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the concentrations of the human platelet lysate in the fourth and fifth differentiation culture media are each from 0.1 % to 20% by volume (claim 14).
Regarding claim 17, further to the discussion of claim 1 above U.S. Co-pending App ‘588 claims the first and second differentiation culture media are further supplemented with a Wnt signaling pathway activator (claim 1), and the Wnt signaling pathway activator in the second differentiation culture medium is same or different and has an equal or lower concentration as compared to the
Wnt signaling pathway activator in the first differentiation culture medium (claim 4) and it would be obvious to combine these separately claimed embodiments.
Regarding claim 18, further to the discussion of claims 1 and 17 above, U.S. Co-pending App ‘588 claims the Wnt signaling pathway activator is selected from the group consisting of Kenpaullone, 1-Azakenpaullone, CHIR99021, CHIR98014, NP031112, TWS119, AZD2858, AZD1080, SB415286, LY2090314, ARA014418, SB216763, BIO-Acetoxime, (5-Methyl-lH-pyrazol-3-yl)-(2- phenylquinazolin-4-yl)amine, 2-Thio(3-iodobenzyl)-5-( 1-pyridyl)[ 1,3,4 ]-oxadiazole, alpha-4- Dibromoacetophenone, 3-(l-(3-Hydroxypropyl)-1H-pyrrolo[2,3-b ]pyridin-3- yl]-4-pyrazin-2-yl-pyrrole-2,5-dione, 2-Chloro-1-( 4,5-dibromo-thiophen-2-yl)-ethanone, GF109203X, and any combination thereof (claim 8).
Regarding claim 19, further to the discussion of claims 1 and 17 above, U.S. Co-pending App ‘588 claims the second differentiation culture medium has the same composition as that of the first differentiation culture medium except that the concentration of the Wnt signaling pathway activator in the second differentiation culture medium is lower than the concentration of the Wnt signaling pathway activator in the first differentiation culture medium (claim 5).
Regarding claim 20, further to the discussion of claims 1 and 17 above, U.S. Co-pending App ‘588 claims the concentration of the Wnt signaling pathway activator in the second differentiation culture medium is from 0.5 to 4 μM (which lies within the claimed 0 to 4 μM and thereby makes it obvious) , and the concentration of the Wnt signaling pathway activator in the first differentiation culture medium is from 4 to 8 μM (claim 6).
Regarding claim 21, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the nicotinamide-based compound comprises nicotinamide, and the heparin-based compound comprises heparin sodium (claim 15).
Regarding claim 24, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the first to fourth differentiation culture media are each independently further supplemented with a VEGF at a concentration of 15 to 100 ng/mL (claim 19).
Regarding claim 25, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the first to fifth differentiation culture media are chemically defined serum-free and xeno-free differentiation culture media (claim 20).
Regarding claim 26, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 claims the method is carried out under 3D culture condition (claim 21).
Regarding claim 49, further to the discussion of claims 1 and 17 above, U.S. Co-pending App ‘588 claims the third differentiation culture medium is further supplemented with a Wnt signaling pathway inhibitor (claim 1).
Regarding claim 50, further to the discussion of claims 1, 17 and 49 above, U.S. Co-pending App ‘588 claims the concentration of the Wnt signaling pathway inhibitor in the third differentiation culture medium is from 1 to 30 μM (claim 7).
Regarding claim 51, further to the discussion of claims 1, 17 and 49 above, U.S. Co-pending App ‘588 claims the Wnt signaling pathway inhibitor is selected from the group consisting of iCRT3, IWP-O1, IWP-2, IWP-3, IWP-4, Ciclopirox, Cardamonin, Diethyl benzylphosphonate, Disodium Pamidronate Hydrate, Ginsenoside Rh4, KY-05009, Isoquercitrin, Gigantol, JW55, MSAB, IWR-1-endo, FH535, WIKI4, KYA1797K, NCB-0846, iCRT14, Adavivint, M435-1279, and XAV939, and any combination thereof (claim 9).
Regarding claim 52, further to the discussion of claims 1, 17 and 49 above, U.S. Co-pending App ‘588 claims the third differentiation culture medium (claim 1) and is silent to a TGF-β signaling pathway inhibitor and it would therefore be obvious not to include a TGF-β signaling pathway inhibitor in this embodiment.
Since the instant application claims are obvious over cited application claims, said claims are not patentably distinct.
Claims 6, 11-12, 27-33 and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-9, 11-15, 19-21 of U.S. Co-pending Application No. 18025588 in view of Unannounced Inventor (CN-111235105-A; ANHUI NUWACELL BIOTECHNOLO GY CO. LTD; Published 5th, June, 2020; citations refer to attached translation; henceforth “Nuwacell”).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of U.S. Co-pending App ‘588 are incorporated herein in their entirety.
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the method for promoting the directed differentiation of pluripotent stem
cells (PSCs) makes obvious the method of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 6, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 is silent to using the same basal medium for the first to third differentiation basal media.
Nevertheless, regarding claim 6, U.S. Co-pending App ‘588 teaches using IMDM as a basal media for multiple steps of differentiating pluripotent stem cells into NK cells (pg. 5).
Therefore, regarding claim 6, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘588 and combine the known prior art element of using the same basal media for the differentiation steps of Nuwacell to obtain the predictable result of a basal media. One of ordinary skill would have been motivate to do so because Nuwacell teaches using the same basal media for differentiation steps is effective in a method for obtaining NK cells from pluripotent stem cells (pg. 5) and also and Nuwacell also provides a reasonable expectation of success for this.
Regarding claim 11, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 does not claim seeding the HP cells on a cell culture surface coated with a Notch pathway activator and an adhesion molecule.
Nevertheless, regarding claim 11, Nuwacell teaches a method step of seeding HP cells on a cell culture surface coated with a Notch pathway activator (claims 6-8; see also pg. 7 and 9) and an adhesion molecule as part of a method to differentiate HP cells into NK cells. Nuwacell teaches the combined use of small molecule reagents, cytokines and cell matrix further increases the proportion of blood precursor cells and facilitates the production of subsequent clinical grade cell preparations (pg. 14 Example 3).
Therefore, regarding claim 11, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘588 and combine the known prior art element of the of seeding HP cells on a cell culture surface coated with a Notch pathway activator and an adhesion molecule to obtain the predictable result of differentiation HP cells into NK cells. One of ordinary skill would have been motivated to do so as taught by Nuwacell to further increase the proportion of blood precursor cells and facilitates the production of subsequent clinical grade cell preparations (pg. 14 Example 3). Regarding the reasonable expectation of success, Nuwacell evidences a method step of seeding HP cells on a cell culture surface coated with a Notch pathway activator (claims 6-8; see also pg. 7 and 9) and an adhesion molecule as part of a method to differentiate HP cells into NK cells (see also pg. 14 Example 3).
Regarding claim 12, further to the discussion claims 1 and 11 above, Nuwacell specifically teaches and suggests the Notch pathway activators of DLL4, DLL1, Jagged-1, Jagged-2, variants thereof, and any combination thereof (claim 8), and the adhesion molecule is selected from VCAMl, Fibronectin, Laminin, Vitronectin, MAdCAM-1, ICAM, variants thereof (claim 8) and it would therefore be obvious to use these specific Notch pathway activators and adhesion molecules suggested by Nuwacell for the reasons set forth above.
Regarding claim 27, further to the discussion of claim 1 above, U.S. Co-pending App ‘588 does not claim a step for expanding and maturing the immature iNK cells.
Nevertheless, regarding claims 27, Nuwacell teaches a method step of contacting NK cells with a differentiation culture medium that is a basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate (“basic differentiation medium to which interleukins and a substance promoting the maturation and expansion of NK cells are added” claim 9 and “the substance promoting NK cell maturation and expansion is selected from one or more of human AB plasma, human platelet lysate, Vitamin A, nicotinamide, Vitamin E and Heparin” claim 10; see also pg. 4 20th para.; pg. 8 4th para.; pg. 13 9th para) to promote NK cell maturation and expansion (pg. pg. 4 20th para.; pg. 8 4th para.; pg. 13 9th para).
Therefore, regarding claim 27, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘588 and combine the known prior art element of the step for expanding and maturing the immature iNK cells by contacting NK cells with a differentiation culture medium that is a basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate of Nuwacell to obtain the predictable result of a method step of expanding and maturing NK cells. One of ordinary skill would have been motivated to do so as taught by Nuwacell to promote NK cell maturation and expansion (pg. pg. 4 20th para.; pg. 8 4th para.; pg. 13 9th para). Regarding the reasonable expectation of success, Nuwacell evidences a method step of expanding and maturing NK cells (pg. 8).
Regarding claim 28, further to the discussion of claims 1 and 27 above, Nuwacell teaches and suggests the expansion medium comprising a basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate and it would be obvious to use this media for the reasons set forth above.
Regarding the feeder cells of claim 28, Nuwacell teaches the method step does not use feeder cells during expansion so that the method is suitable for the production and application of subsequent clinical-grade cell preparations (pg. 9) and it would therefore be obvious to exclude feeder cells during the expansion made obvious by Nuwacell above for this purpose.
Regarding claim 29, further to the discussion of claims 1 and 27-28 above, Nuwacell teaches the expansion and maturation culture medium is further supplemented with one or more of IL-2, IL-10, IL-18(pg. 9) and SB431542 (pg. 12) and it would be obvious to use these supplements for the reasons set forth above.
Regarding claim 30, further to the discussion of claims 1 and 27-28 above, Nuwacell teaches a concentration of nicotinamide of 1-10 mmol/L (pg. 13) (which lies within the claimed range of “from 0.5 to 20 mM”) in the expansion media and it would be obvious to use this nicotinamide concentration for the reasons set forth above.
Regarding claim 31, further to the discussion of claims 1 and 27-28 above, Nuwacell teaches a concentration of heparin-based compound of heparin of 0-100 µg/mL (pg. 13) (which overlaps with the claimed range of “0.1 to 100 μg/mL”) in the expansion media and it would be obvious to use this nicotinamide concentration for the reasons set forth above.
Regarding claim 32, further to the discussion of claims 1 and 27-28 above, Nuwacell teaches a concentration of human platelet lysate of 1-10% (pg. 13) (which lies within the claimed range of “0.1 % to 20% by volume”) in the expansion media and it would be obvious to use this nicotinamide concentration for the reasons set forth above.
Regarding claims 30-32, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. Therefore, the ranges of nicotinamide (instant claim 30), heparin (instant claim 31) and human platelet lysate (instant claim 32), taught and suggested by Nuwacell above which lie within or overlap with the claimed ranges, render the instantly claimed ranges obvious.
Regarding claim 33, further to the discussion of claims 1 and 27-28 above, Nuwacell teaches the nicotinamide-based compound comprises nicotinamide (pg. pg. 4 20th para.; pg. 8 4th para.; pg. 13 9th para). Although Nuwacell is silent to heparin sodium, this is a well-known obvious species of heparin-based compounds and further would be obvious to use because U.S. Co-pending App ‘588 separately claimed heparin sodium as a preferred species of heparin-based compound (claim 15).
Regarding claim 36, further to the discussion of claims 1 and 27-28 above, Nuwacell teaches the expansion and maturation culture medium is a chemically defined serum-free and xeno-free culture medium (“the method uses serum-free medium and does not use feeder cells during induction of differentiation and expansion” pg. 9) for the production and application of subsequent clinical-grade cell preparations (pg. 9) and it would therefore be obvious to use chemically defined serum-free and xeno-free culture medium for this purpose in the expansion and maturation culture medium suggested above.
Since the instant application claims are obvious over cited application claims, in view of Nuwacell, said claims are not patentably distinct.
Pertinent Art
Ditadi
The prior art of Ditadi et al. (Methods. 2016 May 15:101:65-72. Epub 2015 Oct 9.; henceforth “Ditadi”), made of record but not relied upon is considered pertinent to Applicant’s disclosure.
Ditadi teaches a method for promoting the directed differentiation of pluripotent stem cells (PSCs) (“Directed differentiation of definitive hemogenic endothelium and hematopoietic progenitors from human pluripotent stem cells” Title), comprising the steps of:
contacting the PSCs with a maintenance culture medium to form embryoid bodies
(EBs) (see “Resuspend cells gently with minimal trituration into ‘‘Day 0”
SFD media” from “Directed differentiation of hPSCs towards mesoderm” pg. 68 col. 1 steps (5)-(9)))
contacting the EBs with a first differentiation culture medium to form mesodermal cells (“Resuspend EBs gently in ‘‘Day 2” SFD media” pg. 68 col. 2);
contacting the mesodermal cells with a third differentiation culture medium to
form hemogenic endothelial (HE) cells (see “add 2 mL of ‘‘Day 6” SP34 media” from “3.4. Specification and isolation of hemogenic endothelium” pg. 68 col.2 and pg. 69 col. 1);
contacting the HE cells with a fourth differentiation culture medium to form hematopoietic progenitor (HP) cells (see “Resuspend in HE media (Table 4) at 2 x 105 cells per mL from “3.6. Generation of definitive hematopoietic progenitors” pg. 69 col. 2) (see also Figure 2 and Table 4 and “3. Methods” pg. 67-70).
Examiner’s Remark
The prior art does not teach or fairly suggest including basal medium supplemented with the combination of (i) a nicotinamide-based compound, (ii) a heparin-based compound, and (iii) a human platelet lysate during a step of forming hemogenic endothelial (HE) cells or a step of forming hematopoietic progenitor (HP) cells and therefore the claims are free of the prior art. However, the claims are not allowable for the reasons set forth above.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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