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 .
Withdrawn Objections/Rejections
The objection to claim 6/8 is withdrawn. The amendments to the claims remove the duplicate recitation.
The rejection of claim 6, 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. The amendment to the claim overcome the issue of indefiniteness.
Non-Statutory 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 1-15 and 18-22, as amended, previously presented or originally presented, remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 49-52 of copending Application No. 18/025,590 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant and copending claims have overlapping, non-mutually exclusive subject matter.
Regarding claim 1, copending claim 49 discloses 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); contacting the EBs with a first differentiation culture medium supplemented with a Wnt signaling activator, or with the first differentiation culture medium supplemented with a Wnt signaling activator and a second differentiation culture medium supplemented with a Wnt signaling activator sequentially, to form mesodermal cells; contacting the mesodermal cells with a third differentiation culture medium supplemented with a Wnt signaling inhibitor to form hemogenic endothelial (HE) cells. Claim 49 further more narrowly specifies the Wnt signaling pathway activation 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. As such, copending claim 49 discloses an anticipatory species of instant claim 1, rendering claim 1 obvious.
Regarding claim 2, copending claim 49 further recites contacting the HE cells with a fourth differentiation culture medium to form hematopoietic progenitor (HP)cells. As such, copending claim 49 discloses an anticipatory species of instant claim 2, rendering instant claim 2 obvious.
Regarding claim 3, copending claim 49 further recites contacting the HP cells with a fifth differentiation medium to obtain immature iNK cells. As such copending claim 49 discloses an anticipatory species of instant claim 3, rendering it obvious.
Regarding claim 4, copending claim 49 specifies the Wnt signaling pathway activation 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 as claimed in claim 4. Copending claim 49 also additionally contacts the result HE cell with a medium to form HP cells and then contacting the HP cells with another medium to obtain immature iNK cells. As such, claim 49 has a narrower scope than claim 4. Thus, claim 49 is an anticipatory species of instant claim 4.
Regarding claim 5, copending claim 49 specifies the Wnt signaling pathway activation in the second differentiation culture medium is same and has a lower concentration as compared to the Wnt signaling pathway activator in the first differentiation culture medium as claimed in claim 5. Copending claim 49 also additionally contacts the result HE cell with a medium to form HP cells and then contacting the HP cells with another medium to obtain immature iNK cells. As such, claim 49 has a narrower scope than claim 5. Thus, claim 49 is an anticipatory species of instant claim 5.
Regarding claim 6, copending claim 49 teaches the limitation of the method of claim 6 as discussed above. Copending claim 49 does not species that the second medium has a Wnt activator concentration at a range of 0 to 4 µM and the first medium has a Wnt activator concentration at a range of 4 to 8 µM. However, at the time of the copending and instant claims determining optimal concentrations of Wnt activator in the two different differentiation mediums of copending claim 49 was routine optimization in the art. As such, it would have been obvious to choose from a finite number of possible concentration for the Wnt activator in the first and second medium to predictable arrive at the Wnt activation concentration claim through routine optimization using well established optimization protocol. As such, copending claim 49 is an obvious species of instant claim 6.
Regarding claim 7, copending claim 50 teaches the concentration of the third differentiation medium is from 1 to 30 µM. As such, claim 50 is an anticipatory species of claim 7 for reasons discussed above.
Regarding claim 8, copending claim 51 teaches the same list of Wnt activator species as instant claim 8. Thus claim 51 is an anticipatory species of instant claim 8 for reasons discussed above.
Regarding claim 9, copending claim 49 teaches the Wnt inhibitor as discussed above. Copending claim 49 does not teach the species listed in claim 9 for the Wnt inhibitor. However, many of the Wnt inhibitors (such as the IWPs and XAV0939) if not all were art established Wnt inhibitor available for use in the method of claim 49 As such, copending claim 49 is an obvious variant of instant claim 9.
Regarding claim 10, copending claim 52 recites that same limitations as instant claim 10. As such, copending claim 52 is an obvious variant of instant claim 10 for reasons discussed above.
Regarding claim 11, copending claim 49 specifies the basal medium is supplemented with a combination of (i) a nicotinamide-based compound; (ii) heparin-based compound; and/or (iii) a human platelet lysate in the fourth and fifth medium. As such, copending claim 49 is an obvious variant of instant claim 11.
Regarding claim 12-14, These claims specify the concentrations for the nicotinamide-based compound, the heparin-based compound, and the human platelet lysate, which copending claim 49 does not teach. However, optimizing concentrations is routine optimization. As such, copending claim 49 is an obvious variant for instant claims 12-14.
Regarding claim 15, copending claim 49 does not teach the species of nicotinamide and heparin sodium. However, nicotinamide is the most obvious species of a nicotinamide-based compound and heparin sodium is a commonly-used well established species of a heparin based compound. As such, it would have been obvious to used these common forms of nicotinamide and heparin as claimed in claim 15 in the method of copending claim 49.
Regarding claim 18, copending claim 49 does not teach that the base medium is the same. However, often the same base medium is used throughout a differentiation method and thus it would have been obvious to an artisan to use the same medium in copending claim 49 throughout. As such, copending claim 49 is an obvious variant of claim 18.
Regarding claim 20, copending claim 49 does not expressly teach the use of a serum free, xeno-free chemically defined medium. However, before filing, the advantages of using serum-free, xeno-free, chemically-defined medium were well established in the art for clinical application. As such, it would be obvious to use such medium as defined by claim 20 in the method of copending claim 49 with a reasonable expectation of success.
Regarding claim 21, copending claim 49 discloses the culture is of an EB which is a 3D culture condition. As such, copending claim 49 is an obvious variant of instant claim 21.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In the remarks, Applicant requests that the provisional double patenting rejection be held in abeyance until allowable subject matter is identified. In response, the rejection is maintained.
Claim Rejections - 35 USC § 103
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.
(1) Claim(s) 1-10 and 18-21 is/are rejected under 35 U.S.C. 103 as being unpatentable Kaji (WO 2021/041858 A1 pub date:3/4/2021 effectively filed: 8/29/2019) in further view of Sturgeon (Sturgeon et al. Nature Biotech 32(6):554-562).
Regarding claim 1, Kaji teaches pluripotent progenitor cells, including but not limited to embryonic stem cells, grown in the presence of embryonic fibroblasts are induced to form embryoid bodies in a single-cell suspension. Alternative methods may be employed to separate the embryonic stem cells from the embryonic fibroblast feeder cells. The embryonic stem cells may then be cultivated in serum-free differentiation media to form embryoid bodies (p. 15, [63]). Thus Kaji disclose the step of contacting PSC with a maintenance culture medium to form embryoid bodies (EBs). The embryoid bodies are specified to multipotent mesoderm (such as paraxial or lateral plate mesoderm). In some embodiments, embryoid bodies are specified to multipotent mesoderm by cultivating the cells in media comprising a Wnt pathway agonist, including but not limited to, Wntl, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt9A, Wnt9B, WntlOA, Wntl 0B, Wntl 1, Wntl 6, or CHIR99021 (an inhibitor of glycogen synthase kinase (GSK) 3). See p. 16, [67]. Thus Kaji teaches the limitations of contacting EB with a first differentiation medium comprising a Wnt signaling pathway activator to form mesoderm cells.
Kaji does not teach further culturing the mesodermal cells in a differentiation medium comprising a basal medium supplemented with a Wnt signaling pathway inhibitor to obtained hemogenic endothelial (HE) cells. However, before the time of effectively filing, Sturgeon teaches that culturing mesoderm cells ( KDR+CD235a+) in a differentiation medium comprising the Wnt inhibitor, IWP-2, give rise to CD34+CD43- HE that are able to be further differentiated into primitive hematopoietic cell such as erythroid, myeloid, and NK cells (p. 557, paragraph bridging col 1 and 2 to p. 559 and Figure 5).
As such, it would have been obvious to an artisan of ordinary skill at the time of the invention to further differentiate the mesoderm cell into HE cells by contacting the mesoderm cells produced by the method of Kaji with a Wnt inhibitor as taught by Sturgeon. The artisan would have a reasonable expectation of success because Kaji produced mesoderm cells and Sturgeon teaches that applying a Wnt inhibitor to such mesoderm cells derived from pluripotent cells successfully gives rise to HE cells. Further, the artisan would have been motivated to further apply a Wnt inhibitor to the mesoderm cells taught by Kaji because HE cell produced by inhibiting the Wnt signaling pathway gives rise to primitive hematopoietic cells such as erythroid, myeloid, and natural killer cells. As such, Kaji in view of Sturgeon render claim 1 obvious.
Regarding claims 2, Kaji does not teach further contacting the HE cells in a fourth differentiation medium to obtain hematopoietic progenitor (HP) cells as claimed. However, Sturgeon teaches that CD34+ cells (i.e. HE cell) from mesoderm culture had the ability to give rise CD34+KDR+CD325+ HP cells (p. 556, col 1). These teachings encompass the limitations of contacting the HE cells with a fourth differentiation media to obtain HP cells, since the specific HP cell and none of the components of the fourth differentiation media are defined in claim 2.
As such, it would have been obvious to an artisan of ordinary skill before the time of filing to both further culture the HE cells of the combined method of Kaji in view of Sturgeon in a differentiation medium that producing HP cells as taught by Sturgeon to predictably arrive at the limitations of claim 2. The artisan would have a reasonable expectation of success because Sturgeon teaches means of further differentiating cells to a HP cell state. Further, the artisan would be motivated to continue differentiation culture to obtain HP cell derived from pluripotent cells. Thus, Kaji in view of Sturgeon render claim 2 obvious.
Regarding claim 3, Kaji does not teach further contacting the HP cells with a fifth differentiation medium to obtained immature NK cells. However, Sturgeon teaches that CD34+/CD43- (HE cells) and CD34+/CD43+ (HP cells) from mesoderm culture had the ability to give rise NK cells (p. 557, col 1; Figure 5). These teachings encompass the limitations of contacting the HP cells with a fifth differentiation media to obtain HP cells, since none of the components of the media are fourth differentiation media of claim 3 are defined.
As such, it would have been obvious to an artisan of ordinary skill before the time of filing to both further culture the HE cells of the combined method of Kaji in view of Sturgeon in a differentiation medium that producing NK cells as taught by Sturgeon to predictably arrive at the limitations of claim 3. The artisan would have a reasonable expectation of success because Sturgeon teaches means of further differentiating cells to an immature NK cell state. Further, the artisan would be motivated to continue differentiation culture to obtain NK cell derived from pluripotent cells. Thus, Kaji in view of Sturgeon render claim 3 obvious.
Regarding claim 4, it recites wherein the Wnt activator of the first and second differentiation medium are contacted sequentially and the Wnt activator is the same and at equal concentration. This embodiment of claim 4 encompasses the routine medium changes associated with common cell culture maintenance for multiple days. Kaji cultures in the present of Wnt activator for multiple days. As such, it would have been obvious to an artisan in the cell culture to changed the medium in the mesoderm cell derivation method of Kaji as needed with a reasonable expectation of success. As such, claim 4 is an obvious variant of Kaji in view of Sturgeon.
Regarding claim 5, it recites wherein the first and second differentiation culture medium has the same composition except the second culture medium has a lowered concentration of the Wnt activator than the first culture medium. Kaji does not expressly teach the use of a two mediums having different concentrations of the Wnt inhibitor. However, Kaji does teach the use of the Wnt inhibitor CHIR99021 in the mesoderm specification medium in a range of 0.5-10 µM. In some embodiments, the concentration of CHIR99201 is 3-8 µM (p. 16, [67]). As such, one of ordinary skill would understand the use of CHIR99021 anywhere within this range will lead to mesoderm cells as required. Thus it would have been obvious to use the same of any degree lower in the second medium as compared to the first as long as it falls within the designated range. Determining such a lower concentration would be within routine experimentation and optimization. As such, the limitations of claim 5 are rendered obvious by the teachings of Kaji in view of Sturgeon.
Regarding claim 4-6, in a narrower teaching, Kaji teaches culturing mouse EBs in a medium comprising SFD+CHIR99021 at 5µM+LDN-193189 (i.e. 4 to 8 µM as claimed) and then changed to a medium comprising SDF+ LDN-193189 (0 to 4 µM as claimed). As such, Kaji in view of Sturgeon renders claim 6 obvious.
Regarding claim 7, Sturgeon teaches their differentiation medium comprises 3µM IWP2 (see p. 21 of the methods section from the printed supplemental) which is a species of 1 to 30µM Wnt inhibitor claimed. Sturgeon does not teach the full range. However,
MPEP § 2144.05 (I) states, “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 reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”)…. "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005) (claimed alloy held obvious over prior art alloy that taught ranges of weight percentages overlapping, and in most instances completely encompassing, claimed ranges; furthermore, narrower ranges taught by reference overlapped all but one range in claimed invention).
Further MPEP § 2144.05 (II) states, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration range is critical, thus the teaching of 3 µM by Sturgeon renders the claimed concentration range obvious.
Regarding claim 8, Sturgeon teaches CHIR99021 as discussed above.
Regarding claim 9, Sturgeon teaches IWP-2 as discussed above.
Regarding claim 10, Sturgeon teaches the use of two mediums to arrive at HE cells, but that delineate the direction the HE cells can further differentiate. As discussed above, differentiation medium comprising a Wnt inhibitor, IWP-2, allow for the formation of HE+ cell, however, these cells did not have further differentiation potential to T-cells, but did have differentiation potential to NK cells (see figure 5). Sturgeon also culture the mesoderm cells derive from pluripotent cells in a differentiation medium comprising a Wnt activator or the TGFβ inhibitor, SB-431542. Culturing the mesoderm cells in differentiation medium comprising the Wnt activator or the TGFβ inhibitor, also provided HE cell. However, these cells had T cell differentiation potential (p. 555, col 1 and Figure 5).
As such, it would have been obvious to the artisan of ordinary skill before the time of filing to apply a differentiation medium comprising SB-431542 as taught by Sturgeon to the mesodermal cells taught in the mesodermal production method of Kaji to predictably arrive at HE cells. The artisan would have a reasonable expectation of success because Sturgeon teaches that the differentiation medium comprising SB-431542 also successfully produces HE cells. Further, the artisan would be motivated to use the differentiation medium of SB-431542, taught by Sturgeon, with the mesodermal cells of Kaji because Sturgeon teaches that this will allow for the production of HE cells with T cell differentiation potential. As such, Kaji in view of Sturgeon render claim 10 obvious.
Regarding claim 18, Kaji teaches that their first medium is a serum-free differentiation (SDF) medium (p. 15, [636]). Sturgeon also teaches that their differentiation medium, which corresponds to the third culture medium of the claims is an SDF medium (paragraph 1 of methods). As such, both Kaji and Sturgeon are using the same medium. As such Kaji in view of Sturgeon teaches limitations of the claim and rendering it obvious.
Regarding claim 19, Kaji does not teach further adding VEGF at a concentration of 15 to 100 ng/Ml to the first through fourth differentiation medium when the method is used to arrive at HP cells. However, Sturgeon further discloses after adding VEGF (15 ng/ml) to the differentiation medium for differentiation toward hematopoietic lineage (see paragraph 1 under methods in Sturgeon supplement). As such, it would have been obvious to an artisan of ordinary skill before filing to add VEGF at 15 ng/mL, as taught by Sturgeon, to the any or all of the differentiation medium, to the method of Kaji. Further, the artisan would be motivated to add VEGF because it is used in media to support hemopoietic differentiation.
Regarding claim 20, Kaji and Sturgeon chemically defined, serum-free, xeno-free medium as discussed above.
Regarding claim 21, Kaji uses a embryoid body culture, thus using 3D culture conditions as claimed. Thus Kaji in view of Sturgeon render claim 21 obvious.
(2) Claim(s) 11-15 is/are rejected under 35 U.S.C. 103 as being unpatentable Kaji (WO 2021/041858 A1 pub date:3/4/2021 effectively filed: 8/29/2019) and Sturgeon (Sturgeon et al. Nature Biotech 32(6):554-562), as applied to claims 1-10 and 18-21, in view few of Translation (English translation for C111235105B published 8/10/2021, pages 1-20).
Regarding claim 11, Kali and Sturgeon teaches the claim as discussed above. Kali and Sturgeon do not teach the fourth and fifth media further comprises a (i) nicotinamide based compound; (ii) a heparin-based compound; and/or a platelet lysate. However, before filing, Translation teaches adding nicotinamide, heparin and platelet lysate to the fourth and fifth medium to promote NK cell maturation and amplification (p. 6, paragraph 2).
As such, it would have been obvious before the time of effective filing to further add nicotinamide, heparin, and platelet lysate, as taught by Translation, to the last two differentiation mediums of the NK cell production method of Kali and Sturgeon to predictably arrive at the limitations of claim 11. An artisan would have a reasonable expectation of success because Translation successful add these elements to the HP and NK differentiation medium to arrive at NK cells. Further the artisan would be motivated to add nicotinamide, heparin, and platelet lysate because Translation teaches that it will promoter NK cell maturation and amplification. As such, Kali and Sturgeon in further view of Translation render claim 11 obvious.
Regarding claims 12-14, Translation further discloses that the platelet lysate can be added at a concentration of 1-10% (i.e. a subset of 0.1% to 20%). The nicotinamide can be added at a concentration of 0.1-10 mmol/L (i.e. overlapping subset of 0.5 to 50 mM). The heparin can be added at a concentration of 0-100 µg/ml (i.e. overlapping subset of 0.1 to 100µg/ml). See page 9, section 3.
Regarding claim 15, Translation teaches nicotinamide as discussed above. Translation does not teach that the species of heparin is a heparin sodium. However, heparin sodium in a long-established and commonly used for of heparin in cell culture. As such, an obvious variant. Thus, Kali and Sturgeon in view of Translation and well established prior art render claim 15 obvious.
Response to Arguments
Applicant's arguments filed 3/18/2026 have been fully considered but they are not persuasive.
Applicant traverse the rejections on the grounds that Kali does not contact the PSC with maintenance culture medium to form EBs but rather places the cells in differentiation medium to form EBs prior to differentiation of the EB as the claim requires.
In response, Applicant is not giving “contacting PSCs with maintenance culture medium to form embryoid bodies” its broadest reasonable interpretation and is reading limitations into the recited step that are not required. As previously made of record in the claim interpretation section, “maintenance culture medium” is not defined and is only defined by its ability to “maintain”. “Maintenance” broadly encompasses the functional limitations of maintaining cells in ANY way. “To form embryoid bodies” only limits the functional aspects of the medium to one that has the capacity to form embryoid bodies and is conditional language. As such, the breadth of the recites any mediums that has the capacity to form EB. As such, the breadth of the claimed culture step is contact the PSC with ANY medium that has the capacity to form EBs. Kali expressly describes two different ways to contact an PSC that form EBs regardless of the content of that medium and regardless if differentiation is also occurring in that medium, which Examiner is not suggest is the case.
Applicant submits as defined in the specification, maintenance medium is culture medium in which pluripotent stem cells can grow and proliferation; however, as is known in the art, the PSCs remain an undifferentiated state. That is to say, PSC are already in a 3D culture environment before the start of differentiation.
In response, the specification expressly defines a “maintenance culture medium” as follow, citations from pre-grant publication:
[0064] As used herein, the term “maintenance culture medium” refers to a culture medium which can support the survival, growth, propagation, or maintenance of cells in an in vitro environment.
Thus the specification does not limit maintenance culture medium to one which allows pluripotent stem cells to grow and proliferate, as Applicant submits, but rather more broadly and expressly allows for survive or maintain. Thus the breadth of the claimed maintenance medium is ANY medium that allows any type of maintenance and expressly survival. Kali clearly provide such a medium that minimally allows for survival and maintenance and expressly states that is forms embryoid bodies. Thus contrary to Applicant’s arguments, Kali expressly teaches the first contact step.
Applicant submits that Sturgeon teaches culturing EBs simultaneously with a Wnt activator and a Wnt inhibitor, not separately as the claims require. In response, Applicant is reading limitations into the disclosures of Sturgeon and also considering the combined teachings of Kaji and Sturgeon as a whole. Applicant is reminded that Kaji expressly teaches culturing EBs in a differentiation culture medium comprising a Wnt activator that predictable produces mesoderm cells as the claims require. The citation provided by Applicant states “Aggregates were resuspended in SFD3 supplemented with L-glutamine…Activin A, SB-431542 (6µM), CHIR99021 (3µM), and/or IWP2 (3µM).” Applicant appears to be interpreting the term “and/or” as treating with the Wnt activator and the wnt inhibitor simultaneously. However, if one looks at figures 3 and 4, Sturgeon clearly teaches medium the uses either the wnt activator OR the wnt inhibitor. Further, Sturgeon expressly teaches that culturing mesoderm cells ( KDR+CD235a+) in a differentiation medium comprising the Wnt inhibitor, IWP-2, give rise to CD34+CD43- HE that are able to be further differentiated into primitive hematopoietic cell such as erythroid, myeloid, and NK cells (p. 557, paragraph bridging col 1 and 2 to p. 559 and Figure 5). As such, Sturgeon clearly teaches that mesoderm cells, such as the one produced in the method of Kaji, can be further differentiated into HE if they are further cultured in a medium comprising a Wnt inhibitor. As such, considering the cumulative and whole teachings of Kaji and Strugeon one of ordinary skill would have amble teachings of the claimed method with a reasonable expectation of success and motivation to combine these two prior arts to do so.
Applicant submits that Kaji and Strugeon does not teach contacting EBs with a first medium comprising a Wnt activator “and then” a second medium comprising a Wnt activator” and a third medium comprising a Wnt inhibitor. Therefore not all the limitations of the claims are taught.
In response, Applicant is not giving the claims their broadest reasonable interpretation and also not considering the full context of the combined teaching. Applicant implicates that the first and second medium are required to be two different and separate mediums contacting the cell on two separate, independent occasions. However, the claims do not recite this and therefore cannot be given such a narrow interpretation. The only difference between the first medium and the second medium in terms of structural requirements is literally the term “first” and “second”. Other than the terms first and second the medium is identical in structure and function as is the contact of EBs with them. “And then” does not impart any type of separateness or independent nature to the recited first and second medium. It does not specify any particular time point the first and second medium is applied. As such, it does not necessarily impart any further limitations to the medium or mediums contacting the EB with Wnt activator. Even it one was to interpret the term “and then” to mean two applications of an identical medium to the EBs, the breadth of such a limitations includes changing culture medium between days 2-3 or refreshing the medium. As such, it is well within the skill of the ordinary artisan to determine if a media change is necessary or if one application or two applications of the same medium is needed over a multiple day differentiation culture. As such, contacting a first “and then” a second medium of identical structure over multiple day culture is an obvious variant. Sturgeon provides ample teaching of contacting with a different medium with a Wnt inhibitor to mesoderm cells which Kaji’s method produces. As such, an artisan that would have the desire to produce HE cells from the mesoderm cells could the additionally apply the medium of Sturgeon to predictably arrive at HE.
Applicant submits that the Office has not provided motivation for one to combine Kaji and Sturgeon. Kaji differentiates PSC into tenocytes, while Sturgeon differentiates PSCs into HEs. The two end-product cell types a greatly different. Therefore there would be no motivation to use a method that produces tenocytes with a method that produces HEs.
In response, the fact that Kaji further differentiates the mesoderm cells into tenocytes does not negate that Kaji provides a method of producing mesoderm cells that contacts PSC with a medium to form EBs and contacts the EBs with a medium comprising a Wnt activator to produce mesoderm cells as claimed. Further, the rejection of record does provide an express rationale for combining the prior art of Kaji and Sturgeon, which is to allow for the production of HE from the mesoderm cells and further have the ability to give rise to primitive hematopoietic cells such as erythroid, myeloid, and natural killer cells (see the rejection of record reiterated above). As such, the rejection provides ample motivation to combine Kaji and Sturgeon.
Applicant submits that the claimed invention leads to unpredictable results. Applicant refers to paragraph [0107] and states it improves efficiency, length of time, and yield and such results would not have been reasonable expected.
In response, the claims do not recite any type of improvement in efficiency and or yield. The claims only recites promoting directed differentiation of PSCs. As such all that is required from this method is a reasonable expectation that one would obtain HE cells. Kaji provides a predictable method of producing mesoderm cells and Sturgeon provides a predictable method of producing HE cells from mesoderm cells. As such, the claimed results of the claims is not an unexpected results and can be predictable arrives upon through the combined teachings of Kaji and Sturgeon.
Applicant submits that the addition of Translations does not overcome the above described deficiency of Kaji and Sturgeon. Applicant further submits that the medium of Translation, S4, is for the maturation and expansion of NK cells. In contrast, the fourth and fifth medium of the claims are to form PH cells and immature iNK cells.
In response, Applicant’s arguments are not found persuasive because Applicant is reading limitations into the claims that are not recited by the claims. The claims do not recite or imply that the mediums of claims 11-15 results in the production of HP or immature NK cells. As such, these limitations are not required by the claims. However, Sturgeon does teach that the production of NK cells and provides a method of producing HE cells and Translation provide a method using identical mediums to produce NK cells. As such, the combine prior art teaches the requisite predictable means of producing NK cells from HE cells and a motivation to do so.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/ Primary Examiner, Art Unit 1632
Prosecution Insights