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 .
Election/Restrictions
Claims 1-7, 9-10, 12-25, and 27-28 are pending.
Applicant’s election without traverse of Group I, a method, corresponding to claims 1-7, 9-10, and 12-24 in the reply filed on 07/28/2026 is acknowledged.
Claims 25 and 27-28, corresponding to compositions are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/28/2026.
Claims 1-7, 9-10, and 12-24 have been examined on their merits.
Claim Objections
Claims 1, 7, and 17-18 are objected to for the following informalities: the claim recites dashes after wherein clauses (e.g., wherein – the plurality). The dashes are used to visually separate the clauses not for grammatical purposes and therefore are improper (see MPEP 608.01(m), a claim must be a sentence). It is noted that simply removing the dashes would have the same effect of visually separating clauses and also overcome the objection.
Claim 10 is objected to for the following informalities: the claim recites the limitation “the first culture medium.” While it is clear that the first culture medium refers to “a medium” in claim 1 (since the first culture medium is for the first cell aggregates), for uniformity, either reference to a first culture medium in claim 1 should be made or the word “first” should be removed from claim 10.
Claim 16 is objected to for the following informalities: the claim recites “one or more growth factor” which should be “one or more growth factors.” Appropriate correction is required.
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, 5, 9, 12-16, 18-22, and 24 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.
Regarding claim 3, the claim recites in parentheses “(residual)”, Regarding the concentration of BMP4. The claim is indefinite because it unclear if the parenthetical information is a requirement or merely exemplary (see MPEP 2173.05(d)).
Regarding claim 5, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For compact prosecution, the limitation has been interpreted as optional.
Regarding claim 9, the claim recites in parentheses “(through budding)”, Regarding release of hematopoietic stem cells (HSCs) from aggregates. The claim is indefinite because it unclear if the parenthetical information is a requirement or merely exemplary (see MPEP 2173.05(d)).
For compact prosecution, the claims have been interpreted as being optional and allowing for release of HSCs from aggregates by any method.
Additionally, parenthetical or exemplary language is found in claim 15 (“e.g. between 10 and 250 ng/mL”), claim 16 (“such as”) claim 22 (“such as” and “(including alpha/beta T-cells and gamma/delta T cells)”), and claim 24 (“exogenous”) which are likewise indefinite (see MPEP 2173.05(d)). For compact prosecution, parenthetical language is considered optional.
Claims 12-16 and 18-22 are rejected under 35 USC 112(b) for their dependence on claim 9.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 allows for average size diameters of first cell aggregates of 20 – 250 micrometers, 2 – 150 micrometers, etc. However, claim 1 requires that the first cell aggregates have an average size of about 49 or less micrometers in diameter. Therefore, claim 7 is not further limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-7, 9-10, 12-13, 15-19, 22, and 24 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Feng et al., (US20210395684A1, on IDS 09/23/2024).
Regarding claim 1, Feng discloses methods for the generation of hemogenic endothelial cells (HECs) (claim 1). Feng teaches the method comprises (a) providing a plurality of PSC cells in suspension culture to yield 3D spheres (aggregates) of PSCs (claim 1; paragraph [0054]). Feng discloses in step (b) that these aggregates are cultured in a medium to generate a plurality of second cell spheres (aggregates) comprising HECs (claim 1). Feng discloses that the first aggregates have an average size of about 60 micrometers (claim 1). Feng also discloses that the term “about” means “within 20%” (paragraph [0060]) (thus, as small as 48 micrometers), which overlaps with the claimed average size of 49 micrometers or less.
Regarding claim 2, regarding step (b), the step may be further comprises a step (b1) of culturing wherein the culture medium does comprise a SMAD pathway agonist, optionally BMP4, and, a step (b2) of culturing wherein the culture medium is at least partly replaced by fresh medium which does not comprise a SMAD pathway agonist, and, wherein step (b1) is before step (b2).
Turning to the art, Feng discloses that the step (b) may include a medium comprising SMAD pathway agonist BMP4 (claim 9; Fig. 3A; e.g., any of D1-D6), and thus, step (b1). Feng also disclsoes that following this, cells may be cultured in a medium that does not contain a SMAD pathway agonist (Fig. 3A; e.g., D7-12, D13).
While Feng discloses that BMP may be added to multiple medium cocktails (D1-D6), it is noted that the claims only require that at least one medium does not comprise a SMAD pathway agonist and the claim “comprises” the steps (b1) and (b2), which allows for multiple media cocktails which may contain a SMAD pathway agonist. Therefore, the expansion media (D7-12, D13) read on the limitation of step (b2).
In regards to the timings, any of step (b1), D1 through D6, including D1-D6 (six total days) is a duration time that is less than (b2), D7-12 or at least also D13 (which is at least 6 or 7 days) as claimed.
Regarding claim 3, Feng discloses that BMP4 can have a concentration of 25 ng/mL (paragraph [0029]), which overlaps with the claimed range in step (b1).
Regarding claim 5, Feng discloses that the step (b2) medium can comprise GSK3beta inhibitor CHIR099012 (claim 9).
Regarding claim 6, Feng disclosed that the step (b) medium can comprise VEGF or bFGF (claim 9).
Regarding claim 7, as above, Feng discloses that the first spheres (aggregates) can have an average diameter of 60 micrometers (Claim 1), which overlaps with the claimed range of 20 to 250 micrometers.
Regarding claim 9, Feng discloses a step (c) wherein HEC aggregates (the second plurality of aggregates) are further differentiated in media to produce a third sphere (aggregate) that releases cells (hematopoietic progenitor cells) as into single cells in suspension (claim 1; paragraphs [0054, 0056, 0135, 0162]). As taught by Feng, these cells are naturally released from spheres (paragraph [0055]). While Feng is silent as to whether hematopoietic stem cells (HSCs) specifically are released, Feng also discloses that HSCs are found in and can be isolated from the spheres (paragraph [0162-0164]).
Additionally, the instant specification explicitly states that the release of HSCs as single cells is an inherent property of the differentiation process of HECs (see instant paragraph [0083], “During this differentiation process . . . HECs gradually round up, separate from their neighboring cells and bud off, releasing HSC as single cells in the surrounding”).
Therefore, the method of Feng is determined to release HSCs in suspension in the culture medium absent evidence to the contrary.
Regarding claim 10, the claim recites “wherein the plurality of first cell aggregates are provided in the first culture medium at a density of at least 100 aggregates/mL, optionally between 100 – 100000 aggregates/mL.”
It is noted that while the specification describes methods of re-seeding PSC aggregates (“PSC aggregates were formed using bioreactor technology and re-seeded in plates at the start of differentiation. 3 densities where tested, 667 aggregates per ml” (paragraph [0031])).
However, while the claims are interpreted in light of the specification, they must be given their broadest reasonable interpretation (see MPEP 2111), and the specification is not read into the claim (See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)).
Turning to claim interpretation, again, claim 10 recites “wherein the plurality of first cell aggregates are provided.” However, claim 1, from which it depends recites “culturing a suspension of pluripotent stem cells (PSCs) thereby providing.”
Thus, taken together, the plain language of the claim suggests that the “provided” aggregates do not an active method step, but rather the result of culturing PSCs in suspension as in claim 1. Therefore, giving claim 10 its broadest reasonable interpretation consistent with the specification, the plurality of aggregates that are provided and their densities are interpreted as an inherent property of performing the active method step of claim 1, not as subsequent step such as obtaining a number of aggregates and replating those aggregates.
Therefore, since Feng discloses the active method step of culturing a suspension of PSCs thereby providing a plurality of first cell aggregates comprising said PSCs, it would inherently result in the claimed density of aggregates in claim 10, absent evidence to the contrary.
Regarding claim 12, Feng discloses that HSCs can be found in and can be isolated from the spheres (paragraph [0162-0164]). As discussed above, the release of HSCs is an inherent property of differentiated HEC in culture (see instant paragraph [0083]). Therefore, a person of ordinary skill in the art would have recognized that HSCs are being released prior to their specific isolation form the spheres.
Regarding claim 13, regarding the percentages of HSCs, e.g., at least 50%, etc., this is an inherent property of HSCs that have budded off after differentiation of HECs. Moreover, the only active method step is generically differentiating HSCs in a differentiation medium, which the claim suggests is sufficient to obtain the claimed percentages. Since the method of Feng carries out these steps, it is deemed to result in HSCs at the claimed percentages absent evidence to the contrary. Furthermore, Feng discloses that cells express markers including at least CD34 (paragraph [0043])
Regarding claim 15, Feng discloses that the medium for differentiation of HECs can comprise TPO (claims 13 and 15; paragraph [0030]).
Regarding claim 16, Feng discloses that the third medium can comprise FLT3L (paragraph [0030]).
Regarding claim 17, Feng discloses that the HECs are positive for CD73 (paragraph [0038]).
Regarding claim 18, Feng discloses that the HSCs express CD34 (paragraph [0156]).
Regarding claim 19, Feng discloses that the hematopoietic cells can be cryopreserved (paragraph [0054]).
Regarding claim 22, Feng discloses that the HECs are differentiated to lymphoid cells including NK cells (claim 1; paragraph [0165]).
Regarding claim 24, Feng discloses that the method is carrier-free (i.e., without a solid support) and feeder cell-free (paragraphs [0056, 0071, 0111])
Therefore, Feng anticipates the invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Feng et al., (US20210395684A1, on IDS 09/23/2024) and Faudoa (US20070004037A1).
Feng anticipates claim 1 as discussed above.
Regarding claim 4, while Feng teaches that media can be refreshed (paragraphs [00125, 190]), Feng is silent as to the volume of replaced media between (b1) and (b2). However, it would have been prima facie obvious to remove high percentages of media in order to eliminate growth factors on cocktails and maximize the effect of other growth factors in new cocktails (e.g., the differences in growth factors between (b1) and (b2). Furthermore, a person of ordinary skill in the art could have arrived at the claims percentages (concentrations) by routine optimization and the disclosure does not point to a criticality in these percentages.
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 re Aller, 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.”) (See MPEP 2144.05(II)(A)).
In the instant case, because Faudoa teaches that media can be replaced, resulting in mixed media, and in % volumes ranging from about 10% to about 90% (paragraph [0037]), which overlaps with the claimed amounts and establishes replacement of media as a result-effective variable, a person of ordinary skill in the art could have arrived at the claimed percentages by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Feng and Faudoa render the invention unpatentable as claimed.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Feng et al., (US20210395684A1, on IDS 09/23/2024) and Powell et al. (Cytotherapy, 2009).
Regarding claim 14, Feng teaches that that stem cells can be separated by centrifugation (paragraphs [0153, 0193]), but is silent on counterflow centrifugal elutriation (CCE). However, counterflow centrifugal elutriation (CCE) was a long-known method for separating cells, including blood cells. Specifically, a person of ordinary skill in the art would have been motivated to employ a CCE system because Powell teaches that it can enrich blood-cell types (Title, Abstract, p923) and circumvents the need for beads or antibodies to facilitate removal (p924). Furthermore, because Powell teaches known CCE devices for separating cells (p024), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Feng and Powell render the invention unpatentable as claimed.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Feng et al., (US20210395684A1, on IDS 09/23/2024) in view of Yagi et al. (Proc Natl Acad Sci USA, 1999).
Feng anticipates claims 1 and 9 as discussed above.
Regarding claim 20, Feng is silent on proliferating HSCs specifically. However, a person of ordinary skill in the art would have been motivated to expand these cells in order to obtain a larger amount of them for therapeutic or research purposes. Furthermore, because Yagi teaches that is it known that HSCs can be expanded in vitro (Abstract, Introduction, p8126), it could have been done with predictable results and a reasonable expectation of success.
Regarding claim 21, in regards to the expansion ratio of PSCs to HSCs, of at least 50, etc., this is an inherent property of expanding HSCs. Moreover, the only active method step is generically expanding HSCs, which the claim indicates is sufficient to achieve this result. Therefore, since it would be prima facie obvious to expand HSCs as discussed above, it is deemed to result in the same expansion ratio absent evidence to the contrary.
Therefore, the combined teachings of Feng and Yagi render the invention unpatentable as claimed.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Feng et al., (US20210395684A1, on IDS 09/23/2024).
Feng anticipates claim 1 as discussed above.
Regarding claim 23, Feng teaches that the method can be performed in a bioreactor (paragraph [0027]). The method of Feng does not require a specific cell selection or enrichment step. It would have been prima facie obvious to forgo selection or enrichment steps in order simplify experimental steps, or save time, or resources.
Therefore, the teachings of Feng render the invention unpatentable as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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