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 1-3, 6-7, 9-11, 13-14, 18-19, 21, 24, 28-29, 31-32, and 34-37 are pending.
Claims 6-7, 10, 18, 28-29 and 31-32 are withdrawn.
Claims 1-3, 9, 11, 13-14, 19, 21, 24, and 34-37 are under examination.
Election/Restrictions
Note that amended claim 6 is directed to species that are directed to inventions that are not so linked as to form a general inventive concept under PCT Rule 13.1 for the following reasons:
Amended claim 6 has been amended to recite the required limitations of “a hypoxia mimetic, a ROS scavenger, a HIF stabilizer or a combination thereof” which are drawn to the previously non-elected species of reduced reactive oxygen species culture conditions as originally presented in the Lack of Unity mailed on 9th, July, 2025.
Since applicant has received an action on the merits for the originally presented species, this species has been constructively elected by original presentation for prosecution on the merits. Accordingly, amended claim 6 is withdrawn from consideration as being directed to a non-elected species. See 37 CFR 1.142(b) and MPEP § 821.03.
Claims 1-3, 9, 11, 13-14, 19, 21, 24, and 34-37 are under examination.
Withdrawn Claim Objections
The objection to claim 21 due to informalities as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “≤3% oxygen or less” which includes both “≤” and “3% oxygen or less” and is therefore unnecessarily redundant. It is recommended that Applicant amend to either “≤3% oxygen” or “3% oxygen or less.”
Appropriate correction is required.
Moot Claim Rejections 35 USC § 112(b)
The rejection of claim 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is moot in view of the cancellation of this claim.
Withdrawn Claim Rejections 35 USC § 112(b)
The rejection of claims 1, 3, 6, 9, 11, 13-14, 19, 21 and 24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections 35 USC § 112(d)
The rejection of claim 17 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 is moot in view of the cancellation of the claim.
Moot Claim Rejections - 35 USC § 112
Improper Markush
The rejection of claim 6 on the basis that it contains an improper Markush grouping of alternatives as set forth in the previous office actin is moot because amended claim 6 is withdrawn due to species election by original presentation.
Moot Claim Rejections - 35 USC § 102
The rejection of claim 17 under 35 U.S.C. 102(a)(1) as being anticipated by Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as set forth in the previous office action is moot in view of the cancellation of this claim.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims 1, 11, 13-14, 17, 19 and 24 under 35 U.S.C. 102(a)(1) as being anticipated by Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections - 35 USC § 103
The rejection of claim 17 under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as set forth in the previous office action is moot in view of the cancellation of this claim.
The rejection of claim 6 under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Maurer et al. (Transfus Med Hemother. 2013 Oct;40(5):344-50. Epub 2013 Sep 19; henceforth “Maurer”) as set forth in the previous office action is moot because amended claim 6 is withdrawn due to species election by original presentation.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claim 9 under 35 U.S.C. 103 as being unpatentable over Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) in view of Spahr et al. (Springer Berlin Heidelberg, Berlin, Heidelberg, 1 January 1990; see IDS filed 9th, October, 2025, henceforth “Spahr”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 21 under 35 U.S.C. 103 as being unpatentable over Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) in view of Zonari et al. (Stem Cell Reports. 2017 Apr 11;8(4):977-990. Epub 2017 Mar 16.; henceforth “Zonari”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
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.
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.
Claims 1-3, 11, 13-14, 19 and 24 remain rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”).
Regarding claim 1, Tursky discloses a method comprising expanding hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo (“culturing or expanding a HPC and/or HSC population” pg. 5 2nd para. ; see also pg. 5 3rd para, pg. 19 2nd and 5th para., pg. 23 3rd para., pg. 27 5th para., pg. 32 1st para., Example 1 pg. 33 “Ex vivo expansion”; Examples 2-4) in culture medium under conditions comprising reduced atmospheric oxygen levels (“range of oxygen levels (2.5% 5% and 10%; pg. 6 last para. ; see also pg. 7 2nd-3rd para., pg. 8 3rd-4th para., pg. 9 3rd-5th para., pg. 20, pg. 21 last para., pg. 22 1st-2nd para., pg. 26 1st-2nd and 4th para., pg. 27 1st-4th para., pg. 33 3rd and 5th para., pg. 34 1st-2nd para., pg. 36 2nd para., pg. 38 1st-3rd para., pg. 39, pg. 40 1st-3rd para., pg. 41 1st para., pg. 42 2nd-4th para., pg. 43; claims 6-9; Figures 1-3, 5-6, 8) including oxygen levels of 2.5%, which is within the claimed range of an atmosphere of less than or equal to 3% which is the physiologically relevant oxygen level consistent with bone marrow (pg. 33 3rd para.) to thereby generate an expanded population of hematopoietic stem cells and/or hematopoietic progenitor cells (“fold expansion observed in 2.5% oxygen in this study” pg. 34 2nd para.).
Furthermore, regarding the oxygen concentration of claim 1, it is noted that the oxygen level of 2.5% is specifically disclosed by Tursky as the physiologically relevant oxygen level consistent with bone marrow (pg. 33 3rd para.) and it would therefore be obvious to choose this specific concentration of oxygen from the disclosure of Tursky. 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. In the instant case, the specific disclosed embodiment of the oxygen level of 2.5% of Tursky is within the claimed range of less than or equal to 3% Oxygen and therefore makes the instantly claimed range obvious.
Additionally, regarding the oxygen concentration of claim 1, Applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II). Moreover, at the time of the claimed invention, one of ordinary skill in the art would have been motivated by routine practice to optimize the oxygen concentration in the culture method with a reasonable expectation for generating an expanded population of hematopoietic stem cells and/or hematopoietic progenitor cells.
Regarding the term “hypoxic” in the preamble of claim 1, as discussed above, Tursky specifically suggests an atmosphere of 2.5% oxygen which is hypoxic conditions.
However, regarding claim 1, although Tursky discloses expanding hematopoietic stem cells, Tursky does not disclose the method comprises expanding the hematopoietic stem cells in the presence of endothelial cells.
Nevertheless, regarding claim 1, Butler teaches expanding hematopoietic stem cells (LT-HSCs) in the presence of endothelial cells (“Bone marrow endothelial cells (ECs)”) to support in vitro self-renewal of hematopoietic stem cells (summary; see also pg. 261 col. 2 “Hematopoietic Cell Isolation, Hematopoietic Cell Culture, and Flow Cytometry”).
Therefore, regarding claim 1, 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 of Tursky, and combine the known prior art element of expanding hematopoietic stem cells in the presence of endothelial cells of Butler to obtain the predictable result of expanded hematopoietic stem cells. One of ordinary skill would have been motivated to do so as taught by Butler to support in vitro self-renewal of hematopoietic stem cells (LT-HSCs; abstract; see also pg. 261 col. 2 “Hematopoietic Cell Isolation, Hematopoietic Cell Culture, and Flow Cytometry”) and to support clinical scale expansion of the HSCs (summary). Regarding the reasonable expectation of success, Butler evidences expanding hematopoietic stem cells in the presence of endothelial cells (“Bone marrow endothelial cells (ECs)”) (summary; see also pg. 261 col. 2 “Hematopoietic Cell Isolation, Hematopoietic Cell Culture, and Flow Cytometry”).
Regarding claim 2, further to the discussion of claim 1 above, Tursky teaches the reduced atmospheric oxygen levels comprise 1% Oxygen or 0.5% Oxygen which is less than 1% Oxygen (pg. 20 line 16).
Additionally, regarding claim 2, as discussed above (see claim 1 rejection above), differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II), and one of ordinary skill in the art would have been motivated by routine practice to optimize the oxygen concentration.
Regarding claim 3, further to the discussion of claim 1 above, Tursky teaches the culture medium further comprises at least one cytokine (Flt-3 ligand; pg. 7 lines 2 and 18, pg. 9 lines 1-3, pg. 24 line 15, pg. 33 line 14, pg. 34 line 11, pg. 37 line 27, pg. 39 line 7, pg. 42 lines 4-5; claims 11 and 13; see also “interleukins 3, 6 and 11, stem cell factor, stem cell ligand, FL T-3 ligand, and thrombopoietin” claim 16 which are cytokines).
Regarding claim 11, further to the discussion of claim 1 above, the endothelial cells suggested by Butler above express an exogenous wild type adenovirus E4 open reading frame 1 (E4ORF1) polypeptide (“E4ORF1+ ECs” pg. 252 col. 1 2nd para, pg. 252 col. 2, pg. 253 col. 1, pg. 254 col. 2 2nd para., pg. 255 col.2, pg. 256 col. 1 1st para., pg. 256 col. 2, pg. 257 col. 1 2nd-3rd para., pg. 257 col. 2 1st para., pg. 261 col 1 3rd para., pg. 261 col. 2 last para., pg. 262 col. 1 2nd and 4th para., pg. 262 col. 2 2nd-4th para., pg. 263 col. 1 2nd-3rd and 4th para., pg. 263 col. 2 1st para. ; Figures 1-3, 5).
Regarding claim 13, further to the discussion of claim 1 above, Tursky teaches the hematopoietic stem cells are obtained from donor bone marrow, umbilical donor cord blood (“umbilical cord blood or bone marrow” pg. 16 line 24 and pg. 17 lines 23-24), or donor peripheral blood (pg. 17 line 26) (see also claim 19).
Regarding claim 14, further to the discussion of claim 1 above, Tursky teaches a functional result of expanding the hematopoietic stem cells by at least 10 fold or at least 40 fold (Figure 2), and Butler teaches a functional result of expanding the hematopoietic stem cells by at least 10 fold or at least 40 fold (Figure 1C), and it would therefore be obvious that the method as suggested by Tursky in view of Butler would also arrive at this functional result.
Regarding claim 19, further to the discussion of claim 1 above, the hematopoietic stem cells taught by Tursky are from full-term deliveries (Example I; pg. 32 lines 15-21). “Full term” is a condition and therefore the Full term human subjects of Tursky meets the broadest reasonable interpretation of a subject suffering from “a condition.”
Furthermore, regarding claim 19, concerning the claimed limitation of “the hematopoietic stem cells and/or hematopoietic progenitor cells are from a subject suffering from a disease or condition,” this is a product-by-process limitation with respect to the hematopoietic stem cells and/or hematopoietic progenitor cells. Product-by process limitations are not limited by the manipulation of the recited steps, only the structure implied by the steps (see MPEP 2113). Since many disease and conditions do not structurally affect hematopoietic stem cells, the cells taught by Tursky are structurally indistinct from hematopoietic stem cells from a subject suffering from a disease or condition that is not genetic and/or does not involve hematopoietic stem cells.
Regarding claim 24, further to the discussion of claim 1 above, Tursky teaches aliquoting portions of the hematopoietic stem cells into a series of separate receptacles (“Cells from 10 different umbilical cord blood samples were cultured for 8 days in the presence of different combinations of growth factors” pg. 43; Example 3), adding one or more different test agents to the separate receptacles to form a series of test mixtures (“different combinations of growth factors” pg. 43; Example 3; see also “adding ficolins-1, ficolin-2, or ficolin-3 to the culture media at either 50 ng/ml, 100 ng/ml or 200 ng/ml in the presence of TFSI growth factors” Example 4 pg. 43), expanding the hematopoietic stem cells in the test mixtures (total expansion in Example 3 and expanding colony forming units in Example 4), and quantifying the types of cells within the test mixtures after expansion to obtain a series of quantified cell numbers for the different test mixtures (“total expansion of CD34+CD45+ hematopoietic cells” pg. 42 Example 3 and Figures 6-7; “3-fold increase in total colonies” Example 4 and Figures 10-11; see also Figure 1 and pg. 7-8 Figure 1 legend and pg. 22-24).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 4th, March, 2026, have been fully considered but are not found persuasive.
Applicant argues “the cited references, even as combined, do not render amended claim 1, and its dependents, obvious because neither reference teaches or suggests the claimed hypoxic endothelial-cell co-culture at less than or equal to 3% oxygen as a solution to the problem addressed by the present application” (pg. 9).
In response, as set forth in the grounds of rejection above, Tursky specifically discloses an operable embodiment of an oxygen level of 2.5%, and further that the oxygen level of 2.5% is specifically disclosed by Tursky as the physiologically relevant oxygen level consistent with bone marrow (pg. 33 3rd para.) and therefore further makes it obvious to select this specific embodiment from the disclosure of Tursky. MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. In instant case, the prior art of Tursky can reasonably be relied upon to teach the specific embodiment of 2.5% oxygen levels as it clearly discloses this embodiment as an option for reduced oxygen conditions and further makes this option obvious because it is the physiologically relevant oxygen level consistent with bone marrow (pg. 33 3rd para.).
Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
In response to Applicant’s argument that neither reference “teaches or suggests the claimed hypoxic endothelial-cell co-culture less than or equal to 3% oxygen as a solution to the problem addressed by the present application” (pg. 9), this is not found persuasive because MPEP 2144 (IV) states that the reason or motivation to modify a reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). In instant case, as discussed above, the prior art teaches of Turkey specifically teaches and makes obvious the 2.5% oxygen level because it is the physiologically relevant oxygen level consistent with bone marrow (pg. 33 3rd para). The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant further argues “nor does the Office Action identify a technically supported reason why a skilled artisan would have modified Butler's endothelial cell co-culture to operate under the specific hypoxic atmosphere now required by claim 1 with a reasonable expectation of success” (pg. 9).
In response, the motivation to combine the prior art of Tursky and Butler is discussed in the grounds of rejection and response to arguments above. In brief, one of ordinary skill would have been motivated to combine the endothelial cells taught by Butler to support in vitro self-renewal of hematopoietic stem cells and to support clinical scale expansion of the HSCs. Concerning the reasonable expectation of success, Butler evidences expanding hematopoietic stem cells in the presence of endothelial cells and Tursky evidences expanding hematopoietic stem cells and/or hematopoietic progenitor cells in low oxygen conditions, including the 2.5% oxygen condition.
Furthermore, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).
Applicant argues “The instant specification demonstrates that oxygen tension materially alters outcomes and is not a mere routine optimization. in view of these oxygen-dependent biological effects, Applicant respectfully submits that the proposed combination is not supported by a sufficient rationale
establishing that the claimed hypoxic endothelial-cell co-culture would have been expected to provide
the claimed expansion.”
In response, as discussed above, generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II). Criticality of a claimed range is an unexpected result. To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). While Applicant asserts “the instant specification demonstrates that oxygen tension materially alters outcomes and is not a mere routine optimization” this is not “a sufficient number of tests both inside and outside the claimed range” as required by MPEP 2144.05 II and therefore cannot show the criticality of the claimed range.
Further in response, arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements regarding the criticality of the claimed ranges ( which is an alleged unexpected result) are not evidence without a supporting declaration. Specifically, Applicant has not provided objective scientific evidence on the record that the “oxygen-dependent biological effects” are facilitated over prior art products.
Concerning the alleged unexpected results, the burden is on the Applicant to establish results are unexpected and significant (MPEP 716.02(b)(I)), Applicants have the burden of explaining the proferred data (and MPEP 716.02(b)(II)), and the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support (MPEP 716.02(d)(I)). In the instant case, the assertion that “oxygen tension materially alters outcomes” and that there are “oxygen-dependent biological effects” does not establish that the results are unexpected and significant because it is a mere conclusory statement and does not accompany factually objective evidence (see Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.")).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c) (MPEP 716.02(b)(I)). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. (MPEP 716.02(b)(II)).
In the instant case, Applicant’s alleged unexpected results are insufficient to overcome the rejection of record under 35 U.S.C. 103 for several reasons. First, as discussed above, the alleged unexpected results are not supported by factually objective evidence on the record. Next, the unexpected result does not compare with the closest prior art. Because the data cited by Applicant is not compared to the closest prior art, the statistical and practical significance of the date (required by MPEP 716.02(b)(II); see above) are not apparent. Finally, the alleged unexpected results do not appear to be in scope with the claimed invention, as the criticality of the claimed range has not been shown.
Claim Rejections - 35 USC § 103
Claim 9 remains rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Spahr et al. (Springer Berlin Heidelberg, Berlin, Heidelberg, 1 January 1990; see IDS filed 9th, October, 2025, henceforth “Spahr”). The teachings of Tursky and Butler above are hereby incorporated in their entirety.
Regarding claim 9, further to the discussion of claim 1 above, Tursky and Butler are silent to the endothelial cells being in microcarriers.
Nevertheless, regarding claim 9, Spahr teaches culturing endothelial cells in microcarriers to enlarge the surface for growing for anchorage-dependent endothelial cells (pg. 220 1st para.). Spahr further teaches microcarrier cultures are an ideal system to produce large quantities of cultured cells, and cells cultured on microcarriers can also be easily transferred from one experimental system to another (pg. 220 1st para.).
Therefore, regarding claim 9, 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 suggested by Tursky in view of Butler, and combine the known prior art element of culturing the endothelial cells in microcarriers of Spahr to obtain the predictable result of cultured endothelial cells. One of ordinary skill would have been motivated to do so as taught by Spahr to enlarge the surface for growing for anchorage-dependent endothelial cells and to allow for easy transfer of the endothelial cells (pg. 220 1st para.). Regarding the reasonable expectation of success, Spahr evidences culturing endothelial cells in microcarriers (pg. 222-223 “Microcarrier Cultures”).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 4th, March, 2026, have been fully considered and are not found persuasive.
Applicant argues “Butler repeatedly shows expansion only when HSCs form cobblestones in direct apposition to ECs, and transwell separation '·'was unable to expand" the cells (Butler, Figs. 3B---F”)(pg. 11). Applicant further argues “The Office has not identified any teaching in Spahr suggesting that moving from Butler's adherent EC niche to suspended microcarriers would preserve the contact-dependent Notch signaling Butler identifies as essential, nor any reason one of ordinary skin
would expect success.” (pg. 11).
In response, in the grounds of rejection above, the secondary reference of Butler is relied upon only for teaching and suggesting combining endothelial cells and is not relied upon for combining “contact-dependent Notch signaling” conditions. Thus the suggested combination above, which has the primary reference of Tursky, and is a combination of Tursky in view of Butler and Maurer does not require the “contact-dependent Notch signaling” conditions contested by Applicant. Furthermore, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, arguments directed to the conditions of Butler without including the teachings of Tursky, is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references and therefore may be considered to be an argument that attacks the reference(s) individually, as set forth by MPEP 2145 (IV).
Additionally, In response to applicant's argument, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, for the reasons set forth above, the combined teachings of Tursky in view of Butler and Maurer suggest all the required elements of the claimed combination for the reasons set forth above, and the assertation that some of the features of the secondary reference of Butler may not bodily incorporated into the structure of the primary reference (alleged “preserve the contact-dependent Notch signaling Butler identifies as essential”) is not part of the 35 U.S.C. § 103(a) based test for obviousness.
Concerning Applicant’s argument that the office has not identified any reason one would expect success, conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). Applicant is directed to MPEP 2143.02 which states that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, while the prior art suggests the reason for modification, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result, is not necessarily required. In the instant case, Spahr evidences culturing endothelial cells in microcarriers (pg. 222-223 “Microcarrier Cultures”), which is the preparation of the claimed modification and therefore provides a reasonable expectation of success.
Applicant argues “Spahr, by contrast, is about mass production of EC on microcarriers and perfused columns, not J-ISC co-culture or Notch-ligand presentation” (pg. 11).
In response to applicant's argument that Spahr is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, the prior art reference is in the field of the inventor’s endeavor, cell culture and more specifically culture of endothelial cells.
Claim 21 remains rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Zonari et al. (Stem Cell Reports. 2017 Apr 11;8(4):977-990. Epub 2017 Mar 16.; henceforth “Zonari”). The teachings of Tursky and Butler above are hereby incorporated in their entirety.
Regarding claim 21, further to the discussion of claim 1 above, Tursky and Butler are silent to genetically modifying the hematopoietic stem cells to generate genetically modified hematopoietic stem cells.
Nevertheless, regarding claim 21, Zonari teaches a method comprising genetically modifying hematopoietic stem cells to generate genetically modified hematopoietic stem cells (pg. 983-984 “Robust HSC Gene Transfer Using Short Culture Time and Prostaglandin E2”; see also Experimental Procedures pg. 988 col. 1), and then expanding the genetically modified hematopoietic stem cells (“Ex Vivo Expansion of Gene-Modified HSCs Supported by Small-Molecule Compounds” Figure 4; see also Experimental Procedures “Ex Vivo HSPC Expansion” pg. 988 col. 1) for ex vivo genetic engineering of HSPCs for gene therapy with “an optimal, clinically applicable strategy to purify HSCs” (pg. 979 col. 1) for use in transplantation of genetically engineered, autologous HSPCs as a less risky and potentially more efficacious alternative to allogeneic transplantation for a series of non-malignant indications (pg. 986 col. 2 2nd para.).
Therefore, regarding claim 21, 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 suggested by Tursky in view of Butler and combine the known prior art element of genetically modifying hematopoietic stem cells to generate genetically modified hematopoietic stem cells and expanding the genetically modified hematopoietic stem cells of Zonari to obtain the predictable result of a population of HSCs for use in transplantation. One of ordinary skill would have been motivated to do so as taught by Zonari to obtain HSPCs for gene therapy for use in transplantation of genetically engineered, autologous HSPCs as a less risky and potentially more efficacious alternative to allogeneic transplantation for a series of non-malignant indications (pg. 986 col. 2 2nd para.). Regarding the reasonable expectation of success, Zonari evidences genetically modifying hematopoietic stem cells to generate genetically modified hematopoietic stem cells (pg. 983-984 “Robust HSC Gene Transfer Using Short Culture Time and Prostaglandin E2”; see also Experimental Procedures pg. 988 col. 1), and then expanding the genetically modified hematopoietic stem cells (“Ex Vivo Expansion of Gene-Modified HSCs Supported by Small-Molecule Compounds” Figure 4; see also Experimental Procedures “Ex Vivo HSPC Expansion” pg. 988 col. 1).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 4th, March, 2026, have been fully considered and are not found persuasive.
Applicant argues “The Examiner's argument combines three disparate paradigms: hypoxia without stromal cells (Tursky), endothelial co-culture under ambient oxygen (Butler), and feeder-free, short-duration engineering/expansion (Zonari), to reach instant claim 21 's hypoxic/low-ROS endothelial niche and subsequent expansion of genetically modified HSCs. Bm there is no reason why a person of ordinary skill in the art would modify Butler's ambient-oxygen E4ORFH- EC system with Tursky's
stroma-free hypoxia and then further apply Zonari's feeder-free gene-modification workflow” (pg. 12).
Applicant further argues “Butler's expansion hinges on E40:R.F1+ ECs at ambient O2 not hypoxia; Tursky's hypoxia results are in stroma-free systems and do not suggest adding ECs, and Zonari explicitly seeks to avoid prolonged/feeder conditions, noting that extended culture impairs engraftment and advocating ultra-short, feeder-free protocols (Zorn.n1, pp. 977-984 )” (pg. 12)
In response, as discussed above, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, for the reasons set forth above, the combined teachings of Tursky in view of Butler and Zonari suggest all the required elements of the claimed combination for the reasons set forth above, and the assertation that some of the features of the secondary reference of Butler or Zonari may not bodily incorporated into the structure of the primary reference (alleged “three disparate paradigms”) is not part of the 35 U.S.C. § 103(a) based test for obviousness. The reasons for each modification are set forth in the rejection of record above.
Applicant argues “the combination assumes the invention and relies on hindsight” (pg. 12)
In response, Applicant is directed to MPEP 2145 (X)(A) which states that "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). In the instant case, because the each of the claimed elements is made obvious by the combination as set forth above, which takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made, the reconstruction is proper.
Applicant agues an unexpected result (pg. 12). Specifically Applicant argues “The specification shows unexpected synergy precisely where the art is silent: hypoxia plus ECs expands adult and diseased HSCs with long-term, multilineage repopulation. Neither Butler's ambient-oxygen EC platform nor Tursky's stroma-free hypoxia, nor Zonari 's feeder-free engineering, achieves or suggests this effect, especially for gene-modified adult/diseased HSCs” (pg. 12).
In response to Applicant’s arguments, arguments of counsel cannot take the place of
factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145
USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed.
Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus,
Attorney statements regarding the unexpected result are not evidence without a supporting declaration. Specifically, Applicant has not provided objective scientific evidence on the record that the
“long-term, multilineage repopulation” is facilitated over prior art products.
Concerning the alleged unexpected results, the burden is on the Applicant to establish results are unexpected and significant (MPEP 716.02(b)(I)), Applicants have the burden of explaining the proferred data (and MPEP 716.02(b)(II)), and the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support (MPEP 716.02(d)(I)). In the instant case, the assertion that “the specification shows unexpected synergy precisely where the art is silent: hypoxia plus ECs expands adult and diseased HSCs with long-term, multilineage repopulation” does not establish that the results are unexpected and significant because it is a mere conclusory statement and does not accompany factually objective evidence (see Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.")).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c) (MPEP 716.02(b)(I)). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. (MPEP 716.02(b)(II)).
In the instant case, Applicant’s alleged unexpected results are insufficient to overcome the rejection of record under 35 U.S.C. 103 for several reasons. First, as discussed above, the alleged unexpected results are not supported by factually objective evidence on the record. Next, the data cited by Applicant is not compared to the closest prior art. Because the data cited by Applicant is not compared to the closest prior art, the statistical and practical significance of the date (required by MPEP 716.02(b)(II); see above) are not apparent. Finally, because Applicant does not cite data to support the conclusory statement, it is not apparent whether the alleged unexpected results are commensurate in scope with the claimed invention.
Applicant argues “The cited references are inconsistent with the claimed approach, leaving no reasonable expectation of success to apply gene .. modification and subsequent expansion within a hypoxic endothelial niche” (pg. 12).
In response, as set forth above, Zonari evidences genetically modifying hematopoietic stem cells to generate genetically modified hematopoietic stem cells (pg. 983-984 “Robust HSC Gene Transfer Using Short Culture Time and Prostaglandin E2”; see also Experimental Procedures pg. 988 col. 1), and then expanding the genetically modified hematopoietic stem cells (“Ex Vivo Expansion of Gene-Modified HSCs Supported by Small-Molecule Compounds” Figure 4; see also Experimental Procedures “Ex Vivo HSPC Expansion” pg. 988 col. 1) and therefore provides a reasonable expectation of success. As set forth above, absolute predictability is not required for a reasonable expectation of success.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Maurer et al. (Transfus Med Hemother. 2013 Oct;40(5):344-50. Epub 2013 Sep 19; henceforth “Maurer”). The teachings of Tursky and Butler above are hereby incorporated in their entirety.
Regarding claim 34, further to the discussion of claim 1 above, although Tursky teaches an expansion cell culture medium for hematopoietic stem cells comprising thrombopoietin, stem cell factor, Flt3-Ligand, IL-6, and IL-11 (claim 16; see also pg. 31 line 17; see also Figure 1, pg. 35 2nd para., Examples 1-2, claims 16 and 20-23; see in particular claim 16), wherein the culture medium further comprises at least one cytokine (Flt-3 ligand; pg. 7 lines 2 and 18, pg. 9 lines 1-3, pg. 24 line 15, pg. 33 line 14, pg. 34 line 11, pg. 37 line 27, pg. 39 line 7, pg. 42 lines 4-5; claims 11 and 13), Tursky and Butler are silent to including heparin in the cell culture medium.
Nevertheless, regarding claim 34, Maurer teaches an expansion cell culture media for hematopoietic stem cells (CB CD34+ cells) comprising thrombopoietin, stem cell factor, Flt3-Ligand, IL-6, IL-11 and heparin (Summary “Methods”; Material and Methods “Cell Culture” pg. 345). Maurer teaches including Heparin in the expansion cell culture medium for hematopoietic stem cells can significantly enhance the stimulating effects of a combination of TPO, SCF, FL, IL-6, and IL-11 and enhance platelet production from hematopoietic stem cells (CB CD34+ cells) which could represent a promising method to generate CFU-MKs and MKs cells for transfusion to sustain platelet reconstitution following CB transplantation (Summary “Conclusion”).
Therefore, regarding claim 34, 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 suggested by Tursky in view of Butler, and combine the known prior art element of the heparin of Maurer to obtain the predictable result of a cell culture medium for expanding hematopoietic stem cells. One of ordinary skill would have been motivated to do so as taught by Maurer to enhance the stimulating effects of the combination of TPO, SCF, FL, IL-6, and IL-11 in the media as suggested by Tursky and to enhance platelet production from the hematopoietic stem cells to generate cells for transfusion to sustain platelet reconstitution following CB transplantation (Summary “Conclusion”). Regarding the reasonable expectation of success, Maurer evidences preparation of a cell culture medium for expanding hematopoietic stem cells and use of the medium in expanding hematopoietic stem cells (Material and Methods pg. 345).
Hence, the claimed invention as a whole was prima facie obvious.
Examiner’s Remark
It is noted that Applicant’s amendments removed heparin from claim 6, and added new claim 34 with the limitation of heparin. Therefore, arguments directed to claim 6 which are pertinent to the present rejection of claim 34 are addressed below.
Response to Arguments
Applicant’s arguments, filed 4th, March, 2026, have been fully considered but are not found persuasive.
Applicant argues the rejection “never articulates why a skilled artisan would add Maurer's serum-based, cytokine-heparin heavy protocol – aimed at megakaryocyte/platelet output – into Butler’s serum/cytokine-free direct contact EC niche that drives LT-HSC self-renewal via angiocrine signaling” (pg. 9-10). Applicant further argues “the cited prior art solves different problems under incompatible conditions, and the office does not explain how or why heparin would be expected to improve - not disrupt – the Butler niche” (pg. 10) (see pg. 9 last para. and pg. 10 1st-4th para.).
In response, in the grounds of rejection above, the secondary reference of Butler is relied upon only for teaching and suggesting combining endothelial cells and is not relied upon for combining “serum/cytokine-free” conditions. Thus the suggested combination above, which has the primary reference of Tursky, and is a combination of Tursky in view of Butler and Maurer does not require the “serum/cytokine-free” conditions contested by Applicant. Furthermore, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, arguments directed to the conditions of Butler without including the teachings of Tursky, is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references and therefore may be considered to be an argument that attacks the reference(s) individually, as set forth by MPEP 2145 (IV).
Additionally, In response to applicant's argument, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, for the reasons set forth above, the combined teachings of Tursky in view of Butler and Maurer suggest all the required elements of the claimed combination for the reasons set forth above, and the assertation that some of the features of the secondary reference of Butler or Maurer may not bodily incorporated into the structure of the primary reference (alleged “incompatible conditions”) is not part of the 35 U.S.C. § 103(a) based test for obvious.
Further concerning Applicant’s arguments that the cited prior art solves different problems, as discussed above, It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Finally, concerning Applicant’s arguments that “the office does not explain how or why heparin would be expected to improve - not disrupt – the Butler niche” as discussed above, the combined teachings of Tursky in view of Butler and Maurer suggest all the required elements of the claimed combination for the reasons set forth above, and the assertation that some of the features of the secondary reference of Butler may not bodily incorporated into the structure of the primary reference (alleged “incompatible conditions”) is not part of the 35 U.S.C. § 103(a) based test for obvious. Additionally, an improvement is not necessarily required to render a claimed invention obvious (see MPEP 2143). For the reasons set forth above, it would have been obvious to combine the known prior art element of the heparin of Maurer to enhance the stimulating effects of the combination of TPO, SCF, FL, IL-6, and IL-11 in the media as suggested by Tursky and to enhance platelet production from the hematopoietic stem cells to generate cells for transfusion to sustain platelet reconstitution following CB transplantation.
New Claim Rejections - 35 USC § 103
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Csaszar et al. (Cell Stem Cell. 2012 Feb 3;10(2):218-29.; see IDS filed 4th, March, 2026; henceforth “Csaszar”). The teachings of Tursky and Butler above are hereby incorporated in their entirety.
Regarding claim 35, further to the discussion of claim 1 above, Tursky and Butler are silent to including a TGFβ inhibitor or a TGFβ signaling inhibitor in the culture medium.
Nevertheless, regarding claim 35, Csaszar teaches TGFβ has a significant inhibitory
effect on hematopoietic progenitor expansion (pg. 219 col. 1 2nd para.). Csaszar teaches targeted inhibition of TGF-b1 by including SB431542, which is a TGFβ inhibitor or a TGFβ signaling inhibitor, in a cell culture medium during hematopoietic progenitor expansion yielded increases in progenitor cell expansions (pg. 222 col. 1; Figure 3).
Therefore, regarding claim 35, 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 suggested by Tursky in view of Butler, and combine the known prior art element of the TGFβ inhibitor or a TGFβ signaling inhibitor of SB431542 of Csaszar with the cell culture medium to obtain the predictable result of a cell culture medium for hematopoietic progenitor expansion. One of ordinary skill would have been motivated to do so as taught by Csaszar to increase progenitor cell expansions (pg. 222 col. 1; Figure 3). Regarding the reasonable expectation of success, Csaszar evidences performing hematopoietic progenitor expansion in a cell culture medium comprising the TGFβ inhibitor or a TGFβ signaling inhibitor of SB431542.
Hence, the claimed invention as a whole was prima facie obvious.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Bhatia et al. (J Exp Med. 1999 Apr 5;189(7):1139–1148.; henceforth “Bhatia”). The teachings of Tursky and Butler above are hereby incorporated in their entirety.
Regarding claim 36, further to the discussion of claim 1 above, Tursky and Butler are silent to include BMP4 in the medium.
Nevertheless, regarding claim 36, Bhatia teaches that including high concentrations of BMP-4 in cell culture medium of Lin- cells, which include hematopoietic progenitor and stem cells, extended the length of time that repopulation capacity could be maintained in ex vivo culture (summary; pg. 1143 col. 2).
Therefore, regarding claim 36, 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 suggested by Tursky in view of Butler, and combine the known prior art element of the high concentration of the BMP-4 in the cell culture medium of Bhatia to obtain the predictable result of a cell culture medium for proliferation of hematopoietic progenitor and stem cells. One of ordinary skill would have been motivated to do so as taught by Bhatia because including high concentrations of BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture (summary; pg. 1143 col. 2). Regarding the reasonable expectation of success, Bhatia evidences culturing of Lin- cells, which include hematopoietic progenitor and stem cells, in a culture medium comprising a high concentration of the BMP-4 (summary; pg. 1143 col. 2).
Hence, the claimed invention as a whole was prima facie obvious.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Tursky et al. (WO-2013040644-A1; see IDS filed 9th, October, 2025; henceforth “Tursky”) in view of Butler et al. (Cell Stem Cell. 2010 Mar 5;6(3):251-64.; see IDS filed 9th, October, 2025; henceforth “Butler”) as applied to claim 1 above, and in further view of Luo et al. (Transplantation. 2014 Jan 15;97(1):20-9.; henceforth “Luo”). The teachings of Tursky and Butler above are hereby incorporated in their entirety.
Regarding claim 37, further to the discussion of claim 1 above, Tursky and Butler are silent to including mTOR in the cell culture medium.
Nevertheless, regarding claim 37, Luo teaches addition of the mTOR inhibitor rapamycin to the culture during expansion to the culture inhibited the activation of mTOR in LSK cells, which includes hematopoietic stem and progenitor cells, which led to promotion in ex vivo expansion and long term hematopoietic reconstitution of HSCs (pg. 3 2nd para.; see also pg. 3 Results 4th para. “Inhibition of mTOR with rapamycin promotes ex vivo expansion of HSCs” and pg. 5 2nd para.). Luo teaches addition of the mTOR inhibitor rapamycin prevents HSCs from undergoing senescence during ex vivo expansion (abstract “results”).
Therefore, regarding claim 37, 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 suggested by Tursky in view of Butler, and combine the known prior art element of the mTOR Inhibitor rapamycin in the cell culture medium to obtain the predictable result of a cell culture medium for hematopoietic stem or progenitor cell expansion. One of ordinary skill would have been motivated to do so as taught by Luo to promote ex vivo expansion and long term hematopoietic reconstitution of HSCs (pg. 3 2nd para.; see also pg. 3 Results 4th para. “Inhibition of mTOR with rapamycin promotes ex vivo expansion of HSCs” and pg. 5 2nd para.) and to prevent HSCs from undergoing senescence during ex vivo expansion (abstract “results”). Regarding the reasonable expectation of success, Luo evidences expansion of LSK cells, which includes hematopoietic stem and progenitor cells with rapamycin in the culture media (pg. 3 2nd para.; see also pg. 3 Results 4th para. “Inhibition of mTOR with rapamycin promotes ex vivo expansion of HSCs” and pg. 5 2nd para.).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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