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 .
1. Claims 2 and 4 have been cancelled. Claims 1 and 3-9 have been amended.
Claims 1, 3, and 5-11 are pending and under examination.
2. All objections/rejections pertaining to claims 2 and 4 are moot because the claims were cancelled with the reply filed on 06/04/2026.
The objections to claims 3 and 6-9 are withdrawn in response to the amendments filed on 06/04/2026.
The rejection of claims 1, 3 and 5-11 under 35 U.S.C. 103 as being unpatentable
over Timmins1 (PGPUB 2010/0285586), in view of all Timmins 2 (Tissue Eng. Part C, 2011, 11: 1131-1137), Boehm et al. (J. Immunol. Methods, 2010, 360: 20-29), Wojda et al. (Blood, 2002, 99: 3005-3013), and Yeo et al. (Biophysical Reviews, online 15 August 2019, 11: 873-894) is withdrawn in response to the amendment introducing the limitations of the cancelled claim 4 into the independent claim 1.
Claim Objections
3. Claim 1 is objected to because of the recitation “a diameter” in lines 2-3. Correction to “the diameter” is required.
Claim Rejections - 35 USC § 101
4. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
5. Claim 11 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite RBCs, i.e., a product of nature. Since the claim is a product-by-process claim, the judicial exception is not integrated into a practical application. Furthermore, the process steps do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there is no evidence that producing RBCs by using the claimed method results in RBCs that are any different from their naturally-occurring counterparts. The specification discloses that the RBCs prepared by the claimed method are not functionally different from the control peripheral blood RBCs, exhibit the CD71-/GPA+ phenotype; except that they express both fetal hemoglobin (HbF) and adult hemoglobin (HbA), while the control peripheral blood RBCs only expressed HbA (see Example 3; Fig. 9c).
However, there are naturally-occurring RBCs expressing both HbF and HbA, for example, the naturally-occurring infant RBCs (Bard, J. Clin. Invest., 1973, 52: 1789-1795; see Abstract; p. 1792, Fig. 3) and the adult F-cells (rare RBCs present in blood; Steinberg, Blood, 2014, 123: 481-485; see p. 481, column 1 and column 2, first full paragraph). As evidenced by Rallapalli et al. (Cell and Tissue Res., 2019, 375: 437-449), RBCs exhibit the CD71-/GPA+ phenotype regardless of whether they express HbF or not (see p. 442, paragraph bridging columns 1 and 2 and column 2, first and second full paragraphs).
There is nothing in the claim or specification indicating that the method steps result in RBCs which are any different from the naturally-occurring infant RBCs and/or F-cells. The specification teaches that the stationary culture expands the population of immature erythroid progenitors, while the agitation step results in increased maturation and enucleation rate. There is no evidence in the specification or art indicating that expanding under stationary conditions and/or inducing maturation/enucleation under agitation leads to RBCs which are any different from their naturally-occurring counterparts. The claim does not include additional elements sufficient to amount to significantly more than the judicial exception.
Therefore, the rejection under 35 U.S.C. 101 is appropriate.
Claim Rejections - 35 USC § 102
6. 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.
7. Claim 11 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Steinberg et al. (Blood, 2014, 123: 481-485), as evidenced by Rallapalli et al. (Cell and Tissue Res., 2019, 375: 437-449).
In making this rejection it is noted that, although claim 11 does not recite a phenotype for the claimed RBAs, the specification discloses that they are CD71-/GPA+ and express both HbF and HbA (see Example 3; Fig. 9c).
Steinberg et al. discloses F-cells, naturally occurring and normal adult RBCs expressing both HbF and HbA (see Abstract; p. 481, column 1 and column 2, first full paragraph). As evidenced by Rallapalli et al., RBCs exhibit the CD71-/GPA+ phenotype regardless of whether they express HbF or not (see p. 442, paragraph bridging columns 1 and 2 and column 2, first and second full paragraphs).
Thus, Steinberg et al. teach all claim limitations and anticipate the claimed invention.
Claim Rejections - 35 USC § 103
8. 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.
9. Claims 1, 3, and 5-11 are rejected under 35 U.S.C. 103 as being unpatentable over Timmins1 (PGPUB 2010/0285586), in view of all Timmins 2 (Tissue Eng. Part C, 2011, 11: 1131-1137), Boehm et al. (J. Immunol. Methods, 2010, 360: 20-29), Wojda et al. (Blood, 2002, 99: 3005-3013), Yeo et al. (Biophysical Reviews, online 15 August 2019, 11: 873-894), and Bayley et al. (J. Tissue Engineering and Regenerative Medicine, 2018, 12: e368-e378).
Timmins1 teaches a method for the ex vivo production of red blood cells (RBCs) from CD34+ cells, the method comprising in order: (1) an expansion phase entailing culturing the CD34+ cells under static conditions for 21 days at 37º C, in an erythroid expansion medium to allow for the optimal expansion of the erythroid progenitors, and (2) a maturation phase starting at culture day 21, entailing the agitation culture of the erythroid progenitors at 25 rpm in a bioreactor at 37º C, in an erythroid maturation medium, where agitation enhances the enucleation rate compared to the static culture; both static and agitation cultures are performed in the absence of stromal cells (claims 1, 3 and 6-11) (see [0021]; [0087]-[0089]; [0098]-[0100]; [0107]-[0108]; [0110]; [0117]; [0119]; [0128]; Example 1).
Timmins1 does not teach starting the agitation culture when the erythroid progenitors reach a diameter of 10-15 µm (claim 1). Timmins1 does not specifically teach the size of the erythroid progenitors at the start of the agitation culture. Timmins2 discloses that expansion for 21 days, as in Timmins1, results in a population of erythroid progenitors of mixed maturity, the majority having a dimeter of ˃10 µm to ˂ 20 µm (see p. 1132; p. 1133, Fig. 1B).
Thus, Timmins1 starts the agitation culture when the erythroid progenitors reach a diameter of 10-20 µm. Boehm et al. teach that, during ex vivo erythropoiesis from CD34+ cells, agitation at 20 rpm induces loss of viable cells. Boehm et al. teach that the developmental stages between culture days 8-12 are more sensitive to agitation. Boehm et al. teach that culture days 8-12 are characterized by the presence of a mixed population of CD71+/GPA- and CD71+/GPA+ cells, with CD71+/GPA- cells gradually transitioning to CD71+/GPA+ cells; by culture day 12, the majority of the cells are CD71+/GPA+ (see p. 22; p. 24; Fig. 4a). Wojda et al. teach that the shift from CD71+/GPA- to CD71+/GPA+ cells marks the transition from proerythroblasts to basophilic erythroblasts (see paragraph bridging p. 3006 and 3007; p. 3007, Fig. 1). Furthermore, it was known in the prior art that the proerythroblasts have a size of 20-25 µm, basophilic erythroblasts have a size of 16-18 µm, and that basophilic erythroblasts mature into polychromatic erythroblasts having a size of 12-15 µm (see Yeo et al.; p. 874).
Based on all the teachings above, one of skill in the art would have reasonably concluded that the 21-day population of erythroid progenitors in Timmins1 comprises basophilic erythroblasts, which are sensitive to agitation and would lose viability when agitated at 25 rpm. One of skill in the art would have found obvious to modify the method taught by Timmins1 by starting agitation when the basophilic erythroblasts transition to polychromatic erythroblasts (i.e., when the cells reach a diameter of 12-15 µm; claim 1), with the reasonable expectation that doing so would result in enhanced RBC yield (claims 8 and 9). By doing so, one of skill in the art would have increased cell density by supplying oxygen and nutrients through the agitation of the medium (claim 5).
Timmins et al., Timmins2, Boehm et al., Wojda et al., and Yeo et al. do not teach agitation at 200-800 rpm (claim 4). Bayley et al. teach that agitation is a result effective variable with respect to enucleation, with agitation at 450 rpm resulting in increased enucleation (see Abstract; p. e371, Fig. 1; p. e372, column 1; paragraph bridging p. e372 and e373). Based on these teachings, one of skill in the art would have found obvious to modify the method taught by Timmins1, Timmins2, Boehm et al., Wojda et al., and Yeo et al. by using agitation at 450 rpm with the reasonable expectation that doing so would in increase the yield of RBCs.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
10. 35 U.S.C. 101
The applicant refers to Chakrabarty as confirming that a non-naturally occurring product resulting from human ingenuity is eligible, even if its constituents resemble natural materials.
Chakrabarty relates to obtaining non-natural, genetically engineered organisms, which is not the case here. A product does not become automatically eligible just because it was created by human ingenuity or intervention. The key to eligibility is whether the product possesses markedly different characteristics from any naturally occurring counterpart (see MPEP 2106.04(b) II). In this case, there is no evidence that the method steps result in markedly different characteristics from the naturally occurring adult F-cells and infant RBCs. The fact that the cells are isolated does not change this.
The argument that the 101 rejection cannot be reconciled with the obviousness-type rejection is not found persuasive. Eligibility and obviousness are distinct, each requiring separate and distinct considerations. Considerations for obviousness of are of no relevance in determining whether the subject matter of a claim is eligible under § 101. Considerations for eligibility are of no relevance in determining whether the subject matter of a claim is obvious under 3. See MPEP 2106.05 I.
35 U.S.C. 102(a)(1)
The arguments have been considered but not found persuasive because Steinberg discloses all claimed limitations. Claim 11 is a product-by-process claim
and patentability for product by process claims is based on the product itself. MPEP 2113 [R-1 states that “If the product is the same as or obvious from a product of the prior art, the claims are unpatentable even though the prior product was made by a different process.” In the instant case, there is no evidence of record that the claimed blood preparation is any different from the blood preparation disclosed by Steinberg.
The argument that the recited method steps impart-manufacturing derived characteristics is not found persuasive because there is no evidence to this effect. The fact that the control RBCs in Example 3 and Fig. 9c only express HbA does not constitute evidence.
With respect to the argument that Bard does not disclose naturally occurring RBCs expressing both HbF and HbA, it is noted that this reference was not used to reject the claim.
35 U.S.C. 103
The applicant argues that none of the references correlates RBC diameter with the decision to switch culture mode.
This argument is not found persuasive because none of the references has to teach every claim limitation. The 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 this case, the combined teachings of the cited references suggest switching when the cells reach a diameter of 12-15 µm.
The argument of teaching away is not found persuasive because it does not address the combined teaching of the cited references.
Timmins1 starts the agitation culture when the population of erythroid progenitors reaches a diameter of 10-20 µm; this population comprises basophilic erythroblasts, which are sensitive to agitation. As taught by the prior art, basophilic erythroblasts further mature into polychromatic erythroblasts having a size of 12-15 µm. By reading Boehm, one of skill in the art would have reasonably concluded that the polychromatic erythroblasts are not sensitive to agitation. Thus, one of skill in the art would not consider Boehm as teaching away from starting agitation at the polychromatic erythroblast stage (i.e., when the cells reach a size of 12-15 µm).
For these reasons, the argument that there would be no motivation to combine references teaching mutually exclusive agitation conditions is not found persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case the cited prior art indicates starting agitation at the polychromatic erythroblast stage (12-15 µm), which are not sensitive to agitation. Bayley provides the motivation to agitate at 450 rpm to increase enucleation.
The argument of unexpected results is not found persuasive. That switching to agitation too early would kill the progenitors was expected from the teachings in the cited prior art. The cited prior art also indicates the criticality of the cell size to determine the switching point.
Conclusion
11. 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.
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/ILEANA POPA/ Primary Examiner, Art Unit 1633
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