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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/27/2025 has been entered.
Claims 1-2, 5-13, and 19-21, of record 8/27/2025, are pending and subject to prosecution. Claims 1 and 13 are amended. Claims 3-4 are cancelled.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-7, 9-13, and 19-21 under 35 U.S.C. 103 over Spanholtz et al. (PLoS One, 2010), evidenced by Miltenyi (Product webpage, 2008), in view of Xu et al. (Transfusion, 2000):
RE: Rejection of claims 1-13 and 19-21 under 35 U.S.C. 103 over Spanholtz et al. (PLoS One, 2010), of record, evidenced by Miltenyi (Product webpage, 2008), of record, in view of Xu et al. (Transfusion, 2000), further in view of Spanholtz et al. (US 20140080148 A1):
The cancellation of claims 3-4 renders the rejections thereto moot.
The applicant asserts that the teachings of Xu et al. pertain the development of myeloid cells rather than NK cells, rendering the teachings irrelevant to the claimed invention (Applicant Remarks, page 6). The applicant also asserts that Xu et al. show that human serum, required by amended claim 1, did not provide desired results in terms of increased expansion (Applicant Remarks, page 7).
These arguments are not found persuasive. The teachings of Xu et al. are relied upon in the rejections solely to support the seeding of CD34+ cells at a relatively low density for further manipulation. However, in response to the applicant’s argument that the increase in nucleated cells may not actually reflect an increase in CD34+ cells, Xu et al. teach that 6SMF medium supports the proliferation of early precursor cells, rather than myeloid or erythroid development (See page 1301, col. 2, ¶1 and page 1306, col. 1, full ¶2), therefore, at least some cells in the 6SMF experimental group can be assumed to be CD34+. Further, while Xu et al. teach that the expansion achieved by CBS and ABS is less than that by FCS or no serum at all, the results still demonstrate an increase in CFU number with CBS and/or ABS in two of three medium compositions (See fig. 2). Non-preferred and alternative embodiments still constitute prior art, rather than a teaching away. See MPEP 2123(II).
The rejections are maintained in modified form to address amended limitations.
New/Maintained Objections/Rejections
Specification
The use of the terms CliniMACS, Prodigy, GBGM, CytoFLEX, Krome Orange, Vio, GraphPad Prism, and Albuman, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
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.
Claims 1-2, 5-7, 9-13, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Spanholtz et al. (PLoS One, 2010), of record, evidenced by Miltenyi (Product webpage, 2008), of record, in view of Xu et al. (Transfusion, 2000), of record.
Regarding claims 1-2 and 7: Spanholtz et al. teach the seeding of approximately 1 × 104 umbilical cord blood-derived CD34+ cells/ml and culturing them for 14 days (which reads on “at least 7 days”) in basal medium (which reads on “basic culture medium”) comprising human serum, SCF, IL-7, FLT-3L, and TPO (See page 10, col. 2, full ¶2 and fig. 1, Method I). Spanholtz et al. teach that on days 14-35 (which reads on “at least 4 days” and “at least 13 days”), the cells are cultured in a medium comprising IL-15, IL-7, SCF, FLT-3L, and IL-2 (which reads on “a medium comprising IL-15 and IL-7, and one or more of SCF or FLT-3L” and “a culture medium comprising… three or more of SCF, IL-7, IL-15 and IL-2”) (See fig. 1, Method I). This method would produce the cells of step (ii) on day 18 and the cells of step (iii) on day 31. Spanholtz et al. do not teach a starting density of fewer than approximately 10000 cells/ml.
Xu et al. teach optimization of umbilical cord blood CD34+ hematopoietic stem cell culture under different conditions (See Abstract). Xu et al. teach higher serial increases as inoculum density decreases in two of three culture compositions and that all three compositions yielded an increase in nucleated cells with 5000 cells/ml versus 10000 cells/ml and with 1000 cells/ml versus 5000 cells/ml (See fig. 3). Thus, Xu establishes that inoculum density is a result-effective variable.
It would have been obvious, or obvious to try, to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Spanholtz et al. to comprise an inoculum with fewer cells/ml, such as 1000 cells/ml or 5000 cells/ml (which would read on “between 1,000 and 8,000 CD34+ cells/ml” and “between 2,000 and 6,000 CD34+ cells/ml”) via routine optimization. "[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); MPEP 2144.05(ii). One would be motivated to make this modification because the results of Xu et al. suggest that reducing inoculum density below 10000 cells/ml increases the extent of expansion (See fig. 3). There would be a reasonable expectation of success in doing so because the method of Spanholtz et al. could be readily modified to inoculate fewer cells per ml.
Regarding claims 5-6: Following the discussion of claims 1-2 and 7, Spanholtz et al. teach a method for producing a collection of stem cells but do not expressly teach at least 500-fold expansion at day 12 or at least 800-fold expansion at day 15. However, Spanholtz et al. teach an alternate method wherein approximately 3 × 104 CD34+ cells/ml were cultured in GBGM medium with SCF, IL-7, FLT-3L, and TPO for days 0-9, with SCF, IL-7, FLT-3L, and IL-15 for days 9-14, and with SCF, IL-7, IL-15, and IL-2 for days 14-15 (See fig. 1, Method II). The method results in total cell expansion of approximately 100-fold after seven days and approximately 1000-fold after 14 days, which reads on “at least 800-fold expansion of cells… at day 15” (See fig. 3a). It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Spanholtz et al., modified by Xu et al., for differentiating a culture of CD34+ cells to comprise the use of GBGM medium with the cytokine regimen of Method II. One would be motivated to make this modification because Spanholtz et al. teach that the medium components and regimen of Method II yield greater fold expansion than those of Method I (See fig. 2-3). There would be a reasonable expectation of success in doing so because Method II could be readily applied to a lower starting number of CD34+ cells. Given that Spanholtz et al. demonstrate 1000-fold expansion at 14 days and that Xu et al. teach greater expansion with even lower CD34+ cell starting densities, the modified method of Spanholtz et al. and Xu et al. could reasonably be expected to yield expansion of at least 500-fold by day 12.
Regarding claim 9: Following the discussion of claims 1-2 and 7, Spanholtz et al. teach that the CD34 cells were isolated from umbilical cord blood by separation with Miltenyi immunomagnetic beads (See page 10, col. 2, full ¶1). Miltenyi teaches that the CD34 beads are used with MACS columns (which reads on “manual column separation”) (See page 1, section 1.1).
Regarding claim 10: Following the discussion of claims 1-2 and 7, Spanholtz et al. teach that the high-dose cytokine cocktail comprises 27 ng/ml SCF (which reads on “between 2 ng/ml and 200 ng/ml”), 25 ng/ml FLT-3L (which reads on “between 2 ng/ml and 200 ng/ml”), 25 ng/ml TPO (which reads on “between 2 ng/ml and 200 ng/ml”), and 25 ng/ml IL-7 (which reads on “between 2 ng/ml and 200 ng/ml”) (See page 10, col. 2, full ¶2).
Regarding claims 11-12: Following the discussion of claims 1-2 and 7, Spanholtz et al. teach that after four weeks (which reads on “after 28 days of culture”), 60-77% of the cells were CD56+ NK cells (which reads on “at least 50%... fully differentiated NK cells”) (See page 2, col. 2, full ¶1 and fig. 2a). The population comprised 80-96% CD56+ NK cells after five weeks (which reads on “at least 75%... fully differentiated NK cells after 35 days of culture”) (See page 2, col. 2, full ¶1 and fig. 2a).
Regarding claim 13: Following the discussion of claims 1-2 and 5-7, Spanholtz et al., modified by Xu et al., render obvious a method for differentiating CD34+ cells into NK cells using Method II but do not expressly teach the lytic properties of the resulting cells. However, Spanholtz et al. teach that NK cells produced by culturing approximately 3 × 104 CD34+ cells/ml by Method II mediate approximately 90% lysis of K562 cells following 24 h incubation at a 2:1 effector/target ratio (See page 6, col. 2, ¶1 and fig. 6). Use of a lower number of CD34+ starting cells would still be expected to yield NK cells with similar cytotoxic properties, therefore the cells of Spanholtz et al., modified by Xu et al., would also likely mediate the same degree of lysis at the same ratio. While Spanholtz et al. do not teach the percentage of lysed K562 cells at a 1:1 effector/target ratio, one having ordinary skill in the art could readily extrapolate that the extent of lysis would be approximately halved by reducing the number of NK cells by 50%, thereby reading on “NK cells… are able to kill at least 30%... of their target cells”.
Regarding claims 19-21: Following the discussion of claims 1-2 and 5-7, Spanholtz et al. teach the production of NK cells and that NK cells are CD56+CD3- (See page 1, col. 1, ¶1) but do not expressly teach their use in immunotherapy. However, Spanholtz et al. teach that NK cells generated by Method II can efficiently target myeloid leukemia and melanoma tumor cell lines (See Abstract and fig. 6 ). NK cells in media read on “a pharmaceutical composition”. It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to administer the NK cell-comprising pharmaceutical composition of Spanholtz et al., modified by Xu et al., in a therapeutically effective amount to an individual with myeloid leukemia or melanoma (which would read on “a tumour”, “a hematopoietic or lymphoid tumour”, and “a solid tumour”). One would be motivated to modify the in vitro use of the NK cell composition for targeting tumor cells, as taught by Spanholtz et al., for in vivo use in order to treat patients having leukemia or melanoma. There would be a reasonable expectation of success in doing so because Spanholtz et al. suggest that that the cells could be used for adoptive immunotherapy and teach that a clinical trial using NK cells against melanoma had been performed (See page 10, col. 1, full ¶1-2).
Claims 1-2, 5-13, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Spanholtz et al. (PLoS One, 2010), of record, evidenced by Miltenyi (Product webpage, 2008), of record, in view of Xu et al. (Transfusion, 2000), further in view of Spanholtz et al. (US 20140080148 A1), of record.
The teachings of Spanholtz et al., Miltenyi, and Xu et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 8: Following the discussion of claims 1-2, 5-7, 9-13, and 19-21, Spanholtz et al., modified by Xu et al., render obvious a method for producing a collection of NK cells from CD34+ cells but do not expressly teach the use of a fully automatic closed system for selecting the CD34+ cells.
Spanholtz et al. (‘148) teach the isolation of CD34+ stem cells from umbilical cord blood using an automated CliniMACS cell separator equipped with closed tubing (which reads on “a fully automated closed system”) (See ¶0209). It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Spanholtz et al., modified by Xu et al., to comprise the use of an automated system, such as is taught by Spanholtz et al. (‘148), to isolate CD34+ cells. One would be motivated to make this modification in order to reduce the likelihood of operator error during the separation process. There would be a reasonable expectation of success in doing so because Spanholtz et al. (‘148) demonstrate that this system can be used successfully for the isolation of CD34+ cells from umbilical cord blood (See ¶0209).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 7, and 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17, 20-21, 23-25, and 27 of co-pending Application No. 17/780617 in view of Spanholtz et al. (PLoS One, 2010).
Regarding claims 1-2: Co-pending claim 17 recites a method for the manufacturing of a population of cells, genetically modified with a Chimeric Antigen Receptor (CAR) comprising: a first step comprising: providing a sample comprising CD34+ hematopoietic stem cells, purifying the CD34+ hematopoietic stem cells in said sample, culturing the purified CD34+ hematopoietic stem cells in the presence of culture medium I, transducing the purified CD34+ hematopoietic stem cells with a polynucleotide coding for a CAR by culturing the cellular populations in culture medium I in the presence of a vector comprising said polynucleotide for at least 10 hours, thereby obtaining a cellular population comprising CD34+ stem cells expressing said CAR, and culturing the cellular populations in culture medium I for at least 10 hours, wherein culture medium I is a basic culture medium, comprising a collection of cytokines, wherein said collection of cytokines comprises Interleukin-7 and one or more of stem cell factor (SCF), flt-3Ligand (FLT-3L), thrombopoietin (TPO), and two or more of granulocyte-macrophage-colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), and interleukin-6 (IL-6). Co-pending claim 20 recites the method according to co-pending claim 17, wherein the cell culture of step c) is initiated at a cell density of between 500 and 10,000 CD34+ cells/ml. Co-pending claim 21 recites the method according to co-pending claim 20, wherein the cell culture of step c) is initiated at a cell density of between 1,000 and 8,000 CD34+ cells/ml. Co-pending claim 23 recites the method according to co-pending claim 17, further comprising: a second step in which the cellular population from step (i) is expanded and differentiated into a cellular population containing CAR-NK progenitor cells or CAR-NK cells or both, the step comprising culturing the cellular population from step (i) containing CAR-CD34+ stem cells in culture medium III, thereby obtaining a cellular population containing CAR-NK progenitor cells or CAR-NK cells or both, wherein the culture medium III is a basic culture medium comprising a collection of cytokines, wherein said collection of cytokines comprises two or more of SCF, IL-7, IL-15 and interleukin-2 (IL-2) and two or more of GM-CSF, G-CSF, and IL-6. Co-pending claim 24 recites the method according to co-pending claim 17, further comprising: a second step in which the cellular population from step (i) is expanded and differentiated into a cellular population containing CAR stem cells or CAR progenitor cells or both, the step comprising culturing the CAR-CD34+ stem cells from step (i) in culture medium II, thereby obtaining a cellular population containing CAR stem cells or CAR progenitor cells or both, and a third step in which the cellular population from step (ii) is further expanded and differentiated into a cellular population containing CAR-NK progenitor cells or CAR-NK cells or both, wherein culture medium II is a basic culture medium comprising a collection of cytokines, wherein said collection of cytokines comprises two or more of SCF, FLT-3L interleukin-15 (IL-15) and IL-7 and two or more of GM-CSF, G-CSF, and IL-6, and wherein culture medium III is a basic culture medium comprising a collection of cytokines, wherein said collection of cytokines comprises two or more of SCF, IL-7, IL-15 and interleukin-2 (IL-2) and two or more of GM-CSF, G-CSF, and IL-6.
The co-pending claims do not expressly teach a first culture step of at least 7 days in media comprising human serum, SCF, IL-7, and FLT-3L and/or TPO; a second culture step of at least 4 days in media comprising human serum, IL-15, IL-7, and SCF and/or FLT-3L; and a third culture step of at least 13 days in media comprising human serum and SCF, IL-7, IL-15, and/or IL-2.
Spanholtz et al. teach the seeding of CD34+ cells and culturing them for 14 days (which reads on “at least 7 days”) in basal medium (which reads on “basic culture medium”) comprising human serum, SCF, IL-7, FLT-3L, and TPO (See page 10, col. 2, full ¶2 and fig. 1, Method I). Spanholtz et al. teach that on days 14-35 (which reads on “at least 4 days” and “at least 13 days”), the cells are cultured in a medium comprising IL-15, IL-7, SCF, FLT-3L, and IL-2 (which reads on “a medium comprising IL-15 and IL-7, and one or more of SCF or FLT-3L” and “a culture medium comprising… three or more of SCF, IL-7, IL-15 and IL-2”) (See fig. 1, Method I). This method would produce the cells of step (ii) on day 18 and the cells of step (iii) on day 31.
It would have been obvious to one having ordinary skill in the at prior to the effective filing date of the claimed invention to modify the method of the co-pending claims to comprise the culture steps taught by Spanholtz et al. One would be motivated to make this modification because Spanholtz et al. teach these steps as part of a method that efficiently yields high-purity NK cells from CD34+ cells (See Abstract and page 2, col. 1, full ¶1), There would be a reasonable expectation of success in making this modification because the culture methods of Spanholtz et al. could be readily incorporated into the method of the co-pending claims.
Regarding claim 7: Following the discussion of claims 1-2, co-pending claim 25 recites the method according to co-pending claim 17, wherein the sample has been obtained from umbilical cord blood. The co-pending claim renders obvious the instant claim.
Regarding claim 10: Following the discussion of claims 1-2, co-pending claim 27 recites the method according to claim 17, wherein culture medium I comprises SCF at concentration between 4 ng/ml and 300 ng/ml, or Flt3-L at concentration between 4 ng/ml and 300 ng/ml, or TPO at concentration between 4 ng/ml and 100 ng/ml, or IL7 at concentration between 4 ng/ml and 50 ng/ml, or any combination of these cytokines in the specified concentrations. The co-pending claim renders obvious the instant claim.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE whose telephone number is (571)272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633